Subungual melanoma with cartilaginous differentiation: Molecular insights.

Melanoma's rare capacity to undergo heterologous differentiation can create significant diagnostic challenges. The molecular mechanisms underlying this phenomenon are not well understood. We present an unusual case of subungual melanoma exhibiting extensive cartilaginous differentiation and provide insights into its molecular and cytogenomic features. Histopathologically, the tumor was predominantly composed of nodules of malignant cartilage in association with a smaller population of nested epithelioid to rhabdoid cells. Immunohistochemically, the tumor cells in both components were positive for S100, SOX10, and PRAME, and were negative for Melan-A and HMB-45. Molecular analysis by whole exome DNA sequence did not detect any pathogenic variants in genes commonly implicated in melanoma. Additional analysis by SNP chromosomal microarray revealed a complex genome characterized by numerous chromosomal losses and gains, including a homozygous deletion of the CDKN2A locus and a heterozygous deletion of the locus containing EXT2, a tumor suppressor implicated in hereditary multiple osteochondromas and secondary chondrosarcomas. This case underscores the importance of recognizing cartilaginous differentiation as a rare manifestation of melanoma, particularly at subungual sites, and suggests that at least some of these melanomas may be driven by non-canonical molecular pathways.

A novel method to assess copy number variations in melanocytic neoplasms: Droplet digital PCR for precise quantitation of MYC and MYB genes.

INTRODUCTION: While most melanocytic neoplasms can be classified as either benign or malignant by histopathology alone, ancillary molecular diagnostic tests can be necessary to establish the correct diagnosis in challenging cases. Currently, the detection of copy number variations (CNVs) by fluorescence in situ hybridization and chromosomal microarray (CMA) are the most popular methods, but remain expensive and inaccessible. We aim to develop a relatively inexpensive, fast, and accessible molecular assay to detect CNVs relevant to melanoma using droplet digital polymerase chain reaction (ddPCR) technology. METHODS: In this proof-of-concept study, we evaluated CNVs in MYC and MYB genes from 73 cases of benign nevi, borderline melanocytic lesions, and primary and metastatic melanoma at our institution from 2015 to 2022. A multiplexed ddPCR assay and CMA were performed on each sample, and the results were compared. RESULTS: Concordance analysis of ddPCR with CMA for quantification of MYC and MYB CNVs revealed a sensitivity and specificity of 89% and 86% for MYC and 83% and 74% for MYB, respectively. CONCLUSION: We demonstrate the first use of a multiplexed ddPCR assay to identify CNVs in melanocytic neoplasms. With further improvement and validation, ddPCR may represent a low-cost and rapid tool to aid in the diagnosis of histopathologically ambiguous melanocytic tumors.

Anti-PL-7, anti-Ro/SSA, anti-Mi-2, and anti-TIF1-γ correlate with specific patterns of histopathologic features in dermatomyositis: An analysis of 39 skin biopsy specimens from 25 patients.

BACKGROUND: In dermatomyositis (DM), myositis-specific and myositis-associated antibodies have been correlated with clinical features. It is unknown if histopathologic findings in lesional skin biopsies correlate with serologic subtypes of DM. METHODS: A retrospective chart review of patients with DM was performed. Patients with myositis antibodies and DM lesional skin biopsies were included in the study. Skin biopsies were reviewed by blinded dermatopathologists for 20 histopathologic features. RESULTS: There was a statistically significant (p < 0.05) association between anti-PL-7 serology and decreased degree of vacuolar degeneration, necrotic keratinocytes, and thickening of the epidermal basement membrane. Anti-aminoacyl tRNA synthetase (anti-ARS) antibodies had the same significant negative association with degree of vacuolar degeneration, necrotic keratinocytes, and thickening of the epidermal basement membrane. A similar pattern was seen with an anti-cytoplasmic serology; where there was a significant association with an increased degree of vacuolar degeneration and necrotic keratinocytes, and a nonsignificant trend of minimally thickened epidermal basement membrane. There was a statistically significant association between anti-Ro/SSA serology and increased degree of vacuolar degeneration. Anti-TIF1-γ serology was significantly associated with the increased presence of necrotic keratinocytes and pigment incontinence, and displayed a pattern of increased neutrophils. There was a significant association between anti-Mi-2 antibodies and pigment incontinence, as well as between myositis-specific antibodies and pigment incontinence. A statistically significant positive association was found between nuclear antibodies and degree of vacuolar degeneration, thickened epidermal basement membrane, pigment incontinence, and epidermal atrophy. CONCLUSION: In patients with DM, some specific serotypes, including anti-PL-7, anti-Ro/SSA, anti-Mi-2, and anti-TIF1-γ, may have characteristic histopathologic features.

