The elusive BAP1 mutation in pediatric melanocytic tumors.

Cutaneous BAP1-inactivated melanocytomas (BIM) are melanocytic proliferations defined histopathologically by an epithelioid, predominantly dermal melanocytic proliferation with loss of BAP1, and have been largely characterized in adult patients but less well-described in pediatric cohorts. BIM share overlapping histological features with those seen in Spitz nevi; however, unlike Spitz nevi, the majority of BIM carry both BAP1 and BRAFV600E mutations. This study investigated the potential overlap of BIMs with pediatric Spitz nevi by performing immunohistochemical staining of BAP1 and BRAFV600E on pediatric melanocytic tumors with banal Spitz and dermal features. None of the stained tumors in our study exhibited the concurrent BAP1 loss and BRAFV600E positivity that are characteristic of adult BIM, suggesting that this is a low-frequency mutation among banal tumors in the pediatric population.

An atypical presentation of renal mass associated with BAP-1 tumor predisposition syndrome: Case report and review of literature.

BCRA-associated protein-1 (BAP-1) mutation has been associated with the development of a familiar syndrome that predisposes to tumors with a higher incidence than in general population, including melanoma and renal carcinoma. We report a 47-year-old woman diagnosed with a BAPoma (melanocytic tumor characterized by the loss of BAP-1). Due to her extensive family history with multiple neoplasms, a FDG PET-CT was performed. Consequently, she was diagnosed with an atypical renal mass, which is rarely linked to this syndrome. We review and discuss the available literature on the screening, diagnosis and treatment of renal tumors associated with BAP-1 tumor predisposition syndrome.

[Pathoanatomical algorithm for differential diagnosis of Paget's disease of the breast]. / Patologo-anatomicheskii algoritm differentsial'noi diagnostiki bolezni Pedzheta molochnoi zhelezy.

Paget's disease of the breast is a rare type of cancer that affects the skin of the nipple and usually the areola. At the same time, most patients also have one or more tumors in the immediate vicinity of the focus of mammary Paget's disease. This tumor must be distinguished from normal or atypical Toker cells, and also differentiated from diseases such as Bowen's disease of the nipple and melanocytic lesions of the nipple and areola region, including nipple melanoma and BAP1-inactivated nevus (Wiesner nevus). Currently, there is no routine pathological diagnostic algorithm for these conditions. The aim of the work is to formulate a clear clinical and morphological algorithm for diagnosing Paget's disease of the breast and Toker cells, Bowen's disease of the nipple and areola, as well as melanoma and BAP1-inactivated nevi of the above localizations. Surgical material obtained from patients with Paget's disease of the breast (18), Toker cells of the nipple (2), Bowen's disease of the nipple (6), melanoma of the nipple (1), BAP1-inactivated nevus (1) was studied. The material was examined histologically with hematoxylin and eosin staining, Alcian blue and PAS reaction, as well as immunohistochemically with the following panel of antibodies: CD138, p53, CK8, CK7, HER2/neu, EMA, HMB-45, Melan A, S-100, p63, p16 and BAP1. An easy-to-learn pathoanatomical algorithm for diagnosing Paget's cancer has been developed, which will be especially useful for pathologists who encounter pathology of the nipple and areola in their work.

BAP1-inactivated melanocytic tumour with borderline histopathological features (BAP1-inactivated melanocytoma): A case report and a reappraisal.

We describe a case of BRCA1-associated protein (BAP1)-inactivated melanocytic tumour (BIMT) in a 22-year-old woman, documenting for the first time with dermoscopy its sudden development with the onset of an atypical vascular pattern within a Miescher naevus. The tumour was histopathologically atypical because of the presence of confluent pleomorphism, solid sheets of cells and grouped mitotic figures: these features were consistent with a melanocytic neoplasm with intermediate morphology ('BAP1-inactivated melanocytoma'; BIM) between a BAP1-inactivated melanocytic naevus and a BAP1-inactivated melanoma. The atypical histopathological features of the present case were different from the criteria quoted for BIM in the World Health Organization 2018 classification of skin tumours.

A case of molecularly confirmed BAP1 inactivated melanocytic tumor with retention of immunohistochemical expression: A confounding factor.

