management options in_breast_cancer__case_histories__best_practice__and_clinical_decision_making_2

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about the book…

Management Options in Breast Cancer is the only comprehensive resource devoted to exploring the systematic approach to breast cancer diagnosis, surgery, and postoperative care.

This guide is an ideal tool for oncologists, pathologists, radiologists, and gynecologists seeking alternative management options for breast cancer. In addition, trainees will find this text a valuable reference for learning the basic principles and clinical guidelines of the field.

Key features in this stand-alone text:• an international review of the management options in the field of breast

cancer clinical practice• case-based examples designed to aid in optimal clinician decision-making• two chapters devoted to rarely-explored topics: male breast cancer and

geriatric breast cancer

about the editors...

JOHN BENSON is a Consultant Breast Surgeon in the Cambridge Breast Unit, Addenbrooke’s Hospital and a Fellow of Selwyn College, Cambridge. Dr. Benson received his Doctorate (DM) from the University of Oxford and underwent specialist training at The Royal Marsden Hospital and Institute of Cancer Research, London. He is Director of Clinical Studies at Selwyn College and was appointed a Regional Breast Tutor by the Royal College of Surgeons of England in 2007. Dr. Benson has published widely in the field of breast diseases and has coordinated a major article on breast cancer for The Lancet. He is a Fellow of the Royal College of Surgeons of England and Edinburgh and an Examiner for the Intercollegiate Membership Examination (MRCS). His is member of the British Breast Group and the American Association for Cancer Research.

ISMAIL JATOI is Professor of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. He is also Director of the Breast Care Center, National Naval Medical Center, Bethesda, Maryland, USA. Dr. Jatoi received his Ph.D. and M.D. degrees from Saint Louis University, Saint Louis, Missouri, USA. He is Diplomate of the American Board of Surgery and Fellow of the American College of Surgeons. Dr. Jatoi has had a long-standing interest in the management of breast cancer and has published numerous articles, book chapters, and books related to breast cancer local therapy and epidemiology. He has served on the Breast Cancer Executive Committee of the Southwest Oncology Group and the Cancer Prevention Committee of the American Society of Clinical Oncology.

Printed in the United States of America

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Breast CancerCase Histories, Best Practice, and Clinical Decision-Making

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Breast Cancer

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John BensonCambridge University Hospitals NHS Foundation Trust

Addenbrooke’s HospitalCambridge, UK

Ismail JatoiUniformed Services University of the Health Sciences

Bethesda, Maryland, USA



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Management options in breast cancer : case histories, best practice, and clinicaldecision-making / edited by John R. Benson, Ismail Jatoi.

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ISBN-13: 978-0-415-42310-6 (hardcover : alk. paper)

ISBN-10: 0-415-42310-4 (hardcover : alk. paper)1. Breast–Cancer. I. Benson, John R., 1959- II. Jatoi, Ismail, 1955-[DNLM: 1. Breast Neoplasms–therapy. 2. Patient Care Team. WP 870

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Preface

The incidence of breast cancer continues toincrease, and the heterogeneous nature ofthis disease presents unique managementchallenges. Treatments are increasinglybeing tailored to meet the needs of individ-ual patients, although cost issues may influ-ence the decision-making process in somecircumstances. Notwithstanding these com-ments, there are standards of best practice,which are accepted by breast cancer expertsin communities around the world, and muchconsensus now exists in several key areas.This is evident at international meetings,where leading opinion formers share thesame principles and philosophies. It is nowrecognized that diagnostic accuracy, man-agement, and survival rates for breast cancerare superior when practiced within special-ized breast teams. Multidisciplinary team(MDT) meetings have helped ensure thatas many patients as possible receive opti-mum standards of care, which can be aud-ited prospectively. These MDT meetings areunderpinned by shared protocols and guide-lines, though some flexibility and clinicaldiscretion is permissible. There are situa-tions where there is no “right treatment”based on published evidence, and a degreeof clinical judgment and personal experi-ence (and even bias) will prevail.

This book exemplifies how guidelinesshould be followed and the role of clinicaljudgment in determining managementplans for breast cancer patients within thecontext of the MDT. It is based on a selec-

tion of actual clinical cases that have passedthrough the MDT or “tumor board” meet-ings. These represent a spectrum of clinicalscenarios frequently encountered in routinepractice, together with some more unusualand atypical cases. These cases have beengrouped under headings with a dominanttheme, and each one will be presented in astandard format with (1) clinical history,(2) examination, (3) investigations (mam-mogram, ultrasound, core biopsy, fine needleaspiration cytology, and tests as appropriate,such as MRI, bone scan, CT scan chest/abdo-men/pelvis), (4) treatment, and (5) discus-sion. Illustrative material includes schematicdiagrams, breast imaging results, pathologicalslides, and clinical photographs (pre-/postop-erative). Each case will be followed by a list ofsummary points, which is intended as a learn-ing tool. Most cases involve multimodalitytherapies, and cross-referencing has beenincluded to allow the reader to compare andcontrast similar aspects of treatment betweendifferent cases.

This book is aimed for surgeons andoncologists trained in breast disease togetherwith established specialists and clinical nursepractitioners. In addition, physicians in var-ious other disciplines such as radiology andgynecology may find the book a useful guidethat highlights problematic and controver-sial areas within this field.

John R. BensonIsmail Jatoi

v


Acknowledgments

The authors are grateful to several individualsfor their assistance in the preparation of thismanuscript which contains many images andillustrations. Dr Catherine Hubbard andMrMohammed Absar helped collate the radio-logical images whilst Dr Elena Provenzano, DrBrian Rous and Mr James Neale providedrelevant pathological slides for each case. Par-ticular thanks are owed to Catherine Lamoonand Mark Moughton in the departments of

medical photography at Addenbrooke’s andHinchingbrooke Hospitals respectively, forproducing high quality photographs in sensi-tive clinical circumstances. Mrs YvonneGlendenning meticulously uploaded all imagesonto the publisher’s website which greatlyfacilitated preparation of this book. Finally,we are indebted to all the patients who havekindly agreed to inclusion of their clinicaldetails and images in this book.

vii


Contents

Preface vAcknowledgments vii

Chapter 1 Early Symptomatic Breast Cancer 1

Part I: MastectomyCase Study 1 1Case Study 2 6Case Study 3 15Case Study 4 21Case Study 5 25

Part II: Breast Conservation TherapyCase Study 6 30Case Study 7 38Case Study 8 44Case Study 9 51Case Study 10 57Case Study 11 61

Chapter 2 Screen-Detected Breast Cancer 68

Part I: MastectomyCase Study 12 68

Part II: Breast Conservation TherapyCase Study 13 71Case Study 14 75Case Study 15 80

Chapter 3 Incidental Breast Cancer 86

Part I: MastectomyCase Study 16 86Case Study 17 91Case Study 18 95

Part II: Breast-Conservation SurgeryCase Study 19 99

Chapter 4 Ipsilateral Breast Tumor Recurrence 104Case Study 20 104

Chapter 5 Diagnostic Excision Biopsy 111Case Study 21 111

ix


Chapter 6 Bilateral Breast Cancer 116Case Study 22 116Case Study 23 122Case Study 24 129

Chapter 7 Inflammatory Breast Cancer 135Case Study 25 135Case Study 26 140

Chapter 8 Neoadjuvant Chemotherapy 146

Part I: Mastectomy PostchemotherapyCase Study 27 146Case Studies 28 152

Part II: Breast Conservation Surgery PostchemotherapyCase Study 29 158

Chapter 9 Primary Endocrine Therapy 165

Part I: Mastectomy After Primary Endocrine TherapyCase Study 30 165Case Study 31 170

Part II: Breast-Conservation Surgery After Primary Endocrine TherapyCase Study 32 173

Chapter 10 Breast Cancer in the Elderly 180

Part I: Primary Endocrine TherapyCase Study 33 180

Part II: Primary RadiotherapyCase Study 34 182

Chapter 11 Pregnancy-Related Breast Cancer 185

Part I: First Trimester PregnancyCase Study 35 185

Part II: Third Trimester PregnancyCase Study 36 189Case Study 37 193

Chapter 12 Prophylactic Mastectomy 200

Part I: Bilateral Prophylactic MastectomyCase Study 38 200

Part II: Contralateral Prophylactic MastectomyCase Study 39 205

Chapter 13 Lymphedema 210Case Study 40 210

x CONTENTS


Chapter 14 Miscellaneous Conditions 216

Part I: Male Breast CancerCase Study 41 216Case Study 42 221

Part II: Paget’s DiseaseCase Study 43 225

Part III: Phylloides TumourCase Study 44 229

Appendices 234Index 236

CONTENTS xi


1Early Symptomatic Breast Cancer

Part I: Mastectomy

CASE STUDY 1

History

A 65-year-old woman presented with a four-week history of a lump in the superior aspectof the right breast that was slightly tender topalpation but not associated with any nippledischarge. The patient had no previousbreast problems and had undergone regularscreening mammography until the age of64 years (never recalled). Several familymembers had been affected with breast can-cer including the patient’s sister who devel-oped the disease at the age of 47 years. Inaddition, both maternal and paternal grand-mothers had developed pre- and post-menopausal breast cancer, respectivelytogether with a maternal aunt (postmeno-pausal disease). The patient had twochildren both of whom were breast-fed(age at birth of eldest child 22 years). Shepreviously had a hysterectomy with ovarianpreservation and had used hormonereplacement therapy for a duration of twoyears in total.

Clinical Findings

On clinical examination, there was an ill-defined irregular mass lying superior to theright nipple-areolar complex measuring2.5 cm in maximum diameter. This was asso-ciated with subtle indrawing of the skin andwas suspicious for malignancy (E4). There wasno axillary lymphadenopathy (Fig. 1).

Clinical Assessment

The clinical findings were suggestive of aright-sided breast cancer, and the index of

suspicion was heightened by a moderatelystrong family history of breast cancer. Thispatient was informed of the likely diagnosisand the possible need for mastectomy priorto imaging and biopsy.

Investigations

Mammography

An extra density with an irregular outlinewas visible in the superior/central aspect ofthe right breast, which was not present onthe previous screening mammogram carriedout 12 months previously (R5) (Fig. 2A, B).

Breast Ultrasound

The opacity seen on mammography corre-sponded to a 1.8-cm hypoechoic mass lesionthat appeared lobulated and well defined(U5) (Fig. 2C).

Core Biopsy

Image-guided core biopsy (14-gauge needle)of the right breast mass confirmed an

Figure 1

1


invasive carcinoma (grade II, ER positive)without any in situ component [Fig. 3A (lowpower), B (high power)].

Diagnosis

Early-stage right breast cancer (T2aN0)

Multidisciplinary Review 1

Following multidisciplinary review it was rec-ommended that the patient undergo a rightmodified radical mastectomy with standard

level II axillary lymph node dissection (sen-tinel node biopsy not routinely offered at thetime). The tumor lay close to the nipple andwas not amenable to breast-conservation sur-gery, despite its relatively small size on ultra-sound (<2 cm). The tumor appeared largerclinically than the sonographic estimate.

Treatment and Progress

The patient initially expressed some interestin immediate breast reconstruction, and aconsultation was arranged with the plastic

Figure 2

a Clinical assessment T2 but ultrasound measurement <2 cm (T1)

2 CHAPTER 1


surgeons. However, upon further discussionof reconstructive techniques the patientopted for a right mastectomy only. Shemade an excellent postoperative recoverywithout seroma formation, and the mastec-tomy flaps were healthy. There was a goodrange of motion of the right shoulder andno “postmastectomy” pain in the region ofthe axilla and upper inner arm, which is theterritory of the intercostobrachial nerve (sac-rificed at operation).

Definitive Histology

This showed an invasive ductal carcinomameasuring 20 mm in maximum diameterand was well clear of all radial margins(>40 mm) [Fig. 4A (magnification 20�)].

There was associated ductal carcinoma insitu and lymphovascular invasion [Fig. 4B(low power), C (high power)]. However,none of the 17 nodes retrieved containedmetastatic tumor.


It was recommended that the patient com-mence the oral aromatase inhibitor Arimidexas adjuvant systemic therapy for a five-yearperiod.


Arimidex was poorly tolerated with trouble-some side effects and after three months oftreatment was changed to the antiestrogen

Figure 3

Figure 4

EARLY SYMPTOMATIC BREAST CANCER 3


tamoxifen (previously standard adjuvanthormonal treatment for postmenopausalhormone receptor–positive women). Follow-ing treatment with tamoxifen for onemonth, the patient developed bilateral calfpains and pleuritic chest pain. Despite inves-tigations excluding either deep vein throm-bosis or pulmonary embolus, tamoxifen wasdiscontinued and another oral aromataseinhibitor commenced (letrozole 2.5 mgdaily). Unfortunately, the patient reportedpersistent aching pains in the wrist andelbows, which were attributed to letrozole.In view of these sequential side effects ondifferent hormonal agents, it was decided(after discussion with the patient) to with-hold any further endocrine therapy. Her riskof relapse was low and the estimated survivalbenefit from an aromatase inhibitor was 2%to 3% at 10 years. The patient remains welland disease-free at three years following sur-gery and does not desire any form of delayedbreast reconstruction (Fig. 4D).

Discussion

This 65-year-old patient presented with asymptomatic cancer of the right breast hav-ing undergone a routine screening mammo-gram 12 months earlier. Review of thesescreening films revealed no mammographicevidence of any suspicious lesion at thattime. Within the context of a screening pro-gram, cancers appearing symptomatically inthe interval between routine screens can bevisualized retrospectively in up to 20% ofcases. Interestingly, the upper age limit forthe NHS Breast Screening Programme hasbeen increased from 64 to 70 years of age.Randomized controlled trials of breast can-cer screening have now confirmed the effi-cacy of screening in women aged 50 to70 years for whom reductions in mortalitybetween 25% and 30% are attainable(1–4). When the screening program wasimplemented in the United Kingdom inthe late 1980s, it was considered that theage group 50 to 64 years was most cost-effective, with poor levels of complianceamong older women (�65 years). It is nowacknowledged that women within this agegroup are very keen to continue with screen-

ing, and public demand has prompted anexpansion of the screening age group withinthe NHS program.

Breast cancer diagnosis is predicated onthe principle of “triple assessment,” involv-ing a combination of clinical examination,imaging, and some form of tissue biopsy(core biopsy or fine-needle aspiration). Theclinical findings in this case were suspiciousfor but not diagnostic of malignancy (E4).However, the mass had the typical appear-ance of a cancer radiologically (R5, U5) andcore biopsy confirmed the diagnosis.

Primary surgical therapy is the standardtreatment for a 2 cm grade II clinically node-negative breast cancer in a 65-year-oldwoman. The tumor lay in the central portionof the breast, less than 2 cm from the nipple-areolar complex. Its proximity to the nippleprecluded satisfactory breast-conservation sur-gery. Though it might have been possible toobtain satisfactory margin clearance (2–3 mmmicroscopic resection margins) by wide localexcision, this would have yielded a poor cos-metic result with a “squinting” nipple.Patients with very large pendulous breastsmay be suitable for a central segmental resec-tion in which the tumor together with thenipple-areolar complex is incorporated into ahorizontally placed wide local excision.Despite loss of the nipple, much of the breastvolume is retained and an otherwise goodcosmetic outcome is achieved.

At the time this patient underwent sur-gery, formal axillary lymph node dissectionwas the standard method for management ofthe axilla. Patients with a clinically node-negative tumor measuring �3 cm wouldnow be offered sentinel lymph node biopsyas an axillary staging procedure. This partic-ular patient had only a 25% to 30% chanceof nodal involvement, and sentinel nodebiopsy would minimize any potential mor-bidity from a full axillary dissection.

There is currently lack of consensus onthe use of aromatase inhibitors in the adju-vant setting. This patient had a NottinghamPrognostic Index (NPI) of 3.4 and wouldtherefore be in a lower category for risk ofrelapse. Some clinicians would routinely pre-scribe tamoxifen only for five years in theabsence of any contraindication such as a

4 CHAPTER 1


past history of thromboembolism. Otherswould recommend tamoxifen only for twoto three years with an early switch to anaromatase inhibitor. Individual trial datacombined with meta-analysis of selected tri-als suggest that switching from tamoxifen toeither exemestane or anastrozole is associ-ated with statistically significant improve-ments in both disease-free and overallsurvival compared with tamoxifen alone(5 years duration) (5–11). Results of theBIG 1-98 study have failed to demonstrate aclear advantage from an early switch policyin terms of recurrence rates compared with5 years of an aromatase inhibitor. At amedian follow up of 72 months, there wereno significant difference in terms of disease-free survival for 5 years of letrozole com-pared with either of the switch arms (tamox-ifen—letrozole; letrozole—tamoxifen).However, pair wise comparisons suggesteda slight advantage for letrozole (5 years)compared with tamoxifen for 2 years fol-lowed by letrozole for 3 years. The inversesequence was equivalent to monotherapy(5). As a consequence of this and otherdata, some authorities advocate an upfrontaromatase inhibitor for patients deemed tobe at higher risk of local relapse (largertumors, node positive, HER2 positive). Theamplitude of the initial hazard peak is moreeffectively suppressed by an aromatase inhib-itor administered in the first two to threeyears than tamoxifen (12).

Though aromatase inhibitors are associ-ated with a lower risk of thromboembolismcompared with tamoxifen, patients consis-tently report a higher incidence of muscu-loskeletal symptoms that can be troublesomefor older women (13). All patients placed onaromatase inhibitors should have a baselinebone density scan. Within the CambridgeBreast Unit, all patients with an NPI <4.4receive five years of tamoxifen only asadjuvant systemic hormonal therapy. Thosepatients with an NPI �4.4 and �5.4 receivetamoxifen for two to three years followed byan early switch to the aromatase inhibitorexemestane. Patients at higher risk ofrelapse with an NPI >5.4 receive an aroma-tase inhibitor from the outset with thechoice of agent determined by physician

discretion. This policy is based on analysis ofsurvival data according to NPI, which shows ahighly favorable survival for the excellent,good, and moderate I prognostic groups. Itwas, therefore, considered that incorporationof an aromatase inhibitor either upfront orafter –two to three years of tamoxifen (earlyswitch) was cost-effective for the moderate 2and poor prognostic groups only within thelocal healthcare system (14).

Related Cases

Mastectomy without breast reconstruction—Case Studies 2, 22, and 40

Axillary lymph node dissection—Case Studies2, 3, 9, 22, 28, 32, 40, and 41

Aromatase inhibitors—Case Studies 4, 9, 10,22, and 29

Learning Points

1. The diagnosis of breast cancer is oftenestablished following a “triple assess-ment”: clinical exam, imaging (diagnos-tic mammogram/ultrasound), andtissue biopsy (core biopsy or FNA).

2. There are two options available for thelocal therapy of breast cancer: breast-conserving therapy (BCT) or mastectomy.

3. BCT involves removal of only that partof the breast containing the cancer(wide local excision). In BCT, manage-ment of the axilla is identical to that ofpatients opting for mastectomy (sentinelnode biopsy/axillary clearance). Radio-therapy to the breast is generally recom-mended after BCT.

4. Patients who opt for mastectomy gener-ally do not require radiotherapy unlessthe tumor is large (>5 cm) or there isinvolvement of the axillary lymph nodes(generally more than 3 nodes contain-ing metastatic disease).

5. For patients with ER-positive tumors,endocrine therapy is usually administeredpostoperatively. Endocrine therapy gener-ally consists of either tamoxifen (in pre- orpostmenopausal women) or an aromataseinhibitor (for postmenopausal women).



References

1. Shapiro S, Venet W, Strax P, et al. Ten- to fourteen-year effect of screening on breast cancer mortality.J Natl Cancer Inst 1982; 69:349–355.

2. Tabar L, Fagerberg CJG, Gad A, et al. Reduction inmortality from breast cancer after mass screeningwith mammography. Lancet 1985; i:829–832.

3. Fletcher SW, Black W, Harris R, et al. Report of theInternational Workshop on Screening for BreastCancer. J Natl Cancer Inst 1993; 85:1644–1656.

4. Nystrom L, Rutqvist LE, Walls S, et al. Breastscreening with mammography: overview of Swed-ish randomised trials. Lancet 1993; 341:973–978.

5. Mouridsen H, Giobbie-Hurder A, Mauriac L, et al.BIG 1-98: a randomized double-blind phase III studyevaluating letrozole and tamoxifen in sequence asadjuvant endocrine therapy for postmenopausalwomen with receptor-positive breast cancer. 31stSan Antonio Breast Cancer Symposium, Texas,USA, December 2008.

6. Baum M, Buzdar A, Cuzik J, et al. Anastrozole aloneor in combination with tamoxifen versus tamoxifenalone for adjuvant treatment of postmenopausalwomen with early breast cancer: first results of theATAC randomized trial. Lancet 2002; 359:2131–2139.

7. ATAC Trialists Group. Results of the ATAC(Arimidex, Tamoxifen, Alone or in Combination)trial after completion of 5 years adjuvant treatmentfor breast cancer. Lancet 2005; 365:60–66.

8. The Arimidex, Tamoxifen, Alone or in Combina-tion Trialists’ Group. Comprehensive side effect

profile of anastrozole and tamoxifen as adjuvanttreatment for early-stage breast cancer: long-termsafety analysis of the ATAC trial. Lancet Oncol2006; 7:633–643.

9. Coombes RC, Hall E, Gibson LJ, et al. A random-ized trial of exemestane after two to three years oftamoxifen therapy in postmenopausal women withprimary breast cancer. N Engl J Med 2004;350:1081–1092.

10. Jonat W, Gnant M, Boccardo F, et al. Switchingfrom adjuvant tamoxifen to anastrozole in postme-nopausal women with hormone-responsive earlybreast cancer: a meta-analysis of the ARNO 95Trial, ABCSG Trial 8 and the ITA Trial. BreastCancer Res Treat 2005; 94:S11 (abstr 18).

11. Coombes RC, Kilburn LS, Snowdon CF, et al.Survival and safety of exemestane versus tamoxifenafter 2–3 years’ tamoxifen treatment (IntergroupExemestane Study): a randomized controlled trial.Lancet 2007; 369:559–570.

12. Howell A. ATAC trial update. Lancet 2005;365:1225–1226 (letter).

13. ATAC Trialists Group. Effect of anastrozole andtamoxifen as adjuvant treatment for early stagebreast cancer: 100 month analysis of the ATACtrial. Lancet Oncol 2008; 9:45–53.

14. Wishart GW, Greenberg DC, Britton PD, et al.Screen-detected versus symptomatic breast can-cer—is improved survival due to stage migrationalone? Br J Cancer 2008; 98:1741–1741.

CASE STUDY 2

History

A 44-year-old woman presented to the breastclinic with a three-week history of a tenderlump in the right breast. The lump had notchanged in size over this time period, andthere was no associated nipple discharge.There were no previous breast problemsand no family history of breast or ovariancancer. The patient remained nulliparous(premenopausal) and had never used theoral contraceptive pill. She smoked 20 ciga-rettes per day.

Clinical Findings

Clinical examination revealed a rather ill-defined area of thickening in the centraland superolateral aspects of the right breastwith no obviously dominant mass. Therewas no axillary lymphadenopathy (E2/3)(Fig. 5).

Clinical Assessment

An equivocal lesion in the right breast withan element of clinical suspicion

Investigations

Mammography–

This showed a spiculate mass in the superiorand central aspect of the right breast withthe appearances of a carcinoma (Fig. 6A, B).

Figure 5

6 CHAPTER 1

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Breast Ultrasound

The sonographic correlate of this lesion wasa 24-mm hypoechoic mass lesion with poste-rior acoustic attenuation (lying between12 and 1 o’clock) (Fig. 7).

Core Biopsy

Ultrasound-guided core biopsy of the breastmass confirmed an invasive carcinoma(grade II) [Fig. 8A (low power), B (highpower)].

Figure 6

Figure 7



Diagnosis

Early-stage right breast cancer (T2N0)


Though the radiological extent of the lesionwas less than 3 cm, it lay relatively close tothe nipple-areolar complex in the centralzone of the breast. The lesion was not con-sidered amenable to breast-conservation sur-gery , and a right modif ied radicalmastectomy was recommended. Sentinellymph node biopsy was not routinely offeredat the time and primary surgery would there-fore incorporate a level II axillary lymphnode dissection. Immediate breast recon-struction would be offered (relativelyyoung patient).


Though this patient was not suitable forbreast-conserving surgery, she adamantlyrequested a mastectomy whatever the char-acteristics and location of the primarytumor. Moreover, she declined immediatebreast reconstruction with a similar force ofconviction and proceeded to a right modi-fied radical mastectomy two weeks later(Fig. 9). She made an uneventful recoveryand was discharged on the sixth postopera-tive day after removal of the second redivacdrain. On review in the clinic two weeks after

discharge, there was no evidence of anyseroma formation, and the wound was heal-ing nicely. The patient remained well anddisease-free after five years of follow-up whenshe was discharged back to the care of hergeneral practitioner (Fig. 10).

Figure 9

Figure 8

Figure 10

8 CHAPTER 1



This confirmed an invasive carcinoma(grade II) measuring 22 mm in maximumdiameter [Fig. 11A (magnification 10�), B(magnification 20�)]. There was associatedductal carcinoma in situ (DCIS) yielding anoverall tumor size of 34 mm. Three out of 14nodes contained metastatic carcinoma, andthe tumor was ER positive (90% staining forER) [Fig. 12A (low power), B (high power)].


This premenopausal patient had an NPI of[(0.2 � 2.2) þ 2 þ 2 ¼ 4.44] and fell into theone to three nodes positive category. Adju-vant chemotherapy was recommended (AC�4 cycles, see Appendix III) together withradiotherapy to the chest wall (not supra-clavicular fossa). The patient had an estro-gen-sensitive tumor and would be eligible for

hormonal manipulation with ovarian sup-pression and tamoxifen if she remained pre-menopausal after chemotherapy.


The patient commenced the first cycle ofchemotherapy within three weeks of surgery.She was keen to complete chemotherapy assoon as possible in order to go on a pre-viously arranged holiday. She tolerated che-motherapy well, though developed mildnausea, dyspepsia, and hyperactivity (diffi-culty sleeping). Following the third cycle ofadriamycin/cyclophosphamide (AC) che-motherapy, the patient suffered a left-sidedpulmonary embolism (confirmed on V/Qscan). She was anticoagulated and the finalcycle of chemotherapy delayed by four days.The patient had also become increasinglytroubled by daytime hot flushes and night

Figure 11

Figure 12



sweats. These were very incapacitating andvenlafaxine (37.5 mg twice daily) was pre-scribed.

Radiotherapy to the chest wall was givenimmediately upon completion of the finalcycle of chemotherapy (the radiotherapy-planning session took place three days afterthe fourth cycle of AC). The patient received40 Gy in 15 fractions over three weeks, usingmegavoltage photons. There was slight eryth-ema of the chest wall, but this respondedwell to Aqueous Cream.

The patient commenced tamoxifen asadjuvant hormonal therapy after completionof chemotherapy. Despite a history of throm-boembolism (a relative contraindication totamoxifen), the patient remained premeno-pausal after chemotherapy and was not eli-gible for an aromatase inhibitor. At24-month follow-up, the patient reportedintermittent bloodstained vaginal discharge.She was referred for gynecological assess-ment and a transvaginal ultrasound revealedsome endometrial thickening (8.1 mm) butno ovarian lesion. A subsequent hystero-scopy and biopsy showed an atrophic endo-metrium with no polyp formation. Indeed,the endometrial lining was insufficient foradequate biopsy.

In view of the vaginal bleeding and historyof pulmonary embolism, there were concernsabout continuation of tamoxifen (patientwarfarinized indefinitely). Though menstrualactivity had resumed immediately postche-motherapy, the patient had not experienceda “normal” period for almost 12 months.Measurement of FSH and LH levels con-firmed these to be in the postmenopausalrange and, therefore, tamoxifen was switchedto the aromatase inhibitor Arimidex (1 mgper day) almost two and a half years aftersurgery. However, after three months of ther-apy with Arimidex, the patient experienced avery heavy menstrual bleeding promptingadmission to hospital. Interestingly, repeatgonadotrophin levels showed a postmeno-pausal FSH (27.4) but an LH in the normalrange (6.2). It was anticipated that furthermenstrual activity would occur and manage-ment options for ovarian suppressionincluded either a luteinizing hormone–releasing hormone (LHRH) analogue

(Zoladex) injections or laparoscopic bilateraloophorectomy. The patient opted for a totalabdominal hysterectomy and bilateral sal-pingo-oophorectomy after careful discussionwith the gynecologists and oncologists. Sur-gery was expedited on the basis that ovariansuppression constitutes part of the patient’sbreast cancer treatment.

Discussion

The patient had a clinically indeterminatelesion in the right breast for which the initialindex of suspicion was low. At the time ofpresentation, one-stop style breast clinicswith some day imaging had not yet beenestablished. In consequence, there was asignificant time lapse between initial clinicalassessment and subsequent review withresults of radiological investigation andbiopsy (25 days). The majority of patients(irrespective of clinical urgency) are nowseen within 14 days and basic investigationsundertaken in a “one-stop” clinic. Recentevidence suggests that attempts to stratifypatients into urgent (14 days) and nonur-gent can lead to a significant number ofwomen with cancer being diagnosedthrough the routine pathway with concomi-tant delays in treatment. General practi-tioners do not have access to imaging andcannot undertake triple assessment. Clinicaldetermination of whether a patient has adiscrete lump as opposed to a focal area ofnodularity can be difficult. It is, therefore,preferable to refer all patients under thetwo-week rule rather than just those deemedto have a discrete lump (or some other keysymptom).

When provided with fully informed con-sent, some patients will demand mastectomyeven when breast-conservation therapy isfeasible. For borderline cases, patients maybe concerned about risks of local recurrenceand choose mastectomy to minimize thechance of any future problems. It is moredifficult for surgeons to agree to mastectomyfor smaller tumors (<2 cm) situated wellaway from the nipple-areolar complex in amoderate- to large-breasted woman. Somewomen wish to avoid radiotherapy, thoughshould be warned that this may be indicated

10 CHAPTER 1


postmastectomy for larger, higher-gradelesions that are node positive. Ultimately, itis the patient’s choice if she chooses mastec-tomy in preference to breast-conservationtherapy. Similar considerations apply to acontralateral prophylactic mastectomy inthe absence of any strong family history. Itshould not be assumed that all youngerwomen having mastectomy will seek imme-diate breast reconstruction. This particu-lar patient had no wish for any form ofreconstruction—immediate or delayed.

This premenopausal node-positive patientreceived chemotherapy with an anthracy-cline-based regimen. These youngerwomen with nodal involvement are at higherrisk of relapse and were the first group to betargeted with adjuvant chemotherapy. Earlyregimens involved comparison of placebowith either single agents such as melphalanor combination chemotherapy with cyclo-phosphamide, methotrexate, and 5-fluorour-acil (CMF) (1). These early trials of adjuvantchemotherapy for breast cancer were thefirst to show advantages for both disease-free and overall survival. They spawned ageneration of randomized trials investigatingCMF alone (shorter vs. longer courses)(2) or CMF with additional agents andother combinations of chemotherapy(namely the anthracycline-containing regi-mens). Adjuvant chemotherapy was investi-gated in younger node-negative women withadverse prognosticators relating to primarytumor characteristics (3). The higher risk ofrelapse for this group justified the potentialtreatment morbidity from chemotherapyadministered to symptomatically wellwomen for whom individual benefits fromchemotherapy were unclear.

A series of meta-analyses by the EarlyBreast Cancer Trialists Collaborative Group(EBCTCG) have assimilated individualpatient data from more than 50 trials ofchemotherapy involving over 20,000women. These overviews included 11 trialscomparing CMF with anthracycline-contain-ing regimens. The benefits of adjuvant che-motherapy in both younger and olderwomen were confirmed irrespective ofnodal status and baseline relapse level. Theproportional reductions in mortality and

recurrence were higher among youngerwomen under the age of 50 years but similarfor node-positive and node-negative women.For women under the age of 50 years, theproportional reductions in risk of relapseand mortality were 35% and 27%, respec-tively. This translates into absolute mortalityreductions at 10 years of 11% for node-positive and 7% for node-negative tumors.For women over 50 years of age, the propor-tional reductions in risk of relapse and mor-tality were 20% and 11%, respectively. Thecorresponding absolute reductions in mor-tality at 10 years was 3% for node-positiveand 2% for node-negative tumors (4).

Initial results from the EBCTCG overviewsuggested that regimens containing ananthracycline might be more active thanCMF. However, the larger NSABP-B15 trialcomparing four cycles of AC with CMF failedto demonstrate any superior efficacy foranthracycline regimens but great toxicityfor the latter (5). Cardiotoxicity was of par-ticular concern, but nausea, vomiting, andalopecia were also troublesome side effects.An updated analysis by the EBCTCG involv-ing 15,000 (mainly premenopausal) womenin 14 trials of anthracycline-containing regi-mens has confirmed sustained benefits fromthe latter compared with CMF with a hazardratio of 0.88 (6). At 10 years, there is anabsolute benefit of approximately 4% forrecurrence and survival among node-positivewomen. For node-negative patients, theabsolute survival gain at five years is 1.7%.In recent years, regimens incorporating ananthracycline such as AC and FAC havebecome the standard of adjuvant chemo-therapy for early-stage breast cancer. Theshorter duration of treatment, shorter hos-pital stay, and perceived effectiveness haveappealed to oncologists around the world.Interestingly, the value of anthracyclines innode-positive disease has recently beencalled into question; data presented at the30th San Antonio Breast Cancer Symposiumin 2007 suggest that any superior efficacy ofanthracyclines is attributable to a minority(8–9%) of HER2-positive patients who co-overexpress topoisomerase II. By implica-tion, there is little evidence for any clearbenefit from an anthracycline regimen



among the group of HER2-negative patients(75%) (7).

Though all patients undergoing breast-conserving surgery receive some form ofbreast irradiation, radiotherapy is appliedmore selectively to the chest wall followingmastectomy. All trials have consistentlyshown that postmastectomy radiotherapyreduces the proportional risk of local failureby two-thirds to three-quarters. However,there remain unresolved issues about theeffects of local control on longer-term sur-vival from breast cancer. Indeed, an earlymeta-analysis of postmastectomy radiother-apy trials showed a poorer overall survivalamong irradiated patients (8). The EBCTCGpublished a comprehensive meta-analysis of40 unconfounded randomized trials involv-ing 20,000 women in 2000. More than halfthe patients had node-positive disease andradiotherapy fields included not only thechest wall but also the axillary, supraclavicu-lar, and internal mammary nodes. This meta-analysis revealed a reduction in rates of localrecurrence from 27.2% to 8.8% at 10 years(9). Though breast cancer–specific mortalitywas significantly reduced, other causes ofdeath were increased. Many of these datarelated to outdated modes of radiotherapyand adverse effects (especially cardiotoxicity)are minimized by newer techniques employ-ing tangential fields. A reanalysis of theEBCTCG data with exclusion of pre-1970trials and small ones with suboptimal proto-cols supports an overall survival benefit forpostmastectomy radiotherapy in selected sub-groups. It is important that modern techni-ques of radiotherapy are used and treatmentis with standardized fractionation (10).

Two randomized studies of postmastec-tomy radiotherapy have shown a survivalbenefit (approximately 10%) in a subgroupof premenopausal node-positive patientsreceiving chemotherapy, suggesting that per-sistence of local or regional disease can leadto distant metastases and impaired survival(11,12). In the smaller Canadian study, 318node-positive women were randomized tomastectomy and chemotherapy, with or with-out irradiation. At 15-year follow-up, theoverall survival rates were 54% and 46%,respectively for these two groups. In the

larger Danish trial, 1708 node-positive orstage III breast cancer patients were similarlyrandomized, and overall survival rates at10 years were 54% for the irradiated groupcompared with 48% for the nonirradiatedgroup (p < 0.001). The results of these trialshave generated some controversy due to thelow number of nodes harvested at axillarydissection and potential understaging ofpatients due to suboptimal management ofthe axilla.

In a further landmark publication in2005, the EBCTCG showed an overall sur-vival benefit at 15 years from local radiationtreatment to either the breast following BCTor the chest wall after mastectomy. For thosetreatment comparisons where the differencein local recurrence rates at five years was lessthan 10%, survival was unaffected. Amongthe 25,000 women where differences in localrelapse were substantial (>10%), there weremoderate reductions in breast cancer–specific and overall mortality. The absolutereduction in local recurrence at five yearswas 19%, and the absolute reduction inbreast cancer mortality at 15 years was5.0%. This represents one life saved forevery four locoregional recurrences pre-vented by radiotherapy at five years (13).

Postmastectomy radiotherapy does notbenefit all subgroups, and the absolutegains in terms of local control and overallsurvival must be balanced against toxicitiesand inconvenience to patients together withcosts. Patients can be stratified into three riskgroups as follows (14):

High risk (>20% chance of locoregionalrelapse at 10 years)

– Tumors � 5 cm in maximum diameter– �4 nodes positive (pathological confir-mation)

Moderate risk (10–20% chance of locore-gional relapse at 10 years)

– Tumors <5 cm in maximum diameter– 1 to 3 nodes positive (pathological con-firmation)

Low risk (<10% chance of locoregionalrelapse at 10 years)

– Tumors <5 cm in maximum diameter– No pathologically involved nodes

12 CHAPTER 1


For the high-risk group, there is interna-tional consensus for the routine use of chestwall radiotherapy following mastectomy.These patients are also at risk for supracla-vicular failure, and irradiation of the supra-clavicular nodes is usually undertaken forthis group of patients with �4 nodes positive.Conversely, patients in the low-risk groupshould not receive radiotherapy. Thosepatients who fall into the moderate-riskgroup with one to three nodes positivehave less clear benefits from postmastectomyradiotherapy. The Canadian and Danish tri-als showed similar proportional benefits inpatients with 1 to 3 and �4 nodes positive,but with more prolonged follow-up the ben-efits of radiotherapy are statistically morerobust for the higher-risk groups comparedwith moderate-risk groups. The UK/Euro-pean SUPREMO study is presently investigat-ing the role of postmastectomy radiotherapyin patients at moderate risk of relapse withsmaller tumors (<5 cm) and/or one to threenodes positive (15).

The Cambridge Breast Unit have deriveda postmastectomy radiotherapy index to useas a clinical tool for selection of patients forchest wall radiotherapy (16). This rankspatients by a scoring system that is relatedto known risk factors for locoregional failure(Table 1). Patients receive postmastectomyradiotherapy if the score is �3.

Many women over the age of 45 years willexperience chemotherapy-induced amenor-rhea with permanent cessation of ovarianfunction (17). The proportional improve-ment in overall survival from ovarian ablationis 24% in the absence of chemotherapy andonly 8% to 10% in those who have received

chemotherapy—though the absolute benefitsare greatest in those women who continue tomenstruate (18). Formal ovarian ablation isoften not undertaken for women in their midto late 40s in expectation of postmenopausalchange. Unlike younger women (<35 years),chemotherapy alone is considered adequatetreatment within this age group for hormone-sensitive tumors.

This patient underwent delayed ovariansuppression following resumption of men-strual activity after initiation of aromataseinhibitor therapy. This was an unusual situ-ation and bilateral oophorectomy was com-bined with hysterectomy due to heavymenstrual bleeding. It is unclear beyondwhat time interval ovarian ablation ceasesto be effective in terms of the primary tumor.

Related Cases

Postmastectomy radiotherapy—Case Studies3, 18, 22, 25, 26, 27, 28, and 37

Adjuvant chemotherapy—Case Studies 3, 6, 8,11, 36, and 37

Ovarian suppression—Case Studies 6, 8, 23,27, and 37

Learning Points

1. There is considerable geographic vari-ability in the use of BCT. BCT is morecommonly utilized in Europe than inthe United States. Furthermore, thereis considerable variability in the use ofBCT within the United States itself(more commonly utilized in the north-east than in the south).

2. A tumor adjacent to the nipple-areolarcomplex is not necessarily a contraindi-cation for BCT. Excison of the tumorand nipple-areolar complex is feasible.This is generally followed by radiother-apy.

3. Adjuvant chemotherapy generallybegins within six weeks of surgery, andradiotherapy, when indicated, usuallyfollows chemotherapy. Endocrine ther-apy is commenced after completion ofradiotherapy.

Table 1 Postmastectomy Radiotherapy Index

Score 3 2 1

�4 nodes 1–3 nodes Vascularinvasion

tumor size>50 mm/T4

tumor size30–50 mm

tumor size20–29 mm

deep margin<1 mm

grade III orpectoralmuscleinvolvement



4. Adjuvant chemotherapy is usually admi-nistered as a combination of drugs,which is more effective than a singleanticancer agent. Anthracycline-basedregimens have been shown to be moreefficacious than classical CMF (cyclo-phosphamide, methotrexate, 5-fluorour-acil), and addition of taxanes mayconfer additional benefit over andabove that of anthracyclines alone.

5. Tamoxifen is associated with about atwofold increased risk of endometrialcancers and thromboembolic events.

6. Postmastectomy radiotherapy is benefi-cial to both pre- and postmenopausalwomen who are at high risk for locore-gional relapse.

References

1. Bonadonna G, Valagussa P, Moliterni A, et al.Adjuvant cyclophosphamide, methotrexate andfluorouracil in node positive breast cancer. Theresults of 20 years follow up. N Engl J Med 1995;332:901–926.

2. Tancini G, Bonadonna G, Valagussi P, et al. Adju-vant MF in breast cancer: comparative 5 year resultsof 12 versus 6 cycles. J Clin Oncol 1983; 1:2–10.

3. Fisher B, Redmond C, Dimitrov NV, et al. Arandomized clinical trial evaluating sequentialmethotrexate and fluorouracil in the treatmentof patients with node negative breast cancer whohave estrogen receptor negative tumours. N Engl JMed 1989; 320:473–478.

4. Early Breast Cancer Trialists Collaborative Group.Polychemotherapy for early breast cancer: an overviewof the randomized trial. Lancet 1998; 352:930–942.

5. Fisher B, Brown AM, Dimitrov NV, et al. Twomonths of doxorubicin-cyclophosphamide withand without interval reinduction therapy com-pared with 6 months of cyclophosphamide, metho-trexate and 5-fluorouracil in node positive breastcancer patients with tamoxifen non-responsivetumours: results from the National Surgical Adju-vant Breast and Bowel Project B-15. J Clin Oncol1990; 8:1483–1496.

6. 5th Meeting of the Early Breast Cancer TrialistsCollaborative Group, Oxford, UK, September 21–23, 2000.

7. Slamon D. Another genetic approach to predictingresponse to anthracyclines: the importance ofHER2 and topoisomerase IIa. 30th San AntonioBreast Cancer Symposium, San Antonio, Texas,USA, December 2007.

8. Early Breast Cancer Trialists’ Collaborative Group.Effects of radiotherapy and surgery in early breastcancer: an overview of the randomized trials. NEngl J Med 1995; 333:1444–1455.

9. Early Breast Cancer Trialists’ Collaborative Group.Favourable and unfavourable effects on long termsurvival of radiotherapy for early breast cancer. Anoverview of the randomized trials. Lancet 2000;355:1757–1770.

10. Van de Steene J, Soete G, Storme G. Adjuvantradiotherapy for breast cancer significantlyimproves overall survival. Radiol Oncol 2000;55:263–272.

11. Ragaz J, Jackson SM, Le M, et al. Adjuvant radio-therapy and chemotherapy in node positive pre-menopausal women with breast cancer. N Engl JMed 1997; 337:956–962.

12. Overgaard M, Hansen PS, Overgaard J, et al. Post-operative radiotherapy in high risk pre-menopausalwomen with breast cancer who receive adjuvantchemotherapy. Danish Breast Cancer CooperativeGroup 82b trial. N Engl J Med 1997; 337:949–955.

13. Early Breast Cancer Trialists Collaborative Group.Effects of radiotherapy and of differences in theextent of surgery for early breast cancer on localrecurrence and 15 year survival: an overview of therandomized trials. Lancet 2005; 366:2087–2106.

14. Recht A, Edge SB, Solin SJ, et al. Post-mastectomyradiotherapy: clinical practice guidelines of theAmerican Society of Clinical Oncology. J ClinOncol 2001; 19:1539–1569.

15. SUPREMO breast cancer trial. Selective Use ofPostoperative Radiotherapy after Mastectomy.Available at: www.supremo-trial.com. AccessedNovember 17, 2008.

16. Wilson CB, Haba Y, Wishart GC. The identificationof patients for postmastectomy radiotherapy usingthe Cambridge index: audit of a prospective series.Breast Cancer Res Treat 2007; 106:S198 (abstr4093).

17. Del Mastro L, Venturini M, Sertoli MR, et al.Amenorrhoea induced by adjuvant chemotherapyin early breast cancer patients: prognostic role andclinical implications. Breast Cancer Res Treat 1997;43:183–190.

18. Early Breast Cancer Trialists Collaborative Group.Ovarian ablation in early breast cancer: overview ofthe randomized trials. Lancet 1996; 348:1189–1196.

14 CHAPTER 1


CASE STUDY 3

History

A 51-year-old woman presented with a two-week history of an area of fullness and ten-derness of the left breast. There was noassociated nipple discharge and no previousbreast problems or family history of breastcancer. The patient was nulliparous and hadused the oral contraceptive pill for a contin-uous period of almost 20 years.

Clinical Findings

There was a large, firm, irregular mass in theupper outer quadrant of the left breast mea-suring between 4 and 5 cm. The mass wasmobile on the chest wall with no evidence ofany skin tethering or infiltration. A hardnode was palpable in the left axilla measur-ing at least 2 cm in diameter (E5) (Fig. 13).

Clinical Assessment

Clinical carcinoma of the left breast withinvolved axillary lymph nodes

Investigations

Mammography

An asymmetric density was apparent in theupper outer quadrant of the left breast,which contained fine microcalcification(Fig. 14A). Subtle spiculation was seen onthe craniocaudal view (Fig. 14B).

Breast Ultrasound

The sonographic correlate of this density wasa 42-mm hypoechoic lesion with the radio-logical features of a carcinoma (U5) (Fig. 15).

Figure 13

Figure 14



Core Biopsy

Ultrasound-guided core biopsy of the breastmass confirmed an invasive carcinoma(grade II) with associated intermediatenuclear grade DCIS of solid type. RoutineER measurements were not done on corebiopsies at the time, and the axilla was notinterrogated sonographically [Fig. 16A (lowpower), B (high power)].

Diagnosis

Early-stage left breast cancer (T2N1).


It was recommended that the patientundergo a left modified radical mastectomyand be offered immediate breast reconstruc-

tion. The location of the tumor in relation tothe nipple made it unlikely that breast-conserving surgery would be feasible afterinduction chemotherapy. This together withthe grade (II) and size of the lesion (<5 cm)prompted the recommendation for primarysurgery rather than chemotherapy. Thepatient was not eligible for sentinel lymphnode biopsy on account of the clinically sus-picious node in the left axilla (and to someextent tumor size at the time). Radiotherapyto the chest wall would likely be required(large size and clinically node positive).


The patient expressed an interest in imme-diate breast reconstruction and was reviewedby the plastic surgeon. It was noted that the

Figure 15

Figure 16

16 CHAPTER 1


patient had a 34D cup and was likely torequire both chemotherapy and radiother-apy postoperatively. An implant-only proce-dure was excluded by the expectation ofradiotherapy, and the patient had an inade-quate volume of infraumbilical abdominaltissue for a transverse rectus abdominusmyocutaneous (TRAM) flap reconstruction.

The patient proceeded to a left modifiedradical mastectomy and immediate breastreconstruction with a latissimus dorsi flapand implant within four weeks of initial tissuediagnosis. A modified skin-sparing techniquewas employed to incorporate the nipple-areo-lar complex and the skin directly over thetumor. She made an excellent recovery andwas discharged home on the seventh postop-erative day. A seroma was aspirated on twooccasions from the donor site on the back.


This revealed a grade II invasive ductal carci-noma measuring 35 mm microscopically butapproximately 45 mm macroscopically (whichwas more consistent with the clinical/radio-

logical estimate) [Fig. 17A (magnification10�), B (magnification 20�)]. The invasivetumor was associated with both intermediateand high nuclear grade DCIS with focal com-edo necrosis. DCIS did not extend signifi-cantly beyond the invasive tumor that waswell clear (�5 mm) of all margins, includingthe anterior (skin) margin (10 mm). Therewas extensive lymphovascular invasion andfive nodes contained metastatic carcinoma[Fig. 17C (low power), D (high power)].Immunohistochemical staining for ER waspositive, but PgR negative. The Hercep Testfor HER2 was borderline 2+ and HER2 FISHwas amplified (i.e., HER2 overexpression).


This patient had a relatively large tumor withextensive regional disease. The calculatedNPI was [(0.2 � 3.5) þ 2 þ 3 ¼ 5.7], andit was recommended she receive chemother-apy with a taxane-based schedule togetherwith radiotherapy to the chest wall andsupraclavicular fossa. Tamoxifen would begiven as adjuvant systemic hormonal therapy

Figure 17



upon completion of chemotherapy. Fullstaging investigations (hepatic ultrasoundand bone scan) were requested and revealedno evidence of metastatic disease.


The patient proceeded to a course of FEC/docetaxol with four cycles of 5-fluorouracil,epirubicin, cyclophosphamide (FEC) fol-lowed by four cycles of docetaxel (seeAppendix III). This was well tolerated with-out any serious adverse effects and radiother-apy was commenced seven months followingsurgery. The patient developed some edemaof the breast, but otherwise no acute seque-lae from irradiation of the chest wall, recon-structed breast, and supraclavicular fossa.This patient was considered to be at highrisk for relapse and was reviewed clinically ona six-monthly basis (rather than annually).Upon review at 18 months she was noted tohave a degree of capsular formation second-ary to radiotherapy. This was not progressiveand did not lead to implant failure andexplantation. Nonetheless, the overall cos-metic outcome was slightly compromised bythese sequelae of radiotherapy (Fig. 17E–G).

Discussion

This patient presented with a relatively largetumor with a clinically node-positive axilla.Though she was managed with primary sur-gical treatment, a course of preoperative che-motherapy to downstage the tumor wouldhave been an alternative option. However,whatever the degree of tumor response, mas-tectomy would still have been indicated onthe basis of central tumor location. An advan-tage of primary surgery is possession of max-imum information on primary tumorcharacteristics and nodal status prior to mak-ing any decision on adjuvant therapies. Thispatient had involvement of >4 nodes and wastherefore a candidate for both chest wall andsupraclavicular irradiation (1). Furthermore,the absolute nodal count influenced choiceof adjuvant systemic therapy, and this patientreceived taxanes in addition to an anthracy-cline-based chemotherapy regimen (seebelow). In theory, induction chemotherapycould downstage nodal disease such that theinitial extent of involvement prechemother-apy is unknown. It is sometimes possible todiscern pathologically which nodes have been“sterilized” by chemotherapy, but this is

Figure 17 (continued )

18 CHAPTER 1


unreliable. Similarly, ultrasound assessmentof the axilla (with core biopsy) can providehistological evidence of nodal involvement,but does not yield information on the totalnumber of nodes positive.

An increasing proportion of women arenow requiring postmastectomy radiotherapy.Anticipation of chest wall radiation will influ-ence the choice of reconstructive technique;an implant-only based technique (subpectoralimplant) is generally avoided when there is apossibility of the patient requiring postopera-tive irradiation (2,3). All breast implants evokea degree of fibrosis and scar tissue formationaround the implant, and this occurs irrespec-tive of whether reconstruction is carried outwithin an irradiated field or radiotherapyfollows implant-based reconstruction (4).Excessive fibrosis with shrinkage of the scartissue constitutes capsular contracture andresults in distortion of the reconstruction.There is a high rate of capsular contractureunder these circumstances, which may lead toimplant failure. To some extent an implantcan be protected from the adverse effects ofradiation by an overlying latissimus dorsi myo-cutaneous flap. However, emerging data fromseveral units suggests that even when place-ment of an implant is combined with trans-position of a latissimus dorsi flap, thereremains a significant risk of capsular contrac-ture of up to 40% at four years (5,6). Othercase series that involve both implant-only andimplant-assisted latissiumus dorsi flap recon-struction confirm that postoperative radio-therapy worsens capsular contracture withrates varying from 0% to 40% without radio-therapy and 17% to 68% with radiotherapy(7,8). Moreover, severe capsular contractureis confined to the radiotherapy group andnecessitates either capsulotomy (9–31.6%) orcapsulectomy with implant exchange (1.2–11%). Most of these series involve a totalradiation dose of 50 Gy given as 25 fractions(with or without a booster dose of 10–12 Gy tothe scar). Nonetheless, despite these com-ments, when viewed from the other perspec-tive, almost two-third of patients receivingradiotherapy after implant-assisted latissimusdorsi flap reconstruction do not develop clin-ically significant capsular formation and donot require exchange of implant.

Within the Cambridge Breast Unit, a dif-ferent regimen is employed; a dose of 40 Gyis administered in 15 fractions over a three-week period. Among a group of 77 patientswho underwent either implant -only(29 patients) or latissimus dorsi flap andimplant (48 patients) reconstruction withoutradiotherapy, no cases of severe capsularcontracture occurred. By contrast, five casesof severe contracture were found among asimilar group who received radiotherapypostoperatively. These cases occurred inthose with a latissimus dorsi flap and implant(35 patients), while no cases were docu-mented among eight patients with animplant-only-based reconstruction. The actu-arial rate of severe capsular contracture atfour years was 28% (9). The potential prob-lems of capsular contracture in this group ofbreast reconstruction patients receiving radio-therapy has led some surgeons to modify theirsurgical approach with a so-called “delayedimmediate reconstruction” (10). A skin-spar-ing mastectomy can be undertaken initiallywith placement of a temporary tissue expanderthat acts as a scaffolding for the skin flaps(subpectoral or subcutaneous). Chest wall irra-diation can then be given, and definitive recon-struction performed at a later stage (8–12months). There are concerns about the viabil-ity of the mastectomy flaps after radiation, andit may be preferable overall to proceed withimmediate reconstruction with latissimus dorsiflap and implant for all patients and undertakeimplant exchange if and when required. Anextended autologous latissimus dorsi flap is notnecessarily more tolerant of radiotherapy, andthere is significant donor site morbidity. How-ever, delayed immediate reconstruction is amethod that can potentially preserve the aes-thetic benefits of immediate breast reconstruc-tion with preservation of the 3-D skin envelope.The decision for radiotherapy is made oncethe final histology is available and the tempo-rary implant can be deflated prior to irradia-tion and re-inflated immediately afterward.This allows more accurate targeting of thetangential radiotherapy beams.

The taxanes are a new class of chemo-therapeutic agents that are increasinglybeing employed in the adjuvant setting fortreatment of those women at moderate and



high risk of relapse. The two agents in cur-rent clinical usage are paclitaxel (Taxol) anddocetaxel (taxotere). The taxanes have non-cross resistance with conventional agents,and their mechanism of action is to stabilizeand prevent disaggregation of microtubuleswith disruption of the mitotic spindle. Pacli-taxel was the first taxane to be investigatedamong node-positive patients with early-stage breast cancer. It was added to thesequential dose-dense regimen of doxorubi-cin and cyclophosphamide (AC) in theCALGB 9344 trial (11). The addition offour cycles of paclitaxel to four cycles ofAC improved both disease-free (HR 0.83,p ¼ 0.0023) and overall survival (HR 0.82,p ¼ 0.0064). Dose escalation (density/totaldose) for doxorubicin had no impact ofthese outcome parameters, and prolongationof therapy with taxanes led to only a modestincrease in level of side effects. The NSABPB28 trial is of similar design and randomizednode-positive patients to AC alone or ACfollowed by paclitaxel. Initial results showedbenefits for relapse-free (HR 0.83, p ¼ 0.008)but not overall survival (HR 0.94, p ¼ 0.46)(12). Results were otherwise compatible withthose of the CALGB 9344 trial.

Two trials have investigated the efficacy ofthe other taxane, docetaxel in node-positivepatients. These have used more intensiveanthracycline regimens; the BCIRG-01 trialcompared six cycles of 5-fluorouracil, doxor-ubicin, and cyclophosphamide (FAC) with sixcycles of docetaxel, doxorubicin, and cyclo-phosphamide (TAC) (13). The PACS-01 trialcompared six cycles of 5-fluorouracil, epirubi-cin, and cyclophosphamide (FEC) with threecycles of FEC followed by three cycles ofdocetaxol. Both trials have shown statisticallysignificant improvements in overall survivalfor taxane containing regimens (14).

This particular patient received an off-trialregimen similar to the PACS-01 protocol withfour cycles of FEC followed by four cycles ofdocetaxel. It is current policy to offer FEC-taxotere as standard chemotherapy to allHER2-positive patients and those with �4nodes positive. Provisional results from theTACT I trial involving 4000 patients suggestthat there is minimal benefit in terms ofdisease-free and overall survival from adding

four cycles of docetaxel to one of two stan-dard antracycline-containing regimens(E-CMF � 8 cycles or FEC � 8 cycles) (15).

Related cases

Postmastectomy radiotherapy—Case Studies18, 22, 23, 25, 26, 27, and 28

Irradiation of implants—Case Studies 18 and 23

Adjuvant chemotherapy—Case Studies 2, 6,11, 36, and 37

Learning Points

1. At the time of mastectomy, plastic sur-geons may opt to place an expanderprosthesis beneath the pectoralis majormuscle. This allows for expansion ofskin overlying the muscle, and autoge-nous tissue reconstruction is undertakenafter completion of systemic chemother-apy and postmastectomy radiotherapy.

2. Clinical trials have shown that there isno difference in survival betweenpatients receiving pre- and postopera-tive systemic chemotherapy. However,preoperative chemotherapy is routinelyadministered to patients with inflamma-tory or locally advanced breast cancersand those with large tumors who areeager for BCT (preoperative chemo-therapy may shrink the tumor, therebymaking it amenable to BCT).

3. A sentinel node biopsy is contraindi-cated in patients who present with clin-ically suspicious axillary nodes. Thesepatients should undergo a standard axil-lary lymph node dissection. However,some patients will develop palpable axil-lary nodes (reactive lymph nodes) fol-lowing core biopsy of the breast tumor,and sentinel node biopsy is feasible inthese cases. Therefore, in any patientwith a suspicious breast mass, the axillashould be carefully examined, and thestatus of the axillary lymph nodes (clin-ically suspicious or not) is documentedprior to core biopsy.

4. There is some retrospective evidenceto suggest that the taxanes primarily

20 CHAPTER 1


benefit patients with HER2-positive,ER-negative tumors, although patientswith HER2-negative, ER-negative tumorsmay also derive significant absolutegains in disease-free and overall survivalfrom taxanes (16).

References


2. Vandeweyer E, Deraemaecker R. Radiation ther-apy after immediate breast reconstruction withimplants. Plast Reconstr Surg 2000; 106:56–58.

3. Evans G, Schusterman MA, Kroll SS, et al. Recon-struction and the irradiated breast: is there arole for implants? Plast Reconstr Surg 1995; 96:1111–1115.

4. Constant CM, van Geel AN, Van der Holt B, et al.Morbidity of immediate breast reconstruction aftermastectomy by subpectorally placed silicone pros-thesis: the adverse effect of radiotherapy. Eur JSurg Oncol 2000; 26:344–350.

5. Spear SL, Onyewu C. Staged breast reconstructionwith saline-filled implants in the irradiated breast:recent trends and therapeutic implications. PlastReconstr Surg 2000; 105:930–942.

6. Behranwala KA, Dua RS, Ross GM, et al. Theinfluence of radiotherapy on capsule formationand aesthetic outcome after immediate breastreconstruction using biodimensional anatomicalexpander implants. J Plast Reconstr Aesthet Surg2006; 59:1043–1051.

7. Halpern J, McNeese MD, Kroll SS, et al. Irradiationof prosthetically augmented breasts: a retrospectiveon toxicity and cosmetic results. Int J Radiat OncolBiol Phys 1991; 21:339–344.

8. Cordiero PG, Pusic AL, Disa JJ, et al. Irradiationafter immediate tissue expander/implant breastreconstruction:outcomes, complications, aestheticresults and satisfaction among 156 patients. PlastReconstr Surg 2004; 113:877–881.

9. Whitfield GA, Horan G, Irwin MS, et al. Compar-ison of the incidence of severe capsular contrac-ture following implant-based immediate breastreconstruction with or without postoperativechest wall radiotherapy using 40 Gy in 15 fractions.Eur J Cancer 2007; 5(3):23 (abstr 74).

10. Kronowitz S. Delayed-immediate reconstruction inpatients who might require postmastectomy radia-tion therapy. Miami Breast Cancer Conference,Orlando, Florida, 2008.

11. Henderson IC, Berry DA, Demetri GD, et al.Improved outcomes from adding sequential pacli-taxel but not from escalating doxorubicin dose inan adjuvant chemotherapy regimen for patientswith node positive primary breast cancer. J ClinOncol 2003; 21:976–983.

12. Mamounas EP, Bryant J, Lembersky B, et al. Pacli-taxel after doxorubicin plus cyclophosphamide asadjuvant chemotherapy for node-positive breastcancer: results from NSABP B-28. J Clin Oncol2005; 23:3686–3696.

13. Martin M, Pienkowski T, Mackey J, et al. Adjuvantdocetaxol for node positive breast cancer. N Engl JMed 2005; 352:2302–2313.

14. Roche H, Fumoleau P, Spielman M, et al. Sequen-tial adjuvant epirubicin based and docetaxel che-motherapy for node positive breast cancerpatients: The FNCLCC PACS01 trial. J Clin Oncol2006; 24:5664–5671.

15. Ellis PA, Barrett-Lee PJ, Bloomfield D, et al. Pre-liminary results of the UK Taxotere as AdjuvantChemotherapy (TACT) trial. Breast Cancer ResTreat 2007; 106:S21 (abstr 78).

16. Hayes DF, Thor AD, Dressler LG, et al. HER2 andresponse to paclitaxel in node positive breast can-cer. N Engl J Med 2002; 357:1496–1506.

CASE STUDY 4

History

A 72-year-old woman presented with a two-week history of a nontender lump in the leftbreast. There was no associated nipple dis-charge, and the patient had no previousbreast problems. She had undergone regularscreening mammography without recall.There was no family history of breast orovarian cancer, and the patient had threechildren (eldest aged 40 years). She hadnever used the oral contraceptive pill orhormone replacement therapy.

Clinical Findings

Examination revealed a firm irregular 2-cmlump in the upper outer quadrant of the leftbreast. The lump was relatively close to thenipple, and the patient had small breasts.There was no associated axillary lymphaden-opathy (E4) (Fig. 18).

Clinical Assessment

Clinically suspicious lump in the left breast(borderline conservable).



Investigations

Mammography

A spiculate opacity was seen in the upperouter quadrant of the left breast, whichcontained granular clustered microcalcifica-tion (R5) (Fig. 19A, B).

Breast Ultrasound

The palpable mass corresponded to a 12-mmisoechoic lesion without posterior enhance-ment or attenuation (Fig. 20A).

Core Biopsy

Ultrasound-guided core biopsy (16-gaugeneedle) confirmed the clinical and radio-logical impression of malignancy andshowed an invasive ductal carcinoma (notgraded, ER positive) (Fig. 20B) with papil-

lary features (Fig. 20C). The lesion was bor-derline HER2 positive (Fig. 20D).

Diagnosis

Early-stage left breast cancer (T1N0)


Following multidisciplinary discussion, it wasrecommended the patient undergo primarysurgery with either wide local excision ormastectomy. The tumor was borderline con-servable and surgical options should be dis-cussed with the patient. It was unlikely thatchest wall radiotherapy would be required inthe event of mastectomy, and chemotherapywas a similarly improbable option (especiallyin view of the patient’s age).


The patient opted for mastectomy after fullyinformed consent that included discussionof issues such as the chance of further sur-gery after wide excision, cosmetic outcomes,the need for radiotherapy, and local recur-rence rates. Despite her age, the patientexpressed interest in immediate breastreconstruction and consulted with the plas-tic surgeons. She had relatively small breasts,and reconstruction with an implant-only-based technique was considered most appro-priate in view of the patient’s age andunlikely need for radiotherapy.

A left sentinel lymph node biopsy wasundertaken in advance of definitive surgeryand revealed no evidence of metastatic dis-ease (3 nodes harvested) (Fig. 21). Thepatient proceeded with a left simple mastec-tomy (skin-sparing) via a periareolar inci-sion. A subpectoral expander prosthesis wasinserted at the time of extirpative surgery,and the patient was discharged home on thethird postoperative day!


This revealed an invasive ductal carcinoma(grade II) measuring 12 mm in maximum

Figure 18

Figure 19

22 CHAPTER 1


dimension (Fig. 22A, B). The tumorappeared to have arisen from a preexistingintracystic papillary carcinoma (Fig. 22C).There was no lymphovascular invasion andno in situ component.


It was recommended that the patient initiallybe prescribed tamoxifen as adjuvant systemichormonal therapy, and this might beswitched to an aromatase inhibitor aftertwo to three years in the light of emergingtrial data.

Further Progress

The patient continued to make an excellentpostoperative recovery and had adjustmentof the implant size to achieve symmetry. Shewas reviewed annually in the clinic with fol-low-up contralateral mammography at twoand four years postoperatively.

Discussion

This fit and active 72-year-old woman had aborderline conservable carcinoma of the left

Figure 20

Figure 21



breast. Though the tumor measured only12 mm on ultrasound (which correspondedexactly with the final pathological size), it layrelatively close to the nipple-areolar complex.Moreover, the patient had small breasts andwas keen to avoid any second stage surgery(re-excision or completion mastectomy) andto minimize the chance of any local recur-rence. After careful consideration she choseto undergo mastectomy with immediatebreast reconstruction. Fortunately, her smallbreast size made her suitable for an implant-only-based technique. It is rather uncommonto offer reconstruction with autologous tissuetransfer to patients over the age of 70 years,but there is no absolute upper age limit (1). Ithas been reported that older patients have amore attenuated and fragile chest wall mus-culature that can lead to increased rates offailure for reconstruction with a subpectoral

implant only (2). Furthermore, as this patienthad a small non-high grade tumor, it wasunlikely that chest wall radiotherapy wouldbe indicated (3). Reconstruction with a sub-pectoral implant is usually avoided whenradiotherapy is anticipated. Irradiation inthese circumstances significantly increasesthe chance of capsular contracture andimpairs the final cosmetic outcome. Whenchest wall radiotherapy is likely to be recom-mended, reconstruction with a latissimusdorsi flap and implant or an extended autol-ogous latissimus dorsi flap is preferable. It islikely that this patient may have declinedreconstruction had a relatively straightfor-ward (implant only) procedure not beenpossible. She was discharged home on thethird postoperative day and promptlyresumed her regular daily activities includingcycling! This patient had a low risk of relapse

Figure 22

24 CHAPTER 1


with an NPI of 3.24 [2 (grade II) þ 1 (nodenegative) þ 0.24]. She would have been inel-igible for an aromatase inhibitor based oncurrent unit guidelines for adjuvant hor-monal therapy in hormonally responsive post-menopausal women.

This case illustrates the importance ofpatient choice in the decision-making pro-cess; some older patients will readily opt formastectomy rather than breast-conservingsurgery in order to reduce the chance offurther surgery, local recurrence, and some-times radiotherapy (to the breast). Withinreason, patients should be managed accord-ing to physiological and not chronologicalage. The average life expectancy hasincreased and a fit 75-year-old woman mayotherwise be expected to live for a further10 years. Though restrictions may apply tochemotherapy and certain forms of recon-struction, older patients (>75 years) shouldotherwise be managed in a similar mannerto their younger counterparts.

Related Cases

Immediate breast reconstruction—Case Studies3, 5, 18, 36, and 37

Adjuvant hormonal therapy—Case Studies 1,2, 3, 9, 10, and 19

Sentinel lymph node biopsy—Case Studies 5,7, 10, 11, 12, 13, 15, 16, 19, 24, 32, and 37

Learning Points

1. A skin-sparing mastectomy involvesremoval of the breast and nipple-areolarcomplex, but leaves the skin overlying

the breast intact. Breast reconstructionfollowing skin-sparing mastectomy isassociated with a better cosmetic out-come than reconstruction followingstandard mastectomy, which involvesremoval of the nipple-areolar complex,breast, and much of the overlying skin.

