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pregnancy and childbirth, mobilizing emergency transport and availability of safeblood) are interventions as important as construction and staffing of more and easilyaccessible first referral units in or adjacent to rural areas.

The third delay occurs in receiving adequate treatment after the woman reaches thehealth facility. This delay should be actively reduced through sensitizing and trainingall staff at the health facility in the recognition and immediate management of sus-pected life-threatening emergencies. Training in life-saving skills in pregnancy andchildbirth should be an essential part of pre-service and in-service training. Minimumstandards of care in pregnancy and labour that are evidence-based and appropriate tothe region should be established. The World Health Organization is currentlydeveloping guidelines for dealing with emergencies in pregnancy and childbirth.These guidelines could be adapted for developing local standards, if required.

Professional bodies also have a responsibility to advise policy-makers correctly-highlighting issues, prioritizing interventions and influencing change. The RoyalCollege of Obstetricians and Gynaecologists in the United Kingdom initiated thepractice of confidential enquiries into maternal deaths, a practice that has signifi-cantly influenced maternal mortality in that country. In India, paediatricians havebeen successful in creating awareness and initiating action in issues such as oralrehydration, immunization and promotion of breast-feeding. The Federation ofObstetric and Gynaecological Societies of India with more than 14000 membersshould do the same for safe motherhood in India.

REFERENCESI World Health Organization, UNICEF. Revised 1990 estimates of maternal mortality: A new approach by WHO

and UN1CEF.Geneva:WHO/FRHlMSMl96.11. 1996.2 Weil 0, Fernandez H. Is safe motherhood an orphan initiative? Lancet 1999;354:940-3.3 World Health Organization. Maternal and newborn health/safe motherhood estimates. Geneva:World Health

Organization, 1997.4 Family Care International. The safe motherhood action agenda: Priorities for the next decade. Report on the Safe

Motherhood Technical Consultation, 18-23 October 1997, Colombo, Sri Lanka. New York:Family CareInternational, 1998.

5 Navaneetharn K. Levels and trends in maternal mortality in India. In: Shenoy TS, Shenoy KT, Devi CGC (eds).Challenges in safe motherhood initiative in Kerala, 1ndia.Trivandrum:Dr K.T. Shenoy Medical College, 1999:46-51.

6 Kaunitz M, Spence C, Danielson TS, Rochat RW, Grimes DA. Perinatal and maternal mortality in a religiousgroup avoiding obstetric care. Am J Obstet Gynecol 1984;150:826-32.

7 Fortney J. The importance of family planning in reducing maternal mortality. Stud Fam Plann 1987;18: 109-14.8 Maine D.Safemotherhoodprograms: Options and issues. New York:Columbia University, Center for Population

and Family Health, 1991.9 AbouZahr C. Maternal mortality overview. In: Murray CJL, Lopez AD (eds). Health dimensions of sex and

reproduction. Geneva:World Health Organization, 1998:111--64.10 Hogberg U. Maternal mortality in Sweden. Thesis. Umea, Umea University, 1985II Fortney J. Ensuring skilled attendance at delivery. Research Triangle, North Carolina:Family Health Interna-

tional,1997.12 Vaz F, Bergstrom S, da Luz Vaz M, Langa J, Bugalho A. Training medical assistants for surgery. Bull World

Health Organ 1999;77:688-91.

MATTHEWS MATHAI

Department of Obstetrics and GynaecologyChristian Medical College

VelloreTamil Nadu

Sentinel Node and Breast Cancer:A new paradigm?

Breast cancer is the commonest cancer among women in the West. In India, it is thecommonest cancer among women in the Delhi and Bombay Cancer Registries.' Thereported age-adjusted incidence of breast cancer in the Delhi Cancer Registry in 1995was 29.3 per 100000 population (unpublished data). Unlike in the West, most

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patients in India present at an advanced stage. Goelet al. 2 reported that at presentation,about 60% of their patients had locally advanced breast cancer (LABC) or dissemi-nated disease. However, with increasing awareness, more patients are presenting withearly lesions.

