Ghali H, Al-Bzour AN, Boby A
… +12 more, Aflatooni S, DePalo DK, Dugan MM, Coughlin E, Mhaskar R, Tsai K, Zager JS, Sondak VK, Premi S, Storkus WJ, Messina JL, Karapetyan L
Am J Dermatopathol
· 2026 Jun · PMID 41861255
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Pigmentation varies widely in cutaneous melanoma, but its clinicopathologic and immunologic implications are incompletely defined. We retrospectively reviewed 627 patients with stage II-III melanoma treated at H. Lee Mof...Pigmentation varies widely in cutaneous melanoma, but its clinicopathologic and immunologic implications are incompletely defined. We retrospectively reviewed 627 patients with stage II-III melanoma treated at H. Lee Moffitt Cancer Center (2010-2019) and correlated pathologist-graded tumor pigmentation (0-3) with tumor features and sentinel lymph node biopsy results. We then evaluated transcript levels of pigmentation markers (TYR, DCT, MITF) for associations with overall survival (OS), tumor microenvironment (TME) composition, and immune checkpoint inhibitor (ICI) response using TCGA-SKCM bulk RNA-seq (n = 443) and public cohorts (GSE91061, GSE115978, GSE120575). Pigmented tumors (74.2%) showed lower Breslow depth ( P = 0.001), more tumor-infiltrating lymphocytes ( P < 0.001), greater angiolymphatic invasion ( P = 0.03), enrichment for superficial spreading subtype ( P < 0.001), and higher sentinel lymph node biopsy positivity ( P < 0.05) versus nonpigmented tumors. In TCGA, high TYR, DCT, and MITF expression independently correlated with worse OS. xCell analysis showed that low expression groups were enriched for multiple effector T- and B-cell populations, whereas high expression associated with immunosuppressive cell types (e.g., M2 macrophages, Tregs). In an ICI-treated cohort (GSE91061), baseline MITF was higher in nonresponders ( P = 0.023). Single-cell analyses confirmed pigmentation gene expression in malignant cells and demonstrated elevated MITF within myeloid subsets of nonresponders. Overall, both histologic pigmentation and pigmentation-gene signatures associate with tumor characteristics, immune contexture, and clinical outcomes, suggesting potential utility for risk stratification and treatment response prediction.
Involvement of lymph nodes by benign melanocytic neoplasms is a readily accepted concept in the pathology literature. However, little is known or has been discussed in the literature regarding the concept of malignant tr...Involvement of lymph nodes by benign melanocytic neoplasms is a readily accepted concept in the pathology literature. However, little is known or has been discussed in the literature regarding the concept of malignant transformation of benign melanocytic tumors within lymph nodes. In this report, we describe a 49-year-old woman with a cellular blue nevus on the buttock with no evidence of high-grade atypia or malignancy on both the biopsy and re-excision. She later presented with a palpable lymph node in the left inguinal region. Biopsy of the lymph node showed involvement of the lymph node capsule by the cellular blue nevus that had similar cytomorphology to that in the skin. The parenchyma of the lymph node was completely replaced and expanded by a proliferation of highly atypical and mitotically active melanocytes most consistent with malignant cellular blue nevus. Sequencing studies from the malignant blue nevus in the node and the cellular blue nevus on the buttock demonstrated the same GNAQ p.(Q209L) pathogenic variant. However, the malignant cellular blue nevus also had the following additional pathogenic variants: EIF1AX p.(K3M) and EIF1AX p.(N4S). Pathogenic variants in EIF1AX are well known to play a role in tumor progression of blue melanocytic tumors. These findings are most suggestive of malignant transformation of the cellular blue nevus within the lymph node. We believe this case, including the histologic and molecular findings, provides a novel and unique illustration of the phenomenon of malignant transformation of a melanocytic tumor in a lymph node.
INTRODUCTION: Cutaneous mucinoses comprise a heterogeneous group of disorders characterized by abnormal mucin deposition. Neuropathia mucinosa cutanea (NMC) is an exceedingly rare entity, defined by hypertrophic dermal n...INTRODUCTION: Cutaneous mucinoses comprise a heterogeneous group of disorders characterized by abnormal mucin deposition. Neuropathia mucinosa cutanea (NMC) is an exceedingly rare entity, defined by hypertrophic dermal nerves containing mucin within and around the perineurium. Its pathogenesis and nosologic status remain uncertain. CASE REPORT: We report the case of a 15-year-old Romanian girl with severe antithrombin III (AT-III) deficiency and systemic thromboses, who presented with acute ischemic stroke and later developed livedo reticularis and acral discoloration. Skin biopsy of a toe revealed hypertrophic dermal nerve bundles with prominent Alcian blue-positive mucin deposits both inside and around nerve fascicles, consistent with NMC. Immunohistochemistry showed intact Schwann cell architecture. CONCLUSIONS: This case expands the spectrum of intraneural mucin deposition by associating it with severe AT-III deficiency. Although fulfilling the morphologic description of NMC, the findings could also reflect a reactive change to ischemic nerve injury rather than a primary mucinous neuropathy. Further reports integrating clinical and histopathologic data are needed to clarify whether NMC represents a unique neurocutaneous disorder or a nonspecific reactive phenomenon.