2. Although either tamoxifen or an aroma-tase inhibitor is appropriate endocrineagents in postmenopausal women withearly-stage ER-positive tumors, the aroma-tase inhibitors have been gaining wideracceptance. The aromatase inhibitors areeither administered alone for five yearsafter surgery or in sequence with tamox-ifen. Thus, patients can be switched to anaromatase inhibitor after two to threeyears of tamoxifen (completing a total offive years of endocrine therapy), or takefive years of tamoxifen followed by fiveyears of an aromatase inhibitor. The aro-matase inhibitors are associated with anincreased risk of fractures, osteoporosis,arthritis, and arthralgias.

References

1. Rosenqvist S, Sandelin K, Wickman M. Patients’psychological and cosmetic experience after imme-diate breast reconstruction. Eur J Surg Oncol 1996;22:262–266.


3. Barreau-Pouhaer L, Le MG, Rietjens M, et al. Riskfactors for failure of immediate breast reconstruc-tion with prosthesis after mastectomy for breastcancer. Cancer 1992; 70:1145–1151.

CASE STUDY 5

History

A 58-year-old woman presented with a five-week history of a lump in the right breast.She reported no tenderness or nipple dis-

charge and had undergone regular screen-ing mammography since the age of 50 yearsand had never been recalled. There wasotherwise no history of any previous breastinvestigations and no family history of breast



or ovarian cancer. She gave birth to her onlychild at the relatively young age of 18 yearsand had never used any form of exogenoushormonal preparation.

Clinical Findings

Examination revealed a firm and rather ill-defined lump in the lower outer quadrant ofthe right breast, which was mobile with notethering of the overlying skin. There was noaxillary lymphadenopathy. The lump wasrelatively large (4 cm) and suspicious formalignancy (E4) (Fig. 23).

Clinical Assessment

The clinical impression was of a probableinvasive carcinoma of the right breast

Investigations

Mammography

An irregular mass lesion was seen in theupper outer quadrant of the right breast

measuring 40 mm in maximum diameter(Fig. 24A, B). This contained fine granularcluster microcalcification that was not pres-ent on screening mammograms takenalmost three years earlier.

Breast Ultrasound

The sonographic correlate of the mammo-graphic abnormality was a hypoechoic masslesion measuring 40 mm. The mass was het-erogeneous and ill defined with a posterior

Figure 23

Figure 24

26 CHAPTER 1


acoustic shadow highly suspicious for malig-nancy (U4) (Fig. 25).

Core Biopsy

Ultrasound-guided core biopsy of the rightbreast mass (16-gauge needle, 4 passes)revealed high nuclear grade DCIS only withno evidence of invasion (Fig. 26).

Diagnosis

Noninvasive cancer of the right breast pre-senting as a palpable mass (Tis).


The patient’s mammogram was reviewed bythe MDT team, and extensive microcalcifica-tion was noted in the right breast, whichextended beyond the palpable mass andinvolved more than one quadrant. It was rec-ommended that the patient undergo a rightsimple mastectomy with sentinel lymph nodebiopsy. It was commented that invasive cancerwas likely to be found on definitive histology inthe presence of a palpable mass. However,further core biopsies of the mass in an attemptto establish a preoperative diagnosis of invasionwere not considered appropriate.


Despite her age, the patient was keen to pur-sue immediate breast reconstruction and wasreferred to the plastic surgeons for discussionof reconstructive options. A right sentinellymph node biopsy was undertaken in advanceof mastectomy and reconstruction andrevealed no evidence of tumor in any of thenine “sentinel” nodes removed (Fig. 27). Thepatient proceeded to definitive surgeryapproximately eight weeks after initial

Figure 25

Figure 26



presentation to the breast unit. No furtheraxillary surgery was indicated, and reconstruc-tion was undertaken with a latissimus dorsi flapand implant. An extended periareolar incisionwas employed with a skin-sparing technique.The patient made an uneventful recovery andwas discharged home on the sixth postopera-tive day.


This revealed extensive high nuclear gradeDCIS measuring at least 50 mm with comedonecrosis (Fig. 28). There was no evidence ofinvasive tumor, and a single node within theaxillary tail was normal.


In the absence of invasion, the patient hadreceived a potentially curative treatment forDCIS and required no further treatment.She was offered entry into a patient-led fol-low-up program and would receive contrala-teral mammography at two and four yearsposttreatment.


Despite initial satisfaction with the cosmeticresults of immediate breast reconstruction,the patient became increasingly conscious ofthe disparity in size of the two breasts. Shefinally opted to undergo an implantexchange two years later with replacementof the original expander implant with alarger sized prosthesis to achieve better sym-metry.

Discussion

Despite undergoing regular screening withinthe NHS Breast Screening Programme, thispatient presented with an interval cancer thatwas not evident retrospectively (i.e., was not amissed cancer) on previous screening films.It is unusual for a symptomatic interval can-cer to represent pure “DCIS” with no invasivecomponent. Fewer than 5% of palpable can-cers are exclusively DCIS, and suspicion ofinvasion may prompt a repeat core biopsy(1). Prior to sentinel lymph node biopsy, itwas not appropriate to perform axillary dis-section without histological confirmation ofinvasion (2). Sentinel node biopsy can bejustified for extensive high nuclear gradeDCIS, which mandates mastectomy and fora palpable mass (whatever type of breastsurgery).

This patient had a mass lesion measuring40 mm on both mammography and ultra-sound. For cases of DCIS associated withcalcification only, some surgeons wouldattempt wide excision for lesions of this size.However, even if adequate surgical clearanceis achieved, these patients will require radio-therapy to the breast, which can impair theFigure 28

Figure 27

28 CHAPTER 1


final cosmetic result. Moreover, there is afinite rate of local recurrence (<10% at5 years), and half of these will be invasivedisease. Therefore, the opportunity to “cure”a patient may be sacrificed when conservationsurgery is chosen for in situ disease. Forborderline cases, it may be preferable toundertake skin-sparing mastectomy via a peri-areolar incision with immediate breast recon-struction. This patient underwent sentinellymph node biopsy in advance of definitivemastectomy and immediate breast recon-struction. A relatively large number of “sen-tinel” nodes (9 in total) were harvested at thetime of surgery, but this was within the rangethat is commonly cited in the literature (1–10)(3). None of these contained metastases,which was consistent with the absence ofinvasion on definitive histology. In one ofthe author’s own series of 33 patients under-going mastectomy for extensive DCIS, 8(27%) had invasive carcinoma on final his-tology. A total of four patients had a positivesentinel node (14%) of whom three hadinvasive disease with foci measuring between1.5 and 12 mm (mean 5.5 mm). Despiteintensive pathological examination, only asmall focus of microinvasion (<1 mm)could be found in one of these node-positivecases who had extensive DCIS measuring inexcess of 100 mm. There were no cases ofmetastases in the sentinel node without evi-dence of macro- or microinvasion on finalpathology. Furthermore, all four node-posi-tive cases involved a single node only(3 micrometastases, 1 micrometastasis).

It has been suggested that sentinel nodebiopsy for extensive DCIS could serve as asurrogate diagnostic test for invasion; ifmetastases are found in the sentinel node,there must be a focus of invasion somewherein the breast (4). The chance of finding thesevery small areas of invasion depends on thethoroughness and diligence of the patholo-gist. Usually, such deposits can be found uponretrospective examination in those rare casesof node positivity for “pure” DCIS.

This patient required no systemic adjuvanthormonal therapy; in the absence of invasion(or nodal involvement), the recurrence risk

at 5 to 10 years is approximately 1%. The riskof contralateral disease is 4% to 5% for DCISand 2% to 3% for invasive breast cancer (1).Tamoxifen would act in a prophylactic capac-ity for the opposite breast but would yieldminimal absolute benefit for the ipsilateralbreast. A patient, therefore, has an acceptedrisk of at least 5% by not opting for bilateralprophylactic mastectomy.

Related Cases

DCIS—Case Studies 5, 12, 13, 15, 16, 17, 18,and 21

DCIS and sentinel lymph node biopsy—CaseStudy 12

Breast reconstruction—Case Studies 3, 17, 18,36, and 37

Learning Points

1. Ductal carcinoma in situ (DCIS) israrely palpable and generally presentsas a mammographic finding. In coun-tries where mammography screening iswidely utilized, DCIS constitutes 8% to25% of all breast cancer cases diagnosedannually. However, DCIS is much lesscommonly diagnosed in countries thatdo no have systematic mammographyscreening programs.

2. DCIS is generally treated with wide localexcision and radiotherapy. Patients withER-positive DCIS (the vast majority) arethen usually treated with tamoxifen20 mg/day for five years.

3. Axillary lymph node surgery is generallynot indicated for DCIS. However, manysurgeons advocate a sentinel nodebiopsy if a mastectomy is performedfor DCIS. In such instances, an axillaryassessment proves useful if invasive can-cer is ultimately discovered in the mas-tectomy specimen. A mastectomy isindicated for multicentric DCIS (DCISin more than one quadrant of thebreast).



References

1. Hwang ES, Esserman LJ. Management of ductalcarcinoma in situ. Surg Clin North Am 1999; 79(5):1007–1030.

2. Winchester DP, Menck HR, Osteen RT, et al.Treatment trends for ductal carcinoma in situ ofthe breast. Ann Surg Oncol 1995; 2:207–213.

3. Benson JR, Querci della Rovere G. Management ofthe axilla in women with breast cancer. LancetOncol 2007; 8:331–348.

4. Cox CE, Nguyen K, Gray RJ, et al. Importance oflymphatic mapping in ductal carcinoma in situ(DCIS): Why map DCIS? Am Surg 2001; 67:513–519.

Part II: Breast Conservation Therapy

CASE STUDY 6

History

A 38-year-old woman presented with a two-week history of a nontender lump in theright breast. She reported no change in sizeof the lump and no associated nipple dis-charge. She had no previous breast prob-lems and no family history of breast orovarian cancer. The patient had two chil-dren (eldest aged 11 years) and had used theoral contraceptive pill briefly for a period of18 months.

Clinical Findings

There was an area of focal nodularity in theupper inner quadrant of the right breast butno dominant lump was palpable. There wasno axillary lymphadenopathy (E2) (Fig. 29).

Clinical Assessment

There were no clinically suspicious featureson examination, and in particular no dis-crete lump was apparent. The area of focalnodularity was considered most likely to rep-resent an area of fibrocystic change.

Investigations

Mammography

The mammographic interpretation of bothbreasts was normal but revealed dense breastparenchyma (Fig. 30A, B).

Figure 29 Figure 30

30 CHAPTER 1


Breast Ultrasound

Ultrasound examination showed a focalmass lesion within the area of clinical nod-ularity measuring 8 mm in maximum diam-eter. The mass was i l l defined andhypoechoic with posterior acoustic shadow-ing. The appearances were suggestive of asmall carcinoma (U4) (Fig. 31).

Core Biopsy

Ultrasound-guided core biopsy of this smallbreast mass (16-gauge needle, 3 passes) con-firmed an invasive ductal carcinoma (grade II,ER positive, HER2 negative) with associatedintermediate nuclear grade DCIS of solid

type [Fig. 32A (magnification 10�), B (mag-nification 20�)]. Routine ER measurementswere not done on core biopsies at the time,and the axilla was not interrogated sono-graphically.

Diagnosis

Small early-stage cancer of the right breast(T1bN0)


In view of the cancer being mammographi-cally occult, it was recommended that fur-ther radiological evaluation be undertaken

Figure 31

Figure 32



with MRI of the breasts. Should this confirma unifocal lesion of the estimated dimen-sions, this would be amenable to wide localexcision and sentinel lymph node biopsy.

Further Investigations

MRI Breasts

This confirmed a primary lesion measuring10 mm in the upper inner quadrant of theright breast (Fig. 33A) with a time-intensityenhancement curve consistent with malig-nancy (Fig. 33B). A possible second tumorfocus was seen inferior to the right nipple(Fig. 33C). The latter measured 6 mm andwarranted tissue biopsy, though did not

display a malignant type enhancementcurve (Fig. 33D). The patient was informedthat in the event a second focus of malig-nancy was found, then mastectomy (þ/�reconstruction) would be indicated.

Core Biopsy

Core biopsy of this second focal abnormalityafter ultrasound localization revealed afibroadenoma only (Fig. 34A).


The patient proceeded to a right wide localexcision and sentinel node biopsy (no

Figure 33

32 CHAPTER 1


evidence of multifocality from second corebiopsy result) (Fig. 34B). A preoperative skinmarker was applied to assist surgical identi-fication. A single hot and blue sentinel nodewas identified and removed. The patientmade an uneventful recovery and was dis-charged home one day after surgery.She had a very good cosmetic resulton subsequent follow-up at 12 months(Fig. 35A, B).


This confirmed an invasive ductal carcinoma(grade I) measuring 9 mm in maximumdiameter [Fig. 36A (low power), B (highpower)]. The tumor was excised with clearsurgical margins (>5 mm), but the singlesentinel lymph node retrieved contained a6 mmmacroscopic tumor deposit (Fig. 36C).


Following multidisciplinary discussion, it wasrecommended that the patient undergo a

right completion axillary lymph node dissec-tion. The final nodal status would inform thedecision on systemic therapy. On the basis ofa single node positive for macrometastasisand the patient’s relatively young age, shewould likely derive significant benefit fromchemotherapy despite having a small(<1 cm) grade I tumor.


The patient underwent a right completionaxillary lymph node dissection four weeksafter the initial surgery. She made anuneventful recovery and was dischargedhome the following day with a drain in situ.This was subsequently removed by the dis-trict nurse. Histology of the nonsentinellymph nodes showed a further micrometa-static deposit in 1 out of 17 nodes giving anoverall nodal status of 2 out of 18 (2/18)(Fig. 37). Despite further axillary surgery,the patient ultimately had a discrete scar inthe right axilla (Fig. 38A, B).

Figure 34

Figure 35




Following further multidisciplinary review, thepatient was offered adjuvant chemotherapyon the basis of an estimated absolute benefitof approximately 2% to 3% (adjuvantonline.

com). She was eligible for ovarian suppres-sion, having a strongly ER-positive tumor withan Allred score of 8/8.


The patient was initially reluctant toundergo a course of chemotherapy and con-sidered the absolute benefits to be modest(2–3%). However, following further discus-sion and consideration of her age, sheagreed to enter the TACT II trial that eval-uates accelerated adjuvant chemotherapywith capecitabine in early breast cancer.Patients with operable disease are random-ized to one of the following four arms: (i)four cycles of epirubicin (3 weekly) followedby four cycles of classical CMF, (ii) fourcycles of epirubicin (2 weekly) with GCSFsupport followed by four cycles of classical

Figure 36

Figure 37

34 CHAPTER 1


CMF, (iii) four cycles of epirubicin (3 weekly)followed by four cycles of oral capecitabine,and (iv) four cycles of epirubicin (2 weekly)with GCSF support followed by four cycles oforal capecitabine (see Appendix III). Aftercompletion of chemotherapy, the patientproceeded to ovarian suppression with alaparoscopic oophorectomy. She receivedtamoxifen (20 mg daily) as an additionalcomponent of adjuvant hormonal therapy.The patient received a standard schedule ofradiotherapy to the right breast after com-pletion of chemotherapy. This consisted of atotal dose of 40 Gy delivered in 15 fractionsover a three-week period. The patientremains well and disease-free at routinetwo-year follow-up.

Discussion

This patient presented with a clinicallyobscure lesion in the right breast, whichmanifest as an area of focal nodularity withno suspicious features (E2). Moreover, therewas no mammographic correlate, and thetumor was initially detected on ultrasoundassessment. MRI examination has greatersensitivity than mammography for imagingthe breasts of younger women, which aremore dense and can conceal a focal mass

lesion mammographically. Benign lesions suchas fibroadenomas can exhibit a “malignant-type” curve on MRI due to their intrinsicblood flow. This can generate false-positiveresults, which subsequently require biopsy toexclude a (further) focus of cancer. None-theless, MRI is very helpful in clarifying theextent of a tumor and confirming unifocalityprior to breast-conservation surgery (1). Itcould be argued that ideally all such patientsshould undergo breast MRI that will alsoassess the contralateral breast (2). However,there is emerging evidence that breast can-cer patients evaluated with MRI are morelikely to undergo (unnecessary) mastectomyinstead of BCS. Current rates of ipsilateralbreast tumor recurrence (IBTR) are rela-tively low, and additional lesions detectedby MRI might be adequately treated withadjuvant therapies (3).

An ultrasound-guided skin marker is auseful preoperative aid for lesions that haveill-defined margins clinically but that are justpalpable and do not require formal wirelocalization. Care should be taken whenplacing scars in the upper inner quadrantsof the breast; these should lie below the bra-line whenever possible and be curvilinearand follow the natural skin crease lines(Kreislers lines). Adequate subcutaneous

Figure 38



tissue should be preserved to optimize thefinal cosmetic result and avoid an unsightlyscar with an obvious depression.

Dual localization methods with both dye(Patent Blue) and isotope (technetium99 nanocolloid, 20 MBq) permit more con-fident identification of the sentinel lymphnode and are associated with a shorter learn-ing curve and optimal performance indica-tors such as rates of identification (>90%)and false negativity (5–10%) (4). The aver-age number of sentinel nodes removedusing both dye and isotope is 2.9 to 3.0 (4).In theory, if a single node is hot and blue,then no further nodes need be retrieved.However, recent results from the largest sen-tinel lymph node biopsy (SLNB) trial revealan overall false-negative rate of 9.8% withhigher rates when only a single sentinelnode is removed as opposed to two tothree nodes (5). It is perhaps surprisingthat the sentinel node contained a macro-metastastic deposit (6 mm) when the pri-mary tumor was of such favorable size andgrade. Moreover, one of the nonsentinelnodes contained a metastatic deposit yield-ing an overall status of 2/18 nodes positive.This together with the patient’s relativelyyoung age conferred a higher risk of distantrelapse and increased the absolute benefitsfrom chemotherapy in terms of mortalityreduction. It was considered appropriate tocomplete axillary surgery prior to chemo-therapy as this provided maximum informa-tion on nodal status (the patient would stillbe eligible for chemotherapy with a singlesentinel node containing a macrometasta-sis). In circumstances where completionmastectomy with immediate breast recon-struction is indicated, further surgery canbe deferred until after chemotherapy.Planning of breast reconstruction (particu-larly as a joint procedure with the plasticsurgeons) can incur significant time delays(6–8 weeks). When patients are deemed athigher risk for distant metastases, it is pref-erable to commence chemotherapy as soonas possible after initial surgery. This cansometime render subsequent axillary surgerymore difficult technically.

This patient had a strongly ER-positivetumor with a so-called Allred score of 8/8.The Allred system has been developed tomore accurately define ER expression topredict response to endocrine treatments.Tumors are assigned an intensity score(1–3) and a frequency score (0–5), and ERlevels are based on an aggregate score from0 (no expression) to 8 (strong expression)(6). Ovarian ablation has long been knownto improve outcomes in premenopausalwomen with hormonally responsive disease.Clinical trials have confirmed that propor-tional improvements in overall survival arecomparable for ovarian ablation and chemo-therapy within this group of women (24% vs.27%) (7). Ovarian ablation appears to be ofless benefit in women who have receivedchemotherapy (8%), which is most likelyattributable to a “chemical castration.” Men-strual activity is more likely to resume inwomen under the age of 40 years at thetime of chemotherapy, and these womenshould be considered for ovarian suppres-sion. Indeed, up to 80% of women under35 years of age retain or regain menstrualfunction after chemotherapy compared with30% of women over the age of 39 years (8).The latter is most commonly achieved byeither laparoscopic oophorectomy or use ofan LHRH receptor agonist. Surgical ablationcauses an immediate fall in hormone levels,whereas LHRH agonists (and ovarian radia-tion) suppress ovarian function more grad-ually. An advantage of LHRH agonists istheir potentially reversible effects upon ces-sation of treatment (2 years). This may allowsubsequent conception that is increasinglyan issue as more women are being diagnosedwith breast cancer before they have started afamily. There have been reports of the use ofLHRH agonists concurrently with chemother-apy in patients under the age of 40 years in anattempt to preserve fertility (9).

Trials of LHRH agonists are currentlyseeking to answer two crucial questions(10–12):

1. Can LHRH agonists (with or withouttamoxifen) provide an alternative to

36 CHAPTER 1


chemotherapy in patients with ER-posi-tive disease?

2. Do LHRH agonists confer any additionalbenefit when combined with standardtreatment (surgery þ/� radiotherapyþ/� tamoxifen þ/� chemotherapy)?

A recent update of the GROCTA trial hasconfirmed that after more prolonged follow-up (median 12 years) the combination oftamoxifen and ovarian suppression is aseffective as conventional CMF chemotherapyin premenopausal estrogen receptor–positivetumors. There was no statistically significantdifference in progression-free or overall sur-vival (p ¼ 0.7), and multivariate analysisshowed that neither tumor grade nor nodalstatus were independent predictors of recur-rence and mortality (12).

The typical schedule for whole breast irra-diation is delivery of a total dosage of 50 Gyover a period of five weeks in 25 dailyfractions. Each fraction is 2 Gy and patientsmust attend Monday to Friday for a five-weekperiod. This can represent a considerableburden for those patients with limited mobil-ity and who live some distance from theradiotherapy center. In certain geographicallocations, the latter can pose a significantproblem (e.g., highlands of Scotland andparts of rural Australia). Acceleratedhypofractionated whole breast irradiation(AHWBI) is being investigated as a meansfor reducing overall treatment times andmaking radiotherapy more readily availablein some parts of the world. The principle ofAHWBI is to deliver radiotherapy in fewerfractions of larger dosage. The standardiza-tion of breast radiotherapy (START) trial isinvestigating the use of larger fraction sizes(>2 Gy) and evaluates both efficacy and sideeffects (which may be greater with largerfraction sizes). One arm of this trialcompares the standard regimen of 50 Gy in25 fractions with a total dosage of 40 Gydelivered in 15 fractions over a three-weekperiod. Despite an average fraction size of2.67 Gy, rates of local control and late-normal tissue effects are similar to the stan-dard regimen. The majority of patientswithin the Cambridge area now receiveAHWBI with 40 Gy delivered over three

weeks. This applies to both breast andchest wall irradiation. A radiation boost canbe delivered to the tumor bed to minimizethe chance of local recurrence (13,14).

Related Cases

Positive sentinel lymph node biopsy—CaseStudies 10, 11, 24, and 37

Ovarian suppression—Case Studies 1, 8, 23,27, and 37


Preoperative MRI—Case Studies 8, 24, and 37

Breast radiotherapy—Case Studies 8, 9, 10,13, 14, 15, and 19

Learning Points

1. The false-negative rate for mammogra-phy is about 10%. Lobular cancers, inparticular, are often difficult to discernon mammography. Thus, a tissue diag-nosis is warranted for any suspiciousbreast mass, even if the mammogramreported it as benign.

2. The use of breast MRI is increasing, butremains controversial. Recently, it hasbeen suggested that a breast MRI shouldbe obtained prior to surgery in allwomen with newly diagnosed breast can-cers. MRI may reveal additional cancerfoci in the ipsilateral or contralateralbreast that are not evident on mammog-raphy and clinical examination. MRImay therefore result in an increase inmastectomy (and even bilateral mastec-tomy) rates. Yet, the clinical relevance ofthe additional lesions detected on MRIis not clear, and some have argued thatthese lesions could be adequatelytreated with radiotherapy and/or sys-temic therapy.

3. LHRH agonists can be used to induceovarian suppression. In premenopausalwomen with ER-positive tumors, theseagents reduce rates of recurrence and ofdeath following relapse when adminis-tered together with tamoxifen, chemo-therapy, or both.

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References

1. DeMartini W, Lehman C, Partridge S. Breast MRIfor cancer detection and characterization: a reviewof evidence-based clinical applications. AcadRadiol 2008; 15:408–416.

2. Warren R. Is breast MRI mature enough to berecommended for general use? Lancet 2001;358:1745–1746.

3. Morrow M. Magnetic resonance imaging in thebreast cancer patient: curb your enthusiasm. JClin Oncol 2008; 26:352–353.

4. Lyman GH, Guiliano AE, Somerfield MR, et al.The Americal Society of Clinical Oncology Guide-line Recommendations for sentinel lymph nodebiopsy in early stage breast cancer. J Clin Oncol2005; 23:7703–7720.

5. Krag DN, Anderson SJ, Julian TB, et al. Technicaloutcomes of sentinel-lymph node resection andconventional axillary lymph node dissection inpatients with clinically node negative breast cancer:results from the NSABP B-32 randomised phase IIItrial. Lancet Oncol 2007; 8:881–888.

6. Allred DC, Harvey JM, Berardo M, et al. Prognosticand predictive factors in breast cancer by immuno-histochemical analysis. Mod Pathol 1998; 11:155–168.


8. Petrek JA, Naughton MJ, Case LD, et al. Incidence,time course and determinants of menstrual bleed-ing after breast cancer treatment: a prospectivestudy. J Clin Oncol 2006; 24:1045–1051.

9. Recchia F, Sica G, de Filippis S, et al. Ovarianprotection with goserilin during chemotherapyfor early breast cancer: long term results of aphase II study. Proc Am Soc Clin Oncol 2002; 21(abstr 62).

10. Jakesz R, Hausmaninger H, Samonigg E, et al.Comparison of adjuvant therapy with tamoxifenand goserilin versus CMF in premenopausal stage Iand II hormone responsive breast cancer patients:four-year results of Austrian Breast Cancer StudyGroup (ABCSG) Trial 5. Proc Am Soc Clin Oncol1999; 18:67a (abstr 250).

11. Jakesz R, Hausmaninger H, Samonigg E, et al.Complete endocrine blockade with tamoxifen andgoserelin is superior to CMF in the adjuvant treat-ment of premenopausal, lymph node positive andnegative patients with hormone responsive breastcancer. Breast 2001; 10(supp1):S10 (abstr S26).

12. Boccardo F, Rubagotti P, Guglielmini D, et al.Ovarian suppression and tamoxifen as an alterna-tive to chemotherapy in early breast cancer. Longterm results of the GROCTA02 trial. Eur J Cancer2007; 5:2.

13. Venables K, Winfield E, Deighton A, et al. TheSTART trial—measurements in semi-anatomicalbreast and chest wall phantoms. Phys Med Biol2001; 46:1937–1948.

14. The START trialists’ Group. The UK Standardisa-tion of Breast Radiotherapy (START) Trail A ofradiotherapy hypofractionation for treatment ofearly breast cancer: a randomized trial. LancetOncol 2008; 9:331–41.

CASE STUDY 7

History

A 68-year-old woman was found to have anopacity in the lower inner quadrant of theleft breast on routine screening mammogra-phy. The patient had undergone regularscreening within the NHS Breast ScreeningProgramme and had never been recalled.She had no family history of breast cancerand had four children (eldest aged44 years). She had no significant usage ofthe oral contraceptive pill but had takenhormone replacement therapy for a totalperiod of 14 years.

Clinical findings

Clinical examination was normal andrevealed no discrete lumps or areas of focalnodularity in either breast (E1).

Clinical assessment

Screen-detected abnormality of the leftbreast in an asymptomatic patient

Investigations

Mammography (screening)

A rounded opacity associated with microcal-cification was seen in the lower inner quad-rant of the left breast (Fig. 39A, B), whichwas more evident on paddle and compres-sion views (Fig. 39C, D).

Breast Ultrasound–

The sonographic correlate of this mammo-graphic abnormality was an 11-mm hypoe-choic lesion with the appearances of a smallcancer (U5) (Fig. 40).

38 CHAPTER 1


Figure 39

Figure 40



Core Biopsy–

Ultrasound-guided core biopsy confirmed aninvasive carcinoma (grade II, ER positive) withno associated in situ component [Fig. 41A(low power), B (high power)].

Diagnosis

Screen-detected left breast cancer (T1N0)


Following multidisciplinary review, it wasrecommended that the patient undergo aleft guidewire localized wide local excisionand sentinel lymph node biopsy.


The decision of the multidisciplinary teamwas communicated to the patient who suf-fered from spinal stenosis with chronic backpain and restricted mobility. In particular,she was dependent on crutches andexpressed some concern about any morbid-ity from sentinel lymph node biopsy. Thepatient was reassured that there is minimalmorbidity from this form of targeted axillarysampling, and the likelihood of nodalinvolvement (necessitating subsequent axil-lary dissection) was very low. The patientproceeded to surgery one week later, havingrequested an early operation (Fig. 42). Two

blue and hot nodes were identified at oper-ation and the lesion lay close to the anteriormargin on specimen X ray, but appearedwell clear of other margins radiologically.

The patient made an uneventful recoveryand was discharged home on the secondpostoperative day.


This confirmed an invasive ductal carcinoma(grade III) measuring 8 mm in maximumdiameter with associated high nuclear gradeDCIS. The latter was of solid type with cen-tral necrosis and extended beyond the inva-sive component to yield an overall tumordiameter of 19 mm [Fig. 43A (low power); B(higher power)]. DCIS extended to within 1mm of the superior margin (Fig. 43C) butwas clear of all other radial margins by >5mm. Lymphovascular space invasion was

Figure 41

Figure 42

40 CHAPTER 1


present but neither of the two sentinel nodescontained metastases.


Following multidisciplinary review, it was recom-mended the patient undergo re-excision of thesuperior margin and thereafter receive radio-therapy to the breast and tamoxifen for fiveyears as adjuvant systemic hormonal therapy.


Further surgery was arranged within the nextfew days and a 2-cm thickness of tissue wasre-excised from the superior margin of thesurgical cavity. Histopathological evaluationrevealed residual high–nuclear grade DCISmeasuring 10 mm in maximum dimensionand extending to the new superior margin(Fig. 44A, B).

Figure 43

Figure 44




In view of the DCIS being present at the newsuperior margin, further surgery was indi-cated. However, the aggregate diameter ofthe tumor (invasive and noninvasive) wasless than 30 mm, and it was consideredappropriate by members of the multidiscipli-nary team to offer further re-excision in thefirst instance. The patient should be warnedthat completion mastectomy may be neces-sary for adequate surgical management ofthe DCIS.


The patient expressed concerns about thepossible need for radiotherapy in the eventof a further re-excision achieving satisfactorymargins. The patient was specifically worriedabout lying flat on the radiotherapy table forany prolonged period of time. She visitedthe radiotherapy unit and discussed theseissues in more detail with the oncologynurses. She found the prospect of radiother-apy very distressing and did not feel able tocope with a standard three-week course ofradiotherapy. Furthermore, she wished tominimize her chances of any recurrent dis-ease and therefore finally opted for a leftcompletion mastectomy. This was carriedout within the next 10 days and the patientwas encouraged to mobilize as much as pos-sible postoperatively.


Examination of the completion mastectomyspecimen revealed extensive fibrosis and fatnecrosis around the surgical cavity. Therewas no evidence of any residual DCIS orinvasive malignancy.


It was recommended the patient commencetamoxifen for five years as adjuvant systemichormonal therapy. She was entered into thepatient-led follow-up program with contrala-teral mammography at two and four yearspostoperatively.


The patient made an excellent recoveryfrom her final surgery and adjusted verywell psychologically to loss of her breast. Itwas emphasized to the patient that she hadan excellent prognosis with minimal chanceof either locoregional or distant relapse.

Discussion

Despite a localized opacity associated withmicrocalcification on routine screening, thispatient had extensive high–nuclear gradeDCIS that was not evident radiologically.About one-quarter of invasive carcinomashave a coexistent in situ component thatmay extend beyond the limits of the invasivetumor (1,2). Where this has no clinical norradiological correlate, attainment of clearsurgical resection margins can be challeng-ing. There has been lack of uniformity indefinition of a positive resection margin andthis in turn has compounded issues relatingto microscopically negative margins anddegrees of surgical clearance—how widemust a negative margin be to result in accept-able rates of local recurrence (3)? Accordingto the NSABP protocol B-17 positivity impliestumor cells (invasive or in situ) present at theresection margin (4). Hence, negative mar-gins could be associated with tumor cells at adistance of only 1 mm from the edge of thespecimen. Many American surgeons considera margin clearance of 2 to 3 mm to beappropriate and this echoes the view of theBritish Association of Surgical Oncologists.Approximately 30% of breast units in Europestrive for a radial margin clearance of 5 mmthat can lead to re-excision rates of up to50%. It is unusual to find further tumor whenre-excision is performed to achieve a widermargin rather than a negative margin per se.By contrast, further disease will be found inabout 40% to 50% of cases undergoing re-excision for “positive” margins. Singletary hasprovided a useful analysis; for patients with a1-mm negative margin, local recurrence ratesranged from 0% to 7% (median 3%), whilepatients with a 2-mm negative margin hadlocal recurrence rates of 3% to 10% (median6%). However, those patients with margins

42 CHAPTER 1


that were just clear (no tumor cells within1 microscopic field of the cut edge) had thelowest rates of local recurrence, ranging from2% to 4% (median 2%). Thus although ratesof recurrence are determined by negativemargin status, no direct relationship existsbetween margin width and rates of localrecurrence (5).

This patient had a small invasive carci-noma measuring only 8 mm in diameter, butassociated in situ disease that extended wellbeyond the invasive component. The initialexcision revealed an aggregate tumor diam-eter of 19 mm with in situ disease presentwithin 1 mm of the superior margin (otherradial margins >5 mm). This mandated re-excision, which confirmed further DCIS thatextended to the new superior resection mar-gin. When the first re-excision fails toachieve surgical clearance, mastectomy isoften indicated. However, American guide-lines for breast-conservation therapy statethat mastectomy is indicated if marginsremain positive after a “reasonable” numberof surgical attempts (6). Second and thirdattempts are less common but may be con-sidered acceptable if the breast has a satis-factory cosmetic appearance and the patientis keen to preserve her breast. In this partic-ular case, the total extent of tumor(invasive þ in situ) remained <30 mm, andit was once again the superior margin thatwas positive. DCIS could therefore still beconfined to one area (quadrant) of the breastand a further re-excision of the superiormargin could be offered. When re-excisionsare undertaken they should be confined tothe margins that are positive in order tominimize the amount of normal tissue thatis excised.

Interestingly, the patient herself hadstrong views on her management and wasclosely involved in shared decision making.She was adamant that she could not toleratelying flat on a radiotherapy couch and forthis reason opted for mastectomy (to avoidradiotherapy). At an earlier stage in theclinical pathway, the patient had expresseda great abhorrence at the thought of mas-tectomy. However, her views and perspectivehad evolved with the pathological findings. Itwas perhaps fortunate that she was sentinel

node negative and did not require comple-tion axillary lymph node dissection. Thisemphasizes the potential benefit of sentinelnode biopsy for patients with musculoskele-tal comorbidities.

Though this patient ultimately underwentmastectomy, her long-term prognosis wasexcellent.

Related Cases

Re-excision after breast conserving surgery—Case studies 11, 16, and 19Sentinel lymph node biopsy—Case studies 5,6, 7, 8, 10, 11, 12, 13, 15, 16, 24, 32, and 37

Learning Points

1. Randomized clinical trials have shownthat, in women over the age of 50,mammography screening reducesbreast cancer mortality by about 25%.In younger women, the benefit of mam-mography screening is disputed.

2. If a patient with a screen-detected(nonpalpable) cancer opts for breast-conserving surgery, then needle localiza-tion is required. The radiologist localizesthe breast lesion with a wire, and thesurgeon excises a margin of breast tissuearound it. A specimen mammogram isobtained (of the breast tissue and thewire within) to confirm that the screen-detected cancer has been excised.

3. There is considerable debate as to whatconstitutes an adequate margin of resec-tion around a breast tumor at the micro-scopic level. To minimize the risk oflocal recurrence, many surgeons recom-mend at least a 2-mm margin aroundDCIS.

4. If a surgeon is not able to obtain clearmargins after repeated attempts at excis-ing the breast tumor, then mastectomyis indicated.

References

1. Salam S, Jader SN, Benson JR. Invasive breastcarcinoma. In: Querci della Rovere G, Warren R,Benson JR, eds. Early Breast Cancer. London andNew York: Taylor and Francis, 2006:286–318.



2. Holland R, Connolly JL, Gelman R, et al. Thepresence of an extensive intraductal componentfollowing a limited excision correlates with prom-inent residual disease in the remainder of thebreast. J Clin Oncol 1990; 8:113–118.

3. Taghian A, Mohiuddin M, Jagsi R, et al. Currentperceptions regarding surgical margin status afterbreast conserving therapy: results of a survey. AnnSurg 2005; 241:629–639.

4. Fisher ER, Costantino J, Fisher B, et al. Pathologicfindings from the National Surgical AdjuvantBreast and Bowel Project. Protocol B-17. Cancer1995; 75:1310–1319.

5. Singletary SE. Surgical margins in patients withearly stage breast cancer treated with breast con-servation therapy. Am J Surg 2002; 184:383–393.

6. Morrow M, Harris JR. Practice guidelines for breastconserving therapy in the management of invasivebreast cancer. J Am Coll Surg 2007; 205:362–376.

CASE STUDY 8

History

A 35-year-old woman presented with a two-week history of a lump in the left breast. Thelump had not changed in size and was non-tender with no associated nipple discharge.The patient had no previous problems andno family history of breast or ovarian cancer.She had two children (3 pregnancies) bothof whom were breast-fed and gave birth toher first child at the age of 32 years. Therehad been brief usage of the oral contracep-tive pill in the past prior to pregnancy.

Clinical Findings

There was a smooth, round mobile mass inthe upper outer quadrant of the left breastmeasuring 3 cm in maximum diameter. Thiswas clinically benign with no suspicious fea-tures (E2) (Fig. 45).

Clinical Assessment

Probable cyst or fibroadenoma of the leftbreast. There was no index of suspicion, and

the patient was reassured accordingly follow-ing clinical assessment.

Investigations

Mammography

Bilateral mammography showed an ill-defined mass lesion in the superolateralaspect of the left breast. A possible smallerlesion was seen in the retroareolar region onthe right side, but this disappeared on com-pression views (Fig. 46A, B).

Breast Ultrasound

The sonographic correlate of the mammo-graphic opacity was an irregular hypoechoiclesion measuring 2.1 cm in maximum diam-eter, and this corresponded to the palpableabnormality (U5) (Fig. 47A). There was noevidence of enlarged axillary nodes on ultra-sound assessment (Fig. 47B).

Breast MRI

An MRI examination was recommended toclarify the radiological extent of the left breastlesion that had the appearances of a carci-noma (R5). This confirmed a unifocal lesionin the upper outer quadrant of the left breastwith slightly larger dimensions (2.7 cm) thanthe sonographic estimate (2.1 cm). No othersignificant lesions were identified in either theleft or right breasts (Fig. 48).

Core Biopsy

Ultrasound-guided core biopsy (14-gaugeneedle) of the left breast mass confirmedFigure 45

44 CHAPTER 1


Figure 46

Figure 47

Figure 48



an invasive carcinoma (grade II, ER positive)with no in situ component seen. [Fig. 49A(low power), B (high power)].

Diagnosis



The cancer in the upper outer quadrant ofthe left breast was considered amenable tobreast-conservation surgery. It measured<3 cm in size, was more than 2 cm fromthe nipple-areolar complex, and there wasno evidence of any satellite foci/multifocal-ity on further interrogation with MRI exam-ination. Moreover, in the absence of anysonographically suspicious nodes, it wasappropriate to undertake node sampling inthe first instance rather than formal axillarydissection. Radioisotope facilities were notavailable in the unit where surgery was tobe carried out and therefore a blue dye–assisted node sampling (BDANS) was recom-mended rather than sentinel node biopsywith dual localization (dye and isotope).


The patient underwent a quadrantic styleresection with a radial incision and removalof a narrow ellipse of skin (Fig. 50). TheBDANS was carried out through the lateralpart of the incision (and not a separateaxillary incision). Two large blue nodes

were identified together with several non-blue nodes, which were palpably suspiciousand therefore removed. The patient madean uneventful recovery from surgery.


This revealed an invasive ductal carcinoma(grade III) measuring 30 mm in maximumdiameter. There was associated high nucleargrade DCIS that did not extend beyond theinvasive component and lymphovascularinvasion was seen [Fig. 51A (magnification20�)]. Tumor extended to the inferior mar-gin, but a cavity shave was taken at the timeof surgery (9-mm thickness) resulting in allradial margins being clear (�5 mm)—indeed the minimal radial margin was9 mm. Rather surprisingly, all six nodessampled (blue and nonblue) contained meta-static carcinoma (macrometastases > 2 mm)yielding an NPI of (0.2 � 3.0) þ 3 þ 3 ¼ 6.6(Fig. 51B).

Figure 49

Figure 50

46 CHAPTER 1



Following multidisciplinary discussion, it wasrecommended that the patient undergo che-motherapy (taxane containing regimen)before completion axillary lymph node dis-section. The patient would also require radio-therapy to the breast with a booster dose andirradiation of the supraclavicular fossa (� 4nodes positive on sampling alone). Furthersystemic therapy would include ovarian sup-pression (oophorectomy or LHRH analogue)and tamoxifen. Additional investigations wererequested including

1. Chest X-ray2. Hepatic ultrasound—1.5 cm echogenic

lesion in the right lobe with appearancesof hemangioma (confirmed with triple-phase CT scan of the liver)

3. Isotope bone scan—no conclusive evi-dence of metastatic bone disease (Fig. 52).

4. HER2/neu status—positive


The patient proceeded to chemotherapywith four cycles of epirubicin and cyclophos-phamide (EC) followed by four cycles ofdocetaxel (see Appendix III). This was welltolerated and a completion axillary lymphnode dissection was undertaken three weeksafter the final cycle of taxane. Herceptin wascommenced after second-stage axillary sur-gery and continued during radiotherapy tothe breast and left supraclavicular fossa

(40 Gy in 15 fractions over 3 weeks with a9 Gy in 3 fraction boost to the tumor bed).

The patient’s treatment program wascompleted with endocrine manipulation;she requested laparoscopic oophorectomyand this was carried out approximately12 months from the time of the initial diag-nosis of breast cancer. The patient was pre-scribed zoladex for an interim period of twomonths prior to surgical ablation of theovaries. Tamoxifen was subsequently com-menced for a period of five years (followedby letrozole for 2.5 years).

Discussion

This young woman presented with a clinicallybenign lump in the left breast, which wasconsistent with a cyst or fibroadenoma. How-ever, triple assessment combining radiologi-cal imaging and biopsy with clinicalexamination revealed the lesion to be a can-cer. The case demonstrates the importantprinciple of triple assessment for the com-plete evaluation of a discrete breast lump;reliance cannot be placed on clinical find-ings alone (1). Same-day imaging and biopsy(one-stop clinic) ensues that significantdelays are not incurred along the diagnosticpathway. It is inevitable that some patientswill be falsely reassured immediately after theclinical assessment and subsequently beinformed that the lesion has suspicious fea-tures on mammography and ultrasound,which are confirmed on biopsy. Phased infor-mation giving is useful in these circumstances

Figure 51



and is one advantage of the “two-stop” clinicwhen patients must return within a few daysfor the results of core biopsy.

In younger patients with relatively densebreast tissue, MRI is a useful adjunct radio-logically to confirm unifocality and excludeany additional foci of tumor either in thesame or a different quadrant (2,3). The lat-ter would normally mandate mastectomy butbreast conservation may be feasible whensatellite lesions are present in the vicinity ofthe index lesion and are confined to one

quadrant of the breast. MRI examinationalso has an important role in screening thecontralateral breast, though there is no con-vincing evidence that any “earlier” detectionof recurrence has any impact on overallsurvival (4). In particular, younger womenmay opt for a prophylactic procedure whenthere is evidence of any proliferative changesin the other breast. Between 4% and 8% ofwomen with recently diagnosed breast can-cer will be found to have an unsuspectedoccult cancer in the contralateral breast.

Figure 52

48 CHAPTER 1


Some clinicians have advocated MRI exami-nation in all (younger) women in whombreast-conservation surgery is comtemplated.However, this mode of investigation can gen-erate false-positive results, and a degree of“over call” may have inadvertently increasedrates of mastectomy in recent years. A recentanalysis of local recurrence rates at eightyears among breast-conservation patientswith or without preoperative MRI imagingrevealed minimal differences—3% and 4%,respectively (5). Indeed, with modern meth-ods of breast surgery and radiotherapy, ratesof local recurrence are already <5% at10 years.

This patient underwent a quadrantic styleresection with a single radial incision. Thiscan produce excellent cosmetic results fortumors located in the upper outer quadrantand allows the cancer to be removed incontinuity with the lymphatic vessels andaxillary lymph nodes (intervening tissuebetween tumor and nodes is removed).This technique is best suited to small/mod-erate-sized breasts in which the distancebetween the tumor and axilla is not exces-sive. Scar contracture can sometimes com-promise the final cosmetic outcomefollowing breast irradiation. Despite a hightumor load, preoperative axillary ultrasoundfailed to identify any suspicious nodes thatwarranted biopsy. Axillary ultrasound (þ/�core biopsy or fine-needle aspiration cytol-ogy) has been shown to identify up to 50% ofnode-positive cases (with macrometastases)overall and 75% to 90% of those with �3nodes positive (6). This can potentially avoidtwo-stage axillary surgery in a substantialnumber of cases. Those patients with a “neg-ative” axillary ultrasound examination canproceed to sentinel lymph node biopsy,though an axillary dissection is probablyadvisable for patients with tumors >5 cm insize (even when undergoing primary sys-temic therapy with potential downstaging ofnodal status).

The optimal method for staging the axillais sentinel lymph node biopsy using duallocalization techniques (7). The use of tech-netium99 requires a special ARSAC licensethat is not possessed by all breast units withinthe United Kingdom. This had limited the

use of radiocolloid as a tracer agent forsentinel lymph node biopsy. The use ofBDANS has evolved from the original blindsampling technique and permits a degree oftargeting that reduces the chance of a false-negative result. With the technique ofBDNAS, the surgeon aims to remove fourto five nodes as opposed to two to threenodes. Clearly, this is a matter of degreeand some surgeons routinely perform “sen-tinel lymph node biopsy” using blue dyealone (8,9). Techniques for axillary stagingremain variable and standardization ofmethodology is ongoing. Axillary relapserates of 0.12% among a group of morethan 2000 sentinel node-negative patientshave been reported by the Memorial Sloan-Kettering group at three years follow-up(10). Other reports involve smaller numbersof patients but reveal comparably low ratesof axillary relapse varying between 0% or1.4% with relatively short follow-up periodsof less than two years. It is essential that ratesof axillary relapse following sentinel lymphnode biopsy for node-negative disease do notexceed those for axillary lymph node dissec-tion that is the “gold standard” for axillarymanagement (0.8–2.5%). However, A recentshort communication reveals an actualrecurrence rate of 5% at a median follow-up of 6.5 years with a prediction that up to10% of patients may ultimately develop iso-lated axillary recurrence after a negativesentinel lymph node biopsy (11). Any resid-ual disease within the axillary nodes will below volume, and a longer follow-up periodmay be required for clinical manifestation.

Completion axillary dissection was carriedout following chemotherapy; this patient wasat high risk for distant relapse and likely tohave micrometastatic disease at presenta-tion. Commencement of adjuvant systemictherapy was therefore considered a priority.It was already confirmed that >4 axillarynodes were involved histologically, andknowledge of any additional nodal diseasewould not have altered adjuvant therapies(e.g., chemotherapy or radiotherapy to thesupraclavicular fossa). In circumstanceswhere axillary staging has shown macro- ormicrometastatic disease in a single node,then complete information on nodal status



from axillary dissection may be desirableprior to planning further management. Thispatient received an anthracycline-containingregimen with the addition of taxanes basedon the extent of nodal involvement (�4nodes positive) and positive HER2 status.This was a modified regimen similar to fourcycles of doxorubicin and cyclophosphamidefollowed by four cycles of paclitaxel (AC—paclitaxel rather than EC—docetaxel), whichis a more widely used combination based onresults of the CALGB 9344 and NSAPB B28trials (12,13).

Ovarian suppression is usually offeredto premenopausal women with hormone-sensitive tumors (irrespective of age andmenstrual activity postchemotherapy) (14).The additional benefits of ovarian ablationin absolute terms remains controversial, andthere are concerns about the longer-termsequelae of estrogen deprivation in youngerwomen (15). The SOFT study specificallyinvestigates whether the combination ofovarian ablation with chemotherapy in pre-menopausal women offers any additionalbenefit to chemotherapy alone. This patientwas adamant about laparoscopic oophorec-tomy and was fortunate to have completedher family; for those premenopausal womendiagnosed with breast cancer prior to con-ception, LHRH analogues offer an alterna-tive form of ovarian suppression that maypreserve fertility (16). Once rendered post-menopausal, patients can be prescribed aro-matase inhibitors as adjuvant systemichormonal therapy. The current policy ofthe Cambridge Breast Unit is to commencetreatment with tamoxifen for two to threeyears with an early switch to an aromataseinhibitor (arimidex or exemestane) forpatients at moderate risk (NPI � 4.4).Some units use an aromatase inhibitorupfront in patients considered to be athigh risk of locoregional relapse on thebasis of primary tumor parameters andnodal status.

Herceptin was commenced after comple-tion of chemotherapy. There can be poten-tial compound toxicity from Herceptin andanthracyclines with no clear difference inoncological efficacy between concomitantand sequential regimens.

Related Cases

Fertility issues—Case Studies 23, 27, 35, and 37

Adjuvant hormonal therapy—Case Studies 1,9, 10, 15, and 19

Herceptin—Case Studies 11 and 26

Breast-conservation surgery—Case Studies 6,7, 9, 14, 15, and 19

Adjuvant chemotherapy—Case Studies 2, 3,11, 36, and 37

Learning Points

1. Sentinel nodes are identified usingeither blue dye and/or radioactive col-loid. Additionally, any nodes that appearclinically suspicious should be removedand submitted for histological assessment.

2. The status of the sentinel nodes mightalso be determined intraoperatively,using either touch prep (cytology) orfrozen section. If either indicates thepresence of metastatic disease in the sen-tinel node, then an axillary dissectionshould be undertaken at the time of thesentinel node biopsy. However, intraoper-ative assessment is occasionally associatedwith false-negative results. Thus, a secondprocedure (delayed axillary dissection)would be required if intraoperative assess-ment reveals no evidence of metastasis inthe sentinel node, but metastasis is uncov-ered on permanent histology.

3. Patients with breast cancer in whichHER2 is amplified or overexpressedwill benefit from adjuvant trastuzumab(Herceptin) and chemotherapy. Clini-cal trials indicate that Herceptinreduces the risk of recurrence in thesepatients by about 50%.

References

1. Scott S, Morrow M. Breast cancer–making thediagnosis. Surg Clin North Am 1999; 79:991–1005.

2. Kumar NA, Schnall MD. MR imaging: its currentand potential utility in the diagnosis and manage-ment of breast cancer. Magn Reson Imaging ClinN Am 2000; 8:715–728.

3. Mumtaz H, Hall-Craggs MA, Davidson T, et al.Staging of symptomatic primary breast cancerwith MR imaging. Am J Roentgenol 1997;169:417–424.

50 CHAPTER 1


4. Lehman CD, Gatsonis C, Kuhl CK, et al. MRIevaluation of the contralateral breast in womenwith recently diagnosed breast cancer. N Engl JMed 2007; 356:1295–1303.

5. Solin L, Orel S, Hwang W, et al. The relationship ofbreast magnetic resonance imaging to outcomeafter breast conserving treatment with radiationfor women with early stage invasive breast carci-noma or ductal carcinoma in situ. J Clin Oncol2008; 26:386–391.

6. MacMillan RD, Blamey RW. The case for axillarysampling. Adv Breast Cancer 2004; 1:9–10.

7. Lyman GH, Guiliano AE, Somerfield MR, et al.The American Society of Clinical Oncology Guide-line Recommendations for sentinel lymph nodebiopsy in early stage breast cancer. J Clin Oncol2005; 23:7703–7720.

8. Purushotham AD, MacMillan RD, Wishart G.Advances in axillary surgery for breast cancer—time for a tailored approach. Eur J Surg Oncol2005; 31:929–931.


10. Naik AM, Fey J, Gemignani M, et al. The risk ofaxillary relapse after sentinel lymph node biopsy forbreast cancer is comparable with that of axillarylymph node dissection. Ann Surg 2004; 240:462–471.

11. Kujit GP, Roumen RMH. Second thoughts on sen-tinel lymph node biopsy in node negative breastcancer. Br J Surg 2008; 95:310–311.

12. Henderson IC, Berry DA, Demetri GD, et al.Improved outcomes from adding sequential pacli-taxel but not from escalating doxorubicin dose inan adjuvant chemotherapy regimen for patientswith node positive primary breast cancer. J ClinOncol 2003; 21:976–983.

13. Mamounas EP, Bryant J, Lembersky BC, et al.Paclitaxel (T) following doxorubicin/cyclophos-phamide (AC) as adjuvant chemotherapyfor node positive breast cancer: results fromNSABP B-28. Proc Am Soc Clin Oncol 2003; 22:(abstr 12).


15. Davidson N, O’Neill A, Vukov A, et al. Effect ofchemohormonal therapy in premenopausal, nodepositive, receptor positive breast cancer: an EasternCooperative Oncology Group phase III Intergrouptrial (E5188 INT-0101). Breast 1999; 8:232–233.

16. Recchia F, Sica G, de Filippis S, et al. Ovarianprotection with goserilin during chemotherapyfor early breast cancer: long term results of aphase II study. Proc Am Soc Clin Oncol 2002; 21:(abstr 62).

CASE STUDY 9

History

A 60-year-old woman presented with a three-week history of a nontender lump in the leftbreast. The patient had undergone a normalscreening mammogram two years earlier. Shehad no family history of breast cancer and hadnever used any form of exogenous hormones.

Clinical Findings

A rather hard discrete lump was palpableimmediately superior to the left nipple-are-olar complex. This measured approximately1 cm and was associated with subtle skintethering but no indrawing of the nipple.There was no axillary lymphadenopathy(E4) (Fig. 53)

Clinical Assessment

The clinical findings were suggestive of asmall cancer of the left breast lying in closeproximity to the nipple.

Investigations

Mammography

No focal mass lesion or any other abnormal-ity could be seen in either the left breast(Fig. 54A, B) or the right breast (Fig. 54C,D). Previous screening films were requestedfor review and comparison with current filmsand no new lesion was apparent upon reviewof the most recent left (Fig. 55A and B) andright (Fig. 55C, D) screening mammograms.

Figure 53



Breast Ultrasound

An ill-defined hypoechoic mass lesion withposterior acoustic shadowing and measuring1.1 cm was found in the left breast at12 o’oclock (corresponding to the palpableabnormality). The radiological appearanceswere consistent with a small carcinoma,though inflammatory changes could not beexcluded (U4) (Fig. 56).

Core Biopsy

Ultrasound-guided core biopsy (14-gauge nee-dle) of the left breast mass confirmed an

invasive carcinoma (grade II) with mixed duc-tal and lobular features [Fig. 57A (low power),B (high power)]. The tumor was ER positive,but HER2 testing was not routinely performedon core biopsies at that time.

Diagnosis

Small, early-stage cancer of central left breast(T2N1).

Multidisciplinary review 1

The cancer was of small size in relation tothe overall size of the patient’s breast (large

Figure 54

52 CHAPTER 1


and pendulous). The lesion was amenable tocentral segmental resection with wide excisionof the tumor including the nipple-areolarcomplex. It was considered that this proce-dure would yield a satisfactory cosmetic resultand preserve much of the volume and shapeof the breast. A contralateral mastopexy couldbe carried out at a later date were there to beany marked disparity in size between thebreasts. This central segmental mastectomywas combined with a level II axillary lymphnode dissection (standard axillary staging pro-cedure at the time).


The patient was very keen to preserve herbreast and in the event of mastectomy beingadvised, she would have insisted on immedi-ate breast reconstruction. She was not con-cerned about the loss of her nipple andunderstood that irradiation of the breastwould be indicated postoperatively. She pro-ceeded with a central segmental resectionand at operation a generous wide excisionwas performed with removal of a central skinellipse (11 cm � 3 cm), the nipple-areolarcomplex, tumor, and surrounding normal

Figure 55



breast tissue en masse (180 g) (Fig. 58). Thebreast was reconstituted and closed with alinear horizontal wound and deep support-ing sutures. The patient made an uneventfulrecovery and was very pleased with the cos-metic result.


This revealed a grade II invasive ductal car-cinoma measuring 9 mm in maximum diam-eter. There was no associated in situcomponent and tumor was clear of all resec-tion margins by >5 mm [Fig. 59A (magnifi-cation 10�), B (magnification 20�)]. Noneof the nine lymph nodes contained meta-static carcinoma.


It was recommended the patient receiveradiotherapy to the left breast and tamoxifenfor five years as adjuvant systemic hormonaltherapy. She required no further surgeryand the tumor was excised with a good mar-gin of clearance.

Figure 56

Figure 57

Figure 58

54 CHAPTER 1



The patient commenced breast radiotherapytwo months after completion of surgery. Shedeveloped some acute radiation sequelaeand experienced intermittent episodes ofshooting pains in the left breast, whichwere self-limiting. A follow-up mammogramof the ipsilateral breast at 12 monthsrevealed an area of fat necrosis (confirmedon fine-needle aspiration cytology) but oth-erwise the patient had an excellent cosmeticresult (Fig. 60). The patient also had trou-blesome hot flashes and was switched fromtamoxifen to the aromatase inhibitor Arimi-dex. She was in a favorable prognostic groupwith an NPI < 4.4 and was ineligible for aroutine early switch from tamoxifen to anaromatase inhibitor after two to three years.

Discussion

This patient had a small (1 cm) tumor situ-ated close to the nipple-areolar complex in a

relatively large pendulous breast. Conven-tional wide local excision is precluded dueto proximity of the tumor to the nipple andproblems of surgical clearance withoutdevascularization or subsequent cosmeticdistortion of the nipple-areolar complex. Acentral segmental resection can produce anexcellent result in these circumstances com-bining wide excision of the tumor with anacceptable cosmetic outcome. Despite sacri-fice of the nipple-areolar complex, much ofthe breast volume is preserved together withthe natural ptosis of the breast. A completemastectomy without reconstruction wouldleave a large-breasted patient rather lop-sided. Occasionally, tumor excision can beincorporated into a reduction mammoplastyor therapeutic mammoplasty (1). This tech-nique removes the tumor with a wide marginof clearance and refashions the breast that issmaller in overall size. A contralateral sym-metrization procedure is usually required,and there may be problems with re-excisionwhen margins are positive or the width ofclearance is inadequate. There are specificoncoplastic procedures that can preserve thenipple-areolar complex (e.g., Grisotti flap),but careful patient selection and explanationis essential (2–4). A potential advantage ofbreast reduction is minimization of doseinhomogeneity with radiotherapy (5). Thiscan lead to areas of fat necrosis in largerbreasts when focal areas receive an excessivedose of radiotherapy.

There is some evidence that radiotherapycould be omitted in some older women (�50years) with a small favorable tumor that has

Figure 59

Figure 60



been excised with clear surgical margins. Thispatient had a small (9 mm) grade II tumorthat was widely excised as part of a centralbreast excision. Clinical trials involving thissubgroup of patients confirm that IBTR issignificantly decreased with radiotherapyfrom about 8% to 1% at five years. Theabsolute numbers of recurrences are smallin both groups and disease-free survival is76% without radiotherapy compared to 82%with irradiation (1.4% difference in disease-free events) (6–8). It is important to distin-guish between statistical and clinical signifi-cance; the benefits of local control forradiotherapy may not be clinically significantin women aged >70 years with comorbiditiesand limited life expectancy.

At the time this patient underwent surgery,sentinel lymph node biopsy was not routinelyoffered and a standard level II axillary lymphnode dissection was therefore performed.Such a patient has a low probability of nodalinvolvement and is ideally suited to axillarystaging with sentinel node biopsy. Whereradioisotope facilities are not available, analternative staging option is BDANS (9).

This patient had a low risk of relapse andwas initially prescribed tamoxifen only asadjuvant systemic hormonal therapy. Hotflashes are a relatively common side effectof tamoxifen and are an indication forswitching to an aromatase inhibitor. Whenpatients are switched from tamoxifen onaccount of adverse side effects, Arimidex isusually the aromatase inhibitor of choice. Bycontrast, when switched after two to threeyears as part of an “early switch” regimen,exemestane is the preferred agent.

Related Cases



Axillary staging—Case Studies 6, 8, 10, and 24

Learning Points

1. There have been six randomizedprospective trials that have compared

mastectomy to BCT in the treatment ofprimary breast cancer. These two treat-ment options are associated with similarsurvival rates, but locoregional recur-rence is slightly greater among womenwho undergo BCT.

2. For centrally located tumors, resectionof the nipple-areolar complex is feasible,and the wound should be closed withhorizontal approximation of the tissueedges. Alternatively, if the tumor is adja-cent to the nipple-areolar complex butnot immediately beneath it, then anarea around the nipple-areolar complexcan be de-epithelialized. The tumorcan then be excised through this de-epithelialized area, the dermis closed,and the skin re-attached to the nipple-areolar complex with a running stitch.

3. There is some evidence suggesting thatsome women who are aged 70 or oldermight safely avoid radiotherapy afterlumpectomy. Although this puts thesewomen at a small increased risk forlocoregional recurrence, this might notbe clinically significant.

4. In patients with positive sentinel nodes(or those who do not undergo sentinelnode biopsy), dissection should includeboth levels I and II of the axilla. Theselevels refer to the relationship of theaxillary tissue to the pectoralis minormuscle. Thus, a level I dissection refersto extirpation of tissue lateral to thepectoralis minor muscle, level II refersto removal of tissue posterior to the mus-cle, and level III indicates dissectionmedial to the muscle.

References

1. McCulley SJ, Durani P, Macmillan RD. Therapeuticmammoplasty or centrally located breast tumours.Plast Reconstr Surg 2006; 117:366–373.

2. Grissotti A. Immediate reconstruction after partialmastectomy. Oper Tech Plastic Reconstr Surg 1994;1:1–12.

3. Galimberti V, Zurrida S, Zanini V, et al. Centralsmall size breast cancer: how to overcome theproblem of nipple and areolar involvement. Eur JCancer 1993; 29:1093–1096.

4. Benelli LC. Periareolar Benelli mastopexy andreduction: the round block. In: Scott L. Spear, ed.,

56 CHAPTER 1


The Breast. Philadelphia and New York: Lippincott-Raven, 1998.

5. Kestin LL, Sharpe MB, Frazier RC, et al. Intensitymodulation to improve dose uniformity with tangen-tial breast radiotherapy: initial clinical experience.Int J Radiat Oncol Biol Phys 2000; 48:1559–1568.

6. Lim M, Bellon J, Gelman R, et al. A prospective studyof conservative surgery without radiation therapy inselected patients with stage I breast cancer. Int JRadiat Oncol Biol Phys 2006; 65:1149–1154.

7. Fyles A, McCready D, Manchul L, et al. Tamoxifenwith or without breast irradiation in women

50 years of age or older with early breast cancer.N Engl J Med 2004; 351:963–970.

8. Hughes K, Schnaper L, Berry D, et al. Lumpec-tomy plus tamoxifen with or without irradiation inwomen 70 years of age or older with early breastcancer. N Engl J Med 2004; 351:971–977.

9. Purushotham AD, MacMillan RD, Wishart G.Advances in axillary surgery for breast cancer—time for a tailored approach. Eur J Surg Oncol2005; 31:929–931.

CASE STUDY 10

History

A 79-year-old woman presented with a three-week history of a nontender lump in theright breast. There was no associated nippledischarge and the patient had no previousbreast problems. She had undergone ascreening mammogram more than 10 yearsearlier and had no family history of breast orovarian cancer. There was previous usage ofhormone replacement therapy for a periodnot exceeding five years.

Clinical Findings

A 2-cm firm ill-defined lump was palpable inthe upper outer quadrant of the right breast.There was subtle skin dimpling immediatelybelow the inferior aspect of the mass but noindrawing of the nipple and no axillarylymphadenopathy (E5) (Fig. 61).

Clinical Assessment

Clinically suspicious right breast lump in anelderly patient consistent with cancer (con-servable)

Investigations

Mammography

A spiculate mass was seen in the upper outerquadrant of the right breast measuring15 mm in maximum diameter. The appear-ances were of a small carcinoma (R5)(Fig. 62A, B).

Breast Ultrasound

The mammographic abnormality corre-sponded to a 17-mm hypoechoic mass lesionwith posterior acoustic attenuation (U5)(Fig. 63).

Core Biopsy

Ultrasound-guided core biopsy (16-gaugeneedle, 3 passes) of the right breast massconfirmed the clinical and radiologicalimpression of malignancy and showed aninvasive carcinoma (grade II, ER positive,HER2 negative) [Fig. 64A (magnification10�), B (magnification 20�)].

Diagnosis

Early-stage right breast cancer (T2N1).


Following multidisciplinary discussion, it wasrecommended the patient undergo a rightwide local excision and sentinel lymph nodebiopsy. The lesion was unifocal, 3 cm in size,Figure 61



Figure 62

Figure 63

Figure 64

58 CHAPTER 1


and situated well away from the nipple. Theskin dimpling was confined to the areaimmediately adjacent to the tumor and didnot involve the nipple.


The patient was admitted for surgery withinthe next four weeks. At operation the tumorwas widely excised and no more tissue waspresent either superior or lateral to the sur-gical cavity (Fig. 65). Sentinel node biopsy

was carried out via a separate axillary inci-sion and yielded several blue, though coldnodes. The patient made an uneventfulrecovery and was discharged home the fol-lowing day.


This confirmed an invasive ductal carcinoma(grade II) measuring 19 mm in maximumdiameter. Excision was clear of all radialmargins but one out of four sentinel nodescontained micrometastases (1/4) withextracapsular spread [Fig. 66A (low power),B (high power)]. Several foci of lymphovas-cular invasion were seen in the primarytumor [Fig. 66C (low power), D (highpower)].


It was considered appropriate to offer thispatient a completion axillary lymph nodedissection as this was the unit policy formicrometastases in the sentinel node. This

Figure 65

Figure 66



should be followed by radiotherapy to thebreast and tamoxifen for two to three yearswith an early switch to an aromatase inhibi-tor as adjuvant systemic hormonal therapy[NPI: (0.2 � 1.9) þ 2 þ 2 ¼ 4.38].


It was explained to the patient that she had a10% to 12% chance of further disease in thenonsentinel lymph nodes and was unlikely todevelop any regional recurrence in herremaining lifetime. After careful considerationof these and related issues such as potentialmorbidity from further axillary surgery, thepatient adamantly declined any completionaxillary dissection. She felt she had made anexcellent recovery from primary surgery anddid not wish to incur any significant morbidityfrom further axillary surgery. Arrangementswere therefore made for radiotherapy plan-ning and the patient commenced ontamoxifen.

Discussion

This is another example of an older patientdeclining completion axillary lymph node dis-section when fully informed of the risks andbenefits of this procedure. This patient was79 years of age with a 19-mm grade II invasiveductal carcinoma for which one out of foursentinel nodes contained a single micrometa-static deposit. For patients in whom fewerthan half the nodes retrieved contain micro-metastases, the chance of disease in theremaining nonsentinel nodes is about 10%(1–3). There is therefore a 90% chance thatno further disease will be found, but thepatient may suffer significant morbidity fromadditional axillary surgery. Indeed, there isevidence that the morbidity from initial sen-tinel node biopsy followed by delayed axillarydissection may be greater than routine level IIaxillary dissection performed at the outset. Itis unlikely that this patient would have anyresidual axillary disease that would causeproblems with regional recurrence or com-promise survival expectations (4,5).

Related Cases

Completion axillary dissection—Case Studies13 and 24



Learning Points

1. In a clinically node-negative patient, theaxilla can be treated with either surgery(sentinel node biopsy/axillary dissec-tion) or radiotherapy alone.

2. Either surgery or radiotherapy reducesthe risk of local recurrence in the axillaby about 90%. However, the stage of thebreast cancer cannot be determined ifthe axilla is treated with radiotherapyalone.