Cutaneous Collagenous Vasculopathy: A Short Case Series and Literature Review.

ABSTRACT: Cutaneous collagenous vasculopathy (CCV) is a rare and idiopathic microangiopathy of superficial dermal blood vessels. There have been 75 cases described in the literature to date, not including the current report; however, given its clinical similarity to other primary telangiectasias, it is likely to be underreported and underdiagnosed. Here, we describe the clinical and histological features of 2 patients we newly diagnosed with CCV. Both generally fit the profile of prior cases and confirm previously described associations-they both are older White women, have rashes on their lower extremities, and have conditions and medications that are common among other reported cases. However, both are also somewhat atypical, as Patient 1 had symptomatic CCV and Patient 2 had a papular rash. As such, both cases broaden the spectrum of our current understanding of CCV. We also provide a comprehensive review of all published reports of CCV to date and uncover 2 previously unreported associations: one with visceral malignancy, and the other with hypothyroidism. Whether these association are coincidental is worth investigating in future studies.

A Mimicker of Differentiated Vulvar Intraepithelial Neoplasia: Reactive Atypia From Noncompliance With Lichen Sclerosus Therapy.

ABSTRACT: Differentiated vulvar intraepithelial neoplasia (d-VIN) is an HPV-independent precursor to vulvar squamous cell carcinoma. The histology of d-VIN lesions is difficult to differentiate from that of non-neoplastic epithelial disorders, especially lichen sclerosus (LS). The authors present a case of LS, where relying on histopathology alone could have led to misdiagnosis. The patient was a 17-year-old female patient with clinical features of vulvar dermatitis and LS for 2 years. She was counseled to apply clobetasol 0.05% to the affected area daily but reported no improvement after 6 months. A biopsy of the right labia majora revealed histologic findings typical of d-VIN and near-contiguous p53 expression. These features are characteristic of d-VIN. However, d-VIN is exceedingly rare in young patients. The case was reviewed by 6 dermatopathologists and gynecologic pathologists, who observed that the degree of inflammation would be unusual postclobetasol therapy and could be due to noncompliance. A review of the patient's chart revealed that she "does not always remember to apply" clobetasol. The patient's clinician confirmed that there were compliance issues, and the follow-up biopsy was negative for d-VIN. The case was signed out as LS, with a note describing the above, and to rebiopsy if concern persisted. The authors conjecture that inflammatory infiltrates in the biopsied area caused reactive atypia due to lack of adherence to treatment. Although the patient's age helped rule out d-VIN, similar cases in elderly patients may be occurring. Pathologists must be aware that reactive forms of untreated LS can mimic d-VIN, to avoid misdiagnosis.

Squamoid eccrine ductal carcinoma: clinical, histological and immunohistochemical features.

Squamoid eccrine ductal carcinoma (SEDC) is a cutaneous adnexal malignancy that is histologically challenging to distinguish from squamous cell carcinoma. We report three cases of this rare entity and review the present literature regarding clinical, histological, and immunohistochemical features. Patients presented with a single nodule or plaque lesion on their back and temple. The shave biopsies for Patient A and C were interpreted as SEDC. Patient B's initial shave biopsy was interpreted as probable surface of squamous cell carcinoma, and subsequent excision revealed SEDC. Ductal differentiation was confirmed by positive expression of epithelial membrane antigen and carcinoembryonic antigen immunostains in all three patients. Review of the 67 previously reported cases emphasizes the importance of diagnosing SEDC accurately and promptly given its potential for distant metastasis and mortality. Perineural or lymphatic invasion is associated with higher rate of recurrence or metastasis. There should be high pathologic suspicion for SEDC in an elderly patient presenting with a palpable lesion, even if located outside of the head and neck area, particularly when there is suggestion of ductal differentiation in a sample of a squamous neoplasm.