BRCA1-associated Protein 1 (BAP1)-inactivated melanocytic nevi/tumors (BIMT) have distinct morphologic features. A typical case exhibits a biphasic population of cytologically bland conventional melanocytes and a second proliferation of larger epithelioid melanocytes with abundant eosinophilic cytoplasm. The vast majority of cases harbor BRAF V600E in both components with bi-allelic inactivation of BAP1 in the epithelioid component by various molecular mechanisms resulting in loss of nuclear protein expression, which can be demonstrated by immunohistochemistry. We present a case of BIMT with histopathologic features highly suggestive of this entity but unexpected retention of nuclear expression of the BAP1 protein. Subsequent molecular tests showed heterozygous loss of the BAP1 locus on the short arm of chromosome 3 (3p21.1) by chromosomal microarray analysis (CMA) and a suspected c.505C>T p.H169Y pathogenic variant identified by DNA sequencing that was subsequently confirmed by primer-specific SNaPshot mini-sequencing. In light of the heterozygous deletion of BAP1, this variant in the remaining allele encodes a catalytically inactive BAP1 mutant protein as shown in functional studies. The presence of a nonfunctional allele within the nucleus combined with a heterozygous deletion of BAP1 explains the clear and characteristic BIMT morphology observed by histopathology. This case underlines the potential importance of molecular diagnostics when protein expression studies do not correlate with morphology.

Skin Biopsy in the Context of Systemic Disease. / La biopsia cutánea en el contexto de la enfermedad sistémica.

The skin is the largest and most exposed organ in the human body and the ideal place to look for signs that aid in the early diagnosis of systemic diseases with cutaneous effects. As the concepts that underpin our understanding of many of these diseases have evolved or expanded in recent years, there have also been changes in the criteria we use for early diagnosis, including our approaches to skin biopsy and dermatopathologic evaluation. This review focuses on some of the systemic processes with skin manifestations for which our basic understanding has changed most in recent decades.

The difficulty in interpreting gene expression profiling in BAP-negative melanocytic tumors.

BACKGROUND: BAP-negative melanocytic tumors were unrecognized in the medical literature until 2011. While the clinical significance of these tumors is poorly understood, there is concern such lesions represent processes in transition, and malignant degeneration is a concern. We investigated use of a 23-gene expression profiling (23-GEP) test for distinction from melanoma with the aim of better characterizing the biologic potential of such tumors. METHODS: Twenty BAP-negative melanocytic tumors, subjected to 23-GEP (Myriad Genetic Laboratories, Inc. [Salt Lake City, Utah]) testing, were retrospectively analyzed. RESULTS: Tumors exhibited varying degrees of atypia and aberrant immunohistochemical profiles. 23-GEP testing revealed a "malignant" genetic signature in four cases, a "benign" signature in 15 cases, and an "indeterminate" signature in one case. Array-based comparative genomic hybridization (aCGH) testing was performed for two cases with a "malignant" 23-GEP signature, but the aCGH result conflicted with 23-GEP, and supported benignity. Conversely, in one case with a "benign" 23-GEP result, aCGH testing supported assessment as melanoma. Moreover, evolving melanoma could not be wholly excluded by histopathological analysis in 2 "benign" cases. CONCLUSIONS: BAP-negative melanocytic tumors remain a diagnostic dilemma for dermatopathologists. A widely marketed 23-GEP test may not be useful in distinguishing these tumors from spitzoid melanoma, at least in comparison to aCGH technology.

Histomorphologic spectrum of germline-related and sporadic BAP1-inactivated melanocytic tumors.

BACKGROUND: BRCA1-associated protein 1 (BAP1)-inactivated melanocytic tumors (BIMTs) are often the earliest sign of the BAP1 tumor predisposition syndrome. Identification of BIMTs and selection of patients for germline testing affect the lives of patients with germline BAP1 mutations. OBJECTIVE: To describe the spectrum of histomorphologic findings in BAP1-inactivated melanocytic lesions to improve their recognition. We determined the frequency of sporadic versus germline cases in our cohort, assessing whether any features were statistically linked to germline status. METHODS: Histomorphologic features of BAP1-inactivated melanocytic lesions were analyzed by comparing cases with germline mutations with those with unknown or negative status. Available clinical follow-up data were reported. RESULTS: The histomorphologic spectrum of BAP1-inactivated melanocytic lesions is broad; it includes cases with spitzoid cytomorphology (69%), smaller epithelioid cells without spitzoid features (31%), and rhabdoid cytologic features (58%). BIMTs from patients with germline mutations were statistically more likely to have an extensive junctional component of BAP1-inactivated melanocytes (P = .0177). All 11 patients with suspected or confirmed germline mutations had a history of cutaneous melanoma or multiple BIMTs. LIMITATIONS: The unknown germline status of 77 patients. CONCLUSION: Approximately 12% of patients with BIMTs have germline mutations. Extensive junctional involvement in a BIMT and a personal history of melanoma or previous BIMT may be additional indications for germline testing.