3. It should also be emphasized thatpatients with clinically suspicious axillarynodes cannot be treated with axillaryradiotherapy alone. These patientsshould be managed with axillary sur-gery.

References

1. Rescigno J, Taylor LA, Aziz MS, et al. Predictingnegative axillary lymph node dissection in patientswith positive sentinel lymph node biopsy: can asubset of patients be spared axillary dissection?Breast Cancer Res Treat 2005; 94:S35.

2. Benson JR, Wishart GC, Forouhi P, et al. Theincidence of nodal involvement following comple-tion axillary dissection for sentinel node positivedisease. Eur J Cancer 2007; 5:21.

3. Dabbs DJ, Fung M, Landsittel D, et al. Sentinellymph node micrometastases as a predictor ofaxillary tumour burden. Breast J 2004; 10:101–105.

4. Naik AM, Fey J, Gemignani M, et al. The risk ofaxillary relapse after sentinel lymph node biopsyfor breast cancer is comparable with that of axillarylymph node dissection: a follow up study of 4008procedures. Ann Surg 2004; 240:462–471.


60 CHAPTER 1


CASE STUDY 11

History

A 51-year-old woman presented with a nine-month history of a lump in the left breast.Despite the patient’s age, she remained pre-menopausal and the mass did not fluctuatein size with the menstrual cycle. There wasno associated tenderness or nipple dischargeand the patient had no previous breast prob-lems. There was no family history of eitherbreast or ovarian cancer. The patient hadone daughter who was breast-fed. She gavebirth to her first child at the age of 38 yearsand had used the oral contraceptive pill for acumulative duration in excess of 20 years.

Clinical Findings

Examination revealed a firm, ill-definedmass in the extreme upper outer quadrantof the left breast. This measured 2 cm inmaximum diameter and was clinically suspi-cious. There was no axillary lymphadenop-athy (E4) (Fig. 67).

Clinical Assessment

Probable carcinoma of the left breast thatappeared unifocal and potentially conservable

Investigations

Mammography

Bilateral mammography revealed an asym-metric density in the upper outer quadrantof the left breast measuring 25 mm in diam-eter (Fig. 68A, B). This was radiologicallysuspicious for a left breast cancer (R4).

Breast Ultrasound

The sonographic correlate of this density wasa 24-mm hypoechoic mass lesion withoutposterior acoustic enhancement or attenua-tion (U5) (Fig. 69).

Figure 67

Figure 68



Core Biopsy

Ultrasound-guided core biopsy of the leftbreast mass confirmed the clinical and radio-logical suspicion of malignancy and showedan invasive ductal carcinoma (grade II, ERpositiveb) [Fig. 70A (magnification 10�), B(magnification 20�)]. No in situ componentwas identified and the tumor was HER2positive on core biopsy (Fig. 70C).

Diagnosis



Following multidisciplinary review, it wasrecommended that the patient undergo aleft wide local excision and sentinel lymphnode biopsy. It was not considered necessaryto perform breast MRI to exclude multifo-cality. Axillary ultrasound assessment (þ/�core biopsy) was requested prior to anyaxillary surgery. This was carried out at thenext clinic attendance and revealed no evi-dence of metastatic disease on core biopsy.


The patient underwent the proposed sur-gery two weeks following tissue diagnosisusing a curvilinear incision in the upperouter quadrant of the left breast combinedwith a transverse axillary incision (Fig. 71).At operation a single large blue and hotnode was identified together with two fur-ther blue and cold nodes. All three nodeswere removed and there was no residualactivity in the axilla. A wide excision of thebreast mass was performed down to the levelof the pectoral fascia. There was no furthertissue to excise superiorly. The patient madean uneventful postoperative recovery.


This confirmed an invasive ductal carcinoma(grade II) measuring 24 mm in maximumdiameter [Fig. 72A (magnification 10�), B(magnification 20�)]. There was associatedhigh nuclear grade DCIS with a solid growthpattern (no necrosis). The aggregate diam-eter (invasive component and DCIS)reached 48 mm and DCIS was transected at

bAllred score 8/8

Figure 69

62 CHAPTER 1


the inferior margin (Fig. 72C). All othermargins were clear of any cancer cells by>5 mm. Four sentinel nodes were identifiedand one of these contained a macrometa-static focus (>2 mm) (Fig. 72D). A furthernonsentinel node showed focal fat necrosisand a fibroblastic reaction consistent withthe site of previous biopsy.


Following further multidisciplinary review, itwas recommended that the patient undergore-excision of the inferior cavity margin

together with a completion axillary dissec-tion. In terms of adjuvant therapy, thepatient would require radiotherapy to thebreast (conditional upon adequate clear-ance on re-excision) and chemotherapytogether with Herceptin (HER2 positive). Itwas considered appropriate to offer thispatient chemotherapy prior to any furthersurgery in view of the documented nodeinvolvement and HER2 positivity, which con-fers a worse prognosis with higher risk ofdistant relapse.


The patient proceeded to systemic therapywith six cycles of FEC/docetaxol togetherwith Herceptin (see Appendix III). This waswell tolerated, though the patient developeda port-site thrombosis that required reposi-tioning of the port and anticoagulant ther-apy. The patient attended for further surgicalreview after the fifth cycle of chemotherapy.At this stage, she was informed that althoughDCIS involved only the inferior margin ofresection, the total documented tumor

Figure 70

Figure 71



diameter was 48 mm; in the event of exten-sive involvement of the re-excision specimen,the overall extent of DCIS might mandatemastectomy (even if the new inferior marginwas clear). The patient was keen to proceedwith re-excision in the first instance with theunderstanding that mastectomy may yet beindicated. A left cavity re-excision and com-pletion axillary dissection was undertakenfive weeks following the final cycle of chemo-therapy (clexane at a therapeutic dosage of100 mg daily was discontinued five days pre-operatively). Despite the tumor lying in thesuperior aspect of the left breast, further re-

excision did not impair the final cosmeticresult (Fig. 73A, B).


The inferior cavity shave was submitted inentirety and revealed no residual DCIS orinvasive carcinoma. The surgical cavity con-tained fibrous scar tissue and foamy macro-phages with foreign body giant cells. None ofthe 10 lymph nodes retrieved contained anytumor, and there was no evidence of anynodes that had been downstaged by chemo-therapy (final nodal status 1/14).

Figure 72

Figure 73

64 CHAPTER 1



Satisfactory margin clearance had beenachieved, and it was therefore recommendedthe patient proceed to breast radiotherapyfor completion of locoregional treatment. Inview of the history of port-site thrombosis, anaromatase inhibitor was the agent of choicefor adjuvant systemic hormonal therapy (thepatient had been rendered amenorrheic bychemotherapy). Herceptin was continuedperioperatively, but temporarily discontinuedafter a MUGA scan revealed a fall in leftventricular ejection fraction (LVEF) from70% to 49% at 12 weeks. A MUGA scan wasrepeated after a one-month break fromHerceptin (Fig. 74).

Discussion

Though the patient had a unifocal invasivecarcinoma measuring <3 cm, there wasextensive associated DCIS yielding an aggre-gate diameter after initial excision of 48 mm.The invasive component had been excisedwith good clearance, and DCIS was presentat one margin only (inferior). The othermargins ranged from 4 (superior—no fur-ther tissue to take) to 10 mm medially. Onthe basis of the modified Van Nuys PrognosticIndex (VNPI) (see page 90, case study 16),

this patient would have the following score(1):

½3ðsize 48mmÞ þ 2ðmargins 1� 9mmÞ þ 3

ðhigh grade with necrosisÞ þ 2

ðage 51 yearsÞ� ¼ 10

According to the Van Nuys database, thispatient would be at a relatively high risk forrelapse even with breast radiotherapy; mas-tectomy is usually recommended for scoresof 10, 11, and 12 (5- and 10-year recurrence-free survival of 54% and 37%, respectively)(2). This patient was very keen to preserveher breast and requested re-excision in thefirst instance. She was warned that the pres-ence of further DCIS in the re-excision spec-imen might mandate mastectomy whateverthe new inferior margin clearance. Thispatient was at the lower end of the 10 to12 VNPI category, and fortunately no resid-ual tumor was found after re-excision.

This patient was advised to have chemo-therapy first in order to avoid any delays withsystemic therapy. She definitely required thelatter on the basis of macrometastases in oneof the sentinel nodes. However, this patientwas not at an exceptionally high risk fordistant relapse and could have undergonefurther surgery immediately. Sometimes the-atre scheduling issues can influence the deci-sion on the timing of further surgery.Moreover, there was a possibility that thispatient may have required a mastectomyafter re-excision and would have demandedimmediate breast reconstruction. Therefore,completion of all surgery before commenc-ing chemotherapy could have potentially ledto significant delays with systemic treatments.It could be argued that this patient mighthave benefited from completion of locore-gional treatment (i.e., radiotherapy to thebreast) within a 12- to 16-week interval frominitial surgery. There is currently no clearevidence that breast-conservation patientsundergoing delayed radiotherapy (postche-motherapy) have higher rates of localrelapse. Systemic therapies (chemotherapy/hormonal) themselves reduce local recur-rence by about one-third (3).

Herceptin or trastuzumab is a humanizedmonoclonal antibody directed against theextracellular domain of the HER2/neu

Figure 74



growth factor receptor (coded by the cerbB2gene). Overexpression of HER2/neu occursin approximately 30% of invasive breast can-cers and is associated with a worse prognosis(4). When combined with taxane-based che-motherapy for management of advancedbreast cancer, Herceptin improved time todisease progression (4.6 months vs.7.4 months) (5). This was the first exampleof a specific oncogene pathway being tar-geted for breast cancer treatment. ThoughHerceptin has been widely used in the UnitedKingdom for treatment of metastatic diseasesince 2001, its use in the adjuvant setting ismuch more recent and was officiallyapproved by the National Institute for Clini-cal Excellence (NICE) in 2006. Prior to this,adjuvant Herceptin was only used for man-agement of high-risk HER2-positive women,defined as those with an absolute survivalbenefit in excess of 8%—often �4 nodespositive. Adjuvant Herceptin is given as aslow intravenous infusion every three weeksfor one year. Clinical trials have confirmedimprovements in both disease-free and over-all survival. The two American trials (NSABPB31 and the Intergroup) reported a reduc-tion in risk of recurrence of about 50% (HR0.48, p ¼ 0.0000000003) and have shown anearly survival benefit favoring Herceptin attwo years (HR 0.67, p ¼ 0.015) (6). TheEuropean trial (HERA) showed similarreductions in risk of recurrence (HR 0.54, p< 0.00001) but no overall survival advantage(HR 0.76, p ¼ 0.26) (7). In those patientsanalyzed in the American trials, Herceptinwas given concurrently with an anthracyclinebased chemotherapy (4 cycles of AC followedby paclitaxel), while in the European trialHerceptin was prescribed only after comple-tion all chemotherapy (any regimen of � 4cycles). The principle side effect of Herceptinis cardiotoxicity that is potentially greaterwhen the drug is combined with chemother-apy than given sequentially (clinically signifi-cant heart failure 4% vs. 0.5%). Overall,between 2% and 4% of patients receivingHerceptin will have significant cardiotoxicitywithin the first three to six months. Thereappears to be no evidence for any delayed

cardiac effects (e.g., late myocardial infarc-tion). The value of left ventricular ejectionfraction (LVEF) on completion of AC and age>50 years are risk factors for cardiotoxicityand a fall in LVEF that mandates temporarycessation of Herceptin. About 3% of patientson Herceptin will develop congestive cardiacfailure and this can be managed with b-block-ers and ACE inhibitors (may be difficult tosubsequently get patients off medication).

This patient received Herceptin concur-rently with an anthracycline-based chemo-therapy regimen (FEC/taxotere). Thoughthere was a fall in LVEF from 70% to 49%,this was not manifest clinically, andHerceptin was resumed after recovery ofcardiac function. Trials are currently ongo-ing to assess whether there are benefits incontinuing Herceptin for a total duration oftwo years. This will involve a careful analysisof cost-effectiveness, and results on the opti-mal duration of Herceptin usage should beavailable by 2008. Herceptin has beenapproved by the U.S. Food and Drug Admin-istration for the treatment of node-positive,HER2-positive early-stage breast cancer andwill be given with the non-anthracyclinecomponent of chemotherapy for a durationof one year (8). The optimal duration ofHerceptin is unknown, though at presentone year is the favored period of treatment.Patients should receive at least nine weeks oftherapy and a three-weekly schedule is moreconvenient than a weekly course (though ofcomparable efficacy). The HERA study isinvestigating 1 versus 2 years of treatmentwith Herceptin, while a major French trial isaddressing 6 months versus 12 months oftreatment.

Related Cases

Re-excision after breast-conservation surgery—Case Studies 7, 16, and 19

Positive sentinel lymph node—Case Studies 6,10, 24, and 37

Taxane-based adjuvant chemotherapy—CaseStudies 3 and 8

Herceptin—Case Studies 8, 25, 26, and 27

66 CHAPTER 1

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Learning Points

1. A diagnostic bilateral mammogramshould be obtained in any patient whopresents with a clinically suspiciousbreast mass. Ideally, the mammogramshould be obtained prior to tissuebiopsy. However, even if the mammo-gram reported it as benign, the surgeonshould proceed with a tissue biopsy (thefalse-negative rate for mammography isabout 10%). The mammogram is essen-tial for evaluating both breasts for occultlesions, as this could potentially influ-ence the choice of local therapy.

2. Most patients with early-stage breast can-cer are suitable candidates for BCT.However, there are a few contraindica-tions to BCT: multicentric cancers, earlypregnancy (patients require radiother-apy after BCT), previous radiotherapy tothe breast, collagen vascular disease,and large tumors (although tumorscan be downstaged with preoperativesystemic therapy).

3. Women are at greatest risk for recur-rence and death during the first threeyears following surgery for early-breastcancer (peak in the hazard curve). Inpatients with HER2-positive tumors, adju-vant therapy with Herceptin reduces thatrisk by half.

References

1. Silverstein MJ. USC/Van Nuys Prognostic Index.In: Silverstein MJ, ed. Ductal Carcinoma in Situ ofthe Breast. 2nd ed. Philadelphia: Lippincott,Williams and Wilkins, 2002.

2. Woo CS, Skinner KA, Silverstein MJ. Ductal carci-noma in situ: clinical studies and controversies intreatment. In: Querci della Rovere G, Warren R,Benson JR, eds. Early Breast Cancer.London andNew York: Taylor and Francis, 2006:349–374.


4. Slamon DJ, Clark GM, Wong SG, et al. Humanbreast cancer: correlation of relapse and survivalwith amplication of the HER-2/neu oncogene.Science 1987; 235:177–182.

5. Slamon DJ, Leyland-Jones B, Shak S, et al. Use ofchemotherapy plus a monoclonal antibody againstHER2 for metastatic breast cancer overexpressesHER2. N Engl J Med 2001; 344:783–792.

6. Romond EH, Perez EA, Bryant J, et al. Trastuzu-mab plus adjuvant chemotherapy for operableHER2 positive breast cancer. N Engl J Med 2005;353:1659–1684.

7. Piccart-Gebhart MJ, Procter M, Leyland-Jones B,et al. 2 year follow up of trastuzumab after adjuvantchemotherapy in HER2 positive breast cancer.N Engl J Med 2005; 353:1659–1672.

8. FDA Approvals: Herceptin, Eloxatin, Extended-Release Venlafaxine HCI. Medscape MedicalNews. Available on http://www.medscape.com/viewarticle/575596.



2Screen-Detected Breast Cancer

Part I: Mastectomy

CASE STUDY 12

History

A 52-year-old woman was recalled from a first-round screening mammogram for furtherevaluation of an area of extensive microcalci-fication in the right breast. There was no familyhistory either of breast or of ovarian cancer.The patient was asymptomatic and reported nolumps in either breast, no areas of tenderness,and no nipple discharge.

Clinical Findings

No discrete mass lesion or areas of focalnodularity were evident in either breast,though there was a degree of generalizedlumpiness (E2).

Clinical Assessment

Asymptomatic screen-detected microcalcifi-cation of the right breast.

Investigations

Mammography (Screening)

This showed extensive fine granular micro-calcification within the right breast, whichwas suspicious for DCIS (R5) (Fig. 1A, B).

Breast Ultrasound

No sonographic assessment of the breast wasundertaken.

Mammotome Biopsy

Mammotome biopsy using an 11-gauge nee-dle was performed, and all cores showed

microcalcification on specimen radiography.Histopathological examination confirmedthe high radiological index of suspicionwith areas of microcalcification associatedwith high–nuclear grade DCIS of cribriformarchitecture and comedo necrosis. Therewas no definite evidence of invasion (B5)[Fig. 2A (magnification 10�), B (magnifica-tion 20�)].

Diagnosis

Screen-detected extensive DCIS of the rightbreast (Tis)


It was recommended that the patientundergo a right simple mastectomy and sen-tinel lymph node biopsy. The latter would

Figure 1

68


provide valuable axillary staging informationin the event of an incidental finding ofinvasive disease on definitive histology (upto 20% chance).


The patient proceeded with the plannedsurgery within four weeks of tissue diagnosis(mammotome biopsy). Sentinel lymph nodebiopsy on this occasion was performedthrough a separate axillary incision, thoughit can be done using the lateral aspect of themastectomy incision (Fig. 3). When the mas-tectomy incision is placed horizontally, aseparate axillary incision is more likely togain access to level I nodes. A dual localiza-tion technique was employed to identifythree sentinel nodes with patent blue dye(2.5%) and technetium 99m nanocolloid.Two milliliters of the former was useddiluted to 5 mL in total; more recently,

only 1 mL of undiluted blue dye has beenused as a tracer with similar rates of identi-fication of the sentinel node(s). The patientmade an uneventful recovery and was dis-charged home with two suction drains in situ(to be removed by a trained district nurse).


This revealed extensive high–nuclear gradeDCIS with central necrosis extending overan area of 53 mm. There was no evidence ofeither microinvasion or invasive carcinoma[Fig. 4 (magnification 2.5�)]. None of thethree sentinel nodes contained metastaticcarcinoma (0/3 nodes).


In the absence of any invasive component,the patient had undergone a potentiallycurative surgical procedure and required

Figure 2

Figure 3

SCREEN-DETECTED BREAST CANCER 69


no further treatment. She was entered into apatient-led follow-up program with contrala-teral mammography at two and four yearspostoperatively.

Discussion

With the advent of breast-screening pro-grams, the diagnosis of DCIS has increaseddramatically and now constitutes between20% and 25% of all new breast cancer diag-noses. Indeed, within a screened populationalone, this figure rises to 40% (1,2). Usually,DCIS is manifest as a localized cluster ofmicrocalcification, but sometimes calcifica-tion is extensive and extends throughout ahigh proportion of the breast. Such casesmust be managed with simple mastectomy,which is potentially curative (>98%) in theabsence of detectable invasion. Longer-termfollow-up at eight years reveals that only1.5% of patients with DCIS within theNSABP B-17 trial have died of metastaticbreast cancer (3). An incidental invasivecomponent is found in up to 20% of casesin which mastectomy is the choice of opera-tion and extensive DCIS is a risk factor forinvasion from historical studies (4). It is nowacknowledged that extensive high–nucleargrade DCIS on imaging, which mandatesmastectomy (or DCIS presenting as a palpa-ble lesion), is an indication for sentinellymph node biopsy. Up to 10% of caseswith microinvasion will be sentinel lymphnode positive (5), and one of the authors(JRB) has reported a sentinel node positivity

rate of 14% in patients undergoing mastec-tomy for extensive high–nuclear grade DCIS(6). This is likely to incur minimal additionalmorbidity, and not infrequently some level Inodes are inadvertently removed during asimple mastectomy. Such a policy avoids anysubsequent potential dilemma of axillarystaging for small foci of invasive disease.Sentinel lymph node biopsy cannot beundertaken as a delayed procedure postmastectomy and staging would otherwiseinvolve either full dissection or blind sam-pling (which can be technically challengingif immediate breast reconstruction has beencarried out). Sentinel lymph node biopsymust be done prior to removal of breasttissue. The axilla can be approached eitherthrough an incision in the lateral aspect ofthe mastectomy incision or via a separatetransverse axillary incision. The latter maybe more appropriate when a horizontalrather than an oblique mastectomy incisionhas been used.

There was no evidence of any invasivecomponent within the mastectomy speci-men, and none of the three sentinel nodescontained metastases. The patient had anexcellent long-term outlook with an esti-mated risk of local recurrence and mortalityof approximately 0.9% and 1.1%, respec-tively (7). In the absence of invasion, thereis no indication for tamoxifen treatment interms of ipsilateral DCIS managed with mas-tectomy. The latter minimizes the chance oflocal recurrence, and this is not furtherreduced by tamoxifen by any clinically mean-ingful degree. However, tamoxifen would actin a chemopreventive capacity to reduce thechance of contralateral disease (by about40%).

Drain policies are highly variable; all thedistrict nurses within the immediate catch-ment area of a hospital can be trained toremove drains. This allows patients to bedischarged with drains in situ—usually onthe first postoperative day (unless elderly orreluctant to go home with drains). Our cur-rent policy is to remove drains when thevolume is <40 to 50 mL in the preceding24 hours or at 72 hours, i.e., all drains areout at 72 hours. It is important that patientsdo not feel compelled to go home with

Figure 4

70 CHAPTER 2


drains in situ; drain management is bestdiscussed at the time of pre-clerking so thatthe patient knows in advance what to expect.

Related Cases

Screen-detected cancer—Case Studies 13, 14, 15,16, and 17

DCIS and sentinel node biopsy—Case Study 5

Learning Points

1. DCIS is considered a preinvasive lesion,but not all cases progress to invasivebreast cancer. In fact, it has been sug-gested that only one out of every four orfive cases of DCIS would develop intoinvasive cancer. DCIS is usually foundon mammography, and its incidence hasincreased dramatically since the adventof mammographic screening.

2. DCIS is generally treated with wide localexcision. Adjuvant radiotherapy andtamoxifen should also be considered inthe management of DCIS. Following widelocal excision alone, the risk of recur-rence is 25%. However, the risk is 13%with excisionþ radiotherapy and only 8%with excision þ radiotherapy þ tamoxi-fen. Half of the recurrences will be DCIS,and the other half invasive cancers.

3. If the mammogram reveals diffuse(multicentric) DCIS, then mastectomyis indicated.

4. For localized DCIS treated with widelocal excision, a sentinel node biopsy isnot indicated. However, for multicentricDCIS treated with mastectomy, a sen-tinel node biopsy should be considered,as there is a much greater likelihood offinding invasive cancer.

References

1. Sickles EA. Mammographic features of 300 consec-utive nonpalpable breast cancers. AJR Am J Roent-genol 1986; 146:661–663.

2. Silverstein MJ, Gamagami P, Colburn WJ, et al.Nonpalpable breast lesions: diagnosis with slightlyoverpenetrated screen-film mammography andhook wire-detected biopsy in 1014 cases. Radiology1989; 171:633–638.

3. Fisher B, Dignam J, Wolmark N, et al. Lumpectomyand radiation therapy for the treatment of intra-ductal breast cancer: findings from National Sur-gical Adjuvant Breast and Bowel Project B-17.J Clin Oncol 1998; 16:441–452.

4. Meyer JE, Smith DN, Lester SC, et al. Larger-coreneedle biopsy of impalpable lesions. JAMA 1999;281:1638–1164.

5. Intra M, Zurrida S, Maffini F, et al. Sentinel lymphnode metastasis in microinvasive breast cancer.Ann Surg Oncol 2003; 10:1160–1165.

6. Benson JR, Wishart GC, Forouhi P, et al. The roleof sentinel node biopsy in patients with a pre-operative diagnosis of ductal carcinoma in situ.Eur J Cancer 2003; 5(3):22.

7. Woo CS, Skinner KA, Silverstein MJ. Ductal carci-noma in situ: clinical studies and controversies intreatment. In: Querci della Rovere G, Warren R,Benson JR, eds. Early Breast Cancer. London andNew York: Taylor and Francis, 2006:357.

Part II: Breast Conservation Therapy

CASE STUDY 13

History

A 70-year-old woman was recalled from rou-tine breast screening with a spiculate lesion inthe right breast. She had previously under-gone regular screening mammography andnever been recalled. There was no familyhistory of breast or ovarian cancer. Thepatient was asymptomatic and reported no

lumps in either breast, no areas of tendernessand no nipple discharge. She was nulliparousand had never used exogenous hormones.

Clinical Findings

On examination of the right breast, a dis-crete lump in the breast was just palpable inthe upper outer quadrant (E3).



Clinical Assessment

Screen-detected palpable carcinoma of theright breast

Investigations


A spiculate opacity was seen in the upperouter quadrant of the right breast, which wassuspicious for a small carcinoma (Fig. 5A, B).

Breast Ultrasound

The sonographic correlate of the mammo-graphic abnormality was a 16-mm hypoe-choic lesion with posterior acousticshadowing (Fig. 6).

Core Biopsy

Ultrasound-guided core biopsy confirmed aninvasive ductal carcinoma (grade II; ER pos-itive; HER2 negative) [Fig. 7A (low power),B (high power)].

Diagnosis

Early-stage screen-detected right breastcancer (T1N0)


Following multidisciplinary review, it wasrecommended that the patient be offered aright guide wire–localized wide local exci-sion and sentinel lymph node biopsy.Despite the lesion being just palpable, itwas considered appropriate to localize withboth a wire and an ultrasonic skin marker.Figure 5

Figure 6

72 CHAPTER 2



An ultrasound-guided core biopsy of a rightaxillary lymph node was performed as part ofa study and revealed no evidence of malig-nancy. The patient therefore proceeded withthe planned surgery, including sentinellymph node biopsy.

A curvilinear incision was made in thebreast centered on the ultrasound skin marker(Fig. 8). The specimen radiograph was satis-factory and confirmed that the mammo-graphic lesion had been excised with a goodmargin of surrounding tissue. Two hot andblue sentinel nodes were removed at surgery.The patient made an uneventful recovery andwas discharged home the following day.


This revealed an invasive ductal carcinoma(grade II) measuring 22 mm in maximumdiameter [Fig. 9A (magnification 2.5�), B(magnification 40�)]. There was a minorcomponent of high–nuclear grade DCISwithin the invasive tumor, which was clearof all radial margins by >5 mm. One of the

two sentinel nodes contained a micrometa-static focus measuring <2 mm, which wasseen on both H and E sections (Fig. 9C) andimmunohistochemistry (Fig. 9D).

Multidisciplinary Review

Because of the presence of tumor in one ofthe sentinel nodes, it was recommended thatthe patient undergo a level II axillary lymphnode dissection. She would require radio-therapy to the right breast, and systemicadjuvant therapy would be decided afterthe final nodal status was known.


An axillary lymph node dissection was car-ried out as a delayed or second-stage proce-dure one month following the initial surgery.At the time of surgery, several fleshy nodeswere found, but these were probably reac-tive. Histology revealed presence of metasta-ses in one of seven non-sentinel nodes,giving an overall nodal status of two out ofnine. The patient proceeded to irradiationof the right breast and received adjuvanthormonal therapy with tamoxifen for twoto three years followed by an early switch toan aromatase inhibitor.

Discussion

This patient was at the upper age limit forroutine NHS breast screening and was foundto have a typical spiculate opacity corre-sponding to a 2-cm tumor, which was justpalpable. The ultrasound measurement had

Figure 7

Figure 8



slightly underestimated the final pathologi-cal size. Nonetheless, the tumor was excisedwith clear radial margins in excess of 5 mm.One of the two sentinel nodes contained amicrometastasis, and a further metastasis wasfound in one of the non-sentinel nodes.However, this did not affect choice of sys-temic therapy, and it is unclear whethercompletion axillary lymph node dissectionis always indicated for older patients with apositive sentinel node (1). This patient onlyhad two nodes harvested, one of which con-tained a micrometastasis. The chance of non-sentinel lymph node involvement is signifi-cantly higher when macrometastases are pres-ent in the sentinel node and when theproportion of nodes harvested containingmetastases is high (e.g., one out of two asopposed to one out of four) (2,3). As ithappens, this patient did have involvementof a single non-sentinel node, but it remainsunknown whether, if left alone, this wouldhave resulted in axillary recurrence or affectedoverall survival in a 70-year-old woman. Somewomen may decline further axillary surgery

when informed of potential morbidity. Anyrisk:benefit ratio for detection of disease innon-sentinel nodes must consider subgroupsof patients and not individual cases (4).

Related Cases

Screen-detected cancer—Case Studies 12, 13,14, 15, 16, and 17Breast conservation surgery for impalpablelesions—Case Studies 14 and 15


Learning Points

1. Many cancers detected in mammographicscreening programs are palpable. In fact,some investigators have argued thatscreening clinical breast examination(CBE) and screening mammography areequally beneficial in reducing breast can-cer mortality. Therefore, screening CBEshould remain an integral part of allmammographic screening programs.

Figure 9

74 CHAPTER 2


2. The potential benefits of axillary surgeryare often debated. There are three rea-sons for considering axillary surgery(sentinel biopsy/axillary clearance): stag-ing, local control, and improved survival.The status of the axillary lymph nodes isan integral part of tumor staging, whichcan be used to plan adjuvant treatment.Furthermore, axillary clearance reducesthe risk of local recurrence (in theaxilla) by about 90%. Finally, recentstudies indicate that local recurrencesmay have an adverse effect on survival.

References


2. Cserni G, Gregori D, Merletti F, et al. Non-sentinelnode metastases associated with micrometastaticsentinel nodes in breast cancer: metaanalysis of25 studies. Br J Surg 2004; 91:1245–1252.

3. Rescigno J, Taylor LA, Aziz MS, et al. Predictingnegative axillary lymph node dissection in patientswith positive sentinel lymph node biopsy: can asubset of patients be spared axillary dissection?Breast Cancer Res Treat 2005; 94:S35.

4. Benson JR, Wishart GC, Forouhi P, et al. Theincidence of nodal involvement following comple-tion axillary dissection for sentinel node positivedisease. Eur J Cancer 2007; 5:21.

CASE STUDY 14

History

A 51-year-old woman was found to have anopacity in the upper inner quadrant of theright breast on routine screening mammog-raphy. She had never previously been recalledfrom screening and had no family history ofbreast or ovarian cancer. She reported nodiscrete lumps in either breast, no areas oftenderness, and no nipple discharge. Thepatient had four children (eldest 24 yearsold) and had used the oral contraceptive pillfor a cumulative period of two years.

Clinical Findings

Clinical examination was normal, with nopalpable discrete lumps or any areas offocal nodularity (E1).

Clinical Assessment

Radiological abnormality detected on rou-tine screening, with no clinical correlate

Investigations


An ill-defined opacity measuring 10 mm wasseen in the upper inner quadrant of the right

breast. The mammographic appearances weresuspicious for carcinoma (R4) (Fig. 10A, B).

Breast Ultrasound

The opacity seen on mammography corre-sponded to a 9.2-mm hypoechoic mass lesionwith posterior acoustic shadowing (Fig. 11).

Figure 10



Core Biopsy

Ultrasound-guided core biopsy of the breastmass confirmed an invasive carcinoma(grade III) [Fig. 12A (low power), B (highpower)]. The lesion was ER positive andHER2 negative on core biopsy [Fig. 12C(low power), D (high power)].

Diagnosis

Early-stage screen-detected right breast can-cer (T1N0)


It was recommended that the patient beoffered a right guide wire–localized widelocal excision and sentinel node biopsy.


The patient had a history of hypothyroidism,but was clinically and biochemically euthyroid.She proceeded with the planned surgery threeweeks later. The lesion was approached with acurvilinear incision in the medial aspect of theright breast centered over the skin projectionof the radiological abnormality (ultrasoundskin marker) (Fig. 12E). A specimen radio-

graph confirmed that the lesion had beenexcised (reviewed by radiologist) and was posi-tioned centrally with a good margin ofsurrounding breast tissue (Fig. 13). Two blueand hot sentinel nodes were removed. Thepatient made an uneventful recovery and wasdischarged home the following day.


This confirmed an invasive ductal carcinoma(grade III) measuring 13 mm in maximumdiameter [Fig. 14A (low power), B (highpower)]. There was no in situ component,and the tumor was clear of all margins by>10 mm. None of the three sentinel nodescontained any metastases (0/3 nodes).


It was recommended that the patient receiveradiotherapy to the right breast and systemicadjuvant therapy with tamoxifen for two tothree years followed by an early switch to anaromatase inhibitor [NPI: (0.2 � 1.3) þ 3 þ1 ¼ 4.26]. Chemotherapy should be dis-cussed with the patient (modest absolutebenefit of 2–3% only).

Figure 11

76 CHAPTER 2


Discussion

This patient had a small invasive carcinomadetected as an opacity on routine screeningmammography. Though the histology was agrade III invasive ductal carcinoma, this wasotherwise a typical screen-detected breastcancer. Grading of tumors is based on thedegree of tubule formation (t), the numberof mitoses (m), and the degree of nuclear

pleiomorphism (p). Each of these factorsis scored by the pathologist, and the overallscore determines the grade (this patientscored t3, m3, p3—total score 9). There isan element of subjectivity, and the propor-tion of tumors graded as I, II, and III variesfrom one center to another. Non–high gradeand special-type tumors are more commonin the older screened population (1–4).

Figure 12



It is helpful to the surgeon if a skinmarker is placed by the radiologist in addi-tion to the wire at the time of localization.Sometimes the wire enters the breast at somedistance from the radiological abnormality.Under these circumstances, it is preferableto make an incision overlying the lesion anddeliver the wire into the surgical field from amore peripheral entry point. To facilitateplacement of the skin incision, the radiolog-

ists can mark the skin projection of thelesion. The surgeon then aims to excise acolumn of tissue deep to this, which incor-porates the tip of the wire and the adjacentbreast tissue (which should contain thelesion). It is imperative to undertake a spec-imen radiograph that has been appropriatelyorientated with sutures and ligaclips (thelatter are radiopaque). It is conventional toplace two sutures superiorly and a single onelaterally. The specimen radiograph shouldbe viewed by the radiologist who has per-formed the localization (5,6). They shouldcomment on

1. the presence of the radiological abnor-mality (opacity, microcalcification, areaof architectural distortion),

2. the position of the tip of the wire inrelation to this, and

3. the presence of any clip that has beendeployed at the time of core biopsy

In addition, the position of the lesion inrelation to the gross specimen should becommented on; if the lesion appears closeto one particular margin, then further tissuecan be taken before the wound is closed. Thiswill reduce the chance of re-excision at alater stage (7). In this case, the lesion waspositioned centrally with an adequate marginof surrounding tissue. This was confirmed ondefinitive histology, which showed a goodclearance of all margins (>10 mm).

Figure 13

Figure 14

78 CHAPTER 2


Radiotherapy was recommended as adju-vant treatment; there is some evidence thatolder patients (>55 years) with a non–highgrade tumor excised with wide marginsmight safely avoid radiotherapy (8,9). Suchpatients have a low risk of local recurrencewithout irradiation, and the absolute bene-fits therefrom are small. Nonetheless, radio-therapy will still reduce this risk whateverits relative level (e.g., from 4% to 2% at10 years). Though this patient had a small,screen-detected node-negative cancer, itshigh grade pushed up the NPI to 4.25. Thepatient qualified for systemic adjuvant hor-monal therapy with tamoxifen for two tothree years, followed by an early switch toan aromatase inhibitor. However, the abso-lute benefits from chemotherapy were in therange of 3% to 5%, and this was discussedwith the patient.

Related Cases

Screen-detected lesions—Case Studies 13, 15,16, and 17

Breast conservation surgery for impalpablelesions—Case Studies 13 and 15

Aromatase inhibitors—Case Studies 1, 4, 9, 10,and 19

Sentinel lymph node biopsy—Case Studies 5, 6,7, 10, 11, 16, 24, and 26

Learning Points

1. Mammographic screening reducesbreast cancer mortality in postmeno-pausal women by about 25%, but itsbenefit in premenopausal women is dis-puted. However, women should alsoconsider the potential hazards of mam-mographic screening: lead time (theearly detection of cancer may not neces-sarily result in benefit), false positives(finding lesions on mammography thatultimately prove not to be cancer), over-diagnosis (finding lesions such as DCIS

that might never pose a threat to life),and the risks of exposure to low doseradiation.

2. After lumpectomy for breast cancer,omission of radiotherapy may increasethe risk of local recurrence. A meta-analysis of trials comparing lumpectomywith and without radiotherapy foundthat omission of radiotherapy was asso-ciated with an 8% excess in mortality.However, competing causes of mortality(besides breast cancer) are of greaterconcern in older patients, so the benefitof radiotherapy is diminished in thesepatients.

References

1. Anderson TJ, Lamb J, Donnan P, et al. Compara-tive pathology of breast cancer in a randomisedtrial of screening. Br J Cancer 1991; 64:108–113.

2. Cole P, Morrison AS. Basic issues in population screen-ing for cancer. J Natl Cancer Inst 1980; 65:1263.

3. Klemi PJ, Joensuu H, Toikkanen J, et al. Aggres-siveness of breast cancers found with and withoutscreening. BMJ 1992; 304:467–469.

4. Crisp WJ, Higgs MJ, Cowan WK, et al. Screening forbreast cancer detects tumours at an earlier biolog-ical stage. Br J Surg 1993; 80:863–865.

5. Hwang ES, Esserman LJ. Management of ductalcarcinoma in situ. Surg Clin North Am 1999; 79(5):1007–1030.

6. Woo CS, Skinner KA, Silverstein MJ. Ductal carci-noma in situ: clinical studies and controversies intreatment. In: Querci della Rovere G, Warren R,Benson JR, eds. Early Breast Cancer. London andNew York: Taylor and Francis, 2006:349–374.

7. Mokbel K, Ahmed M, Nash A, et al. Re-excisionoperations in nonpalpable breast cancer. J SurgOncol 1995; 58:225–228.

8. Lim M, Bellon J, Gelman R, et al. A prospectivestudy of conservative surgery without radiation ther-apy in selected patients with stage I breast cancer.Int J Radiat Oncol Biol Phys 2006; 65:1149–1154.

9. Hughes K, Schnaper L, Berry D, et al. Lumpec-tomy plus tamoxifen with or without irradiation inwomen 70 years of age or older with early breastcancer. N Eng J Med 2004; 351:971–977.



CASE STUDY 15

History

A 64-year-old woman was recalled from rou-tine screening mammography with bilateralareas of microcalcification. The patient hadundergone a core biopsy from the rightbreast four years previously, which showedbenign changes only. She had a weak familyhistory of breast cancer, having a paternalaunt diagnosed with postmenopausal disease.The patient had two children and was24 years of age at the birth of her first child.She had never used either the oral contracep-tive pill or hormone replacement therapy.

Clinical Findings

Clinical examination was normal with nopalpable discrete lumps or any areas offocal nodularity (E1).

Clinical Assessment

Bilateral microcalcification detected on rou-tine screening with no clinical correlate

Investigations


There were localized areas of fine clusteredmicrocalcification in both breasts with no asso-ciated soft tissue shadow (opacity) (Fig. 15A–D).

Mammotome Biopsy

Percutaneous biopsy with a vacuum-assisteddevice (11-gauge needle) revealed high–nuclear grade DCIS with necrosis on theleft side (Fig. 16) and fibroadenomatoidchanges on the right. Calcium was presentwithin these areas of DCIS and fibroadeno-matoid change corresponding to calciumpresent in the mammotome biopsy speci-mens (Fig. 17A, B). A clip was deployed atthe time of biopsy.

Diagnosis

(1) Localized screen-detected ductal carci-noma in situ left breast (Tis)

(2) Pathologically indeterminate lesionright breast (B3)


Following multidisciplinary review, it was rec-ommended that the patient undergo a leftguide wire–localized wide local excision and aright guide wire–localized diagnostic biopsy.


Wire localization was carried out on themorning of surgery, and the patient wasplaced early on the list (insulin-dependentdiabetic). Once the patient was anesthetized,it was noted that a guide wire was presenton the left side only. Localization of theright side had been omitted in error. Thepatient proceeded with a wide local excisionon the left side (Fig. 18); specimen radiog-raphy confirmed that the clip was present inthe specimen, but calcification was close tothe superolateral aspect of the specimen. Acavity shave was therefore taken. An intra-operative ultrasound failed to visualize thearea of calcification in the right breast, andno surgical procedure was undertaken onthis side.


This showed high–nuclear grade DCIS withcomedo necrosis extending over an area of30 mm. In addition, a small focus (6 mm) ofinvasive ductal carcinoma (grade II; ER pos-itive) was found. All surgical margins wereclear of both invasive and in situ disease by>10 mm [Fig. 19A (magnification 5�), B(magnification 10�)].


In view of the invasive component on the leftside, axillary staging was required. It wasrecommended that a left sentinel lymphnode biopsy be undertaken and this becombined with a right guide wire localizedbiopsy as originally planned.

80 CHAPTER 2



The patient was admitted for further surgerytwo weeks later (i.e., four weeks from thefirst surgical procedure). Two hot and bluenodes were identified in the left axilla, and awire-guided diagnostic biopsy was under-taken from the right breast (Fig. 20). Aspecimen X ray confirmed the presenceof both a clip and calcification (Fig. 21).The patient made an uneventful recoveryand was discharged home one day aftersurgery.

Figure 15

Figure 16




All four nodes retrieved from the left axillawere free of tumor. Histology of the rightbreast lesion confirmed the findings of pre-vious core biopsy and showed fibroadenoma-

toid hyperplasia with microcalcification[Fig. 22 (magnification 5�)]. There was noevidence of atypia or malignancy, and themammotome biopsy site was present in thespecimen.

Figure 17

Figure 18

Figure 19

82 CHAPTER 2



Further adjuvant therapies included radio-therapy to the left breast and tamoxifen(20 mg daily) for five years (low risk ofrelapse with an NPI of <4.4).


The patient proceeded with a three-weekcourse of radiotherapy to the left breast(46 Gy in 15 fractions). She was intolerantof tamoxifen, and the option of discontinu-ing any form of systemic adjuvant hormonaltherapy was discussed. However, the patientwas keen to receive hormonal treatment(estimated benefit <1%), and she wasswitched from tamoxifen to the aromataseinhibitor arimidex after eight months.

Discussion

This case demonstrates a failure of commu-nication and organization. Bilateral guide-wire localization should have been under-taken on the day of surgery, but only the leftside was localized. By the time this wasrecognized, the patient was already undergeneral anesthetic and could not return tothe breast unit for a further localization.Intraoperative ultrasound can often detectthe mammographic abnormality, particu-larly when there is a focal mass lesion. Cal-cification alone may not be visualized onultrasound (as was the case here), and thisis one of the main limitations of ultrasoundfor diagnosis of early breast cancer. Calciumforms an interface, which is opaque to this

Figure 20

Figure 21

Figure 22



frequency of sound waves, but higher fre-quency transducers can detect calcificationwithin small tumors (1). It was perhaps for-tuitous that an invasive tumor was found inthe left breast on definitive histology, whichmandated axillary staging with sentinellymph node biopsy. This provided an oppor-tunity to perform a right guide wire–localizeddiagnostic biopsy at the same time. Sentinelnode biopsy for localized DCIS (wide excisiononly) is indicated only when the lesion ispalpable or possibly when a focal mass lesionis evident radiologically.

The advantage of a vacuum-assisted biopsydevice using an 11-gauge needle (such as amammotome) is retrieval of a larger volumeof tissue than with a conventional corebiopsy. The former varies in size from 8 to14 gauge, while the latter is best undertakenwith either a 14- or a 16-gauge needle. Thesedevices are particularly suitable for biopsy ofscreen-detected areas of microcalcification(2). In the case of a small cluster of micro-calcification, this may be completelyremoved with percutaneous biopsy and ametallic clip must be inserted to mark thebiopsy site if subsequent surgery is required.Mammotome biopsy is less likely to underes-timate disease; when only DCIS is diagnosedwith a vacuum-assisted biopsy, the chance offinding invasive disease at subsequent surgi-cal excision is only 10% (compared with 20%for conventional core biopsy) (3). An unex-pected finding of invasion will mandate axil-lary staging if this has not already beenundertaken. Sometimes this can be com-bined with cavity re-excision or completionmastectomy.

In terms of this patient's in situ disease,the Van Nuys prognostic index (see page 90,case study 16) was [2 (size 30 mm) þ 1(margins > 10 mm) þ 3 (high grade withnecrosis) þ 1 (age 64 years)] ¼ 7.

This patient should receive radiotherapyfor DCIS, but also required this as treatmentfor the invasive component. However, theabsolute risk reduction for local recurrencewill be very small for a 6-mm tumor. Similarly,the benefits from adjuvant systemic therapywill be modest (approximately 1%). In thepresence of troublesome side effects fromtamoxifen, it would be reasonable to withhold

any hormonal treatment (rather than switch-ing to an aromatase inhibitor).

Hot flushes and night sweats can adverselyimpact on a woman's quality of life and areoften exacerbated by tamoxifen (or aroma-tase inhibitors) if preexistent. Simple rem-edies like vitamin B6 may help, but moresevere and persistent symptoms usuallyrequire more specific treatment with agentssuch as clonidine or propanolol. The anti-depressant agent venlafaxine has beenextensively trialed, and studies have showna 40% to 60% reduction in incidence of hotflushes at a dosage of either 37.5 or 75 mgdaily (4). Similarly, the selective serotoninreuptake inhibitor fluoxetine has shownpromising results in pilot studies for man-agement of persistently troublesome hotflushes and night sweats (5). These can bejustifications for switching from tamoxifen toan aromatase inhibitor as adjuvant therapy.

Related Cases

Screen-detected lesions—Case Studies 13, 14,16, and 17

Breast conservation surgery for impalpablelesions—Case Studies 13 and 14


Sentinel lymph node biopsy—Case Studies 5,6, 7, 10, 11, 16, 24, and 26

Learning Points

1. In the United States, approximately 11%of all women who undergo screeningmammograms are recalled. Approxi-mately 0.3% of these women are foundto have either DCIS or invasive cancer,so the false-positive rate for screeningmammography in the United States isabout 10.7%. The false-positive rate ismuch higher in the United States thanin Europe, owing to the heightenedmedicolegal environment.

2. False-positivemammogramsareoneofthemajor drawbacks of breast cancer screen-ing. False positives may result in unneces-sary anxiety and psychological distress.

84 CHAPTER 2


3. In general, cancers detected on mammo-grams have a better prognosis than thosedetected clinically. This is partly attribut-able to lead time bias (screening advan-ces the time of diagnosis, so the intervalof time from diagnosis to death is auto-matically extended). However, the betterprognosis of screen-detected cancers isalso partly attributable to length bias(slow-growing, indolent tumors aremore likely to be detected by screening,while the faster-growing tumors are morelikely to be detected in the intervalsbetween screening sessions). Yet, thebenefit of mammography screening isbest discerned through randomized pro-spective trials, which seem to indicatethat mammography screening reducesbreast cancer mortality by about 25% inpostmenopausal women.

References

1. Cheung YC, Wan YL, Chen SC, et al. Sonographicevaluation of mammographically detected micro-calcifications without a mass prior to stereotacticcore needle biopsy. J Clin Ultrasound 2002;30:323–331.

2. Jackman RJ, Burbank F, Parker SH, et al. Atypicalductal hyperplasia diagnosed at stereotactic breastbiopsy: improved reliability with 14 gauge, direc-tional, vacuum-assisted biopsy. Radiology 1997;204:485–488.

3. Jackman RJ, Nowels KW, Rodriguez-Soto J, et al.Stereotactic, automated, large-core needle biopsyof nonpalpable breast lesions: false-negative andhistologic underestimation rates after long termfollow up. Radiology 1999; 210:799–805.

4. Loprinzi CL, Sloan JA, Perez EA, et al. Phase IIIevaluation of fluoxetine for treatment of hotflashes. J Clin Oncol 2002; 20:1578–1583.

5. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafax-ine in management of hot flashes in survivorsof breast cancer: a randomized controlled trial.Lancet 2000; 356:2059–2063.



3Incidental Breast Cancer

Part I: Mastectomy

CASE STUDY 16

History

A 47-year-old woman presented with a three-week history of a lump in the left breast,which was slightly tender but not associatedwith any nipple discharge. The lump had notchanged in size over this time period.

Clinical Findings

Examination revealed an area of focal nod-ularity in the upper outer quadrant of the leftbreast, but no discrete or dominant lump.There was no axillary lymphadenopathy (E2)(Fig. 1).

Clinical Assessment

The presentation was suggestive of benignbreast disease (fibrocystic changes) with noclinically suspicious features.

Investigations

Mammography

The mammographic appearances of the leftbreast were normal, but multiple clusters ofcoarse granular microcalcification were seen inthe upper outer quadrant of the contralateralbreast (Fig. 2A–D). The calcification extendedover an area of 23 mm and there was a lowindex of suspicion for malignancy (R3/4).

Breast Ultrasound

Several small cysts were present in the upperouter quadrant of the left breast correspond-ing to the area of palpable nodularity. Thesonographic interpretation of both breasts

was benign and consistent with fibrocysticchanges (R2).

Mammotome Biopsy

Stereotactic core biopsy of the microcalcifi-cation in the right breast revealed highnuclear grade DCIS (ductal carcinoma insitu) with comedo necrosis [Fig. 3A (magni-fication 10�), B (magnification 20�)].There were associated foci of lobular neo-plasia (atypical lobular hyperplasia/lobularcarcinoma in situ) (Fig. 3C). Calcium waspresent in the biopsy specimen.

Diagnosis

Incidental noninvasive cancer of the rightbreast cancer (Tis).


Following multidisciplinary review, it wasrecommended the patient undergo a rightguidewire-localized wide local excision ofthe DCIS, which appeared localized to theupper outer quadrant of the right breastradiologically.

Figure 1

86


Figure 2

Figure 3

INCIDENTAL BREAST CANCER 87



The patient proceeded to surgery four weekslater (holiday during interim) as a day case(Fig. 4). A guidewire was inserted on themorning of surgery and a specimen radio-graph confirmed that all calcification hadbeen removed together with a satisfactorymargin of surrounding breast tissue. Thepatient made an uneventful recovery andwas discharged home on the same day.


This revealed extensive ductal [Fig. 5A (lowpower); B (high power)] and lobular (Fig. 5C)carcinoma in situ extending over an area of at

least 52 mm (Fig. 5A–C). Tumor extended tothe lateral and inferior margins (Fig. 5D) andthere was columnar cell change with atypia atthe superior margin. The medial margin wasclear of tumor (>5 mm).


In view of the extent of the lesion (>50 mm)together with involvement of several mar-gins, it was recommended the patientundergo a right completion mastectomytogether with a sentinel lymph node biopsy.She would be offered immediate breastreconstruction.


Immediate breast reconstruction was dis-cussed with the patient, but she was ratherundecided on this issue. After further con-sideration, the patient expressed a wish topursue immediate breast reconstruction andwas referred to the plastic surgeons for dis-cussion of reconstructive options. A rightsentinel lymph node biopsy was undertakenin advance of definitive surgery and revealedno evidence of nodal metastases. The patient

Figure 4

Figure 5

88 CHAPTER 3


proceeded to a right simple mastectomy (nofurther axillary surgery indicated) andimmediate breast reconstruction with a lat-issimus dorsi (LD) flap and implant. A skin-sparing technique was employed and thescar from the previous wide local excisionwas not disturbed. This allowed for preserva-tion of much of the skin envelope and pro-vided optimal cosmetic results (Fig. 6A, B).The patient made an excellent postoperativerecovery and was discharged home on theseventh postoperative day. The time intervalbetween the original diagnosis and definitivesurgery was four months.


This showed extensive residual LCIS aroundthe surgical cavity and within a randomsection taken from the upper outer quad-rant. There was no residual DCIS or invasivedisease (Fig. 7).


Having undergone mastectomy for DCIS/LCIS with no evidence of invasive disease

(sentinel node biopsy negative), the patientrequired no further treatment. There was noindication for either radiotherapy or tamox-ifen as adjuvant systemic hormonal therapyin the context of in situ disease treated bymastectomy. The patient had an excellentprognosis and was entered into the patient-led follow-up program. She would receivecontralateral mammography at two andfour years posttreatment.

Discussion

This patient presented with a symptomaticbreast lump and was found to have inciden-tal calcification in the contralateral breast.This had rather coarse features and theinitial index of radiological suspicion waslow, though sufficiently high to warrantbiopsy. The calcification was associated withhigh nuclear grade DCIS in the core biopsyspecimens. Calcification is commonly seenwith comedo necrosis, where dystrophic cal-cification occurs within necrotic material inthe center of the ducts. The initial radio-logical estimate of the size of this DCIS was23 mm. This was deemed suitable for breast-conserving surgery with wide local excision.Until relatively recently, the majority of DCISwas managed with mastectomy. With theintroduction of screening programs, diagno-sis of DCIS has increased form about 7% ofall breast cancers in 1985 to approximately20% to 25% of current new diagnoses (1).Moreover, most of these screen-detectedcases of DCIS are relatively localized areasinvolving a single quadrant of the breast. It isdifficult to justify mastectomy for such casesand breast conservation surgery has beenincreasingly used for treatment of thesesmall areas of DCIS over the past twoFigure 7

Figure 6



decades. When breast-conserving surgery isundertaken for DCIS, the primary tumormust be excised with clear histological mar-gins as a minimum. The use of radiotherapyafter wide local excision for DCIS remainscontroversial, but the majority of highnuclear grade lesions receive this (2–5).The crucial issue with breast-conserving sur-gery for localized DCIS is the risk ofrecurrence. In most published series, approx-imately half of all local recurrences for DCISwere invasive disease—herein lies the impor-tance of local control and the dilemma itsometimes presents (2,3,6). Clinicians mustbe confident that the risk of local recurrenceis at an acceptable level (<10% at 5–10 years)when anything less than mastectomy is offeredfor surgical treatment of DCIS.

The risk of local recurrence is related tothree principle factors:

1. Size of the lesion2. Margin width3. Grade of the lesion

These are each statistically independentpredictors of local tumor recurrence andhave been quantified in an attempt tomake them clinically useful. The Van NuysPrognostic Index (VNPI) (7) and its recentmodification (which incorporates age)(8) has been popularized in recent years.The scoring system for the VNPI is shown inTable 1. The recommendations for treat-ment based on the VNPI are as follows:

4, 5, 6—excision only7, 8, 9—excision plus radiotherapy10, 11, 12—mastectomy

Although radiotherapy significantlydecreases the risk of local recurrence by

about 50% when compared with excisionalone, it may represent over treatment forsome patients undergoing breast-conservingsurgery. The blanket recommendation byAmerican authorities (4) that radiotherapyis indicated for all patients with high-gradeDCIS does not take account of the hetero-geneity of DCIS or variation in absolutebenefits from radiotherapy between differ-ent subsets. Radiotherapy not only has sig-nificant side effects but also changes thetexture of the breast and renders subsequentmammography more difficult to interpret.Moreover, the breast cannot receive furtherirradiation should an ipsilateral invasivebreast cancer develop at a later date.

Following initial wide local excision, thispatient had a VNPI of:

[3 (size 52 mm) þ 3 (margins < 1 mm) þ3 (high grade with necrosis) þ 2 (age 48 years)]¼ 11

Therefore, completion mastectomy wasappropriate based on the above treatmentrecommendations. From a surgical point ofview, mastectomy is usually indicated for alesion >40 mm in size. However, it may bepossible to excise more extensive DCIS in alarge breast with satisfactory margins of clear-ance (particularly using some of the neweroncoplastic techniques such as therapeuticmammoplasty). If the calculated VNPI isbelow 10, then the estimated risk of recur-rence would be sufficiently low to acceptbreast conservation (with radiotherapy).

This patient opted for immediate breastreconstruction and underwent sentinel lymphnode biopsy in advance of definitive surgery.Final histology revealed no evidence of inva-sive disease and no further treatment wasindicated. Despite having a scar in the upper

Table 1 The Modified University of Southern California/Van Nuys Prognostic (USC/VNPI) Scoring System

Score

1 2 3

Size <15 mm 16–40 mm >41 mm

Margins >10 mm 1–9 mm <1 mm

Pathology Non-high gradewithout necrosis

Non-high gradewith necrosis

High-grade with orwithout necrosis

Age �61 yr 40–60 yr �39 yr

Source: Adapted from Ref. 9

90 CHAPTER 3


outer quadrant of the right breast from initialwide local excision, the patient was very happywith the cosmetic result. A two-stage proce-dure necessarily incurs additional scarringand whenever possible the need for mastec-tomy should be anticipated at the outset. Thiswill avoid a second surgical procedure andconfine scarring to the periareolar region(skin-sparing mastectomy).

Related Cases

DCIS—Case Studies 12, 13, 17, and 18

Immediate breast reconstruction—Case Studies3, 17, 18, and 37

Learning Points

1. Following mastectomy for DCIS, someoncologists might offer a patient tamoxifen(20 mg/day for 5 years) to reduce the riskof contralateral breast cancer. Yet, in gen-eral, tamoxifen is not indicated after totalmastectomy for DCIS.

2. If breast-conserving surgery is attemptedin a patient with a diffuse area of DCIS,then two wires might be placed to local-ize two ends of the lesion, thereby pro-viding guideposts for wide excision ofthe entire lesion.

3. The LD muscle alone generally does notprovide sufficient tissue bulk, so recon-struction with an LD flap usually requiresplacement of an implant. In contrast, thetransverse rectus abdominis muscle(TRAM) flap provides sufficient tissuebulk and an implant is not required.Yet, the TRAM flap procedure is techni-cally more challenging, and it is associ-ated with a greater risk of morbidity. An

extended autologous LD flap providesadditional bulk without the need for animplant but can be associated withincreased donor site morbidity.

References

1. Bland KI, Menck HR, Scott-Conner CE, et al. TheNational Cancer Data Base 10 year survey of breastcarcinoma treatment at hospitals in the UnitedStates. Cancer 1998; 83:1262–1273.

2. Solin L, Kurtz J, Fourquet A, et al. Fifteen results ofbreast conserving surgery and definitive breastirradiation for treatment of ductal carcinoma-in-situ of the breast. J Clin Oncol 1996; 14: 754–763.

3. Fisher B, Dignam J, Wolmark N, et al. Lumpectomyand radiation therapy for the treatment of intra-ductal breast cancer: findings from the NationalSurgical Adjuvant Breast and Bowel Project B-17.J Clin Oncol 1998; 16:441–452.

4. Fisher B, Land S, Mamounas E, et al. Prevention ofinvasive breast cancer in women with ductal carci-noma in situ: an update of the National SurgicalAdjuvant Breast and Bowel Project experience.Semin Oncol 2001; 28:400–418.

5. Julien J, Bijker N, Fentiman I, et al. Radiotherapyin breast conserving treatment for ductal carci-noma-in-situ: first results of EORTC randomizedphase III trial 10853. Lancet 2000; 355:528–533.

6. Silverstein M, Barth A, Poller D, et al. Ten yearresults comparing mastectomy to excision andradiotherapy for ductal carcinoma in situ of thebreast. Eur J Cancer 1995; 31:1425–1427.

7. Silverstein MJ, Lagios MD, Craig PH, et al. Aprognostic index for ductal carcinoma in situ ofthe breast. Cancer 1996; 77:2267–2274.

8. Silverstein MJ. USC/Van Nuys Prognostic Index.In: Silverstein MJ, ed. Ductal Carcinoma In Situ ofthe Breast. 2nd ed. Philadelphia: Lippincott, Wil-liams and Wilkins, 2002.

9. Woo CS, Skinner KA, Silverstein MJ. Ductal carci-noma in situ: clinical studies and controversies intreatment. In: Querci della Rovere G, Warren R,Benson JR, eds. Early Breast Cancer. New York/London: Taylor and Francis, 2005; 365.

CASE STUDY 17

History

A 45-year-old woman presented with a 12-month history of left breast pain. This hadno clear relationship to the menstrual cycleand was not associated with any breast lumpsor nipple discharge. The patient had noprevious breast problems and no family his-tory of breast or ovarian cancer. She had two

children (eldest 16 years of age) and hadused the oral contraceptive pill for a cumu-lative period of 10 years.

Clinical Examination

Examination of both breasts was normal withno areas of nodularity and no dominant



lumps palpable. There was no axillary lym-phadenopathy (E1).

Clinical Assessment

The patient was considered to have non-cyclical breast pain most likely attributed toa degree of fibrocystic change. She wasreassured and provided with informationon evening primrose oil (gamolenic acid160–320 mg daily).

Investigations

Mammography

Mammographic interpretation of the leftbreast was normal, but two separate areasof linear and branching fine microcalcifica-tion were seen in the upper outer quadrantof the right breast (Fig. 8A, B).

Breast Ultrasound

No mass lesion was evident sonographicallyand these areas of suspicious microcalcifica-tion were not seen on ultrasound examina-tion of the breasts.

Mammotome Biopsy

Percutaneous biopsy was undertaken using an11-gauge needle with a vacuum-assisted device.Specimen X ray confirmed that calcium waspresent in the biopsy material (Fig. 9) andhistopathological examination showed highnuclear grade DCIS with comedo necrosis.Biopsies were taken from both areas in theright breast and displayed similar features(Fig. 10).

Diagnosis

Extensive multifocal ductal carcinoma in situof the right breast cancer (Tis).


Following multidisciplinary discussion andcareful review of the mammograms, it wasrecommended the patient undergo a rightsimple mastectomy. The areas of microcalci-fication were separated by several centime-ters and represented multicentric disease.Because of the possibility of a small focusof invasive carcinoma being found on defin-itive histology (approximately 20%) sentinellymph node biopsy was advised. The patientwas suitable for a skin-sparing mastectomy(periareolar incision) and would be offeredimmediate breast reconstruction.


It was very difficult for the patient to come toterms with the prospect of a right mastec-tomy; she had presented with left breast painand was found incidentally to have areasof suspicious microcalcification in the con-tralateral breast, which had no clinical cor-relate. The patient accepted the need for

Figure 8Figure 10

Figure 9

92 CHAPTER 3


mastectomy and was referred to the plasticsurgeons for discussion of reconstructiveoptions. A right sentinel lymph node biopsywas carried out in advance of definitive sur-gery and revealed no evidence of regionalmetastases in any of the five nodes retrieved(Fig. 11).

The patient proceeded to a right skin-sparing mastectomy (no further axillary sur-gery) and immediate breast reconstructionwith a free TRAM flap. A contralateral breastreduction was performed at the same time toachieve symmetrization. The incision chosenfor the skin-sparing mastectomy was modifiedin accordance with the contralateral proce-dure and extirpation of breast tissue wasincorporated into a vertical-type mammo-plasty incision, which permitted a similarpattern of scarring in the two breasts andmaximized the chance of achieving symme-

try of shape and volume (Fig. 12) and(Fig. 13A–C). The patient made an unevent-ful recovery and in particular experiencedno problems with the healing of theabdominal wound.


This revealed extensive high nuclear gradeDCIS involving much of the breast tissue(Fig. 14A). The two main foci of diseasemeasured 30 mm and 40 mm and in addi-tion there was a small focus of invasive car-cinoma (grade II, ER positive) measuring6 mm in maximum extent [Fig. 14B (lowpower), C (high power)].


In the absence of any invasive component, nofurther treatment for extensive DCIS treatedwith mastectomy would be indicated. Inthe presence of a 6 mm focus of grade II,

Figure 11

Figure 12

Figure 13

Figure 14



ER-positive node-negative invasive ductal car-cinoma, adjuvant systemic hormonal therapywith five years tamoxifen is appropriate (with-out an early switch to an aromatase inhibitor).

Discussion

This relatively young woman was found inci-dentally to have multifocal high nuclear gradeDCIS (with comedo necrosis) of the rightbreast. Two areas of suspicious microcalcifica-tion were present in separate quadrants of thebreast, which mandated mastectomy. Defini-tive surgery, including immediate breastreconstruction, could be confidently plannedon the basis of the preoperative investigations,which provided histological evidence of multi-focality. There is up to a 20% chance offinding invasive disease when mastectomy isundertaken for extensive high nuclear gradeDCIS, though this is reduced by use of avacuum-assisted device with a larger bore nee-dle (11 gauge). Sentinel node biopsy is nowroutinely performed in such circumstancesand is best undertaken in advance of mastec-tomy and immediate breast reconstruction;should there be metastases within the sentinelnode, then completion axillary lymph nodedissection can be done at the same time asmastectomy. The latter is usually undertakenwith a periareolar incision that minimizesscarring and yields excellent cosmetic results.In this particular case, a modified skin incisionwas employed that mirrored the vertical mam-moplasty-type incision used to reduce thecontralateral breast (Fig. 13) (1). This typeof incision provides excellent access to theaxillary contents and a counter incision in theaxilla is unnecessary. When autologous tissueis transferred, the nipple-areolar complex canbe replaced with a disc of skin from the donorsite (in this case the lower abdomen).

Final histology revealed two areas of DCISwithin the right breast measuring 30 mmand 40 mm (aggregate size 70 mm). Inaddition, a small 6-mm focus of invasivecarcinoma was found. This was hormonallysensitive and tamoxifen was prescribed forfive years as adjuvant systemic hormonaltreatment (low risk of relapse).

This patient had problems coming to termswith the need for mastectomy; it is importantto emphasize to these women that their long-

term prognosis is excellent following mastec-tomy for extensive DCIS, albeit with a smallinvasive component (at least 90% 10-year sur-vival). In a series of patients from MemorialSloan-Kettering Cancer Center with node-negative and node-positive tumors less thanor equal to 2 cm (T1N0 and T1N1), compar-ison of observed to expected survival at amedian follow-up of 18 years revealed that89% of patients with node-negative tumorsless than or equal to 1 cm were estimated tobe cured (2). Many of these patients will haveachieved a “personal” cure and are likely toeventually succumb from non–breast cancerrelated causes. This patient was dischargedinto a patient-led follow-up program and willhave contralateral mammography at two andfour years and thereafter enter the NHS BreastScreening Programme.

Related Cases


Immediate breast reconstruction—Case Studies3, 17, 18, and 37

Adjuvant hormonal therapy for “minimal”breast cancer—Case Studies 9 and 18

Learning Points

1. This patient presented with mastalgiaand no palpable breast masses. Manyclinicians would not have obtained a mam-mogram in such an instance, unless thepatient was due for an annual screeningmammogram. Patients with mastalgia areoften managed with evening primrose oil,dietary modification (caffeine restriction),and reassurance. If the mastalgia persistsand is severe, a short course of tamoxifentherapy might be considered.

2. In patients with multicentric DCIS, therisk of invasive cancer is about 20% and asentinel node biopsy should be obtainedprior to mastectomy. If the sentinel nodebiopsy had not been obtained, and theinvasive cancer was discovered inciden-tally after the mastectomy, then a level Iand II axillary dissection might berequired (sentinel node biopsy wouldno longer be feasible after mastectomy).

94 CHAPTER 3


References

1. Lejour M. Vertical mammoplasty without infra-mammary scar and with liposuction. PerspectPlast Surg 1990; 4:67.

2. Rosen PP, Groshen S, Saigo P, et al. A long-termfollow up study of survival in stage I (T1N0M0) andstage II (T1N1M1) breast carcinoma. J Clin Oncol1989; 7:355–366.

CASE STUDY 18

History

A 42-year-old woman presented with a two-week history of a non-tender lump in theright breast. This had not changed in sizeand there was no associated nipple discharge.There were no previous breast problems andthe patient did not report having particularly“lumpy” breasts. The patient's maternalgrandmother and great aunt had developedbreast cancer postmenopausally. The patienthad two children both of whom were breast-fed and was aged 28 years when giving birthto her eldest child. The oral contraceptive pillhad been used for a cumulative period of15 years, including 7 years usage prior to thepatient's first pregnancy. She had a relativelyearly menarche at the age of 10 years.

Clinical Findings

Examination revealed large pendulousbreasts with an area of focal nodularity inthe upper inner quadrant and a smoothround tender lump immediately inferior tothe right nipple areolar complex measuring0.5 cm in maximum diameter (E2). Therewas no axillary lymphadenopathy (Fig. 15).

