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The histogenesis of the rare primary cutaneous epithelioid rhabdomyosarcoma (PCERMS) remains unclear, with the morphological and immunophenotypic appearance of a rhabdomyosarcoma but a genomic profile consistent with sarcomatoid undifferentiated malignant melanoma (SUMM). Here, we provide comprehensive clinical, histopathological, and genomic analysis of a putative PCERMS presenting in an elderly patient. Histopathologic examination revealed an ulcerative tumefactive lesion with diffuse replacement of the dermis by sheets of malignant epithelioid cells with a rhabdoid appearance. By immunohistochemistry, the tumor cells were strongly and diffusely positive for desmin and myogenin. Comprehensive genomic analysis with a 542 gene DNA-based sequencing panel revealed likely biallelic NF1 inactivation (mutation and deletion), TERT promoter mutation, and a high tumor mutation burden (>100 mutations/mB) with features of a UV-mutational signature, which are all genomic features that can be seen in undifferentiated malignant melanoma. This case provides evidence of a close relationship at a molecular level between PCERMS and SUMM. Molecular genomic characterization of a larger cohort of PCERMS is warranted for further elucidation., (© 2023 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Solitary circumscribed neuroma formerly known as palisaded encapsulated neuroma is a rare, benign neural tumor that usually presents as a painless firm nodule or papule on the face and within oral cavity, although they can occur elsewhere on the body. No association with neurofibromatosis has been reported in the literature. Herein, we report, a previously unreported unique association of neurofibromatosis type 2 (NF-2) with multiple cutaneous solitary circumscribed neuromas in a 24-year-old female. A 24-year-old female with history of NF-2 presented with two slow-growing soft-to-firm papules on the chin and forehead that had been gradually increasing in size over a period of 5 years. The papule on the chin was increasingly tender to palpation. Histologic sections demonstrated a dermal based almost encapsulated, smoothly contoured tumefactive mass composed of spindle cell proliferation with neuroid structures and foci of palisaded growth (resembling schwannoma) and intralesional cleft like spaces. By immunohistochemistry, the lesional cells were strongly and diffusely positive for S-100 and SOX10 with multifocal neurofilament expression while the "capsule" was diffusely reactive for epithelial membrane antigen. The overall features were considered prototypic for solitary circumscribed neuroma. The patient is 18-months post-surgical resection with no evidence of recurrence. In summary, we report for the first time a case of multiple solitary circumscribed neuromas in a patient with known NF2. We highlight pertinent diagnostic clues relevant to surgical pathologist to facilitate recognition (as this tumor is often mistaken for schwannoma or neurofibroma). The clinical behavior is excellent and surgical resection is considered curative.

