|Year : 2022 | Volume
| Issue : 4 | Page : 425-431
Factors effective on recurrence and metastasis in phyllodes tumors
M Altiok1, F Kurt2
1 Department of Surgical Oncology, Cukurova University, Balcalı Training and Research Hospital, Adana, Turkey
2 Department of General Surgery, Seyhan Goverment Hospital Seyhan, Adana, Turkey
|Date of Submission||30-Mar-2021|
|Date of Acceptance||30-Dec-2021|
|Date of Web Publication||19-Apr-2022|
Dr. M Altiok
Huzurevleri mh 77201 sk No 4/4 Elitpark Sit C Blok Kat 5 Daire 11 Çukurova/Adana
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background and Aim: Phyllodes tumors (PT) are rare biphasic breast tumors containing stromal mesenchyme and epithelial components. It was classified as benign, borderline, and malignant by the World Health Organization (WHO). Although there is no certainty about the size of the desired margin in the surgery to be applied, a tumor-free area of 1 cm is often targeted. Our study aimed to determine the subtype rates in patients with PT and evaluate the surgical margin, recurrence, and survival times obtained after the surgery. Patients and Methods: This study was conducted at Seyhan Goverment Hospital and involved the PT patients treated between January 2010 and June 2020. We analyzed PT patients retrospectively. Sixty-one patients with PT were analyzed. In the patient, demographic characteristics, body mass index (BMI), surgical procedures, tumor type, size, mitosis rate, and distance of tumor to surgical margin were evaluated. During follow-up, reoperation, recurrence, metastasis, survival times, and mortality rates were evaluated. Results: Sixty-one phyllodes breast tumor patients whose histopathology was reported as malignant, borderline, and benign were evaluated and presented in our study. The mean age was 37.84 (15–100), and the BMI was 25.78 (±5.35) mm. Of the 61 patients, 41 (67.2%) were diagnosed with benign phyllodes tumor (BPT), 10 (16.4%) as borderline phyllodes tumor (BLPT), and 10 (16.4%) as malignant phyllodes tumor (MPT). Conclusions: Preoperative diagnosis of PT can reduce the rate of secondary surgical procedures and the loss of extra breast tissue. A large diameter needle and sufficient number of tissue samples for preoperative core biopsy may increase the rate of accurate diagnosis.
Keywords: Phyllodes tumor, prognosis, recurrence, sugical margin
|How to cite this article:|
Altiok M, Kurt F. Factors effective on recurrence and metastasis in phyllodes tumors. Niger J Clin Pract 2022;25:425-31
| Introduction|| |
Phyllodes tumors (PT) are rare biphasic breast tumors containing stromal mesenchyme and epithelial components. PT malignant transformation is usually caused by mesenchymal tissue and <1% of epithelial tissue. In histological examination, it is observed that the stromal component surrounds the epithelial structure. It was classified as benign, borderline, and malignant by the World Health Organization (WHO) in 1982 with histological parameters including stromal cellularity, atypia, mitosis rate, necrosis, stromal overgrowth, and tumor margin status. In clinical practice, benign phyllodes tumor (BPT) is most often diagnosed with a rate of 50%–80%. Fine needle aspiration biopsy (FNAB) is generally insufficient for diagnosis. A higher rate of diagnosis is made with a core biopsy. Surgical excision is the standard approach in diagnosis and treatment. As well as providing post-surgical cure in PTs, it can be seen in different clinical situations ranging from local recurrence and distant metastasis.
Studies indicate no significant difference between breast-conserving surgery and radical mastectomy in terms of metastasis and disease-free survival. High-grade tumor, stromal overgrowth, and tumor necrosis are low prognostic features associated with metastasis. Metastases are mostly by the hematogenous route and most frequently occur in the lung. Although there is no certainty about the size of the desired margin in the surgery to be applied, a tumor-free area of 1 cm is often targeted. For National Comprehensive Cancer Network (NCCN) 2020.6 guideline borderline phyllodes tumor (BLPT) and Malignant phyllodes tumors (MPT), excision with a margin of ≥10 mm is recommended. This border is wider than the target in infiltrative and invasive breast tumors. Our study aimed to determine the subtype rates in patients with PT and evaluate the surgical margin, recurrence, and survival times obtained after the surgery.
| Methodology|| |
Sixty-three patients diagnosed with phyllodes tumor between January 2010 and June 2020 were included in the study. Two patients diagnosed with synchronous ductal carcinoma in situ and invasive ductal cancer with phyllodes tumor were excluded from the evaluation. The methods applied for preoperative diagnosis and biopsy results were examined. WHO classification system was used to define the subtype of PT. In the patients' medical records, demographic characteristics, mean age, and body mass index (BMI) were evaluated. The effect of BMI on the distribution of tumor subtypes was examined. Surgical procedures applied were determined. Among the histopathological features, tumor type, size, mitosis rate, the distance of tumor to surgical margin, Ki-67, and CD10 positivity were evaluated. During follow-up, reoperation, recurrence, metastasis, survival times, and mortality rates were evaluated. Recurrence was considered for masses in the same localization as the first tumor. The relationship between breast BI-RADS scores and histological subtypes in PTs was examined. Ethics committee approval of Adana city hospital dated 23.09.2020 and institution review board (IRB) number 1070 was obtained for the study's publication.
