Cutaneous Melanocytic Tumor With CRTC1::TRIM11 Translocation : An Emerging Entity Analyzed in a Series of 41 Cases.

Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion (CMTCT) is a recently described dermally based neoplasm with melanocytic differentiation. It can easily be confused with clear cell sarcoma and metastatic melanoma. Our understanding of this lesion, including its potential for aggressive disease, has been limited by the small number of previously reported cases (13) and the limited clinical follow-up data. Here, we report a series of 41 CMTCT confirmed by molecular studies. We find that the lesion shows highly uniform and reproducible morphologic, immunohistochemical, and genetic features across a wide variety of anatomic locations and age groups. Among 22 cases with follow-up, 1 local recurrence and 1 nodal metastasis were identified. Our data support the classification of CMTCT as a unique nosologic entity and emphasize the importance of distinguishing this entity from its histologic mimics, especially clear cell sarcoma and metastatic melanoma, to guide therapy and establish accurate prognostic expectations.

Mutational Characteristics of Primary Mucosal Melanoma: A Systematic Review.

BACKGROUND: Primary mucosal melanomas (PMMs) are rare and clinically heterogeneous, including head and neck (HNMs), vulvovaginal (VVMs), conjunctival (CjMs), anorectal (ARMs) and penile (PMs) melanomas. While the prognosis of advanced cutaneous melanoma has noticeably improved using treatments with immune checkpoint inhibitors (ICIs) and molecules targeting BRAF and MEK, few advances have been made for PMMs because of their poorer response to ICIs and their different genetic profile. This prompted us to conduct a systematic review of molecular studies of PMMs to clarify their pathogenesis and potential therapeutic targets. METHODS: All articles that examined gene mutations in PMMs were identified from the databases and selected based on predefined inclusion criteria. Mutation rate was calculated for all PMMs and each location group by relating the number of mutations identified to the total number of samples analysed. RESULTS: Among 1,581 studies identified, 88 were selected. Overall, the frequency of KIT, BRAF and NRAS mutation was 13.5%, 12.9% and 12.1%, respectively. KIT mutation ranged from 6.4% for CjMs to 16.6% for ARMs, BRAF mutation from 8.6% for ARMs to 31.1% for CjMs, and NRAS mutation from 6.2% for ARMs to 18.5% for CjMs. Among 101 other genes analysed, 33 had mutation rates over 10%, including TTN, TSC1, POM121, NF1, MTOR and SF3B1. CONCLUSION: In addition to BRAF, NRAS and KIT genes commonly studied, our systematic review identified significantly mutated genes that have already been associated (e.g., TSC1, mTOR, POLE or ATRX) or could be associated with (future) targeted therapies. PROSPERO ID: CRD42020185552.

Adult diagnosis of Townes-Brocks syndrome with renal failure: Two related cases and review of literature.

Townes-Brocks syndrome (TBS) is a rare autosomal dominant syndrome, resulting from heterozygous variant in SALL1 gene and initially characterized by the triad of anorectal, thumb, and ear malformations. Essentially described in children, adult case reports are uncommon. Renal involvement has already been reported in adults and children but poorly described. Structural abnormalities such as hypodysplasia, unilateral renal agenesis or multicystic kidneys have been described, as well as functional impairment (with or without structural abnormalities) that may progress to end-stage renal disease (ESRD). We report two adult cases (mother and daughter) which exhibited kidney hypoplasia (focal and segmental glomerulosclerosis for the mother) and ESRD. The mother had unilateral polydactyly. TBS was suggested after physical examination. TBS diagnosis was confirmed by identification of a SALL1 variant. We conducted a literature review to evaluate the renal anomalies in TBS cases diagnosed in adulthood. Among 44 adult cases of TBS with genetic confirmation (including our two cases), 10 had kidney disease. The circumstances of renal failure diagnosis were incidental findings (2/5), gout (2/5), or repeated episodes of pyelonephritis (1/5). The median age of kidney disease diagnosis was 30 years old and of renal transplant 49 years old. The most frequent renal malformation was bilateral kidney hypoplasia. TBS is probably underestimated in adulthood and this report highlights that less obvious elements of morphology such as dysplasic ears can facilitate the diagnosis of TBS. As long-term prognosis of renal involvement in TBS patients remains largely unknown, a regular evaluation is required throughout life for patients.

Vasculitides and glomerulonephritis associated with Staphylocococcus aureus infective endocarditis: cases reports and mini-review of the literature.