Angiosarcoma is a rare and aggressive endothelial malignancy that typically affects the skin, soft tissues, and viscera. Although often found in the sun-exposed areas of the head and neck, subsets are associated with chr...Angiosarcoma is a rare and aggressive endothelial malignancy that typically affects the skin, soft tissues, and viscera. Although often found in the sun-exposed areas of the head and neck, subsets are associated with chronic lymphedema, radiation therapy, chemical exposures, and certain syndromes. The cases linked to prior radiation therapy or chronic lymphedema often have MYC (8q24) amplification. A 65-year-old woman developed a primary cutaneous angiosarcoma (pc-AS) on her upper back. She had no history of radiation exposure, lymphedema, or known predisposing genetic syndrome. Histopathology revealed a moderate to poorly differentiated angiosarcoma with high mitotic activity, blood-filled vascular channels, and deep extension near the fascia. Immunohistochemistry confirmed strong CD31 expression and MYC nuclear expression. Fluorescence in situ hybridization revealed a gain of MYC copy number without rearrangement, an atypical finding suggestive of whole or partial gain of chromosome 8. This case stands out as a rare example of MYC gain in a primary, nonchronic lymphedematous and nonradiation-associated angiosarcoma, and raises new questions about the role of MYC-driven pathogenesis even in cases that fall outside the typical secondary angiosarcoma pattern. Moreover, it also suggests that MYC gain might reasonably be included in the ancillary panel in the work-up of pc-AS. Furthermore, this case suggests that MYC oncogene dysregulation might represent a distinct clinicopathologic entity beyond those associated with chronic lymphedema or radiation.
Apocrine carcinoma of the vulva is a rare form of vulvar cancer, with the papillary subtype being even more uncommon. There are less than 20 reported cases of vulvar apocrine carcinoma, and only 2 reported cases specific...Apocrine carcinoma of the vulva is a rare form of vulvar cancer, with the papillary subtype being even more uncommon. There are less than 20 reported cases of vulvar apocrine carcinoma, and only 2 reported cases specifically of the tubulo-papillary subtype. Here we discuss the case of a woman in her mid-50s who presented with recurrent vulvar papillary apocrine carcinoma and was treated with wide local excision. Prognosis and treatment guidelines are not standardized because of the rarity of this condition. Given that the incidence of vulvar cancer has been rising in younger women and can initially present with subtle findings, these rarer subtypes should be considered in the differential for any unusual vulvar lesion.
Antisynthetase syndrome (ASyS), a distinct subset of dermatomyositis, is a heterogeneous entity characterized by multisystem involvement. A classical cutaneous presentation of ASyS is mechanic's hands, manifested by a de...Antisynthetase syndrome (ASyS), a distinct subset of dermatomyositis, is a heterogeneous entity characterized by multisystem involvement. A classical cutaneous presentation of ASyS is mechanic's hands, manifested by a desquamative papulosquamous eruption afflicting the lateral aspects of fingers. It bears clinical resemblance to common benign simulants such as hand eczema, contact dermatitis, and keratolysis exfoliativa. We outline a case showing features of checkerboard hyperkeratosis with apoptotic keratinocytes and review existing literature.
