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Squamoid eccrine ductal carcinoma is a rare infiltrative tumor with morphologic features intermediate between squamous cell carcinoma (SCC) and sweat gland carcinomas such as microcystic adnexal carcinoma. Although currently classified as a sweat gland carcinoma, it has been debated whether squamoid eccrine ductal carcinoma is better classified as a variant of SCC. Furthermore, therapeutic options for patients with advanced disease are lacking. Here, we describe clinicopathologic features of a cohort of 15 squamoid eccrine ductal carcinomas from 14 unique patients, with next-generation sequencing DNA profiling for 12 cases. UV signature mutations were the dominant signature in the majority of cases. TP53 mutations were the most highly recurrent specific gene alteration, followed by mutations in NOTCH genes. Recurrent mutations in driver oncogenes were not identified. By unsupervised comparison of global transcriptome profiles in squamoid eccrine ductal carcinoma (n = 7) to SCC (n = 10), porocarcinoma (n = 4), and microcystic adnexal carcinoma (n = 4), squamoid eccrine ductal carcinomas displayed an intermediate phenotype between SCC and sweat gland tumors. Squamoid eccrine ductal carcinoma displayed significantly higher expression of 364 genes (including certain eccrine markers) and significantly lower expression of 525 genes compared with other groups. Our findings support the classification of squamoid eccrine ductal carcinoma as a carcinoma with intermediate features between SCC and sweat gland carcinoma.

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The JAK-STAT signalling pathway is primarily involved in cytokine signalling and induces various factors namely, erythropoietin, thrombopoietin, interferons, interleukins, and granulocyte colony-stimulating factors. These factors tremendously influenced understanding human health and illness, specifically cancer. Inhibiting the JAK/STAT pathway offers enormous therapeutic promises against cancer. Many JAK inhibitors are now being studied due to their efficacy in various cancer treatments. Further, the Nitrogen-heterocyclic (N-heterocyclic) scaffold has always shown to be a powerful tool for designing and discovering synthetic compounds with diverse pharmacological characteristics. The review focuses on several FDA-approved JAK inhibitors and their systematic categorization. The medicinal chemistry perspective is highlighted and classified review on the basis of N-heterocyclic molecules. Several examples of designing strategies of N-heterocyclic rings including pyrrolo-azepine, purine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrazole, thieno[3,2-d] pyrimidine, and, pyrimidine-based derivatives and their structure-activity relationships (SAR) are discussed. Among the various N-heterocyclic-based JAK inhibitors pyrimidine-containing compound 1 exhibited excellent inhibition activity against JAK2WT and mutated-JAK2V617F with IC50 of 2.01 and 18.84 nM respectively. Amino pyrimidine-containing compound 6 and thiopheno[3,2-d]pyrimidine-containing compound 13 expressed admirable JAK3 inhibition activity with IC50 of 1.7 nM and 1.38 nM respectively. Our review will support the medicinal chemists in refining and directing the development of novel N-heterocyclic-based JAK inhibitors.

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The vulva and perineum are rarely involved by acantholytic dyskeratoses, including Hailey-Hailey disease, Darier disease, papular acantholytic dyskeratosis of the genitocrural area, acantholytic dyskeratotic acanthoma, and warty dyskeratoma. These entities show broad histomorphologic overlap, generally requiring clinical correlation for definitive classification. This institutional series aims to better characterize vulvar acantholytic dyskeratoses and provide a practical literature review and diagnostic aid for gynecologic pathologists. Our institutional archives contained 16 vulvar acantholytic dyskeratoses diagnosed between 1990 and 2023. Affected patients were 36 to 79 (mean, 58) years old and presented with one or more asymptomatic (n = 9) or pruritic (n = 6) lesions involving the vulva (predominantly the labia majora), with additional perineal involvement in 2. Four patients have known Hailey-Hailey disease. Eleven cases comprised singular, raised, erythematous, or skin-colored papules, measuring 0.2 to 0.6 (mean, 0.3) cm. Two patients had oligofocal (both with known Hailey-Hailey disease) vulvar lesions, and 2 had multifocal vulvar lesions (one with known Hailey-Hailey disease). Histologically, all showed acantholysis and dyskeratoses (abundant in 8, focal in 8, with corps ronds generally more conspicuous than corps grains). Additional features included suprabasal clefting (n = 14), dermal papillomatosis (n = 12), and acanthosis (n = 8). Adnexal involvement was rare (n = 1). No histologic features reliably distinguished sporadic versus syndromic acantholytic dyskeratoses. Sporadic lesions were cured by local excision. Patients with Hailey-Hailey disease were variably responsive to corticosteroids. Neither our series nor the literature indicate a significant correlation between sporadic or syndromic acantholytic dyskeratosis and squamous cell carcinoma. Important differential diagnoses include pemphigus vulgaris and pemphigus vegetans, for which direct immunofluorescence may be performed, when indicated.

