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Purpose: Penile squamous cell carcinoma (PSCC) is rare with limited treatment options. We report the first whole-exome sequencing (WES) analysis and compare the molecular landscape of PSCC with other squamous cell carcinomas (SCC), with the goal to identify common novel targets., Experimental Design: PSCC and matched normal penile tissues from 34 prospectively followed patients, underwent genomic WES and human papilloma virus testing. We performed tumor mutation signature estimation by two methods, first to identify APOBEC-related mutation enrichments and second to classify PSCC-enriched mutational patterns based on their association with the Catalogue of Somatic Mutations in Cancer mutation signatures. We performed an extensive genomic comparison between our PSCC cohort and other SCCs in The Cancer Genome Atlas studies., Results: We identified that most PSCC samples showed enrichment for Notch pathway ( n = 24, 70.6%) alterations, comparable with head and neck squamous cell carcinoma (HNSC). PSCC mutation signatures are most comparable with HNSC signatures. PSCC samples showed an enrichment of two distinct mutational signatures, the first, associated with oncogenic activity of AID/APOBEC, and the second, associated with defective DNA mismatch repair and microsatellite instability. MP1 enrichment was positively correlated with increased tumor mutation burden (TMB; CC, 0.71; P < 0.0001) and correlated with significantly worse survival in comparison with those with the MP2 subset [HR, 10.2 (1.13-92.9); P = 0.039]. We show that a subset of PSCC (38%), with enrichment of APOBEC-related mutation signature, had significantly higher TMB and worse overall survival in comparison with non-APOBEC-enriched subset [HR, 2.41 (1.11-6.77); P = 0.042]., Conclusions: This study identified novel druggable targets and similarities in mutational signatures between PSCC and HNSC with potential clinical implications. See related commentary by McGregor and Sonpavde, p. 2375 ., (©2021 American Association for Cancer Research.)

Atypical fibroxanthoma (AFX), spindle cell squamous cell carcinoma (SCSCC) and spindle cell melanoma are the primary entities in the differential diagnosis of a cytologically atypical spindle cell tumor arising on sun-damaged skin. AFX is generally regarded as a diagnosis of exclusion in this context: in the absence of S100 or keratin reactivity, a diagnosis of AFX is favored. However, keratin reactivity may be focal or even absent in SCSCC, and although numerous positive markers of AFX have been proposed, none has shown sufficient sensitivity and specificity for routine diagnostic use. We evaluated 20 AFX and 10 SCSCC with a panel of cytokeratins and p63 to assess the utility of the latter antibody in this differential diagnosis. All 10 SCSCC showed strong expression of p63, whereas all 20 AFX were p63 negative. Two additional cases (excluded from the study) were negative for keratins and S100 on initial shave biopsies, resulting in a favored diagnosis of AFX, but p63 stains performed retrospectively were positive. However, review of the excision specimens in both cases revealed deep subcutaneous extension, excluding AFX. p63 reactivity argues against the diagnosis of AFX and is therefore a useful addition to the standard immunohistochemical panel for cutaneous spindle cell neoplasms.

Atypical fibroxanthoma (AFX) is a spindle cell neoplasm of the skin seen typically on sun-damaged skin of the elderly. Though described as a benign entity, local recurrence and distant metastasis have been reported. This study aims to investigate the potential pathogenic role of CD117, the c-kit receptor in AFX. CD117 was detected in 15 of the 16 cases (94%). The percentage of positive cells for CD117 expression among all tumors was approximately 30%. CD117 proved to be a very sensitive marker of AFX. This antibody may be a useful diagnostic adjunct in AFX.

Basal cell carcinoma and squamous cell carcinoma are common entities in clinical practice. Their distinction can be difficult clinically as well as histologically. CD10 or common acute lymphoblastic leukemia antigen (CALLA) is a metallomembrane endopeptidase expressed on a variety of normal and neoplastic cells. We sought to determine if the CD10 immunostain could have diagnostic utility in distinguishing between early superficial basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). CD10 was strongly expressed in 14 out of 14 superficial BCCs and failed to express in 2 out of 2 deeply infiltrative BCCs. CD10 was negative in the tumor cells in 13 out of 13 superficially invasive SCCs and SCC in situ. CD10 expressed weakly in the surrounding stromal cells of 2 out of 13 SCCs. These findings support the utility of CD10 as a marker for early BCC, especially when SCC cannot be excluded clinically or by conventional stains. Furthermore, these results implicate CD10 in the pathogenesis of BCC.

