MED12 exon 2 and TERT promoter mutations in primary and recurrent breast fibroepithelial lesions.

The genetic alterations in the recurrent breast fibroepithelial tumors are poorly understood. In the present study, we aimed to investigate mediator protein complex subunit 12 (MED12) exon 2 and telomerase reverse transcriptase (TERT) promoter mutations in a series of primary and recurrent fibroepithelial tumors. Sanger sequencing for MED12 exon 2 and TERT promoter was performed in 26 pairs of primary and recurrent fibroepithelial tumors (19 pairs of phyllodes tumors and seven pairs of fibroadenomas). The relationship between the genotypes and clinicopathological variables was also analyzed. MED12 mutation was identified in 19 primary tumors (12 phyllodes tumors and 7 fibroadenomas) and 17 recurrences (14 phyllodes tumors and three fibroadenomas). Most recurrent phyllodes tumors retained the original MED12 variants (17/19). Six recurrent fibroadenomas showed different MED12 variants from their paired primary tumors (6/7). TERT promoter mutation was identified in 13 primary phyllodes tumors (13/19) and 15 recurrent phyllodes tumors (15/19). However, it was only identified in one primary fibroadenoma (1/7). Recurrent phyllodes tumors often retained the original MED12 and TERT promoter mutations, while recurrent fibroadenomas often acquired new MED12 mutations. Our findings suggest that recurrent phyllodes tumors may be "true recurrence," and TERT mutant "benign fibroepithelial tumors" should be treated as phyllodes tumors.

MED12, TERT and RARA in fibroepithelial tumours of the breast.

Fibroepithelial tumours are biphasic neoplasms of the breast comprising the common benign fibroadenomas and the less common phyllodes tumours (PTs), which have recurrent potential. PTs are classified into benign, borderline or malignant, based on five histopathological criteria, with malignant PTs having the highest metastatic capability. Accurate diagnosis can be challenging due to the subjective assessment of histopathological parameters. Fibroadenomas bear morphological similarities to benign PTs, while borderline and malignant PTs can sometimes be difficult to distinguish from other spindle cell tumours of the breast. From clonality studies to whole-genome sequencing, much research has been conducted to elucidate the molecular pathogenesis of fibroepithelial tumours, which, in turn, have allowed leveraging the findings for diagnostic applications, including grading of PTs. The most noteworthy discovery was of recurrent MED12 mutations in both fibroadenomas and PTs. Subsequent studies also uncovered relatively frequent genetic mutations in TERT promoter and RARA A customised panel of 16 most frequently mutated genes in fibroepithelial tissues has been compiled previously and has contributed to resolving a few diagnostic dilemmas. This review will introduce the 16 genes and focus on the top three that are most frequently mutated in fibroepithelial tumours: MED12, TERT, and RARA.

Morphologic, Immunohistochemical, and Molecular Distinction Between Fibroepithelioma of Pinkus and "Fenestrated" Basal Cell Carcinoma.

Fibroepithelioma of Pinkus (FEP) is a rare cutaneous neoplasm with a characteristic fenestrated architecture and a prominent spindle cell stromal component and which invariably pursues an indolent course. The classification of FEP has been much debated since its first description in 1953, with some arguing that it represents a variant of a basal cell carcinoma (BCC) while others view it as a variant of a trichoblastoma. Multiple previous immunohistochemical studies aiming to clarify this issue have yielded conflicting results. To date, there have been no molecular studies of FEP. We identified 16 cases of fenestrated follicular neoplasms and classified them as BCC or FEP based solely on histomorphologic criteria. CK20 immunohistochemistry supported this classification scheme, with FEP showing significantly more CK20-positive Merkel cells than BCC. We then analyzed a subset of these tumors by a targeted next-generation DNA sequencing platform. All the BCC cases harbored pathogenic PTCH1 mutations, confirming the diagnosis. By contrast, none of the FEP cases harbored a PTCH1 mutation or indeed any mutation known to be causally linked to the development of BCC. Our results suggest that FEP can be distinguished from BCC on morphologic, immunohistochemical, and molecular genetic grounds. We argue that FEP is better considered a benign follicular neoplasm and support its classification as a variant of trichoblastoma.

Molecular insights into paediatric breast fibroepithelial tumours.

