phyllodes tumors of the breast prognostic factors

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Journal of the Egyptian Nat. Cancer Inst., Vol. 18, No. 2, June: 125-133, 2006

Predictive Factors of Local Recurrence and Survival FollowingPrimary Surgical Treatment of Phyllodes Tumors of the Breast

HASSAN M. ABDALLA, M.D.* and MONA A. SAKR, M.D.**

The Departments of Surgical Oncology* and Pathology**, NCI, Cairo University.

ABSTRACT

Background and Purpose: The phyllodes tumor ischaracterized by its tendency to recur locally and occa-sionally to metastasize. Local recurrence and death frommetastases are occasional, but consistent, theme in reportsof patients with phyllodes tumors (PTs). The aim of thisstudy was to determine parameters that influence outcomein this uncommon neoplasm.

Patients and Methods: Data from 79 patients withphyllodes tumors were reviewed retrospectively, reclassi-fying the pathological material using the World HealthOrganization (WHO) criteria.

Results: The median age of the patients was 42 years

with a range from 16 to 70 years. The tumor size rangedfrom 2.5 to 24cm, with a median of 11cm. Based on thecriteria proposed by WHO, 31 cases were benign tumors(39.2%), 27 borderline tumors (34.2%), and 21 malignanttumors (26.6%). The median duration of follow up was60 months ranging from 3 to 138 months. Following localexcision, the local recurrence rates were 14.3%, 50%, and75% in patients with benign, borderline, and malignanttumors; respectively, while after wide local excision thelocal recurrence rates were 0%, 36.3% and 40%; respec-tively. Whereas, 0%, 8.3%, and 8.3% of patients withbenign, borderline and malignant tumors; respectively,locally recurred after mastectomy. The 5-year disease freesurvival was 63.3% after local excision, 70% after widelocal excision, and was 87% after mastectomy (p=0.04).

Distant metastases (DM) were recorded in 10 patients(12.6%) after a median duration of 14 months (range 3-36). All cases with DM died after an average of 5 monthswith a range of 1 to 11 months. Distant metastases devel-oped in 3.2%, 11.1%, and in 28.6% of patients with bengin,borderline and malignant tumors; respectively. The 5-yearsurvival with no evidence of disease was 90% for thepatients with benign tumors compared to 69% for border-line and 61% for malignant PTs (p= 0.02).

Conclusions: The histiotype of phyllodes tumors andresection margins were the principal determinants of local

125

recurrence and distant metastases. Complete surgical

excision by either wide local excision or mastectomy ifnecessary is important in the primary surgical treatmentof phyllodes tumors.

Key Words: Phyllodes tumors - Breast - Prognostic factors.

INTRODUCTION

Phyllodes tumors (PTs) are uncommon neo-plasms of the breast, constituting 0.3 to 0.9%of all breast tumors in females [1-2]. Since thefirst description of PTs in 1838 by JohannesMuller, no fewer than 62 different definitions

were used to define this particular tumor of thebreast [3]. The majority of PTs occur in womenbetween the age of 35 and 55 [3,4,5], althoughthere are reported cases in adolescents, as wellas in elderly women [2,6]. These lesions aredifficult, if not impossible, to distinguish fromfibroadenoma on physical examination or byradiologic studies except when quite large. Thetumors are characterized by a combination ofa hypercellular stroma and cleft like or cysticspaces lined by epithelium into which classicallyprojects the stroma in a leaf-like fashion [1,7,8].There are, however, wide variations in histolog-

ical appearance between different tumors, rang-ing from those resembling fibroadenomas, apartfrom increased stromal cellularity and mitoticactivity, to those showing a diffuse overgrowthof highly pleomorphic stromal cells resemblinga soft tissue sarcoma, with a spectrum of ap-pearances intermediate between both extremes[8]. Still, it is often difficult to predict the clin-ical outcome from microscopic features in in-dividual cases [1,7,9], as by no means do allhistologically malignant tumors show a tendencyto local recurrence or metastatic spread, whilst

rarely apparently benign tumors have pursued

Correspondence: Dr Hassan M. Abdalla, Kasr El-Aini

Street, Fom El-Khalig, Cairo, Egypt, [email protected]


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an unexpectedly aggressive course. This variablebehavior might be partly a function of the in-herent qualities of the tumors, which resultedin several histological classification systems:Treves and Sunderland used the terms benignand malignant [9], Pietruszka and Barnes [7],and WHO [10] classified PTs as benign, border-line, and malignant [7]. Similar categories wereassigned by Azzopardi, but using different cri-teria (1). The outcome was also affected byclinical factors such as age, delay in diagnosisor misdiagnosis and inappropriate and inade-quate management.