Clinical Assessment

The clinical impression was of benign breastdisease involving localized fibroadenoticchange and duct ectasia with possible peri-ductal cyst formation. There were no clini-cally suspicious features.

Investigations

Mammography

This showed an area of pleiomorphic micro-calcification in the superior aspect of theright breast extending over at least 40 mm.There was a vague mass lesion associated withmicrocalcification and the appearances werehighly suspicious for DCIS (Fig. 16A–C).

Figure 16Figure 15



Breast Ultrasound

The sonographic correlate of the microcal-cification was an extensive area of alteredechogenicity between 11 and 12 o'clock.In addition, a more well-defined mass lesionwas seen in the lateral aspect of the rightbreast (Fig. 17A, B).

Core Biopsy

Stereotactic core biopsy of the microcalcifica-tion revealed low and intermediate nucleargrade DCIS with no evidence of invasion[Fig. 18A (low power), B (high power)].Calcium was present within the biopsy speci-mens. Ultrasound-guided core biopsy of thelesion in the lateral aspect of the breastrevealed fat and normal breast tissue only.

Diagnosis

Extensive noninvasive right breast cancer(Tis)


The microcalcification involved an area of atleast 40 mm and it was possible the DCISextended beyond the zone of microcalcifica-tion. Following multidisciplinary review, itwas recommended the patient undergo aright simple mastectomy and be offeredimmediate breast reconstruction. It was feltthat MRI examination of the breasts wouldnot influence the patient's management andwas therefore not performed preoperatively.


Reconstructive options were discussed withthe plastic surgeons; the patient's large bodyhabitus precluded reconstruction with aTRAM flap and therefore she proceeded toa right simple mastectomy and immediatebreast reconstruction with an LD flap andimplant. A skin-sparing technique wasemployed using a periareolar incision. Thenipple-areolar complex was replaced with adisc of skin from the dorsal donor site. Thepatient made an uneventful recovery with noinfective complications.


This revealed extensive high nuclear gradeDCIS of comedo, cribriform, andmicropapillarytypes [Fig. 19A (magnification 5�), B (magnifi-cation 20�)]. The DCIS measured up to130 mm and was present within 1 mm of several

Figure 17

Figure 18

96 CHAPTER 3

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resection margins. Two small foci of invasionwere found measur ing 2 mm and6 mm (both grade I) [Fig. 19C (magnification5�)]. An inferior flap shave showed extensiveDCIS while a superior flap shave was free of anytumor.


In view of the total extent of DCIS and itsproximity to several resection margins, chestwall radiotherapy was recommended. Thetwo foci of grade I invasive ductal carcinomahad an aggregate diameter of 8 mm and itwas considered inappropriate to undertake adelayed axillary lymph node dissection dueto the low probability (<5%) of nodalinvolvement. Similarly, the absolute benefitsfrom adjuvant hormonal therapy (tamoxi-fen) were <2% and systemic therapy waswithheld.


The patient proceeded to chest wall radio-therapy with a total dose of 50 Gy given in25 fractions over five weeks. She developed

acute radiation sequelae with marked eryth-ema of the breast but no skin breakdown.The patient was prescribed flamazine creamfor topical usage. Over the next 18 months,she developed progressive hardening anddiscomfort of the reconstructed breast. Exam-ination confirmed a degree of capsule forma-tion with prominent telangiectasia over theregion of the right inframammary fold.Despite the presence of a significant degreeof contracture, this was not of particular con-cern to the patient who declined any offer ofcapsulectomy and implant exchange. She wasfurther reviewed 12 months later when cap-sular contracture had worsened; at this stagethe patient was prepared to undergo furthersurgery to reduce the hardness and heavinessof the breast (Fig. 20).

Discussion

At the time this patient underwent surgery,sentinel lymph node biopsy was not routinelyoffered to all patients undergoing mastec-tomy for extensive high nuclear grade DCIS.There is up to a 20% chance of findinginvasion in these circumstances, which

Figure 19



either mandates subsequent axillary staging(with axillary lymph node dissection) or, asin this case, no axillary surgery with observa-tion only (1). This patient had two foci ofgrade I invasive ductal carcinoma with acombined diameter of 8 mm. The incidenceof nodal involvement for grade I invasiveductal carcinomas or special type cancersmeasuring less than 1 cm is very low(<5%) (2). It would have been difficult tojustify a delayed axillary lymph node dissec-tion in this patient who had undergoneimmediate breast reconstruction with trans-position of a LD flap. Sentinel node biopsyor guided axillary sampling cannot be car-ried out once all the breast tissue has beenremoved. This patient is highly unlikely tohave any adverse clinical consequences interms of regional recurrence or longer-termsurvival from failure to undertake any formof axillary staging (3). Many clinicians intui-tively feel that with the advent of sentinelnode biopsy, all patients with invasive disease(whatever the size) should at least undergothis procedure. Axillary staging can almostcertainly be omitted for some tubular can-cers <1 cm (any age group) and probablysafely omitted in some older women withsmall, ER-positive, non-high-grade tumors.The latter group would be treated with adju-vant hormonal therapy irrespective of nodalstatus. Rates of axillary relapse at five yearsfollow-up have been reported to be only 3%after omission of axillary surgery in a groupof patients with mainly T1c clinically node-negative tumors (4). Despite the detection ofinvasive disease on final histology, this

patient had an excellent prognosis and herabsolute benefit from adjuvant systemictreatment would be <2%. Some cliniciansmay have prescribed five years of tamoxifenas adjuvant hormonal therapy with the pro-portional benefits being similar for pre- andpostmenopausal women.

This patient had relatively large breastsand a TRAM flap would have provided bettervolume replacement. However, the patientwas obese with a BMI in excess of 35 andconsidered to be a high risk for these majortissue-transfer techniques. An extra largeimplant was ordered for this patient and thebreast became very hard and heavy followingcapsular contracture. There is some evidencethat contracture is more likely after irradiationof very large implants. The decision to giveradiotherapy to the chest wall was carefullyconsidered in this patient. She had very exten-sive DCIS (>100 mm) extending close to sev-eral margins of the resected specimen.

Related Cases


Immediate breast reconstruction—Case Studies3, 17, and 37

Omission of completion axillary dissection—Case Studies 10 and 24

Capsular contracture—Case Study 3

Adjuvant hormonal therapy for “minimal”breast cancer—Case Studies 9 and 17

Learning Points

1. In this particular case, some oncologistsmight have opted to place this patienton tamoxifen to reduce the risk of con-tralateral breast cancer. Additionally, inthis patient's case, the axilla might havebeen appropriately treated with eithersurgery or radiotherapy (either willreduce the risk of axillary recurrenceby about 90%). However, this patient'srisk of nodal metastasis was very low, soomission of axillary treatment was a rea-sonable choice.

2. Some plastic surgeons recommend a two-stage reconstruction option for patients

Figure 20

98 CHAPTER 3


undergoing mastectomy for DCIS orinvasive cancer. In the first stage, anexpander prosthesis is placed immedi-ately after the mastectomy. A few monthslater (once the final histology is availableand the patient has completed any radio-therapy or chemotherapy), the secondstage procedure is completed (tissuereconstruction or placing a permanentimplant). One advantage of this option isthat there is less risk of damage to thetissue reconstruction from radiotherapy.

References

1. Dowlatshahi K, Fan, Bloom KJ, et al. Occult metas-tases in sentinel lymph nodes of patients with earlystage breast carcinoma: a preliminary study.Cancer 1999; 86:990–996.

2. Querci della Rovere G, Bonomi R, Ashley S, et al.Axillary staging in women with small invasive breasttumors. Eur J Surg Oncol 2006; 32: 733–737.


4. Greco M, Agresti R, Cascinella N, et al. Breastcancer patients treated without axillary surgery.Ann Surg 2000; 232(1):1–7.

Part II: Breast-Conservation Surgery

CASE STUDY 19

History

A 76-year-old woman presented with a three-week history of a lump in the left breast,which had developed a few weeks after thepatient sustained bruising of the left breastfrom a fall (since settled). There was mini-mal pain but no nipple discharge and thepatient had undergone regular screeningmammograms up to the age of 64 years.She had no family history of breast or ovar-ian cancer and was nulliparous. She hadused HRT (hormone replacement therapy)for a total period of 10 years in the past butnever been prescribed the oral contraceptivepill.

Clinical Findings

Examination revealed a slightly irregularand ill-defined lump in the medial aspectof the left breast, corresponding to thesite of previous bruising. No discrete lumpwas palpable in the right breast andthere was no axillary lymphadenopathy(E3) (Fig. 21).

Clinical Assessment

The lump in the left breast was clinicallyindeterminate, but would be consistent with

a diagnosis of fat necrosis (suggested fromthe history).

Investigations

Mammography

An asymmetric density was seen in the lowerinner quadrant of the left breast, corre-sponding to the palpable abnormality.There was no discrete mass lesion on mam-mography in the left breast. However, in theupper outer quadrant of the contralateral(nonpresenting) side was a spiculate masslesion measuring 22 mm in diameter. Thishad the appearances of a carcinoma (R5)(Fig. 22A, B).

Figure 21



Breast Ultrasound

There was evidence of fat necrosis in thelower inner quadrant of the left breast onultrasound examination. Moreover, thesonographic correlate of the spiculate masslesion in the upper outer quadrant of theright breast was a heterogeneous, ill-definedhypoechoic mass with posterior acousticattenuation. This corresponded in sizewith the mammographic estimate (22 mm)and was sonographically a carcinoma (U5)(Fig. 23).

Core Biopsy

Ultrasound-guided 16-gauge core biopsy ofthe right breast mass confirmed the radio-logical impression of malignancy and showed

an invasive ductal carcinoma (grade I, ER-positivea, HER2 negative) (Fig. 24). Nobiopsy was taken on the left side.

Diagnosis

1. Incidental early-stage impalpable rightbreast cancer (T2N0)

2. Fat necrosis left breast


Following multidisciplinary review, it wasrecommended the patient be offered aright guidewire-localized wide local excisionand sentinel lymph node biopsy. It was con-firmed upon reexamination that the rightbreast lump was impalpable, though therewas a suggestion of subtle skin tethering.


The patient proceeded to surgery withinthree weeks and a quadrantic style resectionwas performed using a single radial incisionand excising a narrow ellipse of skin over-lying the tumor (Fig. 25). The sentinel nodebiopsy was carried out through the lateralone-third of the incision and yielded twoblue and “warm” nodes (one nonsentinelnode was also removed). A specimen radio-graph confirmed that the lesion had beenremoved with an adequate margin of tissue(radiologically) (Fig. 26).

a Allred score 8/8

Figure 22

Figure 23

Figure 24

100 CHAPTER 3


The patient made an uneventful recoveryand was discharged home on the secondrather than first postoperative day for socialreasons (husband disabled).


This revealed an invasive ductal carcinoma(grade I) measuring 24 mm in maximumdiameter (Fig. 27A). There were multipleintratumoral foci of intermediate nucleargrade DCIS, but these did not extendbeyond the invasive component. Perineuralinvasion was noted, but no lymphovascularinvasion was seen. The lateral, superior,and inferior resection margins were clearof tumor by >10 mm, but tumor was presentat the medial margin (Fig. 27B). There wasno evidence of metastases in either of thetwo sentinel nodes or the single nonsenti-nel node.


The patient required re-excision of themedial margin and if satisfactory clearance

of the tumor achieved, this would be fol-lowed by radiotherapy to the right breastand tamoxifen as adjuvant systemic hor-monal therapy (low risk of relapse).


The patient underwent re-excision of themedial cavity margin almost four weeksafter the original surgery (further surgerydelayed at request of patient). There wasno further tumor in the re-excision speci-men and the patient proceeded to radiother-apy planning shortly after completion ofsurgery. Final cosmetic results following sur-gery and radiotherapy were satisfactory withminor loss of volume in the lateral aspect ofthe right breast (Fig. 28A, B).

Discussion

This patient was found to have an incidental,impalpable cancer in the right breast whenshe presented symptomatically with a lumpin the left breast. The history was very sug-gestive of fat necrosis; the patient had sus-tained trauma to the left breast, which hadcaused bruising. This was followed two tothree weeks later by the appearance of alump at the site of bruising. Fat necrosiscan mimic a carcinoma both clinically and

Figure 26

Figure 27

Figure 25



mammographically (1,2). However, theultrasound features are characteristic andwhen the history is consistent with fat necro-sis, no core biopsy is necessary. Oftenpatients cannot recollect any history oftrauma, and if there is doubt about thenature of a lump on clinical and radiologicalcriteria, then core biopsy should be under-taken. The carcinoma in the right breastmeasured 22 mm and was located in theextreme lateral aspect of the breast. It wassuitable for breast-conserving surgery, butrequired localization prior to excision.

The breast excision and sentinel nodebiopsy were undertaken through a singleradial incision rather than two separate inci-sions (curvilinear breast, transverse axilla).This is an ideal incision for a more periph-erally sited tumor in the upper outer quad-rant of the breast. When a formal axillarydissection is undertaken, it allows the breastlesion to be removed in continuity with theaxillary contents. This en bloc dissectionincorporates the intervening breast tissuecontaining the lymphatics coursing towardthe axillary nodes. The lower axilla can easilybe accessed through the lateral one-third ofthe incision for sentinel node biopsy.

Though the specimen radiograph app-eared to show an adequate margin of tissuearound the spiculate mass, tumor was pres-ent at the medial margin histologically.Other radial margins were clear by >10mm. When a quadrantic resection is per-formed for tumors in the upper outer quad-rant, less tissue tends to be resected at themedial and lateral margins and proportion-ately more tissue superiorly and inferiorly.The opposite applies to a curvilinearincision.

Approximately 25% of patients undergo-ing breast-conserving surgery require re-excision to either attain negative marginsor a wider margin of clearance, with negativemargins being achieved in more than 90% ofcases (3). Rates of re-excision tend to behigher when a 5 mm margin is stipulatedrather than 2 to 3 mm. Residual tumor isidentified in approximately 50% of caseswith positive or unknown margins. Whenthere is an extensive in situ component,the chance of residual disease is up to 70%(4–8). Patients should be warned of the pos-sibility of re-excision when consenting tobreast-conserving surgery. This patient hada low risk of distant relapse with an NPI of(0.2 � 2.4) þ 1 þ 1 ¼ 2.48 (24 mm, grade I,node negative). Tamoxifen only for fiveyears was the recommended adjuvant hor-monal treatment.

Related Cases

Re-excision after breast conservation sur-gery—Case Studies 7, 11, and 16


Learning Points

1. A diagnostic mammogram should beobtained whenever a patient presentswith a suspicious breast mass. The mam-mogram may not only help establish adiagnosis, but may also discern occultlesions in the ipsilateral or contralateralbreast, which could prove useful in plan-ning local therapy. In this instance, thepalpable lesion proved to be benign, but

Figure 28

102 CHAPTER 3


the mammogram led to the discovery ofan occult cancer in the contralateralbreast.

2. Approximately 77% of all breast cancersare ER positive. However, ER-positivetumors are more common in the elderlythan in younger women. Breast cancerswith better prognostic features (ER pos-itive, HER2 negative, low grade, nodenegative) are more common in elderlypatients.

3. Population-based statistics indicate thatbreast cancer mortality rates in theindustrialized countries have declinedby about 25% since 1990. However,this decline in mortality rates has largelyaffected women below the age of 70 withER-positive tumors.

References

1. Bilgen IG, Ustun EE, Memis A. Fat necrosis of thebreast: clinical, mammographic and sonographicfeatures. Eur J Radiol 2001; 39:92–99.

2. Harrison RL, Britton P, Warren R, et al. Can we besure about a radiological diagnosis of fat necrosisof the breast? Clin Radiol 2000; 55:119–123.

3. Kearney TJ, Morrow M. Effect of re-excision on thesuccess of breast conserving surgery. Ann SurgOncol 1995; 2:303–307.

4. Schnitt SJ, Abner A, Gelman R, et al. The relation-ship between microscopic margins of resection andthe risk of local recurrence in patients with breastcancer treated with breast conserving surgery andradiation therapy. Cancer 1994; 74:1746–1751.

5. Gage I, Schnitt SJ, Nixon AJ, et al. Pathologicalmargin involvement and the risk of recurrence inpatients treated with breast conserving therapy.Cancer 1996; 78:1921–1928.


7. Taghian A, Mohiuddin M, Jagsi R, et al. Currentperceptions regarding surgical margin status afterbreast conserving therapy: results of a survey. AnnSurg 2005; 241:629–639.

8. Morrow M, Harris JR. Practice guidelines for breastconserving therapy in the management of invasivebreast cancer. J Am Coll Surg 2007; 205:362–376.



4Ipsilateral Breast Tumor Recurrence

CASE STUDY 20

History

A 58-year-old practice nurse presented with alump in the right breast. She had undergonebreast conservation surgery with wide localexcision and axillary sampling for an invasivelobular carcinoma of the right breast 18 yearsearlier. Radiotherapy was administered to theright breast, but the patient received no formof adjuvant systemic hormonal therapy (notstandard of care at the time). She was other-wise well and reported no weight loss, cough,or unusual back pain. There was no familyhistory of breast cancer, and the patient hadtwo children. She had received regular mam-mography within the NHS Breast ScreeningProgramme and never been recalled.

Clinical Findings

On examination there was a firm, irregularmass lying immediately superior to the pre-vious scar in the superior aspect of the rightbreast. This measured approximately 2 cm inmaximum diameter, and there was someassociated skin tethering and indrawing ofthe right nipple. The patient claimed thelatter signs were longstanding, but the lumpin the right breast was new. There weretelangiectatic changes of the skin consistentwith previous radiotherapy but neither axil-lary nor supraclavicular lymphadenopathy.Moreover, the lung fields were clear, therewas no spinal tenderness, and no hepar waspalpable (E4).

Clinical Assessment

Clinically suspicious lump in the ipsilateralbreast almost two decades after conservation

surgery for an invasive carcinoma of theright breast.

Investigations

Mammography

An area of increased density was seen in thecentral zone of the right breast correspond-ing to the site of previous surgery. Thisappeared to have increased since mammog-raphy was last undertaken (Fig. 1A, B).

Breast Ultrasound

The sonographic correlate of this density wasa 25-mm hypoechoic lesion with the radio-logical features of a carcinoma (U5) (Fig. 2).

Core Biopsy

Ultrasound-guided core biopsy of the breastmass confirmed an invasive lobular carcinoma

Figure 1

104


(grade II) (Fig. 3A), which was strongly ER(estrogen receptor) positive (Allred score8/8) and also HER2 positive (Fig. 3B).

Diagnosis

Probable recurrent (rather than de novo)right breast cancer.


It was recommended that the patientundergo a right completion mastectomyand be offered immediate breast reconstruc-tion. The location of the tumor in relation to

the previous scar together with its lobularphenotype supported a diagnosis of recur-rent rather than de novo breast cancer.However, it was noted that almost 20 yearshad elapsed since the time of the patient'soriginal presentation. The risk of ipsilateralbreast cancer recurrence persists for up to15 to 20 years (see below). In view of thistumor most likely representing recurrence,staging investigations were requested,including CT imaging of the chest, abdo-men, and pelvis. These revealed no evidenceof distant metastatic disease, though abnor-malities of bone texture were noted in thelumbar spine and pelvis with evidence ofsclerosis. After careful scrutiny by morethan one radiologist, these changes wereconsidered consistent with Paget's diseaseof bone rather than metastatic tumor.Indeed, it transpired that the patient hadundergone a bone biopsy 10 years earlier,which corroborated this diagnosis. Somepost-radiotherapy changes were noted inthe lung fields, but no evidence of secondarypulmonary deposits was found.

The patient reported that the axillary sam-pling procedure had retrieved 10 nodes at thetime of primary surgical treatment 18 yearsearlier. It was proposed to remove any furthernodes at operation, which lay below the levelof the axillary vein or were palpable.


The patient expressed an initial interest inimmediate breast reconstruction and wasreviewed by the plastic surgeon. After fur-ther consideration, the patient declined anyimmediate reconstructive procedure andunderwent a right completion mastectomywithin only six weeks of tissue diagnosis(core biopsy) (Fig. 4). There was somedelay in definitive surgery because of a plas-tic surgery consultation and reduction ofsurgical activity over the festive season. Atthe time of surgery, the mastectomy flapswere very thin, and a wide skin excision wasperformed to encompass the skin overlyingthe tumor, the previous scar, and areas ofskin damaged by radiotherapy (telangiec-tatic). Some residual axillary tissue wasremoved in continuity with the breast.

Figure 2

Figure 3

IPSILATERAL BREAST TUMOR RECURRENCE 105



This revealed a grade III invasive lobularcarcinoma measuring 30 mm in maximumdiameter [Fig. 5 (magnification 20�)]. Thetumor extended into the dermis of the nip-ple, though there was no evidence of Paget'sdisease. There was no associated DCIS(ductalcarcinoma in situ), but LCIS (lobular carci-noma in situ) was present. A total of sevennodes were identified within the axillary tis-sue. None of these contained metastases, andthere was no lymphovascular invasion.


The final histology confirmed an invasivelobular carcinoma similar to the patient'soriginal breast cancer diagnosed almost20 years previously. The lesion was hormonesensitive and HER2 receptor positive withevidence of neither lymphovascular invasionnor nodal disease. It was recommended thepatient receive a course of anthracycline-based chemotherapy combined with a tax-ane [FEC (5-fluorouracil, epirubicin, cyclo-phosphamide)/taxotere] together withHerceptin. She had previously receivedradiotherapy to the breast and was ineligiblefor chest wall radiotherapy.


The patient proceeded to four cycles of FEC(5-fluorouracil, epirubicin, and cyclophospha-mide) followed by four cycles of docetaxelwith concomitant Herceptin (see AppendixIII). She tolerated FEC well, though shedeveloped grade I nausea, vomiting, andstomatitis with grade II lethargy. After thefirst cycle of docetaxel, she experienced mod-erately severe symptoms of sensory changes(grade III) together with alopecia, arthralgia,myalgia, and lethargy (grade II). The dosageof taxane was therefore reduced, but thepatient received the first cycle of Herceptinin the presence of a satisfactory left ventricularejection fraction [normal MUGA (Multi-gated Acquisition) scan].

Discussion

Ipsilateral breast tumor recurrence (IBTR)persists at a regular rate beyond five years,with patients continuing to be exposed to arisk of 1% to 3% per annum. There is long-standing controversy over the significance ofIBTR following conservation surgery andwhether rates of local recurrence affect over-all survival. Of particular concern is the rela-tionship to distant relapse and whether localrecurrence within the conserved breast acts asa source of distant metastases or is a markerof risk for development of distant disease andde facto poor prognosis. Several studies haveconfirmed that local recurrence confers anincreased risk of distant relapse, varying from2.72- to 4.62-fold, implying that local recur-rence and distant metastases are linked.

The most recent overview by the EarlyBreast Cancer Trialists Collaborative Group(EBCTCG) in 2005 revealed that moderatedifferences in rates of local recurrence atfive years can impact on breast cancer mor-tality after more prolonged follow-up of15 years (1). This suggests that local recur-rence has a determinant role with patientsdeveloping disseminated disease as a directconsequence of failure to remove residualbut viable cancer cells at the time of primarytreatment. By implication, inadequatelocoregional treatment may ultimately com-promise longer-term survival.

Figure 4

Figure 5

106 CHAPTER 4


It can be difficult to distinguish between atrue local recurrence within the conservedbreast and a new primary. The site of recur-rence and morphology can be helpful—alesion occurring within the same quadrantand of the same morphology as the originaltumor is likely to be a true local recurrence.However, most cancers are invasive ductalcarcinomas of no special type (IDC-NST),and therefore, histological type is not a use-ful discriminator unless the tumor types aredifferent. There is usually no progression ofgrade between in situ, invasive, locally recur-rent, and metastatic phases (2). Flow cyto-metric analyses of DNA ploidy in primaryand matching recurrent lesions reveals con-cordance in more than 70% of cases (3).

An analysis of 82 cases of local recurrencein 990 patients undergoing breast conserva-tion surgery concluded that 47 (59%) weretrue local recurrences and 33 (41%) newprimaries (4). The latter were classified onthe basis of (i) relapse at a different site fromthe original tumor, (ii) histology consistentwith a new primary, and (iii) differences inploidy between original tumor (aneuploid)and recurrence (diploid). True local recur-rences are associated with a shorter time torelapse and poorer five-year survival com-pared with a new primary lesion (36% versus89%). Immunohistochemical profiling mayassist in differentiating a true recurrencefrom a new primary; p53 is generally notuseful, but MIBI can be helpful togetherwith a panel of markers including ER, PgR(progesterone receptor), EGFR (epidermalgrowth factor receptor), HER2, and CK (cre-atinine kinase). Microsatellite instability andLOH (loss of heterozygosity) confer a distinc-tive chromosomal pattern, which is shared bya true recurrence and the original tumor(but not a new primary) (5). Comparativegenomic hybridization (CGH) has also beenemployed to show a genetic link between theoriginal tumor and a true recurrence (6).

It remains unclear where new primarytumors come from and whether radiother-apy to the breast induces malignant epithe-lial changes. Furthermore, some cases ofIBTR represent neither a true recurrencenor a new primary but persistence of diseasewithin the breast at the site of surgery. There

is some uncertainty over differential progno-sis between a true local recurrence and anew primary, and some believe that the dis-tinction is irrelevant in terms of the type oftreatment; local recurrence occurring withintwo years has a greater chance of beingassociated with distant disease.

Two factors emerge as principle determi-nants of true local recurrence within theipsilateral breast: (i) margin status (7–12)and (ii) the presence or absence of anextensive intraduct component (EIC)(13,14). Other factors have been implicatedin determining risk of local relapse, butcorrelations are in general much weakerthan for margin status and EIC. Amongstthese, lymphatic invasion (15) and youngage (35 years) (11) have been shown to beprimary predictors for increased risk of localrecurrence. Consistent associations havebeen found for larger tumor size (>2 cm)and higher histological grade but not fortumor subtype or nodal status. These find-ings are consistent with the notion that localrecurrence develops from regrowth of resid-ual cancer cells in peri-tumoral tissue.Increased rates of local recurrence associ-ated with positive margins and EIC suggestthat incomplete removal of tumor may con-tribute to local recurrence. Rates of localrecurrence are more than threefold greaterfor tumorectomy compared with quadran-tectomy in which a larger volume of tissueis excised. Furthermore, true recurrencesoccur within the index quadrant and are ofthe same histological type and grade as theprimary tumor. In the NSABP B-06 (NationalSurgical Adjuvant Breast and Bowel ProjectB-06) trial, the annual local recurrence ratewas 8.5% in the first three years of follow-upand 4.6% in years 4 to 9 for patients under-going WLE (wide local excision) only com-pared with a constant rate of 1.4% forpatients receiving adjuvant RT (radiother-apy). Moreover, within the NSABP B-06trial, 39.2% of patients undergoing WLEonly had developed local recurrence at20 years follow-up compared with only14.3% for those receiving radiotherapypost-lumpectomy (16). Despite great varia-tion in incidence of IBTR, this does nottranslate into survival differences, and it



was concluded that no causal relationshipexisted between IBTR and distant disease(17). IBTR was found to be the strongestpredictor for distant disease and was consid-ered to be a marker for increased risk butnot a cause of distant metastases (3.41-foldincreased risk, 95% CI 2.70–4.30). Early localrecurrence was associated with a shorter dis-ease-free interval, and IBTR was better cor-related with distant disease than with tumorsize, which has been reported to be highlypredictive for development of distant metas-tases (17). IBTR is an independent predictorof distant disease and a marker of risk, butnot an instigator of distant metastases.Though locoregional treatment in the formof surgery or radiotherapy may prevent orreduce chance of expression of the marker,such therapy does not alter the intrinsic riskof developing distant disease.

The meta-analysis by the EBCTCGshowed an overall survival benefit at15 years from local radiation treatment toeither the breast following breast conserva-tion surgery or the chest wall after mastec-tomy (1). For treatment comparisons wherethe difference in local recurrence rates atfive years was less than 10%, survival wasunaffected. Amongst the 25,000 women inwhom differences in local relapse were sub-stantial (>10%), there were moderatereductions in breast cancer–specific andoverall mortality. The absolute reduction inlocal recurrence at five years was 19%, andthe absolute reduction in breast cancer mor-tality at 15 years was 5.0%. This representsone life saved for every four locoregionalrecurrences prevented by radiotherapy atfive years. It is unclear precisely what theproportional contributions of local versusregional reductions were as absolute nodalrecurrence rates were very low.

This important meta-analysis based onindividual patient data from 42,000 womenin 78 randomized treatment comparisonsprovides conclusive evidence that differen-ces in locoregional treatments, which sub-stantially improve rates of local control, willimpact on longer-term survival of breast can-cer patients.

It must therefore be conceded that up toone quarter of local recurrences are a deter-

minant and not simply a marker of risk fordistant metastases and death.

It is clear that IBTR does reflect biology ofa tumor and is a manifestation of risk fordistant relapse (Fisherian paradigm).Though clinical trials should provide conclu-sive evidence on whether surgery affectslocal or distant relapse, there are now rela-tively fewer relapse events. If rates of localrecurrence can be minimized in the first fiveyears, this will eventually impact on overallsurvival (Halstedian paradigm).

When both surgical resection (wide localexcision/quadrantectomy) and radiotherapyhave already been employed as treatment forthe primary tumor, recurrence in the breastshould be treated by mastectomy. This yieldsa 10-year disease-free survival of 50% to 60%,and rates of complications for salvage mastec-tomy are comparable to those for primarymastectomy despite surgery within an irradi-ated field (18,19). In cases where the axillahas not been previously treated, a formalaxillary dissection should be carried out atthe time of salvage mastectomy. Rates of sub-sequent local recurrence are higher inpatients treated with an additional conserva-tion procedure. Nonetheless, further breastconservation surgery can be used selectivelyand should be restricted to local recurrenceswhich are isolated mobile lesions �2 cm indiameter occurring in an originally node-negative patient. Larger recurrences can bemanaged initially with induction chemother-apy either to render them operable or topermit further breast conservation surgery.

More treatment options should be avail-able for local recurrence after BCT (breastconservation therapy). In most breast units,completion mastectomy is the only treat-ment for IBTR. Alternative options includereconserving the breast and possibly furtherSLN (sentinel lymph node) biopsy, thoughprior disruption of lymphatic pathways mayincrease false negative rates for “second timeround” sentinel node biopsy (20). It maybe feasible to consider re-irradiation withbrachytherapy where a booster dose hasnot been employed at the time of primarytreatment.

It remains unclear who should receivesystemic treatment at the time of IBTR, but

108 CHAPTER 4


overtreatment should be avoided (40–50%of patients). Local treatment alone is poten-tially curative in the absence of distantmetastases, and recurrent tumor nodulesmust be excised with clear margins. It issuggested that systemic treatment shouldbe considered for the following:

1. Patients whose original disease was nodepositive

2. Evidence of lymphovascular invasion atthe time of IBTR

3. High nuclear grade4. Short time interval to local recurrence

(IBTR)

The efficacy of chemotherapy after IBTRis unknown; the BIG 1-02 (Breast Interna-tional Group 1-02) trial is an internationalcollaboration, which will randomize patientsto chemotherapy (investigator's choice) orobservation (20). Patients with a recurrenceof HER2-positive disease in the breast shouldreceive Herceptin. HER2 status should bereassessed at the time of IBTR as 10% to12% can change from being HER2 negativeto HER2 positive upon recurrence. There iscurrently no evidence that treatment withchemotherapy at the time of IBTR will pro-long survival and many patients treated withtaxanes at the time of IBTR will eventuallydevelop distant metastases (21).

Estrogen receptor and progesteronereceptor status should be measured at thetime of IBTR and if the result is positive forhormone receptors, then endocrine therapyshould either be changed or introduced.Tamoxifen can prevent further local recur-rence but does not improve overall survivalin this setting.

Related Cases

Mastectomy without reconstruction—CaseStudies 1, 2, and 22



Herceptin—Case Studies 8, 11, and 26

Locally recurrent disease—Case Study 26

Learning Points

1. Approximately 15% of all patients whoundergo breast-conservative surgery andradiotherapy for early breast cancer willexperience an IBTR within 10 years.The risk of IBTR is diminished if clearmargins are obtained around the tumor.

2. There are several factors that increasethe risk of IBTR. The omission of radio-therapy after conservative surgery resultsin a 30% to 40% risk of IBTR. Also, thepresence of lymphatic invasion or posi-tive axillary lymph nodes increases therisk of IBTR. There is now evidence thatIBTR increases mortality risk.

3. If a patient develops IBTR after breast-conserving surgery and radiotherapy,then additional radiotherapy cannot beadministered. A salvage mastectomy istherefore warranted in such instances.

References


2. Millis R, Barnes D, Lampejo OT, et al. Tumourgrade does not change between primary and recur-rent mammary carcinoma. Eur J Cancer 1998;34:548–553.

3. Tsutsui S, Ohno S, Murakami S, et al. Flow cyto-metric analysis of DNA ploidy in primary, meta-static and recurrent breast cancers. Oncol Rep2002; 9:793–799.

4. Haffty B, Carter D, Flynn SD. Local recurrenceversus new primary: clinical analysis of 82 breastrelapses and potential applications for geneticfingerprinting. Int J Radiat Oncol Biol Phys 1993;27:575–583.

5. Regitnig P, Moser R, Thalhammer M, et al. Micro-satellite analysis of breast carcinoma and corre-sponding local recurrences. J Pathol 2002; 198:190–197.

6. Waldman FM, DeVries S, Chew KL, et al. Chromo-somal alterations in ductal carcinomas in situ andtheir in situ recurrences. J Natl Cancer Inst 2000;92:313–320.


8. van Dongen JA, Bartelink H, Fentimen I, et al.Factors influencing local relapse and survival andresults of salvage treatment after breast conservingtreatment in operable breast cancer. EORTC trial



10801. Breast conservation compared with mastec-tomy in TNM stage I and II breast cancer. Eur JCancer 1992; 28A:808–815.

9. Smitt MC, Nowels K, Carlson RW, et al. Predictorsof re-excision findings and recurrence after breastconservation. Int J Radiat Oncol Biol Phys 2003;57:979–985.

10. Fisher ER, Costantino J, Fisher B, et al. Pathologicfindings from the National Surgical AdjuvantBreast and Bowel Project (NSABP) Protocol B-17.Cancer 1995; 75:1310–1319.

11. Kurtz JM, Jacquemir J, Amalric R, et al. Risk factorsfor breast recurrence in premenopausal and post-menopausal patients with ductal cancers treated byconservation therapy. Cancer 1990; 65:1867–1878.

12. Smitt MC, Nowels KW, Zdeblick MJ, et al. Theimportance of the lumpectomy surgical marginstatus in long term results of breast conservation.Cancer 1995; 76:259–267.

13. Vicini FA, Recht A, Abner A, et al. Recurrence inthe breast following conservative surgery and radi-ation therapy for early-stage breast cancer. J NatlCancer Inst Monogr 2002; 11:33–39.

14. Veronesi U, Volterrani F, Luini A, et al. Quadran-tectomy versus lumpectomy for small size breastcancer. Eur J Cancer 1990; 26:671–673.

15. Borger JH. The impact of surgical and pathologicalfindings on radiotherapy of early breast cancer.Radiother Oncol 1991; 22:230–236.

16. Fisher B, Anderson S, Bryant J, et al. Twenty-yearfollow up of a randomized trial comparing totalmastectomy, lumpectomy and lumpectomy plusirradiation for the treatment of invasive breastcancer. N Engl J Med 2002; 347:1233–1241.

17. Fisher B, Anderson S, Fisher ER, et al. Significanceof ipsilateral breast tumour recurrence after lum-pectomy. Lancet 1991; 338:327–331.

18. Osborne MP, Simmons RM. Salvage mastectomyfor recurrence after breast conservation surgery.World J Surg 1994; 18:93–97.

19. Osteen RT. Risk factors and management of localrecurrence following breast conservation surgery.World J Surg 1994; 18:76–80.

20. Hansen N. Sentinel Node Biopsy for Local Recur-rence After Breast Conserving Surgery. MiamiBreast Cancer Conference, Orlando, FL, 2008.

21. International Breast Cancer Study Group, NationalSurgical Adjuvant Breast and Bowel Project(NSABP). Adjuvant chemotherapy in treatingwomen who have undergone resection forrelapsed breast cancer. Clinical Trials.gov 2002;http://clinicaltrials.gov/ct/show/NCT00074152.

110 CHAPTER 4


5Diagnostic Excision Biopsy

CASE STUDY 21

History

A 45-year-old woman presented with a one-week history of asymmetrical lumpiness ofthe left breast. She had not noticed anyparticular lump in the left breast, butthought this felt more “lumpy.” There wasno tenderness or associated nipple dischargeand the patient had not experienced aperiod since the onset of these breast symp-toms. She had no previous breast problemsand no family history of breast or ovariancancer. She had two children and gave birthto her eldest child at the age of 28 years. Theoral contraceptive pill had been used for acumulative period of eight years.

Clinical Findings

Examination revealed a firm area of promi-nent focal nodularity in the upper outerquadrant of the left breast, but no discreteor dominant lump was palpable. There wasno axillary lymphadenopathy (E3) (Fig. 1).

Clinical Assessment

The clinical findings were considered to beslightly suspicious, but likely benign.

Investigations

Mammography

A discrete mass lesion was seen in the upperouter quadrant of the left breast. In closeproximity to this was a small cluster of finegranular microcalcification (Fig. 2A, B). Themammographic appearances were indeter-minate (R3/4).

Breast Ultrasound

A cyst measuring 31 mm in maximum diam-eter was found in the upper outer quadrantof the left breast. This was aspirated to dry-ness with no residual lump. Material was notsent for routine cytology (Fig. 3).

Figure 1 Figure 2

111


Mammotome Biopsy

The patient returned at a later date for amammotome biopsy (11-gauge needle) ofthe area of microcalcification in the upperouter quadrant of the left breast. Calciumwas present in the specimen radiograph(Fig. 4A), and histology showed extensivefibrocystic change with apocrine metaplasiaand columnar cell change. The latter exhib-ited focal areas of mild nuclear atypia andarchitectural atypia but no in situ or invasivemalignancy. Luminal calcification waspresent (B3) (Fig. 4B, C).

Diagnosis

Uncertain; premalignant changes in leftbreast.


The biopsy was classified as B3 on the basisof nuclear and architectural atypia and a leftguidewire localized diagnostic excisionbiopsy was therefore recommended.


The patient proceeded to surgery as a daycase within two weeks of mammotomebiopsy (Fig. 5). An intraoperative specimenradiograph confirmed that the microcalcifi-cation had been removed (Fig. 6). A hema-toma was present from the mammotomebiopsy and this helped guide the surgicalexcision. A medial cavity shave was taken.


Both the main specimen and the medialcavity shave were examined in their entirety.Sections showed similar features to the mam-motome biopsy—fibrocystic change withareas of apocrine metaplasia and columnarcell change with mild nuclear, but no archi-tectural atypia. These areas of atypia occurredaround the site of the previous biopsy and themajority of columnar cell change showed noatypia (Fig. 7A). A single focus of atypicallobular hyperplasia was seen (Fig. 7B).


On account of the single focus of atypicallobular hyperplasia, it was recommendedthat the patient undergo enhanced radio-logical surveillance with annual mammogra-phy until the age of 50 years followed byentry into the NHS Breast Screening Pro-gramme (3 yearly mammographies) withinterim imaging at 18 months.

Discussion

Mammographic abnormalities with a BreastImaging Reporting and Data System (BIR-ADS) classification of 4 or 5 require some

Figure 3

Figure 4

112 CHAPTER 5


form of tissue diagnosis (1). Those lesionswith a BIRADS score of 3 may subsequentlywarrant biopsy if shown to progress on short-term follow-up imaging. Before the introduc-tion of image-guided biopsy techniques, alltissue acquisition involved open excisionbiopsy. For impalpable, screen-detectedlesions, wire localization was necessary (2).Percutaneous needle biopsy techniques cannow provide a definitive diagnosis for themajority of benign and malignant conditions(3,4). Wide bore needle core biopsy is pre-ferred to fine needle aspiration cytology andyields solid cores of tissue that maintain tissuearchitecture and permit distinction betweeninvasive and noninvasive carcinoma (5). Masslesions can be biopsied using ultrasound orstereotactic guidance, whereas microcalcifica-tion usually mandates stereotactic methods(6). The standard core biopsy needle is either14 or 16 gauge (7), but larger volumes oftissue can be obtained from vacuum-assistedcore biopsy devices using a range of needlesizes, most often an 11-gauge needle (8).These latter devices reduce the chance of“underdiagnosis” and increase the chanceof obtaining a definitive preoperative cancerdiagnosis, which allows appropriate planningof breast cancer surgery (9,10).

A B2 core biopsy result indicates benignchanges only, which may include epithelialhyperplasia of the usual type. Any corebiopsy results classified as B3 implies a lesionof uncertain malignant potential such as thefollowing:

1. Atypical ductal hyperplasia with moder-ate degrees of atypia

2. Lobular neoplasia [atypical lobularhyperplasia, lobular carcinoma in situ(LCIS)]

3. Papillary lesions4. Columnar cell change with atypia5. Phylloides tumor

For all such cases, diagnostic excisionbiopsy is necessary (+/� wire localization).In addition to the above histological diagno-ses, surgical excision is also warranted for aradial scar or when there is lack of concor-dance between the clinical, radiological, andcore biopsy findings. A radial scar (otherwisetermed a complex sclerosing lesion) may be

Figure 5

Figure 6

Figure 7

DIAGNOSTIC EXCISION BIOPSY 113


associated with a tubular carcinoma in up to20% of cases (11). A radial scar is not apremalignant lesion, but when atypical hyper-plasia coexists, the relative risk for developingcancer is increased sixfold. As radial scars canbe difficult to distinguish from a carcinomaradiologically, all must be excised. When atyp-ical ductal hyperplasia is diagnosed onconventional core biopsy, DCIS (ductalcarcinoma-in-situ) will be found on excisionbiopsy in 40% to 50% of cases (12). Thisfigure is much reduced for mammotomebiopsy where the larger volume of tissueretrieved is more likely to contain DCIS(12). Though the term lobular neoplasia isused to embrace both atypical lobular hyper-plasia and LCIS, these two lesions should bedistinguished histologically as they possessdifferent risk factors for subsequent develop-ment of malignancy. Both are considered tobe markers of risk rather than precursorlesions of breast cancer. The absolute riskfor development of invasive cancer is 8%and 10% at 15 years for atypical lobularhyperplasia and 25% to 30% at 15 to20 years for LCIS (13,14). Patients with adiagnosis of lobular neoplasia on excisionbiopsy require mammographic surveillancewith annual mammography until the age of50 years and thereafter interimmammographyat 18 months within the NHS Breast ScreeningProgramme (normally triennial screens).

Columnar cell change involves dilatationof the terminal duct lobular unit with pres-ervation of two cell layers. Cytological atypiais usually low grade and is an indication forexcision biopsy. Some authorities recom-mend careful mammographic surveillancefor patients with columnar cell change andatypia on excision biopsy. However, the riskof developing an invasive breast cancerappears to be very low.

Related Cases

Diagnostic excision biopsy—Case Study 15

Learning Points

1. If atypia is found on core biopsy of amammography abnormality, then aneedle-localized excisional biopsy is gen-erally recommended because up to 50%

of these patients may harbor occultDCIS or invasive cancer.

2. Although frequent surveillance (withmammography) is often recommendedfor women with atypia on breast biopsy,there is no evidence to suggest that thisreduces breast cancer mortality.

3. Atypia increases the risk of breast cancer,and chemoprevention with tamoxifen(20 mg/day for 5 years) substantiallyreduces that risk. In clinical trials, tamox-ifen has been shown to reduce the risk ofdeveloping breast cancer by about 50%,but this has not translated to a reductionin breast cancer mortality.

References

1. American College of Radiology. Breast ImagingReporting and Data System (BIRADS). 2nd ed.Reston, VA: American College of Radiology, 1995.

2. Gallagher WJ, Cardenosa G, Rubens JR, et al.Minimal-volume excision of non-palpable breastlesions. AJR Am J Roentgenol 1989; 153:957–961.

3. Dronkers DJ. Stereotactic core biopsy of breastlesions. Radiology 1992; 183:631–634.

4. Britton PD, McCann J. Needle biopsy in the NHSBreast Screening Programme: how much and howaccurate? Breast 1999; 8:5–11.

5. Britton PD, Flower CDR, Freeman AH, et al.Changing to core biopsy in an NHS breast screen-ing unit. Clin Radiol 1997; 52:764–767.

6. Helbich TH, Matzek W, Fuchsjager MH. Stereo-tactic and ultrasound-guided breast biopsy. EurRadiol 2004; 14:383–393.

7. Liberman L, Dershaw DD, Rosen PP, et al. Stereo-taxic 14-gauge breast biopsy: how many core biopsyspecimens are needed? Radiology 1994; 192:793–795.

8. Parker SH, Burbank F, Jackman RJ, et al. Percuta-neous large-core breast biopsy: a multiinstitutionalstudy. Radiology 1994; 193:359–364.

9. Burbank F. Stereotactic breast biopsy of atypicalductal hyperplasia and ductal carcinoma in situlesions: improved accuracy with directional,vaccum-assisted biopsy. Radiology 1997; 202:843–846.

10. Jackman RJ, Nowels KW, Rodriguez-Soto J, et al.Sterotactic, automated, large-core needle biopsy ofnonpalpable breast lesions: false-negative and his-tologic underestimation rates after long term fol-low up. Radiology 1999; 210:799–805.

11. Linell F. Precursor lesions of breast carcinoma.Jackman RJ, Nowels KW, Rodriguez-Soto J, et al.Sterotactic, automated, large-core needle biopsy ofnonpalpable breast lesions: false-negative and his-tologic underestimation rates after long term fol-low up. Breast 1993; 203:202–205.

12. Jackman RJ, Burbank, Parker SH, et al. Atypicalductal hyperplasia diagnosed at stereotactic breast

114 CHAPTER 5


biopsy: improved reliability with 14 gauge, direc-tional, vaccum-assisted biopsy. Radiology 1997;204:485–488.

13. Rosen PP. Lobular carcinoma in situ and atypicallobular hyperplasia. In: Rosen's Breast Pathology.

Philadelphia: Lippincott Williams and Williams,2001:527–538.

14. Page DL, Steel CM, Dixon JM. Carcinoma in situand patients at high risk of breast cancer. Br Med J1995; 310:39–42.

DIAGNOSTIC EXCISION BIOPSY 115


6Bilateral Breast Cancer

CASE STUDY 22

History

A 52-year-old woman presented with a six-month history of hardening and change inconsistency of the left breast. She had noticedthis while “comfort feeding” her child andover the preceding six weeks had beenaware of several red nodules overlying theleft breast (which she described as “mosquitobites”). Furthermore, there had been a pro-gressive change in shape of the left breast,though no discrete lump or nipple dischargewas reported. There were no previous breastproblems except for an episode of mastitis inthe past. The patient’s maternal grandmotherhad developed breast cancer in her 70s, andshe had four children all of whom were breast-fed (first child at age 34 years). The patientwas perimenopausal and had never used anyform of exogenous hormonal preparation.

Clinical Findings

Examination revealed gross changes in theleft breast; the whole of the breast hadundergone generalized contracture and alarge mass was palpable in the central por-tion of the left breast measuring at least 7 cmin maximum diameter. This was associatedwith nipple retraction and skin dimpling. Inaddition, there were multiple cutaneousdeposits overlying the left breast and extend-ing toward the inframammary fold. Severalclinically suspicious, but mobile, nodes werepalpable in the left axilla (E5) (Fig. 1).

Clinical Assessment

Large clinical carcinoma of the left breast,which was locally advanced rather thaninflammatory (no erythema).

Investigations

Mammography

Bilateral mammography revealed a spiculatemass in the upper inner quadrant of the leftbreast measuring 27 mm in maximumdimension (R5) (Fig. 2A, B). Diffuse thick-ening of the skin was noted, and on the rightside, architectural distortion was apparent inthe inner half of the breast on the cranio-caudal view (R4) (Fig. 2C, D).

Breast Ultrasound

The sonographic correlate of the spiculatemass in the left breast was a 26-mm hypo-echoic, poorly defined lesion with posterioracoustic shadowing (U5) (Fig. 3A). A furthersuspicious area measuring 15 mm was seenin the upper outer quadrant (Fig. 3B).Finally, a hypoechoic lesion measuring20 mm was seen in the upper inner quadrantof the right breast (U5) (Fig. 3C).

Core Biopsy

Image-guided core biopsy (14-gauge needle)of both lesions in the upper outer and inner

Figure 1

116


Figure 2

Figure 3

BILATERAL BREAST CANCER 117


quadrants of the left breast revealed invasiveductal carcinoma (grade II, ER positive)[Fig. 4A (low power), B (high power)].Core biopsy of a single tumor focus in theupper inner quadrant of the right breastrevealed an invasive lobular carcinoma(grade II, ER positive) [Fig. 5A (lowpower), B (high power)]. HER2 testing wasnot routinely performed on core biopsyspecimens at the time of diagnosis.

Diagnosis

Bilateral breast cancer; locally advanced andmultifocal with possible inflammatory com-ponent on the left side (T4N1); early-stagebreast cancer on the right side (T2N0).


Following multidisciplinary discussion, it wasrecommended that the patient undergo neo-adjuvant chemotherapy and subsequent

bilateral modified radical mastectomy (with-out immediate breast reconstruction). Thepatient would likely require radiotherapy tothe left chest wall (and possibly supraclavic-ular fossa) and hormonal therapy aftercompletion of chemotherapy. Staging inves-tigations were requested to exclude distantdisease.


1. Isotope bone scan—no evidence of bonymetastases

2. CT scan (chest, abdomen, pelvis)—no evidence of pulmonary or hepaticmetastases

3. HER2 status—negative


The patient underwent four cycles of com-bination chemotherapy with epirubicin and

Figure 4

Figure 5

118 CHAPTER 6

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cyclophosphamide followed by four cycles ofa taxane (EC/docetaxel—see Appendix III).This was tolerated well with minimal sideeffects [mild nausea, constipation (grade I)],and repeat imaging with ultrasound afterthree cycles of EC showed a good tumorresponse in both breasts. On the left sidethe larger lesion in the upper inner quadranthad reduced in size to 21.4 mm (from26 mm) (Fig. 6A) and the smaller one inthe upper outer quadrant to 12.5 mm (from15 mm). The enlarged nodes in the left axillahad also shrunk in size significantly frominitial measurements of 25 mm, 17 mm, and14 mm to 19 mm, 10.5 mm, and 7 mm,respectively (Fig. 6B). An area of poorlydefined shadowing corresponded to thelesion in the right breast that no longer hada distinct radiological correlate.

After completion of the seventh cycle ofchemotherapy (EC � 4 cycles, docetaxol � 3cycles), no further reduction in tumordimensions was evident on the left side.The tumor in the right breast was invisibleat this stage. The patient proceeded to sur-gery six weeks after completion of the eighthand final cycle of chemotherapy (Fig. 7):

1. Left—modified radical mastectomy withlevel III axillary lymph node dissectiona

2. Right—modified radical mastectomywith level II axillary lymph nodedissection

On the left side a very wide skin excisionwas performed to encompass areas of skin

previously involved clinically. Primary clo-sure was achieved and both mastectomywounds healed well with only moderateseroma formation (requiring aspiration)(Fig. 8).

Figure 6

aIntraoperative evidence of gross disease at level II.

Figure 7

Figure 8




1. Left: An invasive ductal carcinoma(grade II) measuring 55 mm in maxi-mum extent and clear of all resectionmargins [Fig. 9A (magnification 10�), B(magnification 20�)]. Nine out of14 lymph nodes contained metastatictumor [Fig. 9C (magnification 10�)]and there was extensive lymphovascularinvasion [Fig. 9D (magnification 10�)].

2. Right: An invasive lobular carcinoma(grade II) measuring 40 mm in maxi-

mum extent. All resection margins wereclear of tumor and only 1 out of13 lymph nodes contained metastatictumor (despite extensive lymphovascu-lar invasion) [Fig. 10A (low power), B(high power)].


Following further discussion, it was recom-mended that the patient receive bilateralchest wall radiotherapy together with irradi-ation of the left supraclavicular fossa (40 Gy

Figure 9

Figure 10

120 CHAPTER 6


in 15 fractions to the right and left chestwalls and a similar dose to the supraclavicu-lar fossa). The decision to irradiate the rightchest wall was based on final pathologicaltumor size and nodal status. Involvement of�4 nodes on the left side reinforced theprevious anticipation of left supraclavicularfossa irradiation. The patient was not eligiblefor Herceptin (HER2 negative), but shouldreceive an aromatase inhibitor as a compo-nent of adjuvant hormonal therapy (highrisk of locoregional relapse).

Discussion

Despite being at the lower age range for theNHS Breast Screening Programme, thispatient presented with a large, locallyadvanced cancer of the left breast and wasfound to have an incidental contralateralbreast cancer. She had a weak family historyof breast cancer and though she had fourchildren (all breast-fed) she bore her firstchild at the relatively late age of 34 years. It isperhaps surprising that she had not becomeconcerned about the lesion in her left breastat an earlier stage. Though several cutane-ous nodules were evident, there was noerythema or edema of the breast and thetumor was therefore considered to be locallyadvanced rather than inflammatory. Theclinical distinction between a locallyadvanced and inflammatory carcinoma canbe difficult, and these may not representdistinct clinicopathological entities, but anadvanced breast cancer continuum with apoor prognosis and high risk of locoregionalrelapse (1). Nonetheless, the patient wasadvised against immediate breast reconstruc-tion because of the high risk of locoregionalrelapse (clinically node-positive disease).The left-sided tumor was not only locallyadvanced but also multifocal and mandatedmastectomy following induction chemother-apy. The right-sided tumor was unifocal and<3 cm in maximum diameter. However, inview of the lobular phenotype and the syn-chronous left-sided tumor, bilateral mastec-tomy was recommended. The patientaccepted this decision and had a very posi-tive outlook to her management plan. Theleft-sided tumor was successfully downstaged

clinically, which facilitated surgical extirpa-tion. Though the residual tumor size was55 mm, this was clear of all resection mar-gins. The right-sided tumor had been under-estimated in size on ultrasound with a finalsize of 40 mm. This justified the decision toperform a mastectomy on that side. Therewas bilateral nodal involvement and there-fore axillary dissection was also indicated onthe right side (clinically node negative).Bilateral axillary dissection can be associatedwith significant morbidity and sentinel nodebiopsy should be offered wherever appropri-ate. Bilateral arm lymphedema can be verydisabling for patients and restrict dailyactivities.

There was a clear indication for irradia-tion of the left chest wall and supraclavicularfossa based on the extent of nodal involve-ment (�4 nodes) (2). The decision to irra-diate the right chest wall was based on thetumor size, extensive lymphovascular inva-sion, and the presence of one to three pos-itive nodes. The latter is not an absoluteindication for inclusion of a supraclavicularfield, and the American Society of ClinicalOncology guidelines (2) conclude that thereis insufficient evidence to make a recom-mendation on this issue, which is currentlybeing investigated in the SUPREMO trial(3).

The patient was not eligible for Herceptin(HER2 negative), but both tumors were ERpositive. Arimidex (upfront) was prescribedas adjuvant hormonal therapy as the patientwas considered to be at high risk for locore-gional relapse. The optimum strategy forincorporation of aromatase inhibitors intostandard adjuvant endocrine schedulesremains unclear. Benefits in terms ofdisease-free and overall survival must be bal-anced against longer-term risks (bonehealth, cognitive function) and costs. Theevidence available at the present time favorsan early switch policy for the majority ofpatients with hormone receptor–positivepostmenopausal breast cancer. The absolutebenefits of an aromatase inhibitor for theaverage patient are very small in the first36 months and some argue that the addi-tional benefit of an aromatase inhibitor inthe first two to three years is difficult to



justify. Fewer than 5% of patients have earlyrelapse in the first two to three years whilereceiving tamoxifen as adjuvant therapy.However, an upfront aromatase inhibitormight be indicated in those patients (suchas in this case) at higher risk of relapse forwhom the amplitude of the hazard peak forrecurrence is proportionately greater inmagnitude (4,5). Though interim results ofthe BIG 1-98 study reveal greater benefitfrom aromatase inhibitors for node-positivepatients (6), the converse is true for theATAC study (7). Moreover, patients withhigher-grade tumors derive no additionalbenefit from upfront aromatase inhibitorsand there is no conclusive evidence forHER2 status being predictive of response toaromatase inhibitors.

Related Cases

Bilateral breast cancer—Case Studies 23, 24,and 32

Mastectomy without reconstruction—CaseStudies 1, 2, and 20


Taxane-based neoadjuvant chemotherapy—Case Studies 25, 26, 27, 28, and 29

Postmastectomy radiotherapy—Case Studies2, 3, 26, and 28

Learning Points

1. Approximately 1.2% of all breast cancerpatients present with synchronous bilat-eral disease. This underscores the needfor a bilateral diagnostic mammogramin the evaluation of all women withprimary breast cancer. Recently, someinvestigators have argued for the use of

breast MRI in the evaluation of womenwith primary breast cancer, whichincreases the detection of bilateral syn-chronous cancers.

2. Preoperative chemotherapy is alsoreferred to as “induction,” “neoadju-vant,” or “primary systemic” chemother-apy. It is widely utilized in women withlocally advanced or inflammatory breastcancer and reduces the tumor burdenin these women, thereby facilitatingmastectomy.

3. Many surgeons advise against immediatebreast reconstruction for women withlocally advanced or inflammatory breastcancer, because the risk of locoregionalrecurrence is relatively high.

References

1. Gluck S. Inflammatory breast cancer. Miami BreastCancer Conference, Orlando, Florida, 2008.


3. NHS Scotland. Selective use of postoperativeradio-therapy after mastectomy. Available at: www.supremo-trial.com. Accessed November 17, 2008.

4. Howell A. ATAC trial update. Lancet 2005;365:1225–1226 (letter).

5. Benson JR, Ravisekar O. Aromatase inhibitors inthe treatment of breast cancer. Curr Cancer TreatRev 2007; 3:67–79.

6. Coates AS, Keshaviah A, Thurlimann B, et al. Fiveyears of letrozole compared with tamoxifen asinitial adjuvant therapy for postmenopausalwomen with endocrine-responsive early breast can-cer: update of study BIG 1-98. J Clin Oncol 2007;25:486–492.

7. ATAC Trialists Group. Effect of anastrozole andtamoxifen as adjuvant treatment for early stagebreast cancer: 100 month analysis of the ATACtrial. Lancet Oncol 2008; 9:45–53.

CASE STUDY 23

History

A 37-year-old professional woman presentedwith a four-week history of a painless lump inthe right breast, which had slightly decreased

in size. There was no associated nipple dis-charge and the patient had no previousbreast problems. Her maternal grandmotherhad developed breast cancer in her 40s andher paternal grandmother had the disease at

122 CHAPTER 6


the age of 79 years. The patient was nullipar-ous and had used the oral contraceptive pillfor a cumulative period of 15 years.

Clinical Findings

On examination there was an area of focalnodularity in the upper outer quadrant ofthe right breast with the impression of amore dominant lump. There was no skintethering or axillary lymphadenopathy (E3)(Fig. 11).

Clinical Assessment

The history of a lump, which had decreasedin size, was suggestive of a benign breastcondition, although clinical examinationwas suspicious of malignancy.

Investigations

Mammography

Two clusters of fine microcalcification wereseen in the right breast, one of whichcoincided with the clinical abnormality(Fig. 12A, B).

Breast Ultrasound

Ultrasound revealed an area of altered tex-ture in the upper outer quadrant of the rightbreast measuring approximately 3 cm (U4)(Fig. 13).

Core Biopsy

Ultrasound-guided core biopsy (14-gaugeneedle) of the right breast mass confirmedan invasive carcinoma with mucinous fea-tures (grade II, ER positive, HER2 negative).No in situ component was seen on corebiopsy [Fig. 14A (low power), B (highpower)].

Diagnosis

Early-stage right breast cancer (T2N0)


Neither mammography nor ultrasound pro-vided clear information on the dimensions ofthe tumor in the right breast (approximately

Figure 11

Figure 12



3 cm). MRI examination of the breasts wasrecommended to clarify the extent of thelesion, which was otherwise borderline con-servable. In the event that the lesion

exceeded 3 cm in maximum size, then eithera right-modified radical mastectomy (+/�immediate reconstruction) or possibly neo-adjuvant chemotherapy would be indicated.


MRI Examination

This upstaged the right breast tumor to amaximum diameter of 4.1 cm (Fig. 15). Fur-thermore, two lesions with high intensity sig-nals were evident in the left breast (Fig. 16).The larger of these measured 7 mm and lay inthe upper outer quadrant of the left breast.The smaller lesion (4.5 mm) lay relatively closeto the nipple-areolar complex.

Figure 13

Figure 14

Figure 15

124 CHAPTER 6


Core Biopsy

Ultrasound-guided core biopsy (14-gaugeneedle) of the 7-mm lesion revealed aninvasive carcinoma (grade II, ER positive,HER2 negative) [Fig. 17A, B (low power),C (high power)] while biopsy of the smallerlesion yielded benign tissue only.


The patient had confirmed bilateral breastcancer with a large, unifocal tumor on theright and a probable multicentric tumor onthe left (though not proven histologically).Treatment options included bilateral mas-tectomy with an axillary clearance on the

Figure 16

Figure 17



right (tumor >4 cm) and some form ofaxillary sampling on the left (aggregatetumor size 11.4 mm). Alternatively, neoadju-vant chemotherapy could be offered thatmay permit breast conservation on theright side after downstaging. It was notedthat the patient was relatively young with afamily history of breast cancer that wouldfavor complete mastectomy rather than widelocal excision on the right whatever the res-ponse to chemotherapy may be. Staging inves-tigations with CT scan of chest/abdomen/pelvis and bone scan were requested.


The patient was very keen to avoid mastec-tomy if at all possible and preferred toembark on neoadjuvant chemotherapy withthe possibility of breast preservation (on theright). Moreover, she wished to explore ovar-ian protection with an LHRH (luteinizinghormone releasing hormone) analogue(Zoladex) as she had not yet borne any chil-dren. Staging investigations revealed no evi-dence of distant metastatic disease and thepatient was commenced on a regimen of fourcycles epirubicin/cyclophosphamide fol-lowed by four cycles of docetaxel (see Appen-dix III). She tolerated chemotherapy wellwith mild (grade II) nausea, fatigue, andindigestion. An ultrasound performed afterthe third cycle chemotherapy showed a par-tial tumor response on the right side. Thebiopsy proven lesion in the upper outer quad-rant of left breast could no longer be seen onultrasound, but the smaller 4-mm lesion (notbiopsy proven cancer) was still present.

Following the seventh cycle of chemother-apy, the patient had a further consultation todiscuss surgical management. Though theright breast cancer had reduced to a sizethat permitted conservation, there were twopotential tumors in the contralateral breast.One of these had disappeared radiologicallyin response to chemotherapy.

It was recommended that the patientundergo bilateral mastectomy (with or withoutimmediate reconstruction) with an axillaryclearance on the right side and an axillarysampling on the left side. The patient was inagreement and did not wish to undergo treat-

ment for either recurrent or de novo treat-ment in the future. She requested immediatebreast reconstruction and was referred to theplastic surgeons for discussion of reconstructiveoptions. The patient had size 36C cup breastsand was of slim build; she had inadequateinfraumbilical abdominal tissue for a bilateral“split” TRAM (transverse rectus abdominusmyocutaneous flap) and was therefore suitablefor either a bilateral procedure with implantonly or latissimus dorsi myocutaneous flap withan implant. The patient expressed a desire tohave a “good and normal” result as possibleand therefore opted for the latter. She wasinformed that this was a major surgical inter-vention and could be associated with muchpostoperative pain and discomfort (from bilat-eral donor sites on the back).

The patient proceeded with surgery sixweeks after completion of chemotherapy. Bilat-eral skin-sparing mastectomies were carried outwith the nipple-areolar complex replaced by adisc of skin from the back (skin island paddleon myocutaneous flap). A formal level II axil-lary lymph node dissection was performed onthe right and a BDANS (blue dye-assisted nodesampling). McGhan style 150 implants wereused for reconstruction in conjunction with 2latissimus dorsi flaps. The patient made an excel-lent postoperative recovery and was well enoughto attend her brother’s wedding two weeks later.


Chemotherapy changes relating to neoadju-vant therapy were evident on the right side(Fig. 18A) with an area of residual highnuclear grade DCIS (ductal carcinoma insitu) measuring 22 m in maximum extent[Fig. 18B (magnification 10�), C, D (magni-fication 20�)]. There was no residual inva-sive disease and no lymphovascular spaceinvasion, but lakes of mucin were seen(Fig. 18E). None of the 15 lymph nodes onthe right side contained metastatic carci-noma, and there was no suggestion of down-staging secondary to chemotherapy. On theleft side there was no evidence of any resid-ual invasive or in situ disease, and the lymphnodes sampled were free of tumor. Thetumors from both breasts were ER positiveand HER2 negative on core biopsy.

126 CHAPTER 6



It was recommended that the patient con-tinue with the LHRH analogue Zoladex fora total period of three years followed bytamoxifen for five years. The patient wishedto conceive in the future and laparoscopicoophorectomy was declined. Moreover, therewas no indication for chest wall radiotherapyin the absence of any evidence of extensivenodal involvement at the outset or followingchemotherapy (HER2 negative).


There was a minor degree of capsular con-tracture on clinical review at six months.

Otherwise there was an excellent cosmeticresult (Fig. 19). However, there was discussionof possible implant exchange on the right sideat the time of nipple reconstruction.

Discussion

This young patient with bilateral synchronoustumors had several risk factors for breast can-cer, including family history, nulliparity, andprolonged usage of the oral contraceptive pillprior to any pregnancy (1). The patient pre-sented with unilateral symptoms on the rightside, and the mammographic and ultrasoundabnormalities were confined to the ipsilateralside. The left-sided lesions were detected onMRI examination, which was undertaken

Figure 18

Figure 19



primarily to clarify the extent of the tumor inthe right breast that had ill-defined marginson routine imaging (2). However, for thosepatients deemed to be at higher risk for devel-opment of breast cancer, MRI examinationhas an important role in screening the con-tralateral breast (3). Bilateral breast cancerhas an incidence of approximately 4%, andone-third of tumors are synchronous and two-thirds metachronous (4, 5). Younger women(<50 years) have been reported to have a 10-to 14-fold higher risk of developing contrala-teral cancers than the general population.Had this patient not undergone MRI exami-nation for investigation of the ipsilateraltumor, it is likely that these small impalpableleft-sided tumors would have presented clini-cally at a future date as metachronous cancer(alternatively they could have been detectedradiologically on routine follow-up mammog-raphy to the contralateral breast). Thisincreased risk of bilaterality strengthens theargument for undertaking MRI examinationin all younger women presenting with unilat-eral breast cancer.

This patient could have been managedwith primary surgery at the outset. Thiswould have necessarily involved bilateral mas-tectomy on the basis of tumor size on theright and multifocality on the left. Neoadju-vant chemotherapy offered the potential fordownstaging the right-sided tumor to permitbreast conservation (6,7). Surgical evaluationafter the seventh cycle of chemotherapy sug-gested that this was technically feasible. How-ever, in view of the patient’s relatively youngage, family history of breast cancer, and theneed for contralateral mastectomy, a right-sided mastectomy was recommended.

The patient was of slim build, and imme-diate reconstruction could have been donewith an implant-only technique. When car-ried out as a simultaneous bilateral proce-dure, subpectoral placement of implants cancreate a good cosmetic result with symmet-rical breasts, matched for size and shape (8).However, the patient wished to have the bestchance of a “normal-looking breast” andopted for autologous tissue transfer. Therewas inadequate infraumbilical tissue for asplit TRAM flap and therefore bilateral lat-issimus dorsi flaps were raised and used in

conjunction with implants as the reconstruc-tive method of choice. There was also apossibility that radiotherapy to the rightchest wall might be required.

