Benign Giant Phyllodes Tumours Presenting as Fungating Breast Masses.

Breast masses presenting as fungating growths usually represent advanced malignancy. One remarkable exception is a benign phyllodes tumour. These tumours of stromal origin often exhibit rapid growth, resulting in pressure necrosis at the summit of the tumor causing fungation. It is difficult to differentiate between benign and malignant types clinically. Here, we describe two cases in which patients presented with fungating growth similar to a case of carcinoma breast, which turned out to be cases of benign phyllodes tumours. We would like to highlight the clinical features that differentiate between benign and malignant fungating growth and provide a brief update on the latest treatment modalities for phyllodes tumours.

Refining the classification of breast phyllodes tumours.

Phyllodes tumours of the breast are uncommon fibroepithelial neoplasms that pose recurrent classification challenges, in large part due to the multiple histological parameters of stromal hypercellularity and atypia, stromal mitotic count, stromal overgrowth and tumour borders, that are used for grading. While the World Health Organization (WHO) Classification of Breast Tumours provides recommendations on diagnostic features, defining criteria are not always applied in routine practice. Lack of concordance among pathologists in typing and grading further underscores the classification difficulties, especially in the borderline category. Although there has been significant molecular information on phyllodes tumours in recent years which has been diagnostically helpful, it has not been translated into daily clinical practice. In order to refine the classification of phyllodes tumours into one that is simple yet comprehensive, reproducible and prognostically precise, a multipronged approach is needed that leverages on global contributions of the International Fibroepithelial Consortium, support by the International Collaboration on Cancer Classification and Research (IC3 R) in amalgamating evidence translation, and guidance from the International Collaboration on Cancer Reporting (ICCR) for standardised reporting. It is hoped that the evidence generated can be used towards refining the classification of phyllodes tumours for the future.

Prognostic factors in phyllodes tumours of the breast: retrospective study on 166 consecutive cases.

BACKGROUND: Phyllodes tumours (PTs) are rare fibroepithelial tumours accounting for <1% of all breast tumours. We assessed clinicopathological features and their prognostic effect in a single-institution patients' cohort. METHODS: Patients diagnosed with PT between 2001 and 2018 at our institution were identified. Clinical, surgical and pathological features were collected. Phyllodes-related relapse was defined as locoregional or distant recurrence (contralateral excluded), whichever first. RESULTS: A total of 166 patients were included: 115 with benign, 30 with borderline and 21 with malignant PTs. Features associated with malignant PT were younger age, larger T size, higher mitotic count, marked cytological atypia, stromal overgrowth, stromal hypercellularity, necrosis and heterologous differentiation (all p<0.01). The majority of patients with malignant PT underwent mastectomy (63.2% vs 3% of benign/borderline, p<0.001) and had negative surgical margins (83.3%). 4-year cumulative phyllodes-related relapse incidence was 7% for benign/borderline PT and 21.3% for malignant PT (p=0.107). In the entire cohort, marked cellular atypia and heterologous differentiation were associated with worse phyllodes-related relapse-free survival (HR 14.10, p=0.036 for marked vs mild atypia; HR 4.21, p=0.031 for heterologous differentiation present vs absent). For patients with benign PT, larger tumour size was associated with worse phyllodes-related relapse-free survival (HR 9.67, p=0.013 for T>5 cm vs T≤2 cm). Higher tumour-infiltrating lymphocytes (TILs) were associated with borderline and malignant PT (p=0.023); TILs were not associated with phyllodes-related relapse-free survival (HR 0.58, p=0.361 for TILs>2% vs≤2%). Overall, four patients died because of PT: three patients with malignant and one with borderline PT. CONCLUSIONS: Patients with malignant PT had increased rates of phyllodes-related relapse and phyllodes-related death. Cellular atypia and heterologous differentiation were poor prognostic factors in the entire cohort; large tumour size was associated with an increased risk of phyllodes-related relapse in benign PT.

Olaratumab administered in two cases of phyllodes tumour of the breast: end of the beginning?