SS18::SSX gene fusions as a result of t(X,18)(p11;q11) have only been described in synovial sarcoma (SS). Recently, an SS18::NEDD4 gene fusion was identified in a single case of primary renal SS exhibiting a hypocellular and myxoid morphology. Herein, we report a case of an unclassified malignant cutaneous spindled and epithelioid neoplasm in a 60-year-old female that resembled an epithelioid sarcoma (ES) and harbored a rare SS18::NEDD4 gene fusion. Briefly, the patient presented with a progressively growing cutaneous mass involving the volar aspect of right hand, warranting an amputation. Histologic sections revealed a cutaneous ulcerative neoplasm composed of spindled and epithelioid cells, bearing a certain semblance to ES, with diffuse invasion into the subcutis and skeletal muscle. Coagulation tumor necrosis and mitotic figures were present. By immunohistochemistry, the tumor cells were positive for keratins (AE1/3 and cam5.2), vimentin, CMYC, BCL2, p53, smooth muscle actin (focal), and TLE1 (multifocal) and negative for p40, p63, CK5/6, CK7, CK20, CD56, CD31, CD34, ERG, desmin, SMMS, H-Caldesmon, myogenin, and S-100. Expression of INI1 stain was retained. The unusual histomorphology and inconclusive immunophenotypic profile lead to next-generation sequencing identifying an SS18::NEDD4 gene fusion with genomic coordinates 5'-SS18 (ex1-9 NM_005637)-NEDD4 (ex14-29 NM_006154). Fluorescence in situ hybridization confirmed SS18 gene rearrangement. Within 2 years, the patient developed widespread metastatic disease. Despite aggressive multimodality treatment, the patient succumbed to disease. In summary, we report a unique case of previously unclassified cytokeratin positive malignant cutaneous spindled and epithelioid sarcoma with aggressive behavior, harboring an SS18::NEDD4 fusion., (© 2022 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Cutaneous fibromyxoid neoplasms (CFMN) comprise a vast category of benign and malignant tumors that include, but are not limited to, low-grade fibromyxoid sarcoma, myxofibrosarcoma, myxoid dermatofibrosarcoma protuberans, myxoid solitary fibrous tumor, and myxoid neurofibroma with differing implications for treatment and prognosis. Herein, a case of CFMN arising as a painless, slow-growing, flesh-colored forearm mass in a 53-year-old female is presented. The neoplasm comprised of copious myxoid material with banal spindle cells, exhibiting mild hyperchromasia, dissecting the dermal collagen table. Focal perivascular accentuation of spindle cells was identified in the absence of vasoformative features. Immunohistochemically, lesional cells were strongly and diffusely positive for CD34 and multifocally for Factor XIIIa and epithelial membrane antigen while negative for CD31, ERG, FLI-1, D2-40, smooth muscle actin, Desmin, S100, HMB-45, STAT6, MUC4, and keratins. RNA- and DNA-sequencing identified a YAP1::TFE3 fusion transcript that were subsequently corroborated by fluorescence in situ hybridization and immunohistochemistry for TFE3 (Xp11.23) locus rearrangement and strong, diffuse TFE3 immunoreactivity, respectively. To date, the YAP1::TFE3 fusion has only been identified in a subset of epithelioid hemangioendotheliomas and clear cell stromal tumors of the lung. This is the first report of a CFMN featuring a YAP1::TFE3 fusion (YAP1 Exon 1 and TFE3 Exon 4). The morphologic findings are unlike those previously described for epithelioid hemangioendothelioma and suggest that this neoplasm may represent a yet unclassified or novel CFMN entity. Although the patient is 1-year status postsurgical excision with no evidence of clinical recurrence, the clinical behavior of this novel entity remains to be fully characterized., (© 2021 Wiley Periodicals LLC.)

Calcifying epithelial odontogenic tumor (CEOT) is an uncommon locally invasive epithelial odontogenic tumor of the jaws associated with amyloid production. Intraosseous presentations are most common and they frequently occur in the posterior mandible. A non-calcifying Langerhans cell-rich variant of CEOT (NCLC CEOT) has been described with predilection for the anterior maxilla. Interestingly, all reported cases of NCLC CEOT have occurred in Asian population. We present a case of a 43-year old Caucasian female with a large radiolucent lesion involving the left anterior maxilla with histologic features of NCLC CEOT. This is the first reported case of this rare variant of CEOT in a Caucasian individual.

Background: Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but typically is associated with low rates of metastasis and high survival rates. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals die each year of this disease., Methods: Because it is difficult to predict which cSCCs are more likely to metastasize, and because to the best of the authors' knowledge there are no targeted therapies specifically designated for patients with metastatic cSCC, exome and/or targeted sequencing of 18 metastatic and 10 primary cSCCs was performed to identify mutations that were more frequent in metastatic tumors and might be targeted for therapeutic benefit. The authors compared their results with published sequencing results of an additional 223 primary tumors and 68 metastatic cSCCs., Results: The authors identified genes demonstrating higher mutation frequencies in metastatic cSCC compared with primary tumors, including the chromatin remodeling gene lysine methyltransferase 2D (KMT2D) and the classic skin tumor suppressor tumor protein p53 (TP53), which was found to be mutated in 54% of primary tumors compared with 85% of metastatic tumors (P<.0001)., Conclusions: These studies appear to uncover potential pathways that are important in metastatic cSCC and that broaden understanding of the biology contributing to aggressive tumor behavior. These results may lead to new therapeutic strategies. Cancer 2017;123:1184-1193. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

More than 3.5 million nonmelanoma skin cancers were treated in 2006; of these 700,000 were cutaneous squamous cell carcinomas (cSCCs). Despite clear environmental causes for cSCC, studies also suggest genetic risk factors. A cSCC susceptibility locus, Skts5, was identified on mouse chromosome 12 by linkage analysis. The orthologous locus to Skts5 in humans maps to 7p21 and 7q31. These loci show copy number increases in ∼10% of cSCC tumors. Here, we show that an additional 15-22% of tumors exhibit copy-neutral loss of heterozygosity. Furthermore, our previous data identified microsatellite markers on 7p21 and 7q31 that demonstrate preferential allelic imbalance (PAI) in cSCC tumors. On the basis of these results, we hypothesized that the human orthologous locus to Skts5 would house a gene important in human cSCC development and that tumors would demonstrate allele-specific somatic alterations. To test this hypothesis, we performed quantitative genotyping of 108 single nucleotide polymorphisms (SNPs) mapping to candidate genes at human SKTS5 in paired normal and tumor DNAs. Nine SNPs in HDAC9 (rs801540, rs1178108, rs1178112, rs1726610, rs10243618, rs11764116, rs1178355, rs10269422 and rs12540872) showed PAI in tumors. These data suggest that HDAC9 variants may be selected for during cSCC tumorigenesis., (© 2013 UICC.)