The aim of this retrospective study was toidentify the parameters that predict local recur-rence and distant metastases in women treatedat NCI Cairo University over a period of 15years and to determine the best surgical approachto this questionable lesion.

PATIENTS AND METHODS

Between January 1988 and December 2003,79 women were diagnosed with PTs on the basis

of histological criteria and were treated at Na-tional Cancer Institute, Cairo University. Onlypatients with full details on clinical outcomewere included in this study. All histopathologicalslides were re-examined and the medical recordswere reviewed. The diagnosis of PTs was madeaccording to WHO criteria as benign if thefollowing characteristics were found: 0-4 mito-ses/10 high power field, pushing margins, min-imal or moderate stromal overgrowth, withminimal stromal cellularity and atypia (Fig. 1).Borderline was assigned in cases were 5-9mitoses/10 high power field, pushing or infil-trating margins, moderate stromal cellularity,

atypia and overgrowth were observed (Fig. 2).Malignant tumors were identified when >10mitoses/10 high power field, infiltrating margins,moderate to marked stromal cellularity, atypiaand overgrowth were detected (Fig. 3). Onlypatients with full details on clinical outcomewere included in this study. Patient characteris-tics, pathologic variables and surgical proce-dures were investigated as predictors of localrecurrence, distant metastases and survival.

126 Predictive Factors of Local Recurrence & Survival Following

Fig. (1): Benign phyllodes tumor. Fig. (2): Borderline phyllodes tumor. Fig. (3): Malignant phyllodes tumor.

Three types of operations were defined ac-cording to the extent of resection and margininvolvement: local excision (LE) with involvedor uninvolved margins 1cm, and mastectomy in any form.All patients were followed up for a medianduration of 60 months with a minimum of 3months and a maximum of 138 months. Five

year survival without evidence of disease wasused as the end point for analysis. The survivaltime was calculated from the day of operation.Statistical analysis was calculated using theFisher exact test. Univariate actuarial curveswere plotted using Kaplan-Meier method andstatistical comparisons were accomplished usingthe log rank test. All reported p values


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RESULTS

Clinical characteristics: The median age ofthe 79 patients was 42 years ranging from 16to 70 years. All patients presented with a breastlump. In 46 cases (58.2%), the tumor was inthe right breast and in 33 (41.8%) in the leftbreast. There were no cases with bilateral dis-ease. Thirty-two patients (40.5%) were post-menopausal, while 47 (59.5%) were pre - meno-pausal. Four (5.1%) cases reported a history ofbenign breast masses. No previous history ofany non-breast malignancy was reported.

Histopathological features: On the basis ofthe criteria adopted by WHO, samples werereclassified as benign PTs in 31 (39.24%) cases,borderline PTs in 27 (34.19%) cases, and 21(26.57%) cases of malignant PTs. The tumorsize ranged from 2.5cm to 24cm, with a medianof 11cm (Fig. 4 A,B,C). Table (1) presents therelationship between histiotype and the size ofthe tumor.

There were 21 patients with clinically sus-pected, but not cytologically verified, axillary

lymph nodes who were managed by modifiedradical mastectomy. Of these patients, metastas-es to axillary nodes were found in one patient,and reactive lesions were observed in the re-maining patients. Table (2) summarizes thetumor related characteristics in relation to theoccurrence of LR and DM.