Statistical Package for the Social Sciences (SPSS) 23.0 package program was used for statistical analysis of the data. Categorical measurements were summarized as numbers and percentages, and continuous measurements as mean, deviation, and median (interquartile range [IQR: 25th percentile to 75th percentile]). The variables' suitability to normal distribution was examined using visual (histogram and probability graphics) and analytical methods (Kolmogorov–Smirnov/Shapiro–Wilk tests). Chi-square test were used in comparing categorical variables. One-way analysis of variance (ANOVA) was used for parameters conforming to the normal distribution, and the Kruskal Wallis test was used in groups that did not comply with a normal distribution. Kaplan–Meier analysis and Log Rank tests were used for survival analysis. Statistical significance level was taken as 0.05 in all tests.
| Result|| |
Sixty-one phyllodes breast tumor patients whose histopathology was reported as malignant, borderline, and benign were evaluated and presented in our study. The mean age was 37.8 ± 16.28, and the BMI was 25.8 (±5.36) mm. Of the 61 patients, 41 (67.2%) were diagnosed with BPT, 10 (16.4%) as BLPT, and 10 (16.4%) as MPT [Table 1]. PT was most common in the age group of 20–30 years. MPT diagnosis was statistically significantly higher in patients >60 years compared to the other age groups (P = 0.007) [Table 2]. All the patients were evaluated with preoperative ultrasound (Usg) examination. In Usg, 41 (67.2%) patients had fibroadenoma, 13 (21.3%) patients had a solid mass, 3 (4.9%) patients had PT, and 4 (6.6%) patients had a prediagnosis of malignancy. Mammography was performed in 24 patients. Eighteen patients were reported as solid masses, three patients with fibrocystic breasts, two patients with no pathological findings, and one patient as a malignancy possibility. Nine patients were evaluated with magnetic resonance image (MRI) preoperatively, and none of the patients had a prediagnosis of PT. In the postoperative histopathological evaluation of these patients preoperatively examined with MRI, three patients were diagnosed as BPT, three patients as BLPT, and three patients as MPT. In the evaluation regarding the lateralization finding, the tumor was in the right breast of 24 patients and the left breast of 37 patients. Differences between tumor types and lateralization findings were not statistically significant (P > 0.05).
It was observed that core biopsy was performed in 33 patients, and FNAB was performed in 3 patients before surgery. Of the patients who had a histopathological evaluation with a core biopsy, sixteen were diagnosed as BPT, four as BLPT, five as MPT, seven as FA, and one as sclerosing adenosis. One of the three patients who underwent FNAB was evaluated as BPT and two as insufficient. A correct diagnosis was made preoperatively in 17(%51.5) patients with core biopsy and 1 (%33) patients with FNAB. In [Table 3], clinicopathological features and surgical resection margin-distribution of tumor types are given.
|Table 3: Distribution of clinical and histopathological features by tumor types|
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In evaluating the surgery performed according to tumor types, it was observed that breast-conserving surgery was applied more frequently in patients diagnosed with BPT and BLPT. It was determined that radical resections were preferred in patients with a diagnosis of MPT. The patients' tumor size in the malignant group was found to be higher than those in the benign and borderline group (P = 0.021). In patients with BI-RADS score of 4 in breast Usg, mammography, and breast MRI, the MPT diagnosis rate was found to be statistically significantly higher compared to BPT and BLPT (P = 0.035) [Table 4].
There were no patients with PT at the surgical margin to evaluate the tumor type and surgical margin status. It was observed that excision was performed in two patients with a border <1 mm. Postoperative histopathological examination revealed a surgical margin of 1-4.9 mm in 13 patients, 5-9.9 mm in 29 patients, and >10 mm in 17 patients. Local recurrence developed in one patient with MPT excised with a margin of <1 mm. Local recurrence was not observed in any patient with a diagnosis of BLPT. Local recurrence was observed in 2 (6.8%) of 29 patients who underwent resection with a border of 1–10 mm in patients diagnosed with BPT. Two patients with a diagnosis of MPT died due to lung metastasis. The cumulative survival of the patients is shown in [Figure 1].