The status of the axillary lymph nodes as assessed by axillary lymph nodedissection (ALND) is still the most important predictor of outcome in breast cancer.Even in experienced hands, clinical evaluation of the axillary lymph nodes has highfalse-positive (25%) and false-negative (30%) rates.' Non-invasive investigationssuch as ultrasound, CT scan and MRI have not been found useful in assessing theaxillary lymph node status. Positron emission tomography (PET) scan has a reportedaccuracy of 68%-84%.4 However, ALND is associated with definite morbidity"which impairs the patient's quality oflife. Thus, there is a need for a procedure whichcan assess the axillary lymph node status as accurately as conventional ALND and atthe same time, is not associated with its attendant complications. In this regard,sentinel node (SN) biopsy appears to hold great promise.

The SN concept is based on the belief that all lymphatics from the tumour-bearingarea drain into the first node (sentinel node). Hence, if this node can be identified andsubjected to histopathology, it should reflect the regional lymph nodal status. How-ever, often the SN is not a single node but a cluster of lymph nodes. The averagenumber of lymph nodes removed varies from 1.4 to 1.8.6,7

The SN concept dates back to 1976 when Cabanas" performed SN biopsy inpatients with penile cancer and provided the basic understanding of its principles.However, the credit for popularizing this concept goes to Morton of John WayneCancer Institute (JWCI). JWCI is the referral centre for melanomas in North America.Confronted with patients of truncal melanomas in whom bilateral axillary andinguinal lymph node dissections had to be performed with considerable morbidityand mortality, Mortonet al. attempted to trace the cutaneous lymphatics in melanomapatients using the blue dye technique." They identified an SN in 82% of cases. Whencompared with the histopathology of conventional lymph node dissection, SN biopsyaccurately predicted the nodal status in 38 of the 40 patients (95%). Subsequently,they published another paper in which they showed that by using SN biopsy, it ispossible to identify patients with negative nodal status, and conventional lymph nodedissection can be avoided in such cases.'? Giuliano et al. II working in the sameinstitute, applied this concept to breast cancer and published the seminal paper in 1994on prediction of axillary lymph node status using SN dissection in 174 cases. At thesame time, Krag et al.'? used a radiotracer-guided technique (with the help of a hand-held gamma probe) and reported successful identification of SN in 18 of 22 patients.Currently, SN can be identified by dye-directed mapping, radio tracer-guided map-ping or a combination of both.

In the dye-directed technique, a blue dye is injected into the tumour or surroundingparenchyma or into the skin overlying the tumour. In Giuliano's experience, injectionof the dye into the peritumoral breast parenchyma gives the best results. The variousblue dyes used are isosulfan blue, patent blue, etc. Following the injection, the breastis gently massaged to improve lymphatic circulation. After a period of 3-7 minutes,depending on the location of the tumour in the breast, an incision is made below thehair -bearing area of the axilla and by blunt dissection, an effort is made to identify theblue-stained lymphatic tract. This is traced to the first draining lymph node (SN)which is excised with the surrounding fat. This technique is simple, inexpensive andit is easy to identify the blue-stained lymph node and the tract against the backgroundof yellow axillary fat. However, it has a strong learning curve. Even in the hands ofthe pioneer of this procedure, in the first 87 cases the SN identification rate was 59%.11In 1997, the same group published another series of 107 patients, in which theyreported a success rate of 94% in identifying SN.13The reported complications areminor allergic reactions such as blue hives (1% of cases), blue staining of the urineand the skin overlying the breast (injection site) which clears over a period of 24-48hours.

In radiotracer-guided mapping, the tracer is injected into the tumour, surrounding

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breast parenchyma or the skin overlying the tumour. The radiotracers commonly usedare 99mTcsulphur colloid and 99mTcalbumin colloid. After a period of 6-24 hours, theSN is identified at operation as a 'hot spot' using a hand-held gamma probe. Theadvantages of this technique are that the hand-held gamma probe provides a 'roadmap' to the SN and can identify the SN in unusual locations. The disadvantages arethat it needs a hand-held gamma probe and also has a strong learning curve. No specialradiation precautions are needed as the radiation exposure to the patient, operatingteam and pathologist is minimal.

