Pathology最新文献

Recent data have redefined the genetic spectrum of pigmented epithelioid melanocytomas (PEMs). PEM is now defined by a secondary genetic event, a protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) inactivation, that confers the specific cytomorphology of the entity, but this event can arise within a naevus with a genetic background of common, blue or Spitz type. PKC-fused melanocytic proliferations, although they can exhibit PEM-like morphological features, have now been regrouped within the blue group of tumours. Past studies have shown that the latter group tends to lose S100 expression. Herein, we studied the nuclear expression of S100 by immunohistochemistry in 73 PKC-fused benign blue naevi. Histologically, the most frequent pattern found in PKC-fused blue naevi (51%) was a dermal biphasic architecture associated with a horizontal band of medium-sized bland melanocytes in the upper papillary dermis, with a deeper dermal expansion combining spindled and dendritic melanocytes with occasional small nests of bland melanocytes within a fibrous background. A PEM-like hyperpigmented hyperplasia of the epidermis was seen in 32% of cases. The immunohistochemical study found in 31 of the 37 (84%) dermal biphasic PKC-fused melanocytic tumour cases a significant loss of nuclear expression of S100 (in more than 50% of cells) in the superficial horizontal dermal band area and in 68% of the biphasic dermal component. However, the hyperpigmented PEM-like junctional components were not assessable by immunohistochemistry. An exploratory analysis of S100 expression in 21 blue naevi and in 25 PEM with confirmed PRKAR1A inactivation was also performed. In blue naevi, a loss of nuclear S100 expression in more than 50% of melanocytes was found in over 70% of these lesions both in the dendritic and epithelioid dermal components. By contrast, nuclear expression of S100 was most often preserved in PEM with PRKAR1A inactivation (85% preservation in the epithelioid component). These results suggest that searching for S100 expression loss by immunohistochemistry may be helpful in the diagnosis of PKC-fused blue naevus similarly as in dendritic and cellular blue naevi. This simple test, especially if a band-like structure is present in the upper dermis, can effectively support this diagnosis, as a genetic confirmation of these benign tumours is not warranted.

Acral melanoma (AM) is the most common subtype of melanoma in the Asian population. Abnormalities in the p16-cyclin D1-CDK4 signalling pathway play a crucial role in the development and progression of AM. However, the CDK4 copy number variations (CNVs) in AM are under-reported. In this study, we investigated CDK4 gene copy number and concurrent molecular changes in a Chinese cohort with AM, to explore CDK4 CNVs and their significance in AM. We examined CDK4 CNVs with fluorescence in situ hybridisation (FISH) in 31 patients with AM. Six patients with CDK4 high-level copy number increase were examined by next-generation sequencing to detect concurrent molecular changes. Using FISH, 12 (12/31, 38.7%) cases showed CDK4 copy number increase, with six (6/31, 19.4%) low-level copy number increase and six (6/31, 19.4%) high-level copy number increase. Five of six CDK4 low-level copy number increase cases were accompanied by polysomy of chromosome 12, while one case was not. Two of six CDK4 high-level copy number increase cases were accompanied by polysomy of chromosome 12, while four cases were not. CDK4 copy number increase was significantly correlated with younger patient age. In six CDK4 high-level copy number increase cases, one case was found to be accompanied by NRAS mutation, one case was accompanied by HER2 mutation, one case was accompanied by BCL2L11 mutation ​and one case was accompanied by BRAF, HER2 and BCL2L11 mutations. Our study confirmed the presence of CDK4 copy number increase in AM cases. Detecting CDK4 copy number increase by FISH can be reliable in the diagnosis of AM. Some CDK4 copy number increases are the results of polysomy of chromosome 12. CDK4 high-level copy number increase coexists with other pathogenic mutations in AM. CDK4 appears to be a promising target for AM treatment and is expected to be combined with other targeted therapies.

Naevoid basal cell carcinoma syndrome (NBCCS) is a rare genodermatosis caused by germline mutations in genes of the Sonic Hedgehog (SHH) pathway and is characterised by early onset of multiple basal cell carcinomas (BCCs). Although skin tumours with follicular differentiation, notably basaloid follicular hamartoma (BFH), have been reported in NBCCS, their relations with BCC are poorly defined. In this context, the aim of this study was to clarify morphological, immunohistochemical ​and molecular features of BFH arising in a context of NBCCS. A total of 140 skin tumours from NBCCS and 140 control BCC tumours were reviewed, blinded to clinical data and classified as BCC or BFH. The morphological characteristics of these two groups were then compared. Twenty cases were submitted for immunohistochemical and molecular analysis. Thirty-three tumours among the exploratory cohort were classified as BFH and were exclusively detected in NBCCS patients. Histopathological criteria that were significantly different from BCC were as follows: a small size (<1.5 mm), connection to a hair follicle, arborescent organoid architecture, lack of cytological atypia and infundibulocystic differentiation. Immunohistochemical analysis confirmed activation of the SHH pathway in these lesions. Targeted next-generation sequencing suggested that MYCN and GLI2/3 amplifications and TP53 mutations might be involved in progression of these follicular tumours to BCC. Our study confirms the high prevalence of BFH, representing up to 24% of skin tumours in NBCCS and potentially being BCC precursors.