AIMS: This study aims to examine the molecular genetics of paediatric breast fibroepithelial tumours through the targeted sequencing of 50 genes. METHODS AND RESULTS: Formalin-fixed paraffin-embedded tissues of fibroepithelial tumours diagnosed in a cohort of patients aged 18 years and below were subjected to next generation sequencing using the Haloplex Target Enrichment System. Twenty-five conventional and 17 juvenile fibroadenomas were studied, with MED12 mutations found in 53.8 and 35% of the tumours, respectively. There was also one benign fibroepithelial neoplasm with hybrid features of juvenile papillomatosis and infarcted benign phyllodes tumour-like areas. Most tumours did not have mutations in well-known cancer driver genes, none harboured TERT promoter mutations, while 25.6% (11 of 43) showed no mutations. Metachronous and synchronous tumours were found to have mutational heterogeneity with some containing mutations in MED12; other genes or no mutations were detected at all. Four of eight giant fibroadenomas (size 5 cm or larger) had no mutations detected, suggesting that there are other molecular mechanisms driving their growth. Tumours with MED12 mutations incidentally had a significantly higher stromal mitotic count compared with those without. CONCLUSION: While paediatric fibroepithelial lesions can have cellular stroma potentially raising concern for phyllodes tumour, their lack of TERT promoter and cancer driver mutations is reassuring. The absence of mutations in a significant proportion of tumours, especially the giant fibroadenomas, warrants investigation of pathogenetic mechanisms beyond those involving the 50 genes.

Fibroepithelial lesions; The WHO spectrum.

Fibroepithelial lesions of the breast comprise a morphologically and biologically heterogeneous group of biphasic tumors with epithelial and stromal components that demonstrate widely variable clinical behavior. Fibroadenomas are common benign tumors with a number of histologic variants, most of which pose no diagnostic challenge. Cellular and juvenile fibroadenomas can have overlapping features with phyllodes tumors and should be recognized. Phyllodes tumors constitute a spectrum of lesions with varying clinical behavior and are graded as benign, borderline or malignant based on a set of histologic features according to recommendations by the World Health Organization (WHO). Recent developments have significantly expanded our understanding of the pathogenesis of fibroepithelial lesions, highlighting fibroadenomas as true neoplasms and underscoring a commonality with phyllodes tumors in the form of recurrent MED12 exon 2 mutations. In addition, sequencing studies have elucidated pathways associated with phyllodes tumor progression. Accurate diagnosis and grading of phyllodes tumors are important for patient management and prognosis, as grade broadly correlates with increasing local recurrence risk, and essentially only malignant tumors metastasize. However, classification of fibroepithelial lesions in many cases remains challenging on both core biopsy and excision specimens. A commonly encountered problem at the benign end of the spectrum is the distinction of benign phyllodes tumor from cellular fibroadenoma, which is largely due to the subjective nature of histologic features used in diagnosis and histologic overlap between lesions. Grading is further complicated by the requirement to integrate multiple subjective and ill-defined parameters. On the opposite end of the histologic spectrum, malignant phyllodes tumors must be distinguished from more common metaplastic carcinomas and from primary or metastatic sarcomas, which can be especially difficult in core biopsies. Immunohistochemistry can be useful in the differential diagnosis but should be interpreted with attention to caveats. This review provides an overview and update on the spectrum of fibroepithelial lesions, with special emphasis on common problems and practical issues in diagnosis.

Lipomatous tumors of the breast: A contemporary review.

Breast tumors with lipomatous or liposarcomatous components are infrequently encountered, but can be a source of diagnostic difficulty if the context of the fatty differentiation is not recognized. Among the true adipocytic tumors, lipoma is the most common lipomatous tumor arising in the breast. Several mammary spindle cell tumors may show adipocytic differentiation, including fibroepithelial tumors and myofibroblastoma. Liposarcomatous components most often arise in malignant phyllodes tumors, as opposed to primary liposarcomas of the breast which are believed to be uncommon. This article will review the spectrum fat-containing tumors of the breast with an emphasis on differential diagnosis and insights from recent molecular studies.

The stem cell renewal and DNA damage response pathways are frequently altered in fibroepithelial tumors of breast in Indian patients.

