Abstract
Phyllodes tumors (PTs) are rare neoplasms of the breast that are a challenge in clinical practice. Though mostly benign, they are notorious for local recurrence, requiring adjuvant treatments. This study was planned to report the clinicopathological features and outcomes of patients with PT treated at our center. Details of all patients who underwent surgery for PT in the last 6 years (December 2017–December 2023) were obtained from our prospectively maintained database. The demographic, clinical, radiological, pathological, and follow-up details were recorded and analyzed. Statistical analyses were carried out with Jamovi version 2.3.18. Out of 61 suspected PTs by triple assessment, 9 were excluded due to a non-phyllodes diagnosis on histopathology. We included 52 women with a mean age of 38.2 ± 11.0 years, most of whom were premenopausal (57.7%). BI-RADS 4 was the most common finding on radiological assessment (65.4%). Core needle biopsy (CNB) was the most frequently employed modality for histological diagnosis preoperatively (65.4% of cases). Wide local excisions (WLE) and mastectomies were done in 63.5% and 36.5% of patients, respectively. Benign, borderline, and malignant phyllodes constituted 67.3%, 15.4%, and 17.3% of tumors, respectively. Patients undergoing breast conservation surgery (BCS) had a significantly smaller mean tumor diameter than those who underwent a mastectomy (p < 0.001). Overall, the margin positivity rate was 34.6%. Patients undergoing mastectomy developed more local recurrence compared to WLE, although the difference was not significant (p = 0.400). The outcome following surgical excisions of large PTs in terms of margin positivity and local recurrence is the same, irrespective of whether BCS or mastectomy is done. A negative pathological margin width of > 1 mm appears acceptable. Malignant phyllodes with positive margins are associated with a higher rate of recurrence but positive margins in patients with other subtypes may not translate into recurrence, at least in the short term.
Keywords: Breast, Breast conservation surgery, Mastectomy, Phyllodes tumors
Introduction
Phyllodes tumors (PT) are a rare but intriguing subset of fibroepithelial neoplasms of the breast. They constitute 0.3–1% of all primary breast neoplasms [1, 2]. They are rapidly growing and can attain massive size at presentation. According to the World Health Organisation (WHO), the histological spectrum of PT varies from benign to borderline to malignant forms, based on a variety of histological characteristics including stromal characteristics (atypia, cellularity, overgrowth), mitotic counts, tumor borders, and the presence or absence of malignant heterologous elements [3]. This is a reflection of the wide variation in biological characteristics, clinical courses, and recurrence rates among different reports.
Diagnosis of PT is challenging and many PTs are revealed only after histological examination of the excised specimen. The benign PT shares characteristics with cellular fibroadenoma (FA). They resemble intracanalicular FAs, which are benign, in terms of morphology but they differ in that they have more stromal cellularity and a leaf-like layout (Johannes Muller called it “cystosarcoma phyllodes”) [4]. On the other hand, the malignant PT can be misdiagnosed as spindle cell metaplastic carcinoma or primary breast sarcoma.
Another unanswered question is the optimal margin width for excision of PT. Studies have linked positive margins to high rates of local recurrence [5–7]. Jang et al. found that the local PT recurrence was significantly predicted by the existence of tumor cells on the resection margin. A 1-cm negative margin thickness, however, had no advantage over a thinner negative margin width in terms of local control [7]. At 11 cancer centers in the United States between 2007 and 2017, significant variation among surgeons in the management of phyllodes tumor margins was noted, with some avoiding re-excision for both close and positive margins and highlighting the need for an individualized approach to margin management [8].
Intratumoral heterogeneity is seen in PT both morphologically and genetically. This leads to variable clinical presentations, overlapping histology, and multiple close differentials. Observational studies provide invaluable insights into the presentations and pathology of PTs. We aimed to analyze our database and report the clinicopathological features and outcomes of patients with PT treated at our center.