Phyllodes tumours of the breast are rare mesenchymal tumours with differential malignant potential. Treatment of choice is radical excision with negative margins. Radiation therapy has shown controversial results in small series. Chemotherapy in the adjuvant setting still remains a matter of debate. Doxorubicin-based chemotherapy is recommended for breast sarcomas' first-line treatment. Herein we present two cases of breast phyllodes tumour treated with the recent combination of doxorubicin and olaratumab.

Diagnosing phyllodes tumours of the breast: how successful are our current preoperative assessment modalities?

BACKGROUND: To assess the efficacy of the diagnostic modalities used in the preoperative assessment of phyllodes tumours. METHODS: In this retrospective study of patients treated at Princess Alexandra Hospital, 51 phyllodes tumours in 49 patients diagnosed between 2005 and 2016 were reviewed with regard to their preoperative findings to assess which modalities, including clinical findings, mammography, ultrasound, fine needle aspiration and core biopsy, were most diagnostically discriminating. Data on demographics and management were also collected. RESULTS: While 90.2% of lesions were clinically palpable and an abnormality was seen in 86.1% of lesions subjected to mammography, the findings in relation to these two modalities were essentially those of non-discriminatory masses. Furthermore, although 100% of the phyllodes lesions were sonographically visible, suspicion of a phyllodes tumour was only noted in 21.6% of cases. Fine needle aspiration yielded results suspicious for phyllodes in 21.1% of cases while core biopsy resulted in confirmed or suspected phyllodes tumour diagnoses in 69.2% of instances. Serial measurements of phyllodes tumours yielded an average growth rate of 8.04 mm per 365 days. CONCLUSION: In the preoperative diagnosis of phyllodes tumours of the breast, ultrasound was a more discriminating imaging modality compared to mammography, and core biopsy demonstrated a superior accuracy of diagnosis over fine needle biopsy. A significant increase in lesion size over a short timeframe should also alert to the possibility of a phyllodes tumour.

Benign phyllodes tumours of the breast: (Over) treatment of margins - A literature review.

BACKGROUND: Phyllodes tumours form a small group of fibroepithelial breast lesions (2-3%). They are classified as benign, borderline, or malignant. (1). Benign phyllodes tumours are the largest subgroup of phyllodes tumours (50-80%), (2) A margin of 1 cm has been suggested as standard of care for all groups of phyllodes tumours.3-6 METHODS: We performed a literature review from January 2009 to April 2016 including the non-English literature. We compared studies taking a 1 mm margin, 10 mm margin and studies with focal margin involvement. RESULTS: We included 12 studies with overall 1702 patients. The range of therapeutic margins differed widely between studies. There is no consensus between studies what constitutes a clear or involved margin. There was a high percentage of margin involvement for benign phyllodes tumours (7.6-43.7%). Despite these inconsistencies, the recurrence rate after excision of benign phyllodes tumours was low in most studies (112 recurrences of 1052 benign phyllodes tumours - 11%; range 0-43%). There is no difference of the recurrence rate between studies aiming for a 10 mm margin (7.9%) compared to a 1 mm margin (5.7%) (p 0.124). The recurrence rate increases when there are tumour cells at the margin (12.9%) (p 0.006). CONCLUSION: There is no difference in recurrence rates between a 1 and a 10 mm margin. 1 mm is an acceptable margin for benign phyllodes tumours. The recurrence rate increases if there is focal margin involvement.

Distant metastases in phyllodes tumours of the breast: an overview

Phyllodes tumours (PTs) of the breast are uncommon fibroepithelial neoplasms, comprising 0.3 ­ 1.0% of all primary breast malignancies in Western countries, but accounting for a higher proportion of primary breast tumours in Asian countries. They are graded as benign, borderline or malignant based on the World Health Organisation (WHO) classification, according to a constellation of 5 histologic parameters. While most PTs carry a good prognosis, malignant and occasionally borderline PTs have the potential to metastasize to distant sites. Although events of distant metastasis are few, the prognosis for such patients is dismal, as they are often unresponsive to chemotherapy with high mortality. This review seeks to provide an overview of this rare but important phenomenon of distant metastases in PTs of the breast (AU)

MED12 exon 2 mutation as a highly sensitive and specific marker in distinguishing phyllodes tumours from other spindle neoplasms of the breast.

