Journal of the Egyptian Nat. Cancer Inst., Vol. 18, No.

2, June: 125-133, 2006

Predictive Factors of Local Recurrence and Survival Following Primary 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 is characterized by its tendency to recur locally and occasionally to metastasize. Local recurrence and death from metastases are occasional, but consistent, theme in reports of patients with phyllodes tumors (PTs). The aim of this study was to determine parameters that influence outcome in this uncommon neoplasm. Patients and Methods: Data from 79 patients with phyllodes tumors were reviewed retrospectively, reclassifying the pathological material using the World Health Organization (WHO) criteria. Results: The median age of the patients was 42 years with a range from 16 to 70 years. The tumor size ranged from 2.5 to 24cm, with a median of 11cm. Based on the criteria proposed by WHO, 31 cases were benign tumors (39.2%), 27 borderline tumors (34.2%), and 21 malignant tumors (26.6%). The median duration of follow up was 60 months ranging from 3 to 138 months. Following local excision, the local recurrence rates were 14.3%, 50%, and 75% in patients with benign, borderline, and malignant tumors; respectively, while after wide local excision the local recurrence rates were 0%, 36.3% and 40%; respectively. Whereas, 0%, 8.3%, and 8.3% of patients with benign, borderline and malignant tumors; respectively, locally recurred after mastectomy. The 5-year disease free survival was 63.3% after local excision, 70% after wide local 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 336). All cases with DM died after an average of 5 months with a range of 1 to 11 months. Distant metastases developed in 3.2%, 11.1%, and in 28.6% of patients with bengin, borderline and malignant tumors; respectively. The 5-year survival with no evidence of disease was 90% for the patients with benign tumors compared to 69% for borderline and 61% for malignant PTs (p= 0.02). Conclusions: The histiotype of phyllodes tumors and resection margins were the principal determinants of local Correspondence: Dr Hassan M. Abdalla, Kasr El-Aini Street, Fom El-Khalig, Cairo, Egypt, habdallah@nci.edu.eg

recurrence and distant metastases. Complete surgical excision by either wide local excision or mastectomy if necessary is important in the primary surgical treatment of phyllodes tumors. Key Words: Phyllodes tumors - Breast - Prognostic factors.

INTRODUCTION Phyllodes tumors (PTs) are uncommon neoplasms of the breast, constituting 0.3 to 0.9% of all breast tumors in females [1-2]. Since the first description of PTs in 1838 by Johannes Muller, no fewer than 62 different definitions were used to define this particular tumor of the breast [3]. The majority of PTs occur in women between the age of 35 and 55 [3,4,5], although there are reported cases in adolescents, as well as in elderly women [2,6] . These lesions are difficult, if not impossible, to distinguish from fibroadenoma on physical examination or by radiologic studies except when quite large. The tumors are characterized by a combination of a hypercellular stroma and cleft like or cystic spaces lined by epithelium into which classically projects the stroma in a leaf-like fashion [1,7,8]. There are, however, wide variations in histological appearance between different tumors, ranging from those resembling fibroadenomas, apart from increased stromal cellularity and mitotic activity, to those showing a diffuse overgrowth of highly pleomorphic stromal cells resembling a soft tissue sarcoma, with a spectrum of appearances intermediate between both extremes [8]. Still, it is often difficult to predict the clinical outcome from microscopic features in individual cases [1,7,9] , as by no means do all histologically malignant tumors show a tendency to local recurrence or metastatic spread, whilst rarely apparently benign tumors have pursued

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an unexpectedly aggressive course. This variable behavior might be partly a function of the inherent qualities of the tumors, which resulted in several histological classification systems: Treves and Sunderland used the terms benign and malignant [9], Pietruszka and Barnes [7], and WHO [10] classified PTs as benign, borderline, and malignant [7]. Similar categories were assigned by Azzopardi, but using different criteria (1). The outcome was also affected by clinical factors such as age, delay in diagnosis or misdiagnosis and inappropriate and inadequate management. The aim of this retrospective study was to identify the parameters that predict local recurrence and distant metastases in women treated at NCI Cairo University over a period of 15 years and to determine the best surgical approach to 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 National Cancer Institute, Cairo University. Only patients with full details on clinical outcome were included in this study. All histopathological slides were re-examined and the medical records were reviewed. The diagnosis of PTs was made according to WHO criteria as benign if the following characteristics were found: 0-4 mitoses/10 high power field, pushing margins, minimal or moderate stromal overgrowth, with minimal stromal cellularity and atypia (Fig. 1). Borderline was assigned in cases were 5-9 mitoses/10 high power field, pushing or infiltrating margins, moderate stromal cellularity, atypia and overgrowth were observed (Fig. 2). Malignant tumors were identified when >10 mitoses/10 high power field, infiltrating margins, moderate to marked stromal cellularity, atypia and overgrowth were detected (Fig. 3). Only patients with full details on clinical outcome were included in this study. Patient characteristics, pathologic variables and surgical procedures were investigated as predictors of local recurrence, distant metastases and survival.

