Apocrine-Eccrine Carcinomas: Molecular and Immunohistochemical Analyses

Apocrine-eccrine carcinomas are rare and associated with poor prognosis. Currently there is no uniform treatment guideline. Chemotherapeutic drugs that selectively target cancer-promoting pathways may complement conventional therapeutic approaches. However, studies on genetic alterations and EGFR and Her2 status of apocrine-eccrine carcinomas are few in number. In addition, hormonal studies have not been comprehensive and performed only on certain subsets of apocrine-eccrine carcinomas. To investigate whether apocrine-eccrine carcinomas express hormonal receptors or possess activation of oncogenic pathways that can be targeted by available chemotherapeutic agent we performed immunohistochemistry for AR, PR, ER, EGFR, and HER2 expression; fluorescence in situ hybridization (FISH) for EGFR and ERBB2 gene amplification; and molecular analyses for recurrent mutations in 15 cancer genes including AKT-1, EGFR, PIK3CA, and TP53 on 54 cases of apocrine-eccrine carcinomas. They include 10 apocrine carcinomas, 7 eccrine carcinomas, 9 aggressive digital papillary adenocarcinomas, 10 hidradenocarcinomas, 11 porocarcinomas, 1 adenoid cystic carcinoma, 4 malignant chondroid syringomas, 1 malignant spiradenoma, and 1 malignant cylindroma. AR, ER, PR, EGFR and HER2 expression was seen in 36% (19/53), 27% (14/51), 16% (8/51), 85% (44/52) and 12% (6/52), respectively. Polysomy or trisomy of EGFR was detected by FISH in 30% (14/46). Mutations of AKT-1, PIK3CA, and TP53 were detected in 1, 3, and 7 cases, respectively (11/47, 23%). Additional investigation regarding the potential treatment of rare cases of apocrine-eccrine carcinomas with PI3K/Akt/mTOR pathway inhibitors, currently in clinical testing, may be of clinical interest

Self-reports of mole counts and cutaneous malignant melanoma in women: Methodological issues and risk of disease

The relation of the presence of moles (nevi) on all four limbs to risk of cutaneous malignant melanoma was explored among 98 incident cases aged 32-59 years at diagnosis and 190 age-matched controls drawn from the Nurses' Health Study, a prospective cohort of female nurses in the United States. Cases diagnosed during follow-up from 1976 to 1982 were included in this study. Participants reported counts of all moles and raised moles alone on postal questionnaires. Distributions of moles were similar for right and left sides on upper and lower limbs for cases and controls. Counts declined with increasing age for all women, from a median of 15 for the youngest tertile of controls (aged 36-46 years) to three for the oldest (aged 54-62 years). Cases had more moles than did controls (medians of 23 and 9, respectively, for total moles on all four limbs): The presence of any mole on a limb gave relative risks for melanoma ranging from 2.2 (95% confidence interval (Cl) = 1.2-4.0) for one or more moles on an arm to 2.9 (95% Cl = 1.6-5.3) for one or more moles on the lower limb. For raised moles, relative risks were 1.7 (95% Cl = 1.0-2.7) for arm, 2.1 (95% Cl = 1.3-3.5) for lower limb, and 3.5 (95% Cl = 2.0-6.3) for leg (below knee). The highest site-specific risk (i.e., for any moles on the same limb as the melanoma vs. no moles on that limb) was for moles on the lower limb (relative risk = 5.0 (95% Cl = 1.8-13.5)). There were positive and significant trends in overall and site-specific risk with increasing numbers of moles on all limbs when absolute mole counts were considered, e.g., for total moles on all four limbs combined, x for trend = 4.0, one-sided

Novel Genetic Mutations in a Sporadic Port-Wine Stain

Importance Port-wine stains (PWSs) are common congenital cutaneous capillary malformations. A somatic GNAQ mutation was recently identified in patients with sporadic PWSs and Sturge-Weber syndrome. However, subsequent studies to confirm or extend this observation are lacking. Observations We report a long-standing, unilateral facial PWS of a man in his early 70s confirmed by histopathological analysis. Staged surgical excision of the vascular malformation was performed, and genomic DNA was extracted from the vascular malformation specimen and normal skin. Targeted next-generation sequencing of the coding sequence of 275 known cancer genes including GNAQ was performed in both specimens. A single-nucleotide variant (c.548G>A, p.Arg183Gln) in GNAQ was identified in the PWS-affected tissue but not in the normal skin sample. In addition, this sequencing approach uncovered several additional novel somatic mutations in the genes SMARCA4, EPHA3, MYB, PDGFR-β, and PIK3CA. Conclusions and Relevance Our findings confirm the presence of somatic mutations in GNAQ in the affected skin of a patient with congenital PWS, as well as alterations in several other novel genes of possible importance in the pathogenesis of PWS that may also offer substantial therapeutic targets

Inhibition of melanoma cell-intrinsic Tim-3 stimulates MAPK-dependent tumorigenesis.

T-cell immunoglobulin and mucin domain 3 (Tim-3) is an immune checkpoint receptor that dampens effector functions and causes terminal exhaustion of cytotoxic T-cells. Tim-3 inhibitors are under investigation in immuno-oncology (IO) trials, because blockade of T-cell-Tim-3 enhances antitumor immunity. Here, we identify an additional role for Tim-3 as a growth-suppressive receptor intrinsic to melanoma cells. Inhibition of melanoma cell-Tim-3 promoted tumor growth in both immunocompetent and immunocompromised mice, while melanoma-specific Tim-3 overexpression attenuated tumorigenesis. Antibody (Ab)-mediated Tim-3 blockade inhibited growth of immunogenic murine melanomas in T-cell-competent hosts, consistent with established antitumor effects of T-cell Tim-3 inhibition. In contrast, Tim-3 Ab administration stimulated tumorigenesis of both highly and lesser immunogenic murine and human melanomas in T-cell-deficient mice, confirming growth-promoting effects of melanoma-Tim-3 antagonism. Melanoma-Tim-3 activation suppressed, while its blockade enhanced, phosphorylation of pro-proliferative downstream mitogen-activated protein kinase (MAPK) signaling mediators. Finally, pharmacologic MAPK inhibition reversed unwanted Tim-3 Ab-mediated tumorigenesis in T-cell-deficient mice and promoted desired antitumor activity of Tim-3 interference in T-cell-competent hosts. These results identify melanoma-Tim-3 blockade as a mechanism that antagonizes T-cell-Tim-3-directed IO therapeutic efficacy. They further reveal MAPK targeting as a combination strategy for circumventing adverse consequences of unintended melanoma-Tim-3 inhibition