Facilities for radioisotope usage were notavailable; sentinel lymph node biopsy withdual localization was not possible. On thebasis of the original tumor size on the rightside, a level II axillary dissection was per-formed. Both tumors visualized in the leftbreast on MRI were small (7 mm and4.5 mm). The chance of nodal involvementon this side was low and a blue dye–assistednode sampling was carried out.

Definitive histology revealed a completepathological response bilaterally in respect ofinvasive carcinoma. Often there is residualDCIS as this is less responsive to inductionchemotherapy (lower rate of cell cycling)(9). Furthermore, there was no suggestionthat any of the axillary nodes on the rightside had previously been involved by tumorand subsequently downstaged by chemother-apy. The patient elected to have ovariansuppression with an LHRH analogue, whichwould potentially allow restoration of ovarianfunction in the future. This case illustratesthe increasing problem of professionalwomen developing breast cancer prior toconception. Childbearing is deferred due tocareer commitments, and women are facedwith a diagnosis of breast cancer while nulli-parous or possibly during pregnancy.

Related Cases


Immediate breast reconstruction—Case Studies3, 16, 17, 18, and 37

Blue dye–assisted node sampling—Case Study8

Neoadjuvant chemotherapy—Case Studies27–29

Ovarian suppression—Case Studies 8 and 27

Learning Points

1. Breast MRI has been increasingly utilizedin the evaluation of women with primarybreast cancer. In about 3% of all women

128 CHAPTER 6


with primary breast cancer, MRI willdetect lesions in the contralateral breastthat are not evident on mammography.The wider use of breast MRI may there-fore increase bilateral mastectomy rates.

2. There is mounting evidence to suggestthat the anthracylines (epirubicin anddoxorubicin) are primarily effective inpatients with HER2-positive tumors.Thus, its use in women with HER2-negative tumors may diminish in theyears ahead.

3. Important information on primarytumor characteristics might be lost fol-lowing preoperative chemotherapy. Forinstance, node-positive tumors mightconvert to node-negative status. Thiscould potentially result in under treat-ment (e.g., postmastectomy radiother-apy might be withheld in patients withextensive nodal involvement who con-vert to node-negative status after preop-erative chemotherapy).

References

1. Sellers TA, Grabrick DM. The epidemiology ofbreast cancer. In: Jatoi I, ed. Manual of Breast

Diseases. Philadelphia: Lippincott Wilkins &Williams, 2002:149–175.

2. Kumar NA, Schnall MD. MR imaging: its currentand potential utility in the diagnosis and manage-ment of breast cancer. Magn Reson Imaging ClinN Am 2000; 8:715–728.

3. Lehman CD, Gatsonis C, Kuhl CK, et al. MRIevaluation of the contralateral breast in womenwith recently diagnosed breast cancer. N Engl JMed 2007; 356:1295–1303.

4. Wanebo HJ, Senofsky GM, Fechner RE, et al.Bilateral breast cancer: risk reduction of contrala-teral biopsy. Ann Surg 1985; 201:667–677.

5. Robbins GF, Berg JW. Bilateral primary breastcancers: a prospective clinicopathological study.Cancer 1964; 17:1501–1527.

6. Makris A, Powles TJ, Ashley SE, et al. A reduction inthe requirements for mastectomy in a randomizedtrial of neoadjuvant chemoendocrine therapy in pri-mary breast cancer. Ann Oncol 1998; 9:1179–1184.

7. Bonadonna G, Veronesi U, Brambilla C, et al.Primary chemotherapy to avoid mastectomy intumours with diameters of three centimeters ormore. J Natl Cancer Inst 1990; 82:1539–1545.

8. Nava M, Bonavita M, Arioli N, et al. Breast recon-struction with subpectoral prosthesis or tissueexpanders. In: Querci della Rovere G, Benson JR,Breach N, Nava M, eds. Oncoplastic and Recon-structive Surgery of the Breast. London: MartinDunitz, 2004 (ISBN 1 84184 351 2).

9. Fisher B, Brown A, Mamounas E, et al. Effect ofpreoperative chemotherapy on loco-regional diseasein women with operable breast cancer: findings fromthe National Surgical Adjuvant Breast and BowelProject B-18. J Clin Oncol 1997; 15:2483–2493.

CASE STUDY 24

History

An 81-year-old woman presented with a four-week history of a lump in the right breast.She had noticed some dimpling of the skinoverlying the lump, but no indrawing of thenipple or discharge therefrom. There was nofamily history of breast or ovarian cancer,and the patient had no previous breast prob-lems. She had never used any form of exog-enous hormones.

Clinical Findings

Examination revealed a hard irregular massin the upper outer quadrant of the rightbreast lying well away from the nipple-areolarcomplex. There was tethering of the over-lying skin, but the mass was mobile on the

chest wall. There was no axillary lymphaden-opathy (E4) (Fig. 20).

Clinical Assessment

The lesion in the right breast was highlysuspicious for malignancy.

Figure 20



Investigations

Mammography

An asymmetric density was apparent in theupper outer quadrant of the right breast. Thismeasured 25 mm in maximum extent andhad the features of a carcinoma (R5)(Fig. 21A, B). A further radiologically

suspicious lesion was seen in the lower innerquadrant of the left breast measuring 20 mmin maximum diameter (R5) (Fig. 21C, D).

Breast Ultrasound

The sonographic correlate of the rightbreast lesion was a 27-mm ill-defined hetero-genous mass with a hypoechoic pattern andposterior attenuation (U5) (Fig. 22A). A19-mm mass was seen in the left breast withsimilar ultrasound features (U5) (Fig. 22B).

Core Biopsy

Ultrasound-guided core biopsy of the rightbreast mass showed an invasive lobular car-cinoma (grade II) (Fig. 23A) while the left-sided lesion was an invasive ductal carci-noma (grade II). Both lesions were ER pos-itive and HER2 negative on core biopsy(Fig. 23B).

Diagnosis

Bilateral breast cancers: right (T2N0), left(T1N0).


Both breast cancers were potentially suitablefor breast-conserving surgery with bilateralwide local excision and sentinel lymphnode biopsy. In view of the left breast cancerbeing of the lobular phenotype and associ-ated with skin tethering, it was recom-mended that MRI imaging of the breasts beundertaken prior to surgery. On review of

Figure 21

Figure 22

130 CHAPTER 6


the mammogram, there was a suggestion of afurther opacity in the right breast lying sev-eral centimeters from the main index lesion.MRI examination of the breasts wasrequested to clarify the extent of the right-sided breast cancer and to further elucidatethe nature of the second opacity on the rightside, close to the index lesion. Bilateral axil-lary ultrasound and possible core biopsy wasalso recommended preoperatively.

Investigations

MRI Breasts

MRI examination revealed multifocal tumorsof both breasts; on the right side there weretwo enhancing lesions lying in separate quad-rants measuring 22.7 mm and 7.3 mm(Fig. 24A). These showed time-intensity curveswith malignant-type enhancement (Fig. 24B);on the left side a further lesion was seen

Figure 23

Figure 24

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lateral to the main tumor in the superioraspect of the breast (Fig. 24C). This alsodisplayed a malignant enhancement curve(Fig. 24D).

Axillary Ultrasound

Bilateral axillary ultrasound and core biopsyof axillary nodes revealed no evidence ofmalignancy.


The MRI had confirmed that both right andleft tumors were multifocal and thereforebilateral mastectomy and sentinel lymphnode biopsy were mandated.


The patient was keen to proceed with sur-gery as soon as possible and was issued withan operation date some eight days later. Atthe time of surgery, sentinel lymph nodebiopsy was carried out through the lateralend of the mastectomy incision, and therewere no suspicious nodes on intraoperativedigital examination. A wide skin ellipse was

performed on the right side to encompassthe area of skin tethering (Fig. 25).

The patient made an excellent postoper-ative recovery and was discharged home witha single drain each side on the third postop-erative day. There was extensive bruising ofthe chest wall, but no discrete hematoma.The patient developed bilateral seromas thatwere aspirated in the clinic.


Right: An invasive lobular carcinoma (gradeII) with the main index lesion measuring23 mm in maximum diameter (concordantwith radiological estimate) [Fig. 26A (low

Figure 25

Figure 26

132 CHAPTER 6


power), B (high power)]. There were severalsatellite foci and associated DCIS. One of thetwo sentinel lymph nodes harvested on theright contained a micrometastasis on stan-dard H&E sections (Fig. 26C), which wasconfirmed on staining with anticytokeratinCam5.2 antibody (Fig. 26D).

Left: An invasive carcinoma (grade II) ofmicropapillary subtype with associated highnuclear grade cribriform DCIS (with com-edo necrosis) [Fig. 27A (low power), B (highpower)]. The aggregate diameter of invasiveand noninvasive components was 21 mm,and there was evidence of lymphovascularinvasion. None of the four sentinel lymphnodes on the left side contained metastases.


It was recommended that the patient undergoa completion axillary lymph node dissectionon the right side on the basis of a focus ofmicrometastasis in one out of two sentinellymph nodes. Radiotherapy to the chest wallwas not indicated, and tamoxifen with anearly switch (2–3 years) to an aromatase inhib-itor was prescribed as adjuvant systemic hor-monal therapy NPI (Nottingham PrognosticIndex): (0.2 � 2.3) + 2 + 2 = 4.46].


It was explained to the patient that there wasa relatively low probability (~15%) of findingfurther disease in the nonsentinel nodes.Furthermore, at the age of 81 years, anycompletion axillary dissection was unlikely

to impact on either regional disease controlor overall survival. The patient initiallyaccepted the recommendation of the multi-disciplinary team and a date for further sur-gery was arranged. However, upon reflectionand discussion between the patient and herfamily, she decided not to proceed with for-mal axillary dissection. She was an otherwisefit and active person for her age and did notwish to risk incurring significant morbidityfrom further surgery.

Discussion

In a seminal study involving more than20,000 breast cancers, only 3.7% of caseswere found to be bilateral, of which one-third were synchronous and two-thirds weremetachronous (1). Though the incidence ofbilateral synchronous carcinoma is low(1.2%), this case illustrates the benefit ofMRI examination, which can detect notonly ipsilateral multifocal disease but alsoclinically occult contralateral breast cancer.The latter occurs in 4% to 8% of patientswith a prior carcinoma, and for youngerpatients, there is a greater chance of clinicalmanifestation in their remaining lifetime.Moreover, MRI is a more sensitive investiga-tion than mammography in the relativelydense breast tissue of premenopausalwomen (2). In the case described, MRIdetected multifocal disease in both breasts,which was not readily apparent on eithermammography or ultrasound examinationof the breasts. The threshold for undertak-ing breast MRI examination should be much

Figure 27



lower in younger patients. This elderlypatient was potentially faced with bilateralaxillary surgery for staging purposes. Withinthe older age group (�70 years), the risks ofaxillary surgery are proportionately greaterand the benefits less.

The disease-free survival of some olderpatients is unlikely to be improved by axillarysurgery when there are competing causes ofdeath and life expectancy is less. Similararguments for omission of axillary stagingapply to the issue of completion axillarydissection following a positive sentinellymph node biopsy. For some patients, therisk-benefit ratio for detection of nonsenti-nel lymph node–positive cases may not justifyany delayed procedure. The chance of non-sentinel lymph node involvement is relatedto the volume of disease in the sentinelnode; when only micrometastatic deposits(>0.2 mm and �2 mm) are present in thesentinel node, the risk of nonsentinel nodeinvolvement is 15% compared with 25% to50% for macrometastases (>2 mm) (3).Axillary recurrence remained relatively low(2% at 3 years follow-up) when completionaxillary dissection was selectively omitted in agroup of more than 200 sentinel node–positive patients who either refused axillarydissection or were considered to be at lowrisk of relapse (4). The low rates of axillaryrelapse are unlikely to translate into anymeaningful reduction in long-term survivalamong an older group of patients. The Cam-bridge Breast Unit has recently elected toomit completion axillary dissection in thefollowing group of patients:

– Micrometastases only in sentinel node– Age �70 years– Tumor size �3 cm– ER positive– Grade I or II (consider grade III)

The morbidity from further axillary sur-gery could be quite significant for this oldergroup of patients. It has been suggested thatthe lower age limit for this policy be reducedto 60 years (grade I and II, �2 cm). How-ever, some of the patients in this groupmight receive chemotherapy in the eventof further nodal involvement.

Related Cases


Preoperative MRI—Case Studies 6 and 8


Learning Points

1. The incidence of bilateral synchronousbreast cancers increased in the 1970s,soon after bilateral mammography wasintroduced for the evaluation of womenwith primary breast cancer. The inci-dence of bilateral breast cancers islikely to increase even further in theyears ahead, as the use of breast MRIincreases.

2. Axillary lymph node dissection decreasesthe risk of local (axillary) recurrences,but is associated with significantly greatermorbidity than sentinel node biopsyalone. Axillary recurrences are of lessconcern in the elderly because theyoften have tumors with a better prognosisand also because competing causes ofmortality might intervene before regionalrecurrence becomes a threat.

References

1. Wanebo HJ, Senofsky GM, Fechner RE, et al.Bilateral breast cancer: risk reduction of contrala-teral biopsy. Ann Surg 1985; 201: 667–677.

2. Warren R. New radiological techniques: digitalmammography, MRI scintimammography, PETand some more for ‘‘Tomorrow’s World’’. In:Querci della Rovere G, Warren R, Benson JR,eds. Early Breast Cancer. London and New York-Taylor and Francis, 2006: 175–199.

3. Cserni G, Gregori D, Merletti F, et al. Non-sentinelnode metastases associated with micrometastaticsentinel nodes in breast cancer: metaanalysis of25 studies. Br J Surg 2004; 91:1245–1252.

4. Naik AM, Fey J, Gemignani M, et al. The risk ofaxillary relapse after sentinel lymph node biopsyfor breast cancer is comparable with that of axillarylymph node dissection: a follow up study of 4008procedures. Ann Surg 2004; 240:462–471.

134 CHAPTER 6


7Inflammatory Breast Cancer

CASE STUDY 25

History

A 39-year-old woman presented to the breastclinic having noticed a reddened area overthe medial aspect of the right breast for thepreceding six weeks. The area was tender topalpation and the patient had been pre-scribed a course of antibiotics by her generalpractitioner. However, the erythematousarea failed to respond and indeed extendedto involve much of the right breast. Thepatient was not aware of any discrete lumpor change in consistency of the right breast.She was otherwise well and reported noweight loss or unusual cough or back pain.There had been no previous breast prob-lems, but there was a strong history of breastcancer in the family; her mother had beenrecently diagnosed with breast cancer in her60s and the patient's maternal grandmotherdied from bone secondaries relating to aprimary breast cancer. The patient had3 children (eldest aged 9 years) and under-went menarche at the age of 10 years. She hadused the oral contraceptive pill for a cumula-tive period of four years prior to her firstpregnancy and remained premenopausal.

Clinical Findings

Examination revealed gross swelling of theright breast with extensive erythema, edema,and peau d'orange. No discrete mass lesionwas palpable but the consistency of the rightbreast was much firmer than the left side.There was an ill-defined mass in the rightaxilla, which clinically may have representedeither lymphadenopathy or a mass in theaxillary tail of the right breast (E5) (Fig. 1).

Clinical Assessment

The history and findings were highly sugges-tive of an inflammatory carcinoma of theright breast. The patient was informed ofthe likely diagnosis and probable manage-ment with primary chemotherapy.

Investigations

Mammography

Extensive edema and thickening of the rightbreast tissue was evident with no focal masslesion (R5) (Fig. 2A, B).

Breast/Axillary Ultrasound

Sonographic assessment of the right breastcorroborated the mammographic findingsand showed edema of the tissues with nodiscernable mass lesion (Fig. 3A). Malignantappearing nodes were seen in the right axilla(U5) (Fig. 3B, C).

Figure 1

135


Core Biopsy

Ultrasound-guided core biopsy (16-gaugeneedle) of the right axillary mass confirmedan invasive carcinoma (grade III, ER nega-tive) [Fig. 4A (low power), B (high power)].Epithelial elements were more readily visual-ized on immunohistochemical staining withanticytokeratin antibody (5D3) comparedwith H&E staining (Fig. 5).

Diagnosis

Inflammatory cancer of the right breast in apremenopausal patient (T4dN1)


Following multidisciplinary discussion, it wasrecommended that full staging investigationsbe carried out, including chest X ray, liverfunction tests, calcium, CT chest/abdomen/pelvis, and bone scan. In the absence of anyevidence of distant metastases, the patientwould be offered neoadjuvant chemotherapyfollowed by a right modified radical mastec-tomy (without immediate breast reconstruc-tion) and irradiation of the chest wall andsupraclavicular fossa. HER2 status wasrequested as this was not routinely done oncore biopsy at time of this patient's diagnosis.


The patient commenced chemotherapywithin 10 days of tissue confirmation of a

Figure 2

Figure 3

136 CHAPTER 7


breast cancer diagnosis. She received fourcycles of epirubicin/cyclophosphamide fol-lowed by four cycles of taxanes (EC/doce-taxel—see Appendix III). The patienttolerated treatment well with partial resolu-tion of the inflammatory changes in theright breast and a complete clinical responsein respect of the right axillary nodes. Breastimaging with MRI after the eighth cycle ofchemotherapy revealed a mass lesion in theupper inner quadrant of the right breastmeasuring 4.2 cm. Interestingly, this wasthe first accurate measurement of thedimensions of the right breast cancer—atthe time of previous assessment, the marginsof the tumor were masked by the inflamma-tory component.

It was noted at the time of further breastimaging that some inflammatory changeshad developed in the contralateral breast,with erythema and peau d'orange (Fig. 6).However, there was no radiological evidence

of malignancy in the left breast on MRI(opinion of a second radiologist sought). Itwas proposed to carry out a skin biopsy of theleft breast at the time of definitive surgery ofthe right breast cancer or alternatively ran-dom core biopsies of the left breast (fan-shaped distribution). The patient proceededto a right modified radical mastectomy sixweeks after completion of the final cycle ofdocetaxel (blood counts satisfactory).

At the time of surgery, there was muchedema of the breast and evidence of someskin infiltration by tumor. A wide skin inci-sion was therefore performed together witha level III axillary lymph node dissection(macroscopic evidence of nodal disease inright axilla with at least two frankly malig-nant nodes).

The patient made an excellent postoper-ative recovery and arrangements were madefor core biopsies of the left breast to beundertaken prior to discharge home.

Figure 4

Figure 5

Figure 6

INFLAMMATORY BREAST CANCER 137



This revealed characteristic chemotherapyeffects at the site of the tumor [Fig. 7A(magnification 5�), B (magnification10�)], but extensive viable tumor was evidentwithin the right breast measuring 110 mm inmaximum diameter [Fig. 7C (low power), D(high power)]. There was also tumor inrandom sections taken from other parts ofthe breast with lymphovascular invasion ofdermal lymphatics. Thirteen out of 15 nodescontained metastatic carcinoma with extrac-apsular extension. All core biopsies takenfrom the left breast showed invasive carci-noma, which was metastatic from the rightbreast.


The patient had a very aggressive tumor,which had shown minimal response to che-motherapy with a taxane-containing sched-ule and had not only progressed within theipsilateral breast, but had also metastasizedto the contralateral breast. HER2 status waspositive and it was recommended the patientbe immediately commenced on Herceptin

following assessment of left ventricular ejec-tion fraction (LVEF) with a baseline echo-cardiogram. A repeat ultrasound scan of theliver showed no evidence of metastases. Itwas anticipated that locoregional controlwould be a potential problem; in additionto receiving radiotherapy to the right chestwall and supraclavicular fossa, considerationwould be given to primary radiotherapy ofthe left breast (depending on response toHerceptin).


The patient underwent irradiation of theright chest wall and supraclavicular fossawithin four weeks of surgery. She developeda right chest wall recurrence shortly aftercompletion of radiotherapy and was com-menced on capecitebine (concurrent withthree-weekly Herceptin). Further staging CTscan showed no evidence of distant metasta-ses. Almost 12 months following surgery, thepatient started a course of taxol combinedwith the antiangiogenic agent avastin (bev-acizumab). This was associated with grade IInausea and vomiting, which settled withondansetron. The patient otherwise remains

Figure 7

138 CHAPTER 7


generally well in herself and continues tobe active and to care for her three youngchildren.

Discussion

Inflammatory carcinoma is one of the mostaggressive forms of breast cancer, which his-torically constitutes about 1% to 5% of allbreast cancers and has been associated witha poor prognosis (1,2). It is a form of locallyadvanced breast cancer, though it remainsunclear whether these reflect an advancedbreast cancer continuum or represent dis-tinct clinicopathological entities. Inflamma-tory cancers are usually high-grade lesionswith fewer than half staining positive foreither ER or PR. Between 30% and 50%overexpress HER2 together with e-cadherinand p53. With single modality therapies, thefive-year survival rate for surgery alone was2% to 10% and not much better for primaryradiotherapy (3%) (2). Multimodality ther-apy with a combination of chemotherapy,radiotherapy, and surgery has significantlyimproved both local control and disease-free survival (approximately 50% 5-year sur-vival) (3–5). The majority of patients withinflammatory carcinoma are in the youngerage group and are managed with a sequenceof primary chemotherapy followed by mas-tectomy (with axillary dissection) and irradi-ation of the chest wall and supraclavicularfossa. The latter reduces locoregional recur-rence by two-thirds. Those patients who areHER2 positive receive Herceptin and mostchemotherapy regimens incorporate a tax-ane. Many surgeons are reluctant to offerimmediate breast reconstruction to thisgroup because of the relatively high risk oflocoregional relapse. Delayed reconstructionmay be considered if patients are alive anddisease-free after 18 to 24 months. Whenthere is overt evidence of tumor progressionafter initial chemotherapy, patients can betreated with radiotherapy prior to surgery.

Complete staging investigations should becarried out prior to initiation of chemother-apy as these patients have a high risk ofdistant metastases. Moreover, treatmentplanning for this group of patients must beundertaken in a multidisciplinary setting

with surgeon, radiation, and medical oncolo-gist. Patients with a complete clinicalresponse to initial chemotherapy have adisease-free survival rate of almost 50% at15 years compared with only 9% for thosewith a partial response (6). Inflammatorybreast cancer can be mistaken clinically fora benign inflammatory condition of thebreast such as periductal mastitis or a breastabscess. This patient's general practitionerhad initially prescribed a course of antibioticsand it was the failure to respond to these thatprompted referral to a breast unit. Thepatient had not noticed any lump or changein consistency of the breast herself, thoughclinical examination revealed marked eryth-ematous changes with edema, peau d'orange,and a generalized firmness of the breast.Breast imaging likewise failed to show anyfocal mass lesion, but revealed extensiveedema and thickening of the breast tissue.A mass lesion subsequently became evidenton MRI after the final cycle of chemotherapy;the inflammatory components of the tumorhad precluded assessment of margins at thetime of previous breast imaging.

A variety of preoperative chemotherapyschedules have been employed for treatmentof inflammatory breast cancer. Most of theseincorporate an anthracycline (doxorubicinor epirubicin) with complete and partialresponse rates averaging 12% and 60%,respectively (7,8). It is better to switch to ataxane than continuing with chemotherapy.If there is no response to an anthracycline-based chemotherapy, then patients shouldswitch to docetaxol (4 cycles). In this partic-ular case, the standard preoperative scheduleof EC/docetaxel was used though a relatedschedule is eight cycles of TAC (docetaxel,adriamycin, and cyclophosphamide). Therewas only minimal response to chemotherapyand the tumor not only progressed within theipsilateral breast but had metastasized to thecontralateral breast. Further systemic therapyincluded Herceptin together with capecite-bine for chest wall recurrence postmastec-tomy. The patient subsequently receivedtaxol combined with an antiangiogenicagent. This case illustrates the potential prob-lems with local control for inflammatory can-cers when patients have not succumbed from

INFLAMMATORY BREAST CANCER 139SW

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distant disease. Occasionally uncontrolledlocal disease can lead to “cancer en cuir-asse,” which can restrict respiratory move-ments and be very distressing for the patient.The histopathological features of the rightbreast cancer were typical for an inflamma-tory carcinoma; high grade, ER negative,and HER2 positive with extensive infiltrationof lymphovascular spaces, dermal lym-phatics, axillary nodes, and extranodal fattytissue. In addition, the tumor had metasta-sized throughout much of the contralateralbreast. The presence of dermal lymphaticinvasion does not predict response to treat-ment. Refractory cases of inflammatorybreast cancer can be managed with thetyrosine kinase inhibitor, lapatinib, which isa dual inhibitor of both EGFR and HER2,though in reality functions mainly as aninhibitor of HER2 (9).

Related Cases

Inflammatory breast cancer—Case Study 26

Taxane-based neoadjuvant chemotherapy—Case Studies 25–29

Herceptin—Case Studies 8, 11, 26, and 27

Postmastectomy radiotherapy—Case Studies2, 3, 26, and 28

Learning Points

1. Inflammatory breast cancer is the mostaggressive manifestation of primarybreast cancer. These patients are treatedwith neoadjuvant (preoperative) che-motherapy, which generally includesanthracyclines and taxanes. This is fol-lowed by locoregional treatment (mas-tectomy and radiotherapy) and then

hormonal intervention for those withER-positive disease.

2. A pathological complete response (pCR)indicates no histological evidence oftumor after neoadjuvant chemotherapy.pCR is a favorable prognostic factor, andthese patients have better survival rates.

References

1. Levine PH, Steinhorn SC, Ries LG, Aron JL. Inflam-matory breast cancer: the experience of the Surveil-lance, Epidemiology and End Results (SEER)program. J Natl Cancer Inst 1985; 74:291–297.

2. Jaiyesimi IA, Buzdar AU, Hortobagyi GN, et al.Inflammatory breast cancer: a review. J ClinOncol 1992; 10:1014–1024.

3. Pisansky TM, Schaid DJ, Loprinzi CL, et al. Inflam-matory breast cancer: integration of irradiation,surgery and chemotherapy. Am J Clin Oncol1992; 15:376–387.

4. Brun B, Otmezquine Y, Feuilhade F, et al. Treat-ment of inflammatory breast cancer with combina-tion chemotherapy and mastectomy versus breastconservation. Cancer 1988; 61:1096.

5. Fein DA, Mendenhall NP, Marsh RD, et al. Resultsof multimodality therapy for inflammatory breastcancer: an analysis of clinical and treatment factorsaffecting outcome. Ann Surg 1994; 60:220–225.

6. Hortobagyi GN, Buzdar AU. Treatment of meta-static breast cancer. In: Singletary SE, Robb GL,eds. Advanced Therapy of Breast Disease. Ontario:BC Decker Inc., 2000:281–289.

7. Rouesse J, Friedman S, Sarrazin D, et al. Primarychemotherapy in the treatment of inflammatorybreast cancer: a study of 230 cases from the InstituteGustave-Roussy. J Clin Oncol 1986; 4:1765–1771.

8. Smith IE, Walsh G, Jones A, et al. High completeremission rates with primary neoadjuvant infu-sional chemotherapy for large early breast cancer.J Clin Oncol 1995; 13:424–429.

9. Gluck S. Management of inflammatory breast can-cer. Miami Breast Cancer Conference, Orlando,Florida, 2008, February 20–23.

CASE STUDY 26

History

A 52-year-old woman underwent a routinescreening mammogram that showed a carci-noma of the left breast radiologically. Ondirect inquiry, the patient reported a lump

in the left breast, which had been present fora relatively short period of two weeks. Shehad no previous breast problems and nofamily history of breast or ovarian cancer.The patient had two children and was aged26 years at the birth of her first child. She

140 CHAPTER 7


had used the oral contraceptive pill for abrief period of 12 months.

Clinical Findings

On examination there was a firm irregularmass in the upper outer quadrant and retro-areolar regions of the left breast. There wasassociated peau d'orange but no erythema ofthe breast and with slight indrawing of theleft nipple. There were hard, but mobilenodes in the left axilla (E5) (Fig. 8).

Clinical Assessment

The clinical signs were suggestive of a carci-noma of the left breast with an inflammatorycomponent.

Investigations

Mammography

An asymmetric density was apparent in theupper outer quadrant of the left breast mea-suring 80 mm in maximum diameter. Therewere multiple clusters of coarse granularmicrocalcifications highly suspicious formalignancy (R5) (Fig. 9A, B).

Breast and Axillary Ultrasound

A solid mass lesion was seen on ultrasoundexamination measuring 60 mm in maximumdiameter (Fig. 10A). The echo pattern washypoechoic with posterior acoustic attenua-tion. Multiple pathological nodes werevisualized in the left axilla, the largest mea-suring 29 mm in its longitudinal axis. Inaddition there was radiological evidence of

Figure 8

Figure 9

Figure 10



lymphedema with skin thickening (U5)(Fig. 10B, C).

Core Biopsy

Image-guided core biopsy of the breast massconfirmed an invasive carcinoma (grade III,ER negative, HER2 positive) [Fig. 11A (lowpower), B (high power)]. There was histo-logical evidence of nodal involvement frompercutaneous biopsy of the largest axillarynode (Fig. 11C).

Diagnosis

Large inflammatory carcinoma of the leftbreast (T4dN1).


It was recommended that the patientundergo neoadjuvant chemotherapy fol-lowed by a left modified radical mastectomyand radiotherapy to the chest wall and supra-clavicular fossa (documented nodal diseaseprechemotherapy). The presence of aninflammatory component contraindicatedimmediate breast reconstruction. Staginginvestigations were requested including CT(chest/abdomen/pelvis) and bone scan.


The patient was very distressed upon beinginformed of the diagnosis of breast cancerand the need for mastectomy following che-motherapy. She appeared particularly upsetat being told that immediate reconstructionwould not be offered and enquired aboutdelayed reconstruction. Staging investiga-tions revealed no evidence of distant meta-static disease, though CT imaging showed a

questionable sclerotic area in one of thevertebral bodies but a subsequent bonescan was normal.

The patient commenced a course of fourcycles of epirubicin/cyclophosphamide(EC) followed by four cycles of taxoterewith Herceptin given concurrently (seeAppendix III). The patient tolerated chemo-therapy well with a partial tumor response.After seven cycles of chemotherapy, thetumor was much softer and measured 3 to4 cm clinically and 32 mm sonographically.There was no peau d'orange or erythema ofthe breast and the palpable nodes in the leftaxilla had reduced in size. The patient wasreviewed surgically and operative manage-ment discussed further. Despite havingbeen informed at the time of diagnosis thata left modified radical mastectomy would beundertaken without reconstruction, thepatient was adamant that she would notcontemplate removal of the entire breastwithout immediate reconstruction. At notime had the patient ever been led to believethat she might be eligible for breast conser-vation. Inflammatory carcinoma is not anabsolute contraindication to immediatebreast reconstruction and it was the impres-sion of various health professionals (breast/plastic surgeons, oncologist, breast carenurse) that the psychological benefits ofreconstruction for this particular patient out-weighed any potential disadvantages in thisscenario. The patient was aware that she wasat higher than average risk for locoregionalrecurrence and was prepared to accept this.She was referred to the plastic surgeon fordiscussion of reconstructive options andreceived appropriate psychological supportfrom a senior nurse practitioner. It was con-sidered that reconstruction with a latissimus

Figure 11

142 CHAPTER 7


dorsi flap and implant would be most appro-priate for this patient based on the followingfactors:

1. Patient's age2. Need for postoperative radiotherapy3. Proposed wide skin excision (inflamma-

tory component)

The patient proceeded to surgery sixweeks after completion of the final cycle ofchemotherapy. A left modified radical mas-tectomy was performed with removal ofmuch of the breast skin that had originallyshown peau d'orange changes. A corre-spondingly large island of skin was takenfrom the donor site on the back. The patientmade an uneventful recovery and was dis-charged home on the seventh postoperativeday. She was very pleased with the final cos-metic result (Fig. 12A, B).


There was invasive carcinoma (grade III)within the breast extending over an area of60 mm, though this represented low volumeresidual disease (Fig. 13A, B). Tumor wasclear of all margins and 5 out of 10 nodes

contained metastatic carcinoma [Fig. 13C(magnification 5�), D (magnification10�)].

Figure 12

Figure 13



Discussion

This case illustrates how a diagnosis ofinflammatory breast cancer may not bestraightforward and this can generate dilem-mas in the clinical decision making process.Inflammatory carcinoma is a clinical entityand not a histological type. It represents asuperficial manifestation of an underlyingcarcinoma within the breast parenchyma.These cutaneous features are often associ-ated with dilated vascular spaces and inva-sion of dermal lymphatics by carcinoma cells(tumor emboli). This patient had no signs oferythema at the time of initial clinical pre-sentation. There were signs of peau d'orangebut minimal edema of the skin and subcuta-neous tissues. However, there was radiolog-ical evidence of breast lymphedema withskin thickening; the patient was diagnosedas an inflammatory carcinoma on the basisof the radiological appearances. This wouldnot have presented any practical issuesunless the patient had not been insistenton immediate breast reconstruction. Inflam-matory carcinoma is a relative contraindica-tion to immediate breast reconstruction andwould not have been offered routinely in thisparticular case. However, the patient wasvery insistent on reconstruction as an imme-diate procedure and would not even con-sider a delayed procedure. It was felt onbalance that the psychological benefits ofimmediate breast reconstruction in this par-ticular case outweighed any disadvantages interms of increased risk of locoregionalrelapse. The cancer was not typically inflam-matory, though there was a transient episodeof erythema of the breast after completion ofthe final cycle of chemotherapy.

From an oncological point of view, it wasmandatory to perform a wide skin excisionthat incorporated the area of peau d'orangeand also that of the transient erythema. Thearea of skin removed was more than for aconventional (non–skin sparing) mastec-tomy and this was replaced with a largeskin island from the donor site. Thereforeperforming immediate breast reconstructionwith a latissimus dorsi flap (and implant)had facilitated a wide surgical clearance.Final histology of the resected specimen

had revealed no evidence of tumor cellswithin the dermal tissues at the edge of thespecimen. Residual tumor, though extend-ing over a large area, appeared to have beenexcised with satisfactory margins. Thoughthis together with radiotherapy would mini-mize the chance of local recurrence, thepatient was carefully monitored clinicallyfor any signs of locoregional relapse.Unfortunately she developed an area oferythema over the lateral aspect of thereconstructed breast for which a punchbiopsy revealed invasive carcinoma. Thispatch of erythema was initially attributed topost-radiotherapy changes, but its persis-tence and texture raised an element of clin-ical suspicion (Fig. 14).

Despite development of local recurrencein the native mastectomy flap, the patient waspleased with the outcome of surgery and didnot regret having undergone immediatebreast reconstruction. In retrospect, the deci-sion to undertake immediate breast recon-struction appears to have been justified fromthe patient's perspective. Herceptin had beenresumed two weeks postoperatively and thelocal recurrence was managed initially withfurther systemic therapy (capecitebine).

Related Cases

Inflammatory breast cancer—Case Study 25

Taxane-based neoadjuvant chemotherapy—Case Studies 22, 25, 27, 28, and 29

Herceptin—Case Studies 8 and 11

Figure 14

144 CHAPTER 7


Postmastectomy radiotherapy—Case Studies2, 3, 22, 25, 27, and 28

Locally recurrent disease—Case Study 20

Learning Points

1. Inflammatory breast cancer is a clinicaldiagnosis based upon the following fea-tures: diffuse erythema, edema involvingmore than two-thirds of the breast, peaud'orange, tenderness, induration, warmth,enlargement, and diffuseness of the tumoron palpation.

2. About 1% to 6% of all breast cancerpatients present with inflammatorybreast cancer. In the United States, theincidence of inflammatory breast canceris higher among African Americans thanother ethnic groups.

3. Women with inflammatory breast can-cer are at increased risk for locoregionalrecurrence, so immediate breast recon-struction is discouraged.



8Neoadjuvant Chemotherapy

Part I: Mastectomy Postchemotherapy

CASE STUDY 27

History

A 25-year-old woman sought a second opin-ion following initial assessment of a lump inthe right breast, which was erroneously diag-nosed as a sebaceous cyst. No preliminaryinvestigations such as breast imaging hadbeen undertaken, and the patient was sched-uled for excision of the lump under localanesthetic as a day case. At the time of herattendance for surgery it was noted that thebreast lesion was clinically more ominousthan a simple sebaceous cyst and formalbreast assessment was arranged. The lumphad been present for approximately twomonths and had progressively increased insize. There was no fluctuation in size with themenstrual cycle, and no associated nippledischarge. The patient had no previous his-tory of breast problems and no family historyof breast or ovarian carcinoma. She wasnulliparous and had used the oral contra-ceptive pill continuously since the age of18 years. The patient's general health wasotherwise good, and she reported no unusualcough, back pain, or weight loss. Interest-ingly, she had been treated for a Wilm'stumor of the right kidney at the age offour years and received adjuvant treatmentwith both radiotherapy and chemotherapy.There was no evidence of any disease recur-rence at a recent routine follow-up.

Clinical Findings

Examination revealed a large tumor occupy-ing much of the right breast and measuringapproximately 5 to 6 cm in maximum diam-

eter. There was a small area of skin involve-ment in the upper inner quadrant, whichpresumably corresponded to the area con-sidered to be a “sebaceous cyst” on initialclinical assessment elsewhere. There was noevidence of any inflammatory component,and soft, mobile nodes were palpable in theright axilla. Much of the right breast was firmand hard to palpation (E5). There were softmobile nodes palpable in the right axilla,which were not suspicious clinically (Fig. 1).

Clinical Assessment

Locally advanced cancer of the right breastin a young woman.

Investigations


Sonographic assessment of the clinical carci-noma was difficult due to the generalizedhardness of the tissues. The main tumormass measured at least 4.8 cm, and several

Figure 1

146


satellite foci were detected each measuring5 mm (U5) (Fig. 2).

Core Biopsy

Review of pathology from the ultrasound-guided core biopsy (14-gauge needle) ofthe right breast mass performed originallyconfirmed an invasive carcinoma (grade III,ER negative).


Following multidisciplinary review, full stag-ing investigations were undertaken andHER2/neu status was requested. In addition,ER immunohistochemical assay was repeatedat the secondary referral center. There wereconcerns about possible compromised renalfunction as a consequence of treatment for aprevious Wilm's tumor. It was recommendedthe patient undergo neoadjuvant chemo-therapy followed by surgery. The patientwas informed that breast conservation sur-gery would not be feasible whatever theresponse to primary chemotherapy. How-ever, she would be eligible for immediatebreast reconstruction in the absence of anyinflammatory component.


1. CT scan of head/chest/abdomen/pelvis—this showed no evidence of

distant metastatic disease in the lungs,liver, or brain (or elsewhere)

2. Routine blood tests—full blood count,urea and electrolytes, liver function tests,and calcium were all within the normalrange

3. Repeat ER assay—Allred score of 4/8(weakly positive) (Fig. 3)

4. HER2/neu assay—positive (Fig. 4).

Diagnosis

Locally advanced but operable right breastcancer (T4N1M0).


The patient commenced a modified regi-men of chemotherapy considered to be

Figure 2Figure 3

Figure 4

NEOADJUVANT CHEMOTHERAPY 147


compatible with previous chemotherapy fora Wilm's tumor. This consisted of six cyclesof docetaxel and carboplatin combined withHerceptin. She had an excellent clinicalresponse and repeat imaging at threemonths showed a dramatic response withreduction of tumor size by more than 50%.The patient proceeded to a right modifiedradical mastectomy with level II axillarylymph node dissection upon completion ofchemotherapy (the patient declined imme-diate breast reconstruction, see discussionbelow) (Fig. 5). She made an excellent post-operative recovery and Herceptin was con-tinued throughout the perioperative period.Herceptin had been withheld from the finalcycle of chemotherapy due to a fall in leftventricular ejection fraction (LVEF) from52% to 38%. Cardiac function subsequentlyrecovered and Herceptin was recommenced.


Extensive sampling of the mastectomy spec-imen revealed no evidence of any residualviable invasive carcinoma (Fig. 6A). A nodu-lar focus of dense hyaline fibrosis (Fig. 6B)surrounded by tissue containing numerouspigment-containing macrophages (Fig. 6C)and mast cells was identified as the pre-sumed site of pretreatment invasive tumor.Neither in situ carcinoma nor any intravas-cular tumor was found, and none of the20 lymph nodes removed contained anymetastases but showed fibrosis suggestive ofprevious nodal involvement and downstageddisease (Fig. 6D and E).


Despite a complete pathological tumorresponse, it was recommended the patientundergo irradiation of the right chest wall inview of the initial tumor size at presentation.The patient had elected to undergo a subse-quent contralateral prophylactic mastectomywith bilateral breast reconstruction at thesame time (i.e., immediate breast recon-struction on the left side and delayed breastreconstruction on the right). Herceptinwas continued for a minimum period of12months and tamoxifen commenced as adju-vant systemic hormonal therapy. The option ofovarian suppression was discussed (patient ofyoung age, though still nulliparous).

Discussion

Though this 25-year-old patient had no fam-ily history of breast cancer, she was inad-equately assessed at the time of her initialpresentation to a neighboring breast unit.There was failure to appreciate clinically thatthe patient had an extensive tumor extend-ing throughout much of the right breast.This had directly infiltrated the skin andled to the erroneous diagnosis of a seba-ceous cyst (1). No breast imaging had beenundertaken, and some might omit any radio-logical investigation when there is a confi-dent clinical diagnosis of a skin lesion withno intraparenchymal abnormality. This caseillustrates the importance of excluding thelatter with appropriate imaging. This patienthad a history of Wilm's tumor that wastreated with chemotherapy (doxorubicinand ifosfamide) and radiotherapy. Thispotentially compromised both cardiac andrenal function (nephrectomy), and a modi-fied neoadjuvant regimen was employedconsisting of docetaxel and carboplatintogether with Herceptin.

The underlying rationale for neoadjuvantchemotherapy is based on several potentialadvantages and opportunities. These includeimproved overall survival, increased chanceof breast preservation and assessment ofindividual tumor sensitivity to particular

Figure 5

148 CHAPTER 8


chemotherapeutic agents, and eventual cor-relation of tumor response to long-term out-come (2,3). Neoadjuvant or primarychemotherapy was originally employed formanagement of inoperable, locally advancedcancers that could be rendered technicallyoperable (4). Neoadjuvant approaches haveincreasingly been advocated for operablebreast cancers with the expectation ofimproved outcomes and possible breast con-servation (5,6). Though there is evidence ofincreased overall survival from preoperativechemotherapy in a rat model of breast can-cer, this has not translated into any clinical

gains (2). A meta-analysis of neoadjuvantversus adjuvant systemic therapy for early-stage breast cancer reveals that overall anddisease-free survival are comparable for thetwo schedules (7). If the act of surgery itselfcauses a systemic perturbation that can beoffset by induction chemotherapy, thiswould provide biological underpinning forneoadjuvant therapy. Nonetheless, it is per-haps naïve to assume that a modest shift inthe timing of chemotherapy relative to sur-gery would have any significant clinicalimpact (2). There is some evidence thatpatients with a complete pathological

Figure 6

NEOADJUVANT CHEMOTHERAPY 149SW

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response to neoadjuvant chemotherapy havea more favorable longer-term outcome.However, only about 10% of patients achievesuch a response and are difficult to identifyprospectively (5,8). In an analysis of six ret-rospective case series of neoadjuvant chemo-therapy, a complete pathological responsewas observed among only 300 out of 2584patients with invasive ductal carcinoma (9).

For patients with a large unifocal tumor,which is situated away from the nipple-areolarcomplex, neoadjuvant chemotherapy candownstage the tumor and permit breast con-servation (10,11). Clinical trials suggest thismay be accomplished in 25% to 50% of casesthat would otherwise have required mastec-tomy. Tumors do not necessarily shrink in aconcentric manner in response to chemo-therapy. Even if no viable cancer cellsremain at the site of the original tumorperiphery, this zone may contain unstableepithelium that is prone to malignantchange (12). Furthermore, tumor regressionis difficult to assess radiologically, and clin-icoradiopathological correlation in the neo-adjuvant setting is generally poor (even withuse of MRI). The NSABP B-18 trial random-ized patients between four cycles ofdoxorubicin and cyclophosphamide chemo-therapy given before or after surgery. Ratesof local recurrence are higher followingbreast conservation postchemotherapy com-pared with primary breast-conserving sur-gery (15% and 7%, respectively) (13). Thisparticular patient would not have been suit-able for breast-conserving surgery whateverthe response to chemotherapy. Despite acomplete pathological response, the tumoroccupied much of the central portion of thebreast, and the tissue in this area had to beexcised at the time of surgery.

Neoadjuvant chemotherapy allows serialcore biopsies to be undertaken, which pro-vide potential information on pathologicaland molecular predictors of response.Together with imaging parameters, this ena-bles nonresponders to be identified early onand therapy changed accordingly.

This patient opted to undergo a contrala-teral prophylactic mastectomy as a delayedprocedure. Despite absence of any familyhistory of breast cancer, this patient had a

significant lifetime risk of developing a fur-ther contralateral breast cancer. As youngerpatients are being treated more successfullyfor breast cancer, they are living long enoughto develop another cancer—whether this be acontralateral breast cancer or a de novo can-cer in the ipsilateral breast. The risk of afurther malignancy is approximately 1% peryear. If a patient is treated at the age of25 years for a breast cancer and survives foranother 30 to 40 years, she will likely developanother breast cancer.

The decision to undergo this contrala-teral prophylactic procedure influenced thetiming of the ipsilateral breast reconstruc-tion. Moreover, the requirement for chestwall radiotherapy (based on initial tumorsize) was a factor in the final surgical man-agement plan. The chance of severe capsu-lar contracture following irradiation of animplant (with a latissimus dorsi flap) is up to20% at four years (14). Women shouldbe warned of this if they are likely toneed postmastectomy radiotherapy. Somesurgeons now prefer to delay definitivebreast reconstruction until approximately12 months after radiotherapy. Skin-sparingmastectomy can be undertaken with inser-tion of a temporary tissue expander (subcu-taneous or submuscular) that remains forthe duration of radiotherapy. Transpositionof an autologous flap and insertion of adefinitive implant can be carried out as adelayed procedure (15). There is a risk thatthe quality of the skin flaps may be compro-mised under these circumstances and analternative option is to perform immediatebreast reconstruction in all patients and per-form implant exchange in those casesaffected by capsular contracture after radio-therapy. Increasing numbers of women arereceiving postmastectomy radiotherapy, andthis is often routine after neoadjuvant che-motherapy for a large primary tumor (withor without supraclavicular irradiation) (16).

Trastuzumab or Herceptin is a human-ized recombinant monoclonal antibody thattargets the HER2/neu receptor (17). This isexpressed in normal and malignant breastepithelial cells, but overexpressed in 20% to30% of all breast cancers (18). In the pre-clinical studies, overexpression of the

150 CHAPTER 8


HER2/neu oncogene results in increasedrates of proliferation and a more tumori-genic phenotype in vivo with greater meta-static potential. Recent trials have shown thatthe use of Herceptin for one to two yearsfollowing standard chemotherapy regimensin HER2-positive patients prolongs disease-free survival and reduces rates of relapse byup to 50% (19,20). The relative magnitudeof gains from Herceptin is similar across allsubgroups and there is less than a 20%chance that these benefits will be lost withmore prolonged follow-up. There is com-pound cardiotoxicity from combined ther-apy with Herceptin and taxanes that shouldbe sequenced when baseline LVEF is subop-timal. This patient received concomitantchemotherapy with docetaxel/carboplatinand Herceptin. Measurement of LVEF fellfrom 52% to 38% during treatment, andHerceptin was withheld temporarily untilresumption of satisfactory left ventricularfunction. Cardiac function is particularlysusceptible to the combination of an anthra-cycline, taxane, and herceptin. Current rec-ommendations are for combination ofherceptin with the nonanthracycline compo-nent of chemotherapy (usually a taxane).

This patient's repeat ER assay revealed anAllred score of 4/8. She was therefore eli-gible for hormonal treatment. Options forpremenopausal women include bothtamoxifen and ovarian suppression. Ameta-analysis by the Early Breast CancerTrialists Collaborative Group confirmedthat the proportional benefits from tamox-ifen were similar in pre- and postmeno-pausal women, though the former aresusceptible to a supraphysiological surge ofestrogens secondary to competitive block-ade of the estrogen receptor (21). Tamox-ifen is additive to chemotherapy inpremenopausal women (22). However, itremains unclear whether ovarian suppres-sion confers any additional benefits overand above the combined effects of chemo-therapy and tamoxifen. There is evidencethat women under 35 years of age whobecome amenorrheic after chemotherapyhave a better prognosis. Ovarian suppres-sion should probably be recommendedafter chemotherapy for the majority of

higher-risk ER-positive premenopausalwomen under the age of 40 years. Most ofthese women will resume ovarian functionafter chemotherapy, while fewer than 50%of those over this age will do so. The useof LHRH agonists allows preservationof ovarian function and the possibility ofsubsequent conception (23). However, ifthe anticipated survival gains from ovariansuppression are modest, it is preferable touse tamoxifen alone in hormone-sensitivewomen. For those higher-risk women under35 years of age who do not become amenor-rheic (or whose menses resume) afterchemotherapy, ovarian suppression is man-datory. Chemotherapy alone is insufficientfor this group of patients.

Related Cases

Neoadjuvant chemotherapy—Case Studies 23,28, and 29

Ovarian suppression—Case Studies 8 and 23

Contralateral prophylactic mastectomy—Case Study 39

Capsular con tracture—Case Studies 3 and 18

Herceptin—Case Studies 8, 11, and 26

Chest wall radiotherapy—Case Studies 2, 3,22, and 26

Learning Points

1. In patients with locally advanced orinflammatory breast cancers, neoadju-vant chemotherapy reduces tumor bur-den, thereby facilitating mastectomy.For patients with large tumors, the rateof breast-conserving surgery is increasedwith neoadjuvant chemotherapy.

2. In theory, neoadjuvant chemotherapymight allow for the in vivo assessmentof tumor response, enabling oncologiststo tailor chemotherapy to achieve max-imum response. Several clinical trialsare further evaluating this approach,but there is as yet no evidence thatneoadjuvant chemotherapy results inimproved survival.



References

1. Argy O, Hughes KS, Roche CA. Managing thepatient with a breast mass. In: Jatoi I, ed. Manualof Breast Disease. Wilkins, Williams: Lippincott,2002, 135–148.

2. Davidson NE, Morrow M. Sometimes a greatnotion—an assessment of neoadjuvant systemictherapy for breast cancer. J Natl Cancer Inst2005; 97:159–161.

3. Wolff AC, Davidson NE. Primary systemic therapyin operable breast cancer. J Clin Oncol 2000;18:1558–1569.

4. Gilles R, Guinebretiere JM, Toussaint C, et al.Locally advanced breast cancer: contrast-enhancedsubtraction MR imaging of response to preopera-tive chemotherapy. Radiology 1994; 191:633–638.

5. Bonadonna G, Valagussa P, Bramnilla C, et al.Primary chemotherapy in operable breast cancer:eight year experience at the Milan Cancer Insti-tute. J Clin Oncol 1998; 16:93–100.

6. Smith IE, Walsh G, Jones A, et al. High completeremission rates with primary neoadjuvant infu-sional chemotherapy for large early breast cancer.J Clin Oncol 1995; 13:424–429.

7. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvantversus adjuvant systemic treatment for breast can-cer: a meta-analysis. J Natl Cancer Inst 2005; 97:188–194.

8. Fisher B, Brown A, Mamounas E, et al. Effect ofpreoperative chemotherapy on locoregional dis-ease in women with operable breast cancer: find-ings from the National Surgical Adjuvant Breastand Bowel Project. B-18. J Clin Oncol 1997; 15:2483–2493.

9. Katz A, Saad ED, Porter P, et al. Primary systemicchemotherapy of invasive lobular carcinoma of thebreast. Lancet Oncol 1997; 55–62.

10. Bonadonna G, Veronesi U, Brambilla C, et al.Primary chemotherapy to avoid mastectomy intumours with diameters of three centimeters ormore. J Natl Cancer Inst 1990; 82:1539–1545.

11. Makris A, Powles TJ, Ashley SE, et al. A reduction inthe requirements for mastectomy in a randomizedtrial of neoadjuvant chemoendocrine therapy in pri-mary breast cancer. Ann Oncol 1998; 9:1179–1184.

12. Veronesi U, Bonadonna G, Zurrida S, et al. Con-servation surgery after primary chemotherapy inlarge carcinomas of the breast. Ann Surg 1995;222:612–618.

13. Wolmark N, Wang J, Mamounas E, et al. Preoper-ative chemotherapy in patients with operablebreast cancer: nine-year results from the NationalSurgical Adjuvant Breast and Bowel Project. B-18.J Natl Cancer Inst Monogr 2001; 30:96–102.

14. Behranwala KA, Dua RS, Ross GM, et al. Theinfluence of radiotherapy on capsule formationand aesthetic outcome after immediate breastreconstruction using biodimensional anatomicalexpander implants. J Plast Reconstr Aesthet Surg2006; 59:1043–1051.

15. Kronowitz S. Delayed-immediate reconstruction inpatients who might require postmastectomy radia-tion therapy. Miami Breast Cancer Conference,Orlando, Florida, February 20–23, 2008.


17. Slamon DJ, Clark GM, Wong SG, et al. Humanbreast cancer: correlation of relapse and survivalwith amplication of the HER-2/neu oncogene.Science 1987; 235:177–182.

18. Slamon DJ, Leyland-Jones B, Shak S, et al. Use ofchemotherapy plus a monoclonal antibody againstHER2 for metastatic breast cancer overexpressesHER2. N Engl J Med 2001; 344:783–792.

19. Romond EH, Perez EA, Bryant J, et al. Trastuzu-mab plus adjuvant chemotherapy for operableHER2 positive breast cancer. N Engl J Med 2005;353:1659–1684.

20. Piccart-Gebhart MJ, Procter M, Leyland-Jones B,et al. 2 year follow up of trastuzumab after adjuvantchemotherapy in HER2 positive breast cancer.N Engl J Med 2005; 353:1659–1672.

21. Early Breast Cancer Trialists Collaborative Group.Tamoxifen for early breast cancer: an overview ofthe randomized trials. Lancet 1998; 351:1451–1461.

22. Albain KS, Green SJ, Ravdin PM, et al. for SWOG,ECOG, CALGB, NCCTG and NCIC-CTG. Adjuvantchemohormonal therapy for primary breast cancershould be sequential instead of concurrent: initialresults from the Intergroup Trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 2002; 21(abstr 143).

23. Recchia F, Sica G, de Filippis S, et al. Ovarianprotection with goserilin during chemotherapyfor early breast cancer: long term results of aphase II study. Proc Am Soc Clin Oncol 2002; 21(abstr 62).

CASE STUDY 28

History

A 46-year-old woman of Eastern Europeanextraction was referred to the breast clinicwith altered breast contour and dimpling ofher right breast. The patient reported a

lump in the right breast, which had beenpresent for almost five years. She attributedthis to an innate “structural” or anatomicalabnormality, but the lump had increased insize during the preceding four weeks. There

152 CHAPTER 8


was no associated nipple discharge, and thepatient was otherwise well with no unusualback pain, cough, or weight loss. There wasno family history of breast or ovarian cancer,and the patient had two children both ofwhom were breast-fed. She underwentmenarche at the age of 12 years and hadused the oral contraceptive pill for a briefperiod of six months prior to her firstpregnancy.

Clinical Findings

There was an ill-defined mass in the lowerouter quadrant of the right breast measuringapproximately 3 cm. There was dimpling ofthe overlying skin and retraction of the rightnipple. The mass was mobile on the chest walland two enlarged hard nodes were palpablein the right axilla (E5) (Figs. 7 and 8A–C).

Clinical Assessment

Locally advanced clinical carcinoma of theright breast with nodal involvement.

Investigations

Mammography

An irregular spiculate opacity was seen in thelower outer quadrant of the right breastmeasuring 30 mm in maximum diameter(R5) (Fig. 9A and B).

Breast Ultrasound

The sonographic correlate of this opacitywas a 32-mm heterogeneous solid mass witha hypoechoic pattern (no acoustic enhance-ment or attenuation) (U5) (Fig. 10). Three

Figure 7

Figure 8

Figure 9



nodes were seen in the right axilla measur-ing no more than 8 mm each.

Core Biopsy

Ultrasound-guided core biopsy of the rightbreast mass confirmed the clinical and radio-logical impression of malignancy with an

invasive carcinoma (grade II, ER positive,a

HER2 negative) [Fig. 11A (magnification10�) and B (magnification 20�)]. Corebiopsy of a right axillary node showed meta-static carcinoma (Fig. 11C).

Diagnosis

Locally advanced cancer of the right breast(T4bN1).


Following multidisciplinary review, it wasrecommended that the patient undergo pri-mary chemotherapy within the NEOTANGOtrial. She would require right mastectomyand axillary dissection after completion ofchemotherapy together with irradiation ofthe chest wall and supraclavicular fossa.It was likely the patient would be renderedpostmenopausal by chemotherapy (aged45 years) and be eligible for hormonal

a Allred score 8/8

Figure 10

Figure 11

154 CHAPTER 8


therapy with tamoxifen for two to three yearsfollowed by an early switch to an aromataseinhibitor.


Breast MRI

Initial MRI examination revealed the tumormeasuring 30 mm in maximum diameter,which corresponded to the mammographicand sonographic estimates.

CT Chest/Abdomen/Pelvis

No evidence of distant metastases.


Chemotherapy was discussed with the patientboth within the context of the NEOTANGOtrial and standard regimens (see below). Thepatient was keen to participate in the trialand was provided with relevant information.Chemotherapy was commenced one weeklater. Following three cycles of Taxol, thetumor in the right breast had become softerbut remained approximately 3 cm in size.The patient suffered mild nausea and arthral-gia (grade I) as side effects of treatment. Arepeat MRI scan confirmed that the tumorhad reduced in size to 22 mm and wasunifocal. However, simultaneous ultrasoundshowed a persistent abnormality at the site ofthe original MRI lesion, suggesting that therehad not been concentric shrinkage of thetumor. It was, therefore, reaffirmed that thepatient should proceed to a right modifiedradical mastectomy (with level II axillarylymph node dissection) and would not besuitable for breast-conserving surgery. Thepatient underwent a skin sparing mastectomy

and immediate reconstruction with latissimusdorsi flap and implant after completion ofchemotherapy. At the time of operation, amodified periareolar incision was made toencompass the area of skin dimpling justlateral to the nipple (Figs. 12 and 13). Thepatient made an excellent recovery andwas discharged home on the fifth postopera-tive day.


This revealed significant residual invasiveductal carcinoma, measuring at least50 mm and extending to the deep surfaceof the nipple. There was a central area ofsclerosis consistent with a chemotherapyresponse (<50%) (Fig. 14A and B). No def-inite lymphovascular invasion was seen, andfocal perineural invasion was present. Fourout of 14 lymph nodes contained metastaticcarcinoma (Fig. 14C).


Following further multidisciplinary review, itwas recommended the patient be prescribedtamoxifen as adjuvant systemic hormonaltherapy and be offered ovarian suppression.She would receive irradiation of the chestwall and supraclavicular fossa as part of theneoadjuvant protocol (�4 nodes positive).


The patient proceeded to laparoscopic bilat-eral salpingo-oophorectomy five weeks fol-lowing mastectomy. There was no evidenceof any intra-abdominal nor pelvic malignancyat the time of laparoscopic exploration. AFigure 12

Figure 13



course of radiotherapy to the chest wall andsupraclavicular fossa followed shortly thereaf-ter, and hormonal therapy was completedwith tamoxifen for five years. The patienthad an excellent cosmetic result three monthsfollowing completion of radiotherapy (Fig. 15Aand B).

Discussion

This relatively young patient presented witha locally advanced breast cancer with histo-

logically confirmed nodal involvement.Locally advanced tumors encompass thosethat exceed 5 cm in size or that involve theskin or chest wall (T3 or T4). This classifica-tion also includes patients with fixed (N2 orN3) axillary nodes but not supraclavicularnodal disease. Approximately 20% to 30% ofall breast cancer patients have locallyadvanced disease at the time of presentation,though this figure is falling with heightenedpublic awareness and screening programs.Indeed, among women who undergo regular

Figure 14

Figure 15

156 CHAPTER 8


screening, fewer than 5% are diagnosed withlocally advanced disease (1). Single modalitytherapies in the past yielded poor resultswith five-year survival rates from surgeryand radiotherapy alone of 41% and 29%,respectively (2). This group of patients arenow managed with a combination of surgery,radiotherapy, and systemic therapy (3).These patients are likely to have dissemi-nated micrometastatic disease at the timeof presentation, and primary chemotherapyis a more rationale approach and hasimproved outcomes significantly. Youngerpatients (�50 years) usually have inductionchemotherapy irrespective of hormonereceptor status. Preoperative chemotherapyreduces tumor volume that can facilitatesubsequent surgical excision. In selectedcases, breast conservation surgery ratherthan mastectomy may be feasible (4), butoften mastectomy is indicated based on ini-tial tumor size, location, and involvementof skin and/or chest wall musculature.These patients are at greater risk of localrecurrence, which is minimized by mastectomyand irradiation of the chest wall. Radiother-apy has been combined with chemotherapyfor more than 50 years, and all trials haveshown that postmastectomy radiotherapyreduces the proportional risk of local failureby two-thirds to three-quarters (5). Most ofthis effect is seen in the first five years, and arecent meta-analysis by the EBCTCG con-firms that for women with node-positive dis-ease, there is also a mortality gain of 5.4% at15 years (6). Furthermore, for patients with�4 nodes positive, the incidence of supra-clavicular failure is sufficiently high to recom-mend routine irradiation of the supra-clavicular fossa in this group. For those withone to three positive nodes, it remainsunclear whether supraclavicular irradiationis justified, and this issue is being addressedin the ongoing SUPREMO study (7).

Patients with locally advanced and inflam-matory cancers will often be given chest walland supraclavicular irradiation after mastec-tomy. However, for less-advanced tumors, theextent of nodal involvement prechemother-apy may be unclear; core biopsy or sentinellymph node biopsy may confirm that at least

one node is positive. This may be insufficientto warrant either chest wall radiotherapy orsupraclavicular fossa irradiation in somepatients with T1/T2 tumors. Nodal down-staging can occur following neoadjuvant che-motherapy, and sometimes it is possible todiscern pathologically those nodes that pre-viously were “positive” but no longer containviable tumor. This patient was offered pri-mary chemotherapy within the NEOTANGOtrial, which is a four-arm randomization to apreoperative schedule of sequential epirubi-cin, cyclophosphamide, and paclitaxel withor without gemcitabine (Table 1). She wasgiven the option of having a standard neo-adjuvant regimen (EC/docetaxel or FEC/docetaxel) but opted for trial entry. Patientswho have operable tumors who failed torespond to an anthracycline-based regimenand/or taxanes can undergo immediatemastectomy. For those patients with inoper-able tumors who do not respond to induc-tion systemic therapy, primary radiotherapyis an option. It is important that patients areprovided with adequate verbal informationthat can be supplemented with leaflets.Patients should understand why they arebeing offered primary chemotherapy, partic-ularly when breast conservation surgery isimprobable whatever the response to induc-tion chemotherapy.

At the age of 46 years, it is likely that thispatient would be rendered postmenopausalby chemotherapy. She would, therefore, beeligible for treatment with an aromataseinhibitor as part of systemic adjuvant hor-monal therapy (ER-positive tumor).

Table 1 NEOTANGO Trial Schema

ARM A1 4 cycles EC Followed by 4 cyclesPaclitaxel

ARM A2 4 cycles Paclitaxel Followed by 4 cyclesEC

ARM B1 4 cycles EC Followed by 4 cyclesPaclitaxel +Gemcitabine

ARM B2 4 cycles Paclitaxel+ Gemcitabine

Followed by 4 cyclesEC

Abbreviations: E, epirubicin; C, cyclophosphamide.



Related Cases

Locally advanced tumors—Case Studies 27,30, and 31

Neoadjuvant chemotherapy—Case Studies 27and 29

Aromatase inhibitors—Case Studies 1, 8, 9,10, 19, and 22

Supraclavicular irradiation—Case Studies 2and 22

Learning Points

1. In patients with locally advanced breastcancers, preoperative chemotherapyreduces tumor burden, thereby facilitat-ing mastectomy.

2. Even though locally advanced tumorsare often downstaged following preop-erative chemotherapy, these patientsshould still receive postmastectomyradiotherapy to minimize the risk oflocoregional recurrence.

3. In some patients with locally advancedbreast cancer, preoperative chemother-apy might result in a substantial reduc-tion in tumor burden, making breast-conserving surgery feasible. However,these patients will have a significantlygreater risk of local recurrence, when

compared to patients who undergobreast-conserving surgery followed byadjuvant chemotherapy.

References

1. Seidman H, Gelbs K, Silverberg E, et al. Survivalexperience in the Breast Cancer Detection Dem-onstration Project. CA Cancer J Clin 1987; 37:258–290.

2. Hortobagyi GN. Comprehensive management oflocally advanced breast cancer. Cancer 1990;66:1387–1391.

3. Swain SM, Sorace RA, Bagley CS, et al. Neoadju-vant chemotherapy in the combined modalityapproach of locally advanced nonmetastatic breastcancer. Cancer Res 1987; 47:3889–3894.

4. Singletary SE, Mcnees MD, Hortobagyi GN. Feasi-bility of breast conservation surgery after inductionchemotherapy for locally advanced breast carci-noma. Cancer 1992; 69:2849–2852.

5. Early Breast Cancer Trialists' Collaborative Group.Effects of radiotherapy and surgery in early breastcancer: an overview of the randomized trials. NEngl J Med 1995; 333:1444–1455.


7. SUPREMO breast cancer trial. Selective Use ofPostoperative Radiotherapy after Mastectomy.Available at: www.supremo-trial.com. AccessedNovember 17, 2008.

Part II: Breast Conservation SurgeryPostchemotherapy

CASE STUDY 29

History

A 51-year-old woman presented with a two-month history of a lump in the left breast.She noticed this shortly after sustaining mildtrauma to the breast after a fall. There wasno bruising of the breast at the time, but shebecame aware of the lump immediatelyafterward. The lump was nontender andthere was no associated nipple discharge.

The patient had no previous breast prob-lems and had not yet undergone a firstround screening mammogram in the NHSprogram. There was neither family history ofbreast nor ovarian cancer. She had two chil-dren (3 pregnancies) both of whom werebreast-fed and gave birth to her eldest childat the age of 25 years. The oral contraceptivepill had been used for a cumulative period of10 years both before and after pregnancy.

158 CHAPTER 8


Clinical Findings

There was a large mobile mass in the lowerouter quadrant of the left breast, which wasfirm and quite hard on palpation (E5). Itmeasured at least 5 to 6 cm clinically and wasassociated with distortion of the outer aspectof the breast, but no erythema or peaud'orange. There was palpable left axillarylymphadenopathy. Some minor bruisingwas evident overlying the mass (Fig. 16).

Clinical Assessment

Large clinical carcinoma of the left breast.

Investigations

Mammography

Bilateral mammography showed a well-cir-cumscribed 5-cm opacity in the lower outerquadrant of the left breast at the level of thenipple (right side normal) (R4/5) (Fig. 17Aand B).


The mammographic opacity correspondedto a heterogeneous mass measuring 52 mmin maximum dimension with areas ofenhanced vascularity (Fig. 18A). A 2-cmnode was seen in the left axilla with focalcortical thickening. The overall radiologicalappearances were suspicious for carcinoma(U5) (Fig. 18B).

Figure 18

Figure 16

Figure 17



Core Biopsy

Image-guided core biopsy (14-gauge needle)of the breast mass confirmed an invasive car-cinoma (grade III, ER/PR negative) [Fig. 19A(low power) and B (high power)]. Biopsy ofthe left axillary node showed reactive changesonly (lymphoid hyperplasia).

Diagnosis



Following multidisciplinary review, it wasrecommended that the patient be managedwith neoadjuvant chemotherapy that mightdownstage the tumor permitting breast con-servation at a later stage. Though the tumormeasured up to 5 cm on imaging, itappeared unifocal and away from the nipple-areolar complex. The patient was very keento preserve her breast and avoid mastectomyif possible. A final decision on surgical man-agement would be made after assessment ofresponse to chemotherapy. Despite a nega-tive axillary node core biopsy, sentinel lymphnode biopsy was not advised prechemother-apy due to primary tumor size (5 cm). Thepatient would therefore undergo axillarylymph node dissection at the time of defin-itive surgery irrespective of breast conserva-tion or mastectomy.

