Two Cases of Cutaneous Sarcomatoid Squamous Cell Carcinoma Resembling Cutaneous Giant Cell Tumor of Soft Tissue.

ABSTRACT: Cutaneous sarcomatoid squamous cell carcinoma is well-described with histology resembling pleomorphic undifferentiated sarcoma featuring collagenous or myxoid stroma with or without elements of keratinizing squamous carcinoma. This report presents 2 cases of dedifferentiated squamous cell carcinoma (SCC) composed of sheets of malignant mononuclear cells with malignant osteoclast-like multinucleated giant cells, extravasated blood, and hemosiderin resembling cutaneous giant cell tumor (cGCT). In the first case, an exophytic facial mass of a 96-year-old woman removed by shave showing extensive cGCT-like tumor but with microscopic elements of SCC in situ and positivity for cytokeratin 5/6 in the malignant spindle cells and SCC. The second case involved a 32-year-old man with a pedunculated penile mass removed by shave biopsy, displaying malignant cytology resembling cGCT, focal staining for cytokeratin AE1/AE3 and p63, and CD68 highlighting the osteoclast-like giant cells. Molecular analysis revealed CDKN2A, TP53, and TERT. Upon reexcision, case 2 showed focally invasive keratinizing SCC associated with differentiated penile intraepithelial neoplasia and lichen sclerosus. Skin specimens with an exophytic mass histologically resembling cGCT but with malignant cytology should be meticulously evaluated for elements of SCC. Molecular analysis, detecting mutations like H3F3 or HMGA2-NCOR2 fusion, can aid in distinguishing cutaneous sarcomatoid squamous cell carcinoma from GCT bone or GCT soft tissue.

Lymphangitic Melanomatosis: Case Report of Intralymphatic Spread of Melanoma in a 66-year-old Man.

ABSTRACT: Melanoma with lymphatic invasion has been associated with increased risk of metastasis, but the mechanisms and clinical implications are poorly understood. Although current reports have documented angiotropic spread of melanoma and suggest lymphatic spread of melanoma to increase the likelihood of metastasis, to our knowledge, lymphangitic metastatic melanoma resembling cutaneous carcinomatosis or presenting with facial hyperpigmentation has not been described. In this case report, we describe extensive cutaneous intralymphatic spread of melanoma, or lymphangitic melanomatosis, producing macular skin pigmentation in a 66-year-old man.

Molecular Profiling of Syringocystadenocarcinoma Papilliferum Reveals RAS-Activating Mutations.

CONTEXT.­: Syringocystadenocarcinoma papilliferum (SCACP) is a rare adnexal carcinoma and the malignant counterpart of syringocystadenoma papilliferum (SCAP), which is commonly located on the head and neck and may arise in association with a nevus sebaceus. RAS mutations have been identified in both SCAP and nevus sebaceus. OBJECTIVE.­: To evaluate the clinicopathologic and molecular features of SCACPs, which have not been previously explored. DESIGN.­: We obtained 11 SCACPs from 6 institutions and reviewed the clinicopathologic features. We also performed molecular profiling using next-generation sequencing. RESULTS.­: The cohort comprised 6 women and 5 men with ages ranging from 29 to 96 years (mean, 73.6 years). The neoplasms occurred on the head and neck (n = 8; 73%) and extremities (n = 3; 27%). Three tumors possibly arose in a nevus sebaceus. A total of 4 cases showed at least carcinoma in situ (adenocarcinoma, n = 3; squamous cell carcinoma [SCC], n = 1), and 7 cases were invasive (SCC, n = 5; mixed adenocarcinoma + SCC, n = 2). A total of 8 of 11 cases (73%) had hot spot mutations consisting of HRAS (n = 4), KRAS (n = 1), BRAF (n = 1), TP53 (n = 4), ATM (n = 2), FLT3 (n = 1), CDKN2A (n = 1), and PTEN (n = 1). All 4 cases with HRAS mutations occurred on the head and neck, whereas the KRAS mutation occurred on the extremity. CONCLUSIONS.­: RAS-activating mutations were detected in 50% of the cases, of which most (80%) involved HRAS and occurred on the head and neck, which shows overlapping features with SCAP, supporting that a subset may arise as a result of malignant transformation and likely an early oncogenic event.

ANCA vasculitis expands the spectrum of autoimmune manifestations of activated PI3 kinase δ syndrome.