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The incidence of acute myocardial infarction is increasing in younger age groups, with differences in treatment and outcomes based on gender. ST-elevation myocardial infarction (STEMI) in young adults, however, is incompletely understood as most of the current studies were performed in homogenous populations, did not focus on STEMI, and lack direct comparisons with older adults. We performed a retrospective observational study using the Statewide Planning And Research Cooperative System for all admissions in New York State with a principal diagnosis of STEMI from 2011 to 2018. There were 58,083 STEMIs with the majority being male (68.2%) and non-Hispanic White (64.8%), with an average age of 63.9 ± 13.9 years. Of these, 8,494 (14.6%) occurred in patients aged <50 years. The proportion of STEMIs in women increased with age, from 19.2% in the <50-year-old age group to 48.9% in the ≥70-year-old age group. Young adults with STEMI had greater prevalence of obesity, current tobacco use, other substance use, and major psychiatric disorders, were more likely to receive revascularization, and had lower 1-year mortality than older age groups. Revascularization was associated with at least a 3 times lower odds ratio of 1-year mortality in all age groups. In conclusion, young adults with STEMI had a unique set of risk factors and co-morbidities and were more likely to undergo revascularization than older age groups. In all age groups, female gender was associated with a higher burden of co-morbidities, decreased use of revascularization, and increased 1-year mortality.

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Pleomorphic dermal sarcoma (PDS) is a rare cutaneous/subcutaneous neoplasm of purported mesenchymal differentiation that exists along a clinicopathologic spectrum with atypical fibroxanthoma (AFX). While PDS and AFX share histopathologic and immunohistochemical features, PDS exhibits deeper tissue invasion and has a higher rate of metastasis and local recurrence than AFX. Given its aggressive clinical course, early recognition and clinical management of PDS are essential for optimizing patient outcomes. This review aims to provide a brief overview of the clinicopathologic and molecular features, prognosis, and treatment of PDS.

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Subcutaneous leiomyosarcoma (LMS) is a rare, poorly understood variant. The current literature on the subject is sparse, consisting of isolated case reports and small clinicopathologic studies compromised by the inclusion of both its more common and indolent counterpart, cutaneous LMS (atypical intradermal smooth muscle neoplasm), as well as highly aggressive deep-seated tumors. Thus, precise clinicopathologic characterization is limited. Cases of subcutaneous LMS reviewed at the University of Michigan and Cleveland Clinic from 1994 to 2022 were included in this retrospective study. A total of 39 cases were identified. The mean age was 61 years, and the cohort was predominantly male (23/39; 59%). Tumors averaged 4.2 cm and most commonly arose on the extremities (32/39; 82%). The majority (38/39; 97%) were diagnosed at an early pathologic stage (pT1 or pT2). Histopathologically, most tumors were well-circumscribed and were assigned a Fédération Nationale des Centers de Lutte Contre le Cancer grade of either 1 or 2 (24/39; 62%). The majority (22/39; 56%) appeared to arise in association with a blood vessel. Of the 36 cases with accessible clinical data and follow-up (mean 34 mo, range 0 to 94 mo), 12 (33%) were noted to have metastasized, with the lung representing the most common anatomic location. One case recurred locally. Six of 36 patients (17%) died from the disease at an average of 47 months after diagnosis (range 16 to 94 mo). Metastasis or death from disease was significantly associated with the Fédération Nationale des Centers de Lutte Contre le Cancer grade ( P =0.0015), the presence of necrosis ( P =0.032), tumor size ( P =0.049), and AJCC tumor stage ( P =0.036). These data demonstrate that subcutaneous LMS are more aggressive than dermal-based tumors and have a prognosis akin to that of deep-seated LMS.