Further investigations were requestedincluding an MRI examination of the

breasts, liver ultrasound, bone scan, andHER2 status. These were considered appro-priate in view of the primary tumor sizeat presentation (no evidence of nodalinvolvement).

1. Breast MRI—this confirmed that lesionin the lower outer quadrant of the leftbreast was unifocal

2. Liver ultrasound—normal3. Isotope bone scan—normal4. HER2 status—negative


The patient proceeded with four cycles ofepirubicin/cyclophosphamide (EC) fol-lowed by four cycles of taxotere, whichwere well tolerated (see Appendix III).After six cycles of chemotherapy, there hadbeen an excellent clinical response with noobviously palpable tumor in the left breastand no axillary lymphadenopathy. Repeatimaging at this stage with ultrasound con-firmed the impression of a dramatic clinicalresponse and showed a residual tumor focusmeasuring 7 mm. A coil was inserted forfuture reference to identify the site of theoriginal tumor in the event of breast conser-vation surgery. At subsequent surgicalreview, the tumor was now deemed amena-ble to a guidewire localized wide local exci-sion. The residual tumor (and coil) lay morethan 2 cm from the nipple-areolar complex,and there were no areas of skin dimpling oralteration of breast contour.

Figure 19

160 CHAPTER 8

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The patient underwent a left quadranticstyle resection with removal of the axillarynodes (level II dissection) in continuity withthe breast excision (single radial incision).At the time of operation, there was no mac-roscopic evidence of any tumor, and a widearea of tissue around tip of the wire wasexcised down to the pectoral serratus ante-rior fascia (Fig. 20). A specimen radiographconfirmed a satisfactory margin of tissuearound the wire tip (about 2 cm) togetherwith the presence of the coil. The patientmade an uneventful postoperative recoveryand required aspiration of seroma from theleft axilla on two occasions.


There was no evidence of any residual tumor(invasive or in situ) in the breast excisionspecimen, and all 16 nodes retrieved werefree of metastases. There was evidence ofreactive stromal changes and collections offoamy macrophages consistent with tumorresponse to induction chemotherapy[Fig. 21A–C (magnification 20�)]. This areaof tissue did not reach the radial margins ofthe excised specimen, but was present atthe deep margin. Moreover, there wasno evidence of any previous metastaseswithin any of the lymph nodes [Fig. 22(magnification 40�)]. Therefore, a completepathological response had occurred in atumor initially measuring in excess of 5 cm.


The patient received radiotherapy to thebreast but no further systemic therapy inview of having a “triple negative tumor”(hormone receptor negative and HER2/neu negative). A follow-up mammogramat 12 months revealed no evidence of

Figure 20

Figure 21



recurrent disease (Fig. 23A and B) and thepatient had a very good cosmetic result withan inconspicuous scar in the lateral aspect ofthe left breast (Fig. 24).

Discussion

A lump that turns out to be a breast cancermay be noticed by a patient following anepisode of trauma to the breast. Patientsoften erroneously conclude that trauma hasa causative role in development of the breastcancer; this is not the case and the bruisingand discomfort associated with the traumadraw the patient's attention to the lump thathas often been present for some time.

This patient had a large T3 cancer locatedin the lower outer quadrant of the left breastaway from the nipple-areolar complex. Shewas very keen to preserve her breast atthe outset, and downstaging with preopera-tive chemotherapy was the desired objective.The tumor was too large initially for breast-conserving surgery and imaging confirmedthe lesion to be unifocal. Neoadjuvant chemo-

therapy increases rates of breast conservationand is the only clear benefit of primaryversus adjuvant chemotherapy after almost25 years of managing patients with upfrontsystemic treatments. Makris and colleaguesreported a decrease in rates of mastectomyfrom 22% to 11% after neoadjuvant chemo-therapy (1). Rates of subsequent mastectomyare generally reduced by 25% to 50% afterinduction chemotherapy, which is associatedwith response rates of 80% to 90% (2). Thispatient had a dramatic clinical response to astandard preoperative regimen (4 cycles ofepirubicin and cyclophosphamide followedby 4 cycles of taxotere), with residual tumormeasuring less than 1 cm radiologically aftersix cycles. Despite initial placement of a coilat the site of the tumor and re-excision ofpositive margins when indicated, rates oflocal recurrence remain higher whenbreast-conserving surgery follows ratherthan precedes chemotherapy (3). Tumorregression may be “honeycombed” ratherthan concentric with viable tumor cellsremaining some distance from the residualtumor (corresponding to the periphery ofthe original tumor) (4).

Figure 22

Figure 23

Figure 24

162 CHAPTER 8


This patient had a complete pathologicaltumor response with no evidence of anyresidual invasive or noninvasive disease.Though a complete pathological responseappears to be associated with a better clinicaloutcome, there remain uncertainties aboutthe longer-term prognosis of patients receiv-ing breast conservation surgery after neo-adjuvant chemotherapy. Though initialresponse rates for neoadjuvant chemother-apy exceed 80%, clinical response rates arein general poorly correlated with disease-free and overall survival (5,6). It is nowacknowledged that local recurrence can actas a determinant of distant metastases andadversely affect overall survival (7). It isessential that women receive fully informedconsent when being offered breast -conserving surgery after a course of primarychemotherapy—particularly if there is a poorresponse or concerns about the true extentof disease based on ultrasound, CT, or MRIof the breast. When there is residual tumorpresent, mastectomy must be consideredwhen margins would remain compromisedafter re-excision or there is multifocal dis-ease in the excision specimen. The optimalregimen for neoadjuvant chemotherapyremains to be determined, but usually con-tains an anthracycline and a taxane—in thiscase epirubicin and taxotere. Other sched-ules include

1. 5-Fluorouracil, epirubicin, cyclophos-phamide (FEC) � 4 cycles þ weeklypaclitaxel � 12

2. Adriamycin and docetaxel (AT) � 4cycles

3. Adriamycin and cyclophosphamide(AC) � 4 cycles þ weekly paclitaxel �12 cycles

The use of epirubucin rather than doxor-ubucin is associated with less cardiotoxicityand fewer gastrointestinal symptoms such asnausea and vomiting. This allows for anescalation of dose for epirubicin, whichmay have advantages in the neoadjuvant set-t ing. Epirubucin is more commonlyemployed in Europe and the preferred choiceof anthracycline. Preoperative EC-taxotere isa popular off-trial neoadjuvant schedule thatis similar to the American NSABP B-27 study

of preoperative AC-docetaxel (switch ofanthracycline only) (6).

New treatment strategies must focus onachieving complete pathological response ina much higher proportion of patients (8).Neoadjuvant schedules incorporating bothchemotherapy and Herceptin have shownpromising results in respect of completepathological response rates, which appearhigher among ER-negative patients. How-ever, within the large NSABP B-27 study,increased rates of pathological responsewere not associated with improved overallsurvival (6). Though identification of thisgroup will allow amended regimens withshorter courses of treatment and perhapsreduced dosages of chemotherapeuticagents, complete pathological responsemay not be the best way of tailoring treat-ments. Multivariate models incorporatingtumor size, proliferative indices (Ki67),and ER can help predict those patientswho will relapse and may benefit from che-motherapy. Moreover, molecular profilingof tumors with assessment of changes ingene expression over a two-week periodmay identify short-term predictors of lon-ger-term outcomes. There is some evidencethat neoadjuvant chemotherapy may causedifferential downstaging between sentineland nonsentinel lymph nodes (9). For thisreason, it has been argued that sentinellymph node biopsy should be undertakenprior to commencing chemotherapy to min-imize the risk of a false-negative result (thiswould occur if the sentinel node respondedto chemotherapy but not the nonsentinelnodes). This patient's tumor size precludedsentinel lymph node biopsy (>5 cm), and aformal axillary dissection was carried out atthe time of surgery (previous axillary nodecore biopsy revealed reactive changes only).

When the sentinel lymph node biopsy ispositive prior to chemotherapy, there is noquantification of metastatic load in theregional nodes. If these are subsequentlydownstaged by chemotherapy, it remainsunclear whether the patient falls into nodalcategory 1 to 3 or � 4 nodes. (the latterwould receive chest wall radiotherapy aftermastectomy and supraclavicular irradiation).Of course, some patients will receive



postmastectomy radiotherapy based on pri-mary tumor size, grade, and status of thedeep margin. It is customary to consider thatthe nodal status at presentation is relevant toprognosis and decisions on adjuvant radio-therapy. However, when nodes are down-staged by chemotherapy (in 30–40% ofcases), then patients may be renderednode negative and could avoid full axillarydissection when sentinel node biopsy is car-ried out postchemotherapy. Identificationrates are between 72% and 100% in thesecircumstances and the overall false-negativerate using a meta-analysis with a pooled esti-mate is 12% (10). This figure is similar toconventional sentinel node biopsy (9%).When nodes are positive before neoadjuvantchemotherapy, the false negative rate forsentinel lymph node biopsy after chemother-apy is 25%.

Within the Cambridge Breast Unit, sen-tinel node biopsy is undertaken prechemo-therapy. This provides accurate nodalstaging before neoadjuvant chemotherapyand helps decision making for radiotherapy.It is helpful if the result is negative, butnegative nodes on completion axillary dis-section after neoadjuvant chemotherapy anda prior positive sentinel node biopsy are ofuncertain significance. It is unclear whetheronly the sentinel node was originallyinvolved or further nodes that have subse-quently been downstaged. Those in favor ofsentinel node biopsy after induction chemo-therapy maintain that this will spare axillarydissection in up to 40% of patients becauseof downstaging (10).

Related Cases

Breast conservation surgery before chemo-therapy—Case Studies 8 and 11

Neoadjuvant chemotherapy—Case Studies 23,27, and 28

Sentinel node biopsy before neoadjuvantchemotherapy—Case Studies 27 and 28

Learning Points

1. Preoperative chemotherapy decreasesmastectomy rates. However, breast con-servation following preoperative chemo-

therapy might be associated with agreater risk of local recurrence.

2. A pathological complete response(pCR) following preoperative chemo-therapy is associated with improved sur-vival rates. However, this improvedsurvival might possibly be attributed tomore favorable tumor biology (amongpatients who experience pCR) ratherthan to the preoperative chemotherapyitself.

References

1. Makris A, Powles TJ, Ashley SE, et al. A reductionin the requirements for mastectomy in a randomizedtrial of neoadjuvant chemoendocrine therapy in pri-mary breast cancer. Ann Oncol 1998; 9:1179–1184.

2. Veronesi U, Bonadonna G, Zurrida S, et al. Con-servation surgery after primary chemotherapy inlarge carcinomas of the breast. Ann Surg 1995;222:612–618.

3. Wolmark N, Wang J, Mamounas E, et al. Preoper-ative chemotherapy in patients with operablebreast cancer: nine-year results from the NationalSurgical Adjuvant Breast and Bowel Project. B-18. JNatl Cancer Inst Monogr 2001; 30:96–102.

4. Chafare H, Limongelli S, Purushotham AD. Neo-adjuvant chemotherapy in breast cancer. Br J Surg2005; 92:14–23.

5. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvantversus adjuvant systemic treatment for breast cancer:a meta-analyis. J Natl Cancer Inst 2005; 97:188–194.

6. Bear HD, Anderson S, Smith RE, et al. A random-ized trial comparing preoperative (preop) doxor-ubicin/cyclophosphamide (AC) to preop ACfollowed by preop docetaxel (T) and to preopAC followed by postoperative (postop) T inpatients with operable carcinomas of the breast:results of the NSABP B-27. Breast Cancer Res Treat2004; 88(suppl):S16.


8. Davidson NE, Morrow M. Sometimes a greatnotion—an assessment of neoadjuvant systemictherapy for breast cancer. J Natl Cancer Inst2005; 97:159–161.

9. Mamounas E. Sentinel lymph node biopsy afterneoadjuvant systemic therapy. Surg Clin N Am2003; 83:931–942.

10. Mamounas E. When should sentinel node biopsybe done when giving preoperative chemotherapy?Miami Breast Cancer Conference, Orlando, Flor-ida, February 20–23, 2008.

164 CHAPTER 8


9Primary Endocrine Therapy

Part I: Mastectomy After PrimaryEndocrine Therapy

CASE STUDY 30

History

A 71-year-old woman presented with a two-month history of a lump in the right breastassociated with altered breast contour andskin dimpling. There was no nipple dischargeand the patient had no previous breast prob-lems. She had undergone a screening mam-mogram several years earlier that wasreported as normal. The patient had no fam-ily history of breast or ovarian cancer and hadtwo children (eldest aged 40 years). She hadused hormone replacement therapy for abrief period of two months only.

Clinical Findings

Examination revealed an ill-defined mass inthe upper outer quadrant of the right breast,associated with alteration in contour of thebreast laterally. There was overt skin dim-pling but no evidence of infiltration or ulcer-ation of the skin. A firm nonmobile node waspalpable in the right axilla (E5) (Fig. 1).

Clinical Assessment

Locally advanced right breast cancer withprobable nodal involvement.

Investigations

Mammography

This revealed a spiculated mass lesion in thelower outer quadrant of the right breast mea-suring 35 mm in maximum diameter with theappearances of a carcinoma (Fig. 2A, B).

Breast Ultrasound

The sonographic correlate of this mammo-graphic abnormality was a 25- mm hypoechoicmass lesion with posterior attenuation (U5)

Figure 1 Figure 2

165


(Fig. 3A). Ultrasound examination of theright axilla confirmed the clinical impressionof malignant adenopathy (Fig. 3B).

Core Biopsy

Ultrasound-guided core biopsy (16-gauge nee-dle) of the right breast mass confirmed theclinical and radiological impression of malig-nancy and showed an invasive ductal carci-noma (grade II, ER positive, HER2 negative)[Fig. 4A (low power), B, C (high power)].

Diagnosis

Locally advanced right breast cancer (T4cN1).


It was recommended that the patientundergo primary endocrine treatment for aperiod of four months followed by a rightmastectomy and axillary surgery. Ultrasoundand possible core biopsy of the right axillarynodes were arranged to determine thepathological node status. In the event of a

Figure 3

Figure 4

166 CHAPTER 9


positive axillary node core biopsy, thepatient would proceed to a right axillarylymph node dissection (rather than sentinellymph node biopsy).


Core Biopsy Right Axillary Node

Metastatic carcinoma was present in a clini-cally suspicious right axillary node [Fig. 5A(low power), B (high power)].

CT Chest/Abdomen/Pelvis

No evidence of visceral metastases.

Bone Scan

No evidence of bony metastases.


The patient had a strongly ER-positive tumor(8/8) and received primary endocrine

treatment within the context of the MONETstudy, which randomizes patients to eitherfour months of exemestane or four monthsof tamoxifen as a preoperative schedule. Shesubsequently proceeded to a right modifiedradical mastectomy with a level II axillarylymph node dissection exactly four monthsafter initial presentation. A wide ellipse ofskin was removed to incorporate skin over-lying the tumor and the area of breast dis-tortion (Fig. 6).


This showed a grade III invasive ductal car-cinoma measuring 35 mm in maximumdiameter with associated DCIS. There wasno lymphovascular invasion but perineuralinvasion was noted (Fig. 7A). Five out of 18nodes harvested contained metastatic carci-noma and there was evidence of extra-capsular spread around one of the nodes[Fig. 7B, C (magnification 5�), D (magnifi-cation 10�)].

Discussion

This 74-year-old patient had a locallyadvanced right breast cancer that was tech-nically operable at presentation. Studies ofprimary endocrine treatment for locallyadvanced breast cancers have focused onhormonal manipulation as an alternative tosurgery rather than as neoadjuvant therapy.These studies often involved elderly patientswho were unfit for surgery, and the aim oftreatment was to control the tumor locallywithout surgical intervention using relativelynontoxic agents. Tamoxifen was initiallyFigure 5

Figure 6

PRIMARY ENDOCRINE THERAPY 167


used as primary endocrine therapy for thisgroup of patients with randomization toeither tamoxifen alone or surgery (with orwithout adjuvant tamoxifen) (1,2). A semi-nal study involving almost 400 patientsrandomized women over 70 years of agewith operable breast cancer to either tamox-ifen alone (40 mg) or tamoxifen followed byappropriate surgery (breast conservationor mastectomy). At a median follow-up of34 months, rates of local failure were higherin the tamoxifen-only group compared withthoseundergoing subsequent surgery (35%vs.20.5%) (1). Other studies have also reportedhigher local relapse rates in the tamoxifen-only group, particularly with longer follow-up(25–80%). However, no differences in overallsurvival were apparent for primary endocrinetreatment versus surgery or combined treat-ment. The GRETA trial randomized elderlypatients with hormone receptor–positivebreast cancer to either tamoxifen alone (235patients) or surgery followed by tamoxifen

(239 patients). The overall response rate was41.6% (complete clinical response rate 9.2%;partial clinical response rate 32.4%) andmedian duration of response 19 months. At amedian follow-up of 80 months, more thanhalf the patients had died, but there was nodifference in overall or breast cancer–survival.Local failure rates were fourfold higher in thetamoxifen-only group (2).

These early studies of tamoxifen as pri-mary endocrine therapy confirmed this to bean acceptable management option inselected patients, especially those consideredunfit for surgery. More recent studies haveaddressed the specific issue of neoadjuvantendocrine therapy in which a preoperativetreatment schedule with a hormonal agentforms a component of a planned, multimo-dality management strategy. Aromataseinhibitors have been compared with tamox-ifen in trials of neoadjuvant hormonal ther-apy and appear superior both in terms ofclinical response rates and eligibility for

Figure 7

168 CHAPTER 9


breast conservation surgery (3–5). TheMONET study compares tamoxifen withexemestane in a four-month preoperativeschedule. Though the possibility of breast-conserving surgery is a potential advantageof neoadjuvant endocrine treatment, somepatients will require mastectomy whateverthe tumor response. The case describedherein was borderline for breast conserva-tion; there was extensive skin tethering withalteration of breast contour. Nonetheless,the initial tumor size was <5 cm and themain tumor mass was not in proximity to thenipple.

It may be feasible to omit surgery inelderly patients who constitute a high anes-thetic risk when there has been a goodclinical/radiological response to primaryendocrine treatment. However, optimalmanagement incorporates surgical excisionafter a three- to four-month period of hor-monal treatment. This strategy will minimizepotential problems with local failure in thelonger term.

Patients should undergo sonographicassessment of the axilla and any suspiciousnodes biopsied. Those patients who arenode negative on clinical and ultrasoundassessment can proceed to sentinel lymphnode biopsy prior to commencement ofneoadjuvant endocrine treatment; for thosepatients who are less fit, a decision can bemade on whether to perform a level I or IIaxillary dissection at the time of surgerybased on primary tumor characteristics. Itis difficult to justify an additional surgicalprocedure (and general anesthetic) in thisgroup of older women.

Patients undergoing initial endocrinetreatment must be closely monitored andproceed to immediate surgery if there aresigns of clinical progression. A second-linehormonal agent can be used if the patient isunfit for surgery. Neoadjuvant endocrinetreatment may be an appropriate manage-ment option for younger premenopausalwomen with ER/PR-positive tumors whoare either unfit or unwilling to undergoneoadjuvant chemotherapy. An aromataseinhibitor could in theory be combined withan LHRH analogue in this setting to max-imize response rates and clinical outcomes.

Related Cases

Primary endocrine treatment—Case Studies31, 32, and 33

Locally advanced breast cancer—Case Studies27, 28, 29, and 31

Learning Points

1. There are several ongoing clinical trialscomparing the use of pre- and post-operative endocrine therapy. To date,there is no evidence that preoperativeendocrine therapy is associated with asurvival advantage.

2. Preoperative endocrine therapy takeslonger to achieve an objective response(3–6 months) than preoperative chemo-therapy (2–3 months).

3. In patients with ER-positive tumors, pre-operative endocrine therapy results inan objective response rate of about 70%,but it generally takes at least threemonths to achieve a response.

4. Preoperative endocrine therapy hasfewer side effects than preoperative che-motherapy. Additionally, the endocrinetherapy can be continued during theperioperative period.

References

1. Bates T, Riley DL, Houghton J, et al. Breast cancerin elderly women: a Cancer Research Campaigntrial comparing treatment with tamoxifen and opti-mal surgery with tamoxifen alone. The ElderlyBreast Cancer Working Party. Br J Surg 1991;78:591–594.

2. Mustacchi G, Milani S, Pluchinotta A, et al. Tamox-ifen or surgery plus tamoxifen as primary treat-ment for elderly patients with operable breastcancer: The GRETA Trial. Group for Researchon Endocrine Therapy in the Elderly. AnticancerRes 1994; 14:197–200.

3. Eiermann W, Paepke S, Appfelastaedt J, et al. Pre-operative treatment of post-menopausal breast can-cer with letrozole: a randomized double-blindmulticenter study. Ann Oncol 2001; 12:1527–1532.

4. Smith I, Dowsett M, Ebbs SR, et al. Neoadjuvanttreatment of post-menopausal breast cancer withanastrozole, tamoxifen or both in combination: theImmediate Preoperative Anastrozole, Tamoxifenor Combined with Tamoxifen (IMPACT) Multi-center Double-Blind Randomized trial. J ClinOncol 2005; 23:5108–5116.



5. Semiglazov V, Kletzel A, Semiglazov V, et al.Exemestane versus tamoxifen as neoadjuvantendocrine therapy for postmenopausal women

with ER positive breast cancer. ASCO AnnualMeeting, Orlando, Florida, 2005.

CASE STUDY 31

History

A 57-year-old woman was recalled from rou-tine screening mammography with a largeclinical carcinoma of the left breast. Thepatient suffered from schizophrenia andlived in a nursing home. On direct question-ing, the lesion in the left breast had beenpresent for several months and had recentlybecome ulcerated and malodorous. Thepatient reported no nipple discharge andthough she had lost some weight over thepreceding few months, there was no historyof any unusual cough or back pain. Therewas no family history of breast cancer andthe patient was nulliparous with no priorusage of either the oral contraceptive pillor hormone replacement therapy.

Clinical Findings

There was a large diffuse tumor involvingpredominantly the lower outer quadrant ofthe left breast. The tumor measured at least5 cm clinically and was associated withindrawing of the nipple and general contrac-ture of the breast. A minor degree of ulcer-

ation and infection was present close to thenipple. There was no axillary lymphadenop-athy and no hepar (E5) (Fig. 8A and B).

Clinical Assessment

Locally advanced left breast cancer present-ing through the screening program.

Investigations

Mammography

Mammography was not feasible due to thebulky nature of the tumor and ulceration(patient referred directly from the screeningservice without mammography being under-taken).

Breast Ultrasound

The size of the tumor precluded accuratesonographic measurement (U5) (Fig. 9).

Core Biopsy

Freehand core biopsy of the large left breastmass confirmed an invasive lobular carcinoma

Figure 8

170 CHAPTER 9


(grade II) [Fig. 10A (magnification 20�)].This stained positively for ER [Fig. 10B (mag-nification 20�)].

Diagnosis

Locally advanced left breast cancer (T4cN0).


Following multidisciplinary discussion, it wasrecommended that the patient be com-menced on letrozole as primary endocrinetreatment. Though technically inoperable atthe time of presentation, it was anticipatedthat the tumor would become amenable tosurgery at a future date.


The patient commenced primary endocrinetreatment and was monitored three monthlyin the breast clinic. It was apparent that thepatient was not keen on any form of surgicalintervention, whatever the subsequentresponse of the tumor to endocrine treat-ment. Upon review after three months, thetumor measured approximately 40 mm inmaximum diameter with the impression of apartial response. Letrozole was continuedand calcium and vitamin D supplementscommenced to prevent bone attrition(bone density scan not undertaken). It isanticipated this patient will undergo mastec-tomy at an appropriate juncture.

Discussion

In the absence of bony metastases, largelocally advanced breast cancers are usuallypainless and do not interfere with a patient'sdaily activities. Referral for a medical opin-ion is often prompted by the offensive odorfrom secondary infection of an ulcerated,fungating lesion. Occasionally troublesomebleeding from an exophytic tumor causes apatient to seek medical attention.

Breast screening is futile when a patientpresents with a clinically advanced lesion.There is now much greater public awarenessof breast cancer within the general popula-tion, but sometimes there is an element ofdenial and patients may fear being told agrowth is malignant. This patient had a his-tory of mental illness and curiously lived in anursing home. It is perhaps odd that hercarers had not noticed the breast cancer atan earlier stage, which was eventually pickedup by radiographers at the time of attendancefor routine breast screening.

Figure 9

Figure 10



This patient's tumor was technically inop-erable and fixed to the underlying chest wall.It was anticipated that surgical resectionwould be possible after downstaging withprimary endocrine therapy. As the patientwas relatively young without evidence of dis-tant metastases, local control of disease wasimportant. It was unlikely that sequentialendocrine therapy would adequately controlthe tumor in the longer term and specificlocoregional treatment would be necessary.

By analogy with neoadjuvant chemother-apy, hormonal treatment can be used preop-eratively with the intention of downstagingtumors (1–3). This may render inoperabletumors operable and permit breast conserva-tion in patients who might otherwise requiremastectomy (4,5). Hormonal therapies areless toxic and potential side effects of che-motherapy can be avoided in elderly patientsand those with a poor performance status.This particular patient was relatively youngand physically fit, but her schizophrenia wasconsidered a relative contraindication tochemotherapy. Interestingly, patients withhormone receptor–positive disease are lesslikely to achieve a complete pathologicalresponse from the preoperative chemother-apy schedule (6). The aromatase inhibitorshave consistently outperformed tamoxifen inthe neoadjuvant setting, when endpointsinclude not only response rates but alsobreast conservation rates.

In a study of patients with hormonallyresponsive locally advanced and inoperablebreast cancer, letrozole (2.5 mg/day) admin-istered as a preoperative schedule for fourmonths yielded significantly better responserates compared with tamoxifen (20 mg/day)given over a similar period (55% vs. 36%,p < 0.001) (7). A significantly higher pro-portion in the letrozole group was suitablefor breast conservation after induction hor-monal treatment (45% vs. 35%, p < 0.022).The IMPACT study (Immediate Preopera-tive Arimidex, Tamoxifen or Combinedwith Tamoxifen) randomized patients to athree-month preoperative schedule of anas-trozole, tamoxifen, or a combination of thetwo. There was no statistically significant

difference in response rates (37.2%, 36.1%,and 39.4%,), though anastrozole was moreeffective at downstaging tumors to permitbreast-conserving surgery according to sur-geon assessment (8). Therefore, letrozole isassociated with higher response rates in theneoadjuvant setting (55% vs. 37.2%), and invitro studies suggest that letrozole is morethan 10-fold potent than anastrozole atinhibiting aromatization. Moreover, letro-zole induces a more profound decrease inwhole body aromatization and levels ofplasma estrogen in postmenopausal breastcancer patients than anastrozole (9). Forpatients with locally advanced tumors,which demonstrate relatively rapid clinicalprogression or are bleeding, radiotherapymay help with local control until hormonaltherapies have taken effect (2–3 months).

Related Cases


Locally advanced breast cancer—Case Studies27, 28, 29, and 30

Learning Points

1. Preoperative endocrine therapy maydownstage breast cancer, either makinginoperable tumors operable or reducinglarge operable tumors to a size at whichbreast-conserving surgery rather thanmastectomy can be performed.

2. Patients with ER-positive tumors are lesslikely to achieve a complete pathologicalresponse from preoperative chemother-apy than those with ER-negative tumors.Only patients with ER-positive tumorsare suitable candidates for preoperativeendocrine therapy.

3. In the preoperative setting, betterresponse is generally achieved with thearomatase inhibitors than tamoxifen.

References

1. Veronesi U, Frustaci S, Tirelli U, et al. Tamoxifentherapy in post-menopausal advanced breast

172 CHAPTER 9


cancer: efficacy at the primary tumour site in 46evaluable patients. Tumori 1981; 67:235–238.

2. Gazet JC, Ford HT, Coombes RC, et al. Rando-mised trial of chemotherapy versus endocrine ther-apy in patients presenting with locally advancedbreast cancer (a pilot study). Br J Cancer 1991;63:279–282.

3. Ellis MJ, Coop A, Singh B, et al. Letrozole is moreeffective neoadjuvant endocrine therapy thantamoxifen for ErbB-1 and/or ErbB-2 positive estro-gen receptor positive primary breast cancer:evidence from a phase III randomized trial.J Clin Oncol 2001; 19:3808–3816.

4. Fisher B, Bryant J, Wolmark N, et al. Effect ofpreoperative chemotherapy on the outcome ofwomen with operable breast cancer. J Clin Oncol1998; 16:2672–2685.

5. Wolmark N, Wang J, Mamounas E, et al. Preoper-ative chemotherapy in patients with operablebreast cancer: nine year results from National Sur-gical Adjuvant Breast and Bowel Project. B-18.J Natl Cancer Inst Monogr 2001; 30:96–102.

6. Buzdar A, Valero V, Theriault RL, et al. Patholog-ical complete response to chemotherapy is relatedto hormone receptor status. Breast Cancer ResTreat 2003; 82:(abstr 302).

7. Eiermann W, Paepke S, Appfelastaedt J, et al. Pre-operative treatment of post-menopausal breast can-cer with letrozole: a randomized double-blindmulticenter study. Ann Oncol 2001; 12:1527–1532.

8. Smith I, Dowsett M, Ebbs SR, et al. Neoadjuvanttreatment of post-menopausal breast cancer withanastrozole, tamoxifen or both in combination: theImmediate Preoperative Anastrozole, Tamoxifenor Combined with Tamoxifen (IMPACT) Multi-center Double-Blind Randomized trial. J ClinOncol 2005; 23:5108–5116.

9. Geisler J, Haynes B, Anker G, et al. Influence ofletrozole and anastrozole on total body aromatiza-tion and plasma estrogen levels in postmenopausalbreast cancer patients evaluated in a randomized,cross-over study. J Clin Oncol 2002; 20:751–757.

Part II: Breast-Conservation SurgeryAfter Primary Endocrine Therapy

CASE STUDY 32

History

A 56-year-old woman presented with a two-week history of a lump in the right breast.There was no associated nipple dischargeand the lump was nontender. Curiously,the patient had undergone a routine screen-ing mammogram two weeks earlier and wasawaiting results of this. She had never beenrecalled from any screening mammogramsand had no previous breast problems. Thepatient had a maternal aunt with postmeno-pausal breast cancer and was currently tak-ing hormone replacement therapy (totalduration of usage 20 years). She had brieflyused the oral contraceptive pill for a periodnot exceeding 12 months in her youth.

Clinical Findings

An ill-defined but firm mass was palpable inthe upper outer quadrant of the right breastmeasuring 3 cm in maximum diameter.There was dimpling of the overlying skinbut no nipple abnormalities. A clinically sus-picious node was palpable in the right axilla(E5) (Fig. 11).

Clinical Assessment

The clinical impression was highly suggestiveof a right breast cancer with an involvedaxillary lymph node (despite a recent screen-ing mammogram).



Investigations

Mammography (Right)

A spiculate opacity was seen in the upperouter quadrant of the right breast measuring

28 mm in maximum diameter (R5)(Fig. 12A and B). Previous screening mam-mograms were requested for review and aleft-sided mammogram was not repeated.

Breast Ultrasound

The sonographic correlate of this opacitywas a slightly smaller hypoechoic lesionwith a maximum diameter of 23 mm. Thelesion was heterogeneous with posterioracoustic enhancement and had the radiolog-ical features of a carcinoma (U5) (Fig. 13A).The palpable right axillary node was sono-graphically suspicious (Fig. 13B).

Core Biopsy

Ultrasound-guided core biopsy of the rightbreast mass confirmed a carcinoma. The

Figure 11

Figure 12

Figure 13

174 CHAPTER 9


appearances were of a solid papillary lesionwith probable areas of focal invasion (ERpositive, HER2 negative) (Fig. 14).

Diagnosis

Probable early-stage invasive right breast can-cer with nodal involvement (T2N1)


Recent screening mammograms (performedelsewhere) were reviewed together withresults of the right breast core biopsy.Though the core biopsies had not shownunequivocal evidence of invasion, there waspalpable right axillary lymphadenopathy.Core biopsy of the right axillary node (withultrasound guidance) was therefore recom-mended to confirm invasive carcinoma. Inaddition to a right-sided breast cancer, therecent screening films revealed a localizedarea of suspicious microcalcification in theleft breast, which required further evaluationand probable biopsy (Fig. 15A–D).


Arrangements were made for the patient toattend for further investigations as follows:

1. Core biopsy right axillary lymph node—ultrasound-guided core biopsy of theright axillary node revealed extensive

replacement with metastatic carcinoma[Figs. 16A (magnification 10�), B (mag-nification 20�)].

2. Left breast ultrasound—the area ofmicrocalcification in the left breast wasassociated with a 4 mm mass lesion (U5)(Fig. 17).

3. Core biopsy left breast—ultrasound-guided core biopsy of the mass/area ofcalcification showed an invasive carci-noma (grade I, ER positive) [Figs. 18A(magnification 10�), B (magnification20�)]. There was a single fleck of cal-cium on specimen radiology (Fig. 19).


The patient had a histologically documentednode-positive breast cancer on the right sideand a small 4-mm grade I clinically node-negative cancer of the left breast. After thor-ough multidisciplinary discussion, it was

Figure 14

Figure 15



recommended the patient be treated withprimary endocrine therapy in the event ofHER2 negativity (subsequently confirmedfrom core biopsy results). The alternativemanagement option was neoadjuvant che-motherapy, but the estimated absolute ben-efits from chemotherapy were less than 2%,which were insufficient to justify this treat-ment option. Following induction endocrinetreatment, the patient would undergo surgeryas follows (i) a right wide local excision andaxillary dissection and (ii) a left guidewire-localized wide local excision. A left sentinellymph node biopsy would be carried outshortly after commencement of endocrinetreatment to stage the left axilla early on.


Bilateral breast coils were inserted to aidsubsequent identification of the tumors atthe time of surgical excision. A left sentinel

node biopsy was carried out three weeks aftercommencement of primary endocrine treat-ment and revealed no evidence of nodalmetastases. The patient received primaryendocrine treatment within the MONETstudy, which randomizes older patients withhormone sensitive locally advanced tumors toeither exemestane or tamoxifen for a periodof four months prior to definitive surgery.

Discussion

This patient with bilateral breast cancers wasfaced with complex management options,which included primary surgery, primarychemotherapy, or primary endocrine treat-ment. It is perhaps unusual for a singlepatient to be potentially suitable for initialtreatment with these three modalities. Thispatient had a moderate sized, node positive,right-sided breast cancer and a smallnode negative left-sided lesion (both ERpositive). Primary surgery would be the con-ventional management with a right widelocal excision and axillary dissectiontogether with a left-sided wire-localizedwide local excision and sentinel lymphnode biopsy. Though this patient hadnode-positive disease, her postmenopausalstatus, tumor size, and negative HER2 statusconferred an absolute benefit from chemo-therapy of less than 2%. It is inappropriate togive neoadjuvant chemotherapy when apatient is unlikely to derive significant ben-efit based on known tumor parameters andnodal status.

Figure 16

Figure 17

176 CHAPTER 9


Neoadjuvant endocrine treatment offersseveral advantages for older, postmeno-pausal women with hormone receptor–positive breast cancer (1). Like neoadjuvantchemotherapy, primary endocrine treat-ment permits translational studies on

predictive and prognostic markers—the pri-mary tumor remains in situ and is accessiblefor serial core biopsies. The proliferationmarker Ki67 can be measured immunohis-tochemically and shows a dramatic responseto neoadjuvant endocrine treatment (2).Moreover, clinical response can be assessedduring induction therapy, which is an indi-cation of the efficacy of a hormonal agent ata biological level, though generally corre-lates poorly with clinical outcomes. Effectiveagents in the neoadjuvant setting could beassessed with surrogate predictors of clinicaloutcome (e.g., Ki67) and incorporatedsooner into standard treatment protocols(3). Though this patient had relativelysmall tumors, larger more locally advancedtumors that invade the skin or chest wall andhave extensive nodal involvement can pres-ent technical challenges at operation. Aperiod of treatment with primary endocrinetherapy can downstage tumors and permitsurgical resection. In a recent study involvingalmost 100 women with T4 tumors, morethan 90% became resectable after three tosix months of tamoxifen (1).

Primary endocrine treatment with tamox-ifen has been used as the exclusive treatmentfor elderly unfit patients with breast cancer(4,5). Though longer-term local controlrates are poorer when surgery does not fol-low induction endocrine treatment, earlyresponse rates are high in ER-positivepatients (30–40%) (6). Moreover, diseaseprogression within three to six months isuncommon and neoadjuvant endocrinetherapy does not compromise overall sur-vival. Neoadjuvant endocrine therapy canbe employed in fit older patients with theaim of improving rates of breast conserva-tion as well as operability (7). Several trialshave now confirmed the superiority of aro-matase inhibitors in this context, which con-sistently outperform tamoxifen whenendpoints include not only response ratesbut also breast conservation rates.

These highly favorable response rates forletrozole in the neoadjuvant setting havebeen exceeded by exemestane in a trialcomparing this steroidal aromatase inhibitorwith tamoxifen (8). The overall clinicalresponse rates to three months of neoadjuvant

Figure 18

Figure 19



exemestane (25 mg daily) or tamoxifen were76.3% and 40% (p < 0.05). MONET is anongoing study that randomizes postmeno-pausal women with hormone receptor–positive locally advanced breast cancer(>2 cm ultrasound size) to either fourmonths of exemestane or tamoxifen as apreoperative schedule. This patient hadbilateral breast cancers, which were alreadypotentially conservable and could have beenmanaged with bilateral wide local excision. Itis possible that a survival advantage mightensue from neoadjuvant endocrine treat-ment. The act of surgery is associated witha systemic perturbation, which involves therelease of various growth factors (vascularendothelial growth factor, epidermal growthfactor, insulin-like growth factor) and loss oftumor suppressor factors (angiostatin). Pre-operative systemic therapy could theoreti-cally offset any tumor-promoting effects ofsurgical excision (namely on distant micro-metastases) (9).

Therefore primary hormonal therapies inolder postmenopausal women with hor-mone-responsive disease can avoid thepotential toxicities of chemotherapy, whileachieving good response rates, which in turntranslate into improved rates of operabilityand breast conservation. Tumors are usuallymore than 3 cm in size, but smaller tumorscan be managed with neoadjuvant endo-crine treatment, as with the case reportedherein. The optimal duration of primaryendocrine treatment is unknown, but maxi-mum tumor responses are seen after 12 to15 months of treatment. In about 20% ofcases, maximal responses are seen at12 months and there is an argument formore prolonged therapy to increase thechance of breast-conserving surgery. Com-plete pathological responses are uncommonand neoadjuvant endocrine treatmentshould ideally be incorporated into a preop-erative schedule rather than single modalitytreatment, which might involve sequentialendocrine therapies but ultimately poorrates of local control in the longer term.Though rates of tumor regression may beslower with neoadjuvant endocrine treat-ment compared with chemotherapy, overallresponse rates appear similar for this group

of ER-positive women. Sentinel lymph nodebiopsy has been investigated following neo-adjuvant endocrine treatment (10), but theoptimal timing of this procedure remainsunclear; within the MONET study, sentinellymph node biopsy is undertaken at thebeginning of endocrine treatment andinvolves a separate operation that is notalways appropriate in older patients.

Related Cases



Learning Points

1. Prior to preoperative systemic therapy,metal clips are often inserted within thetumor (at time of core biopsy). After pre-operative systemic therapy, these clipsenable the radiologist to visualize thesite of the original tumor mammograph-ically, thereby facilitating placement of awire to aid in wide local excision.

2. Longer follow-up of clinical trials isneeded to determine if there are anydifferences in local recurrence or sur-vival rates between patients receiving pre-and postoperative endocrine therapy.

References

1. Beresford MJ, Ravichandran D, Makris A. Neo-adjuvant endocrine therapy in breast cancer. Can-cer Treat Rev 2007; 33:48–57.

2. Ellis MJ, Coop A, Singh B, et al. Letrozole inhibitstumour proliferation more effectively than tamox-ifen independent of HER1/2 expression status.Cancer Res 2003; 63:6523–6531.

3. Dowsett M, Smith IE, Ebbs SR, et al. Short-termchanges in Ki-67 during neoadjuvant treatment forprimary breast cancer with anastrozole or tamox-ifen alone or combined correlate with recurrence-free survival. Clin Cancer Res 2005; 11:951s–958s.

4. Allan SG, Rodger A, Smyth JF, et al. Tamoxifen asprimary treatment of breast cancer in elderly orfrail patients: a practical management. Br Med J1985; 290:358.

5. Akhtar SS, Allan SG, Rodger A, et al. A 10 yearexperience of tamoxifen as primary treatment ofbreast cancer in 100 elderly and frail patients. Eur JSurg Oncol 1991; 17:30–35.

178 CHAPTER 9


6. Bates T, Riley DL, Houghton J, et al. Breast cancerin elderly women: a Cancer Research Campaigntrial comparing treatment with tamoxifen and opti-mal surgery with tamoxifen alone. The ElderlyBreast Cancer Working Party. Br J Surg 1991;78:591–594.

7. Gazet JC, Ford HT, Coombes RC, et al. Prospectiverandomized trial of tamoxifen versus surgery inelderly patients with breast cancer. Eur J SurgOncol 1994; 20:207–214.

8. Semiglazov V, Kletzel A, Semiglazov V, et al.Exemestane versus tamoxifen as neoadjuvantendocrine therapy for postmenopausal women

with ER positive breast cancer. ASCO AnnualMeeting, Orlando, Florida, 2005.

9. Baum M, Benson JR. Current and future roles ofadjuvant endocrine therapy in managementof early carcinoma of the breast. In: Senn H-J,Goldhirsch RD, Gelber RD, et al., eds. RecentResults in Cancer Research 140—Adjuvant Ther-apy of Breast Cancer. Hiedelberg: Springer–Verlag,1996:215–226 (ISBN 3-540 58454-4).

10. Aihara T, Munakata S, Morino H, et al. Feasibilityof sentinel node biopsy for breast cancer afterneoadjuvant endocrine therapy: a pilot study.J Surg Oncol 2004; 85:77–81.

PRIMARY ENDOCRINE THERAPY 179SW

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10Breast Cancer in the Elderly

Part I: Primary Endocrine Therapy

CASE STUDY 33

History

A 92-year-old woman presented with a four-week history of a lump in the left breast.There was no associated nipple dischargeand the patient had no previous breast prob-lems being otherwise fit and active for herage. She had a very weak family history ofbreast cancer with a paternal cousin havingthe disease in her 40s. The patient wasnulliparous and had never used hormonereplacement therapy.

Clinical Findings

Examination revealed a firm, ill-definedmass in the upper outer quadrant of theleft breast measuring approximately 2 cm(Figs. 1 and 2A). The mass was mobile onthe chest wall with subtle evidence of skintethering in the vicinity of the lump, whichwas more evident with the arms elevated(Fig. 2B). No axillary lymph nodes werepalpable (E4).

Clinical Assessment

Clinical carcinoma of the left breast withoutinvolved axillary lymph nodes.

Investigations

Mammography

A spiculate opacity measuring 20 mm inmaximum diameter was seen in the upperFigure 1

Figure 2

180


outer quadrant of the left breast correspond-ing to the palpable lump (Fig. 3).

Breast Ultrasound

The sonographic correlate of this mass was a20-mm hypoechoic lesion with the radiolog-ical features of a carcinoma (U5) (Fig. 4).

Core Biopsy

Ultrasound-guided core biopsy of the breastmass confirmed an invasive carcinoma(grade II) that was strongly ER positive(Fig. 5A (magnification 10�), B (magnifica-tion 20�)]a

Diagnosis



It was recommended that the patient bemanaged with primary endocrine treatment.Though the patient was very fit for her agewith no significant comorbidities, she wasreluctant to embark upon any surgery, andthis was considered inappropriate in anonagenerian.


The patient was initially reviewed fourmonthly within the breast unit, but subse-quently discharged back to the care of hergeneral practitioner for clinical monitoring.This avoided unnecessary visits to the hospi-tal and both the district nurse and generalpractitioner were able to undertake domicil-iary visits.

Figure 3

Figure 4

Figure 5

a Allred score ¼ 8/8

BREAST CANCER IN THE ELDERLY 181


Discussion

See discussion for Case Study 30.

Related Cases

Breast cancer in the elderly—Case Studies 24,34, and 43


Learning Points

1. Elderly women with ER-positive breastcancer are sometimes offered endocrine

therapy alone (without surgery). This isreferred to as primary endocrine therapy.

2. Primary endocrine therapy for ER-positive breast cancers is generally offeredto elderly women who are unfit for orrefuse surgery.

3. In elderly women with breast cancer,surgery achieves better local control ofthe tumor than does primary endocrinetherapy, but it does not seem to extendsurvival.

Part II: Primary Radiotherapy

CASE STUDY 34

History

An 87-year-old woman presented with a six-month history of a lump in the left breast.The lump had progressively increased in sizeand recently had become ulcerated andstarted bleeding when touched. The patientlived alone and friends had prompted her toseek medical attention due to the malodor-ous nature of the lesion. There was noassociated nipple discharge and no previousbreast problems or family history of breastcancer. The patient had not experiencedany recent weight loss, unusual back pain,or cough.

Clinical Findings

On examination there was a florid exophyticlesion in the inferior aspect of the leftbreast, which was ulcerated and infected.The lesion measured at least 5 cm in max-imum dimension and was partially fixed tothe chest wall. The surface of the lesion wasvery friable and readily bled. No enlargednodes were palpable in the left axilla (E5)(Figs. 6 and 7).

Clinical Assessment

Large fungating cancer of the left breast withulceration and secondary infection.

Investigations

Mammography

Mammography was precluded by the sizeand ulceration of the lesion.

Breast Ultrasound

A solid mass was seen in the lower outerquadrant of the left breast, which was ill

Figure 6

182 CHAPTER 10


defined and homogeneous. The echo patternwas hypoechoic and the appearances were of alarge fungating tumor (U5) (Fig. 8A, B).

Core Biopsy

Freehand core biopsy of the left breast massconfirmed an invasive carcinoma (grade III)that was ER negative (Fig. 9A (low power), B(high power)). The Allred score was 0/8 andthis was repeated to reaffirm hormone insen-sitivity. Interestingly, there was a suggestionhistologically that this might be a squamouslesion and this would be consistent with thegross morphology.

Diagnosis

Locally advanced fungating left breast cancer(T4N0).


Following multidisciplinary discussion, it wasfelt appropriate to embark on primary radio-therapy. The patient was elderly and unfitfor surgery and the tumor was ER negative.

Radiotherapy would help reduce the degreeof ulceration and “dry up” the lesion.Arrangements were made for the patient tobe seen in the radiotherapy clinic later onthat day and for treatment to commence assoon as possible. It was noted that the patienthad been admitted as an inpatient since heroriginal attendance in the breast clinic oneweek earlier. This was attributable to thepatient's psychological rather than physicalcondition and routine blood tests includingfull blood count, urea and electrolytes, liverfunction tests, and calcium were within thenormal range.


The patient received a single fraction ofradiotherapy using a direct field of 260 kVto a dose of 8 Gy. She tolerated this well andclinical review after 14 days showed amarked improvement in the tumor withattainment of hemostasis.

Figure 7

Figure 8

BREAST CANCER IN THE ELDERLY 183


Discussion

This elderly patient had a locally advancedcarcinoma that had become ulcerated withtroublesome bleeding. She was otherwisewell with no evidence of any distant meta-static disease and had previously lived aloneand independently. She was unfit for anyprimary surgical intervention and thetumor was hormone receptor negative. Shetolerated a short course of radiotherapy tothe breast and there was evidence of amarked clinical improvement within twoweeks.

Primary radiotherapy for locally advancedtumors is usually a salvage option andemployed in lieu of surgery or endocrinetreatment for elderly and/or unfit patients(1,2). Studies have shown that relatively highdoses of radiation must be used to achieveoptimal control (up to 60 Gy) (1) and thiscan be associated with significant side effectssuch as skin ulceration and rib necrosis (3).

This patient had a relatively small dose of8 Gy as a single fraction with the aim ofdrying up the tumor and preventing furtherbleeding. More definitive local control isonly possible with either much higherdoses of radiotherapy or a combination ofradiotherapy and surgery, which can resultin local control rates of more than 70% to80% (4). However, combined treatments donot lead to improvements in overall survivalcompared with either modality alone (5).

Related Cases

Locally advanced breast cancer—Case Studies28, 30, and 31

Breast cancer in the elderly—Case Studies 24,33, and 43

Learning Points

1. Elderly patients with locally advancedER-negative breast cancers might beoffered radiotherapy alone. This is referredto as primary radiotherapy. Elderly womenwho undergo primary radiotherapy havegenerally refused or are unfit for surgery.

2. Primary radiotherapy may achieve localcontrol of a locally advanced breast can-cer and thereby result in an improvedquality of life.

References

1. Harris JR, Sawicka J, Gelman R, et al. Managementof locally advanced carcinoma of the breast byprimary radiation therapy. Int J Radiat OncolBiol Phys 1983; 9:345–349.

2. Sheldon T, Hayes DF, Cady B, et al. Primary radi-ation therapy for locally advanced breast cancer.Cancer 1987; 60:1219–1225.

3. Spanos WJ Jr., Montague ED, Fletcher GH. Latecomplications of radiation only for advancedbreast cancer. Int J Radiat Oncol Biol Phys 1980;6:1473–1476.

4. Sorace RA, Lippman M. Locally advanced breastcancer. In: Lippman M, Lichter A, Danforth D,eds. Diagnosis and Management of Breast Cancer.Philadelphia: WB Saunders, 1988.

5. Hortobagyi G, Buzdar AU. Locally advanced breastcancer: a review including the MD Anderson expe-rience. In: Ragaz J, Ariel I, eds. High Risk BreastCancer. Berlin: Springer-Verlag, 1991.

Figure 9

184 CHAPTER 10


11Pregnancy-Related Breast Cancer

Part I: First Trimester Pregnancy

CASE STUDY 35

History

A 34-year-old woman who was nine-weekspregnant presented with a lump in the supe-rior aspect of the right breast that had beenpresent for approximately two years. Thelump had been previously investigated else-where and fine needle aspiration cytologyperformed—the latter was classified as “C1.”The patient felt that the lump had recentlyincreased in size and therefore sought asecond opinion. There was no family historyof breast or ovarian cancer and this was thepatient's first pregnancy. She had used theoral contraceptive pill for a cumulativeperiod of more than 10 years.

Clinical Findings

Examination revealed a rather ill-definedmass in the upper outer quadrant of theright breast measuring 3 cm in maximumdiameter. There was an adjacent noduleestimated at no more than 1 cm in size andno skin tethering or axillary lymphadenop-athy (E3) (Fig. 1).

Clinical Assessment

Clinically suspicious, though likely benignlump in first trimester of pregnancy.

Investigations

Breast Ultrasound

This showed a dumbbell solid mass in theupper outer quadrant of the right breastmeasuring 37 mm in maximum diameter.The mass was ill-defined, though homoge-neous with a hypoechoic pattern andposterior acoustic enhancement. Theappearances were indeterminate and couldnot distinguish between a possible fibroade-noma or a carcinoma (U3).

Core Biopsy

Ultrasound-guided core biopsy (14-gaugeneedle) of the right breast mass confirmedan invasive carcinoma (grade II, ER positive)(Fig. 2).

Figure 1 Figure 2

185


Diagnosis

Early-stage right-sided breast cancer in thefirst trimester of pregnancy (T2N0).


The patient was adamant from the outsetthat she wished to continue with the preg-nancy; this was a “cherished” pregnancy in a34-year-old woman with no existing children.Two potential treatment pathways were out-lined and carefully discussed with thepatient:

1. Neoadjuvant chemotherapy (commenc-ing at 12 weeks) followed by surgery anda possible course of taxanes postdelivery.It was likely that surgery would involve aright modified radical mastectomy andimmediate breast reconstruction couldbe offered in the postpartum period.

2. Proceed with mastectomy within three-to four-weeks time and prescribe chemo-therapy as adjuvant treatment. Thepatient could subsequently undergodelayed breast reconstruction at a laterdate.


The patient expressed some reluctanceabout receiving chemotherapy during preg-nancy, but was reassured that there was noevidence for any detrimental effects on thefetus when chemotherapy is given during the

second or third trimester (when organogen-esis is complete). The patient enquiredabout the possibility of undergoing primarysurgery and delaying chemotherapy untilafter the birth of her child. It was pointedout that any significant delay in commencingchemotherapy might impact on overall sur-vival. It was suggested that adjuvant chemo-therapy, should this be required, could begiven in the third trimester. This could befollowed by early induction and safe deliveryof the baby and completion of chemother-apy thereafter.

After much detailed discussion, includ-ing the possibility of breast-conserving sur-gery after any downstaging by neoadjuvantchemotherapy, the patient opted for pri-mary surgery with a modified radical mas-tectomy and level II axillary lymph nodedissection (level III axillary dissection ifevidence of extensive nodal disease at thetime of surgery). Surgery was planned forthe beginning of the second trimester and adating scan was carried out at 12 weeks.There were no fetal complications and thepatient made an uneventful recovery fromsurgery. She had a normal full term deliveryat 39 weeks.


This revealed a grade II invasive ductal car-cinoma measuring 15 mm in maximumdiameter (Fig. 3A). There was associatedDCIS but this did not extend beyond the

Figure 3

186 CHAPTER 11

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invasive component. Lymphovascular inva-sion was not present and none of the 28nodes contained metastatic tumor (Fig. 3B).


The final pathological tumor size was muchless than the clinical and sonographic esti-mate. The calculated NPI was [0.2 � 1.5] þ2 þ 1 ¼ 3.30 and the patient would receive anabsolute benefit from chemotherapy of <3%.It was therefore recommended that shereceive tamoxifen as adjuvant systemic hor-monal therapy and ovarian suppressionshould be discussed (ER-positive tumor).


The patient declined tamoxifen and did notwant any form of ovarian suppression. Shesubsequently become pregnant for a secondtime and has recently given birth to a secondhealthy child almost three years after herinitial cancer diagnosis. She remains welland will undergo biennial mammographyof the contralateral breast until the age of50 years when she will enter the NHS BreastScreening Programme.

Discussion

It is estimated that pregnancy-associatedbreast cancer has an incidence of approxi-mately 3% and about 3 out of every 10,000pregnant women are diagnosed with breastcancer (1). Increasing numbers of womenare pursuing careers and deferring child-birth until the fourth or even fifth decade.Not only is this a likely contributory factor tothe inexorable rise in incidence of breastcancer, but women will bear children at anage when breast cancer is much more com-mon (2).

This 34-year-old professional woman wasdiagnosed with breast cancer during the firsttrimester of her pregnancy. This set of cir-cumstances therefore intensified the emo-tional impact of a breast cancer diagnosis.Moreover, the lump had been present foralmost two years and was previously investi-gated with an inadequate (C1) cytology spec-imen, which should have been repeated—or

a core biopsy undertaken. It is possible thepatient was falsely reassured by these earlierinvestigations and did not seek further med-ical opinion despite persistence of the lump.It was the recent increase in size of the lumpthat had prompted a second opinion. Per-haps ironically, physiological changes in thebreast during pregnancy can obscurea breast mass and cause significant delays(6–12 months) in diagnosis. This applies toboth clinical assessment and mammographywhere the increased breast density and watercontent reduce the innate sensitivity. Thepatient was below the age threshold forsymptomatic mammography (35 years) butpregnancy itself is not a contraindication tothis mode of imaging provided that appro-priate abdominal shielding is employed (3).However, many breast units rely exclusivelyon breast ultrasound examination that can beused to guide percutaneous tissue biopsy (4).

Management options for the pregnantpatient with breast cancer can be complex(5); there are potentially two lives at risk withcompeting priorities for treatment programs.On the one hand the mother's breast cancermust be optimally managed to maximize sur-vival outcome. On the other, the health andviability of the fetus must be preserved andnot compromised by cancer treatments (6).

Therapeutic abortion should be consid-ered during the first trimester. This patientpresented at nine weeks with a “cherished”pregnancy and adamantly refused to con-template termination. The options of pri-mary chemotherapy versus primary surgerywere discussed and it was explained thatthere was no evidence for any overall survivaldifference in the absence of a completepathological response to induction chemo-therapy. The patient was particularly averseto receiving chemotherapy during preg-nancy (7,8) and opted for primary surgerywith a modified radical mastectomy. Nocomplications were reported among agroup of 24 patients treated mainly duringthe second and third trimesters of preg-nancy with 5-fluorouracil, cyclophospha-mide, and doxorubicin (4 cycles) (7). Ifchemotherapy must be given during thefirst trimester, it is preferable to considertermination. Sentinel lymph node biopsy

PREGNANCY-RELATED BREAST CANCER 187


was not undertaken to avoid the possibility ofa delayed axillary dissection. However, thereare no documented adverse side effects frominjections of radiocolloid or blue dye. Thetumor size and grade justified the decision toundertake axillary dissection (>50% chanceof nodal involvement with a 37 mm grade IIIinvasive ductal carcinoma in a patient under40 years of age). Interestingly, the final his-tology was somewhat discordant with thepreoperative assessment; not only was thetumor size less than half the sonographicestimate, but the tumor was downgradedfrom III to II. The patient had a favorableprognostic index (NPI 3.30) and any bene-fits from chemotherapy would have beenminimal (<3%). Therefore any discussionsof possible delayed adjuvant chemotherapybecame irrelevant. Despite having a hormo-nally sensitive tumor, the patient declinedboth tamoxifen and ovarian suppression andhad a further successful pregnancy. In view ofthis patient's relatively young age and hor-mone-sensitive tumor, a two-year course ofan luteinising hormone releasing hormone(LHRH) agonist immediately following thebirth of her first child would have been areasonable treatment option and may havepermitted a subsequent pregnancy (9). Hadthe patient been at higher risk of relapse, shemay have accepted this endocrine option.

When a first trimester pregnancy continuesto term, there are potential concerns aboutthe effect of the hormonal milieu of preg-nancy (oestrogen friendly) on dormant breastcancer cells, which may persist after surgery.Studies have not revealed any statistically sig-nificant differences in 5- and 10-year survivalfigures for pregnant women compared withstage-matched nonpregnant counterparts. Fur-thermore, pregnancy subsequent to breastcancer treatment does not have any deleteri-ous impact on recurrence and survival (10,11).

Related Cases

Pregnancy and breast cancer—Case Studies36 and 37

Modified radical mastectomy—Case Studies 1,2, and 36


Learning Points

1. Although surgery is generally safe dur-ing pregnancy, the anesthesia may posea small risk to the fetus. Therefore, thesurgeon, obstetrician, and anesthesiolo-gist should work together to ensure asafe outcome.

2. Radiotherapy is contraindicated duringpregnancy, so some surgeons maintainthat breast-conserving surgery (whichrequires radiotherapy) should be avoidedduring early pregnancy. For women diag-nosed with breast cancer late in preg-nancy, breast-conserving surgery mightbe feasible because radiotherapy can bedelayed until after delivery of the baby.

3. Most of the internal organs of the fetusdevelop during the first trimester ofpregnancy, so chemotherapy shouldnot be administered during this period.

4. The effects of hormone therapy in preg-nant women are largely unknown, butthere have been reports linking tamox-ifen usage with birth defects.

References

1. Fiorica JV. Special problems. Breast cancer andpregnancy. Obstet Gynecol Clin North Am 1994;21:721–732.

2. Osteen RT. Unusual presentations of breast can-cer. In: Jatoi I, ed. Manual of Breast Diseases.PhiladelphiaLippincott, Wilkins & Williams:2002:353–364.

3. Liberman L, Geiss C, Dershaw D, et al. Imaging ofpregnancy-associated breast cancer. Radiology1994; 191:245–248.

4. Gupta R, McHutchinson A, Dowle C, et al. Fine-needle aspiration cytodiagnosis of breast masses inpregnant and lactating women and its impact onmanagement. Diagn Cytopathol 1993; 9:156–159.

5. Clark RM, Chua T. Breast cancer and pregnancy:the ultimate challenge. Clin Oncol 1989; 1:11.

6. Theriault RL. Breast cancer during pregnancy. In:Singletary SE, Robb GL, eds. Advanced Therapy ofBreast Disease. Ontario: BC Decker Inc., 2000:167–173.

7. Berry DL, Theriault RL, Holmes FA, et al. Man-agement of breast cancer during pregnancy usinga standardized protocol. J Clin Oncol 1999; 17:855–861.

8. Doll DC, Ringenberg QS, Yarbro JW. Antineoplas-tic agents and pregnancy. Semin Oncol 1989;16:337–346.

188 CHAPTER 11


9. Jakesz R, Hausmaninger H, Samonigg E, et al.Comparison of adjuvant therapy with tamoxifenand goserelin versus CMF in premenopausal stageI and II hormone responsive breast cancerpatients: 4 year results of Austrian Breast CancerStudy Group (ABCSG) Trial 5. Proc Am Soc ClinOncol 1999; 18:67a(abstr 250).

10. Danforth DN. How subsequent pregnancy affectsoutcome in women with a prior breast cancer.Oncology 1991; 5:23–30.

11. Petrek JA, Dukoff R, Rogatko A. Prognosis ofpregnancy-associated breast cancer. Cancer 1991;67:869–872.

Part II: Third Trimester Pregnancy

CASE STUDY 36

History

A 33-year-old woman presented with a two-week history of a lump in the left breast. Shewas 36-weeks pregnant with her first childand had noticed a distinctive difference inthe consistency of her left breast but noepisodes of redness or unusual nipple dis-charge. There were no previous breast prob-lems and no family history of breast orovarian cancer.

Clinical Findings

A firm and irregular, though ill-defined masswas palpable in the central zone of the leftbreast. This measured approximately 4 cm indiameter and was not associated with skintethering, erythema, or peau d'orange.There was no axillary lymphadenopathy(E4) (Fig. 4).

Clinical Assessment

Clinically suspicious lump in a pregnantpatient with no evidence of any inflamma-tory features.

Investigations

Breast Ultrasound

This showed the normal physiologicalchanges of pregnancy with prominent ductdilatation. An echo-poor lesion measuring 2cm was apparent in the centre of the leftbreast lying close to the chest wall. This wassuspicious for carcinoma (U4). Ultrasoundmeasurement may have underestimatedthe true size of the tumor that seemed atleast twice this size on clinical examination(Fig. 5A, B).

Figure 4 Figure 5



Core Biopsy

Ultrasound-guided core biopsy (14-gaugeneedle) of the central breast mass confirmedan invasive carcinoma (grade II) with no insitu component [Fig. 6A (low power) and B(high power)]. Immunohistochemical stain-ing for both estrogen receptor (ER) andprogesterone receptor (PR) was negative.

Diagnosis

Early-stage noninflammatory left-sidedbreast cancer in the third trimester of preg-nancy (T1/T2N0).


Following multidisciplinary discussion, it wasrecommended that the patient be inducedat 38 weeks and primary surgery be per-formed shortly thereafter. The central loca-tion of the tumor mandated mastectomy andthe patient expressed interest in immediatebreast reconstruction. The patient wouldreceive adjuvant chemotherapy on the basisof primary tumor characteristics (2 cm size,hormone receptor negative) and patient'sage irrespective of final nodal status. It wasconsidered unlikely that chest wall radiother-apy would be required and this was commu-nicated to the plastic surgeons. The patient'sgravida status prevented use of MRI to clarifythe extent of the tumor in the left breast(discordance between clinical and sono-graphic measurements).


The patient was referred to the plastic sur-geons for further discussion of reconstruc-tive options and the relevant midwife wascontacted and informed of the diagnosis andmanagement plan. The patient expressedsome concerns over the longevity of breastimplants and preferred a totally autologousreconstruction with a possible free TRAMflap. The plastic surgeons were reluctant toundertake the latter procedure so soon afterdelivery and considered a delayed recon-struction to be more appropriate if thistype was the preferred option.

The patient decided against immediatebreast reconstruction and underwent a leftmodified radical mastectomy two weeks aftergiving birth to a healthy baby son (Fig. 7).The patient made an excellent recovery withno complications and was discharged homeon the fourth postoperative day followingremoval of both drains.

Figure 6

Figure 7

190 CHAPTER 11



This revealed a grade III invasive ductal car-cinoma measuring 35 mm in maximumdiameter with no in situ component orlymphovascular invasion [Fig. 8A (magnifi-cation 10�) and B (magnification 20�)].The lesion extended to within 1.7 mm ofthe deep margin, but was otherwise clear ofall radial margins by more than 20 mm.None of the 10 lymph nodes retrieved con-tained metastatic carcinoma.


Adjuvant chemotherapy was recommendedand the patient was eligible for entry into theTANGO trial. This is a randomized phase IIItrial to determine whether sequential epiru-bicin (E) and cyclophosphamide (C) (4cycles) followed by paclitaxel (T) and gem-citabine improves disease-free survival com-pared with EC-T alone. Women are eligiblefor entry into the trial who have early-stagebreast cancer, but are at higher risk ofrelapse. She would otherwise receive stan-dard chemotherapy with eight cycles of E-CMF (4 cycles of epirubicin followed by fourcycles of cyclophosphamide, methotrexate,and 5-fluorouracil) (see Appendix III).There was no indication for either tamoxifenor ovarian suppression in view of the lack ofhormonal receptor expression (<10% ofcells stained). Though the tumor was gradeIII, it was below the size threshold for chest

wall radiotherapy in the absence of lympho-vascular invasion, involvement of the deepmargin or regional nodal involvement.


The patient agreed to enter the TANGOtrial and received four cycles of epirubicin/cyclophosphamide followed by four cycles ofpaclitaxel plus gemcitabine. She experi-enced some side effects including nauseaand vomiting (worse with gemcitabine), neu-rosensory symptoms (grade I), fatigue, myal-gia, and arthalgia. Though the latter weretemporary and resolved spontaneously, thepatient required a course of a nonsteroidalanti-inflammatory agent for symptom control.

The patient subsequently underwent adelayed reconstruction with a free TRAMflap and was delighted with the final resultsof reconstructive surgery (Fig. 9).

Figure 8

Figure 9



Discussion

This 33-year-old woman was diagnosed with alarge tumor in the third trimester of her firstpregnancy. The physiological changes withinthe breast associated with pregnancy mayhave obscured the mass and delayed initialpresentation (1,2). Most breast cancers havebeen present for several years prior to clin-ical detection and this patient most likelyhad a subclinical breast cancer for much ofthe duration of her pregnancy. Neither clini-cal examination (E4) or sonographic assess-ment were diagnostic of breast cancer.Ultrasound can be useful in differentiatingdiscrete solid from cystic lesions and in par-ticular for diagnosing breast cancer againstthe physiologically altered parenchyma ofpregnancy (3). Moreover, ultrasound can pro-vide a confident diagnosis of mastitis whensmall fluid collections and dilated ducts arepresent. Nonetheless, a biopsy is requiredto definitively exclude or confirm an inflam-matory cancer (4). Furthermore, the tumormargins were poorly defined on imaging withlack of concordance between the ultrasoundmeasurement and the pathological tumorsize.

Definitive treatment of third trimesterbreast cancers is usually deferred untilafter induction at, or around, 38 weeks.This removes many of the restrictions ontreatment that may apply to women who areconcurrently pregnant. Radiotherapy isabsolutely contraindicated and cannot beadministered during any stage of pregnancydue to fetal radiation exposure (5). Thoughthe effects of radiation on the fetus aregreatest during the first trimester, thesepersist throughout the second and thirdtrimesters when there are risks of sterility/malignancy and radiotherapy must bedelayed to the postpartum period (6).Though most forms of chemotherapy canbe given safely during the second and thirdtrimesters when organogenesis and limbformation is complete, there remains asmall risk of fetal malformation (1.5%)together with spontaneous abortion. It ispreferable to undertake all treatmentsafter delivery of the baby if possible, butthis may impact on overall survival of the

mother. Delays of adjuvant chemotherapyfor more than three months from the timeof diagnosis have been reported to decreaseeight-year relapse-free survival from 77% to44% (7). For second trimester breast can-cers, there would be significant delays inactive treatments if the latter were deferreduntil postdelivery. Both surgery as well aschemotherapy can be safely undertakenafter 12 weeks and the longer-term survivalof the mother should not be compromisedunnecessarily.