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a combined immunodeficiency with a broad clinical phenotype, including not only an increased propensity for sinopulmonary and herpesviruses infections but also immune dysregulation, such as benign lymphoproliferation, autoimmunity, and malignancy. Autoimmune complications are increasingly recognized as initial presenting features of immune dysregulation in inborn errors of immunity (IEIs), including APDS, so awareness of the spectrum of autoimmune features inherit within these disorders is critical. We present here a patient vignette to highlight cutaneous antineutrophil cytoplasmic antibody (ANCA) vasculitis as an underrecognized autoimmune manifestation of APDS. The genetic defects underlying APDS result in increased PI3Kδ signaling with aberrant downstream signaling pathways and loss of B- and/or T-cell immunologic tolerance mechanisms, which promote the development of autoimmunity. An understanding of the molecular pathways and mechanisms that lead to immune dysregulation in APDS has allowed for significant advancements in the development of precision-medicine therapeutics, such as leniolisib, to reduce the morbidity and mortality for these patients. Overall, this case and review highlight the need to maintain a high index of suspicion for IEIs, such as APDS, in those presenting with autoimmunity in combination with a dysregulated immune phenotype for prompt diagnosis and targeted intervention.

Increased tryptophan, but not increased glucose metabolism, predict resistance of pembrolizumab in stage III/IV melanoma.

Clinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to show additional clinical benefit compared to PD1-alone inhibition. We reasoned that a tryptophan-metabolizing pathway other than the kynurenine one is essential. We immunohistochemically stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1. We assessed tryptophan and glucose metabolism by performing baseline C11-labeled α-methyl tryptophan (C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective clinical trial of pembrolizumab in MM (clinicaltrials.gov, NCT03089606). We found higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating lymphocytes (TILs) within MM tumors (n = 68). Melanoma cell-specific TPH1 and LAT1 expressions were significantly anti-correlated with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression were associated with worse overall survival (OS) in MM. Exploratory optimal cutpoint survival analysis of pretreatment 'high' vs. 'low' C11-AMT SUVmax of the hottest tumor lesion per patient revealed that the 'low' C11-AMT SUVmax was associated with longer progression-free survival in our clinical trial (n = 26). We saw no such trends with pretreatment FDG PET SUVmax. Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO expression and kynurenine production in addition to suppression of serotonin production. High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving the latter of an essential amino acid.

Concomitance of Hidradenitis Suppurativa and Porokeratoses.

Objective: No known studies have attempted to describe the pathophysiological relationship between patients who develop both porokeratosis and hidradenitis suppurativa (HS). The purpose of this report is to present possible immunological mechanisms that predispose patients to developing both porokeratosis and HS. Methods: In this case series, patients were identified during routine clinical encounters and data was extracted from the electronic medical record from October 2010 until April 2021. This study is a single center case series including patients from the department of dermatology at the UNC School of Medicine in Chapel Hill, North Carolina. Patients were selected via digital chart review if they had simultaneous diagnoses of disseminated porokeratosis and HS. Two eligible patients were identified as actively receiving care. One patient is a Black female and the other a White male. No primary study outcomes were planned. This investigation utilized chart review to identify disease time course, which was subsequently used to elucidate study outcomes. Results: Patient A is a 54-year-old Black female and Patient B is a 65-year-old White male. Both patients developed porokeratosis after multiple years of living with HS. Immunosuppression with adalimumab, corticosteroids, or other medications did not clearly precede porokeratosis development in either patient. Limitations: Limitations include that this study was conducted at a single center and prevalence of patients with concomitance of both conditions is low. Conclusion: In patients who demonstrate simultaneous HS and porokeratosis, activation of the innate immune system and associated IL-1 production may lead to autoinflammation and a phenotype of hyperkeratinization. Mutations in genes such as mevalonate kinase may predispose subjects to the development of porokeratoses and HS.

InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma.