Secondary syphilis, caused by Treponema pallidum and known as the "the great imitator," presents with varied manifestations that may mimic other skin conditions. Histopathology is critical when clinical or serologic find...Secondary syphilis, caused by Treponema pallidum and known as the "the great imitator," presents with varied manifestations that may mimic other skin conditions. Histopathology is critical when clinical or serologic findings are atypical, and this study analyzed its key features to improve recognition and reduce diagnostic errors. A systematic search was conducted in PubMed, Embase, and Cochrane. Statistical analyses were performed using R, version 4.3.2. A random-effects model was used to determine the proportion with 95% confidence interval (CI). Heterogeneity was assessed using Cochrane Q test and I2 statistics. Eight studies encompassing 384 patients and 460 lesions were included. The mean age was 38.1 years, and approximately 24% of the patients were female. The most common histological features were endothelial swelling, reported by five studies, with a prevalence of 85% (95% CI 0.75-0.96; I2 = 82.6%), and moderate to dense plasma cell infiltration, as reported by six studies, with a prevalence of 83% (95% CI 0.74-0.92; I2 = 90.7%). Acanthosis was observed in six studies, with a prevalence of 66% (95% CI 0.47-0.86; I2 = 96.0%), followed by perivascular inflammatory infiltrate, reported in five studies, with a prevalence of 64% (95% CI 0.37-0.90; I2 = 96.9%). Histopathology reveals consistent features, particularly endothelial swelling and plasma cell-rich infiltrates, in secondary syphilis, reinforcing its diagnostic value when clinical or serologic findings are inconclusive.
Pilomatrix carcinoma is a rare, locally aggressive malignant adnexal tumor derived from hair follicle matrix cells. Although secondary malignancies are a well-known concern in Hodgkin lymphoma (HL) survivors, the occurre...Pilomatrix carcinoma is a rare, locally aggressive malignant adnexal tumor derived from hair follicle matrix cells. Although secondary malignancies are a well-known concern in Hodgkin lymphoma (HL) survivors, the occurrence of pilomatrix carcinoma in this setting is infrequent. We present the case of a 62-year-old man who was treated for Stage 1 Nodular Sclerosing Classical HL in 2018 with ABVD chemotherapy and radiotherapy. In January 2024, while in remission, he presented with a mass on the right posterior crus, distinct from the previous radiation field. Excision and histopathologic examination revealed pilomatrix carcinoma. Diagnosis was confirmed by immunohistochemistry, which showed a high Ki-67 index, nuclear beta-catenin positivity, and BerEP4 negativity. Owing to the aggressive nature of the tumor, wide re-excision and inguinal lymph node sampling were performed. This case report discusses the diagnostic challenges of this rare tumor and highlights its emergence as a second primary malignancy in a HL survivor, potentially linked to prior chemotherapy and systemic immune dysregulation.
Metellus R, Flint ND, Childs J
… +2 more, Hossler E, Horissian M
Am J Dermatopathol
· 2026 Jun · PMID 41847982
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We report 3 cases of localized occipital alopecia after greater occipital nerve block injections containing triamcinolone acetonide 40 mg (1 mL). In 1 case, alopecia areata was initially suspected based on clinical and h...We report 3 cases of localized occipital alopecia after greater occipital nerve block injections containing triamcinolone acetonide 40 mg (1 mL). In 1 case, alopecia areata was initially suspected based on clinical and histologic features. However, deeper review revealed subcutaneous fat atrophy consistent with steroid-induced lipoatrophy. In all cases, alopecic patches corresponded precisely to prior injection sites. These findings highlight an underrecognized iatrogenic cause of patchy scalp alopecia that may mimic alopecia areata. Recognition of this entity is important to avoid misdiagnosis and unnecessary treatment.
Radiation-induced angiosarcomas of the breast are rare malignancies that carry a poor prognosis. Expected immunohistochemical profiles reflect vascular differentiation: CD31 and ERG positivity, with variable CD34 positiv...Radiation-induced angiosarcomas of the breast are rare malignancies that carry a poor prognosis. Expected immunohistochemical profiles reflect vascular differentiation: CD31 and ERG positivity, with variable CD34 positivity. GATA-3 is a transcription factor important for mammary gland development, playing a role in ductal epithelial cell differentiation. It serves as an important immunohistochemical marker of breast-origin carcinomas and is not associated with angiosarcomas. We report a case of an 83-year-old woman with breast radiation-induced angiosarcoma, which displayed diffuse GATA-3 positivity, which has not been previously reported in the literature. The patient had a history of inflammatory carcinoma of the left breast (histologically a high-grade invasive ductal carcinoma of no special type) treated with lumpectomy and radiation therapy. Ten years later, she presented with skin thickening and 3 tender nodules (ranging from 0.6 to 2 cm) confined to the left breast skin. Biopsy showed a high-grade, epithelioid dermal neoplasm with abundant hemorrhage. The tumor was diffusely positive for GATA-3, CD31, and ERG, with focal CD34 positivity. Strong and diffuse MYC positivity with an increased Ki-67 proliferative index was also demonstrated. CK5/6, AE1/AE3, MOC-31, CK5/6, CK7, ER, PR, S100, Melan A, and synaptophysin were all negative. The histopathologic features and immunohistochemical profile were consistent with radiation-induced angiosarcoma. With this case, we highlight a diffusely positive GATA-3 staining pattern in radiation-induced angiosarcoma of the breast, which has not been previously documented. Awareness of this potential staining pitfall is essential for arriving at the correct diagnosis particularly when recurrent or metastatic high-grade carcinoma is a diagnostic consideration.