Fig. (1): Benign phyllodes tumor.

Fig. (2): Borderline phyllodes tumor.

Fig. (3): Malignant phyllodes tumor.

Three types of operations were defined according to the extent of resection and margin involvement: local excision (LE) with involved or uninvolved margins <1cm or no clear margins, wide local excision (WLE) with clear margins >1cm, and mastectomy in any form. All patients were followed up for a median duration of 60 months with a minimum of 3 months and a maximum of 138 months. Five

year survival without evidence of disease was used as the end point for analysis. The survival time was calculated from the day of operation. Statistical analysis was calculated using the Fisher exact test. Univariate actuarial curves were plotted using Kaplan-Meier method and statistical comparisons were accomplished using the log rank test. All reported p values <0.05 were considered significant.

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RESULTS Clinical characteristics: The median age of the 79 patients was 42 years ranging from 16 to 70 years. All patients presented with a breast lump. In 46 cases (58.2%), the tumor was in the right breast and in 33 (41.8%) in the left breast. There were no cases with bilateral disease. Thirty-two patients (40.5%) were postmenopausal, while 47 (59.5%) were pre - menopausal. Four (5.1%) cases reported a history of benign breast masses. No previous history of any non-breast malignancy was reported. Histopathological features: On the basis of the criteria adopted by WHO, samples were reclassified as benign PTs in 31 (39.24%) cases, borderline PTs in 27 (34.19%) cases, and 21 (26.57%) cases of malignant PTs. The tumor size ranged from 2.5cm to 24cm, with a median of 11cm (Fig. 4 A,B,C). Table (1) presents the relationship between histiotype and the size of the tumor. There were 21 patients with clinically suspected, but not cytologically verified, axillary lymph nodes who were managed by modified radical mastectomy. Of these patients, metastases to axillary nodes were found in one patient, and reactive lesions were observed in the remaining patients. Table (2) summarizes the tumor related characteristics in relation to the occurrence of LR and DM. Local recurrence and distant metastases in relation to surgical intervention: Of the 31 patients with benign tumors, 3 developed LR and one patient developed a DM after surgical resection. The initial surgery in 14 cases was LE. In this group, ten patients remained diseasefree while three locally recurred, and one had a DM. The patients who developed LRs remained disease free after treatment of their recurrence; whereas, the patient who developed lung metastases died after 14 months. Eight patients with benign tumors were treated with LE followed by immediate WLE. These patients were all free of disease. Seven of the 31 patients with benign tumors were treated by LE followed by immediate total mastectomy. All these patients were free of disease. Two patients with benign tumors were treated with immediate mastectomy and they both remained free of disease.

In the group of patients with borderline PTs (n=27), 4 underwent LE; two of them developed local recurrence. After successful wide excision, the latter 2 cases remained disease free. Eleven patients with borderline tumors were treated with WLE or quadrantectomy after initial lumpectomy. Four of these eleven patients had local recurrence and one patient developed lung and bone metastases. Wide excision of local recurrence was performed in 2 patients, while mastectomy was unavoidable in the other 2 patients. One of the 4 patients, who developed LR after WLE, developed a second local recurrence together with brain metastases. Twelve patients with borderline PTs underwent mastectomy after initial LE; only one of them developed both LR and pleural effusion. Four patients in the malignant PTs (n=21) underwent LE; 2 of them developed LR, and one developed both local and systemic relapse. Five patients with malignant PTs underwent WLE; one of them developed LR, while another patient had both LR and DM. Twelve patients with malignant PTs underwent mastectomy after initial LE. Of the latter group, one case developed both LR and DM, while 3 developed DM. Table (3) shows the outcome based on histiotype and 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 malignant PTs; respectively, recurred locally after mastectomy. Distant metastases occurred in 10 patients (12.6%) after a median duration of 14 months (range 3- 36). DM developed in 3.2% (1/31), 11.1% (3/27) and in 28.6% (6/21) of patients with benign, borderline and malignant PTs; respectively. In five patients (50%) with DM, LR preceded the diagnosis of DM. All patients who developed DM were treated with chemotherapy radiotherapy and they all died after an average of 5 months (range 1 to 11 months) after the diagnosis of DM. Adjuvant radiotherapy was given to 2 patients after mastectomy; one of them remained disease free, while the other developed pleural effusion after

