Metastatic and Malignant Phyllodes Tumors of the Breast: An Update for Current Management

Abstract

Metastatic, malignant phyllodes tumor (PT) of the breast is a rare and aggressive neoplasm. Currently, there is no agreed upon consensus as to best management practices. A systematic review of literature was conducted investigating surgical, chemotherapeutic, and radiotherapeutic management for metastatic PT. Databases employed to identify articles included Embase, PubMed, and SAGE Journals. Diagnosis of metastatic PT has been of significant difficulty to radiologists as it is often confused with fibroadenomas. Surgically, metastatectomy has been correlated with increased overall survival (of 25.9 versus 9.9 months; P = .01). Radiotherapy has often been associated with palliation and pain control in metastatic, malignant neoplasia. However, one study showed that in malignant PT, radiation was associated with significantly lower rates of local recurrence (OR: 0.048 versus 0.209). Anthracycline containing chemotherapy regimens has been associated with improved overall survival (22.4 months versus 13.2 months; P = .040). Further research must be conducted into this rare malignancy to elucidate accurate diagnosis and care for patients with advanced metastatic or malignant phyllodes tumors.

Keywords

Breast surgical oncology

Introduction

Phyllodes tumors (PTs) are rare fibroepithelial neoplasms of the breast, accounting for .3%-1% of all tumors, and are predominantly seen in females ages 40 to 50.^1,2

The WHO staging is based on histology (cellular atypia, stromal cellularity, and the number of mitoses) and is defined as benign, borderline, or malignant.³ Diagnosis of malignant PT is made by the presence of infiltrating margins, severe stromal atypia greater than or equal to 10 mitoses per high-powered field, and the presence of stromal overgrowth.⁴ PT neoplasia can be further classified based on its size, considered “giant” if larger than 10 cm.⁵ Malignant phyllodes tumors have a high recurrence rate and, although uncommon, the potential to metastasize.⁵

Phyllodes tumors often present as painless lobulated or smooth, well-circumscribed masses.^6,7 Phyllodes masses may proliferate quickly, causing distension of the superficial veins and stretching of the overlying skin.¹ Possibly due to the rarity of this malignancy, there is little consensus on etiology. However, there is some consensus on genetic predisposition to disease development. The most common genetic mutations in PT are MED12 exon two and TERT, found in roughly 70% of cases.⁸ Li Fraumeni TP53 mutations are also strongly associated with the development of this neoplasia.⁹ It is hypothesized that MDM2 mutations may be seen in early neoplasia development; however, the evidence remains limited.¹⁰ The most common sites of metastasis are the lungs, bone, and brain (66%, 28%, and 6%, respectively).¹¹ Local recurrence rates of malignant phyllodes breast tumors are between 23 and 30%, and distant metastatic recurrence rates are between 9.5 and 50%.¹² When distant metastasis occurs, the prognosis is often grim.¹³ There needs to be more data regarding the optimal management of metastatic and malignant phyllodes tumors. Here, we systematically review the literature surrounding metastatic malignant phyllodes breast tumors.

Method

A systematic literature review explored the most up-to-date information on the medical and surgical management of metastatic and malignant phyllodes tumors. Databases employed to identify articles included Embase, PubMed, and SAGE Journals. For a paper to be had, it must be within the last three years. Information from papers dated the past three years was only included if deemed seminal or if there needed to be newer data. Articles were not excluded based on their study type (sans basic science papers), language, or country of origin.

Diagnosis

Phyllodes tumors can be challenging to diagnose, as a core needle biopsy may fail to differentiate phyllodes from fibroadenoma,¹⁴ thus requiring an excisional biopsy. However, despite excisional biopsy, it remains challenging to histologically distinguish phyllodes from sarcomas and spindle cell metaplastic breast carcinoma, which have different courses of treatment.¹⁵ Diagnosing phyllodes is essential due to malignant stromal transformation, which means a more considerable margin of tissue should be removed during surgery than for non-phyllodes pathology. Advanced imaging studies are recommended to be performed along with tissue diagnosis as research has found the sensitivity of a needle core biopsy’s phyllodes diagnosis to increase from 63% to 76% when combined with radiologic studies.^16,17 Sufficient resection of the tumors leads to fewer subsequent surgeries.¹⁸