Studies have suggested that somatic events in tumors can depend on an individual's constitutional genotype. We used squamous cell carcinomas (SCC) of the skin, which arise in high multiplicity in organ transplant recipients, as a model to compare the pattern of somatic alterations within and across individuals. Specifically, we performed array comparative genomic hybridization on 104 tumors from 25 unrelated individuals who each had three or more independently arisen SCCs and compared the profiles occurring within patients to profiles of tumors across a larger set of 135 patients. In general, chromosomal aberrations in SCCs were more similar within than across individuals (two-sided exact-test p-value<1x10(-7)), consistent with the notion that the genetic background was affecting the pattern of somatic changes. To further test this possibility, we performed allele-specific imbalance studies using microsatellite markers mapping to 14 frequently aberrant regions of multiple independent tumors from 65 patients. We identified nine loci which show evidence of preferential allelic imbalance. One of these loci, 8q24, corresponded to a region in which multiple single nucleotide polymorphisms have been associated with increased cancer risk in genome-wide association studies (GWAS). We tested three implicated variants and identified one, rs13281615, with evidence of allele-specific imbalance (p-value=0.012). The finding of an independently identified cancer susceptibility allele with allele-specific imbalance in a genomic region affected by recurrent DNA copy number changes suggest that it may also harbor risk alleles for SCC. Together these data provide strong evidence that the genetic background is a key driver of somatic events in cancer, opening an opportunity to expand this approach to identify cancer risk alleles., Competing Interests: The authors have declared that no competing interests exist.

Squamous cell carcinoma (SCC) is the second most frequently diagnosed skin cancer. It has a higher incidence in immunosuppressed individuals such as organ transplant recipients and human immunodeficiency virus (HIV) carriers. Recently, a newly described polyoma virus, Merkel cell polyomavirus (MCPyV), was found in Merkel cell carcinoma (MCC), a rare aggressive skin cancer also associated with immunosuppression. We hypothesized that MCPyV would be present in SCCs. To test for the presence of MCPyV in immunocompetent SCC patients, we used PCR primer sets directed against the large T (LT) antigen and VP1 gene of MCPyV. We detected MCPyV in 15% (26/177) of SCC DNA samples and 17% (11/63) of adjacent skin DNA samples from 21 of 58 (36%) individuals studied. We did not detect MCPyV in any matched normal blood DNA (0/57), but observed the presence of MCPyV DNA in 1 of 12 normal mouthwash DNAs. All sequenced SCC samples had a common mutation truncating the LT antigen that provides indirect evidence of viral integration. The presence of MCPyV in approximately 15% of SCCs from immunocompetent individuals warrants evaluation of MCPyV as an etiologic agent in the carcinogenesis of SCC.

Extramammary Paget's disease (EMPD) is a rare malignant neoplasm with a predilection for the apocrine-rich anogenital skin and less commonly for the axilla. The tumor rarely occurs in non-apocrine bearing regions where it is referred to as ectopic EMPD. Here, we report a case of a patient that presented with a poorly circumscribed, erythematous plaque with patchy alopecia on the scalp. Histology showed pagetoid infiltration of the epidermis by atypical single and nested cells with abundant amphophilic cytoplasm with nuclear hyperchromasia, extending along the adnexae. Immunohistochemistry showed that the tumor cells stained positively for mucicarmine, periodic acid schiff, cytokeratin-7, polyclonal carcinoembryonic antigen, epithelial membrane antigen, gross cystic disease fluid protein, androgen receptor and Her-2-neu; and negatively for S-100, HMB-45, CDX-2, thyroid transcription factor-1, estrogen receptor and progesterone receptor, thus, establishing the diagnosis of ectopic EMPD. Subsequent workup showed no underlying malignancy. To our knowledge, we report the second case, and the first in the English literature, of an ectopic EMPD involving the scalp without any associated malignancy.