Local recurrence and distant metastases inrelation to surgical intervention: Of the 31patients with benign tumors, 3 developed LRand one patient developed a DM after surgicalresection. The initial surgery in 14 cases wasLE. In this group, ten patients remained disease-free while three locally recurred, and one hada DM. The patients who developed LRs re-mained disease free after treatment of theirrecurrence; whereas, the patient who developedlung metastases died after 14 months. Eightpatients with benign tumors were treated withLE followed by immediate WLE. These patientswere all free of disease. Seven of the 31 patientswith benign tumors were treated by LE followedby immediate total mastectomy. All these pa-tients were free of disease. Two patients with

benign tumors were treated with immediatemastectomy and they both remained free ofdisease.

In the group of patients with borderline PTs(n=27), 4 underwent LE; two of them developedlocal recurrence. After successful wide excision,the latter 2 cases remained disease free. Elevenpatients with borderline tumors were treatedwith WLE or quadrantectomy after initiallumpectomy. Four of these eleven patients hadlocal recurrence and one patient developed lungand bone metastases. Wide excision of localrecurrence was performed in 2 patients, whilemastectomy was unavoidable in the other 2patients. One of the 4 patients, who developedLR after WLE, developed a second local recur-rence together with brain metastases. Twelvepatients with borderline PTs underwent mastec-tomy after initial LE; only one of them devel-oped both LR and pleural effusion.

Four patients in the malignant PTs (n=21)underwent LE; 2 of them developed LR, andone developed both local and systemic relapse.Five patients with malignant PTs underwentWLE; one of them developed LR, while anotherpatient had both LR and DM. Twelve patientswith malignant PTs underwent mastectomy afterinitial LE. Of the latter group, one case devel-

oped both LR and DM, while 3 developed DM.Table (3) shows the outcome based on histiotypeand surgical procedure performed.

After a median of 60 month (range 3-168),the LR rates after LE were 14.3% (3/14), 50%(2/4) and 75% (3/4) in patients with benign,borderline and malignant PTs; respectively.After WLE, the LR rates were 0% (0/8), 36.3%(4/11) and 40% (2/5) in patients with benign,borderline and malignant PTs; respectively.Whereas, 0% (0/9), 8.3% (1/12) and 8.3% (1/12)of patients with benign, borderline and malig-nant PTs; respectively, recurred locally aftermastectomy. Distant metastases occurred in 10patients (12.6%) after a median duration of 14months (range 3- 36). DM developed in 3.2%(1/31), 11.1% (3/27) and in 28.6% (6/21) ofpatients with benign, borderline and malignantPTs; respectively. In five patients (50%) withDM, LR preceded the diagnosis of DM. Allpatients who developed DM were treated withchemotherapy radiotherapy and they all diedafter an average of 5 months (range 1 to 11months) after the diagnosis of DM. Adjuvantradiotherapy was given to 2 patients after mas-tectomy; one of them remained disease free,while the other developed pleural effusion after

Hassan M. Abdalla & Mona A. Sakr 127


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one year and died 6 months later. A third womanreceived postoperative adjuvant radiotherapyafter WLE and remained free of disease duringfollow up. Adjuvant chemotherapy was providedto one woman only after simple mastectomyfor borderline tumor.

Five-year disease free survival: Of the 79treated patients, 58 (73.4%) survived for 5years with no evidence of disease after surgicaltreatment. Survival curves, according to histio-type, and extent of surgery are presented inFigs. (2,3) respectively. Clinical variables suchas: Age (p=0.59), tumor size (p=0.06), laterality

(p=0.15) and menopausal status (p=0.07) werenot of prognostic value. The histiotype of thePTs assessed on the basis of the criteria pro-posed by WHO, not single microscopic param-eters, correlated significantly with prognosis(p=0.02). The 5-year survival with no evidenceof disease was 90% for the patients with benign

tumors compared to 69% for borderline and61% for malignant PTs (benign vs malignant,

p=0.02) Fig. (5). After LE, 5-year disease freesurvival was 63.3%, while after WLE was 70%and after mastectomy was 87%, with a signif-icant difference (p=0.04). Fig. (6) demonstratesthe results of treatment according to the extentof surgery.

Table (1): The relationship between histiotype and thesize of the tumor.