Ultrasonographic features of size (malignant PT > 7 cm), irregular shape and cystic echogenicity, clefts, a higher Bi-RADS score, and mass vascularization are used to differentiate between malignant and benign phyllodes,^15,18,19 especially in older patients.²⁰ Elastography on ultrasound may differentiate fibroadenomas from phyllodes based on lesion stiffness, with fibroadenomas demonstrating lower and malignant stiffness values.¹⁹ Phyllodes also tend to show less calcification than fibroadenomas.¹⁵ However, there is still significant overlap between benign and borderline or malignant features of phyllodes in sonographic studies.²⁰ Some studies suggest no significant association between ultrasonographic characteristics and the grade of phyllodes tumor.¹⁹

In mammography, the features that differentiate fibroadenomas from phyllodes are size, shape, and margins.¹⁸ Borderline and malignant tumors are generally larger. Borderline and malignant tumors have a more robust lobulation pattern in mammography.²¹ Despite the information obtained from mammography, studies that have looked at distinguishing different subtypes of phyllodes to grade the tumors have failed to find an association between the mammographic images and tumor grade.¹⁹

When distinguishing benign from malignant tumors, the imaging features of sonography and mammography are non-specific.²² MRI has been demonstrated to be a more efficient tool than mammography or ultrasound for grading phyllodes tumors²¹ and is also a valuable tool in diagnosing and differentiating borderline and malignant tumors.²² Perfusion-related incoherent microcirculation derived from intravoxel incoherent motion as well as apparent diffusion coefficient has also been shown in MRI studies to differentiate between benign phyllodes and fibroadenomas,¹⁶ as well as between benign and malignant phyllodes tumors.²³

Features such as older age, recurrence, strong lobulation, larger size [benign (3.5 cm), borderline (6.6 cm), and malignant (8.2 cm)], high signal intensity on T2-weighted MRI images, and internal cysts are associated with phyllodes more than fibroadenomas.^15,18,19,24 Studies investigating the association between MRI and histological grading have suggested that tumors with higher signal intensity and an irregular cyst wall on MRI T1-weighted images are histopathologically associated with more hemorrhagic infarction and necrosis. In comparison, tumors with lower signal intensity and a lower apparent diffusion coefficient on MRI T1-weighted images are histopathologically associated with stromal hypercellularity.²⁵

Texture analysis is a quantitative imaging feature of MRI that may be utilized as a low-cost and non-invasive tool for cancer diagnosis.²⁴ Tissue analysis is regarded as a radiomics technique capable of revealing tumor heterogeneity. This helps improve the effectiveness of the diagnosis of borderline and malignant phyllodes when using conventional magnetic resonance images by providing additional quantitative and objective data.²⁶ Features such as Clinical and standard MRI features (CCMF) and tissue analysis on axial short TI inversion recovery T2-weighted (T2W-STIR) have been found to help make predictive assessments of tumors larger than 3 cm, which leads to fewer postoperative complications. Therefore, it is believed that these advanced MRI features, including tissue analysis based on dynamic contrast-enhanced MR (DCE-MRI), can become biomarkers for the diagnosis and management of fibroepithelial cancers and a tool for pathological grading of phyllodes.^21,24,26,27

Staging

The most prevalent type of breast cancer, invasive ductal carcinoma, offers a wide range of prognostic models and grading systems. In contrast to invasive ductal carcinoma, phyllodes tumors do not have a distinct staging system for patients.²⁸ Phyllodes tumors are distinguished by their larger size, increased rate of growth, and microscopic findings of stromal hyperplasia and atypia. The World Health Organization (WHO) classifies phyllodes tumors as benign, borderline, or malignant depending on the level of stromal hyperplasia and atypia, with malignant tumors making up 25% of resected tumors. These classifications have significant effects on prognosis and treatment. Four characteristics serve as the basis for classification: degree of stromal cellular atypia, mitotic activity, the presence of stromal overgrowth, and if the tumor margin is well-defined vs infiltrative.^29,30