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CONTEXT.­: Hypertrophic lichen planus (HLP) is a variant of lichen planus that can be difficult to diagnose based on histopathologic features alone. Thus, patient clinical history and clinicopathologic correlation are essential considerations to make the correct diagnosis. OBJECTIVE.­: To discuss the clinical and histologic presentation of HLP and provide a thorough review of commonly encountered mimickers in the differential diagnosis. DATA SOURCES.­: Data were derived from a literature review, personal clinical and research experiences, and a review of cases in the archives of a tertiary care referral center. CONCLUSIONS.­: In general, HLP involves the lower extremities and is characterized by thickened, scaly nodules and plaques that are often pruritic and chronic in nature. HLP affects both males and females and is most common in adults 50 to 75 years of age. Unlike conventional lichen planus, HLP tends to have eosinophils and classically displays a lymphocytic infiltrate most concentrated around the tips of rete ridges. The differential diagnosis for HLP is broad and encompasses numerous entities in many different categories, including premalignant and malignant neoplasms, reactive squamoproliferative tumors, benign epidermal neoplasms, connective tissue disease, autoimmune bullous disease, infection, and drug-related reactions. Therefore, a high index of suspicion must be maintained to avoid a misdiagnosis and potential inappropriate treatments.

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Basal cell carcinoma (BCC) is the most common human malignancy and is a leading cause of nonmelanoma skin cancer-related morbidity. BCC has several histologic mimics which may have treatment and prognostic implications. Furthermore, BCC may show alternative differentiation toward a variety of cutaneous structures. The vast majority of BCCs harbor mutations in the hedgehog signaling pathway, resulting in increased expression of the GLI family of transcription factors. GLI1 immunohistochemistry has been shown to discriminate between several tumor types but demonstrates high background signal and lack of specificity. In this study, we evaluated the utility of GLI1 RNA chromogenic in situ hybridization (CISH) as a novel method of distinguishing between BCC and other epithelial neoplasms. Expression of GLI1 by RNA CISH was retrospectively evaluated in a total of 220 cases, including 60 BCCs, 37 squamous cell carcinomas (SCCs) including conventional, basaloid, and human papillomavirus infection (HPV)-associated tumors, 16 sebaceous neoplasms, 10 Merkel cell carcinomas, 58 benign follicular tumors, and 39 ductal tumors. The threshold for positivity was determined to be greater than or equal to 3 GLI1 signals in at least 50% of tumor cells. Positive GLI1 expression was identified in 57/60 BCCs, including metastatic BCC, collision lesions with SCC, and BCCs with squamous, ductal, or clear cell differentiation or with other unusual features compared to 1/37 SCCs, 0/11 sebaceous carcinomas, 0/5 sebaceomas, 1/10 Merkel cell carcinomas, 0/39 ductal tumors, and 28/58 follicular tumors. With careful evaluation, GLI1 RNA CISH is highly sensitive (95%) and specific (98%) in distinguishing between BCC and nonfollicular epithelial neoplasms. However, GLI1 CISH is not specific for distinguishing BCC from most benign follicular tumors. Overall, detection of GLI1 RNA by CISH may be a useful tool for precise classification of histologically challenging basaloid tumors, particularly in the setting of small biopsy specimens, metaplastic differentiation, or metastatic disease.

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Cutaneous vascular tumors constitute a heterogeneous group of entities that share overlapping morphologic and immunohistochemical features, which can be diagnostically challenging for pathologists and dermatopathologists. Our understanding and knowledge of vascular neoplasms have improved over time, resulting in both a refinement of their classification by the International Society for the Study of Vascular Anomalies (ISSVA) and an improvement in the accurate diagnosis and clinical management of vascular neoplasms. This review article aims to summarize the updated clinical, histopathological, and immunohistochemical characteristics of cutaneous vascular tumors, as well as to highlight their associated genetic mutations. Such entities include infantile hemangioma, congenital hemangioma, tufted angioma, spindle cell hemangioma, epithelioid hemangioma, pyogenic granuloma, Kaposiform hemangioendothelioma, retiform hemangioendothelioma, pseudomyogenic hemangioendothelioma, Kaposi sarcoma, angiosarcoma, and epithelioid hemangioendothelioma.