Patient and Methods
A retrospective cohort study was planned to include all patients with PTs of the breast, managed in the last 6 years (December 2017–December 2023) in our department. We did not include patients who were diagnosed to have PT after undergoing the excision of a breast lump without any suspicion of PT preoperatively. Demographic, clinical, pathological, radiological, surgical, and follow-up data were obtained from our prospectively maintained database. Both involved and close (≤ 1 mm) margins were considered positive, excluding the anterior margin. Thus, five margins (superior, inferior, medial, lateral, and deep) were analyzed per tumor. Continuous variables were expressed as mean ± SD and categorical ones as frequency and percentages (%). For continuous variables, an independent sample t-test, or one-way analysis of variance (ANOVA), was employed, depending on the number of groups. For categorical data, the chi-square test of association, or Fischer’s exact test, was used. Statistical analyses were carried out using Jamovi version 2.3.18 (The Jamovi Project (2022), retrieved from https://www.jamovi.org). Statistical significance was set at p < 0.05.
Results
Out of 61 patients who were preoperatively suspected or diagnosed with a phyllodes tumor, 9 were excluded from the final analysis because of a non-phyllodes diagnosis in final histopathology. We included 52 women with a mean age of 38.2 ± 11.0 years, most of whom were premenopausal (57.7%). Demographic and clinicopathological profiles of the included patients are described in Table 1. Twenty-one percent (21.2%) of the patients presented to us with recurrent tumors. Core needle biopsy (CNB) and fine needle aspiration cytology (FNAC) were used for preoperative diagnosis in 65.4% and 34.6% of cases, respectively. The mean follow-up duration in our study was 38.8 ± 19.2 months.
Table 1.
Clinicopathological details
| Variable | Results |
|---|---|
| Mean age ± SD (n = 52) | 38.2 ± 11.0 years |
| Menopausal status, n (%) | |
|
Premenopausal Postmenopausal |
30 (57.7%) 22 (42.3%) |
| Laterality, n (%) | |
|
Right Left |
26 (50.0%) 26 (50.0%) |
| Mean duration ± SD (months) | 28.5 ± 43.3 |
| Recurrent | 11 (21.2%) |
| Pain | 23 (44.2%) |
| Ulcer | 4 (7.70%) |
| Preoperative imaging | |
|
Mammography Ultrasonography |
35 (67.3%) 31 (59.6%) |
| Preoperative pathological test | |
|
FNAC Core needle biopsy |
18 (34.6%) 34 (65.4%) |
| BI-RADS category, n (%) | |
|
BIRADS 2 BIRADS 3 BIRADS 4 BIRADS 5 Not reported |
1 (1.9%) 4 (7.7%) 34 (65.4%) 4 (7.7%) 9 (17.3%) |
| Operative procedure n (%) | |
|
WLE without reconstruction WLE with reconstruction Mastectomy Mastectomy with reconstruction (LD flap) |
19 (36.5%) 14 (26.9%) 14 (26.9%) 05 (9.6%) |
| Final histopathology | |
|
Benign Borderline Malignant |
35 (67.3%) 8 (15.4%) 9 (17.3%) |
| Mean pathological tumor size ± SD (cm) | 10.1 ± 5.3 |
CNB Core needle biopsy, FNAC Fine needle aspiration cytology, LD latissimus dorsi, WLE wide local excision
A wide local excision (WLE) was the most frequent surgical procedure (63.5% cases); others (36.5%) had a mastectomy. Patients undergoing breast conservation surgery (BCS) had a significantly smaller mean tumor diameter than those who underwent mastectomy (8.0 ± 4.4 cm versus 13.8 ± 4.7 cm, p < 0.001). A positive margin was obtained in 33.3% of patients undergoing BCS, and 36.8% of those undergoing mastectomy (p = 0.798). Overall, out of a total of 260 margins (evaluating 5 margins per tumor in 52 patients), 27 (10.4%) [19 (11.5%) in patients having BCS and 8 (8.4%) in patients undergoing mastectomy, p = 0.431] were reported to be positive. Local recurrence was more frequent following mastectomy than BCS (p = 0.40) (Table 2). Out of a total of 9 patients with malignant histology, 7 (77.8%) had positive margins. Similarly, 2 out of 8 patients (25%) with borderline histology had margin positivity. As per our institutional policy, we gave adjuvant radiation after re-excision of positive margins to patients with borderline and malignant histology. Thus, adjuvant radiation was given to n = 7 (13.5%) patients; 2 patients were lost to follow-up. Re-excision was not done in patients with benign PT.
Table 2.