The patient had a centrally locatedtumor measuring 4 cm clinically that pre-cluded breast conservation. Moreover, mas-tectomy would still be necessary in the eventof a response to neoadjuvant chemother-apy. Primary surgical treatment with modi-fied radical mastectomy was considered themost appropriate management option; alevel II axillary lymph node dissection wasundertaken on the basis of primary tumorsize (rather than to avoid any delayed axil-lary lymph node dissection). There wassome discordance between the clinical andsonographic estimates of tumor size and itwas not possible to undertake MRI exami-nation to further evaluate tumor dimen-sions. There are concerns that sentinellymph node biopsy may be less accurate fortumors exceeding 3 cm in size (8) and trialsare ongoing to assess the value of sentinellymph node biopsy for tumors between 3 and5 cm in size (9).

Though the patient was keen to undergoimmediate breast reconstruction, she pre-ferred to have a free TRAM flap and avoidany implant. The plastic surgeons thoughtit inappropriate to undertake such a majorprocedure so soon after delivery. A delayedreconstruction was therefore plannedand the patient underwent a conventionalmastectomy with an oblique scar on thechest wall. This would remain a nonirradi-ated field, thus favouring elevation oftissues from the chest wall and subsequentreconstruction. Interestingly, it has beenreported that a delayed postpartumTRAM can safely be performed with main-tenance of abdominal wall integrity thatcan withstand the strain of any futurepregnancy (10).

192 CHAPTER 11


The patient was very pleased with the finalresults of delayed reconstruction (Fig. 9).

Related Cases


Adjuvant chemotherapy—Case Studies 3, 6, 8,11, and 37

Breast reconstruction—Case Studies 3, 4, 16,17, and 18

Learning Points

1. During pregnancy, hormone changescause the breast to enlarge and becomemore glandular and tender. Thesechanges may make it difficult to detect amalignant breast lump on clinical exami-nation.

2. Several studies have now shown thatcertain chemotherapeutic agents canbe safely administered during the sec-ond and third trimesters of pregnancy(with no increased risk of stillbirths orbirth defects). However, the long-termeffects of these drugs on the fetus is notknown so, if possible, chemotherapyshould be administered after delivery.

3. Chemotherapy lowers blood counts andshould not be administered within threeto four weeks before delivery. Chemo-therapy administered during this periodmay cause bleeding or increase therisk of infection during the perinatalperiod.

References

1. Anderson BO, Petrek JA, Byrd D, et al. Pregnancyinfluences breast cancer's stage at diagnosis inwomen 30 years of age and younger. Ann SurgOncol 1996; 3:204–211.

2. Noyes RD, Spanos WJ, Montague ED. Breast can-cer in women aged 30 and under. Cancer 1982;49:1302–1307.

3. Frazier TG, Murphy JT, Furlong A. The selecteduse of ultrasound to improve diagnostic accuracyin carcinoma of the breast. J Surg Oncol 1985;29:231–232.

4. Hayes R, Mitchell M, Nunnerley HB. Acute inflam-mation of the breast: the role of breast ultrasoundin diagnosis and management. Clin Radiol 1991;44:253–256.

5. The Steering Committee on Clinical PracticeGuidelines for the care and Treatment of BreastCancer. Breast radiotherapy after breast conserv-ing surgery. CMAJ1998; 158:S35–S42.

6. Brent RL. The effects of embryonic and fetalexposure to X-ray, microwaves and ultrasound.Clin Obstet 1983; 26:484–510.

7. Brufman G, Sulkes A, Biran S. Adjuvant chemo-therapy with and without radiotherapy in stage IIbreast cancer. Biomed Pharmacother 1988;42:351–355.

8. Benson JR, Querci della Rovere G. Managementof the axilla in women with breast cancer. LancetOncol 2007; 8:331–348.

9. Gill PG. Sentinel lymph node biopsy versus axillaryclearance in operable breast cancer. The RACSSNAC trial, a Multicenter randomized trial of theRoyal Australian College of Surgeons (RACS) Sec-tion of Breast Surgery, in collaboration with theNational Health and Medical Research CouncilClinical Trials Center. Ann Surg Oncol 2004;11:216S–221S.

10. Parodi PC, Osti M, Longhi P, et al. Pregnancy andTRAM flap breast reconstruction after mastectomy:a case report. Scand J Plast Reconstr Surg HandSurg 2001; 35:211–215.

CASE STUDY 37

History

A 43-year-old woman presented in the 35thweek of pregnancy with a four-month historyof a lump in the right breast. The lump wasnontender with no associated nipple dis-charge. There was a weak family history of

breast cancer with a maternal and paternalaunt having postmenopausal breast cancer.The patient had five other children agedbetween 18 months and 18 years and was25 years of age at the time of birth of her firstchild. She had used the oral contraceptive



pill for a cumulative period of five years inthe past.

Clinical Findings

Examination revealed a smooth mobilelump in the upper outer quadrant of theright breast that had a slightly irregular sur-face. There was no skin tethering or axillarylymphadenopathy (E3) (Fig. 10).

Clinical Assessment

A clinically indeterminate lump in a preg-nant patient.

Investigations

Breast Ultrasound

This showed a cyst in the upper outer quad-rant of the right breast measuring 35 mm inmaximum diameter. The cyst was aspiratedto dryness (non-bloodstained fluid), but aresidual lump remained. This appearedsonographically to be a focus of dense breasttissue, but core biopsy was performed as aprecaution.

The patient was informed that the find-ings were consistent with benign disease. Shewas to return in one week's time for results ofcore biopsy and arrangements were madefor a mammogram to be done postdelivery.

Core Biopsy

Ultrasound-guided core biopsy (14-gaugeneedle) of the right breast mass confirmedan invasive carcinoma (grade I, ER positivea,HER2 negative) with no in situ component(Fig. 11).

Diagnosis

Early-stage right-sided breast cancer present-ing in the third trimester of pregnancy(T2N0).


Following histological diagnosis of a rightbreast cancer, it was recommended that thebaby be delivered within the next two weeksand the patient thereafter undergo surgery.Further radiological investigations wererequested postdelivery to clarify the extentof disease in the breast and exclude multi-focality.

1. Mammography—This revealed moder-ately dense breast tissue with no focalbreast lesion.

2. Breast MRI—This showed the rightbreast tumor to be more extensive thanthe original estimate from ultrasoundexamination alone. The main indexlesion in the upper outer quadrant

a Allred score 7/8.

Figure 11

Figure 10

194 CHAPTER 11


measured 25 mm with several satellitefoci yielding an aggregate diameter of 37mm. In addition, a further enhancinglesion measuring 8 mm in diameter wasseen in the retroareolar region. Figure 12is a coronal MRI section showing atumour in the upper outer quadrant ofthe right breast (cardiac artefact is appar-ent in this relatively early MRI image).

The multifocal nature of the breast cancermandated mastectomy, but the patient wouldbe eligible for sentinel lymph node biopsy.


The patient was induced at 37 weeks anddelivered a healthy child. She had expressedan interest in immediate breast reconstruc-tion on being informed that mastectomy wasnecessary. Various reconstructive optionswere discussed with the plastic surgeonsand the patient elected to undergo recon-struction with a subpectoral implant only.

She underwent sentinel lymph node biopsyin advance of definitive surgery shortly aftergiving birth. She was advised to discontinuebreastfeeding after sentinel node biopsy, butin the interim period could continue. It wasnot considered appropriate to be breastfeed-ing at the time of mastectomy and immedi-ate breast reconstruction.

Sentinel lymph node biopsy was under-taken three weeks postdelivery and showedmetastatic involvement in one out of foursentinel nodes [macrometastases (4 mm)][Fig. 13A (low power) and B (high power)].The patient proceeded to a right mastec-tomy with axillary lymph node dissectionand immediate breast reconstruction twoweeks later. She made an uneventful postop-erative recovery.


This revealed a grade II invasive ductal car-cinoma measuring 42 mm in maximumdiameter. There was associated DCISextending beyond the invasive componentyielding a total size of 54 mm [Fig. 14A(magnification 20�) and B (magnification40�)]. None of the 10 lymph nodes retrievedfrom completion axillary lymph node dissec-tion contained metastatic carcinoma giving anoverall nodal status of 1 out of 14 nodes (1 outof 4 sentinel lymph nodes positive).


Following multidisciplinary discussion it wasrecommended that the patient proceed withadjuvant chemotherapy (standard regimen

Figure 13

Figure 12



of E-CMF—see Appendix III) and thereafterreceive radiotherapy to the right chest wall.On completion of chemotherapy, hormonalmanipulation would be undertaken in accor-dance with menopausal status. In view of thepatient's age (>40 years), it was likely that shewould be rendered postmenopausal by che-motherapy and formal ovarian suppressionwould be inappropriate. In the event thatmenses persisted, resumed, or luteinising hor-mone/follicle stimulating hormone levelsremained in the premenopausal range, ovar-ian ablation could be achieved either surgi-cally by laparoscopic oophorectomy orchemically with an LHRH analogue (for2–3 years). Irrespective of ovarian suppression,the patient would receive tamoxifen for fiveyears as adjuvant systemic hormonal therapy.Emerging trial data suggest an overall survivalbenefit in node-positive patients for sequentialhormonal therapy with tamoxifen (5 years)followed by the aromatase inhibitor letrozole(2.5 years). The patient's estimated 10-yeardisease-free survival without additional treat-ment was 64% and improved to 81% withsystemic therapies (chemotherapy/hormonaltherapy) (www.adjuvantonline.com).

The patient would receive radiotherapy tothe chest wall upon completion of chemo-therapy. She had one positive node only andtherefore did not qualify for supraclavicularirradiation. Moreover, the patient was HER2negative and therefore not eligible for Her-ceptin.


The patient proceeded to chemotherapywith four cycles of epirubicin followed byfour cycles of cyclophosphamide, methotrex-ate, and 5-fluorouracil (E-CMF). Initiation ofchemotherapy was delayed by two weeks atthe request of the plastic surgeons due topoor wound healing (minor infection). Thepatient developed profound neutropeniaafter the second cycle of chemotherapy(neutrophil count 0.8) and required granu-locyte colony stimulating factor (GCSF) sup-port. This indicated an extreme sensitivity toepirubicin and the dose for the third cycle ofchemotherapy was reduced to 85%. Interest-ingly, the patient had a family history ofneutropenia, but there was no evidence forany primary hereditary hematological abnor-mality. The neutropenia persisted and thechemotherapy schedule was changed fromE-CMF to FEC (5 cycles of the latter).

The patient received a standard scheduleof radiotherapy to the chest wall after comple-tion of chemotherapy (commenced approxi-mately 8 months after definitive surgery). Thisconsisted of a total dose of 40 Gy delivered in15 fractions over a three-week period.

The patient remained premenopausaland underwent laparoscopic oophorectomy10 months after mastectomy and immediatebreast reconstruction; shortly prior to thisshe had become amenorrheic while takingtamoxifen.

Figure 14

196 CHAPTER 11


Discussion

This patient's breast cancer might easily havebeen missed on “triple assessment.” Shereported having a right breast lump for aperiod of four months and it remainsunclear whether this was considered to beinnocent by the patient herself. There wasno suggestion that the lump had changed insize over this time period. The palpable massin the right breast corresponded to a cystmeasuring 35 mm; the residual mass post-aspiration was probably not palpable at pre-sentation. Core biopsy was undertaken “as aprecaution” and the area of biopsy was con-sidered most likely to represent benignbreast tissue. This biopsy yielded invasivecarcinoma and a subsequent MRI examina-tion revealed multifocality with an aggregatediameter of 37 mm. The patient thereforerequired a mastectomy and desired immedi-ate breast reconstruction. Therapy com-menced three weeks after delivery, whichwas induced at 37 weeks. Though sentinellymph node biopsy was not contraindicated,a formal axillary lymph node dissection at theoutset would have been reasonable based onthe aggregate tumor size in the context ofmultifocality. The rationale for undertakingsentinel lymph node biopsy in advance ofdefinitive mastectomy and reconstruction isto avoid a delayed axillary clearance afterreconstructive surgery. This can be technicallychallenging when a latissimus dorsi flap hasbeen used (not an issue in this case). Thispatient had a positive sentinel lymph nodebiopsy and proceeded to completion axillarylymph node dissection at the time of mastec-tomy and immediate breast reconstruction.

A potential disadvantage of immediatebreast reconstruction is delay in commenc-ing chemotherapy. Minor infection in thepresence of an implant can lead to implantfailure (and explantation) when theimmune system is suppressed by chemother-apy. The standard adjuvant chemotherapyregimen for patients at average risk ofrelapse within the Cambridge Breast Unitand several other units within the United

Kingdom is E-CMF. The rationale for usingthis regimen is based on results of two trialsdesigned to specifically address the efficacyof epirubicin as adjuvant treatment for early-stage breast cancer (1). Epirubicin is a morepopular anthracycline in Europe and a meta-analysis comparing epirubicin with doxoru-bicin in the metastatic setting showed theformer to be equally efficacious but associ-ated with fewer side effects. The NationalEpirubicin Adjuvant Trial (NEAT) com-pared four cycles of epirubicin followed byfour cycles of CMF with six cycles of CMFalone. By contrast, the related Scottish Can-cer Therapy Network Trial (BR9601) had aslightly amended regimen and comparedthe same with eight cycles of CMF aloneevery three weeks. The two trials combinedinvolved more than 2000 patients and at amedian follow up of 48 months, relapse free,and overall survival rates were significantlyimproved in the E-CMF than CMF alonegroups. The calculated five-year relapse-freesurvival rates were 76% versus 69% (p <0.001) and overall survival rates 82% versus75%, respectively. The hazard rates forrelapse and death from any cause favoredepirubucin schedules. This study is the moststrongly positive among the few individualtrials demonstrating an advantage foranthracycline-based chemotherapy. More-over, it is anticipated that this schedule willnot only prove more effective than dosedense 5-fluorouracil, epirubicin, and cyclo-phosphamide (FEC) but also be safer in thelonger term. It is current policy to offerhigher-risk (HER2 positive, �4 nodes posi-tive) patients FEC-docetaxol as adjuvant che-motherapy (2).

Despite having six children already, thispatient enquired about the possibility of afurther pregnancy. She initially opted forovarian suppression with the LHRH ana-logue with Zoladex for two years, which ispotentially reversible. However, upon com-pletion of Zoladex, the patient would bealmost 47 years of age (and still remain ontamoxifen). It was considered highly unlikelythat she would successfully conceive after



completion of chemohormonal therapies. Itshould be noted that there is no clear evi-dence that any further pregnancy wouldincrease the risk of breast cancer relapseand adversely influence long-term outcome(3).

This patient was node positive and there-fore eligible for extended adjuvant hormonaltherapy. Though more than three-quarters ofrecurrences occur within the first five years,late events do occur and patients remain atchronic risk of relapse. Dormant cancer stemcells can be “kick started” many years afterprimary treatment of breast cancer. The MA-17 trial randomized 5187 patients who weredisease-free upon completion of five-yearsstandard tamoxifen therapy to either letro-zole (2.5 mg/day) or placebo for a furtherfive years. All patients had started letrozolewithin three months of stopping tamoxifen.An interim analysis was carried out at amedian follow up of 30 months when thenumber of events had exceeded a predeter-mined figure. These initial results showed asignificant improvement in disease-free sur-vival for those patients receiving extendedadjuvant therapy with letrozole (HR 0.58;95% CI, 0.45–0.75; p ¼ 0.0004). In additionto a reduction in risk of recurrence by 42%,there was also a statistically significantdecrease in distant metastases and anincrease in overall survival in the node posi-tive group (HR 0.61; p ¼ 0.04). An updatedanalysis of this trial established letrozole asthe first aromatase inhibitor to improve out-come after completion of five-years tamoxifentherapy (4). Indeed, the treatment effect wasso strong that the trial was unblinded andletrozole was licensed for use as extendedadjuvant endocrine therapy. An analysis ofthis trial post-unblinding revealed a signifi-cant improvement in several endpoints forwomen who switched to letrozole comparedwith continuation of placebo (5). Theseincluded (i) disease-free survival (HR 0.31;p < 0.001) (ii) distant disease-free survival(HR 0.28; p < 0.002) and (iii) overall survival(HR 0.53; p < 0.05). There was also a furtherreduction in contralateral breast cancer (HR0.23; p < 0.012). Thus extended adjuvantendocrine treatment with letrozole canimprove outcomes even when commenced

after a period without adjuvant hormonaltherapy. However, this post-unblinding analy-sis was not based on randomized data andclearly the two arms were not balanced forpatient and tumor characteristics. Thosepatients who were switched from placebo toletrozole were more likely to be youngerpatients with more aggressive node positivetumors and treated with prior chemotherapy.Thus the group who switched to letrozolefrom placebo had a greater risk of relapseand a worse prognosis, which has been citedas justification for the decision to unblind.Breast cancer patients remain at chronic riskof relapse, and reintroduction of endocrinetherapy at any point along the pathway willimprove outcomes. Dormant cancer cells canbe activated or “kick started” many years afterprimary treatment of breast cancer. Examina-tion of hazard rates for recurrence within theextended adjuvant endocrine setting of theMA-17 trial implies that there is a residual riskof recurrence in patients completing fiveyears of tamoxifen. The hazard ratio forrecurrence (letrozole:placebo) shows atrend to decrease over time and there isgreater benefit from letrozole with moreprolonged therapy (6).

Related Cases


Ovarian suppression—Case Studies 8, 23, and27

Fertility issues—Case Study 23

Postmastectomy radiotherapy after breastreconstruction—Case Studies 3 and 18



Learning Points

1. Most chemotherapeutic and endocrinetherapy agents can enter breast milkand be passed on to the newborn infant.Therefore, if a woman is receiving

198 CHAPTER 11


chemotherapy or endocrine therapy,she should not breast-feed her baby.

2. During the first seven to nine years fol-lowing breast cancer diagnosis, womenwith ER-negative tumors are at greaterrisk for relapse than those with ER-pos-itive tumors. Thereafter, the risk ofrelapse is greater for patients with ER-positive tumors. Thus, extended endo-crine therapy should be considered forwomen with node-positive ER-positivetumors as these women are at increasedrisk for relapse many years after initialbreast cancer diagnosis.

References

1. Poole CJ, Earl HM, Dunn JA, et al. For the NEATand SCTBG Investigators. NEAT (National Epiru-bicin Adjuvant Trial) and SCTBG BR9601 (ScottishCancer Trials Breast Group) phase III adjuvant

breast trials show significant relapse-free and over-all survival advantage for sequential E-CMF. ProcAm Soc Clin Oncol 2003; 22:(abstr 13).

2. Dang CT, Moynahan ME, Dickler MN, et al. PhaseII study of dose-dense (DD) 5-fluorouracil, epiru-bicin and cyclophosphamide followed by alternat-ing weekly paclitaxel (P) and docetaxel (D) in highrisk node positive breast cancer: feasibilityand efficacy. Proc Am Soc Clin Oncol 2003; 22:(abstr 46).

3. Von Schoultz E, et al. Influence of prior andsubsequent pregnancy on breast cancer prognosis.J Clin Oncol 1995; 13:430–434.

4. Goss PE, Ingle JN, Martino S, et al. Randomisedtrial of letrozole in postmenopausal women afterfive years of tamoxifen therapy for early stagebreast cancer. N Engl J Med 2003; 349:1793–1802.

5. Goss PE, Ingle JN, Palmer MJ, et al. Updatedanalysis of NCIC CTG MA.17 (letrozole vs placeboto letrozole vs placebo) post unblinding. BreastCancer Res Treat 2005; 94:S10(abstr 16).

6. Ingle JN, Goss PE, Tu D, et al. Analysis of durationof letrozole extended adjuvant therapy as mea-sured by hazard ratios of disease recurrence overtime for patients on NCIC CTG MA.17. BreastCancer Res Treat 2005; 94:S11(abstr 17).



12Prophylactic Mastectomy

Part I: Bilateral Prophylactic Mastectomy

CASE STUDY 38

History

A 31-year-old woman was referred by theClinical Genetics Department for discussionof bilateral prophylactic mastectomy. Thepatient's mother and maternal grandmotherboth developed breast cancer at 33 and39 years of age, respectively, and the patientherself was increasingly conscious that shewas approaching this age. In addition, tothese two relatives, the patient's family his-tory included two maternal great aunts withpostmenopausal disease and a maternalgrandfather with prostate cancer. Thoughfamilial cancer history was incompletelydocumented, the patients estimated lifetimerisk for development of breast cancer was80% to 85%. There was a high probability ofeither BRCA-1 or BRCA-2 mutation carriageand genetic testing of the patient's motherand sister was pending at the time of refer-ral. In particular, the patient understoodthat in the absence of any gene mutation,her risk of developing breast cancer wascomparable to an age-matched population.She was keen to pursue prophylactic surgerywithout information from formal genetictesting (though both the patient and hersister were subsequently confirmed to carrya BRCA-2 gene mutation). This was a care-fully considered decision by the patient whohad a very balanced and informed point ofview. She was a single parent and ratherpreoccupied with the risk of developingbreast cancer and the possible impact onher child. The patient wished to minimizeher risk and was provided with quantitative

information on risk reduction from prophy-lactic surgery.

The patient was otherwise fit and healthy;she had undergone excision of a fibroade-noma from the left breast a few years ago.She had one daughter aged four years whowas breast-fed and used the oral contracep-tive pill for a cumulative period of five years.

Clinical Findings

Examination revealed no discrete or domi-nant lumps in either breast and no areas offocal nodularity. There was no axillary lym-phadenopathy.

Investigations

1. Breast ultrasound—imaging of the breastswith ultrasound was normal (patient tooyoung for mammography) (U1).

2. MRI breasts—normal.3. Genetic testing—BRCA-2 carrier.


The patient proceeded to bilateral prophy-lactic surgery almost 12 months after herinitial consultation in the breast clinic. Bythis time, she had received confirmation ofBRCA mutation carriage and this strength-ened her conviction and provided objectiveevidence for risk reduction from prophylac-tic surgery. The patient had discussed recon-structive options with the plastic surgeonsand was not keen on autologous tissue

200


transfer. She had smallish-sized breasts andwas suitable for an implant-only based tech-nique. Skin-sparing mastectomy was per-formed without nipple preservation andbilateral subpectoral tissue expanders wereinserted at the time of mastectomy. Thecentral defect resulting from excision ofthe nipple-areolar complex was closed witha transverse incision rather than a purse-string suture (no skin island imported froman autologous tissue flap). The patient madean excellent postoperative recovery andthe implants were gradually expanded overthe course of the next four to six weeks via asubcutaneous port.

The patient was reviewed in the clinic twoweeks following discharge and was relievedto be informed that histological examinationof the resected breast tissue had revealed noevidence of hyperplasia, atypia, or malig-nancy.

Discussion

This patient had both a strong family historyof breast cancer and a confirmed mutationin a known breast cancer susceptibility gene(BRCA-2). Though many individuals maypossess a relative with breast cancer, only aminority of cases (5–10%) have an autoso-mally dominant pattern of inheritance con-sistent with vertical transmission of a high-risk genetic predisposition from one gener-ation to another. The level of genetic riskand probability of carriage of a mutation in arecognized gene is determined by an indi-vidual's family cancer history. Contemporarymethods of clinical risk assessment involveaccurate ascertainment of information relat-ing to the following points:

1. Number of first- and second-degree rel-atives with cancer—though the historyshould focus on breast/ovarian cancer,details of other familial malignanciesshould be sought to identify possible“cancer syndromes.” Furthermore, infor-mation should be collated from bothmaternal and paternal relatives. Breastcancer can be inherited through thepaternal lineage and cases may be con-fined to this side of the family.

2. The age at diagnosis (not death) of eachaffected relative—early-onset breast can-cer is arbitrarily defined as developmentof disease among relatives under the ageof 40 years. This patient's mother andmaternal grandmother were diagnosedwith breast cancer at 33 and 39 years,respectively. It was partly for this reasonthat the patient wished to pursue a spe-cific interventional procedure aroundthe age of 31 years.

3. Bilateral breast cancer—an inheritedgenetic predisposition affects all somaticcells and within this setting bilaterality ismuch more likely to occur than amongsporadic cases.

The normal lifetime risk for breast canceris approximately 10% (1 in 10 womenaffected). A method termed linkage analysiswas previously used to calculate lifetime riskfor development of breast cancer based oninformation from family cancer history (asabove). For some individuals the estimatedlifetime risk was of the order 80% to 90%,i.e. they were almost certain to suffer thedisease assuming they lived for a reasonableperiod of time and did not succumb fromany competing cause of death. This heredi-tary predisposition is conferred by cancersusceptibility genes, which conform to Knud-son's model or “two-hit hypothesis” (1,2).Thus, mutations in both alleles of a genepair are a prerequisite for cancer develop-ment. Individuals with an inherited predis-position already possessed a mutation in oneallele (present in all cells) and thus requiredonly one further somatic mutation for tumorformation. Sporadic forms of the cancerwere dependent on two somatic mutations,the chances of which were correspondinglysmaller for any equivalent mutation rate.Knudson's hypothesis is especially applicableto those tumors arising from loss of functionin tumor suppressor genes; usually inactiva-tion of both alleles is essential before levelsof the gene product fall sufficiently to inducemalignant change. The breast cancer suscep-tibility genes BRCA-1 and BRCA-2 are tumorsuppressor genes located on chromosomes17q21 and 13q12, respectively and display anautosomal dominant pattern of inheritance

PROPHYLACTIC MASTECTOMY 201


with variable penetrance (3,4). Mutationswithin these two genes account for approx-imately three-quarters of hereditary breastcancer cases and confer a lifetime risk of80% to 85% by age 70 years (i.e., a 10-foldincrease). At the cellular level, the effects ofBRCA-1 and BRCA-2 are recessive and bothcopies of an allele must be lost or mutatedfor cancer progression. Individuals with agermline mutation in these genes have adominantly inherited susceptibility and thesecond “hit” occurs in the somatic copy.Tumors from genetically predisposedpatients show loss of heterozygosity in thewild-type BRCA-1 allele, but interestinglymutations of BRCA-1 and BRCA-2 areuncommon in sporadic breast cancers (5,6).

Other genes involved in genetic predisposi-tion to breast cancer include p53 (Li-Fraumenisyndrome) (7), AT (ataxia-telangiectasia, andPTEN (breast and thyroid cancer) (8). Thesehigh-risk genes only account for 2% of allbreast cancers. The majority of family clustersare not attributable to any of these high-risksusceptibility genes and attention has recentlyturned to “low risk” genes such as FGFR2 andTNCR9, which may collectively be responsiblefor up to 25% of familial breast cancer overall.

Mutations within the mid portion of theBRCA-1 gene are associated with breast andovarian cancer as opposed to breast cancer–specific disease. The overall risk of ovariancancer for patients with a BRCA-1 mutation isbetween 20% and 40% (9). A single relativewith both breast and ovarian cancer is suffi-cient to raise suspicion of a BRCA-1 genemutation within a family in the absence ofany other affected members. Similarly, BRCA-2 mutations are linked to male breast cancerand prostate cancer (10). Sometimes there arefew female members within a family and thiscan conceal the clinical manifestation of anyunderlying genetic predisposition. It is alsorecognized that sporadic tumors can occurwithin families that harbor a known BRCA-1or BRCA-2 gene mutation. This phenomenonof “phenocopy” can lead to overestimation ofgenetic risk, particularly if a mutation in thesegenes has yet to be identified.

The discovery and subsequent cloning ofthe breast cancer genes BRCA-1 and BRCA-2

has spawned demand for genetic testing.However, mutations within these two genesare relatively uncommon in sporadic formsof breast cancer and in consequence theprevalence within the population is only ofthe order 0.001% (11). The proportion ofhereditary cancers is much higher in certainpopulation groups such as the AshkenaziJews, where “founder” mutations are com-mon (12). Genetic testing for BRCA-1 andBRCA-2 are therefore only relevant in asmall percentage of individuals who belongto families with “hereditary” breast cancer.Within the United Kingdom, genetic testingis only undertaken after formal risk evalua-tion by clinical geneticists—it is not available“on demand.” At least 300 different muta-tions have been found for each of thesegenes and genetic testing must screen forall the known mutations as well as searchingfor any potential “new” mutation for thatfamily. Once a mutation has been character-ized, it is easier to then screen other relativesfor this specific change in nucleotidesequence. It is possible that no mutationwill be found after exhaustive testing whichcan be frustrating for individuals who comefrom families where there is clearly a stronghistory of breast/ovarian cancer. Genetictesting is expensive ($2,500) and it is notfeasible to carry out blanket screening of allinterested women (13). Where “founder”mutations are present, genetic testing iseasier and cheaper. The American Societyof Clinical Oncology has issued guidelinesfor breast cancer predisposition testing, andthe following criteria must be fulfilled:

l The individual has a strong family historyof cancer and/or early age of onset.

l The test can be adequately interpreted.l The results will guide management deci-

sions for the patient or other family mem-bers (14).

A great advantage of genetic testing isprovision of accurate risk quantitation.Once a mutation has been identified for aparticular family, those members who testnegative have no increased risk of develop-ing breast cancer than an age-matchedindividual from the general population

202 CHAPTER 12


(no specific surveillance or treatment is indi-cated). By contrast, a family member with adocumented mutation has a very highchance of developing the disease withoutsome form of intervention. Herein lies apotential dilemma; when women consentto genetic testing, they must be counseledappropriately and be able to cope with theinformation gained from the test—whateverthe result (15). Most women overestimatetheir risk, and genetic testing allows accuraterisk assessment that more confidentlyinforms any proposed management deci-sions (16).

Though MRI has much greater sensitivitythan mammography for detecting cancer inyounger women with denser breast tissue,there is no evidence for any reduction inmortality from enhanced radiological sur-veillance of high-risk women (17). MRIscreening has a lower specificity and 10-foldhigher cost compared with mammography(18). Moreover, chemoprevention withagents such as tamoxifen and raloxifenecan reduce the incidence of breast cancerby up to 50%, but have no effect on survivalfrom all causes of death (19–22). All chemo-preventive agents have potential side effectsand it should be remembered that these areadministered to otherwise healthy women.The risk elevation for entry into chemopre-vention trials is a projected risk of 1.66% atfive years (23).

Bilateral prophylactic surgery reduces theexpected risk of breast cancer by more than90%. In a retrospective study of more than600 women at moderate to high risk whohad undergone bilateral prophylactic mas-tectomy, the incidence of breast cancer wasreduced by 89.5% (p < 0.001) (24). Anestablished Gail model for risk estimationwas used to predict the number of breastcancer cases expected in these two groupswithout surgical intervention. This togetherwith several smaller studies have validatedbilateral prophylactic mastectomy as a man-agement option for women at increased riskfor development of breast cancer (25). Pro-phylactic surgery cannot remove all breasttissue and when the nipple-areolar complexis preserved (subcutaneous mastectomy) up

to 15% of breast tissue may remain. Interest-ingly, most women do not opt for prophy-lactic mastectomy even when good-qualityimmediate breast reconstruction is available.There can be profound psychological seque-lae from this radical form of interventionand studies have shown that a small minority(3–6%) of women do regret their decision tochoose a surgical option for risk reduction(26). This is more likely when women havebeen “talked into” the operation. Healthprofessionals should inform rather than“sell” this option; there is a differencebetween offering and recommending bilat-eral prophylactic mastectomy and the finaldecision must be left to the patient (15).Women should be allowed plenty of time toreach a final decision and must fully under-stand the risks, benefits, and limitations ofbilateral prophylactic surgery, which shouldprobably not be undertaken under the ageof about 25 years. Conversely, the older awomen is when she has prophylactic surgery,the smaller are the absolute benefits due to acorresponding reduction in estimated life-time risk (27). The mean age of patients inmost studies of prophylactic mastectomy is42 years, and there is minimal benefit fromcarrying out this procedure over the age of60 years. The gains in life expectancy withbilateral prophylactic mastectomy are typi-cally between three and five years and maybe a matter of months for older patients(27). A patient with a BRCA-2 gene mutationwho has a 70% to 80% lifetime risk ofdeveloping breast cancer would reduce herabsolute risk of death from breast cancer byonly 2.5%. Moreover, it should be remem-bered that survival rates from breast cancerhave greatly improved, and these patientsare likely to have a screen-detected lesionor at least a small palpable tumor.

Patients undergoing bilateral prophylacticmastectomy within the Cambridge BreastUnit do not have preservation of thenipple-areolar complex, though it is acknowl-edged that this practice is acceptable.However, patients must be warned of thefinite risk of subsequent cancer develop-ment, particularly when a sliver of breasttissue is left deep to the nipple-areolar



complex. It is preferable to employ a later-ally placed incision for nipple-sparing mas-tectomy to minimize the chance of nippleischemia. There is no role for routine sen-tinel lymph node biopsy in the absence ofany evidence of cancer on preoperativeinvestigations.

This patient elected to undergo prophy-lactic oophorectomy in addition to bilateralprophylactic mastectomy. BRCA-2 mutationsare associated with a 10% to 20% risk fordevelopment of ovarian cancer (lower thanfor BRCA-1 mutations) (9). Oophorectomynot only reduces the risk of ovarian cancerby removal of ovarian tissue, but significantlyimpacts on the subsequent risk of breastcancer—irrespective of any genetic predis-position to the latter. Indeed, iatrogenicoophorectomy in women under the age of40 years reduces breast cancer risk byapproximately two-thirds. Studies haveshown that among women who carry muta-tions of BRCA-1 and BRCA-2, oophorectomyreduces breast cancer risk between 50% and75% (28,29). Therefore, prophylacticoophorectomy can potentially reduce theincidence of both breast and ovarian cancerand this should be discussed in those womenwith a hereditary predisposition. Studies sug-gest that bilateral salpingo-oophorectomy ismore “acceptable” as a risk-reducing strategythan bilateral prophylactic mastectomy andis chosen by more than 85% of heterozygotesfor the major susceptibility genes BRCA-1and BRCA-2. There are uncertain issuesrelating to hormone replacement for controlof menopausal symptoms in these relativelyyoung women. A limited period of usage atthe lowest dose compatible with control ofacute climacteric symptoms seems sensible.Calcium and vitamin D supplements shouldbe recommended in the longer term formaintenance of bone health.

Related Cases

Contralateral prophylactic mastectomy—Case Study 39

Implant-only based reconstruction—CaseStudy 4

Learning Points

1. Approximately 5% to 10% of all breastcancers have a recognized genetic pre-disposition, with the majority of thesehaving mutations in the BRCA-1 orBRCA-2 genes.

2. For women with a genetic predispositionfor breast cancer, there are three optionsavailable: surveillance (including breastMRI), prophylactic surgery (bilateral mas-tectomy may reduce breast cancer risk by90% and bilateral salpingo-oophorec-tomy before age 40 may reduce breastcancer risk by 50% and ovarian cancerrisk by 90%), and chemoprevention (withtamoxifen). However, there are norandomized prospective trials that havespecifically addressed the impact of theseinterventions in mutation carriers.

3. If a patient decides to undergo bilateralmastectomy to reduce breast cancerrisk, then skin-sparing mastectomy(removal of the breast and nipple-areo-lar complex with preservation of theoverlying skin) is the procedure ofchoice. Alternatively, total mastectomyis an acceptable option. However, nip-ple-sparing mastectomy (subcutaneousmastectomy) should be discouragedbecause the patient would remain atrisk for developing breast cancer withinthe ducts of the nipple-areolar complex.

References

1. Knudson AG Jr. Genetics of human cancer. AnnRev Genet 1986; 20: 231–251.

2. Knudson AG Jr. Hereditary cancer, oncogenes,and antioncogenes. Cancer Res 1985; 45:1437–1443.

3. Hall JM, Lee MK, Newman B, et al. Linkage ofearly onset familial breast cancer to chromosome17q21. Science 1990; 250:1684.

4. Wooster R, Neuhausen S, Mangion J, et al. Local-isation of a breast cancer susceptibility gene,BRCA-2 to chromosome 13q12-13. Science 1994;265:2088.

5. Ford D, Easton DF. The genetics of breast andovarian cancer. Br J Cancer 1995; 72(4):805–812.

6. Ford D, Easton DF, Stratton M, et al. Geneticheterogeneity and penetrance analysis of theBRCA-1 and BRCA-2 genes in breast cancer fami-lies. Am J Hum Genet 1998; 62:676–689.

204 CHAPTER 12

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7. Borresen AL, Andersen TI, Garber J, et al. Screen-ing for germline TP53 mutations in breast cancerpatients. Cancer Res 1992; 52:3234–3236.

8. Tsou HC, Teng DH, Ping XL, et al. The role ofMMAC1 mutations in early-onset breast cancer:causative in association with Cowden syndromeand excluded in BRCA-1 negative cases. Am JHum Genet 1997; 61:1036–1043.

9. Ford D, Easton DF, Bishop DT, et al. Breast CancerLinkage Consortium. Risks of cancer in BRCA-1mutation carriers. Lancet 1994; 343:692–695.

10. Breast Cancer Linkage Consortium. Cancer risks inBRCA-2 mutation carriers. J Natl Cancer Inst 1999;91:1310–1316.

11. Claus EB, Risch N, Thompson WD. Genetic anal-ysis of breast cancer in the Cancer and SteroidHormone study. Am J Hum Genet 1991; 48:232–242.

12. Struewing JP, Hartge P, Wacholder S, et al. Therisk of cancer associated with specific mutations ofBRCA-1 and BRCA-2 among Ashkenazi Jews. NEngl J Med 1997; 336:1401–1408.

13. Gauthier-Villars M, Gad S, Caux V, et al. Genetictesting for breast cancer predisposition. Surg ClinNorth Am 1999; 79:1171–1187.

14. Statement of the American Society of ClinicalOncology. Genetic testing for cancer susceptibility,adopted on February 20, 1996. J Clin Oncol 1996;14:1730–1736.

15. Geller G, Bernhardt BA, Doksum T, et al. Decision-making about breast cancer susceptibility testing:how similar are the attitudes of physicians, nursepractitioners and at risk women? J Clin Oncol1998; 16:2868–2876.

16. Black WC, Nease RF Jr., Toteson ANA. Perceptionsof breast cancer risk and screening effectiveness inwomen younger women than 50 years of age. J NatlCancer Inst 1995; 87:720–731.

17. MARIBS study group. Screening with magneticresonance imaging and mammography of a UKpopulation at high familial risk of breast cancer: aprospective multicentre cohort study (MARIBS).Lancet 2005; 365: 1769–1778.

18. Warner E, Causer PA. MRI surveillance for hered-itary breast cancer. Lancet 2005; 365:1747–1749.

19. Fisher B, Constantino JP, Wickerman DL, et al.Tamoxifen for prevention of breast cancer: reportof the National Surgical Adjuvant Breast and Bowel

Project P-1 study. J Natl Cancer Inst 1998; 90:1371–1388.

20. Veronesi U, Maisonneuve P, Costa A, et al. Preven-tion of breast cancer with tamoxifen: preliminaryfindings from the Italian randomized trial amonghysterectomised women. Lancet 1998; 352:93–99.

21. Powles T, Eeles R, Ashley S, et al. Interim analysisof the incidence of breast cancer in the RoyalMarsden Hospital tamoxifen randomized chemo-prevention trial. Lancet 1998; 362:98–101.

22. Wickerham DL, Costantino JP, Vogel V, et al. Thestudy of tamoxifen and raloxifene (STAR): initialfindings from the NSABP P-2 breast cancer pre-vention study. 2006 ASCO Annual Meeting Pro-ceedings Part 1. J Clin Oncol 2006; 24: No. 18SLBA5.

23. Cheblowski R, Col N, Weiner E, et al. AmericanSociety of Clinical Oncology technology assessmentof pharmacological interventions for breast cancerrisk reduction including tamoxifen, raloxifene andaromatase inhibition. J Clin Oncol 2002; 20:3328–3343.

24. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacyof bilateral prophylactic mastectomy in womenwith a family history of breast cancer. N Engl JMed 1999; 340:77–84.

25. Bilimoria MM, Morrow M. The woman atincreased for breast cancer: evaluation and man-agement strategies. CA Cancer J Clin 1995; 45:263–278.

26. Montgomery LL, Tran KN, Heelan MC, et al.Issues of regret in women with contralateral pro-phylactic mastectomies. Ann Surg Oncol 1999;6:546–552.

27. Schrag D, Kuntz KM, Garber JE, et al. Decisionanalysis—effects of prophylactic mastectomy andoophorectomy on life expectancy among womenwith BRCA-1 and BRCA-2 mutations. N Engl J Med1997; 336:1465–1471.

28. Kauff ND, Satagopan JM, Robson ME, et al. Riskreducing salpingo-oophorectomy in women with aBRCA-1 or BRCCA-2 mutation. N Engl J Med 2002;346:1609–1615.

29. Rebbeck TR, Lynch HT, Neuhausen SL, et al.Prophylactic oophorectomy in carriers of BRCA-1or BRCA-2 mutations. N Engl J Med 2002;346:1616–1622.

Part II: Contralateral Prophylactic Mastectomy

CASE STUDY 39

History

A 60-year-old woman was found to have anarea of microcalcification in the right breast

on routine screening mammography. Shehad undergone a left modified radical mas-tectomy for a grade III node-negative



invasive ductal carcinoma of the right breasteight years earlier and received adjuvantchemotherapy that was poorly tolerated.She sustained a deep vein thrombosis duringtreatment. She remained well with no evi-dence of recurrent disease, but tended tobecome anxious at the time of breast imag-ing lest any further malignancy be detectedin the contralateral breast. There was nofamily history of breast or ovarian cancer.

Clinical Findings

A well-healed mastectomy scar was presenton the left side with no evidence of anylocoregional recurrence. No discrete masslesion or areas of focal nodularity weredetectable in the right breast, which wasnoted to be rather heavy and pendulous (E1).

Clinical Assessment

Asymptomatic screen-detected microcalcifi-cation of the right breast in a patient with aprevious invasive cancer of the left breast.

Investigations

Mammography (Right)

A cluster of relatively coarse microcalcifica-tion was seen in the upper outer quadrant ofthe right breast with no associated masslesion.

Breast Ultrasound

Breast ultrasound was not performed.

Mammotome Biopsy

Percutaneous biopsy of the left breast wascarried out with a mammotome (11-gaugeneedle) that yields a larger volume of tissuethan standard core biopsy. A radiograph ofthe biopsy material confirmed that calcifica-tion was present in the specimen (Fig. 1).Histopathological evaluation revealed local-ized fibrous sclerosis containing coarsemicrocalcification consistent with a zone offat necrosis (B2) (Fig. 2).

Diagnosis

Incidental area of fat necrosis of the rightbreast with no antecedent history of trauma.


Following multidisciplinary review thepatient was reassured and discharged backinto the screening program. There was noindication for further tissue acquisition andopen surgical biopsy was not necessary onthe basis of the mammotome result.


The patient accepted the results of themammotome biopsy and was relieved that

Figure 1

Figure 2

206 CHAPTER 12


no malignancy had been detected. However,she felt unable to cope with fear of develop-ing cancer in the contralateral breast andhad been traumatized psychologically by theadjuvant treatments previously received forher left-breast cancer (namely chemother-apy). Moreover, she felt very lopsided with asingle breast and had no desire for anyreconstructive procedure to the left side.She therefore requested a contralateral pro-phylactic mastectomy and understood thatthough this would not prolong her life, itwould minimize the chance of a secondbreast cancer and avoid the need for anyfurther treatments such as chemotherapy.Interestingly, it was pointed out to thepatient that a contralateral cancer is oftenof a more favorable grade and stage thatmakes the need for chemotherapy less likely.Despite these comments, the patient wasadamant that she wished to proceed with acontralateral procedure and this wasarranged within two months. A right simplemastectomy was carried out (without anyform of axillary surgery) and the patientmade an uneventful recovery. She was verypleased that she had undergone contrala-teral prophylactic surgery.


This revealed benign breast changes onlywith no evidence of atypia, in situ or invasivemalignancy.

Discussion

The greatest risk factor for breast cancer is apersonal history of the disease. The risk fordevelopment of contralateral breast canceris approximately 0.7% per year and the riskof dying from a contralateral lesion about0.2% per year (1). Between 4% and 15% ofpatients surviving breast cancer will developcancer in the opposite breast (2). Patientswho undergo breast conservation surgeryhave a risk of de novo cancer in both thecontralateral and the remaining ipsilateralbreast tissue. In the latter scenario, a trueipsilateral breast tumor recurrence must bedistinguished from a new cancer. There is noevidence that scatter from external beam

radiotherapy (5–10% of total dosage) signifi-cantly increases the chance of malignantchange in the remaining breast tissue. Sys-temic adjuvant chemohormonal therapiesreduce ipsilateral breast tumor recurrenceby approximately one-third (3–5) and hor-monal therapies such as tamoxifen decreasethe risk of contralateral disease by up to 40%(6). More women are now being successfullytreated for breast cancer at an earlier stageof disease. For younger women who do notsuffer from non–breast-cancer relateddeaths, survival is sufficiently prolonged toallow manifestation of a second, contrala-teral malignancy. For women with breastcancer diagnosed under the age of 50years, the risk of contralateral breast canceris 10- to 14-fold higher than for the generalpopulation. It has been estimated that fewerthan 5% of women will have developed acontralateral breast cancer by 4 years andonly 7% at 10 years (7). Patients with aknown BRCA-1 mutation have at least a60% risk of a contralateral breast cancerand usually bilateral mastectomy is recom-mended for this group of patients if breastcancer develops prior to any ipsilateral pro-phylactic procedure (8).

Some women will opt for a contralateralprophylactic mastectomy on the basis of aprior diagnosis of breast cancer in theabsence of any strong family history orgenetic predisposition. This is a personalchoice and a woman has a right to chooseher destiny. Nonetheless, it is important toemphasize to these patients that a contrala-teral procedure will not necessarily prolongtheir life, but will reduce the chance of fur-ther developing a breast cancer. A patient'sfate is determined by the index tumor andsecond contralateral cancers are usually of amore favorable prognosis and probably con-tribute to only about 5% of breast cancermortality (9). This is partly related to detec-tion at an earlier stage from routine follow-up surveillance. However, with heightenedpublic awareness and breast-screening pro-grams, cancers are presenting at a smallersize and earlier stage. In consequence, anyprognostic advantage of contralateral can-cers will be eroded and therefore secondcancers could become more important in



the future. This would strengthen any argu-ment for a contralateral prophylactic mas-tectomy in patients with an early-stage indexlesion as it might confer an overall survivalbenefit for an individual patient and not justavoid further cancer treatment.

Many patients request a contralateral pro-phylactic mastectomy because they do notwish to endure further treatments for anynew breast cancer. Such concerns oftenrelate to chemotherapy rather than surgeryper se despite prophylactic mastectomybeing relatively radical surgery. Somepatients feel very lopsided after a unilateralmastectomy for cancer and seek to be flatchested. Occasionally a single remainingheavy and pendulous breast can lead toback problems. Several of these factors per-tained in the case described herein.

Contralateral prophylactic mastectomymay be requested because of a fear of fur-ther cancer per se and patients may seek tominimize the chance of any recurrence orsecond malignancies. It may be impossible toreassure patients that long-term survival isunlikely to be compromised in the event of acontralateral cancer. In younger women,increased density of breast tissue rendersmammographic surveillance more difficult.Use of MRI as a screening tool may fail toreassure these younger patients that theopposite breast is tumor-free (there is norole for random contralateral biopsies) (10).

Though contralateral prophylactic mastec-tomy may be demanded by a patient frompersonal choice and in accordance with theprinciple of autonomy, there are situationswhere this may be surgically recommended:

1. Moderately strong family history ofbreast cancer.

2. The presence of florid lobular carci-noma in situ in association with a lobularphenotype in the ipsilateral breast can-cer (higher chance of bilaterality).

3. Dense nodular breast parenchyma or amammographically occult index lesion.This limits the sensitivity of clinical andradiological surveillance.

4. Patients who have received mantel irra-diation for Hodgkin's disease are at highrisk for bilateral breast cancers and a

contralateral prophylactic mastectomyshould be considered when a unilateraltumor develops in this group of patients.

Related Cases

Bilateral prophylactic mastectomy—CaseStudy 38

Simple mastectomy without immediatebreast reconstruction—Case Study 44

Learning Points

1. Women who have been diagnosed withbreast cancer are at increased risk fordeveloping contralateral breast cancer(0.7% per year). For women treatedwith endocrine therapy, this risk ishalved. For some women, the fear ofdeveloping contralateral breast canceris so great that contralateral prophylac-tic mastectomy is undertaken to reduceanxiety.

2. Recent retrospective studies have sug-gested that contralateral prophylacticmastectomy may improve breast cancersurvival rates. However, there are norandomized prospective trials that haveaddressed this issue.

3. In the United States, the number ofwomen electing to undergo contrala-teral prophylactic mastectomy followinga breast cancer diagnosis has increasedsubstantially in recent years. This maypartly reflect the wider use of breastMRI, and the false-positives associatedwith it.

References

1. Robbins GF, Berg JW. Bilateral primary breastcancers: a prospective clinicopathological study.Cancer 1964; 17:1501–1527.

2. Wanebo HJ, Senofsky GM, Fechner RE, et al.Bilateral breast cancer: risk reduction of contrala-teral biopsy. Ann Surg 1985; 201:667–677.

3. Fisher B, Redmond C, Dimitrov NV, et al. Arandomized clinical trial evaluating sequentialmethotrexate and fluorouracil in the treatmentof patients with node negative breast cancer whohave estrogen receptor negative tumours. N Engl JMed 1989; 320:473–478.

4. Early Breast Cancer Trialists Collaborative Group.Polychemotherapy for early breast cancer: an

208 CHAPTER 12


overview of the randomized trial. Lancet 1998;352:930–942.

5. Early Breast Cancer Trialists Collaborative Group.Tamoxifen for early breast cancer: an overview ofthe randomized trials. Lancet 1998; 351: 1451–1461.

6. Cuzik J, Baum M. Tamoxifen and contralateralbreast cancer. Lancet 1985; 2:282.

7. Morrow M. Insurance policies for prophylacticsurgery: to cover or not to cover?. Ann SurgOncol 2000; 7:321–322.

8. Mann GB, Borgen PI. Breast cancer genes and thesurgeon. J Surg Oncol 1998; 67:267–274.

9. Rosen PP, Groshen S, Kinne DW, et al. Contrala-teral breast carcinoma: an assessment of risk andprognosis in stage I and stage II patients with 20year follow up. Surgery 1989; 106:904–910.

10. Cody HS. Routine contralateral breast biopsy: help-ful or irrelevant? Experience in 871 patients, 1979–1993. Ann Surg 1997; 225:370–376.



13Lymphedema

CASE STUDY 40

History

A 71-year-old woman presented with aneight-week history of a lump in the rightbreast. There was no associated nipple dis-charge but the patient had noticed recentinversion of the right nipple. The patienthad no previous breast problems and hadundergone a screening mammogram sevenyears earlier within the NHS Breast Screen-ing Programme. There was no family historyof breast or ovarian cancer. The patient hadgiven birth to her first child at the age of 24years and had never used either hormonereplacement therapy or the oral contracep-tive pill.

Clinical Findings

Examination revealed a hard irregular masslying superior to the right nipple-areolarcomplex and measuring 3 cm in maximumdiameter. There was associated tethering ofthe overlying skin and indrawing of the rightnipple. A hard, fixed node was palpable inthe right axilla (E5) (Fig. 1).

Clinical Assessment

Clinical carcinoma of the right breast (notconservable) with involved axillary lymphnodes.

Investigations

Mammography

A spiculated mass was seen in the rightretroareolar region measuring 35 mm in

maximum diameter with the appearancesof a carcinoma (R5) (Fig. 2A, B).

Breast Ultrasound

The sonographic correlate was a 34-mm ill-defined heterogeneous mass lesion, whichwas hypoechoic without posterior acousticenhancement or attenuation (U5) (Fig. 3).

Figure 1

Figure 2

210


Core Biopsy

Ultrasound-guided core biopsy (16-gaugeneedle) of the breast mass confirmed aninvasive carcinoma (provisionally grade II, butonly a tiny fragment of tumor tissue present incore biopsy, ER positivea) (Fig. 4).

Diagnosis

Early-stage right-breast cancer (T2N2).


It was recommended that the patient undergoa right modified radical mastectomy and alevel II axillary lymph node dissection. Thepatient had a centrally located tumor exceed-ing 3 cm in size and associated with nippleindrawing, which precluded breast conserva-tion. Moreover, the patient was not eligible for

sentinel node biopsy due to the presence ofa firm, fixed node in the right axilla.Radiotherapy to the chest wall wouldlikely be required on account of therelatively large tumor size and clinically posi-tive node.


The patient proceeded to a right modifiedradical mastectomy within four weeks of ini-tial presentation (2 weeks from tissue diag-nosis). A wide skin excision was performedtogether with a level III axillary lymph nodedissection (Fig. 5). The patient made anuneventful recovery and both drains wereremoved after 72 hours.


This revealed a multifocal invasive carci-noma, which was upgraded to III from thecore biopsy [Fig. 6A (low power) and B(high power)]. There was associated high-grade cribriform and micropapillary DCISand the largest lesion measured 32 mm inmaximum extent (invasive and in situ com-ponent). Two other principle foci measuring19 mm and 6.5 mm were identified lying justinferior to the main lesion and deep to thenipple, respectively. Lymphovascular invasionwas present (Fig. 6C) and 7 of 26 lymph nodescontained metastatic tumor with evidence ofextranodal spread (Fig. 6D).


In view of the multifocality and extensivenodal involvement (>4 nodes positive),

Figure 3

Figure 5

Figure 4

a Allred score 8/8

LYMPHEDEMA 211


radiotherapy to the chest wall and supraclavic-ular fossa was recommended. Tamoxifen wascommenced as adjuvant systemic hormonaltherapy (tumor strongly ER positive) with aplanned early switch to an aromatase inhibitorafter two to three years (NPI � 4.4).


The patient underwent a course of radiother-apy to the chest wall and supraclavicular fossacommencing six weeks after surgery. Shetolerated this well with no acute radiationsequelae. Four months following surgery,she presented with moderate lymphedemaof the right arm and was referred to thelymphedema clinic (Fig. 7A–C). She was fit-ted with a standard sleeve and reviewed everysix months (Fig. 8A, B). A routine contrala-teral mammogram performed at two yearsrevealed no significant abnormality in theleft breast.

Discussion

This patient developed moderately severelymphedema four months following breast

surgery, which incorporated a level III axil-lary lymph node dissection. Despite recentadvances in treatments for breast cancer,lymphedema remains a common complica-tion that can lead to major physical andpsychological morbidity. Though it is oftenthe nondominant upper limb that is affected(most breast cancers occur on the left side),lymphedema causes symptoms of heavinessand discomfort with associated functionalimpairment and an unsightly appearance(Fig. 6). The swelling of early lymphedema-tous change is soft with pitting on pressureand improvement with arm elevation. Theaccumulation of protein-rich fluid within theextracellular compartment renders the limbprone to recurrent superficial infection,which contributes to more chronic inflam-matory changes with fibrosis. Disruption andblockage of the lymphatics raises hydrostaticpressure within other parts of the lymphaticsystem and promotes further tissue edema byhampering absorption of excess fluid backinto the lymphatic vessels. The precise etiol-ogy of lymphedema remains unclear, but isrelated to the extent of axillary dissection.The latter disrupts lymphatic drainage

Figure 6

212 CHAPTER 13


pathways and thus compromised function ismore likely when surgical dissection is moreextensive. The overall incidence of lymphe-dema is cited as between 10% and 30% (1–4), though there are variations in the defini-tion of lymphedema. Some reports are basedon subjective assessment of arm swellingwhile others relate to measurements oflimb volume excess. It is impractical to mea-sure the latter by volume displacement tech-niques and the preferred method is serialcircumferential measurements with calcula-

tion of lymph volume using equations for atruncated cone (frustum) (5). A relativelysimple method for assessing differential limbvolume is to take measurements of limbcircumference 10 cm above and below theolecranon; a difference of �2 cm is generallyaccepted as definition of lymphedema in apatient of average body habitus (6).

A level II axillary lymph node dissectioninvolves clearance of all tissue below theaxillary vein with no attempt to skeletonizethe latter. Some fatty tissue remains inferiorto the vein and this extent of dissectionshould be associated with lymphedemarates of less than 10% to 15%. When alevel III dissection is undertaken, rates oflymphedema increase to approximately25%, though some surgeons believe thatremoval of three to four nodes maximumat level III is unlikely to significantly impacton documented rates of lymphedema. More-over, some surgeons loosely refer to level II/III dissection within the literature and thisconfounds interpretation of data on rates oflymphedema formation. The addition ofaxillary irradiation to a formal clearancecan lead to rates in excess of 40%. There isFigure 7

Figure 8

LYMPHEDEMA 213


rarely any justification for combined dissec-tion and irradiation nowadays.

Lymphedema can develop many yearsafter surgery (up to 20 years) and followsoon after an episode of heavy lifting orvigorous/prolonged usage of the arm. How-ever, three-quarters of cases occur within thefirst 12 months and the onset may be insid-ious with a gradual progression to a severelyswollen and impaired limb (7). Minor cutsand grazes and even venepuncture havebeen reported as precipitating factors. Lym-phedema appears to be more common inpatients who suffer postoperative infectionand this may be related to obesity (8).Chronic lymphedema can be complicatedby malignant change with development ofsecondary lymphangiosarcoma (Stewart–Treeves syndrome).

Lymphedema can be graded clinically asfollows:

I—Swelling, which pits on pressure and mayreduce with limb elevation;II—Firmer, non-pitting edema; skin and nailchanges with hair loss;III—Elephantiasis of the limb with grosslythickened skin and large redundant folds.

Though a precipitating factor may beidentified, there is usually no obvious reasonwhy lymphedema has developed at a partic-ular point in time after surgery. Duplexultrasound should be carried out to excludevenous obstruction and a CT scan per-formed to determine whether an axillarymass (recurrent tumor) has a causativerole. The majority of patients have mild tomoderate lymphedema and conservativemeasures are the mainstay of treatment.Drug treatment and surgery are reserved forsevere forms of chronic lymphedema withelephantiasis of the limb. The aims of treat-ment are to control edema, prevent infection,and maximize the function and appearanceof the affected limb. Conservative treatmentencompasses the following areas:

Hygiene—meticulous skin and nail care. Avoidbreaks in skin and thorough antisepsis followingminor cuts and abrasions. Commencement ofantibiotics promptly or long-term prophylaxis.Massage—manual lymphatic drainage (MLD) bya trained therapist initially. Gentle massage will

facilitate lymph flow. MLD is a more formal typeof massage that starts within non-lymphedema-tous zones of the trunk and moves more periph-erally along the limb after these watershed areashave been “prepared” for receipt of extralym-phatic fluid (9).Elevation—this simple maneuver can effectivelytreat mild forms of chronic lymphedema. Ideallythe limb should be elevated overnight but a noc-turnal schedule is unlikely to be conducive to agood night's sleep.Compression bandaging—this compensates for theloss of tissue elasticity in lymphedematous tissues.Most patients should wear compression garments,especially following a session of massage, to hin-der reaccumulation of fluid. These compressionsleeves can be custom made and class II or IIIprovide an adequate level of support for upperlimb lymphedema (30–40 mmHg and 40–50mmHg), respectively. A compression sleeveshould be worn day and night and a separateglove is available for the hand.Exercise—flow of lymph within the lymphatic ves-sels is passive and contraction of the limb muscu-lature stimulates onward movement of lymph in aproximal direction. Dynamic exercises are lesslikely to increase limb blood flow comparedwith static exercises and should be undertakenwhile wearing a compression garment.

Complex decongestive therapy is an inte-grated program that incorporates skin care,massage, compression devices, and regularexercise. The course lasts about four weeksand can lead to a 20% decrease in limb swell-ing (10). This patient was initially managed bya breast care nurse in a lymphedema clinicand was subsequently referred to a specialistlymphedema facility for more intensive ther-apy. With the advent of sentinel lymph nodebiopsy, the majority of clinically node-negativebreast cancer patients no longer undergo rou-tine axillary lymph node dissection at the out-set. This is likely to reduce the number ofcases of lymphedema in the future. There isno evidence at present that rates of lymphe-dema may ultimately be higher amongpatients who undergo a positive sentinellymph node biopsy followed by a delayedaxillary dissection (despite more technicallychallenging surgery). Those patients withinvolvement of a single sentinel lymph node(particularly when only micrometastases arepresent) should have axillary dissection con-fined to level II.

214 CHAPTER 13


Related Cases

Lymphedema—Case Study 41


Postmastectomy radiotherapy—Case Studies2, 3, 18, 22, 23, 25, 26, 27, and 28

Axillary management—Case Studies 8, 9, 10,18, and 24

Learning Points

1. Lymphedema is associated with axillarysurgery and radiation to the axilla. Areview of several studies found that therisk of lymphedema was approximately17% for breast cancer patients treatedwith axillary surgery alone and 41% forthose treated with axillary radiation andsurgery.

2. Reports concerning the incidence oflymphedema in breast cancer patientshave varied considerably, largely due tothe lack of uniform diagnostic criteria.Lymphedema is not detectable clinicallyuntil the interstitial volume is 30%above normal (11).

References

1. Kissin MW, Querci della Rovere G, Easton D, et al.Risk of lymphoedema following the treatment ofbreast cancer. Br J Surg 1986; 73:580–584.

2. Jacobsson S. Studies of the blood circulation inlymphoedematous limbs. Scan J Plast ReconstrSurg 1967; 3:1–81.

3. Schuneman J, Willich N. Lympheodema of the armafter primary treatment of breast cancer. Anti-cancer Res 1998; 18:2235–2236.

4. Mortimer PS, Bates DO, Brassington HD, et al. Theprevalence of arm oedema following treatment forbreast cancer. Q J Med 1996; 89:377–380.

5. Pain SJ, Purushotham AD. Lymphoedema follow-ing surgery for breast cancer. Br J Surg 2000;87:1128–1141.

6. Gerber LH. A review of measures of lymphoedema.Cancer 1998; 83:2803–2804.

7. Olson JA, Petrek JA. Breast cancer–related lym-phoedema. In: Singletary SE, Robb GL, eds.Advanced Therapy of Breast Disease. Ontario, Cal-ifornia: BC Decker Inc., 2000:307–313.

8. Mozes M, Papa MZ, Karasik A, et al. The role ofinfection in post-mastectomy lymphoedema. AnnSurg 1982; 14:73–83.

9. Vodder E. Lymphdrainage ad modem Vodder.Aesthet Med 1965; 14:190–191.

10. Casely-Smith JR, Casely-Smith JR. Modern treatment oflymphoedema. Complex physical therapy: the dirst 200Australian limbs. Australas J Dermatol 1992; 33:61–68.

11. Erickson VS, Pearson ML, Ganz PA, et al. Armoedema in breast cancer patients. J Natl CancerInst 2001; 93:96–111.

LYMPHEDEMA 215


14Miscellaneous Conditions

Part I: Male Breast Cancer

CASE STUDY 41

History

A 77-year-old man presented to the breastunit with a one-week history of a lump in theleft breast. He described the lump as beingon the “edge of the nipple” and had noticedsome indrawing thereof but no nipple dis-charge. His general health was otherwisegood, and he reported no recent weightloss or unusual cough or back pain. He wastaking no regular medication and had nofamily history of breast cancer.

Clinical Findings

Examination revealed a firm discrete lumplying close to the left nipple areolar complexand encroaching deep to this. There wasdimpling of the periareolar skin and indraw-ing of the left nipple [Fig. 1A–C (post–corebiopsy)]. The lump was partially fixed to theunderlying pectoralis muscle and severalhard, but mobile, nodes were palpable inthe left axilla (E5) (Fig. 2).

Figure 1

216


Clinical Assessment

Clinical carcinoma of the left breast in anelderly male with involved axillary lymphnodes.

Investigations

Mammography

A spiculate mass lesion was seen in the leftretroareolar region measuring 15 mm inmaximum diameter (R5) (Fig. 3A, B).

Ultrasound Breast/Axilla

The mammographic lesion corresponded toan ill-defined, heterogeneous mass measur-ing 15 mm on ultrasound. The echo patternwas hypoechoic with posterior acoustic atten-uation (U5) (Fig. 4). The axilla was notinterrogated sonographically.

Core Biopsy

Ultrasound-guided core biopsy (16-gaugeneedle) confirmed an invasive carcinoma(grade III, ER positive, HER2 negative)[Fig. 5A (low power), B (high power)].

Diagnosis

Early-stage left-sided male breast cancer(T1N1).


It was recommended the patient be offered aleft modified radical mastectomy with a level

Figure 2

Figure 3

Figure 4

Figure 5

MISCELLANEOUS CONDITIONS 217


II/III axillary lymph node dissection (fit andhealthy patient). Ultrasound assessment ofthe left axilla was not requested as thepatient was ineligible for sentinel nodebiopsy in the presence of clinically palpablenodes.


The patient underwent the proposed sur-gery and at operation there was macroscopicevidence of axillary lymph node involve-ment. A wide ellipse of skin was removedto incorporate the nipple areolar complextogether with the skin overlying the tumor(Fig. 6). The skin flaps were readily approxi-mated without tension. The patient made anuneventful recovery and was dischargedhome on the third postoperative day afterremoval of both drains. On subsequentreview in the clinic 10 months after surgery,there was a well-healed mastectomy scar.However, the patient had recently developedlymphedema of the left upper limb, whichnecessitated the use of an elasticated sleeve(Fig. 7A, B).


This confirmed an invasive ductal carcinoma(grade III) measuring 18 mm in maximumdiameter (Fig. 8A). The tumor was invadingthe overlying dermis, but not the underlyingmuscle (no muscle resected at the time ofsurgery) (Fig. 8B, C). There was associatedhigh nuclear grade ductal carcinoma in situ(DCIS), but this did not extend beyond theinvasive component. Lymphovascular inva-sion was present (Fig. 8D) and 10 of the 18nodes removed were infiltrated with carci-noma (Fig. 8E).


It was recommended that the patient receiveradiotherapy to the left chest wall and supra-clavicular fossa on account of the extensivenode involvement. The tumor was hormonesensitive, and tamoxifen for five years wasadvised as adjuvant systemic hormonaltherapy.

Discussion

Male breast cancer is uncommon, represent-ing 0.5% to 1% of all breast malignancies(1). The mean age at diagnosis is between 60and 70 years, which is approximately 10 yearsmore than that for female breast cancer.Nonetheless, men of all ages can be affectedwith this disease. Male breast cancer tends topresent at a later stage with a higher inci-dence of axillary metastases at the time ofdiagnosis, though prognosis is similar to thedisease in females when matched stage forstage (2–4). This may be attributable eitherto late clinical presentation or to earlierlymphatic infiltration consequent to thesmaller volume of breast and fatty tissue.

Figure 6

Figure 7

218 CHAPTER 14


Predisposing risk factors include radiationexposure (4), estrogen administration, anddiseases associated with hyperestrogenismsuch as cirrhosis of the liver and Kleinfelter'ssyndrome (5–8). Genetic predispositionoccurs in some cases of male breast cancer,with an increased incidence in patients whohave several female relatives affected withthe disease. A higher risk of male breastcancer (6% risk) has been reported in fam-ilies for whom a mutation in the BRCA-2gene has been identified (9,10).

This man presented with overt signs ofclinical carcinoma of the left breast. How-ever, breast cancer in males can be difficultto distinguish clinically from gynecomastia,which is a much more common condition.

This is often bilateral and associated with amore generalized enlargement of the breastdisc rather than a discrete lump. Gyneco-mastia may be tender whereas male breastcancer usually presents with a firm, slightlyirregular, painless subareolar mass; the lattermay be associated with skin changes andtethering to the overlying muscle.