INTRODUCTION: We are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients. We also evaluated tissue-derived predictors of extracted nucleic acids' quality and success in downstream testing. This ongoing study will target 1,000 melanomas within the international InterMEL consortium. METHODS: Following a pre-established protocol, participating centers ship formalin-fixed paraffin embedded (FFPE) tissue sections to Memorial Sloan Kettering Cancer Center for the centralized handling, dermatopathology review and histology-guided coextraction of RNA and DNA. Samples are distributed for evaluation of somatic mutations using next gen sequencing (NGS) with the MSK-IMPACTTM assay, methylation-profiling (Infinium MethylationEPIC arrays), and miRNA expression (Nanostring nCounter Human v3 miRNA Expression Assay). RESULTS: Sufficient material was obtained for screening of miRNA expression in 683/685 (99%) eligible melanomas, methylation in 467 (68%), and somatic mutations in 560 (82%). In 446/685 (65%) cases, aliquots of RNA/DNA were sufficient for testing with all three platforms. Among samples evaluated by the time of this analysis, the mean NGS coverage was 249x, 59 (18.6%) samples had coverage below 100x, and 41/414 (10%) failed methylation QC due to low intensity probes or insufficient Meta-Mixed Interquartile (BMIQ)- and single sample (ss)- Noob normalizations. Six of 683 RNAs (1%) failed Nanostring QC due to the low proportion of probes above the minimum threshold. Age of the FFPE tissue blocks (p<0.001) and time elapsed from sectioning to co-extraction (p = 0.002) were associated with methylation screening failures. Melanin reduced the ability to amplify fragments of 200bp or greater (absent/lightly pigmented vs heavily pigmented, p<0.003). Conversely, heavily pigmented tumors rendered greater amounts of RNA (p<0.001), and of RNA above 200 nucleotides (p<0.001). CONCLUSION: Our experience with many archival tissues demonstrates that with careful management of tissue processing and quality control it is possible to conduct multi-omic studies in a complex multi-institutional setting for investigations involving minute quantities of FFPE tumors, as in studies of early-stage melanoma. The study describes, for the first time, the optimal strategy for obtaining archival and limited tumor tissue, the characteristics of the nucleic acids co-extracted from a unique cell lysate, and success rate in downstream applications. In addition, our findings provide an estimate of the anticipated attrition that will guide other large multicenter research and consortia.

A unique case of concurrent cutaneous lichen amyloidosis and myxedema.

Lichen amyloidosis is believed to be caused by damage to keratinocytes, often by chronic scratching. It has also been associated with autoimmune conditions, including thyroid disease. Dermatologic manifestations of poorly controlled thyroid disease are well described within the medical literature, within both hypothyroid and hyperthyroid states. Myxedema is a rare complication of Graves disease. We report a unique case of concurrent myxedema and lichen amyloidosis in a 63-year-old patient with uncontrolled hypothyroidism in the setting of post-ablative Graves disease.

Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study.

It is unclear why some melanomas aggressively metastasize while others remain indolent. Available studies employing multi-omic profiling of melanomas are based on large primary or metastatic tumors. We examine the genomic landscape of early-stage melanomas diagnosed prior to the modern era of immunological treatments. Untreated cases with Stage II/III cutaneous melanoma were identified from institutions throughout the United States, Australia and Spain. FFPE tumor sections were profiled for mutation, methylation and microRNAs. Preliminary results from mutation profiling and clinical pathologic correlates show the distribution of four driver mutation sub-types: 31% BRAF; 18% NRAS; 21% NF1; 26% Triple Wild Type. BRAF mutant tumors had younger age at diagnosis, more associated nevi, more tumor infiltrating lymphocytes, and fewer thick tumors although at generally more advanced stage. NF1 mutant tumors were frequent on the head/neck in older patients with severe solar elastosis, thicker tumors but in earlier stages. Triple Wild Type tumors were predominantly male, frequently on the leg, with more perineural invasion. Mutations in TERT, TP53, CDKN2A and ARID2 were observed often, with TP53 mutations occurring particularly frequently in the NF1 sub-type. The InterMEL study will provide the most extensive multi-omic profiling of early-stage melanoma to date. Initial results demonstrate a nuanced understanding of the mutational and clinicopathological landscape of these early-stage tumors.

Melanoma In Situ of the Hard Palate.

Mucosal melanoma of the oral cavity is rare and highly aggressive, thought to represent less than 1% of melanomas. Within this subgroup, melanoma in situ has been rarely described. We describe the case of a 54-year-old male with history of tobacco use presented with extensive pigmented changes to the hard and soft palate. Biopsy demonstrated melanoma in situ. Mucosal surgical resection was performed with all peripheral epithelial margins involved and negative deep margins. After extensive multidisciplinary discussion, remaining mucosal margins were re-resected to the teeth and posteriorly onto the soft palate. Deep margins remained negative with melanoma in situ still present peripherally. The patient is routinely surveilled without evidence of recurrence. Oral cavity melanoma in situ has been rarely described. The treatment of choice is surgical excision, ranging from wide local excision to composite resections, with consideration given to medical adjuncts. This unique entity should be considered in pigmented oral abnormalities.

Theragnostic significance of tumor-infiltrating lymphocytes and Ki67 in BRAFV600-mutant metastatic melanoma (BRIM-3 trial).