Tumore size

Histiotype

Benign (31)

Borderline (27)

Malignant (21)

0-5cm 5-10cm 10>cm

(29)

(33.4)

(47.6)

(%)

9

9

10

No.

(32.2)

(37)

(28.6)

(%)

10

10

6

No.

(38.8)

(29.6)

(23.8)

(%)

12

8

5

No.

Table (2): The relation between tumor-related characteristics and the occurrence of local recurrence or distant metastases.

Recurrent site

Both

0

3

0

3

0

1

2

1

1

2

3

0

1

11

Distant

1

4

1

4

1

1

3

1

1

2

4

1

1

13

Local

7

5

6

6

3

6

3

3

6

3

4

8

7

50

Histopathologicparameters

Stromal overgrowth:

Slight

Severe

Tumor margins:

Pushing

Infilterating

Cellular atypia:

Mild

Moderate

Severe

Mitosis:

Low

Moderate

High

Tumor necrosis:

Present

Absent

Extent of resection:

Local Excision

Wide Local ExcisionMastectomy

40%

60%

35%

65%

20%

40%

40%

21%

42%

37%

55%

45%

45%

35%20%

Percent withinrecurrence

0.18

0.022*

0.58

0.75

0.07

0.04*

p value

*p values 0.05 are considered significant.


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Fig. (4-A,B,C): Phyllodes tumor can reach a huge size.

(C)

Table (3): Outcome in relation to histiotype and type of surgical intervention.

OutcomeNo

Local Excision:

Benign, n=14

Borderline, n=4

Malignant, n=4

Local excision, followed by immediate wide

local excision:

Benign, n=8Borderline, n=11

Malignant, n=5

Local excision followed by mastectomy:

Benign, n=9

Borderline, n=12

Malignant, n=12

13

4

3

89

4

9

11

8

Survivor

1

0

1

02

1

0

1

4

DeathMetastasis

1

0

1

02

1

0

1

4

Localrecurrence

3

2

3

04

2

0

1

1

No evidenceof disease

10

2

1

86

3

9

11

8

(A) (B)


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DISCUSSION

The most important problem regarding PTsis that its clinical course is unpredictable anddoes not exactly correlate with the histologicparameters [3,4,10,11,12]. Although metastasesmainly occur in malignant and borderline tu-mors, still metastatic spread from histologically

benign tumors has also been described[5,13,14,15]. This case was observed in thepresent study. Clinico-pathological parametersstudied as prognostic factors in PTs gave con-flicting results in the published series. Ourfindings were in agreement with those of otherauthors [4,14,16], in that clinical variables suchas: Age (p=0.59), tumor size (p=0.06), laterality(p=0.15) and menopausal status (p=0.07) werenot of prognostic value.

Opinions on the relation between the histo-logical appearance of the tumor and prognosisvary in literature for two reasons. Firstly, due

to lack of standard interpretation of histologicfeatures which explain why the balance betweenbenign, borderline and malignant PTs is differentin various series. Our balance between benign,borderline, and malignant lesions were 39.2%,34.2% and 26.6%; respectively. Our figuresresembled that of Salvadori [3] , but differedfrom other investigators [17,18]. As a conse-quence, we must be on guard when comparingour results with those presented in the literature.Secondly, some authors question the existenceof this correlation [15,19,20] while the majority

who acknowledge it do not agree as to whichfeature of the histological appearance is vitalin prognosis. Hawkins et al. [21] and Chany etal. [22] insisted that the most reliable predictorof malignancy is the presence of stromal over-growth. The importance of the presence ofdisproportionate overgrowth of stromal elementsat the expense of the ductal element was alsoconfirmed [23]. Cohen-Cedermark and their co-workers emphasized the prognostic significanceof tumor necrosis and the presence of stromalelements other than fibromyxoid tissue [5].