The standard surgical treatment for malebreast cancer is a modified radical mastec-tomy, which includes a level II axillary dis-section (11). The paucity of breast tissueprecludes any form of conservation due tothe high tumor:breast size ratio and proxim-ity of the cancer to the nipple. Where tumoris found to invade the pectoral muscle, asliver of muscle can be removed at the time

Figure 8



of mastectomy. There is little experience ofsentinel node biopsy for male breast cancer,but this would be precluded for clinicallypositive axillae (12–14). The higher inci-dence of nodal involvement justifies formalaxillary clearance at the outset for mostpatients. Male patients tend to present withmore advanced stages of disease thanfemales and often with a significant delaybetween onset of symptoms and diagnosis.Even though larger tumors may be morelikely to be associated with nodal metastases,axillary ultrasound can be undertaken pre-operatively in all clinically node-negativepatients or confined to those with tumors>1.5 cm. Up to 60% of male breast cancerpatients are reported to have nodal involve-ment at presentation (15), and axillary ultra-sound can detect up to 40% of node-positivepatients and permit axillary lymph node dis-section (ALND) to be performed at the out-set (16). With increasing awareness of thecondition, men may seek medical attentionat an earlier stage in the future.

Tamoxifen has been the standard adjuvantsystemic treatment for ER-positive tumors. It isunclear whether aromatase inhibitors areeffective for male breast cancer. The synthesisof estrogens by peripheral aromatization in fattissue is probably quantitatively less importantin males; it may therefore be more appropri-ate to use tamoxifen, which is a competitiveantagonist for the ligand-binding site of theER. For younger men with breast cancer,chemotherapy may be indicated. However,male breast cancer occurs in an older popu-lation in whom there may be significantcomorbidities. Were this 77-year-old patientto have had an ER-negative tumor, no form ofsystemic therapy would have been given.

Related Cases

Male breast cancer—Case Study 42

Modified radical mastectomy in females—Case Studies 1, 2, and 36

Lymphedema—Case Study 40

Learning Points

1. Male breast cancer is extremely rare,accounting for about 1% of all breast

cancer cases. The risk of male breastcancer increases with age, with a medianage of approximately 67 years.

2. Infiltrating lobular carcinoma is rare inmales, likely due to the rarity of terminallobules in the male breast. Thus, the vastmajority of male breast cancers arereported as either ductal or unclassified(93.7%).

3. Overall survival rates for men withbreast cancer, when stratified by stageof disease, are lower than that forwomen. As in women, breast cancers inmales tend to metastasize to the bone,lungs, and liver.

References

1. Greenlee RT, Murray T, Bolden S, et al. Cancerstatistics, 2000. CA Cancer J Clin 2000; 50:7–33.

2. Heller S, Rosen PP, Schattenfeld DD, et al. Malebreast cancer: a clinicopathological study of 97cases. Ann Surg 1978; 188:60–65.

3. Borgen PI, Senie RT, McKinnon WMP, et al. Car-cinoma of the male breast: analysis of prognosiscompared to matched female patients. Ann SurgOncol 1997; 4:385–388.

4. Goss PE, Reid C, Pintilie M, et al. Male breastcarcinoma: review of 229 patients who presentedto the Princess Margaret Hospital during 40 years:1955–1996. Cancer 1999; 85:629–6639.

5. Visfeldt J, Shieke O. Male breast cancer. Histologictyping and grading of 187 Danish cases. Cancer1973; 32:985–990.

6. Demers PA, Thomas BD, Rosenblatt KA, et al.Occupational exposure to electromagnetic fieldsand breast cancer in men. Am J Epidemiol 1991;134:340–347.

7. Sasco AJ, Lowenfels AB, Pasker-deJong P. Epidemi-ology of male breast cancer. A meta-analysis ofpublished case-control studies and discussion ofselected aetiological factors. Int J Cancer 1993;53:538–549.

8. Evans DB, Critchlow RW. Carcinoma of malebreast and Kleinfelter's syndrome—is there anassociation? CA Cancer J Clin 1987; 37:246–250.

9. Couch FJ, Farid LM, DeShano ML, et al. BRCA-2germline mutations in male breast cancer casesand breast cancer families. Nat Genet 1996;13:123–125.

10. Thorlacius S, Tryggvadottir L, Olafsdottir GH, et al.Linkage to BRCA-2 region in hereditary malebreast cancer. Lancet 1995; 346:544–545.

11. Donegan WL, Redlich PN, Lang PJ, et al. Carci-noma of the breast in males: a multi-institutionalsurvey. Cancer 1998; 83:498–509.

12. Hill AD, Borgen PI, Cody HS III. Sentinel nodebiopsy in male breast cancer. Eur J Surg Oncol1999; 25:442–443.

220 CHAPTER 14


13. Gentilini O, Chagas E, Zurrida S, et al. Sentinellymph node biopsy in male patients with earlybreast cancer. Oncologist 2007; 12:512–515.

14. Rusby JE, Smith BL, Dominguez FJ, et al. Sentinellymph node biopsy in men with breast cancer: areport of 31 consecutive procedures and review ofthe literature. Clin Breast Cancer 2006; 7:406–410.

15. Joshi MG, Lee AK, Loda M, et al. Male breastcarcinoma: an evaluation of prognostic factorscontributing to a poorer outcome. Cancer 1996;77:490–498.

16. MacMillan RD, Blamey RW. The case for axillarysampling. Adv Breast Cancer 2004; 1:9–10.

CASE STUDY 42

History

A 41-year-old man presented to the breastunit with a five-month history of intermittentbloodstained discharge from the right nip-ple. The discharge was spontaneous andassociated with some tenderness of theright breast, but no lump therein. Thepatient had no previous history of any breastproblems and no family history of breast,ovarian, or prostate cancer. The patienthad a history of depression, and medicationincluded citalopram (20 mg daily). He wasotherwise fit and healthy with average alco-hol consumption and reported no usage oftobacco products or recreational drugs.

Clinical Findings

On examination, there was an area of focalnodularity in the right retroareolar regionbut no discrete or dominant mass was palpa-ble. A clear discharge could be elicited fromthe right nipple, which was positive for bloodon chromogenic testing. There was no axil-lary lymphadenopathy.

Clinical Assessment

Though the findings on palpation were notsuspicious, there was clinical concern aboutthe history of bloodstained discharge, whichwas confirmed on formal assessment.

Investigations

Mammography

This revealed an area of asymmetrical den-sity in the right breast with no focal masslesion (Fig. 9A, B).

Ultrasound Breast/Axilla

The sonographic correlate of these indeter-minate mammographic findings were twohypoechoic lesions measuring 6 and 9 mmin the right retroareolar region. These werepartially cystic lesions and were suspiciousfor malignancy (U4) (Fig. 10).

Figure 9

Figure 10



Core Biopsy

This showed features of an encapsulatedpapillary carcinoma with two foci of invasionjust exceeding the 1 mm threshold [Fig. 11A(magnification 5�)]. The invasive componentwas too small (1.2 mm) to be graded but wasstrongly estrogen receptor positive (Allredscore 8/8) [Fig. 11B (magnification 10�)].

Diagnosis

Early-stage right-sided male breast cancer(T1N0).


Following multidisciplinary review, it wasrecommended the patient undergo a rightsimple mastectomy and sentinel lymph node(SLN) biopsy. A possible contralateral pro-phylactic mastectomy was discussed with thepatient, but he chose to proceed with unilat-eral surgery in the first instance and considera left mastectomy at a later date.


The patient proceeded to a right mastec-tomy and SLN biopsy. Mastectomy was car-ried out with a narrow ellipse of skin thatencompassed the nipple areolar complexand SLN biopsy was performed initiallythrough the lateral one-third of the uppermastectomy incision. Dual localization meth-ods were used with injection of technetium99m–labeled nanocolloid (20 MBq) twohours (minimum) prior to surgery and1 mL of patent blue dye at the time ofsurgery. Blue dye was injected in the 10o'clock position (subareolar/intradermal)

with massage of the breast for five minutes.A single blue and very hot node was identifiedwith an SLN:ex vivo count >10:1. No otherblue nodes were seen, and there was noresidual activity in the axilla following removalof the single SLN. A simple mastectomy wassubsequently carried out using standard tech-niques and the wound was closed with twoclosed suction drains (Fig. 6). The skin flapswere readily approximated without tension.The patient made an uneventful recovery andwas discharged home on the third postopera-tive day after removal of both drains.


This revealed an 18-mm grade I invasiveductal carcinoma with mucinous features(final histological size was comparable to theaggregate radiological estimate) [Fig. 12A(low power), B (high power)]. There wasassociated intermediate nuclear grade ductalcarcinoma in situ with papillary and cribri-form architecture. The latter extended alongthe main lactiferous ducts to the nipple. Thesingle SLN was tumor-free.


It was recommended the patient receive radio-therapy to the chest wall together with tamox-ifen for five years as adjuvant systemichormonal therapy. A contralateral prophylacticmastectomy remained an option at a later date.

Discussion

This patient had a small primary tumor thatwas unlikely to have spread to axillary lymphnodes (1). This together with his relatively

Figure 11

222 CHAPTER 14


young age made him very suitable for SLNbiopsy, which would potentially avoid ALNDand concomitant morbidity. Lymphedemacan develop in male patients just like theirfemale counterparts and sentinel nodebiopsy should be considered for smaller,clinically node-negative tumors in men.There is clear evidence that SLN biopsy isassociated with reduced arm morbidity,including lymphedema, shoulder stiffness,and paresthesia of the ipsilateral arm (2).This may be particularly relevant to the malepopulation who constitute a high proportionof manual workers and up to 90% of thoseemployed in heavy industries such as miningand construction (3). Male breast cancerpatients are more likely to be sole breadwin-ners and there are economic consequencesfor upper limb morbidity at a personal level.In addition to a lower chance of long-termproblems with impairment of upper limbfunction, SLN biopsy can shorten the dura-tion of hospital stay and facilitate an earlierreturn to work.

A review by the American Society of Clin-ical Oncology Technology Assessment panel

concluded that there was no a priori reasonto suppose that SLN biopsy was intrinsically“less accurate in men than it is in women”(4). Cadaver studies have confirmed that thepattern of lymphatic distribution and drain-age is similar in males and females (5); thecutaneous plexus of lymphatics is linked tolymphatics within the breast parenchyma viaspecialized subareolar and circumareolarplexuses, which drain directly to axillarynodes (6). On the basis of this commonanatomy and physiology, SLN biopsy shouldbe feasible in clinically node-negative malepatients. A limited number of publicationshave emerged in the literature supportingthis contention demonstrating high rates ofdetection and low rates of false negativity andaxillary recurrence (7–12). However, the num-ber of patients in these studies are necessarilyvery low, and calculations of relevant perfor-mance indicators must be interpreted withcaution. Cimmino and colleagues reportedon 18 male patients treated for breast cancer(mean tumor size 1.6 cm) of whom 6 under-went SLN biopsy (8). Most of these had aconfirmatory ALND (4 of 6 patients) andhalf had a positive SLN biopsy. The authorsconcluded that SLN biopsy was suitable formale breast cancer patients with clinicallynode-negative tumors measuring �2 cm(T1). It was unclear whether the techniquecould be applied to larger tumors where thechance of nodal involvement and false nega-tive rates were higher. Veronesi's group inMilan also reported an identification rate of100% among a group of 32 male patients whounderwent SLN biopsy for mainly T1 tumors(75%) (11). The mean number of SLNsremoved at operation was 1.5 (range 1–3).Twenty-six of these 32 patients were SLN neg-ative and were spared ALND. Among the sixSLN biopsy–positive patients, only two hadinvolvement of non-sentinel lymph nodes(NSLNs) and no axillary recurrences in SLN-negative patients had occurred at 30 monthsfollow-up. Other studies have confirmed highrates of identification of the SLN in clinicallynode-negative male patients using dual local-ization techniques with or without lymphoscin-tigraphy; the latter may only identify SLNs inapproximately two-thirds of patients (13).Boughey and colleagues emphasized thatmale patients present with larger tumors on

Figure 12



average than females and are more likely to beSLN positive (37.0% vs. 22.3%, p = 0.1) and toharbor additional disease in NSLN (62.5% vs.20.7%, p = 0.01) (10). These conclusions wereechoed in a recent series of 78 male breastcancer patients from Memorial Sloan-Ketter-ing Cancer Center. The SLN was successfullyidentified in 76 patients (97%) and the 37 ofthese had a positive SLN (node positivity rate49%). Both patients with a failed SLN biopsyproceeded to ALND and were found to havenodal metastases. Further more, in threepatients with a negative SLN (8%), a positiveNSLN was found by digital palpation at oper-ation (14). Goyal and colleagues investigatedSLN biopsy in nine male patients with T1 (4)and T2 (5) cancers and documented an SLNpositivity rate of 56%, with half of all SLN-positive patients having further involvementof NSLN on completion of ALND (14). Thehigh proportion of SLN-positive patients inthis study may be attributable to more thanhalf having tumors exceeding 2 cm in size.

The overall benefits of SLN biopsy formen may be less than that for their femalecounterparts who may undergo regularbreast screening and present with earlierstage disease or “minimal” breast cancer(15). Nonetheless, the procedure is feasibleand appears safe and justified in a selectedgroup of younger, clinically node-negativepatients with tumors �2 cm.

Related Cases

Male breast cancer—Case Study 41

Sentinel lymph node biopsy in females—Case Studies 5, 6, 7, 10, 11, 16, 24, and 26

Learning Points

1. Although breast-conserving surgery(lumpectomy) is an option for mostwomen with early breast cancer, it israrely feasible in men because theyhave only a small amount of breast tissueand this is located immediately deep tothe nipple. Therefore mastectomy isgenerally indicated for male breast cancer.

2. Sentinel node biopsy can be offered tomost male breast cancer patients with

clinically negative axillary nodes. However,breast cancer in males is often diagnosedat a more advanced stage, making sentinelnode biopsy inappropriate.

3. Breast cancer in males is extremely rare,and management of this disease has notbeen assessed in large randomized trials.Thus, the optimal management ofmale breast cancer has not been fullydelineated.

References

1. Querci della Rovere G, Bonomi R, Ashley S, et al.Axillary staging in women with small invasive breasttumours. Eur J Surg Oncol 2006; 32:733–737.

2. Purushotham AD, Upponi S, Klevesath M, et al.Morbidity following sentinel lymph node biopsy inprimary breast cancer—a randomized controlledtrial. J Clin Oncol 2005; 23:4312–4321.

3. Port ER, Fey JV, Cody HS III, et al. Sentinel lymphnode biopsy in patients with male breast carci-noma. Cancer 2001; 91:319–323.

4. Lyman GH, Guiliano AE, Somerfield MR, et al.The Americal Society of Clinical Oncology guide-line recommendations for sentinel lymph nodebiopsy in early stage breast cancer. J Clin Oncol2005; 23:7703–7720.

5. Suami H, Pan WR, Mann GB, et al. The lymphaticanatomy of the breast and its implications forsentinel lymph node biopsy: a human cadaverstudy. Ann Surg Oncol 2008; 15:863–871.

6. Romrell LJ, Bland KI. Anatomy of the breast, axilla,chest wall and related metastatic sites. In: Bland KI,Copeland EM, eds. The Breast. Vol 1, 3rd ed.Philadelphia: Saunders, 2004.

7. Hill AD, Borgen PI, Cody HS III. Sentinel nodebiopsy in male breast cancer. Eur J Surg Oncol1999; 25:442–443.

8. Cimmino VM, Degnim AC, Sabel MS, et al. Efficacyof sentinel lymph node biopsy in male breast can-cer. J Surg Oncol 2004; 86:74–77.

9. Rusby JE, Smith BL, Dominguez FJ, et al. Sentinellymph node biopsy in men with breast cancer: areport of 31 consecutive procedures and review ofthe literature. Clin Breast Cancer 2006; 7:406–410.

10. Boughey JC, Bedrosian I, Meric-Bernstam F, et al.Comparative analysis of sentinel lymph node oper-ation in male and female breast cancer patients. JAm Coll Surg 2006; 203:475–480.

11. Gentilini O, Chagas E, Zurrida S, et al. Sentinellymph node biopsy in male patients with earlybreast cancer. Oncologist 2007; 12:512–515.

12. Flynn LW, Park J, Patil SM, et al. Sentinel lymphnode biopsy is successful and accurate in malebreast carcinoma. J Am Coll Surg 2008; 206:616–621.

13. Albo D, Ames FC, Hunt KK, et al. Evaluation oflymph node status in male breast cancer patients: a

224 CHAPTER 14


role for sentinel lymph node biopsy. Breast CancerRes Treat 2003; 77:9–14.

14. Goyal A, Horgan K, Kissin M, et al. Sentinel nodebiopsy in male breast cancer patients. Eur J SurgOncol 2004; 30:480–483.

15. Cady B, Stone MD, Schuler J, et al. The new era inbreast cancer: invasion, size and nodal involvementdramatically decreasing as a result of mammo-graphic screening. Arch Surg 1996; 131:301–308.

Part II: Paget's Disease

CASE STUDY 43

History

A 97-year-old woman presented with a six-month history of eczematous change andsoreness of the left nipple. There was nopalpable mass in the retro-areolar region ofthe breast. She had no previous breast prob-lems and no family history of breast cancer.The patient was nulliparous and had neverused any form of exogenous hormones.

Clinical Findings

There was an area of florid eczematouschange involving the left nipple and areolar,which extended just beyond the margin ofthe latter. The area was weeping slightly butwas not frankly ulcerated. There was no pal-pable mass in the retroareolar region and noaxillary lymphadenopathy (E5). No eczema-tous changes were noted in the other nipple(nor elsewhere on the cutis) (Figs. 13 and14A, B).

Clinical Assessment

Paget's disease of the left breast associatedwith an impalpable tumor.

Investigations

Mammography

A normal parenchymal pattern was seen inboth breasts with no focal lesion.

Breast Ultrasound

In view of the normal mammographicappearances, breast ultrasound was not per-formed.

Punch Biopsy

A punch biopsy of the left areola performedin the clinic showed infiltration of theFigure 13

Figure 14



epidermis by nests of large epithelioid cellswith abundant eosinophilic cytoplasm andmarked nuclear pleomorphism (Fig. 15A(high power)). These cells were stronglypositive for cytokeratin 5.2 (Fig. 15B) andnegative for HMB45 and MelanA. The find-ings were consistent with Paget's disease ofthe nipple associated with DCIS.

Diagnosis

Paget's disease of the left breast with associ-ated noninvasive breast cancer [Tis (Paget's)].


It was recommended that this patient ini-tially be managed expectantly. She was a fraillady of advanced age and surgical interven-tion was not deemed appropriate. Therewere concerns about commencing primaryendocrine therapy with the aromatase inhib-itor letrozole in the absence of documented

hormone-sensitive (ER positive) invasive car-cinoma. It was commented that there is noevidence for any benefit from either tamox-ifen or aromatase inhibitors as primaryendocrine treatment for in situ disease.


The patient was therefore managed expect-antly and the nipple was dressed regularly bythe district nurse. Upon review after threemonths, the lesion appeared static and thepatient was discharged back to the care ofthe general practitioner for further monitor-ing. Six months later, the general practitio-ner contacted the breast unit to specificallyrequest further review.

On reassessment of the left nipple lesion,there was clear evidence of disease progres-sion with frank ulceration of the lesion, butno underlying palpable mass. The patientreported some mild shortness of breath onexertion, but was otherwise generally well.


Following further multidisciplinary review, itwas recommended that the patient be com-menced on letrozole (2.5 mg/day). A rou-tine chest X ray was requested and revealedno evidence of metastatic pulmonary dis-ease.


The patient was reviewed in the clinic afterthree months, at which time she appearedwell in her general self (she continued to liveindependently at home). Repeat clinicalexamination revealed a marked improve-ment in the appearance of the left nippleand areola with regression of the ulceratedareas and reduction in extent of the eczem-atous changes. The patient was instructed tocontinue taking letrozole and get the dress-ing changed by the district nurse every twoto three days.

Discussion

The original description of this condition bySir James Paget in 1874 referred to nipple

Figure 15

226 CHAPTER 14


changes as “a florid, intensely red, raw sur-face . . . like the surface of a very acuteeczema” (1). Paget's disease of the nipple isusually a unilateral lesion affecting one orother nipple, and this is an important fea-ture serving to differentiate Paget's diseasefrom simple eczema. Moreover, the condi-tion primarily affects the nipple itself, withencroachment onto the adjacent areolar.The surface of the nipple is rough or “veryfinely granular” with erythema, ulceration,and scaling. Ulceration of the nipple occursin 90% of cases and is more likely when thecondition involves both the nipple and are-olar (as in the case described here) (2).Patients usually complain of itching andburning of the nipple, together with bleed-ing and oozing from the surface. Nippleretraction may develop in more advancedcases. Delays in diagnosis are common; thecondition may improve or heal temporarilyand subsequently relapse (3). The differen-tial diagnosis includes not only eczema, butalso Bowen's disease (intraepithelial neopla-sia) and the cutaneous manifestations ofduct ectasia and periductal mastitis. Malig-nant melanoma and psoriasis should be con-sidered clinically and can be excluded withimmunohistochemical markers. Cliniciansmust maintain a high index of suspicionfor Paget's disease among patients with aneczematous lesion of the nipple.

Paget's disease constitutes approximately1.5% to 2.0% of all breast cancers and occursin an age range from 26 to 88 years, but mostcommonly between 50 and 70 years of age(median age 56 years) (4). The condition isassociated with an underlying breast cancerin >90% of cases, which can be eitherinvasive or in situ carcinoma (invasive ductalmore common than invasive lobular) and isusually centrally located and close to thenipple surface (5). The nipple changes char-acteristic of Paget's disease result from pro-liferation of cancer cells within theepidermis of the nipple. Pathognomoniccells infiltrating the dermis are readily dis-tinguished from keratinocytes, especiallywhen large numbers are present. ThesePagetoid cells are relatively large with abun-dant cytoplasm and prominent, hyperchro-matic, pleomorphic nuclei. They resemble

melanocytes, and special markers may beneeded to differentiate them from this celltype. Pagetoid cells contain mucin, whichcan be highlighted with periodic acid-Schiff(PAS) or mucicarmin stains (3,5). Stainingfor S-100 and HMB45 is positive in melano-mas, while cytokeratins are positive for bothPaget's and Bowen's disease. Pagetoid cellsalso stain positive for milk fat globulin, CAM5.2, CEA, and CK7. Both ER and PgR areexpressed in Paget's disease and interestinglyHER2/neu tends to be overexpressed (6).

It is unclear whether Pagetoid cells resultfrom migration of malignant ductal epithe-lial cells from an underlying breast cancer orfrom transformation of cells within the nip-ple itself. The immunohistochemical profileof Pagetoid cells supports the former theorywith concordance observed in more than90% of cases. However, pre-Paget cells havebeen identified with features of both kerati-nocytes and Paget's cells, which supports atransformation theory. Approximately halfof all Paget's cases will have a radiologicalabnormality, and mammography should beperformed in all patients with a suspiciouseczematous lesion of the nipple (2,7). MRIcan be helpful in confirming multifocalityand distance of any unifocal lesion from thenipple.

Historically, all cases of Paget's diseasehave been managed with mastectomy (8);disease within the breast is often multifocaland the true extent of disease may be diffi-cult to assess preoperatively. Central segmen-tal mastectomy may be suitable for patientswith a unifocal lesion in the vicinity of thenipple-areolar complex and who have largependulous breasts (9–11). Resection marginsmust be clear histologically (2–3 mm micro-scopic margin width). Radiotherapy shouldbe administered postoperatively and studieshave shown a high rate of local recurrence(40% at 5 years) when wide local excisionalone is performed for Paget's disease (12).An axillary staging procedure is essential inall patients with documented invasive diseaseon percutaneous biopsy. Sentinel lymphnode biopsy should be undertaken in allpatients with Paget's disease; approximately50% of all patients with a palpable mass willhave axillary nodal involvement compared



with 11% for an impalpable lesion. Nonsur-gical treatment of Paget's is appropriate inelderly and/or unfit patients. However,results of primary radiotherapy alone arevariable with many patients having toundergo subsequent salvage mastectomy(13).

There is little data on the response ofPaget's disease to primary endocrine treat-ment. Both ER and PgR are expressed inPaget's disease and can be useful markers toguide therapy. This patient did respond clini-cally to a course of letrozole with a markedimprovement in appearance of the nippleafter three months of treatment. It is likelythat for most patients optimal local control willbe achieved when primary radiotherapy orendocrine treatment is followed by local exci-sion. Current trials are evaluating wide localexcision followed by radiotherapy as an alter-native to mastectomy in otherwise fit patients.

Related Cases


Breast cancer in the elderly—Case Studies 33and 34

Learning Points

1. If Paget's disease of the nipple is sus-pected, then a punch biopsy of the nip-ple skin should be obtained. Thediagnosis of Paget's disease is confirmedif Paget's cells are found on biopsy.

2. Approximately 95% of patients withPaget's disease of the nipple have anunderlying breast cancer (either DCISor invasive cancer). A careful physicalexamination and mammography aregenerally used to identify the underlyingcancer.

3. In most patients, Paget's disease istreated with either a modified radicalmastectomy (for invasive cancer) ormastectomy alone (for DCIS). Alterna-tively, if the disease is confined to thenipple and an area immediately aroundit, then breast-conserving surgery is fea-

sible (the nipple, areola, and involvedpart of the breast is removed). For inva-sive breast cancer, a sentinel nodebiopsy/axillary clearance is also indi-cated. For patients treated with breastconservation, radiotherapy is generallyadministered afterward. Systemic ther-apy is administered using the sameguidelines as that used for any patientwho presents with invasive breast canceror DCIS.

References

1. Paget J. Disease of the mammary areola precedingcancer of the mammary gland. St Bart Hosp Rep1874; 10:89.

2. Kollmorgen DR, Varanasi JS, Edge SB, et al. Paget'sdisease of the breast: a 33 year experience. J AmColl Surg 1998; 187:171–177.

3. Dixon AR, Galea NH, Ellis IO, et al. Paget's diseaseof the nipple. Br J Surg 1991; 78:722–723.

4. Wertheim U, Ozello L. Neoplastic involvement ofnipple and skin flap in carcinoma of the breast. AmJ Surg Pathol 1980; 4:543–549.

5. Chaudary MA, Millis RR, Lane EB, et al. Paget'sdisease of the nipple: a 10 year review includingclinical, pathological and immunohistochemicalfindings. Breast Cancer Res Treat 1986; 8:139–146.

6. Ramachandra S, Machin L, Ashely S, et al. Immu-nohistochemical distribution of c-erbB-2 in situbreast carcinoma: a detailed morphological analy-sis. J Pathol 1990; 161:7–14.

7. Ikeda DM, Helvie MA, Frank TS, et al. Paget'sdisease of the nipple: radiologic-pathological cor-relation. Radiology 1993; 189:89–94.

8. Freund H, Maydovnik M, Laufer N, et al. Paget'sdisease of the breast. J Surg Oncol 1997; 9:93–98.

9. Lagios MD, Westdahl PR, Rose MR, et al. Paget'sdisease of the nipple: alternative management incases without or with minimal extent of underlyingcarcinoma. Cancer 1984; 54:545–551.

10. Bijker N, Rutgers EJ, Duchateau L, et al. Breastconserving surgery for Paget's disease of the nip-ple: a prospective European Organisation forResearch and Treatment of Cancer study of 61patients. Cancer 2001; 91:472–477.

11. El-Sharkawi A, Waters JS. The place for conserva-tive treatment in the management of Paget's dis-ease of the nipple. Eur J Surg Oncol 1992; 18:301–303.

12. Jamali FR, Ricci A Jr, Deckers PJ. Paget's disease ofthe nipple areola complex. Surg Clin North Am1996; 76:365–381.

13. Stockdale AD, Brierley JD, White WF, et al. Radio-therapy for Paget's disease of the nipple: a conser-vative alternative. Lancet 1989; 2:664–666.

228 CHAPTER 14


Part III: Phyllodes Tumor

CASE STUDY 44

History

A 56-year-old woman was referred to thebreast unit after she was admitted to hospitalfive days previously with a deep vein throm-bosis of the right leg. She had been noted tohave a huge mass in the right breast, whichwas not a presenting symptom. On directquestioning it transpired that the mass hadbeen present for at least six months, but hadrecently become ulcerated and prone tobleeding on light contact. The patientreported weight loss of approximately 1stone over this period, but no unusualcough or back pain. A recent chest X raywas normal with no evidence of any pulmo-nary lesions. The patient was taking lowmolecular weight heparin and had not beenwarfarinized. She otherwise had no history ofany breast problems, and of note, had neverundergone screening mammography. Therewas a weak family history of breast cancer withthe patient's maternal grandmother develop-ing the disease at 50 years of age. She had twochildren and was 19 years of age at the time ofbirth of her first child. She had never used anyform of exogenous hormones.

Clinical Findings

On clinical examination there was a hugeulcerated tumor of the central right breast,which was partially fixed to the chest walland measured at least 10 cm (Fig. 16). Therewas frank fungation over the inferior aspectof the breast, which bled on direct contact(Fig. 17A, B). There was no axillary lympha-denopathy. The mass was relatively mobileon the chest wall, and the skin of the breastaround the mass was normal with no evidenceof tumor infiltration (E5) (Fig. 18A, B).

Clinical Assessment

The clinical impression was of a large locallyadvanced cancer of the right breast. The

mass was perhaps unusually mobile on thechest wall and well circumscribed.

Investigations

Mammography

It was not possible to compress the rightbreast between the plates of a mammogrammachine. Mammography of the contrala-teral breast was normal (Fig. 19A, B).

Figure 16

Figure 17



Breast Ultrasound

Ultrasound confirmed the presence of ahuge tumor of the right breast, which wasimpossible to measure. Interestingly, the tex-ture of the mass raised the possibility of asarcoma or phyllodes tumor rather than acarcinoma (U4).

Core Biopsy

Biopsy of the mass was undertaken with twopasses of a 16-gauge needle (patient not

warfarinized and therefore no contraindicationto biopsy). Histology supported the sono-graphic images and revealed a fibroepitheliallesion with no evidence of in situ or invasivemalignancy. There were no mitotic figures inthe biopsy material which was classified as abenign phyllodes tumor (B3) [Fig. 20A (lowpower), B (high power)].

Figure 18

Figure 19

Figure 20

230 CHAPTER 14


Diagnosis

Benign phyllodes tumor of the right breast.


In view of the relatively large size of the mass,excision and complete pathological evalua-tion was mandatory. In practical terms, thisnecessitated a right simple mastectomy withprimary skin closure (plenty of healthy,mobile skin around the lesion). Despiteresults of core biopsy, there were concernsabout the patient's recent DVT and weightloss. A staging CT scan was thereforerequested to exclude any distant (meta-static) disease.

Investigations

1. Hepatic ultrasound (Fig. 20C)—normal2. CT chest, abdomen, and pelvis—normal


The patient proceeded with a right simplemastectomy. At the time of operation, themass was found to be well circumscribedwith a clear plane of dissection between themass and surrounding tissues (includingpectoral/serratus anterior muscles). Largefeeding vessels were individually ligated.Mastectomy flaps were easily apposed with-out tension and skin closed with interruptedsutures (to facilitate evacuation of any post-operative hematoma). The patient made anexcellent recovery and was warfarinized onthe fourth postoperative day.


This confirmed a massive phyllodes tumor ofthe right breast with ulceration through theskin (Fig. 21A). A fibroepithelial lesion wasseen with moderate stromal cellularity(Fig. 21B) and a prominent leaf-like archi-tecture [Fig. 21C (low power)]. The stromalcomponent consisted of spindle cells withfocal mild cytological atypia and a lowmitotic index [Fig. 21D (high power)].Though the lesion had an infiltrative pattern Figure 21



of growth and involved the surrounding fat,there was no evidence of overtly malignantfeatures. The lesion was considered border-line between benign and malignant.


As this patient had undergone a right simplemastectomy, no further resection of breasttissue was indicated. In the absence of anyfrank malignancy, no adjuvant therapies wereindicated and the patient was discharged fromformal clinical follow-up. She would undergocontralateral follow-up mammography withinthe NHS Breast Screening Programme.

Discussion

Cystosarcoma phyllodes is a tumor with thebasic structure of a fibroadenoma, but ischaracterized by marked proliferation of con-nective tissue stroma and have potential forlocal recurrence and metastasis. The namecystosarcoma phyllodes was coined by Mullerin 1938, describing a large fleshy tumor with apapillary “leaf-like” appearance on its cut sur-face (1). The biological behavior of thesetumors is unpredictable; even the histologicalappearance is not a good prediction of subse-quent behavior, but these lesions are usuallyclassified as benign (80%) or malignant(20%). The principle histological featuresare (i) the number of mitoses, (ii) a pushingor infiltrative margin, and (iii) nuclear pleio-morphism (2). The tumors occur in middle-aged women, with the maximum incidence inthe fifth decade. However, the tumors havebeen reported in adolescent as well as elderlywomen. Phyllodes tumors characteristicallygrow slowly initially and then rapidly attain alarge size. Although they are usually largerthan a typical fibroadenoma, size alone is nota reliable diagnostic criterion, and there is noway of differentiating a fibroadenoma from abenign phyllodes tumor on gross appearance.They present clinically as a large circum-scribed tumor within the breast, which canmeasure up to 10 to 20 cm in maximum

diameter. Cutaneous ulceration may occur,but is a late manifestation (3).

This patient presented with a huge fun-gating tumor of the right breast. She camefrom the Fenland community and had notbeen particularly troubled by the mass. It wasunclear why she had never attended forroutine screening mammography or whyshe had not sought a medical opinion ear-lier. Though it was unusually mobile on thechest wall, the lesion otherwise had the mac-roscopic appearance of an invasive carci-noma (E5). Interestingly, the sonographictexture was more suggestive of a phyllodestumor or sarcoma rather than a carcinoma.Core biopsy revealed a fibroepithelial lesionwith no mitotic activity. This accorded withthe final histopathological evaluation of theresected tumor. Staging investigations wererequested preoperatively despite a benigncore biopsy result in view of the patient'shistory of recent DVT, anemia, and weightloss. No formal follow-up or adjuvant therapywas indicated and the patient made an excel-lent recovery with a well-healed and neatmastectomy scar.

Related Cases

Simple mastectomy—Case Study 39

Learning Points

1. Approximately 80% of phyllodes tumorsare benign and 20% are malignant.Although the benign tumors do notmetastasize, they do have a tendency togrow aggressively and recur locally. Themalignant tumors metastasize hemato-genously, similar to other sarcomas.

2. In most cases, phyllodes tumors shouldbe treated with wide local excision, anda rim of normal tissue obtained aroundit. Phyllodes tumors should not be“shelled out” (as is often done for afibroadenoma). For large phyllodestumors, a simple mastectomy is war-ranted. An axillary node dissection

232 CHAPTER 14


should only be performed if clinicallysuspicious nodes are evident.

References

1. Muller J. Uber den feinern Bau und die Formender Krankhaften Geschwulste. Berlin: G Reimer,1838:54–60.

2. Norris HJ, Taylor HB. Relationship of histologicalfeatures to behaviour of cystosarcoma phyllodes:analysis of 94 cases. Cancer 1967; 20:2090–2099.

3. Moffat C, Pinder S, Dixon AR, et al. Phyllodestumour of the breast: a clinicopathological reviewof thirty two cases. Histopathology 1995; 27:205–218.


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Appendices

APPENDIX I

The Nottingham prognostic index (NPI)divides patients into five prognostic groupsbased on scores calculated as follows:

NPI ¼ 0.2 � tumour size þ grade(1 to 3) þ lymph node status (1 to 3)

where grade I ¼ 1; grade II ¼ 2; grade III ¼ 3and node negative ¼ 1; 1 to 3 nodes positive ¼2; �4 nodes ¼ 3)

The five prognostic groups have 10-yearsurvival figures as follows:

Excellent �2.4 94%

Good �3.4 83%

Moderate 1 �4.4 70%

Moderate 2 �5.4 51%

Poor >5.4 19%

APPENDIX II

l Adjuvantonline.com is a decision supporttool that is now widely used in manycountries. It allows for a more objective(rather than intuitive) estimates of bene-fits from hormonal and chemotherapy.

l Information on individual patients(including age, tumour size, tumourgrade, and nodal status) is fed into avalidated computerized program andabsolute mortality benefits are calculated

for chemotherapy, hormonal therapy, andcombined chemohormonal therapy.

l Chemotherapy would be recommendedfor patients with an absolute benefit of�5% and discussed for those with benefitsof �3% and <5%.

l It is the policy of the Cambridge BreastUnit not to mention chemotherapy topatients whose benefit falls below the 3%discussion threshold.

APPENDIX III

Adjuvant Chemotherapy Regimens

Drug Dose Route Days Frequency

CMF

Cyclophosphamide 600 mg/m2 i.v. Day1 and day 8

every 28 days

For 6 cycles

Methotrexate 40 mg/m2 i.v. Day1 and day 8

every 28 days

For 6 cycles

5-Fluorouracil 600 mg/m2 i.v. Day1 and day 8

every 28 days

For 6 cycles, 3 weekly, cycles 1–4

234

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E-CMF

Epirubicin 100 mg/m2 i.v. Day1

Cyclophosphamide 600 mg/m2 i.v. Day1 and day 8 4 weekly, from day 1, cycles 5–8

Methotrexate 40 mg/m2 i.v. Day1 and day 8 4 weekly, from day 1, cycles 5–8

5-Fluorouracil 600 mg/m2 i.v. Day1 and day 8 4 weekly, from day 1, cycles 5–8

AC

Doxorubicin* 60 mg/m2 i.v. Day1 Every 3 weeks (4 or 6 cycles)

Cyclophosphamide 600 mg/m2 i.v. Day1 Every 3 weeks (4 or 6 cycles)

Maximum cumulative lifetime dose of Doxorubicin (Adriamycin*) ¼ 450 mg/m2.

Neoadjuvant Chemotherapy Regimens


EC

Epirubicin 90 mg/m2 i.v. bolus Day1 21 days � 6

Cyclophosphamide 600 mg/m2 i.v. bolus Day1 21 days � 6

EC/Docetaxel

Epirubicin 90 mg/m2 i.v. bolus Day1 21 days � 4

Cyclophosphamide 600 mg/m2 i.v. bolus Day1 21 days � 4

Docetaxel 100 mg/m2 i.v. infusiona Day1 21 days � 4

a0.9% sodium chloride 250 mL over one hour.

Neoadjuvant/Adjuvant Chemotherapy Regimens


FEC/Docetaxel

5-Fluorouracil 500 mg/m2 i.v. Day1 Cycles 1, 2, and 3 every 3 weeks

Epirubicin 100 mg/m2 i.v. Day1 Cycles 1, 2, and 3 every 3 weeks

Cyclophosphamide 500 mg/m2 i.v. Day1 Cycles 1, 2, and 3 every 3 weeks

Docetaxel 100 mg/m2 i.v. Day1 Cycles 4, 5, and 6 every 3 weeks

Adjuvant Trastuzumab (Herceptin)


Trastuzumab (initial cycle) 100 mg/m2 i.v. Day1 Cycle 1 only

Trastuzumab (subsequent cycles) 100 mg/m2 i.v. Day1 Cycles 2–18 every 3 weeks

Assessment of cardiac function [left ventricular ejection fraction (LVEF)] at baseline and three monthly

APPENDICES 235SW

IN|x

ancP

Oi2

5B1C

kpP2

ICoe

Vw

==

|125

1240

352

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Index

AC. See Adriamycin/cyclophospha-mide (AC) chemotherapy

Accelerated hypofractionated wholebreast irradiation (AHWBI), 37

Adjuvant chemotherapy, 9, 19,34, 50, 63

TANGO trial, 191Adjuvant hormonal therapy, 3, 10,

17, 25, 56, 60, 101Adjuvantonline.com, 196Adriamycin/cyclophosphamide

(AC) chemotherapy, 9AHWBI. See Accelerated

hypofractionated whole breastirradiation (AHWBI)

ALND. See Axillary lymph nodedissection (ALND)

Allred score, 36, 100, 147, 183, 211American Society of Clinical

Oncology, 121, 202, 223Anastrozole, 5Antiestrogen tamoxifen, 3–4Aromatisation, 172, 200Aromatase inhibitors, 5, 25, 50, 84,

122, 168, 172, 177, 220as upfront therapy, 122, 123male breast cancer, 226

ARSAC licence, 49Arthralgia, 25, 106Arthritis, 25ATAC trial, 5, 122Atypia, 82, 88, 112, 113, 114, 201,

231Atypical ductal hyperplasia, 113Axillary lymph node dissection

(ALND), 8, 16, 56, 119, 154,218, 176, 210

levels I, II and III (ALND), 56, 212Axillary management, 49, 60, 98, 134Axillary staging, 36, 46, 60, 134male breast cancer, 220

Axillary ultrasoundbilateral breast cancer, 132neoadjuvant chemotherapy and,

146, 159Axillary vein, 105, 213

BCIRG-01 trial, 20BDANS. See Blue dye-assisted node

sampling (BDANS)BIG 1-02 trial. See Breast International

Group 1-02 (BIG 1-02) trialBIG 1-98, 5

Bilateral breast canceraxillary ultrasound, 132breast ultrasound, 116, 123, 130case studies, 116–122, 122–129,

129–134clinical assessment, 116, 123, 129clinical findings, 116, 123, 129clinical history of patient with,

116, 122, 129core biopsy, 116, 123, 125, 130diagnosis, 118, 123, 130histology, 120, 126, 132–133mammography, 116, 123, 130MRI of, 124, 131–132treatment and progress, 118–119,

126, 127, 132, 133Bilateral prophylactic mastectomycase study, 200–204

BIRADS. See Breast Imaging Report-ing and Data System (BIRADS)

Blue dye-assisted node sampling(BDANS), 46, 49, 126

Bone density scan, 5, 171Bone scan, 48, 47, 118, 126primary endocrine therapy and, 167

BRCA-1, BRCA-2 gene mutations,200, 207, 219

BR9601. See Scottish Cancer TherapyNetwork Trial (BR9601)

Breast cancer, in elderlybreast ultrasound, 181, 182–183case studies, 180–182, 182–184clinical assessment, 180, 182clinical findings, 180, 182clinical history of patient, 180, 182core biopsy, 181, 183diagnosis, 181, 183mammography, 180–181, 182primary endocrine therapy,

180–182primary radiotherapy, 182–184treatment and progress, 181, 183

Breast-conservation surgeryafter primary endocrine therapy,

173–178incidental breast cancer,

99–103postchemotherapy, case study 29,

158–164Breast conservation therapyearly-stage symptomatic breast

cancercase studies, 30–37, 38–43, 44–50,

51–56, 57–60, 61–67

screen-detected breast cancer,71–84

Breast feeding, 1, 44, 61, 95, 116,121, 152, 153, 158, 200

Breast Imaging Reporting and DataSystem (BIRADS), 112–113

Breast International Group 1-02(BIG 1-02) trial, 109

Breast radiotherapy, 47, 55, 65, 73,79, 83, 101

Breast reconstruction. Seeimmediate breast reconstruction

Breast ultrasoundbilateral breast cancer,

116, 123, 130breast cancer in elderly, 181, 182–183contralateral prophylactic

mastectomy, 206diagnostic excision biopsy and, 111early-stage symptomatic breast

cancer, 2, 7, 15–16, 22, 26, 30,38, 44, 52, 57

first trimester pregnancy-relatedbreast cancer, 185

IBTR, 104incidental breast cancer, 86, 92,

95–96, 100inflammatory breast cancer, 135,

141–142lymphedema, 210male breast cancer, 217, 221neoadjuvant chemotherapy and,

146, 153, 159Paget’s disease, 225–228phyllodes tumor, 229–232primary endocrine therapy,

165–166, 170, 174, 175screen-detected breast cancer, 68,

72, 75third trimester pregnancy-related

breast cancer, 189, 194

CALGB 9344 trial, 20Cancer en cuirasse, 140Capsular contracture, 18, 98Carboplatin, 148, 151Cardiotoxicity, 11

Herceptin, 66Chemotherapy, adjuvant, 9, 19, 34,

50, 63Central necrosis, 69CGH. See Comparative genomic

hybridization (CGH)

236


Chemotherapy, 9Chemotherapy, neoadjuvant, 186axillary ultrasound, 146, 159breast conservation surgery

postchemotherapy, 158–164breast MRI, 155breast ultrasound, 146, 153, 159case studies, 146–151, 152–158,

158–164clinical assessment, 146, 153, 159clinical findings, 146, 153, 159clinical history of patient, 146core biopsy, 146, 154, 160diagnosis, 147, 154, 160histology, 148, 155, 161mammography, 153, 159mastectomy postchemotherapy,

146–158treatment and progress,

147–148, 155–156, 160–162Clinical assessmentbilateral breast cancer, 116, 123, 129breast cancer in elderly, 180, 182contralateral prophylactic


cancer, 1, 7, 15, 21, 26, 30, 38,44, 51, 57, 61


of IBTR, 104incidental breast cancer, 86, 91,

95, 99inflammatory breast cancer, 135, 141lymphedema, 210male breast cancer, 217, 221neoadjuvant chemotherapy and,

146, 153, 159Paget’s disease, 225phyllodes tumor, 229primary endocrine therapy, 165,

170, 173screen-detected breast cancer, 68,

72, 75, 80third trimester pregnancy-related

breast cancer, 189, 194Clinical breast examination (CBE), 74Clinical findingsbilateral breast cancer, 116, 123, 129bilateral prophylactic mastectomy,

200breast cancer in elderly, 180, 182contralateral prophylactic


cancer, 1, 6–7, 15, 21, 26, 30,38, 44, 51, 57, 61



95, 99inflammatory breast cancer, 135,

141lymphedema, 210male breast cancer, 216, 221neoadjuvant chemotherapy and,



71, 75, 80third trimester pregnancy-related

breast cancer, 189, 194CMF, 11Columnar cell change, 88, 112, 113,

114Comedo necrosis, 68, 80Comparative genomic hybridization

(CGH)in IBTR, 107

Completion axillary dissection, 74,134

Completion mastectomy, 24, 42, 88,105

Core biopsyaccuracy, 113

Complete pathological response,after primary chemotherapy, 150 ,

163after primary endocrine

treatment, 178Complex decongestive therapy,

lymphedema, 214Compression bandaging,

lymphedema, 214Computed tomography (CT)chest/abdomen/pelvis, 155, 167,

231Contralateral mastopexy, 53, 148Contralateral prophylactic

mastectomycase study, 205–208

Core biopsybilateral breast cancer, 116, 123,

125, 130breast cancer in elderly, 181, 183early-stage symptomatic breast

cancer, 2, 8, 16, 22, 26, 30–31,32, 40, 44–46, 57, 62


in IBTR, 104–105incidental breast cancer, 96, 100inflammatory breast cancer, 136,

142lymphedema, 211male breast cancer, 217, 222

neoadjuvant chemotherapy and,146, 154, 160

phyllodes tumor, 230primary endocrine therapy, 166,

170–171, 174–175screen-detected breast cancer,


breast cancer, 190, 194Cribriform architecture, 68Cyclophosphamide, 160for bilateral breast cancer,

118–119, 126inflammatory breast

cancer, 137NSABP B-18 trial for, 150

Cystosarcoma phyllodes. SeePhyllodes tumor

DCIS. See Ductal carcinoma in situ(DCIS)

Deep vein thrombosis, 3Delayed immediate breast

reconstruction, 19Diagnosisbilateral breast cancer, 118, 123,

130breast cancer in elderly, 181, 183contralateral prophylactic


cancer, 2, 8, 16, 22, 31, 40, 46,52, 57, 62



96, 100inflammatory breast cancer, 136,

142lymphedema, 211male breast cancer, 217, 222neoadjuvant chemotherapy and,




breast cancer, 190, 194Diagnostic excision biopsy, of breast

cancerbreast ultrasound, 111case study, 111–114clinical assessment, 111clinical findings, 111clinical history of patient, 111

INDEX 237


[Diagnostic excision biopsy, ofbreast cancer]

diagnosis, 112histology, 112mammography, 111mammotome biopsy, 112treatment and progress, 112

Docetaxol, 18, 63, 119, 142, 163inflammatory breast cancer, 137

Dormant cancer cells, 198Ductal carcinoma in situ

(DCIS), 9, 27, 68, 73, 89,80, 86, 95

bilateral breast cancer, 126central necrosis, 69comedo necrosis, 68, 80, 86, 92cribriform architecture, 68invasive tumor, 73

Early Breast Cancer TrialistsCollaborative Group(EBCTCG), 11, 106, 108

Early-stage symptomatic breast cancerbreast conservation therapycase studies, 30–37, 38–43,

44–50, 51–56, 57–60,61–67

breast ultrasound, 2, 7, 15, 22, 26,30, 38, 44, 52, 57, 61

clinical assessment, 1, 7, 15, 21, 26,30, 38, 44, 51, 57, 61

clinical findings, 1, 6–7, 15, 21, 26,30, 38, 44, 51, 57, 61

clinical history of patient with, 1,6, 15, 21, 26, 30, 38, 44, 51,57, 61

core biopsy, 2, 8, 16, 22, 26, 30–31,32, 40, 44–46, 52, 57, 62

diagnosis, 2, 8, 16, 22, 26, 31, 40,46, 57, 62

histology, 3, 9, 17, 22, 28, 33, 40,42, 46, 54, 59, 62, 64

mammography, 1–2, 7, 15, 22, 26,30, 38, 44, 57, 61

mastectomycase studies, 1–5, 6–13, 15–21,

21–25, 26–30MRI breast, 32, 44treatment and progress, 3, 8,

9–10, 16–17, 22, 26–28, 32,33–35, 40, 41, 42, 46,47–50, 53–54, 55, 59, 60,62, 63–64

Early switch policy, 56EBCTCG. See Early Breast Cancer

Trialists Collaborative Group(EBCTCG)

EIC. See Extensive intraductcomponent (EIC)

Elephantiasis, and lymphedema, 214

Elevation, lymphedema, 214Epirubicin, 34, 160, 197for bilateral breast cancer,

118–119, 126inflammatory breast

cancer, 137ER. See Estrogen receptor (ER)Estrogen receptor (ER)immunohistochemical staining,

190Exercise, lymphedema, 214Extensive intraduct component

(EIC), 107Extracapsular/nodal spread,

138, 211

Fat necrosis, 53, 101, 102FEC. See 5-fluorouracil, epirubicin,

and cyclophosphamide (FEC)Fertility, 127, 197Fibroadenoma, 32, 35, 47, 82, 185,

200, 232Fine needle aspiration cytology

(FNAC), 55, 113, 185First trimester pregnancycase study, 185–188

5-fluorouracil, epirubicin, andcyclophosphamide (FEC)

for IBTR, 106Fisherian paradigm, 108Fluoxetine, 84Flow cytometry, 107

Gamolenic acid, 91GCSF. See Granulocyte colony

stimulating factor (GCSF)Granulocyte colony stimulating

factor (GCSF), 196GRETA trial, 168GROCTA trial, 37Guide-wire localization, 73, 76, 80,

100, 112, 160Gynaecomastia, 219

Halstedian paradigm, 108HER2. See Herceptin (HER2)

receptorHerceptin, 47, 50, 63, 65–66, 109,

121, 138, 139, 142, 148,150–151, 196

Herceptin (HER2) receptor, 5, 17,20, 22, 47, 63, 65, 109, 142

in IBTR, 106, 109inflammatory breast cancer, 136,

138Histologycontralateral prophylactic

mastectomy, 207

early-stage symptomatic breastcancer, 3, 9, 17, 22, 28,33, 42, 46, 54, 59, 62, 64


incidental breast cancer, 88, 89,93, 96–97, 101

lymphedema, 211male breast cancer, 218, 222phyllodes tumor, 231–232screen-detected breast cancer, 69,

73, 76–77, 80, 82third trimester pregnancy-related

breast cancer, 191, 195Histology, definitivebilateral breast cancer, 120, 126,

132–133diagnostic excision biopsy, of

breast cancer, 112IBTR, 106inflammatory breast cancer, 138,

143neoadjuvant chemotherapy, 148,

155, 161primary endocrine therapy, 167

Historyincidental breast cancer, 86, 91,

95, 99lymphedema, 210male breast cancer, 216, 221Paget’s disease, 225phyllodes tumor, 229screen-detected breast cancer, 68,

71, 75, 80Hormone replacement therapy, 21Hot flashes, 55Hyperestrogenism, 219Hygiene, lymphedema, 214Hypoechoic mass lesion, 57

IBTR. See Ipsilateral breast tumorrecurrence (IBTR)

Image-guided biopsy, 113Immediate breast reconstruction,

18, 89, 98, 127, 155, 191, 196Immediate Preoperative Arimidex,

Tamoxifen or Combinedwith Tamoxifen (IMPACT)study, 172

IMPACT study. See ImmediatePreoperative Arimidex,Tamoxifen or Combined withTamoxifen (IMPACT) study

Implant-only based reconstruction,24

Incidental breast cancerbreast conservation surgerycase study, 99–103

breast ultrasound, 86, 92,95–96, 100

238 INDEX


clinical assessment, 86, 91, 95, 99clinical findings, 86, 91, 95, 99core biopsy, 96, 100diagnosis, 86, 92, 96histology, 88, 89, 93history, 86, 91, 95, 99mammography, 86, 91–92, 95, 99mammotome biopsy, 86, 92mastectomycase studies, 86–91, 91–94,

95–99treatment, 88–89, 92–93, 97

Inflammatory breast canceraxillary ultrasound, 135, 141–142breast ultrasound, 135, 141–142case studies, 135–140, 140–145clinical assessment, 135, 141clinical findings, 135, 141clinical history of patient with,

135, 140–141core biopsy, 136, 142diagnosis, 136, 142histology, 138, 143mammography, 135, 141treatment and progress, 136–137,

138–139, 142–143Intergroup Exemestane Study

(IES), 5Intra-operative assessment of

sentinel nodes, 50Invasive tumor, 73Ipsilateral breast tumor recurrence

(IBTR), 35breast ultrasound, 104case studies, 104–109clinical assessment, 104clinical findings, 104clinical history of patient with, 104diagnosis, 105factors responsible for, 107HER2 receptor in, 106, 109histology, 106mammography, 104treatment and progress, 105, 106ultrasound-guided core biopsy,

104–105

Lapatinib, 140Laparoscopic oophorectomy for

breast cancer, 155–156Latissimus dorsi flap, 25Latissimus dorsi (LD), 89LCIS. See Lobular carcinoma in situ

(LCIS)LD. See Latissimus dorsi (LD)Left ventricular ejection fraction

(LVEF), 65, 148Letrozole, 198in primary endocrine therapy of

breast cancer, 171

LHRH. See Luteinizing hormonereleasing hormone (LHRH)

Li-Fraumeni syndrome, 202Limb volume measurement, 213Lobular carcinoma in situ (LCIS)Lobular neoplasia, 86, 113with IBTR, 106

Locally advanced tumours, 146, 152,165, 170

Locally recurrent breast cancer, 104,144

Luteinizing hormone releasinghormone (LHRH), 10, 126, 188

receptor agonist, 36LVEF. See Left ventricular ejection

fraction (LVEF)Lymphadenopathy, 1, 6Lymphangiosarcoma, 214Lymphedemabreast ultrasound, 210case studies, 210–214clinical assessment, 210clinical findings, 210core biopsy, 211diagnosis, 211histology, 211history, 210mammography, 210treatment, 211, 212

Lymphovascular invasion, 187Non-sentinel lymph nodes, 33, 60,

134, 163

Macrometastases, 46, 49, 63, 74, 134Magnetic resonance imaging (MRI),

breastbilateral breast cancer, 124,

131–132breast conservation surgery, 32, 44neoadjuvant chemotherapy, 155

Male breast canceraxilla, 217, 221breast ultrasound, 217, 221clinical assessment, 217, 221clinical findings, 216, 221core biopsy, 217, 222diagnosis, 217, 222histology, 218, 222history, 216, 221mammography, 217, 221treatment, 218, 222

Mammographybilateral breast cancer, 116,

123, 130breast cancer in elderly, 180–181,

182contralateral prophylactic

mastectomy, 206and diagnostic excision biopsy,

111

diagnostic excision biopsy and, 111early-stage symptomatic breast

cancer, 1–2, 7, 15, 22, 26, 30,38, 57, 61

false negative rate, 37false positive rate, 84of IBTR, 104incidental breast cancer, 86,

91–92, 95, 99inflammatory breast cancer, 135,

141lymphedema, 210male breast cancer, 217, 221neoadjuvant chemotherapy, 153,

159Paget’s disease, 225phyllodes tumor, 229primary endocrine therapy, 165,


72, 75, 80Mammotome biopsyincidental breast cancer, 86, 92of microcalcification in left

breast, 112prophylactic mastectomy, 206screen-detected breast cancer,

68, 80Manual lymphatic drainage (MLD),

214Massage, lymphedema, 214Mastectomyafter primary endocrine therapy,

165–172early-stage symptomatic breast

cancercase studies, 1–5, 6–13, 15–21,

21–25, 26–30incidental breast cancer, 86–99postchemotherapycase studies, 146–151, 152–158

screen-detected breast cancer,68–71

skin-sparing, 201Memorial Sloan-Kettering Cancer

Center, 49, 94Microcalcificationmammography, 111mammotome biopsy, 112treatment of, 112

Micrometastases, 59, 74, 133, 134Micrometastatic disease, 49, 157Microsatellite instability, 107MLD. See Manual lymphatic

drainage (MLD)Modified radical mastectomy, 2, 8,

190For male breast cancer, 217

MONET studyprimary endocrine therapy, 167,

169, 177, 178

INDEX 239


MRI. See Magnetic resonanceimaging (MRI)

MRI breastsearly-stage symptomatic breast

cancer, 32, 44MUGA scan, 65

National Epirubicin Adjuvant Trial(NEAT), 197

National Institute for ClinicalExcellence (NICE), 66

National Surgical Adjuvant Breastand Bowel Project B-06 (NSABPB-06) trial, 107–108

NEAT. See National EpirubicinAdjuvant Trial (NEAT)

Neoadjuvant chemotherapy, 186axillary ultrasound, 146, 159breast conservation surgery

postchemotherapy, 158–164breast MRI, 155breast ultrasound, 146,

153, 159case studies, 146–151, 152–158,

158–164clinical assessment, 146,

153, 159clinical findings, 146, 153, 159clinical history of patient, 146core biopsy, 146, 154, 160diagnosis, 147, 154, 160histology, 148, 155, 161mammography, 153, 159mastectomy postchemotherapy,

146–158treatment and progress, 147–148,

155–156, 160–162NEOTANGO trial, 154, 155NHS Breast Screening Programme, 4,

28, 94NICE. See National Institute for

Clinical Excellence (NICE)Nipple-areolar complex, 1Non-sentinel lymph nodes (NSLN),

33, 60, 134, 163male breast cancer, 223, 224

Nottingham Prognostic Index(NPI), 5, 237

NPI. See Nottingham PrognosticIndex (NPI), 5, 9, 17, 25,46, 55, 79, 83, 102, 133, 187,212, 237

NSABP B-06 trial. SeeNational SurgicalAdjuvant Breast and BowelProject B-06 (NSABP B-06) trial

NSABP B-18 trialfor doxorubicin and

cyclophosphamide, 150NSABP B-17 trial, 42NSABP B-31 trial, 66

NSLN. See Non-sentinel lymph nodes(NSLN)

Nulliparity, 6, 13

One-stop clinic, 10, 47Oral contraceptive pill, 30, 38, 61,

95, 111, 135, 152, 176, 185,193, 200

Ovarian suppression, 10, 36, 37, 47,50, 128, 151, 197

PACS-01 trial, 20Paget’s diseasebreast ultrasound, 225clinical assessment, 225clinical findings, 225diagnosis, 226history, 225IBTR and, 105mammography, 225punch biopsy, 225–226treatment, 226

Peau d’orange, 135, 141, 143, 159,189

Phyllodes tumorbreast ultrasound, 230clinical assessment, 229clinical findings, 229core biopsy, 230diagnosis, 231histology, 231–232history, 229mammography, 229treatment, 231

Positive sentinel lymph node biopsy,59, 63, 73, 133, 195

Posterior attenuation, 130, 165Postmastectomy radiotherapy, 13,

19, 98, 121, 139, 142, 154, 157Postmastectomy radiotherapy and

immediate breastreconstruction, 19, 98

Postmastectomy radiotherapyindex, 13

PR. See Progesterone receptor (ER)Pregnancy-related breast cancerbreast ultrasound, 185, 189, 194clinical assessments, 185, 189, 194clinical findings, 185, 189, 194clinical history of patient with,

185, 189, 193core biopsy, 185, 190, 194diagnosis, 186, 190, 194first trimester pregnancycase study, 185–188

histology, 186, 191, 195third trimester pregnancycase study, 189–193, 193–198

treatment and progress, 186, 187,190, 191, 195, 196

Primary endocrine therapybreast cancer in elderly, 180–182breast-conservation surgery after,

173–178breast ultrasound, 165–166, 170, 174left, 175

clinical assessment, 165, 170, 173clinical findings, 165, 170, 173clinical history of patient, 165,

170, 173core biopsy, 166, 170–171, 174–175left breast, 175right axillary lymph node, 175right axillary node, 167

diagnosis, 166, 171, 175histology, 167mammography, 165, 170, 174mastectomy after, 165–172tamoxifen in, 167–169treatment andprogress, 167, 171, 177

Primary radiotherapybreast cancer in elderly, 182–184

Primary surgical therapynode negative breast cancer, 4

Progesterone receptor (PR)immunohistochemical staining, 190

Prophylactic mastectomybilateral prophylactic mastectomy,

200–204breast ultrasound, 206clinical assessment, 206clinical findings, 200, 206clinical history of person with,

200, 205–206contralateral prophylactic

mastectomy, 205–208diagnosis, 206histology, 207mammography, 206mammotome biopsy, 206treatment and progress, 200–201,

206–207Psychological support, 142Psychological morbidity, 212Pulmonary embolism, 9Punch biopsyPaget’s disease, 225–226

Quadrantectomy, 107, 108, 167

Radiotherapychest wall, 10postmastectomy, 12

Radial scar, 113Raloxifene, 203Re-excision after breast conservation

surgery, 24, 41, 43, 65, 84, 101,102, 163

Rib necrosis, 184

240 INDEX


San Antonio Breast CancerSymposium (SABCS), 11

Sarcoma, 230Schizophrenia, 170Scottish Cancer Therapy Network

Trial (BR9601), 197Screen-detected breast cancer, 68,

80, 91, 71, 80breast conservation therapycase study, 71–75, 75–79, 80–84

breast ultrasound, 68, 72, 75clinical assessment, 68, 72,

75, 80clinical findings, 68, 71, 75, 80core biopsy, 72, 75diagnosis, 68, 72, 75histology, 69, 73, 76–77, 80, 82history, 68, 71, 75, 80mammography, 68, 72, 75, 80mammotome biopsy, 68, 80mastectomycase study, 68–71

treatment, 69, 73, 75–76, 80,81, 83

Sebaceous cyst, 146Sentinel lymph node biopsy

(SLNB), 27, 32, 36, 40, 60, 63,73, 130, 176

immediate breast reconstruction,88

neoadjuvant chemotherapy, 164male breast cancer, 222, 223

Serial core biopsies, 150Simple mastectomy, 207, 231SLN. See Sentinel lymph nodes (SLN)

biopsy, male breast cancerSLNB. See Sentinel lymph node

biopsy (SLNB)SOFT study, 50Specimen radiograph, 40, 73, 78, 80,

88, 92Spindle cell, 231Split TRAM flap, 126, 128

Squinting nipple, 4Standardization of breast

radiotherapy (START), 37Stereotactic core biopsy, 86, 96START. See Standardization of

breast radiotherapy (START)Supraclavicular irradiation, 13, 18,

47, 118, 121, 138, 157, 163SUPREMO trial, 13, 121, 157

TACT I trial, 20TACT II trial, 34Tamoxifen, 4, 5, 10, 14, 17, 23,

25, 29, 37, 42, 47, 56, 60, 73,84, 94, 97, 122, 133, 151,169, 187

in male breast cancer, 218in primary endocrine therapy,

167–169Taxanes, 19Taxotere, 20, 66, 160Taxol, 20Technetium, 49Telangiectasia, 97, 105, 202Third trimester pregnancycase studies, 189–193, 193–198

Thromboembolism, 10Time-intensity curves, 131TRAM. See Transverse rectus

abdominis muscle (TRAM);Transverse rectus abdominusmyocutaneous flap (TRAM)

Transverse rectus abdominis muscle(TRAM), 91

Transverse rectus abdominusmyocutaneous flap (TRAM),126, 17

Treatmentbilateral prophylactic mastectomy,

200–201contralateral prophylactic

mastectomy, 206–207

early-stage symptomatic breastcancer, 3, 8, 9–10, 16–17, 22,26–28, 32, 33–35, 40, 41, 42,46, 47–50, 53–54, 55, 59, 60,62, 63–64

first trimester pregnancy-relatedbreast cancer, 186, 187

incidental breast cancer, 88–89,92–93, 96, 97, 100–101, 101

lymphedema, 211, 212male breast cancer, 218, 222Paget’s disease, 226phyllodes tumor, 231screen-detected breast cancer, 69,

73, 75–76, 80, 81, 83third trimester pregnancy-related

breast cancer, 190, 191,195, 196

Triple assessment principle, 4Triple negative tumour, 161Tumour emboli, 144Tumour regression, 162, 178Tyrosine kinase inhibitor, 140

Vaginal discharge, 10Van Nuys Prognostic Index

(VNPI), 90Venlafaxine, 84VNPI. See Van Nuys Prognostic

Index (VNPI)

Wide local excision (WLE), 4, 5, 22,29, 32, 40, 55, 57, 62, 71, 76, 80,86, 90, 91, 100, 104, 108, 160,176, 178, 232

Wilm’s tumorchemotherapy for, 148

WLE. See Wide local excision(WLE)

Zoladex, 197bilateral breast cancer, 126, 127

INDEX 241

Template_7x10_Walsworth,indd

about the book…

Management Options in Breast Cancer is the only comprehensive resource devoted to exploring the systematic approach to breast cancer diagnosis, surgery, and postoperative care.

This guide is an ideal tool for oncologists, pathologists, radiologists, and gynecologists seeking alternative management options for breast cancer. In addition, trainees will find this text a valuable reference for learning the basic principles and clinical guidelines of the field.

Key features in this stand-alone text:• an international review of the management options in the field of breast

cancer clinical practice• case-based examples designed to aid in optimal clinician decision-making• two chapters devoted to rarely-explored topics: male breast cancer and

geriatric breast cancer

about the editors...

JOHN BENSON is a Consultant Breast Surgeon in the Cambridge Breast Unit, Addenbrooke’s Hospital and a Fellow of Selwyn College, Cambridge. Dr. Benson received his Doctorate (DM) from the University of Oxford and underwent specialist training at The Royal Marsden Hospital and Institute of Cancer Research, London. He is Director of Clinical Studies at Selwyn College and was appointed a Regional Breast Tutor by the Royal College of Surgeons of England in 2007. Dr. Benson has published widely in the field of breast diseases and has coordinated a major article on breast cancer for The Lancet. He is a Fellow of the Royal College of Surgeons of England and Edinburgh and an Examiner for the Intercollegiate Membership Examination (MRCS). His is member of the British Breast Group and the American Association for Cancer Research.

ISMAIL JATOI is Professor of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. He is also Director of the Breast Care Center, National Naval Medical Center, Bethesda, Maryland, USA. Dr. Jatoi received his Ph.D. and M.D. degrees from Saint Louis University, Saint Louis, Missouri, USA. He is Diplomate of the American Board of Surgery and Fellow of the American College of Surgeons. Dr. Jatoi has had a long-standing interest in the management of breast cancer and has published numerous articles, book chapters, and books related to breast cancer local therapy and epidemiology. He has served on the Breast Cancer Executive Committee of the Southwest Oncology Group and the Cancer Prevention Committee of the American Society of Clinical Oncology.

Printed in the United States of America

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Case H

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John Benson and Ismail Jatoi

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