|Figure 1: Tumor subtypes and cumulative surveillance evaluation 1: BPT, 2: BLPT, 3: MPT|
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In histopathological examination, the decrease in ki-67 levels in the BPT group was statistically significant compared to the BLPT and MPT groups (P < 0.05). Similarly, mitosis numbers were statistically significantly lower in BPT, than BLPT and MPT (P < 0.05). CD10 positivity rates, according to histopathological type in the patients included in the study, are shown in [Table 3]. Histopathological and radiological images of PT subtypes are shown in [Figure 2],[Figure 3],[Figure 4].
|Figure 2: BPT radiological and histopathology image. [Figure 2] (a–d): BPT, Usg; heterogeneous internal structure solid lesion with lobulated contours (a), Mammography; high density asymmetric opacity appearance (b), MRI; heterogeneous mass with contrast enhancement in its internal structure (c), pathological examination; hypercellular stroma under cavities lined with benign glandular epithelium in the periductal region HE × 40 (d)|
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|Figure 3: BLPT radiological and histopathology image. [Figure 3] (a–d): BLPT, Usg; solid lesion with lobulated cystic areas (a), Mammography; lobulated hyperdense borders selected lesion (b), MRI; hyperintense lesion with multilobule contrast showing enhancement from early phases (c), pathological examination; moderately heterogeneous stromal cell distribution, three to five mitosis in magnification fields, HE:×40 (d)|
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|Figure 4: MPT radiological and histopathology image. [Figure 4] (a–d): MPT, Usg; solid lesion with internal echogenicity with a cystic and thin septal component (a), Mammography; heterogeneous solid dense mass with lobulated contours, partially irregular borders (b), MRI; Giant hyperintense mass with irregular borders, covering all breast tissue with pectoral muscle border (c), pathological examination; Intense mesenchymal dominance, nuclear atypia, and increased mitotic activity, extension of malignant epithelial cells to the glandular lumen in proliferated areas HE:×40 (d)|
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| Discussion|| |
PT accounts for <1% of all breast cancers. It was originally considered as a benign giant fibroadenoma variant. It was understood that it exhibits malignant behavior in later times. It is seen in all age groups. PT is frequently confused with fibroadenoma in preoperative examinations. Generally, it cannot be posed correctly preoperatively. There is no consensus on standard approaches to treating PT. Surgical treatment is the most effective and first option. Histopathological features, tumor size, and surgical margins are effective in metastases and recurrences. Although malignancy rates increase in older ages, it is reported that recurrence rates are independent of age. In our study, the mean age was 37.84 (±16.28), and no statistically significant difference was observed between the age groups and tumor type findings of the patients. The rate of malignancy was found to be statistically significantly higher in patients >60 years with a diagnosis of PT (P = 0.007). We encountered a younger group in our case series compared to the average age stated in published studies. We think that these average ages stated in the literature will indicate a younger population with the application of screening programs to large masses and the early examination of women with a family history of breast malignant diseases.
Betty et al. reported BPT (78.1%), BLPT (10.4%), and MPT (11.5%), while Philou et al. reported BPT (70%), BLPT (5%), and MPT (12%). In our study, the rates of BPT, BLPT, and MPT of the patients were similar to the rates given in the literature.
It is known that insulin resistance, which develops with central obesity and excessive fat, is a predisposing factor in invasive breast cancer in postmenopausal women. Risk of breast cancer increases by 30%–50% through increased abdominal fat and elevated levels of estrogen, testosterone, and insulin-like growth factor-1. An increase in tumor burden, histopathological grade, and lymph node metastasis rates have been found to be associated with obesity. There is not much information about the effect of obesity on PT in the literature. In our study, the relationship between PT subtypes and BMI findings was evaluated. Although there was no statistically significant relationship between tumor type and BMI, the BMI of the patients in the MPT group was found to be higher with 28.57% (±5.5) compared to the other groups (P = 0.179).
PTs cannot be easily distinguished from fibroadenoma by mammography and breast USG due to their similar features with other fibroepithelial lesions. In imaging methods, they are detected as smooth, well-defined, multilobular, and hypoechoic masses. Sotheran et al. reported the false negativity rate as 97.5% for mammography and 83% for USG. In our study, as a result of USG applied to 41 patients, 7 (17%) patients were prediagnosed with PT and malignancy. PT was not prediagnosed in any patient evaluated with mammography, and the possibility of malignancy was reported in only one patient. The false negativity rate was determined as 95.8%. PT prediagnosis has not been reported for patients evaluated by breast MRI. Three patients identified as BIRADS-4 lesions were diagnosed with MPT. In the absence of PT-specific findings, it is not possible to make a diagnosis with only imaging methods before surgery.
