INTRODUCTION

Phyllodes tumors are rare fibroepithelial lesions consisting of 2%-3% of all fibroepithelial tumors and 0.3%-0.5% of all breast tumors in women, which are clinically confused with fibroadenomas. A large, rapidly growing mass and detection of stromal hyperplasia and atypia on histopathological examination should suggest a phyllodes tumor. Due to their rarity, literature data are limited. The World Health Organization (WHO) classifies phyllodes tumors into three histological subtypes based on the number of histopathological parameters, i.e., benign, borderline, and malignant (1,2).

Surgery forms the basis for phyllodes tumor treatment. Preoperative diagnosis is very important for correct surgical planning. Difficulties in diagnosis during the preoperative period cause mistakes in treatment planning. Traditionally, considering the risk of local recurrences, wide local excision with a tumor-free border of 1 cm or more is recommended regardless of the subtype. Lumpectomy or partial mastectomy is the preferred surgical treatment. Total mastectomy is only necessary when negative margins are not achieved with breast-conserving surgery. Considering that a phyllodes tumor rarely metastasizes to the axillary lymph nodes (10%-15%), surgical axillary staging is not required unless lymph nodes are palpated upon clinical examination (3,4).

The borderline and malignant phyllodes tumor metastasis rate is approximately 25%-31%, whereas the overall rate of all phyllodes tumor metastases is 4%. In addition, WHO reported a local recurrence rate of 21% (17%, 25%, and 27% for benign, borderline, and malignant phyllodes tumors, respectively) (5,6). Surgical margin positivity was reported in the literature to be associated with tumor size, surgical treatment technique, and tumor-related histopathological features (7,8).

Evidence from randomized controlled trials and available data in the literature is insufficient to determine the treatment approach for phyllodes tumors. Therefore, this study aimed to examine the demographic characteristics, clinicopathological findings, follow-up results, and treatment methods of patients treated for phyllodes tumors of the breast in light of the literature.

METHODS

After obtaining approval from the Ethical Committee of Adana City Training and Research Hospital on January 27, 2021 (approval number: 75/1269), data about patients with phyllodes tumors treated in our hospital between 2013 and 2020 were retrospectively analyzed. Data were gathered from the results of pathological examinations and soft and hard copies of the patient files. Missing information about the patients was obtained by phoning them. Patients were divided into three groups based on the histopathological examination results, benign, borderline, and malignant. Age, complaints on admission, tumor location, surgery, breast imaging-reporting and data system (BIRADS) score, pathological features, tumor size, postoperative recurrence, and metastasis were compared in these groups.

Ultrasonography (USG) and mammography (MMG) were used as primary imaging methods. Histopathological diagnosis was made through core needle, excisional, and incisional biopsy methods. Pathologically, phyllodes tumors were classified into benign, borderline, and malignant based on the criteria reported by the WHO (1).

In the present study, the presence of 0-4 mitoses in each field examined under 10 X magnification, minimal stromal cellularity, and minimal and moderate stromal development was considered benign phyllodes tumor. The presence of 5-9 mitoses in each field examined under 10 X magnification, moderate stromal cellularity, and atypia was regarded as a borderline phyllodes tumor. The presence of >10 mitoses in each field examined under 10 X magnification, moderate or severe stromal cellularity, atypia, and overgrowth and infiltrates to the surrounding tissues indicated a malignant phyllodes tumor.

A wide local excision, breast-conserving surgery, mastectomy, or mastectomy, and axillary lymph node dissection [modified radical mastectomy (MRM)], which are the treatment methods to be performed, were selected to leave a clean surgical margin of at least 1 cm according to the location, size, and histopathological diagnosis of the tumor. The close surgical margin was considered a clean surgical margin of <1 cm in all types.

Statistical Analysis

Statistical analysis was made using the Statistical Package Program for Social Sciences 24.0 (IBM Corporation, Armonk, NY, USA). Descriptive data were expressed in mean and standard deviation for quantitative variables and in frequency and percentage for qualitative variables. Data with a normal distribution were evaluated using the Student’s t-test, whereas data without a normal distribution were evaluated using the Fisher’s Exact or Pearson’s chi-square test. A p-value of <0.05 was considered statistically significant.

RESULTS

A total of 14 patients were included in the study, wherein 6, 3, and 5 were assigned into the benign, borderline, and malignant groups, respectively. The mean age was similar in the groups (p=0.654). Tumors were more frequently located in the right breast accounting for 78.6% of the cases; however, no significant difference was found in terms of laterality (p=0.514). All patients presented with a palpable mass. The tumor diameter was significantly smaller in the benign group (benign group: 32 mm, borderline group: 72 mm, and malignant group: 80 mm, p=0.036). A higher rate of tumors in the benign and malignant groups was BI-RADS 3 and BI-RADS 5; however, the difference was not statistically significant (p=0.141).