Fewer than 1% of all breast cancers are breast sarcomas, which develop from the connective tissues of the breast. They can be further divided into primary breast sarcomas, which develop spontaneously and have a wide range of histological characteristics, and secondary breast sarcomas, which develop as a result of radiation or lymphedema and are typically angiosarcomas. The breast can also develop phyllodes tumors and desmoid tumors, two connective tissue neoplasms that show a wide range of characteristics. The biology of malignant phyllodes tumors and primary breast sarcomas is comparable for sarcomas, a core needle biopsy is typically necessary to confirm the diagnosis. MRI and chest imaging are part of the staging workup, albeit they are not necessary for benign phyllodes or desmoid tumors.³⁰ For the treatment of breast phyllodes tumors, the National Comprehensive Cancer Network (NCCN) guidelines advise broad excision without axillary staging.²⁹

Breast sarcomas are staged using the American Joint Committee on Cancer/Union for International Cancer Control system, which considers the primary tumor characteristics, involvement of local lymph nodes, the presence or absence of distant metastases, and histologic grade. Only tumor size determines the stage of a primary tumor. Regional lymph node metastases are a sign of stage IV cancer because, unlike carcinomas, sarcomas infrequently disseminate to these nodes. The degree of differentiation, rate of mitosis, and level of necrosis are used to determine the histologic grade. Similar to metastatic soft tissue sarcomas originating from other anatomic locations, metastatic breast sarcomas and malignant phyllodes tumors are treated with first-line doxorubicin-based chemotherapy.³⁰

Primary tumor (T) - Tx = unable to assess, T0 = indicates absence of primary tumor, T1 = tumor ≤5 cm in greatest dimension, T2 = tumor >5 cm and ≤10 cm in greatest dimension, T3 = tumor >10 cm and ≤15 cm in greatest dimension, and T4 = tumor >15 cm in greatest dimension.

Regional lymph nodes (N)- N0 = unknown lymph node status or no local lymph node metastases and N1 = metastasis to local lymph nodes.

Distant metastasis (M)- M0 = absence of distant metastases and M1 = distant metastasis.

Grade (G)- GX = unable to be evaluated, G1 = total grade score of 2-3, G2 = total grade score of 4-5, and G3 = total grade score of 6-8.

Grade Scoring- 1: sarcomas that closely resemble normal adult mesenchymal tissue, 2: sarcomas with certain histologic typing, and 3: embryonal and undifferentiated sarcomas, sarcomas of doubtful type, synovial sarcomas, soft tissue osteosarcoma, and Ewing sarcoma/primitive neuroectodermal tumors of soft tissue.

Mitotic count- 1: 0-9 mitoses per 10 HPF, 2: 10-19 mitoses per 10 HPF, 3: ≥ 20 mitoses per 10 HPF

Necrosis- 0: No necrosis, 1: < 50% tumor necrosis, 2: ≥ 50% tumor necrosis

Staging- IA = T1, N0, M0, GX or G1, IB = T2-4, N0, M0, GX or G1, II = T1, N0, M0, G2-3, IIIA = T2, N0, M0, G2-3, IIIB = T3-4, N0, M0, G2-3, and IV = any T, N1 or M1.^30,31

Surgical management

Currently, there is minimally published evidence on overall survival, disease-free survival, or optimal surgical approach to metastatic malignant disease. One study in 2020 of 51 patients with MPT states that in metastatic malignant disease, metastasis surgery was associated with a higher overall survival of 25.9 vs 9.9 months (HR .33; 95% CI 0.14-0.78; median; P = .01).³² Previously, it was believed that only isolated lung metastasis should be considered for metastasectomy. This study does not specify the approach to metastasectomy and margin size. However, treating metastatic lesions may offer some promise.

Previously, mastectomy was the standard surgical approach to all phyllodes tumors.³³ However, wide-local excision with greater than 1 cm surgical margins is the preferred primary treatment for malignant and borderline phyllodes tumors.³⁴ Macdonald et al³⁵ analyzed the SEER database to assess factors that predict cause-specific survival (CSS) in 821 patients with malignant phyllodes tumors. This study determined that the employment of wide excision was associated with better CSS compared to wide excision with radiation therapy and mastectomy with or without radiotherapy (P = .0001). The analysis concluded that mastectomy did not provide a benefit in CSS relative to wide local excision in the case of malignant phyllodes tumor management.