Cutaneous myoepithelioma with EWSR1 gene rearrangement and its differentials: A diagnostic challenge.

Cutaneous myoepithelioma is a rare benign soft tissue neoplasm of myoepithelial cells involving the skin and subcutis. These tumors can be diagnostically challenging. The plasticity of myoepithelial cells leads to wide variability in the cytomorphology, immunophenotype, and genetic features of myoepithelioma. Their protean presentations may mimic malignant neoplasms. Therefore, distinction from malignancy is essential. Herein, we report a case of cutaneous myoepithelioma presenting similarly to Ewing sarcoma, with small round blue cells and an EWSR1 rearrangement. Our case highlights the important morphologic, immunohistochemical, and cytogenetic features of this benign basaloid cutaneous tumor.

Adnexotropic and granulomatous mycosis fungoides following TNF-α inhibitor treatment.

Recent publications have documented an increased prevalence of cutaneous T-cell lymphoma (CTCL) in patients undergoing tumor necrosis factor alpha (TNF-α) inhibitor therapy. Herein, we present an uncommon manifestation of mycosis fungoides (MF) with unique pathological findings after the initiation of adalimumab therapy for the treatment of psoriasis. One year after starting treatment, the patient noticed a slowly growing, eroded plaque on the left cheek, the biopsy of which demonstrated mixed granulomatous and adnexotropic lymphocytic infiltrate with features characteristics of MF. In the following months, the patient developed pink- and violet-colored scaly plaques on the right posterior upper arm and right medial upper arm. Biopsy of these plaques also revealed findings compatible with MF. T-cell receptor (TCR) clonality studies by PCR revealed identical T-cell clones in the samples obtained from the cheek, right posterior upper arm, and right medial upper arm. TCR clonality studies of a long-standing psoriatic plaque on the right thigh failed to reveal similar T-cell clones. Blurring of histopathologic presentation by TNF-α inhibitors could greatly complicate the identification of MF subtypes. Providers treating patients with TNF-α inhibitors must be aware of the risk of cutaneous lymphoma development and the potential deviations from their expected presentations. In patients without an initial biopsy, the possibility of pre-existing CTCL with psoriasiform presentation should be considered.

A novel method to assess copy number variation in melanoma: Droplet digital PCR for precise quantitation of the RREB1 gene in formalin-fixed, paraffin-embedded melanocytic neoplasms, a proof-of-concept study.

BACKGROUND: Melanocytic neoplasms can be challenging to diagnose. One well-established diagnostic aid is the detection of copy number variation (CNV) in a few key genetic loci using conventional methods such as fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA). Droplet digital polymerase chain reaction (ddPCR) is a novel, cost-effective, rapid, and automated method to detect CNV. METHODS: We perform the first investigation of ddPCR to assay Ras-responsive element-binding protein-1 (RREB1), the most common CNV in melanoma using formalin-fixed, paraffin-embedded (FFPE) melanocytic lesion samples; CMA data are used as the gold standard. Archival samples from 2013 to 2021 were analyzed, including 153 data points from 39 FFPE samples representing 34 patients. Benign, borderline, malignant, and metastatic melanocytic neoplasms were examined. RESULTS: ddPCR showed a sensitivity and specificity of 93.8% and 95.7% using one reference gene, and 87.5% and 100% using a different reference gene for RREB1 gain detection. CONCLUSIONS: Here we show that ddPCR can provide inexpensive, rapid, and robust data on the commonest copy number alteration in melanoma. Future development and validation could provide a useful ancillary tool in the diagnosis of challenging melanocytic lesions.

Histiocytoid melanoma: Diagnostic pitfall and mimicker of non-Langerhans cell histiocytoses including reticulohistiocytoma.

Melanoma and benign histiocytic proliferations can sometimes show considerable clinical and histopathologic overlap. Recently, cases of melanomas resembling xanthogranuloma and Rosai-Dorfman disease have been reported, and herein we report a case of melanoma closely mimicking reticulohistiocytoma. An 84-year-old man presented with a 1 cm purple-red nodule on his arm concerning for squamous cell carcinoma. While the biopsy findings resembled reticulohistiocytoma, the clinical context and regression changes at the lesion perimeter raised stronger concern for melanoma, which was confirmed with immunohistochemistry. We review prior rare reports of melanomas resembling non-Langerhans cell histiocytic proliferations and summarize helpful clinical and histopathologic clues to avoid a diagnostic pitfall when confronted with this unusual quandary.