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one year and died 6 months later. A third woman received postoperative adjuvant radiotherapy after WLE and remained free of disease during follow up. Adjuvant chemotherapy was provided to one woman only after simple mastectomy for borderline tumor. Five-year disease free survival: Of the 79 treated patients, 58 (73.4%) survived for 5 years with no evidence of disease after surgical treatment. Survival curves, according to histiotype, and extent of surgery are presented in Figs. (2,3) respectively. Clinical variables such as: Age (p=0.59), tumor size (p=0.06), laterality (p=0.15) and menopausal status (p=0.07) were not of prognostic value. The histiotype of the PTs assessed on the basis of the criteria proposed by WHO, not single microscopic parameters, correlated significantly with prognosis (p=0.02). The 5-year survival with no evidence of disease was 90% for the patients with benign

tumors compared to 69% for borderline and 61% for malignant PTs (benign vs malignant, p=0.02) Fig. (5). After LE, 5-year disease free survival was 63.3%, while after WLE was 70% and after mastectomy was 87%, with a significant difference (p=0.04). Fig. (6) demonstrates the results of treatment according to the extent of surgery.
Table (1): The relationship between histiotype and the size of the tumor. Tumore size Histiotype 0-5cm No. Benign (31) Borderline (27) Malignant (21) 12 8 5 (%) (38.8) (29.6) (23.8) 5-10cm No. 10 10 6 (%) (32.2) (37) (28.6) 10>cm No. (%) 9 9 10 (29) (33.4) (47.6)

Table (2): The relation between tumor-related characteristics and the occurrence of local recurrence or distant metastases. Histopathologic parameters 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 Excision Mastectomy
*p values 0.05 are considered significant.

Recurrent site Local 7 5 Distant 1 4 Both 0 3

Percent within recurrence

p value 0.18

40% 60% 0.022*

6 6

1 4

0 3

35% 65% 0.58

3 6 3

1 1 3

0 1 2

20% 40% 40% 0.75

3 6 3

1 1 2

1 1 2

21% 42% 37% 0.07

4 8

4 1

3 0

55% 45% 0.04*

7 5 0

1 1 3

1 1 1

45% 35% 20%

Hassan M. Abdalla & Mona A. Sakr

Table (3): Outcome in relation to histiotype and type of surgical intervention. Outcome No No evidence of disease Local Excision: Benign, n=14 Borderline, n=4 Malignant, n=4 Local excision, followed by immediate wide local excision: Benign, n=8 Borderline, n=11 Malignant, n=5 Local excision followed by mastectomy: Benign, n=9 Borderline, n=12 Malignant, n=12 Local recurrence Metastasis Death

129

Survivor

10 2 1

3 2 3

1 0 1

1 0 1

13 4 3

8 6 3

0 4 2

0 2 1

0 2 1

8 9 4

9 11 8

0 1 1

0 1 4

0 1 4

9 11 8

(A)

(B)

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

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Survivial Functions 1.0 + + 0.8 + Cum Survival 0.6 + + + + + + +

Predictive Factors of Local Recurrence & Survival Following

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

0.4

0.2

0.0 0.00 50.00

Path Malignant Borderline Benign + High-censored + Intermediatecensored + Low-censored 100.00 rec-dur 150.00 200.00