Local recurrence risk significantly increases from benign to borderline to malignant phyllodes tumors.³⁶ In a retrospective study by Ditsatham and Chongruksut,⁶ 188 cases of phyllodes tumors were investigated based on tumor characteristics, with surgical management as the mainstay for treatment, and assessed the risk of recurrence in the patients who underwent surgical excision was to obtain a negative margin of at least 1 cm. A surgical margin less than 1 cm did not affect recurrence in benign and borderline phyllodes tumors (P = .334 and .668, respectively). However, the risk of recurrence of malignant phyllodes tumors was significant in cases of inadequate margin excision (P = .022). Breast-conserving surgery vs mastectomy (OR 2.32, 95% CI: 1.01-5.30; P = .05) and positive vs negative margins (OR 6.85, 95% CI: 1.58-29.64; P = .05) correlated with significantly higher local recurrence risk in malignant phyllodes tumors.³⁶

For non-metastatic, malignant disease, the current standard of care is wide local excision with negative margins ≥1 cm without lymph node excision.^36–38 A review by Papas et al³⁹ recommends that the surgical approach to treat malignant phyllodes tumors should be breast-conserving surgery with clear microscopic margins of at least 1 cm. Malignant phyllodes tumors are associated with a high local recurrence rate (55.6%) and require re-excision in the case of inadequate margins. According to NCCN guidelines, the appropriate management for recurrence without metastatic disease is re-excision with wide margins considering postoperative radiation therapy. To assess for the presence of metastatic disease, chest imaging should be performed in case of any recurrence. A total mastectomy is an option for recurrent disease; however, it is often reserved for large tumors where wide local excision would not allow for successful oncologic and cosmetic results.

A recent analysis by Yu et al⁴⁰ compared the recurrence outcome of malignant phyllodes tumors in patients who received postoperative adjuvant radiotherapy and those who underwent surgery alone. In this meta-analysis, findings revealed a significantly reduced recurrence rate of malignant phyllodes tumors with adjuvant radiation therapy (OR: 0.048, 95% CI: 0.006-0.089) compared with no radiation therapy (OR: 0.209, 95% CI: 0.136-0.282) (P = .017).

Radiotherapy

Radiotherapy is often considered for palliation and pain control in metastatic malignant neoplasia.³² As the risk of recurrence after wide local excision has been found to range from 10% to 40%, several studies have investigated the role of adjuvant radiotherapy to control the rate of local recurrence postoperatively, with inconsistent results.^41–43 In one case study, the researchers report that using adriamycin/ifosfamide (AI), resection, and whole brain radiotherapy (3750 cGy) resulted in the patient being tumor free for 116 months.⁴⁴

A 2021 study by Zhao et al⁴⁵ of the surveillance, epidemiology, and results (SEER) database found that of 1353 with malignant phyllodes tumors, 16.7% received adjuvant radiotherapy. Patient clinicopathological characteristics were balanced using propensity-score matching (PSM), and the post-PSM survival analysis showed no improvement in both disease-specific survival (DSS) and overall survival (OS) with the use of radiotherapy. The study did offer some survival benefits in patients with tumors >50 mm and who underwent breast conservation surgery (BCS). A similar study in 2017 by Kim Y et al of the SEER database (1983-2013) investigated the effects of postoperative RT on cancer-specific survival in 1974 patients with malignant phyllodes tumors of the breast and found that irrespective of surgery (mastectomy vs BCS), postoperative RT was not correlated with cancer-specific survival CSS (P = .997).⁴⁶