PRAME expression in cutaneous melanoma does not correlate with disease-specific survival.

BACKGROUND: Immunohistochemistry-based protein biomarkers can provide useful prognostic information in cutaneous melanoma. The independent prognostic value of Ki-67 has been studied with variable results. PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry is a useful new ancillary tool for distinguishing cutaneous nevi from melanoma; however, its prognostic value has not been well studied. We evaluated PRAME as a prognostic marker in cutaneous melanoma, compared to Ki-67. METHODS: We analyzed the immunohistochemical expression of PRAME and Ki-67 in 165 melanocytic lesions, including 92 primary melanomas, 19 metastatic melanomas, and 54 melanocytic nevi using tissue microarrays. PRAME immunostaining was scored based on the percentage of positive nuclei: 0 <1%, 1+ 1%-25%, 2+ 26%-50%, 3+ 51%-75%, and 4+ >75%. The percentage of Ki-67-positive tumor nuclei was used to calculate the proliferation index. RESULTS: PRAME and Ki-67 both showed significantly increased expression in melanomas compared to nevi (p < 0.0001 and p < 0.001, respectively). There was no significant difference in PRAME expression in primary versus metastatic melanomas. By contrast, the Ki-67 proliferation index was higher in metastatic melanoma than in primary melanoma (p = 0.013). Increased Ki-67 index correlated with ulceration (p < 0.001), increased Breslow depth (p = 0.001), and higher mitotic rate (p < 0.0001), whereas increased PRAME expression correlated with higher mitotic rate (p = 0.047) and Ki-67 index (p = 0.007). Increased Ki-67 index correlated with worse disease-specific survival in patients with primary melanoma (p < 0.001), but PRAME expression did not show prognostic significance in disease-specific survival (p = 0.63). In a multivariable analysis of patients with primary melanoma, tumor Breslow depth, ulceration, mitotic rate, and Ki-67 index were each independent predictors of disease-specific survival (p = 0.006, 0.02, 0.001, and 0.04, respectively); however, PRAME expression was not predictive of disease-specific survival (p = 0.64). CONCLUSION: Ki-67 is an independent prognostic marker; although increased PRAME expression correlates with the Ki-67 proliferation index and mitotic rate, PRAME is not an independent prognostic marker for cutaneous melanoma. PRAME and Ki-67 are useful ancillary tools for distinguishing benign from malignant melanocytic lesions.

Gain of CCND1 May Occur Too Infrequently in Cutaneous Melanoma, and Too Late in Melanomagenesis, to Be Diagnostically Useful: Genomic Analysis of 88 Cases.

ABSTRACT: Genomic analysis is an important tool in the diagnosis of histologically ambiguous melanocytic neoplasms. Melanomas, in contrast to nevi, are characterized by the presence of multiple copy number alterations. One such alteration is gain of the proto-oncogene CCND1 at 11q13. In melanoma, gain of CCND1 has been reported in approximately one-fifth of cases. Exact frequencies of CCND1 gain vary by melanoma subtype, ranging from 15.8% for lentigo maligna to 25.1% for acral melanoma. We present a cohort of 72 cutaneous melanomas from 2017-2022 in which only 6 (8.3%) showed evidence of CCND1 gain by chromosomal microarray. This CCND1 upregulation frequency falls well below those previously published and is significantly lower than estimated in the literature ( P < 0.05). In addition, all 6 melanomas with CCND1 gain had copy number alterations at other loci (most commonly CDKN2A loss, followed by RREB1 gain), and 5 were either thick or metastatic lesions. This suggests that CCND1 gene amplification may be a later event in melanomagenesis, long after a lesion would be borderline or equivocal by histology. Data from fluorescence in situ hybridization, performed on 16 additional cutaneous melanomas, further corroborate our findings. CCND1 gain may not be a common alteration in melanoma and likely occurs too late in melanomagenesis to be diagnostically useful. We present the largest chromosomal microarray analysis of CCND1 upregulation frequencies in cutaneous melanoma, conjecture 3 hypotheses to explain our novel observation, and discuss implications for the inclusion or exclusion of CCND1 probes in future melanoma gene panels.