There are some technical caveats associated with both techniques. In dye-directedmapping, the volume of injection and the time interval between the injection anddissection are critical. The transit time from an upper outer quadrant lesion is shorterthan that from a lower inner quadrant one. We recommend a time interval of 3 minutesfor a high upper outer quadrant tumour, 5 minutes for most upper outer, upper innerand lower outer quadrant lesions and 7 minutes for lower inner quadrant tumours.Skin flaps should not be raised before identifying blue-stained lymphatic channels asfailure to do so may transect the lymphatics. It is important to look for a blue-stainedtract and trace it to the lymph node rather than blindly dissect for a stained lymph node.

In the radiotracer-guided technique, there is no uniform definition of a 'hot node'.Kraget al. 12defined a 'hot' SN by a radioactive count of30 per 10 seconds before skinincision and 25 per 10 seconds after resection. Albertiniet al. 14defined any lymphatictissue with a radioactive count of more than 150% of the baseline as SN, whereasVeronesiet al. 6 excised all the lymphatic tissue with a radioactive count varying from10 to 2000 counts per second. As in dye-directed mapping, the timing of SN dissectionis also important. A long delay between injection and dissection may result in removalof second- or third-echelon lymph nodes just because they emit radioactivity. In suchinstances, the blue dye can help to differentiate between first- and second-echelonnodes. Similarly, if the blue-stained tract is disrupted during SN dissection, thegamma probe can guide the surgeon to the SN. Hence, some investigators recommendusing a combination of the two techniques. Albertiniet al. 14were the first to report theuse of a combination of both techniques with a 92% success rate. In addition, all blue-stained nodes may not be radioactive and all radioactive nodes may not take up bluedye. Coxet al.15 reported that 32% of blue-stained nodes were not hot and 30% of hotnodes were not blue.

Till date, about 20 series comprising 2536 patients of SN biopsy followed byconventional ALND have been reported." The inclusion criteria, technique of SNbiopsy and success rates in these series are variable. However, all the studies show thatit is possible to trace the lymphatics of the breast to an SN and histopathology of thisnode accurately predicted axillary lymph node status in breast cancer.

Histopathological validation of the SN concept has been provided by Turneret al. 17They examined both SNs and non-SNs by routine histopathology and immunohisto-chemical staining in 103 patients. In 60 patients with negative SN by both techniques,1087 non-SNs were examined at two levels by immunohistochemistry and only oneadditional metastatic lymph node was identified. They concluded that if SN is nega-tive on routine histopathology and immunohistochemistry, it is likely that the rest ofthe axilla is also free of tumour. A recently published meta-analysis of 11 series of912patients who underwent SN biopsy followed by ALND showed an SN detection rateof 84%, a concordance rate of 98% between SN and ALND and a false-negative rateof 5%.18The reported contraindications for SN dissection are multicentric tumoursand an excision biopsy cavity of >6 ern.

Thus, it is reasonable to state that SN accurately predicts axillary lymph node statusin breast cancer. It can provide all the information that a conventional ALND provideswithout the attendant morbidity. In addition, unlike ALND wherein a pathologist hasto examine 15-20 lymph nodes, SN biopsy permits a focused pathological analysis,as the pathologist needs to examine only 1 or 2 nodes. Lastly, in patients with anegative SN and early breast cancer, it may be possible to avoid routine ALND.

However, certain issues need to be addressed with regards to SN biopsy for breastcancer in general and its application to Indian patients in particular.

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All the reports on the utility of SN have reported a 100% specificity and positivepredictive value for SN biopsy. However, there cannot be any false-positive SNbiopsy as any positive SN with negative ALND is taken as positive and there is no wayto find out whether it is truly positive or not. Hence, the identification rate, concord-ance rate with ALND and false-negative rate of SN biopsy are better assessors of itsutility.