FNAB and core biopsy are frequently performed for histopathological examination of radiologically detected masses. Making the correct diagnosis with preoperative tissue sampling will prevent second surgical interventions to be applied to the patient. The sensitivity of FNAB in the preoperative evaluation of PT is low. Especially in BPT and BLPT's, wrong diagnoses up to 80% are made. Kubilay et al. reported in their study that the correct diagnosis was made preoperatively in 50% of patients with core biopsy. Foxcroft et al. reported 65% correct diagnosis rates with core biopsy. Vega-Bolivar et al. stated that taking at least three samples from the lesion with the core biopsy method will decrease the rate of false negativity. It has been stated that more reliable results are obtained in separating PTs from FA with the increase of needle diameter in core biopsy procedures. In some reported case series, the false negative rate of core biopsy is between 17% and 39%. In our study, only one out of three patients who underwent FNAB had a correct diagnosis before surgery. PT was diagnosed in 26 (78.7%) of our 33 patients who underwent core biopsy. The rate of correctly identifying the subtypes in these patients with preoperative PT was found to be 17/33 (51%).
Adesoye et al. reported in their study that size increases in PT increased recurrence rates. On the other hand, Olaya et al. reported that there was no relationship between tumor size and recurrence rates in their study. Philou et al. reported in their study that there was a statistically significant relationship between increased PT size and the diagnosis of MPT. In our study, the effect of tumor size on recurrence and subtype distribution was evaluated. There was no significant relationship between tumor size increase and recurrence, but it was found that the tumor size was higher in patients in the MPT group compared to the BPT and BLPT groups (P = 0.021).
There is no consensus for the targeted surgical margin in PT surgical treatment. In a review of 1702 patients with BPT, Shaaban stated that there was no significant difference in local recurrence between surgical groups between 10 mm surgical margin and 1 mm surgical margin. It has been noted that recurrence rates increase in the presence of BPT at the surgical margin. There are studies suggesting excision with a surgical margin of >10 mm in MPT and BLPT. However, in some studies comparing 10 mm surgical margin with R0 resection, it was reported that there was no statistically significant difference between overall survival and disease-free survival. In our study, local recurrence was observed in 1 of 7 patients who underwent resection with a 1–4.99 mm margin and in 1 of 22 patients who underwent resection with a 5–9.9 mm margin. The patients were re-excised. In one patient who underwent mastectomy in surgical treatment with a diagnosis of MPT, resection was performed at the posterior surgical margin <1 mm. In the follow-up of the patient, local recurrence occurred in the sixth postoperative month. We found that our local recurrence rate was 2/41 (4.86%) in BPT, 0/10 (0%) in BLPT, and 1/10 (10%) in MPT in patients who were resected with a margin <10 mm.
In metastatic lesions of PTs, stromal component rather than epithelial component is detected. Behaving like sarcomas and metastasis often occurs by hematogenous route. It is assumed that PTs do not cause lymphatic metastasis. Ben Hassouna et al. reported in their study that 20 patients detected metastasis in 1 patient in axillary dissection. Although axillary dissection was not routinely performed in our study, axillary lymph nodes in the resection area were also included in the specimen in one patient who underwent mastectomy due to the axillary extension of the mass and there was no lymph node metastasis.
Tan et al. reported 12 cases with distant metastases in their series of 605 cases. The most common metastases were stated as lung, liver, pleural, soft tissue, and vertebra. It has been reported that no metastasis was found in BLPT and BPT. Regarding mortality, Olaya et al. reported a rate of 6.6% in the article they published. In the present study, two patients with MPT had distant metastasis. Metastases were found to be in the lung and bone tissues. Metastasis did not develop in patients diagnosed with BLPT and BPT. Mortality developed in two patients with MPT who developed distant metastases.
The effectiveness of adjuvant chemotherapy, radiotherapy, and hormone replacement therapy in PTs is uncertain. There are studies reporting a good response to treatment when doxorubicin and dacarbazine agents are combined with cisplatin or ifosfamide in large, necrotic, and metastatic tumors. Neron et al. recommended chemotherapy and radiotherapy to patients with large and necrotic tumors, but stated that they had no effect on overall survival in accordance with previous studies. They stated that radiotherapy can be applied in patients undergoing breast conserving surgery. In our study, two patients with metastatic PT received chemotherapy. Doxorubicin, dacarbazine, and ifosfamide were preferred as chemotherapeutic agents. Radiotherapy treatment was not applied to our patients. No comment could be made due to the effectiveness of chemotherapy and the low number of cases.
Lack of knowledge of needle diameters used for core biopsy and lack of standard approach in biopsy numbers were determined as the reasons for limitations in our study.
| Conclusion|| |
Preoperative diagnosis of PT can reduce the rate of secondary surgical procedures and the loss of extra breast tissue. A large diameter needle and sufficient number of tissue samples for preoperative core biopsy may increase the rate of accurate diagnosis. Randomized controlled prospective studies with large case series are needed to determine the required surgical margins and clear margins.
Consent for publication was obtained from patient whose data are included in this manuscript.
MA: Collected data, written manuscript, edited and critically reviewed the manuscript.
FK: Collected data, written manuscript, edited and critically reviewed the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]