Similarly, Murad and his colleagues [23] con-firmed that tumor necrosis, infiltrating marginsand mixed mesenchymal component correlatedwell with the malignant course. However, otherauthors concluded that high mitotic activity isthe most important prognostic factor [1,7]. Inthe series presented by Grimes, metastasescorrelated best with high mitotic rates, hyper-cellularity, stromal atypia and stromal over-growth [19]. Other authors suggested that severalcombinations of individual parameters couldexplain recurrence [3,7,8,24,25]. In the currentstudy, the histiotype of the PTs assessed on thebasis of the criteria proposed by WHO, notsingle microscopic parameters, correlated sig-nificantly with prognosis (p=0.02).


Fig. (6): Patients disease free survival according to extentof surgery.

Fig. (5): Patients disease free survival according to histio-type.

+++++++++++++

++

+ + + + +

+

+ + +

+ + + +++

0.00 50.00 100.00 150.00 200.00

rec-dur

1.0

0.8

0.6

0.4

0.2

0.0

CumS

urvival

Survivial Functions

Sur-modLEMastectomyWLELE-censoredMatectomy-censored

WLE-censored

+

+

+

+++++ ++

+

+

++ + + + + + +++

+++ + + + +

1.0

0.8

0.6

0.4

0.2

0.0

CumS

urvival

0.00 50.00 100.00 150.00 200.00

rec-dur

Survivial Functions

PathMalignantBorderlineBenignHigh-censored

Intermediate-censoredLow-censored

+

+

+


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Although surgery remains the mainstay oftreatment for patients with PTs, the extent ofsurgical approach historically has been contro-versial, and continues to evolve. It is evidentthat PTs may be cured by limited surgical exci-sion, but with the increased likelihood of recur-rence regardless of their histology. In individualseries that are large enough to make compari-sons, borderline and malignant PTs were morelikely to recur than benign PTs after local exci-sion alone. Zurrida and his co-authors [13] re-ported that 9% (10/107), 44% (4/9) and 33%(1/3) of benign, borderline and malignant PTsdeveloped local recurrence. In the current study,

the in-breast recurrence rates after LE were21.5% (3/14), 50% (2/4) and 75% (3/4) forbenign, borderline and malignant PTs; respec-tively. The LR rates were significantly higherin borderline and malignant PTs after LE(p=0.04). Collective data of similar studiesdemonstrated that around 20% (111/540) ofbenign PTs recurred in the breast, whereas, 46%(18/39) of borderline and 65% (26/40) of ma-lignant PTs treated by LE recurred [26]. Of note,although the tumor was grossly removed byLE, the histologic presence or absence of tumor

at the surgical margin was not specificallyaddressed in the majority of studies [26]. Thus,from the findings of the present study and thedata recorded in literature, it seems that thehistologic categorization of PTs influenced theLR rate after LE.

Analysis of most individual series indicatedthat borderline and malignant PTs were morelikely to develop an in-breast recurrence afterWLE than benign PTs. In the current series, theLR after WLE was 0% (0/8), 36.4% (4/11) and

40% (2/5) for benign, borderline and malignantPTs; respectively. Since the number of patientstreated by WLE in each individual series waslimited in number, all series which categorizedPTs by histologic type and treated the patientwith a WLE (ranging from margins of 1cm toquadrantectomy) were collected in a meta-analysis [26]. In the latter review, only 8%(17/212) of patients with benign PTs locallyrecurred after WLE; whereas, 29% (20/68) ofpatients with borderline PTs and 36% (16/45)of patients with malignant PTs recurred in thebreast [26]. Therefore, analysis of this collectivedata clearly indicated that LR rates after WLEof borderline or malignant PTs are higher thanthe LR rates after WLE of benign PTs.

Mastectomy has been the most commonlyperformed surgery for borderline and malignantPTs with LR rates of 5% and 12%; respectively[9,25,26]. In the present study, the LR after mas-tectomy for both borderline and malignant PTswas 8.3%. This was significantly lower thanthe LR rate after WLE of borderline (36.4%)and malignant PTs (40%) (p=0.04). WhetherLR is a predictor or instigator for the develop-ment of DM and impaired survival in PTs isstill controversial. Whilst some authors haveshown that up to 60% of patients with metastaticPTs develop LR prior to systemic spread [7,8],currently most investigators refuse this associ-ation and favor a WLE [16,22,24,27,28] . The find-ings of the latter studies indicated that WLEmight not be a good option to prevent LR;however, there was no evidence that breastconserving surgery for patients with PTs resultedin reduced patient survival compared to mas-tectomy. It was further emphasized that LR didnot imply associated systemic spread, and canusually be controlled with repeated excision ormastectomy [27,28].