Comparison of outcomes following breast conservation surgery (BCS) and mastectomy
| Breast conservation surgery (n = 33) (63.5%) | Mastectomy (n = 19) (36.5%) | p-value | |
|---|---|---|---|
| Pathological tumor size, mean ± SD (cm) | 8.0 ± 4.4 | 13.8 ± 4.7 | < 0.001 |
| Patient-wise positive margin (n = 52) (%) | 11 (33.3%) | 07 (36.8%) | 0.798 |
| Margin-wise positivity rate (n = 260) (%) | 19 (11.5%) | 8 (8.42%) | 0.431 |
| Local recurrence, n (%) | 03 (9.1%) | 04 (21.1%) | 0.400 |
The mean pathological tumor size was significantly higher in the malignant histological subtype as compared to benign and borderline types (p = 0.040). Margin positivity (p = 0.012) and local recurrences (p = 0.021) were also significantly higher with malignant subtypes as compared to benign counterparts (Table 3). Out of 18 patients (34.6%) having a positive margin, one-third (n = 6) developed local recurrence. The rate of local recurrence in patients with clear margins was only 2.9% (p = 0.005) (Table 4).
Table 3.
Comparison of outcomes across histological subtypes of phyllodes tumors
| Benign (n = 35) (67.3%) | Borderline (n = 8) (15.4%) |
Malignant (n = 9) (17.3%) |
p-value | |
|---|---|---|---|---|
| Mean age ± SD (years) | 37.9 ± 11.8 | 37.3 ± 9.5 | 40.0 ± 9.9 | 0.827 |
| Mean tumor size ± SD (cm) | 9.0 ± 4.7 | 12.0 ± 7.73 | 13.11 ± 3.62 | 0.040 |
| Positive margin, n (%) | 9 (25.7%) | 2 (25.0%) | 7 (77.8%) | 0.012 |
| Local recurrence, n (%) | 3 (8.6%) | 0 | 4 (44.4%) | 0.021 |
Table 4.
Comparison of local recurrence rate vis-a-vis margin status
| Margin status | Local recurrence | Total | |
|---|---|---|---|
| Yes | No | ||
| Negative, n (%) | 1 (2.9%) | 33 (97.1%) | 34 (100%) |
| Positive, n (%) | 6 (33.3%) | 12 (66.7%) | 18 (100%) |
| Total, n (%) | 7 (13.5%) | 45 (86.5%) | 52 (100%) |
| p = 0.005 | |||
Discussion
Most of our patients presented with large tumors (Fig. 1), the mean pathological tumor size being 10.1 ± 5.3 cm. Triple assessment provided a false-positive rate of 14.7% in diagnosing a PT of the breast in this study. Despite excluding patients with non-phyllodes histology and having a suspected/confirmed diagnosis of phyllodes tumor preoperatively, unsatisfactory or positive margins were obtained in 18 out of these 52 patients (34.6%). Patients undergoing mastectomy showed a non-significant trend towards having more positive margins (p = 0.798) and more local recurrence (p = 0.4) than patients undergoing BCS. One possible reason for this could be the significantly larger tumor size in patients undergoing mastectomy (13.8 ± 4.7 vs 8.0 ± 4.4 cm).
Fig. 1.
a Preoperative image of left breast recurrent phyllodes tumor. b Latissimus dorsi flap used for resurfacing the postmastectomy defect. c Immediate postoperative image. d Phyllodes specimen. e Postoperative image at day 7
The mean age of presentation in this study (38.2 ± 11.0 years) is comparable to previous cohorts [9–11]. Also, a tendency of increasing age for malignant histology was noted as observed by other authors [12, 13]. Similar to other studies in the Indian subcontinent, our patients presented with large masses, the mean tumor size being 10.1 ± 5.3cm [14, 15]. This reflects both the rapidly growing nature of the tumor and the general unawareness of women towards breast lumps in the Indian population.
The accuracy of triple assessment in diagnosis of breast masses approaches 100% but it is known to produce inferior results in patients having PT [16]. This may be accounted for by significant intratumoral heterogeneity found in phyllodes tumors which makes representative sampling difficult [17]. As observed by Lawton et al., out of a total of 21 specimens of fibroepithelial lesions that were difficult to classify as cellular fibroadenoma or PTs, there was a uniform agreement among expert pathologists only in 2 cases [18]. Thus, PT may resemble fibroadenomas on the benign end, spindle cell metaplastic carcinoma, or a primary breast sarcoma on the malignant end of the spectrum [1, 3]. This has prompted some authors to advocate the usage of immunohistochemistry in the preoperative diagnosis of PT. For instance, cytokeratins and p63 are typically positive in the spindle cells of metaplastic sarcoma, in contrast to malignant PT, where p63 is present in only 20% of tumors and cytokeratins are negative [1, 19].