Another important issue is the training of the surgeon, nuclear medicine physicianand pathologist involved in the SN programme. It is essential to validate theexperience of individual surgeons and centres. Training by didactic lectures andhands-on experience under the supervision of an experienced surgeon should bemandatory before using SN biopsy as a treatment procedure. The surgeon shouldacquire an SN identification rate of>90% with a false-positive rate of 5%-10% beforeusing sentinel lymphadenectomy without ALND as a treatment procedure. We feelthat a surgeon should perform at least 30 sentinel lymphadenectomies followed byroutine ALND before using sentinel lymphadenectomy alone as a treatment proce-dure. The nuclear medicine physician should also be trained in performinglymphoscintigraphy of the breast and marking the site of SN on the skin accuratelywith the upper arm in the same position as it is kept during surgery. The most criticalrole in the SN programme is that of the pathologist. The pathologist should not onlybe well-trained in immunohistochemical techniques, but he/she should also becommitted and dedicated. Even in the best centres in India, pathologists are oftenoverburdened and it may be prudent to plan further treatment based on routinehistopathology rather than frozen section examination of an SN alone.

Currently, the role of frozen section examination, imprint cytology and immuno-histochemical evaluation of the SN is not clear. Frozen section evaluation by theroutine technique has been shown to be of limited reliability. Frozen sectionevaluation, which includes examination of about 30 sections from each SN, has beenshown to be fairly accurate but may not be practical at most centres." Though casestudies have shown that micrometastasis detected by immunohistochemical methodsalter survival, its impact on long term outcome needs to be studied in a randomizedtrial. One such trial is already underway and should be able to answer this question.

Till date, all the reports of SN biopsy include only T1 and T2 tumours. However,in India most patients present with LABC. It is important to know whether it will bepossible to identify SN in these patients and whether this accurately reflects theregional nodal status just as in early tumours. We feel that SN biopsy should beperformed in all patients of operable breast cancer (including LABC following neo-adjuvant chemotherapy). It presents the node that is 'most likely to harbour metasta-sis' to the pathologist and it can be subjected to intense examination to detect micro-metastasis. Use of SN biopsy prior to institution of any treatment in LABC may helpin staging the axilla more accurately, as absence of disease at surgery followingneoadjuvant chemotherapy may be due to a lack of involvement or complete responseto treatment. Kuerer et al. 19 studied 191 patients of LABC with cytologically provenaxillary nodal metastases who had received neoadjuvant chemotherapy and reportedthat only 10% of the patients who had complete response to chemotherapy showedoccult metastases on further histopathological evaluation including immunohisto-chemistry. Thus, SN biopsy may be used as an alternative to conventional ALND ina select group of patients of LABC who show complete response to chemotherapy.

Further refinements are necessary in the dyes that are currently available. Thecurrently used dyes (both blue dyes and radiotracers) are lymph node-seeking agentsand not tumour-seeking agents. Thus, if one can identify dyes that are selectivelytaken up by the tumoral cells and also by the lymphatics, SN biopsy could he moreaccurate. In India, isosulfan blue for human use is not currently marketed. Hence,there is a need for efforts to make it available and also look at some other indigenousdyes. Hand-held gamma probes are not available at any centre. Efforts are underwayat some centres to procure the same.

In conclusion, SN biopsy is a 'state-of-the-art' minimally invasive procedure,which accurately predicts axillary lymph node status in breast cancer. However, a

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successful SN programme needs a multidisciplinary team comprising a surgeon,nuclear medicine physician and pathologist. It permits an in-depth pathologicalanalysis offew nodes. It may help in avoiding routine ALND in a select group of node-negative early breast cancer patients. However, randomized controlled trials areessential before recommending it as a treatment of choice for node-negative patientsoutside trial settings.

ACKNOWLEDGEMENTSThis study was supported by funding from the Ben B and Joyce E. Eisenberg Foundation (Los Angeles),

the Associates for Breast Cancer Research and the Fashion Footwear Association of New York.