We reported two cases of Staphylococcus aureus Infective Endocarditis associated with vasculitides and glomerulonephritis respectively, before conducting an online search of previously published similar cases reports. Twenty five references were selected: 15 cases of glomerulonephritis; 2 cases of vasculitis and 8 cases involving both glomerulonephritis and vasculitis. Vasculitides and glomerulonephritis associated with Staphylococcus aureus definite Infective Endocarditis have been reported since 1976. All cases except one described clinical symptoms occurring before or during initial antibiotics treatment. Except kidney, organs that were more frequently affected by vasculitis process were skin, gastrointestinal tract and peripheral nerve and the vessels involved were small to medium size vessels. When antineutrophil cytoplasmic antibodies were evidenced (6 out of the 25 cases (24%)), kidney was the most frequently affected organ. The most commonly observed pattern in Kidney biopsy was membranoproliferative glomerulonephritis with endocapillary proliferation sometimes associated with extra capillary crescents, whether or not antineutrophil cytoplasmic antibodies were evidenced. Right-sided Infective Endocarditis (especially in intravenous drug users) were overrepresented (14 of the 25 cases (56.0%)) in this review. Besides antibiotics, corticosteroids were the most frequently prescribed immunosuppressive treatment both for vasculitides or glomerulonephritis. KEY MESSAGES Vasculitides and glomerulonephritis associated with Staphylococcus aureus definite Infective Endocarditis have been reported since 1976. Except kidney, organs that were more frequently affected (by small to medium size vessel vasculitis) were skin, gastrointestinal tract and peripheral nerve. The most commonly observed pattern in Kidney biopsy was membranoproliferative glomerulonephritis with endocapillary proliferation and right-sided Infective Endocarditis (especially in intravenous drug users) were overrepresented in this review.

Prognostic factors and incidence of primary mucosal melanoma: a population-based study in France.

Few population-based studies on the incidence and prognosis of primary mucosal melanoma (PMM) are available. The first objective was to evaluate disease-specific survival of PMM, overall and according to specific locations, and to identify prognostic factors. The second objective was to assess the global incidence of PMM compared to cutaneous melanoma and to specify the relative frequency of each affected location. A retrospective population-based study of incident PMM diagnosed between 2004 and 2014 was conducted, relying on the regional melanoma registry of the French Champagne-Ardenne region (1.34 million inhabitants). Thirty-nine cases were identified, including 17 head and neck (13 sinonasal and four oral), 12 vulvovaginal, six conjunctival, and four anorectal PMMs. Some 76.9% of cases were revealed by late symptoms. The median disease-specific survival time was 23.9 months and the five-year disease-specific survival rate was 31.8%. Univariate and multivariate analyses led to identification of primary tumour size and the presence of nodal or visceral macrometastases at diagnosis as adverse prognostic factors, while Breslow thickness and ulceration were unreported in 41% of cases and failed to display any prognostic value. Compared to other locations, conjunctival PMMs had a smaller tumour size and better prognosis. The annual incidence rate was 0.18/100,000 and the incidence ratio between PMM and cutaneous melanoma was 1/50. This population-based study confirms the rarity, delayed diagnosis, and severity of PMM, suggesting that improving prognosis will require specific, targeted therapies.

BRCA Share: A Collection of Clinical BRCA Gene Variants.

As next-generation sequencing increases access to human genetic variation, the challenge of determining clinical significance of variants becomes ever more acute. Germline variants in the BRCA1 and BRCA2 genes can confer substantial lifetime risk of breast and ovarian cancer. Assessment of variant pathogenicity is a vital part of clinical genetic testing for these genes. A database of clinical observations of BRCA variants is a critical resource in that process. This article describes BRCA Share™, a database created by a unique international alliance of academic centers and commercial testing laboratories. By integrating the content of the Universal Mutation Database generated by the French Unicancer Genetic Group with the testing results of two large commercial laboratories, Quest Diagnostics and Laboratory Corporation of America (LabCorp), BRCA Share™ has assembled one of the largest publicly accessible collections of BRCA variants currently available. Although access is available to academic researchers without charge, commercial participants in the project are required to pay a support fee and contribute their data. The fees fund the ongoing curation effort, as well as planned experiments to functionally characterize variants of uncertain significance. BRCA Share™ databases can therefore be considered as models of successful data sharing between private companies and the academic world.

BRAFV600E Gene Mutation in Colonic Adenocarcinomas. Immunohistochemical Detection Using Tissue Microarray and Clinicopathologic Characteristics: An 86 Case Series.

The detection of BRAF mutation in colorectal cancer has several clinical applications: enabling the discrimination between sporadic and Lynch syndrome-related colorectal carcinoma, and providing warning of a poorer prognosis. Few immunohistochemical studies using whole-tissue tumor section staining have recently been performed on colorectal cancer. The aim of this study was to evaluate the detection of BRAF mutation by immunohistochemistry (IHC) on tissue microarray (TMA). IHC was performed with the BRAF-specific antibody using TMA on a retrospective series of 86 colonic adenocarcinomas with known BRAF status. IHC using BRAF-specific antibody allowed to detect 20/21 BRAF mutated colonic adenocarcinomas and 60/65 BRAF wild-type cases. The staining was equivocal because of equivocal staining in 4 cases and heterogeneity in 3 cases. When compared with TaqMan real-time PCR, the sensitivity and specificity were 95.2% and 92.3%, respectively. Comparison with the whole section immunostaining improved sensitivity to 100% and specificity to 95.4%. Furthermore, in this study we found that BRAF mutated colonic adenocarcinoma were significantly more frequent in women, older patients, and right-sided. Moreover, morphologic features significantly associated with BRAF mutation were: serrated adenocarcinoma subtype, adenocarcinomas with a mucinous component, high histologic grade, pushing margins, stromal inflammation. BRAF-specific antibody can be used on TMA to screen BRAF-mutated colorectal carcinomas. Cases with equivocal or heterogenous staining must be compared with whole section staining. Moreover, BRAF mutated colonic carcinomas have distinct clinical and histopathologic features.