A Novel Method to Detect Copy Number Variation in Melanoma: Droplet Digital PCR for Quantitation of the CDKN2A Gene, a Proof-of-Concept Study.

ABSTRACT: A definitive diagnosis of nevus or melanoma is not always possible for histologically ambiguous melanocytic neoplasms. In such cases, ancillary molecular testing can support a diagnosis of melanoma if certain chromosomal aberrations are detected. Current technologies for copy number variation (CNV) detection include chromosomal microarray analysis (CMA) and fluorescence in situ hybridization. Although CMA and fluorescence in situ hybridization are effective, their utilization can be limited by cost, turnaround time, and inaccessibility outside of large reference laboratories. Droplet digital polymerase chain reaction (ddPCR) is a rapid, automated, and relatively inexpensive technology for CNV detection. We investigated the ability of ddPCR to quantify CNV in cyclin-dependent kinase inhibitor 2A ( CDKN2A ), the most commonly deleted tumor suppressor gene in melanoma. CMA data were used as the gold standard. We analyzed 57 skin samples from 52 patients diagnosed with benign nevi, borderline lesions, primary melanomas, and metastatic melanomas. In a training cohort comprising 29 randomly selected samples, receiver operator characteristic curve analysis revealed an optimal ddPCR cutoff value of 1.73 for calling CDKN2A loss. In a validation cohort comprising the remaining 28 samples, ddPCR detected CDKN2A loss with a sensitivity and specificity of 94% and 90%, respectively. Significantly, ddPCR could also identify whether CDKN2A losses were monoallelic or biallelic. These pilot data suggest that ddPCR can detect CDKN2A deletions in melanocytic tumors with accuracy comparable with CMA. With further validation, ddPCR could provide an additional CNV assay to aid in the diagnosis of challenging melanocytic neoplasms.

Molecular analysis of NUT-positive poromas and porocarcinomas identifies novel break points of YAP1::NUTM1 fusions.

BACKGROUND: Poromas, and their malignant counterparts, porocarcinomas, harbor recurrent translocations involving YAP1-MAML2, YAP1-NUTM1, and infrequently WWTR1-NUTM1; YAP1-NUTM1 being the most common in porocarcinomas. NUT immunohistochemistry (IHC) can be used to identify NUTM1-translocated tumors. This study sought to investigate potential novel NUTM1-fusion partners among NUT IHC-positive poromas and porocarcinomas. METHODS: Thirteen NUT IHC-positive poroid tumors (four poromas and nine porocarcinomas) were identified within a multi-institutional international cohort. Next-generation sequencing (NGS) assessed for NUTM1 fusion partners. RESULTS: NGS detected a NUTM1 fusion in 12 of 13 cases: YAP1-NUTM1 (11/12 cases) and WWTR1-NUTM1 (1/12 cases). Two of the cases (2/12) with NUTM1 fusion were not called by the NGS algorithm but had at least one read-spanning YAP1-NUTM1 break point upon manual review. A NUTM1 fusion was not identified in one case; however, the sample had low RNA quality. The following fusion events were identified: YAP1 exon 4::NUTM1 exon 3 in six cases, YAP1 exon 6::NUTM1 exon 2 in one case, YAP1 exon 3::NUTM1 exon 3 in three cases, WWTR1 exon 3::NUTM1 exon 3 in one case, and YAP1 exon 8::NUTM1 exon 3 fusion in one case. CONCLUSION: While no novel NUTM1 fusion partners were identified within our cohort, 12 of 13 cases had discoverable NUTM1 fusions; YAP1-NUTM1 fusion was detected in 11 cases (92%) and WWTR1-NUTM1 in 1 case (8%). These data corroborate findings from other recent investigations and further substantiate the utility of NUT IHC in diagnosing a subset of poroid neoplasms. In addition, two of our cases harbored fusions of YAP1 exon 6 to NUTM1 exon 3 and YAP1 exon 8 to NUTM1 exon 2, which have not been reported before in poroid neoplasms and indicate novel break points of YAP1.