Background: Epidermal growth factor receptor (EGFR) and HER2, members of the Erb family of transmembrane receptor tyrosine kinases (RTK), are responsible for communicating extracellular signals to the nucleus. Moreover, EGFR and HER2 are implicated in tumorgenesis. Immunohistochemical studies have demonstrated that approximately 80% of cutaneous squamous cell carcinomas (SCC) express EGFR. To date, the expression of EGFR and HER2 has not been evaluated in primary cutaneous spindle squamous cell carcinoma (SSC). In extracutaneous spindle squamous cell carcinoma, there is evidence implicating the expression of RTK as a strong, independent prognostic indicator of potentially poor outcome. The purpose of this study is to investigate the expression of EGFR and HER2 in SSC, using immunohistochemical methods., Materials and Methods: Thirteen cases of primary nonmetastatic cutaneous SSC archived at a large veterans' hospital and tertiary referral dermatopathology service were retrieved via a computer-assisted search. Immunohistochemistry was used to evaluate the presence of EGFR and/or HER2 expression. All cases were confirmed before study by a single, board-certified dermatopathologist., Results: All 13 cases (100%) evaluated for the presence of HER2 were nonimmunoreactive for the receptor. Only one of the 13 cases (<8%) stained positive for EGFR., Conclusions: In several malignancies, the overexpression EGFR and HER2 is associated with clinically aggressive behavior. Despite a limited sample size, EGFR and HER2 are not overexpressed in SSC; this is cognate with the current opinion that SSC possesses limited metastatic potential. With prior reports demonstrating that approximately 80% of cutaneous SCC express EGFR, the negative expression of EGFR and HER2 in SSC presents the potential variable nature of the histologic subtypes of SCC, which can have prognostic and therapeutic implications.

Ets-1 oncoprotein is a transcription factor known to regulate the expression of numerous genes important in extracellular matrix remodeling and angiogenesis. Up-regulation of Ets-1 has been shown to be important in a variety of human malignancies and to correlate with prognosis. To our knowledge, this oncoprotein has not been examined in melanocytic lesions. A series of 10 cutaneous melanomas and 24 benign melanocytic lesions with patient records were independently examined for diagnosis confirmation and immunohistochemical expression by two dermatopathologists. The immunohistochemical expression for Ets-1 (Novocastra, Newcastle upon Tyne, UK) was scored by an average of the mean labeling intensity; no nuclear staining = 0, weak nuclear staining = 1, moderate = 2, and intense = 3. Ets-1 expression was statistically assessed by the one-way analysis of variance (ANOVA) comparing the mean labeling intensity of melanoma to benign melanocytic nevi. All of the benign melanocytic lesions exhibited negative to weak nuclear staining, with an average mean labeling intensity of 0.4. Melanoma in situ exhibited moderate nuclear staining, for a mean labeling intensity of 2.0, whereas all conventional invasive melanomas exhibited moderate to strong nuclear staining, with a mean labeling intensity of 2.7. Metastatic melanoma exhibited very strong nuclear staining, with a mean labeling intensity of 3.0. Invasive desmoplastic melanoma, like melanoma in situ, showed moderate nuclear staining with a mean labeling intensity of 2.1. There was a trend toward more intense staining with melanoma progression. A statistically significant difference in the mean labeling intensity of Ets-1 was seen between invasive melanoma and benign melanocytic nevi (P <.0001). Ets-1 oncoprotein expression, however, does not distinguish among benign melanocytic lesions. Staining intensity and pattern might be a useful adjunct with histomorphology in distinguishing invasive melanoma from benign melanocytic nevi. Furthermore, Ets-1 expression may be an important pathogenic mechanism and predictor of aggressive biologic behavior of cutaneous melanoma, with a trend toward staining intensity increasing as Clark stage increases.

Introduction: Histopathologic criteria are usually sufficient for the accurate distinction of benign from malignant dermal vascular tumors. A minority of cases, however, pose a vexing diagnostic dilemma. Recent studies suggest that caveolin, a scaffolding cell membrane protein, may prove helpful in predicting the biologic behavior of endothelial-derived neoplasms., Methods: We analyzed a series of 30 dermal vascular tumors including 12 lobular capillary hemangiomas (LCH), 4 cases of targetoid hemosiderotic hemangiomas (TH), 4 cases of tufted angioma (TA), 12 cases of Kaposi's sarcoma (KS), 4 epithelioid (EH) and 1 spindle cell hemangioendothelioma (SH), and 4 cases of angiosarcoma (AS). The distribution of immunoreactivity was analyzed by quantifying cell membrane staining in each case., Results: There was a statistically significant difference in the expression of caveolin between LCH (mean labeling index=91.6), TH (mean labeling index=89.7), and TA (mean labeling index=87.2) and the cases of KS (mean labeling index=21.6, EH mean labeling index= 23.1), and the AS (mean labeling index=6.3)., Conclusions: These results indicate that antibodies to caveolin may be useful in separating benign and malignant dermal vascular tumors and possibly implicates this peptide in their pathogenesis.