Regarding the biopsy method, a core-needle biopsy was performed in eight patients (57.1%), excisional biopsy in five patients (35.7%), and incisional biopsy in one patient (7.1%). No significant difference was found in the biopsy methods between groups (p=0.178).

Breast-conserving surgery was performed with a wide local excision in all six patients with benign phyllodes tumors. Two patients had close resection margins. These patients did not undergo re-excision surgery. No local recurrence was observed in the benign phyllodes group during the follow-up.

Three patients had borderline phyllodes tumors (5%). One of these patients immediately underwent a simple mastectomy after the core needle biopsy due to advanced tumor size. Another patient had a positive resection margin after breast-conserving surgery and underwent a mastectomy. She also had a submuscular prosthesis for cosmetic reasons. The last patient underwent re-excision due to the proximity of the surgical margin after wide local excision.

Five patients had malignant phyllodes tumors (35.7%). Three of them underwent breast-conserving treatment, one underwent a mastectomy, and one underwent MRM. One of the patients who underwent breast-conserving surgery was found with malignant phyllodes tumor and low nuclear grade intraductal carcinoma foci within the tumor on the permanent pathology sections after wide local excision. No tumor was left in the surgical resection margins. Sentinel lymph node biopsy was not performed. The tumor diameter was 12 cm in the patient who underwent a mastectomy, which was performed immediately after incisional biopsy. The patient who underwent MRM had a malignant phyllodes tumor accompanied by invasive ductal carcinoma detected on segmental resection. Positivity was found in some parts of the surgical margins and axillary lymph node involvement on USG. Therefore, MRM was subsequently performed.

None of the patients with benign and borderline phyllodes tumors received chemotherapy or radiotherapy (RT). All patients with malignant phyllodes tumors received RT, and the patient with invasive cancer and malignant phyllodes tumors received chemotherapy and hormone therapy.

The mean follow-up period was 53.8±25.4 months (13-96 months). Local recurrences occurred in two patients during the follow-up. One of them had a malignant phyllodes tumor and underwent re-excision surgery due to tumor-positive resection margins. However, she had a malignant relapse in the tenth month, thus a mastectomy was performed. The other patient developed a borderline phyllodes tumor recurrence locally 14 months after the primary breast-conserving surgery despite the excision surgery for borderline phyllodes tumor. This patient was also treated with mastectomy. No distant metastases or deaths were observed Table 1.

DISCUSSION

The uncertain and heterogeneous biological behavior of phyllodes tumors makes the diagnosis and management more difficult. Therefore, clinicians relied heavily on reports from retrospective studies of this tumor’s behavior to improve early diagnosis and use correct treatment strategies. In the present study, data of 14 female patients diagnosed with phyllodes tumor in our tertiary hospital over an 8-year-period were reviewed, and obtained results will contribute to the reported data.

Phyllodes tumors are more common in women aged 35-55 years and the frequency of malignant phyllodes tumors increases in the older age group (9,10). The mean age in our series was 34.5 years; however, no relationship was found between the histological subtype and age. In a large case series in the literature, benign, borderline, and malignant tumors were found in 72.7%, 18.4%, and 8.9% of 605 patients, respectively. In another study, benign, borderline, and malignant phyllodes tumors were reported in 60%, 20%, and 20% of patients, respectively (11,12). In our series, benign, borderline, and malignant phyllodes tumors were detected in 42.9%, 21.4%, and 35.9% of cases, respectively. The rate of malignant phyllodes tumors in this series was higher than that reported in the literature.

Phyllodes tumors widely vary in size. This variation in tumor size is due to the late diagnosis of the tumor caused by diagnostic difficulties and the benign or malignant nature of the tumor. In general, tumor size varies with benign and borderline or malignant phyllodes tumors (9). In a study by Wang et al. (9), the mean primary tumor diameter of the histological subtypes benign, borderline, and malignant phyllodes tumors was found to be 3.7 cm, 4.8 cm, and 7.5 cm (p<0.000), respectively. Based on multivariate analysis, larger masses were reported to be more likely malignant (p=0.052, odds ratio: 1.127) (9). In our series, the mean tumor diameter was 5.4 cm, and borderline and malignant tumors had a larger tumor diameter.

