A population-based analysis of germline BAP1 mutations in melanoma.

Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma.

Breast Neoplasms with Dermal Analogue Differentiation (Mammary Cylindroma): Report of 3 Cases and a Proposal for a New Terminology.

Salivary gland-like and dermal analogue tumours of the breast are rare lesions that can be diagnostically challenging for pathologists. Data on the clinical behaviour and molecular characterisation of these mammary tumours are limited and their designation is mainly based on similar salivary gland or skin lesions. In this study, we present three cylindromatous breast tumours. These lesions were located within the breast, had ill-defined margins and were composed of nests containing a dual population of cytologically bland cells, surrounded at least partially by basement membrane-like material. The lack of cytological atypia and absence of mitoses led to the diagnosis of benign mammary cylindroma in 1 case. The expression of oestrogen receptor, focal absence of basement membrane material and the focal infiltrative nature together with patchy absence of peripheral basement membrane supported the diagnosis of malignancy in the other 2 cases. We discuss the morphological criteria, immunohistochemical profile and diagnostic pitfalls of these tumours. We also review the literature including previously reported cases of mammary cylindroma and differential diagnoses to be considered before making a diagnosis. We propose the term 'mammary tumours with cylindromatous differentiation', implying their uncertain malignant nature, and propose management strategies.

Using the CES-D with custodial grandmothers: cross-validation and convergent validity.

OBJECTIVE: This study is the first to analyze the factor structure of the Center for Epistemological Studies Depression (CES-D) Scale with custodial grandmothers involving both cross validation and convergent validity analyses. METHOD: Cross validation was accomplished with two different samples of custodial grandmothers (GCM) to calibrate (n=733; Average Age=52) and then validate (n=343; Average Age=52.5) the model. RESULTS: Radloff's originally proposed four factor model (Depressed Affect, Well-Being, Somatic Symptoms, and Interpersonal Problems) was found to best fit the data for both calibration (RMSEA=0.049) and validation samples (RMSEA=0.050). The construct validity of the four CES-D factors was supported by the correlations observed between these factors and conceptually related psychosocial measures. CONCLUSION: four CES-D factors as proposed are psychometrically sound when applied to custodial grandmothers and that each factor contributes unique and meaningful information in its own right.

Facial paediatric desmoid fibromatosis: a case series, literature review and management algorithm.

Desmoid fibromatosis (also known as infantile or aggressive fibromatosis) is a rare soft tissue tumour that is occasionally seen in children. Although histologically benign, its growth pattern is highly aggressive often showing invasion of surrounding musculature and bone. Frequently found in cosmetically sensitive areas, complete excision can present a challenging problem. However, incomplete surgical excision is associated with high recurrence rates and although the disease responds to chemo and radiotherapy, both carry significant risks in young children. The management of four paediatric desmoid fibromatoses occurring in the midface is discussed. The recent and pertinent literature is comprehensively reviewed and an algorithm for the management of paediatric desmoid fibromatoses is proposed.