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SATB2 can be used as an immunohistochemical marker for osteoblastic differentiation. The differential diagnosis of a cutaneous sarcomatoid neoplasm sometimes includes osteosarcoma when the tumour concomitantly involves the skin, soft tissue, and bone, or when there is a past medical history of osteosarcoma. As the utility of SATB2 immunohistochemistry in these scenarios was unclear, we aimed to determine the frequency and the pattern of SATB2 expression in a variety of cutaneous sarcomatoid neoplasms. SATB2 expression by immunohistochemistry was evaluated by intensity (0-3) and extent (0-100%) of staining to generate an h-score for each case. Expression levels were classified into high-positive (h-score ≥100), low-positive (20-99), and negative (<20) groups. Positive SATB2 expression was observed in 18/23 (78%) atypical fibroxanthomas (AFX), 10/19 (53%) pleomorphic dermal sarcomas, 9/20 (45%) cutaneous sarcomatoid squamous cell carcinomas, 14/39 (36%) sarcomatoid melanomas, 2/13 (15%) poorly differentiated cutaneous angiosarcomas, 10/17 (59%) high-grade cutaneous leiomyosarcomas, and 7/8 (88%) osteosarcoma controls. With the exception of AFX, all cutaneous neoplasms showed significantly lower average h-scores than osteosarcoma. AFX gave the highest average h-score (71) and percentage of high-positive cases (48%) among all examined cutaneous neoplasms. Only two (1.5%) of all cutaneous cases showed strong intensity of staining. Common SATB2 expression in various cutaneous sarcomatoid neoplasms poses a potential diagnostic pitfall when the differential diagnosis includes osteosarcoma. Requirement of strong staining and a high-positive h-score improves the specificity of SATB2 in differentiating these tumours from osteosarcoma.

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Mesenchymal tumours with melanocytic expression can pose a diagnostic challenge because they frequently demonstrate both morphological and immunohistochemical overlap with other cutaneous melanocytic neoplasms. Therefore, they present potential pathological pitfalls that may lead to a misdiagnosis of malignant melanoma. Mesenchymal neoplasms that closely mimic melanoma include malignant melanotic nerve sheath tumour (melanotic schwannoma), epithelioid schwannoma, malignant peripheral nerve sheath, cutaneous syncytial myoepithelioma, clear cell sarcoma of soft tissue, and perivascular epithelioid cell tumour. Awareness of these melanoma mimics is necessary for establishing the correct diagnosis so that the appropriate clinical management can be rendered to the patient. This in-depth review highlights key diagnostic features and molecular genetics and also discusses the differential diagnosis and treatment of mesenchymal tumours that exhibit melanocytic expression.

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Sarcoidosis is a systemic inflammatory disorder characterized by the formation of non-caseating granulomas. Cutaneous involvement of sarcoidosis is common and has a wide variety of clinical presentations. Herein, we present a case of cutaneous sarcoidosis mimicking pigmented purpuric dermatosis (PPD) in a 26-year-old female treated with topical tofacitinib cream and a literature review of all other reported cases of cutaneous sarcoidosis with PPD-like features.

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Diagnosis of spindle cell/sarcomatoid melanoma may be challenging due to frequent loss of expression of melanocytic marker(s) and histomorphologic resemblance to various mesenchymal tumours, particularly malignant peripheral nerve sheath tumour (MPNST). Overexpression of PReferentially expressed Antigen in MElanoma (PRAME) supports a diagnosis of melanoma when evaluating challenging melanocytic tumours. PRAME expression in MPNST and other cutaneous sarcomatoid neoplasms, however, has not been well characterised. We aimed to determine the utility of PRAME immunostain in distinguishing spindle cell melanoma from MPNST and other sarcomatoid mimics. PRAME expression was scored by extent (0 to 4+) and intensity (0 to 3) of staining. A strong positive correlation was observed between the extent and intensity scores (r = 0.84). An extent score of 4+, defined by staining in 76-100% of tumour cells, was seen in 56% (23/41) of spindle cell melanomas, 18% (7/38) of MPNSTs, 15% (4/27) of cutaneous sarcomatoid squamous cell carcinomas (SCCs), 33% (5/15) of poorly differentiated cutaneous angiosarcomas, 12% (4/33) of atypical fibroxanthomas (AFXs), 4% (1/25) of pleomorphic dermal sarcomas (PDSs), and none (0/16) of the high-grade cutaneous leiomyosarcomas. A significant difference was found between spindle cell melanoma and all other examined sarcomatoid neoplasms except angiosarcoma. While diffuse (and often strong) PRAME expression is more frequently observed in spindle cell melanoma than MPNST, sarcomatoid SCC, AFX, PDS, and high-grade leiomyosarcoma, its limited sensitivity and specificity caution against its use as a standalone diagnostic marker. PRAME may complement other epigenetic or lineage-specific markers and should only be used as part of an immunohistochemical panel when evaluating these sarcomatoid neoplasms.

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