In the meta-analysis performed to further

understand PTs, the relationship between typeof surgery, histology, and survival was studied.It was demonstrated that the mortality rate afterLE, WLE , and mastectomy for borderline PTswas 7% (2/27), 9% (4/46), and 3% (1/34); re-spectively, while for malignant PTs was 22%(8/36), 8% (2/25), and 21% (38/179); respec-tively [26]. Whereas, mortality rate after LE andWLE was less than 1% for benign PTs (1/432for LE and 1/168 for WLE). In the current studythe mortality after LE, WLE and mastectomyfor borderline PTs was 0% (0/4), 18.2% (2/11)

and 8.3% (1/12); respectively, while for malig-nant PTs the mortality rates were 25% (1/4),20% (1/5) and 33.3% (4/12); respectively. Basedon the findings presented in this study, it couldbe concluded that mastectomy for borderlinePTs could be avoided. Only four patients withborderline PTs underwent LR after WLE. Twoof the latter group was salvaged by WLE whiletwo cases underwent mastectomy; 3 of themremained disease free.

As regards malignant PTs, our findings werenot really sufficient to provide conclusionsconcerning breast conserving surgery in thishistologic subtype. This was because only 5 ofour malignant PTs patients were treated with



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WLE; still three of them survived without LRor DM. Although the patients in this group weresmall in number, still our results were in agree-ment with the opinions of Salvadori et al. [3],Zurrida et al. [13], and Grimes [19], that thebreast affected by boredrline or malignant PTsshould only be totally removed if the tumorsize does not allow either an adequate resectionmargin or good cosmetic results by less exten-sive procedure. If the breast is large enough, alarge tumor may be radically removed by con-servative surgery. Nevertheless, it was empha-sized that mastectomy is recommended for LRof borderline and malignant PTs [3,12,13,19].

Lymphatic spread is rare in PTs. Although10-15% of patients presented with clinical ax-illary lymphadenopathy, less than 1% had nodesthat were pathologically involved [2,25]. Theclinical lymphadenophathy associated with PTsis usually due to reactive hyperplasia fromtumor necrosis or secondary to ulcerated lesions(2). In the present study, 21 women (27%) hada modified radical mastectomy for clinicallypalpable lymph nodes, but lymph node metastas-es were found in only one patient with malignant

PT. Similar findings were reported in most otherstudies [24,25,27]. So, our conclusion was inagreement with that of other investigators[16,22,24,25,27,28,29] that lymph node dissectionplays a very limited role in the treatment of PTsand that there is no indication for elective axil-lary dissection even in malignant lesions.

The reported rates of DM for patients withPTs ranged from 25 to 48% [2,6,7,14,27], and itwas 33.3% (7/21) in the current study. Salvadoriet al. [3] stated that borderline PTs did notsignificantly differ from malignant lesions in

terms of biological behavior. The 5-year diseasefree survival in our group of patients was 73.4%;being 90% for the patients with benign tumors,69% for the patients with borderline and 61%for malignant PTs. The difference betweenbenign and malignant PTs in terms of diseasefree survival was statistically significant(p=0.02). Our results compared favorably tothe experience of other investigators who re-ported 5-years survival rates ranging from 54to 82% [16,22,24,25,27,28] .

In conclusion, the histiotype of PTs assessedon the basis of the criteria proposed by WHOand resection margins were the only prognosticfactors in this study. A WLE, with an adequate

margin of normal breast tissue, is the preferredinitial treatment for PTs. Routine axillary dis-section is not indicated as lymph node involve-ment is extremely rare. As PTs is a rare disease,data from centers that treat this disease frequent-ly should be pooled, with central pathologyassessment, to determine the optimum strategy,which could form the potential basis of a pro-spective clinical trial.

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phyllodes tumors of the breast prognostic factors

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