We conducted a retrospective tumor tissue analysis as part of the BRIM3 trial to evaluate the theragnostic significance of tumor-infiltrating lymphocytes (TILs) and melanoma cell proliferation. Using manual semi-quantitative analyses, we assessed the density of TILs by pathology review of tissue sections stained with hematoxylin and eosin (H&E TIL score) and by immunohistochemistry (IHC) with an anti-CD8 antibody (CD8 TIL score); also, the melanoma cell proliferation by IHC with an anti-Ki67 antibody. Three hundred and fifty-three, 280, and 172 patients' tumor tissue samples were available for H&E, CD8, and Ki67 IHC analysis, respectively. There was no association between high (2+, 3+) peritumoral and intratumoral H&E and/or TIL CD8 score or high Ki67 proliferation index (>15%) with serum LDH level and stage IV melanoma. Neither high Ki67 proliferation, nor high peritumoral and/or intratumoral TIL score was significantly associated with objective antitumor response in any treatment arm. High intratumoral and high peritumoral CD8 TIL score was significantly associated with progression-free survival (PFS) only in DTIC-treated patients (P = 0.002 and 0.037, respectively); in vemurafenib-treated patients, high intratumoral and/or peritumoral CD8 TIL score was not significant (log-rank P = 0.053 and 0.062, respectively). Nevertheless, a high peritumoral CD8 TIL score was a significant predictor of PFS and overall survival after adjustment for age, sex, serum LDH, ECOG performance status, and treatment arm in a Cox regression model. Vemurafenib does not only benefit patients bearing brisk TILs; even vemurafenib-treated patients with absent and/or non-brisk TILs tend to have longer PFS compared to DTIC-treated patients with brisk TILs. High peritumoral CD8 TIL score is a favorable prognostic factor independent of well-established AJCC staging factors.

The clinical significance of adenomatous polyposis coli (APC) and catenin Beta 1 (CTNNB1) genetic aberrations in patients with melanoma.

BACKGROUND: Melanoma-intrinsic activated ß-catenin pathway, the product of the catenin beta 1 (CTNNB1) gene, has been associated with low/absent tumor-infiltrating lymphocytes, accelerated tumor growth, metastases development, and resistance to anti-PD-L1/anti-CTLA-4 agents in mouse melanoma models. Little is known about the association between the adenomatous polyposis coli (APC) and CTNNB1 gene mutations in stage IV melanoma with immunotherapy response and overall survival (OS). METHODS: We examined the prognostic significance of somatic APC/CTNNB1 mutations in the Cancer Genome Atlas Project for Skin Cutaneous Melanoma (TCGA-SKCM) database. We assessed APC/CTNNB1 mutations as predictors of response to immunotherapies in a clinicopathologically annotated metastatic patient cohort from three US melanoma centers. RESULTS: In the TCGA-SKCM patient cohort (n = 434) presence of a somatic APC/CTNNB1 mutation was associated with a worse outcome only in stage IV melanoma (n = 82, median OS of APC/CTNNB1 mutants vs. wild-type was 8.15 vs. 22.8 months; log-rank hazard ratio 4.20, p = 0.011). APC/CTNNB1 mutation did not significantly affect lymphocyte distribution and density. In the 3-melanoma institution cohort, tumor tissues underwent targeted panel sequencing using two standards of care assays. We identified 55 patients with stage IV melanoma and APC/CTNNB1 genetic aberrations (mut) and 169 patients without (wt). At a median follow-up of more than 25 months for both groups, mut compared with wt patients had slightly more frequent (44% vs. 39%) and earlier (66% vs. 45% within six months from original diagnosis of stage IV melanoma) development of brain metastases. Nevertheless, time-to-development of brain metastases was not significantly different between the two groups. Fortunately, mut patients had similar clinical benefits from PD-1 inhibitor-based treatments compared to wt patients (median OS 26.1 months vs. 29.9 months, respectively, log-rank p = 0.23). Less frequent mutations in the NF1, RAC1, and PTEN genes were seen in the mut compared with wt patients from the 3-melanoma institution cohort. Analysis of brain melanoma tumor tissues from a separate craniotomy patient cohort (n = 55) showed that melanoma-specific, activated ß-catenin (i.e., nuclear localization) was infrequent (n = 3, 6%) and not prognostic in established brain metastases. CONCLUSIONS: APC/CTNNB1 mutations are associated with a worse outcome in stage IV melanoma and early brain metastases independent of tumor-infiltrating lymphocyte density. However, PD1 inhibitor-based treatments provide comparable benefits to both mut and wt patients with stage IV melanoma.

Carbol fuchsin stain enhances detection of poly-(d, l-lactide-co-glycolide) microspheres in exenatide extended-release cutaneous injection-site foreign body reaction.

Injection of high-viscosity fluids into subcutaneous tissues may lead to a granulomatous reaction called sclerosing lipogranuloma (SL). Poly-(d,l-lactide-co-glycolide) (PLG or PLGA) microspheres are used as vehicles for extended-release drugs. Here we describe the histopathologic features of a case of SL induced by exenatide extended-release injections, and the staining pattern of PLG microspheres and microsphere remnants with carbol fuchsin.