Development and validation of a molecular tool to predict pathologic complete response in esophageal adenocarcinoma.

Pathologic complete response (pCR) to neoadjuvant chemoradiation for locally advanced esophageal adenocarcinoma (EAC) confers significantly improved survival. The ability to infer pCR may spare esophagectomy in some patients. Currently, there are no validated biomarkers of pCR. This study sought to evaluate whether a distinct signature of DNA copy number alterations (CNA) can be predictive of pCR in EAC. Pretreatment biopsies from 38 patients with locally advanced EAC (19 with pCR and 19 with pathologic partial/poor response) were assessed for CNA using OncoScan assay. A novel technique was employed where within every cytogenetic band, the quantity of bases gained by each sample was computed as the sum of gained genomic segment lengths weighted by the surplus copy number of each segment. A threefold cross-validation was used to assess association with pCR or pathologic partial/poor response. Forty patients with locally advanced EAC from The Cancer Genome Atlas (TCGA) constituted an independent validation cohort. Gains in the chromosomal loci 14q11 and 17p11 were preferentially associated with pCR. Average area under the receiver operating characteristic curve (AUC) for predicting pCR was 0.80 among the threefold cross-validation test sets. Using 0.3 megabases as the cutoff that optimizes trade-off between sensitivity (63%) and specificity (89%) in the discovery cohort, similar prediction performance for clinical and radiographic response was demonstrated in the validation cohort from TCGA (sensitivity 61%, specificity 82%). Copy number gains in the 14q11 and 17p11 loci may be useful for prediction of pCR, and, potentially, personalization of esophagectomy in EAC.

Comparison of adipophilin and recently introduced PReferentially expressed Antigen in MElanoma immunohistochemistry in the assessment of sebaceous neoplasms: A pilot study.

BACKGROUND: We and others have noticed consistent staining of sebaceous glands with PReferentially expressed Antigen in MElanoma (PRAME). We aimed to determine whether PRAME was as sensitive, specific, and interpretable as adipophilin for distinguishing sebaceous neoplasms (SNs) from other neoplasms. METHODS: Twenty SNs and 32 control cases were stained for PRAME and adipophilin. Extent of staining was scored as follows: 0, no staining; 1, <5% positivity; 2, 5% to 50% positivity; and 3, >50% positivity. Intensity was scored as negative, weak, moderate, or strong. A composite score was determined by adding the scores for extent and intensity. RESULTS: PRAME had positive composite scores in all 20 SNs in the more differentiated areas, whereas adipophilin had positive composite scores in 19/20 cases. PRAME showed positivity in the basaloid cells in 15/16 cases, whereas adipophilin was positive in 14. Among controls, PRAME and adipophilin had positive composite scores in 3/32 cases and 6/32 cases, respectively. CONCLUSIONS: PRAME and adipophilin are comparable in terms of distribution and intensity for staining sebocytes. In the basaloid cells, PRAME expression is often more diffuse and easier to detect than adipophilin. In comparing the SNs to the controls, PRAME was more sensitive and more specific than adipophilin. PRAME could be used as an additional marker of sebaceous differentiation in everyday practice.

A machine learning algorithm for simulating immunohistochemistry: development of SOX10 virtual IHC and evaluation on primarily melanocytic neoplasms.

Immunohistochemistry (IHC) is a diagnostic technique used throughout pathology. A machine learning algorithm that could predict individual cell immunophenotype based on hematoxylin and eosin (H&E) staining would save money, time, and reduce tissue consumed. Prior approaches have lacked the spatial accuracy needed for cell-specific analytical tasks. Here IHC performed on destained H&E slides is used to create a neural network that is potentially capable of predicting individual cell immunophenotype. Twelve slides were stained with H&E and scanned to create digital whole slide images. The H&E slides were then destained, and stained with SOX10 IHC. The SOX10 IHC slides were scanned, and corresponding H&E and IHC digital images were registered. Color-thresholding and machine learning techniques were applied to the registered H&E and IHC images to segment 3,396,668 SOX10-negative cells and 306,166 SOX10-positive cells. The resulting segmentation was used to annotate the original H&E images, and a convolutional neural network was trained to predict SOX10 nuclear staining. Sixteen thousand three hundred and nine image patches were used to train the virtual IHC (vIHC) neural network, and 1,813 image patches were used to quantitatively evaluate it. The resulting vIHC neural network achieved an area under the curve of 0.9422 in a receiver operator characteristics analysis when sorting individual nuclei. The vIHC network was applied to additional images from clinical practice, and was evaluated qualitatively by a board-certified dermatopathologist. Further work is needed to make the process more efficient and accurate for clinical use. This proof-of-concept demonstrates the feasibility of creating neural network-driven vIHC assays.

