Am J Dermatopathol
· 2026 Jan · PMID 41459816
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Mutations in the guanosine nucleotide-binding protein Q gene (GNAQ) lead to complex pathologies involving both vascular and melanocytic components, which may seem surprising at first glance. Traditionally, melanocytes ha...Mutations in the guanosine nucleotide-binding protein Q gene (GNAQ) lead to complex pathologies involving both vascular and melanocytic components, which may seem surprising at first glance. Traditionally, melanocytes have been considered cells derived from the neural crest, while blood vessels are derived from mesodermal mesenchyme. However, in recent years, the understanding of ectomesenchyme, a mesenchymal derivative originating from the neural crest, has revealed how this embryonic layer gives rise not only to structures of the head and neck but also to those of the trunk. This discovery has allowed the contextualization of GNAQ mutations within a new ontogenetic interpretation, wherein neural crest cells, capable of differentiating into both ectodermal and mesodermal derivatives, can lead to a variety of dermatological lesions. In this article, we review the major pathological entities observed in dermatopathology associated with GNAQ mutations and place them within this new understanding of ectomesenchyme. In doing so, we explain how a single gene can influence the development of various vascular and melanocytic pathologies, while also challenging the traditional relationship between melanocytes and endothelial cells and their common origin in the neural crest.
İzol H, Kolak Gözüküçük G, Bağbudar S
… +2 more, Caşkan P, Kuşku Çabuk F
Am J Dermatopathol
· 2026 Mar · PMID 41452344
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INTRODUCTION: PReferentially expressed Antigen in Melanoma (PRAME) antibody is a crucial biomarker for differentiating melanoma from benign lesions. However, its diagnostic value in dysplastic nevi (DN) remains controver...INTRODUCTION: PReferentially expressed Antigen in Melanoma (PRAME) antibody is a crucial biomarker for differentiating melanoma from benign lesions. However, its diagnostic value in dysplastic nevi (DN) remains controversial. OBJECTIVES: This study investigates its diagnostic potential and clinicopathologic correlations. METHODS: PRAME was immunohistochemically assessed in 115 low-grade DN (LG-DN) and 18 high-grade DN (HG-DN). Staining was scored from 0 (no staining) to 4+ (75% or more). The relationship of PRAME expression with age, sex, location, and histologic grade was examined. RESULTS: We analyzed 133 DNs from 107 patients. Of these, 49.5% were female patients and 50.5% were male patients, with a mean age of 36.6 years (range 7-91). Female patients presented lesions at a younger age than male patients (31.7 vs. 40.6 years; P < 0.001). Histologic grade increased with age ( P = 0.017). Most lesions were located on the trunk (51.9% back, 27.1% chest) followed by the head and neck (7.5%). PRAME expression was score 0 in 84.3% of LG-DN and 77.8% of HG-DN. Score 4+ expression was observed in 7% of LG-DN and in 11.2% of HG-DN. Although a trend toward higher PRAME positivity in HG-DN was noted, it did not reach statistical significance. No correlations were found between PRAME expression and age, sex, location. CONCLUSIONS: The findings indicate that PRAME expression is not associated with histologic grade or clinical parameters in DN, suggesting that this marker may have limited prognostic or diagnostic value in these lesions. These results need to be supported by larger sample-sized and comparative studies.
A 66-year-old woman presented with multiple nonpruritic subcutaneous nodules measuring up to 1.8 cm on the left forearm. An excision was performed, and histopathologic evaluation demonstrated a well-circumscribed intrava...A 66-year-old woman presented with multiple nonpruritic subcutaneous nodules measuring up to 1.8 cm on the left forearm. An excision was performed, and histopathologic evaluation demonstrated a well-circumscribed intravascular lesion composed of a dense lymphoplasmacytic infiltrate among histiocytes and eosinophils. There was no significant surrounding inflammation in the subcutaneous adipose tissue. Further evaluation with immunohistochemistry and special stains did not reveal any hematolymphoid neoplasm or infectious etiology but did reveal >200 polytypic IgG4+ plasma cells per high-powered field and an IgG4:IgG ratio of >0.5, supporting a diagnosis of IgG4-related disease with obliterative phlebitis of a medium-sized subcutaneous vein. This presentation expands the current classification of cutaneous IgG4-related disease and highlights the need for broader recognition of vascular and clinical manifestations in this disease spectrum.