REFERENCESNational Cancer Registry Programme, Biennial Report 1988--89. An epidemiological study. New Delhi:IndianCouncil of Medical Research, 1992.

2 Goel AK, Seenu V, Shukla NK, Raina VK. Breast cancer presentation at a regional cancer center.Natl Med J India1995;8:6-9.

3 Fisher B, Wolmark N, Bauer M, Redmond C, Gebhardt M. The accuracy of clinical nodal staging and of limitedaxillary dissection as a determinant of histological nodal status in carcinoma of the breast. Surg Gynecol Obstet1981;152:765-72.

4 Hoh CK, Schieppers C. 18-FDG imaging in breast cancer. Semin Nucl Med 1999;29:49-56.5 Ivens D, Hoe AI, Podd TJ, Hamilton CR, Taylor I, Royle GT. Assessment of morbidity from complete axillary

dissection. Br J Cancer 1992;66: 136-8.6 Veronesi U, Paganelli G, Viale G, Galimberti V, Luini A, Zurrida S,el al. Sentinel lymph node biopsy and axillary

dissection in breast cancer: Results in a large series. J Nail Cancer Inst. 1999;91:368-73.7 Morton DL, Giuliano AE, Reintgen DS, Roses DF, Ross MI, Thompson JF. Symposium: Lymphatic mapping and

sentinel node biopsy in patients with breast cancer and melanoma. Conlemporary Surgery 1998;53:281-98.8 Cabanas R. An approach for the treatment of penile carcinoma. Cancer 1977;39:456-6.9 Morton DL, Wen D, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative

lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392-9.10 Morton DL, Wen D, Cochran A. Management of early stage melanoma by intraoperative lymphatic mapping and

selective lymphadenectomy: An alternative to routine lymphadenectomy.Surg Oncol Clin N Am 1992;1:247-59.II Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for

breast cancer. Ann Surg 1994;220:391-8.12 KragDN, Weaver DL, AlexJC, FairbankJT. Surgical resection and radiologicalization of the sentinel lymph node

in breast cancer using a gamma probe. Surg OncoI1993;2:335-9.13 Giuliano AE, Jones RC, Brennan M, Statman R. Sentinel lymphadenectomy in breast cancer. J Clin Oneol

1997 ;15:2345-50.14 Albertini JJ, Lyman GH, Cox C, Yeatmen T, Balducci L, Ku N ,et al. Lymphatic mapping and sentinel node biopsy

in patients with breast cancer. JAMA 1996;276:1818-22.15 Cox CE, Pendas S, Cox JM, Joseph E, Shons AR, Yeatman T, et al. Guidelines for sentinel node biopsy and

lymphatic mapping of patients with breast cancer. Ann Surg 1998;227:645-53.16 Hill ADK, Mann GB, Borgen PI, Cody HS 3rd. Sentinel lymphatic mapping in breast cancer. JAm Coll Surg

1999;188:545-9.17 Turner RRM, Ollila DW, Krasne SL, Giuliano AE. Histopathologic validation of sentinel lymph node hypothesis

for breast carcinoma. Ann Surg 1997;226:271-8.18 Miltenburg DM, Miller C, Karamlou TB, Brunicardi Fe. Meta-analysis of sentinel lymph node biopsy in breast

cancer. J Surg Res 1999;84:138-42.19 Kuerer HM, Sahin AA, Hunt KK, Newman LA, Breslin TM, Ames FC,el al. Incidence and impact of documented

eradication of breast axillary lymph node metastases before surgery in patients treated with neoadjuvantchemotherapy. Ann Surg 1999;230:72-8.

V. SEENUDepartment of Surgical Disciplines

All India Institute of Medical SciencesAnsari Nagar

New Delhi

NIZAR HABAL

ARMANDO GIULIANO

Joyce Eisenberg Keefer Breast Cancer FoundationJohn Wayne Cancer Institute

St John's Health CentreSanta Monica

CaliforniaUSA