Spindle neoplasms of the breast (SNB) primarily include metaplastic breast carcinoma (MBC), phyllodes tumour (PT), fibromatosis and primary nonspecific sarcoma (PNS). Mutations in MED12 exon 2 have been reported in PTs. Because spindle tumour components are shared by SNB, we assessed the diagnostic use of MED12 exon 2 mutation in SNB. We investigated MED12 exon 2 mutations in a total of 91 samples of SNB, including 49 PT cases that have been previously analysed. Mutations were identified using direct sequencing. MED12 exon 2 mutation was absent in all cases of MBC, fibromatosis and PNS, in contrast to the 71.4% positivity in PTs. MED12 mutations were identified in four of six previously diagnosed monophasic sarcomatous MCB cases, however, these four cases were revised as malignant PT based on additional bcl-2 staining, albeit very focal. Consistence in the MED12 mutational status between a paired core biopsy and a surgical specimen was observed in all 20 tested PT cases. In conclusion, we demonstrated the restriction of MED12 exon 2 mutation to PTs (73.6%, 39/53) and its absence in other SNB. MED12 exon 2 mutational analysis can be included in the differential diagnosis between PT and other SNB, especially with limited specimen where diagnostic clues are not evident.

Mutational analysis of MED12 exon 2 in a spectrum of fibroepithelial tumours of the breast: implications for pathogenesis and histogenesis.

AIMS: Fibroadenomas (FAs) and phyllodes tumours (PTs) are fibroepithelial tumours. Mutations in MED12 exon 2 have been reported in FAs. This study investigated the MED12 mutations in a spectrum of fibroepithelial tumours. METHODS AND RESULTS: Using direct sequencing, we analysed MED12 exon 2 mutations on 121 samples, including PTs and FAs and variants. We found MED12 mutations in 71.4% of PTs. No significant difference in the mutation frequency was observed between benign, borderline and malignant PTs, and a general lack of correlation existed between mutations and pathological factors associated with PT grading. The mutation patterns were similar between PTs and FAs, with codon 44 being involved most frequently. MED12 mutations were identified in 47.1, 52.6 and 50.0% of complex FAs, juvenile FAs and tubular adenomas (TAs), respectively, and the frequency and mutation patterns were similar between these FA variants and usual FAs. CONCLUSIONS: The high frequency and similar patterns of MED12 mutations in FAs and various grades of PTs implies that the MED12 mutation is a common and early pathological event in these fibroepithelial tumours. The similar frequency and patterns of the MED12 mutation between FAs and variants suggests that FA variants are bona fide FAs, with identical pathogenesis involving MED12 mutations.

Gene expression-based classifications of fibroadenomas and phyllodes tumours of the breast.

Fibroepithelial tumors (FTs) of the breast are a heterogeneous group of lesions ranging from fibroadenomas (FAD) to phyllodes tumors (PT) (benign, borderline, malignant). Further understanding of their molecular features and classification might be of clinical value. In this study, we analysed the expression of 105 breast cancer-related genes, including the 50 genes of the PAM50 intrinsic subtype predictor and 12 genes of the Claudin-low subtype predictor, in a panel of 75 FTs (34 FADs, 5 juvenile FADs, 20 benign PTs, 5 borderline PTs and 11 malignant PTs) with clinical follow-up. In addition, we compared the expression profiles of FTs with those of 14 normal breast tissues and 49 primary invasive ductal carcinomas (IDCs). Our results revealed that the levels of expression of all breast cancer-related genes can discriminate the various groups of FTs, together with normal breast tissues and IDCs (False Discovery Rate < 5%). Among FTs, the levels expression of proliferation-related genes (e.g. CCNB1 and MKI67) and mesenchymal/epithelial-related (e.g. CLDN3 and EPCAM) genes were found to be most discriminative. As expected, FADs showed the highest and lowest expression of epithelial- and proliferation-related genes, respectively, whereas malignant PTs showed the opposite expression pattern. Interestingly, the overall profile of benign PTs was found more similar to FADs and normal breast tissues than the rest of tumours, including juvenile FADs. Within the dataset of IDCs and normal breast tissues, the vast majority of FADs, juvenile FADs, benign PTs and borderline PTs were identified as Normal-like by intrinsic breast cancer subtyping, whereas 7 (63.6%) and 3 (27.3%) malignant PTs were identified as Claudin-low and Basal-like, respectively. Finally, we observed that the previously described PAM50 risk of relapse prognostic score better predicted outcome in FTs than the morphological classification, even within PTs-only. Our results suggest that classification of FTs using gene expression-based data is feasible and might provide clinically useful biological and prognostic information.