Even after removing patients with non-phyllodes histology and including only those who had a preoperative diagnosis of PT, negative margins could be obtained in only 65.4% of patients. This may be explained by the larger pathological tumor sizes and higher breast conservation rates in our study. A higher positivity rate was observed in mastectomy patients as compared to those who underwent BCS. Further analysis showed that the margin-wise positivity rate was higher in the BCS group than in the mastectomy group. Both these values were however statistically insignificant (Table 2). To the best of our knowledge, none of the authors in the past have done a margin-wise analysis of positivity rates. The ideal negative margin for PT remains a clinical enigma. Newer data indicates that a positive surgical margin for benign PT may not be associated with a local recurrence [20]. According to a recent meta-analysis of 54 observational studies, a positive margin corresponded with a significantly higher local recurrence risk only for malignant phyllodes tumors and not for benign or borderline cases [21]. In the retrospective review of PT patients over a period of 51 years (1954–2005) at the Memorial Sloan Kettering Cancer Centre, New York, USA, a margin of < 1 mm was considered positive [13]. Through their multi-institutional review of 11 cancer centers expanding 10-year period (2007–2017), Rosenberger et al. demonstrated the importance of achieving at least a 1-mm margin after lumpectomy or mastectomy to minimize the risk of local recurrence. With a wider negative margin width (≥ 2 mm versus < 2 mm), local recurrence was not reduced [8]. Our study also found an acceptable local recurrence of 2.9% among those who had a > 1-mm margin on histopathology.
The proportion of benign, borderline, and malignant phyllodes in our study was 67.3%,15.4%, and 17.3%, respectively, comparable to previous cohorts [5, 22]. Out of the 52 patients in our cohort, 33 (63.5%) had breast conservation surgery, and 19 (36.5%) had mastectomy. The pathological tumor size in the breast conservation arm was significantly lower as compared to mastectomy (p < 0.001). Our study’s overall local recurrence rate (13.5%) was lower than in previous cohorts [5, 14, 22]. This may be because we did not include patients undergoing “excision biopsy/enucleation” but our cohort included patients who had a preoperative diagnosis of PT; hence, the patients underwent either a wide local excision or mastectomy [14, 22–24]. In our study, the proportion of local recurrence was significantly higher in the malignant histological subtype (44.4%) as compared to the benign one (8.6%) (p = 0.021). The meta-analysis by Lu et al. comprising 54 studies (between 1995 and 2018) including a total of 9234 patients also showed significantly higher rates of local recurrence in the malignant subtype [21].
In our study, malignant histology and margin positivity were predictive of local recurrence. Other studies also support this notion of higher local recurrence with margin positivity and malignant histology [14, 22, 25, 26]. Ravindhran and Rajan have employed a multivariate analysis identifying the histological parameters predicting local recurrence, namely, high mitotic rate, positive margin, and stromal overgrowth [22]. The experience from the Memorial Sloan-Kettering Cancer Centre, New York, USA, was however different. In their large cohort of 293 phyllodes tumor patients expanding over 51 years, margin positivity was associated with local recurrence in univariate analysis, but it failed to reach statistical significance in multivariate analysis. Also, a statistically significant association could not be established between malignant phyllodes and local recurrence (p = 0.79) [13]. We could not perform a multivariate analysis of factors predicting local recurrence in this study as the number of local recurrences was very low (n = 7), and there is a lack of uniformity in histopathological reporting of phyllodes specimens over 6 years in our institution.
Study limitations include a retrospective study design. A prospective study trying to predict the impact of clinical, surgical, and histological parameters on local recurrence using univariate and multivariate analyses is recommended.
Conclusion
The outcome following surgical excisions of large PTs in terms of margin positivity and local recurrence is the same, irrespective of whether BCS or mastectomy is done. A negative pathological margin width of > 1 mm appears acceptable. Malignant phyllodes with positive margins are associated with a higher rate of recurrence but positive margins in patients with other subtypes may not translate into recurrence, at least in the short term.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declarations
Conflict of Interest
The authors declare no competing interests.
Footnotes
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