A clinical mimicker of melanoma with distinctive histopathology: Topical silver nitrate exposure.

Exposure to silver-containing compounds can result in reversible discoloration of the skin, presenting as an irregular brown or black macule, which can have a clinical appearance similar to melanoma. Both the clinical scenario and the histopathology are unique. Silver nitrate darkens with exposure to light, and the area can appear to change over time. On microscopic examination, there are coarse pigmented granules dispersed throughout the corneal layer, and largely absent from the remainder of the epidermis-although the precise location may depend on the duration of topical exposure. While argyria, its irreversible counterpart, has been well-characterized, only a single source has previously reported the histopathology of transient topical silver nitrate exposure. We present two cases, review the clinical and histopathologic differentials, and detail the distinctive histopathology that enables a diagnosis to be suggested in this clinical mimicker of melanoma.

Expanding the differential of cutaneous epithelioid tumors: A case of dedifferentiated liposarcoma with epithelioid features involving the skin, with review of the literature.

Liposarcomas are categorized into four distinct histopathological subtypes: atypical lipomatous tumors (ALT)/well-differentiated liposarcoma (WDL), dedifferentiated, myxoid, and pleomorphic. Dedifferentiated liposarcomas account for approximately 18% of all liposarcomas, characteristically arising in the deep soft tissue. They are reported to have lower rates of metastasis compared to other pleomorphic sarcomas.1 -3 The classic histopathologic appearance is ALT/WDL admixed or juxtaposed with a predominantly nonlipogenic sarcoma. Epithelioid features are rare, appearing in as few as 3% of tumors, and have not previously been reported in a superficial location. Herein, we present a 57-year-old male with intradermal and subcutaneous metastasis of his known deep dedifferentiated liposarcoma with epithelioid features. By H&E the tumor featured cords and sheets of crowded, plump, epithelioid cells with thick nuclear membranes and prominent nucleoli, which raised a broad differential including carcinoma and melanoma. By immunohistochemistry the tumor was diffusely positive for MDM2 and CDK4, on the other hand stains for Sox10, Melan A, MITF, CKAE1/3, desmin, and S100 protein were negative. This case serves as an opportunity to raise awareness of this rare morphological subtype, which can involve the skin and mimic epithelial and melanocytic malignancies. It can be a potential diagnostic pitfall, especially if metastases are the first presentation.

Melanocytic aggregates with unique morphology associated with regression of basal cell carcinoma.

BACKGROUND: Spontaneous regression of basal cell carcinomas (BCC) is a well-documented phenomenon. In practice, we have observed melanocytic aggregates associated with BCC at various stages of regression showing unique morphologic features. METHODS: Fourteen cases featuring melanocytic aggregates were retrospectively identified through a pathology database search. Clinical and histopathologic features were systematically evaluated, and additional immunohistochemical studies were performed. Melanocyte density within tumor nodules was compared to a group of control BCCs. RESULTS: All cases showed BCC at various stages of regression with associated melanocytic aggregates, as highlighted by Melan-A and SOX10 immunostains. Three of 14 cases (21.4%) had only dermal melanocytic nests, while 11 (78.6%) had both junctional and dermal nests. The melanocytic aggregates all had similar asymmetrical architecture and lacked maturation. The melanocytes were small, uniform, bland, and had minimal cytoplasm. Their nuclei were overlapping and hyperchromatic, and had inconspicuous nucleoli. None of the melanocytic aggregates stained for BRAFV600E by immunohistochemistry. No patient developed a recurrent or metastatic melanocytic lesion (median follow-up 42 months). Melanocyte density was higher in the case series than in the control BCCs (P = 0.0008). CONCLUSION: We described the unique morphology of melanocytic aggregates associated with BCC regression.