Phyllodes tumor diagnosis is difficult in daily clinical practice. Failure to preoperatively diagnose malignant phyllodes tumors causes short-term recurrences and even distant metastases due to insufficient excision. Contrarily, radiological and histopathological examinations of phyllodes tumors often yield similar findings to the examinations of fibroadenomas, thus clinical suspicion is essential for diagnosis (13). MMG and USG used in the diagnosis of breast masses are not very reliable methods in making the differential diagnosis of phyllodes tumors from fibroadenomas (14). Fine needle aspiration biopsies are generally inadequate due to their high false-negative rates. Core needle biopsies play an important role in the diagnosis of phyllodes tumors; however, false-negative results at the rates of 25%-30% were reported (15,16). In our series, the BIRADS 4-5 was more common in patients with the malignant subtype.

The treatment of phyllodes tumors is surgical excision with sufficient margins. Recurrences and the need for reoperation increase after inadequate surgery (17). In a multivariate analysis performed with 172 patients, insufficient margins were found to play a role in the emergence of local recurrences and metastases (18). Different opinions were presented on the surgical method to be chosen in the literature. Sotheran et al. (19) recommended a wide local excision in phyllodes tumors, whereas Sotheran et al. (19) recommended mastectomy (20). Kapiris et al. (21) could not find a difference between wide local excision and mastectomy in the presence of negative margins. In the current study, segmental mastectomy was performed in patients for whom clean surgical margins are achieved, and mastectomy or subcutaneous mastectomy was performed in the patients in whom clean surgical margins were not achieved or poor cosmetic results were likely to appear after excision.

The benefit of adjuvant chemotherapy for phyllodes tumors is controversial. No prospective or randomized studies were reported about the effect of adjuvant chemotherapy on this type of tumor. Using adjuvant RT is also controversial in the literature. The National Comprehensive Cancer Network and other studies recommend the use of RT in cases of recurrent malignant phyllodes. Other studies recommend adjuvant RT to reduce the likelihood of local recurrences in patients with borderline and malignant phyllodes tumors treated with breast-conserving surgery. Contrarily, RT did not increase the overall survival (OS) and disease-free survival rates (22,23). In our series, five patients received RT who had malignant phyllodes tumors. The patient receiving chemotherapy are those with invasive carcinoma.

In the series of the MD Anderson cancer center, 5-year OS rates in patients with benign and malignant phyllodes tumors were 91% and 82%, respectively (24). According to data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, the 5-year OS rate was 91% for malignant cases (25). In another study, the 3-year survival rate for benign/borderline tumors was 100%, whereas 53.4% in patients with malignant phyllodes tumors (26). Acar et al. (14) reported that the 5-year OS rate was 89% for borderline and malignant cases. Kündeş et al. (27) found that the 5-year survival was 93.8% and 70% in borderline and malignant tumors, respectively. In our series, none of the patients died during the 53-month follow-up.

Local recurrence rates in the follow-up of patients with phyllodes tumors were reported to range from 10% to 40% in different studies. Local recurrences are often detected in the breast tissue, but rarely, local-regional recurrences including the chest wall can be detected. Especially in borderline and malignant phyllodes tumors, the probability of local recurrence was reported to be 21% even if the surgical margins are negative (28,29). Metastasis rates for phyllodes tumors vary between 13% and 40%. The most common site of metastasis is in the lungs. The current approach to the treatment of metastatic lesions is surgical excision (28). In our series, during the 53-month follow-up period, local recurrences developed in two patients with borderline and malignant phyllodes tumors. Three patients underwent re-excision due to positive surgical margins and one of them had a local recurrence. In the present study, the total local recurrence rate was 14% and none of the patients developed distant organ metastasis.

CONCLUSIONS

Phyllodes tumors are rare breast tumors with variable biological behavior and heterogeneous radiological and clinical manifestations. Histopathological features and classification guide the management plan. Extensive analysis of phyllodes tumors is still lacking, and more studies are necessary to understand the behavior of this rare breast tumor.

ETHICS

Ethics Committee Approval: The study were approved by the Adana City Training and Research Hospital of Local Ethics Committee (protocol number: 27.01.2021/75/1269).

Informed Consent: Consent form was filled out by all participants.

Authorship Contributions

Surgical and Medical Practices: O.İ., O.E., Concept: O.E., A.P., Design: O.E., O.İ., Data Collection or Processing: Z.A.T., U.T., Analysis or Interpretation: U.T., O.E., Literature Search: U.T., O.E., O.İ., Writing: O.E., U.T.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.