Phyllodes tumours of the breast diagnosed as B3 category on image-guided 14-gauge core biopsy: analysis of 51 cases from a single institution and review of the literature.

AIMS: Image-guided 14-gauge (G) core biopsy (CB) has been shown to be an accurate method providing histological diagnosis of breast lesions. The purpose of this study was to evaluate the reliability of image-guided 14-G CB in the diagnosis of phyllodes tumours (PT) reported as B3 category and its accuracy in distinguishing this lesion from fibroadenomas (FA). MATERIALS AND METHODS: The records of 10 000 image-guided 14-G CB of the breast performed from January 2001 to August 2011 at the Diagnostic Senology Unit of Careggi University Hospital were reviewed; 2554 (25.5%) were fibroepithelial lesions: 56 of them (2%) were diagnosed as PT and reported as B3 category. The database of the Pathological Anatomy Unit of Careggi University Hospital was then searched to verify the histological diagnosis after surgical excision. Fifty-one cases of PT diagnosed as B3 category in 51 women were included in the present study. RESULTS: Of the 51 cases of PT diagnosed as B3 category on 14-G CB, 39 (76.5%) lesions were confirmed as PT on SE (30, 4 and 5 as benign, borderline and malignant PT respectively) with a PPV of 76.5%. Twelve lesions (23.5%) were diagnosed as FA after surgical excision. CONCLUSIONS: Our study shows that 14-G CB is a valuable tool, in a preoperative setting, in diagnosing PT.

Immunohistochemical expression of homeoproteins Six1 and Pax3 in breast phyllodes tumours correlates with histological grade and clinical outcome.

AIMS: Homeoproteins are transcription factors which critically regulate developmental processes. Deregulated expression of homeoproteins is observed in several malignancies, such as breast cancer and rhabdomyosarcoma, and contributes to malignant progression. We aimed to investigate the expression and prognostic importance of Six1 and Pax3 homeoproteins in phyllodes tumours - a group of uncommon biphasic tumours comprising both epithelial and stromal components. METHODS AND RESULTS: A total of 272 cases diagnosed from January 2003 to December 2010 were included in this study - 189 (69.5%) benign, 60 (22.1%) borderline and 23 (8.4%) malignant tumours. Immunohistochemistry was performed on tissue microarray sections using antibodies against Six1 and Pax3. Staining H-score was assessed in epithelium and stroma separately, and correlated with tumour grade, clinicopathological parameters and prognosis. Tumour grade was associated positively with stromal cytoplasmic expression (P < 0.001; P = 0.011) but correlated negatively with epithelial nuclear expression (P = 0.013; P = 0.007) of both Six1 and Pax3. High stromal cytoplasmic expression of Six1 was associated with metastasis (P = 0.044) and shorter time to recurrence (P = 0.056). Pax3 stromal cytoplasmic expression was associated with poorer overall survival (P = 0.033). CONCLUSIONS: Six1 and Pax3 expression is correlated with tumour grade, unfavourable clinicopathological parameters and poorer clinical outcome, suggesting that both proteins may play a role in malignant progression.