benign tumors has also been described [5,13,14,15] . This case was observed in the present study. Clinico-pathological parameters studied as prognostic factors in PTs gave conflicting results in the published series. Our findings were in agreement with those of other authors [4,14,16], in that clinical variables such as: Age (p=0.59), tumor size (p=0.06), laterality (p=0.15) and menopausal status (p=0.07) were not of prognostic value. Opinions on the relation between the histological appearance of the tumor and prognosis vary in literature for two reasons. Firstly, due to lack of standard interpretation of histologic features which explain why the balance between benign, borderline and malignant PTs is different in various series. Our balance between benign, borderline, and malignant lesions were 39.2%, 34.2% and 26.6%; respectively. Our figures resembled that of Salvadori [3] , but differed from other investigators [17,18] . As a consequence, we must be on guard when comparing our results with those presented in the literature. Secondly, some authors question the existence of this correlation [15,19,20] while the majority who acknowledge it do not agree as to which feature of the histological appearance is vital in prognosis. Hawkins et al. [21] and Chany et al. [22] insisted that the most reliable predictor of malignancy is the presence of stromal overgrowth. The importance of the presence of disproportionate overgrowth of stromal elements at the expense of the ductal element was also confirmed [23]. Cohen-Cedermark and their coworkers emphasized the prognostic significance of tumor necrosis and the presence of stromal elements other than fibromyxoid tissue [5] . Similarly, Murad and his colleagues [23] confirmed that tumor necrosis, infiltrating margins and mixed mesenchymal component correlated well with the malignant course. However, other authors concluded that high mitotic activity is the most important prognostic factor [1,7]. In the series presented by Grimes, metastases correlated best with high mitotic rates, hypercellularity, stromal atypia and stromal overgrowth [19]. Other authors suggested that several combinations of individual parameters could explain recurrence [3,7,8,24,25]. In the current study, the histiotype of the PTs assessed on the basis of the criteria proposed by WHO, not single microscopic parameters, correlated significantly with prognosis (p=0.02).

Fig. (5): Patients disease free survival according to histiotype. Survivial Functions 1.0 + + + + + + + 0.8 + Cum Survival 0.6 + + + + + + + + + 0.4 + + + ++ + + + + + +

+ + Sur-mod LE Mastectomy WLE + LE-censored + Matectomycensored + WLE-censored

0.2

0.0 0.00 50.00 100.00

150.00

200.00

rec-dur Fig. (6): Patients disease free survival according to extent of surgery.

DISCUSSION The most important problem regarding PTs is that its clinical course is unpredictable and does not exactly correlate with the histologic parameters [3,4,10,11,12]. Although metastases mainly occur in malignant and borderline tumors, still metastatic spread from histologically

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Although surgery remains the mainstay of treatment for patients with PTs, the extent of surgical approach historically has been controversial, and continues to evolve. It is evident that PTs may be cured by limited surgical excision, but with the increased likelihood of recurrence regardless of their histology. In individual series that are large enough to make comparisons, borderline and malignant PTs were more likely to recur than benign PTs after local excision alone. Zurrida and his co-authors [13] reported that 9% (10/107), 44% (4/9) and 33% (1/3) of benign, borderline and malignant PTs developed local recurrence. In the current study, the in-breast recurrence rates after LE were 21.5% (3/14), 50% (2/4) and 75% (3/4) for benign, borderline and malignant PTs; respectively. The LR rates were significantly higher in borderline and malignant PTs after LE ( p =0.04). Collective data of similar studies demonstrated that around 20% (111/540) of benign PTs recurred in the breast, whereas, 46% (18/39) of borderline and 65% (26/40) of malignant PTs treated by LE recurred [26]. Of note, although the tumor was grossly removed by LE, the histologic presence or absence of tumor at the surgical margin was not specifically addressed in the majority of studies [26]. Thus, from the findings of the present study and the data recorded in literature, it seems that the histologic categorization of PTs influenced the LR rate after LE. Analysis of most individual series indicated that borderline and malignant PTs were more likely to develop an in-breast recurrence after WLE than benign PTs. In the current series, the LR after WLE was 0% (0/8), 36.4% (4/11) and 40% (2/5) for benign, borderline and malignant PTs; respectively. Since the number of patients treated by WLE in each individual series was limited in number, all series which categorized PTs by histologic type and treated the patient with a WLE (ranging from margins of 1cm to quadrantectomy) were collected in a metaanalysis [26] . In the latter review, only 8% (17/212) of patients with benign PTs locally recurred after WLE; whereas, 29% (20/68) of patients with borderline PTs and 36% (16/45) of patients with malignant PTs recurred in the breast [26]. Therefore, analysis of this collective data clearly indicated that LR rates after WLE of borderline or malignant PTs are higher than the LR rates after WLE of benign PTs.