Genetic and epigenetic alterations in genes associated with distinct cellular pathways were checked in fibroepithelial tumors, including fibroadenomas, benign and malignant phyllode and atypical ductal hyperplasia. A panel of 22 genes associated with different cellular pathways such as stem cell renewal (Wnt and Hedgehog), DNA damage response [homologous recombination (HR), mismatch repair (MMR) and nucleotide excision repair (NER)] and cell proliferation signaling pathway were tested. Alterations (genetic/epigenetic) of the genes associated with Wnt signaling pathway were detected in 100% (20/20) of the breast tumors for at least one out of the six Wnt antagonists tested. Frequent molecular alterations (57-64%) were detected in HR and MMR pathway and low frequency of alterations (8-25%) were seen in cell-proliferation and cell signaling pathways showing a differential pattern of alterations in different tumor types. The patterns of alterations, in particular the epigenetic alterations, differed little from that seen previously in breast carcinoma cells, suggesting epigenetic alterations to be an early event in the development of the tumors. In gene ontology analysis, it was evident that Wnt signaling pathway [GO: 0030111, Kegg: 04310], cell proliferation pathway [GO: 0008285] and pathways in cancer [Kegg: 05200] were significantly enriched by differentially altered genes in fibroadenoma and phyllode tumor types. All these results may provide a new breakthrough in early diagnosis, prognosis and treatment of these tumors.

Immunosuppression-related fibroproliferative polyps: a substantial subset of acquired pediatric mucocutaneous polyps.

A distinct group of fibroproliferative polyps of the tongue arising in immunosuppressed children and often associated with chromosomal breakpoints at chromosomes 9p34 or 22q11 was recently described. Based on this finding, we reviewed fibroepithelial polyps arising in nonlingual sites in the pediatric population to investigate a possible relationship with immunosuppression. We identified 8 fibroepithelial polyps arising in 6 immunosuppressed patients (4 males and 2 females, median age 17 years) in a wide range of mucocutaneous sites. Histologic features were identical to the common fibroepithelial polyp, or skin tag, with a variably collagenous fibrovascular core covered by unremarkable squamous epithelium. No viral cytopathic changes were identified in any case. Although cytogenetic studies were not performed on any of the biopsy material, 1 patient had a constitutional deletion of chromosome 22q11. We suggest that there may be a relationship between these polyps and the previously described tongue lesions and that immunosuppression may be an important factor in their pathogenesis.

Expression of androgen receptor by fibroepithelioma of Pinkus: evidence supporting classification as a basal cell carcinoma variant?

The classification of fibroepithelioma of Pinkus as basal cell carcinoma or trichoblastoma remains controversial. Immunohistochemical stains for androgen receptor may be useful in differentiating basal cell carcinoma from trichoepithelioma or trichoblastoma. We studied androgen receptor expression in 13 fibroepitheliomas of Pinkus, 11 basal cell carcinomas, 12 trichoepitheliomas, and 3 trichoblastomas. Androgen receptor expression was present in 77% (10/13) of fibroepitheliomas of Pinkus, 73% (8/11) of basal cell carcinomas, 17% (2/12) of trichoepitheliomas, and 0% (0/3) of trichoblastomas. Androgen receptor expression was significantly higher in fibroepitheliomas of Pinkus compared with trichoepitheliomas and trichoblastomas (P = .0007), but not basal cell carcinoma (P = 1.00). Tumor-associated Merkel cells, a feature of benign follicular tumors, was identified by cytokeratin 20 stains. Merkel cells were identified in 85% (11/13) of fibroepitheliomas of Pinkus, 27% (3/11) of basal cell carcinoma cases, and 73% (11/15) of benign follicular tumors. Cytokeratin 20 expression was significantly higher in fibroepithelioma of Pinkus and benign follicular tumors compared with basal cell carcinomas (P = 0.0111 and P = 0.025, respectively). No significant difference was found between fibroepitheliomas of Pinkus and trichoepitheliomas and trichoblastomas (P = 1.00). Similar to basal cell carcinomas, fibroepitheliomas of Pinkus express androgen receptors, potentially supporting classification as a basal cell carcinoma. Conversely, fibroepithelioma of Pinkus demonstrates retention of Merkel cells, a feature of benign follicular tumors. Immunophenotypic evidence for the classification of fibroepithelioma of Pinkus remains inconclusive. In small, partial biopsy specimens, coexpression of androgen receptor and cytokeratin 20 may aid in the diagnosis of fibroepithelioma of Pinkus.