Am J Dermatopathol
· 2026 Jun · PMID 41812034
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Rosai-Dorfman disease (RDD) is a rare histiocytic disorder that most commonly affects lymph nodes but can also present in extranodal sites. Involvement of the male breast is rare and may clinically and radiologically mim...Rosai-Dorfman disease (RDD) is a rare histiocytic disorder that most commonly affects lymph nodes but can also present in extranodal sites. Involvement of the male breast is rare and may clinically and radiologically mimic malignancy. A comprehensive review will be valuable for histologic assessment and treatment of similar cases. We report a case of extranodal RDD in a 65-year-old man, who presented with a 48 × 40 × 25 mm left breast mass. The mass was excised with clear surgical margins. Histopathologic examination showed sheets and clusters of large histiocytes with emperipolesis on a background of lymphoplasmacytic inflammation. Immunohistochemistry showed that the lesional cells were positive for S100 and CD68, and negative for CD1a. The morphology and immunohistochemistry confirmed the diagnosis of extranodal RDD limited to the subcutaneous tissue of the breast. The literature review yielded 13 cases of extranodal RDD of the male breast. Four cases lacked sufficient details to be included in the synthesis. All patients presented with unilateral palpable breast masses. Radiologic evaluation was suspicious for malignancy in all 7 patients with imaging reported. Microscopy revealed sheets of large histiocytes with emperipolesis, which were positive for S100 and CD68 and negative for CD1a. No evidence of systemic disease was found. All patients were treated conservatively, with 2 recurrences at 24 months of follow-up. Extranodal RDD of the male breast is exceedingly rare and can mimic carcinoma both clinically and radiologically. Accurate diagnosis requires histologic and immunohistochemical confirmation. Awareness of this entity is critical to avoid overtreatment.
Am J Dermatopathol
· 2026 May · PMID 41785045
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Lepromatous leprosy, more commonly seen in endemic areas, is a severe multi-bacillary granulomatous infection of the skin and peripheral nerves, which leads to facial disfigurement and digital auto-amputation. Although t...Lepromatous leprosy, more commonly seen in endemic areas, is a severe multi-bacillary granulomatous infection of the skin and peripheral nerves, which leads to facial disfigurement and digital auto-amputation. Although treatable with multidrug therapy, diagnosis and early intervention remains of paramount importance. The bacilli are strongly positive with Fite special stain, and to this day this stain remains most widely used especially in areas that do not have access to PCR testing. Herein, we describe a case where the M. leprae bacilli were Fite positive but also very strongly GMS positive. This case highlights the value of using multiple special stains in diagnosis of leprosy.
Corey Z, Wiredja D, Willard N
… +2 more, Wisell J, Raghavan SS
Am J Dermatopathol
· 2026 May · PMID 41779666
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Spitz neoplasms comprise a spectrum of melanocytic lesions with overlapping clinical and histologic features. BRAF fusions account for only 5%-6% of Spitz neoplasms with a limited number of fusion partners being characte...Spitz neoplasms comprise a spectrum of melanocytic lesions with overlapping clinical and histologic features. BRAF fusions account for only 5%-6% of Spitz neoplasms with a limited number of fusion partners being characterized. We report 2 Spitz nevi with novel BRAF fusions and reproducible morphologic findings. The first case, a 35-year-old man with a finger mass, morphologically demonstrated intraepidermal and dermal proliferation of enlarged epithelioid melanocytes without maturation, and a striking pattern of neurotropism and angiotropism. Immunohistochemistry revealed <30% PRAME expression and retained p16, while next-generation sequencing identified a novel in-frame AHNAK::BRAF fusion. The second case, a 47-year-old man with an atypical skin lesion on the back of his neck, exhibited a circumscribed intradermal proliferation of epithelioid and spindle melanocytes with Spitzoid cytomorphology, again characterized by the striking pattern of neurotropism and entrapment of epithelioid cells within a fibrous stroma. This lesion was PRAME-negative with retained p16, and molecular studies identified a novel PDE4DIP::BRAF fusion. Both fusions preserved the BRAF kinase domain while eliminating its N-terminal regulatory regions. These cases expand the molecular spectrum of Spitz neoplasms and underscore neurotropism as a potential morphologic clue for BRAF fusion-driven Spitz nevi.