Mastectomy has been the most commonly performed surgery for borderline and malignant PTs with LR rates of 5% and 12%; respectively [9,25,26]. In the present study, the LR after mastectomy for both borderline and malignant PTs was 8.3%. This was significantly lower than the LR rate after WLE of borderline (36.4%) and malignant PTs (40%) ( p =0.04). Whether LR is a predictor or instigator for the development of DM and impaired survival in PTs is still controversial. Whilst some authors have shown that up to 60% of patients with metastatic PTs develop LR prior to systemic spread [7,8], currently most investigators refuse this association and favor a WLE [16,22,24,27,28]. The findings of the latter studies indicated that WLE might not be a good option to prevent LR; however, there was no evidence that breast conserving surgery for patients with PTs resulted in reduced patient survival compared to mastectomy. It was further emphasized that LR did not imply associated systemic spread, and can usually be controlled with repeated excision or mastectomy [27,28]. In the meta-analysis performed to further understand PTs, the relationship between type of surgery, histology, and survival was studied. It was demonstrated that the mortality rate after LE, WLE , and mastectomy for borderline PTs was 7% (2/27), 9% (4/46), and 3% (1/34); respectively, while for malignant PTs was 22% (8/36), 8% (2/25), and 21% (38/179); respectively [26]. Whereas, mortality rate after LE and WLE was less than 1% for benign PTs (1/432 for LE and 1/168 for WLE). In the current study the mortality after LE, WLE and mastectomy for borderline PTs was 0% (0/4), 18.2% (2/11) and 8.3% (1/12); respectively, while for malignant PTs the mortality rates were 25% (1/4), 20% (1/5) and 33.3% (4/12); respectively. Based on the findings presented in this study, it could be concluded that mastectomy for borderline PTs could be avoided. Only four patients with borderline PTs underwent LR after WLE. Two of the latter group was salvaged by WLE while two cases underwent mastectomy; 3 of them remained disease free. As regards malignant PTs, our findings were not really sufficient to provide conclusions concerning breast conserving surgery in this histologic subtype. This was because only 5 of our malignant PTs patients were treated with

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WLE; still three of them survived without LR or DM. Although the patients in this group were small in number, still our results were in agreement with the opinions of Salvadori et al. [3], Zurrida et al. [13] , and Grimes [19] , that the breast affected by boredrline or malignant PTs should only be totally removed if the tumor size does not allow either an adequate resection margin or good cosmetic results by less extensive procedure. If the breast is large enough, a large tumor may be radically removed by conservative surgery. Nevertheless, it was emphasized that mastectomy is recommended for LR of borderline and malignant PTs [3,12,13,19]. Lymphatic spread is rare in PTs. Although 10-15% of patients presented with clinical axillary lymphadenopathy, less than 1% had nodes that were pathologically involved [2,25]. The clinical lymphadenophathy associated with PTs is usually due to reactive hyperplasia from tumor necrosis or secondary to ulcerated lesions (2). In the present study, 21 women (27%) had a modified radical mastectomy for clinically palpable lymph nodes, but lymph node metastases were found in only one patient with malignant PT. Similar findings were reported in most other studies [24,25,27] . So, our conclusion was in agreement with that of other investigators [16,22,24,25,27,28,29] that lymph node dissection plays a very limited role in the treatment of PTs and that there is no indication for elective axillary dissection even in malignant lesions. The reported rates of DM for patients with PTs ranged from 25 to 48% [2,6,7,14,27], and it was 33.3% (7/21) in the current study. Salvadori et al. [3] stated that borderline PTs did not significantly differ from malignant lesions in terms of biological behavior. The 5-year disease free 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 between benign and malignant PTs in terms of disease free survival was statistically significant ( p =0.02). Our results compared favorably to the experience of other investigators who reported 5-years survival rates ranging from 54 to 82% [16,22,24,25,27,28]. In conclusion, the histiotype of PTs assessed on the basis of the criteria proposed by WHO and resection margins were the only prognostic factors in this study. A WLE, with an adequate

margin of normal breast tissue, is the preferred initial treatment for PTs. Routine axillary dissection is not indicated as lymph node involvement is extremely rare. As PTs is a rare disease, data from centers that treat this disease frequently should be pooled, with central pathology assessment, to determine the optimum strategy, which could form the potential basis of a prospective clinical trial. REFERENCES
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