A review by Zeng et al⁴⁷ assessing the efficacy of RT on borderline and malignant phyllodes tumors found a decrease in local recurrence for patients with borderline and malignant phyllodes who received RT post-BCS (HR = 0.31, 95% CI: −0.10-0.72). However, there was no difference in LR for patients who underwent total mastectomy (TM) with and without adjuvant RT (HR = 0.68, 95% CI: −0.28-1.64). These results contrast with a previous study by Belkacéim et al which suggested better response in patients that had undergone total mastectomy than BCS (P = .0019).⁴³ Kim S et al indicated that the local recurrence rate was independent of radiation therapy, particularly benign PT.⁴⁸

Despite the inconsistency in the efficacy of adjuvant radiotherapy against local recurrence of phyllodes tumors, there is evidence of increased utilization. Gnerlich et al⁴⁹ identified 3120 patients with malignant phyllodes tumors from the National Cancer Database between 1998 and 2009, of which 14.3% underwent treatment with adjuvant radiotherapy. Over the course of the study, radiotherapy utilization increased (9.5% in 1998-1999 vs 19.5% in 2008-2009). Factors such as age between 50 and 59 years old, tumor >10 cm, and lymph node removal increased the likelihood of radiotherapy. The study demonstrated a significant reduction in local recurrence (adjusted HR 0.43, 95% CI 0.19-0.95) but no impact on disease-free survival (DFS) or overall survival (OS). Ultimately, there is no firm consensus on the use of radiation for malignant phyllodes tumors, and the benefits of radiotherapy for this condition remain unclear.

Chemotherapy

In metastatic malignant phyllodes tumors, most literature focuses on systemic chemotherapy. In 2020, one of the most extensive studies on metastatic malignant phyllodes tumors of the breast discerned that alkylating agents such as anthracyclines offered the best clinical benefit of chemotherapy (CBCT) rate than other agents (P = .049). Neron et al³² define CBCT as 6 months of stability or complete or partial response. In their study of 51 patients, the researchers noticed that alkylating agents did not significantly improve overall survival. In 2021, another large study of 50 patients was conducted, showing adriamycin/ifosfamide (AI) containing systemic therapy to have better overall survival rates than non-ifosfamide managing groups, with significantly improved progression-free survival (9.10 months; 95% CI: 5.03, 14.2 vs 3.65 months 95% CI: 1.17, 7.90) overall survival (22.4 months; 95% CI: 10.3, 33.0 vs 13.2 months; 95% CI: 2.0, 16.5; P = .040), and response rate (2 of 18 patients achieved complete remission (11%); 8 of 18 with partial remission (42%) -- 56% objective response rate).⁵⁰ A retrospective analysis of 295 patients with phyllodes tumors of the breast found that in 37 patients with distant metastases, a combination of adriamycin/ifosfamide had better mean survival than other systemic therapies.⁵¹

Some small studies report the potential benefits of liposomal doxorubicin. One case study demonstrated combining neoadjuvant liposomal doxorubicin and bevacizumab allowed adequate tumor shrinkage for resection and metastasectomy.⁵² A second case report demonstrated that liposomal doxorubicin in conjunction with albumin-bound paclitaxel, cisplatin, and accelerated radiotherapy led to the patient being disease-free after two years of follow-up.⁵³

Immunotherapy

There is limited evidence on the benefit of immunotherapies for treating malignant phyllodes tumors of the breast. One case study of a 26-year-old woman with multiple metastases to the lungs and a pelvic bone mass had sustained remission past 8 months following 500 mg/day of apatinib (rivoceranib and tyrosine kinase inhibitor).⁵⁴ There needs to be more data regarding the use of immunotherapy in this condition.

Conclusion

Malignant phyllodes tumors are challenging to manage due to a high recurrence rate. When distant metastasis occurs, the prognosis is grim. MRI techniques may assist with diagnosis and grading when advanced imaging is performed. There remains to be a firm consensus regarding management once metastasis occurs. Metastasectomy has, in some cases, been correlated with increased overall survival. In some cases, anthracycline-based chemotherapy regimens have been associated with improved progression-free survival, response rates, and overall survival. Radiotherapy remains a mainstay for non-metastatic malignant PT; however, its role remains limited and uncertain in metastatic disease. Further work must elucidate how to accurately diagnose and care for patients with advanced metastatic or malignant phyllodes tumors.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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