Am J Dermatopathol
· 2026 Mar · PMID 41432118
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Granuloma annulare (GA) is a benign, granulomatous skin condition characterized by ring-shaped papules or plaques on the dorsal aspects of the hands and/or feet. It is most frequently seen in children and young adults, w...Granuloma annulare (GA) is a benign, granulomatous skin condition characterized by ring-shaped papules or plaques on the dorsal aspects of the hands and/or feet. It is most frequently seen in children and young adults, with a female predominance. Although many cases are idiopathic, associations with certain diseases include autoimmune disorders, diabetes mellitus, and thyroid disease. Drugs have also been implicated including allopurinol, diclofenac, topiramate, amlodipine, thalidomide, and TNF-α inhibitors. The clinical and morphologic distinction from the interstitial granulomatous drug reaction (IDG) can be challenging. Acetazolamide, a carbonic anhydrase inhibitor (CAI) commonly used for idiopathic intracranial hypertension, has recently been associated with subcutaneous granuloma annulare (SGA). We report a 16-year-old girl who developed multiple firm subcutaneous nodules on her hands shortly after initiation and dose escalation of acetazolamide. Histopathology demonstrated subcutaneous palisading granulomas with central necrobiosis, consistent with SGA. Nodules resolved nearly completely within 2 weeks of drug discontinuation. Pharmacologic inhibition of carbonic anhydrase may promote endothelial cell apoptosis leading to ischemic changes in the connective tissue fiber matrix and also modulate macrophage activation resulting in an influx of histiocytes at the site of anoxia, suggesting a potential immunologic mechanism shared with other weak CAIs, such as topiramate. This case highlights acetazolamide-induced SGA and further explores the spectrum of granulomatous inflammation associated with drugs of the CAI class.
Am J Dermatopathol
· 2026 Mar · PMID 41428638
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Scurvy is an uncommon diagnosis in developed countries, yet it remains an important clinical consideration in patients with restrictive diets. In this study, we report a case of a male patient with a history of sclerosin...Scurvy is an uncommon diagnosis in developed countries, yet it remains an important clinical consideration in patients with restrictive diets. In this study, we report a case of a male patient with a history of sclerosing mesenteritis and chronic dietary restriction who presented with bilateral leg purpura, perifollicular hemorrhage, and gingival bleeding. His cutaneous findings initially raised concern for vasculitis or coagulopathy. However, histopathology revealed classic features of scurvy and an undetectable vitamin C level confirmed the diagnosis. Oral vitamin C supplementation led to rapid clinical improvement. This case emphasizes the importance of a thorough dietary history and skin examination in patients presenting with mucocutaneous bleeding.
Am J Dermatopathol
· 2026 Mar · PMID 41428601
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Tumor of follicular infundibulum (TFI) is a rare cutaneous lesion of unclear histogenesis. Various benign and malignant cutaneous neoplasms have been reported in association with TFI, including most commonly basal cell c...Tumor of follicular infundibulum (TFI) is a rare cutaneous lesion of unclear histogenesis. Various benign and malignant cutaneous neoplasms have been reported in association with TFI, including most commonly basal cell carcinoma (BCC). Indeed, some authors have suggested that TFI may represent a variant of BCC. Because BCC are well established to be driven by alterations in the Hedgehog signaling pathway, most often secondary to ultraviolet (UV)-induced mutagenesis, we undertook next-generation DNA sequencing of a cohort of TFI to determine their molecular relatedness to BCC. Four TFI cases were successfully sequenced, with 3 of the 4 patients being men, and a mean age at diagnosis of 57.8 years (range: 46-68 years). All 4 tumors were located on the face and showed typical histologic features of TFI, including a plate-like proliferation of bland keratinocytes with peripheral palisading and multiple points of connection to the epidermis. Two of the lesions were solitary and 2 occurred as part of eruptive TFI. No recurrences were reported. Molecular profiling failed to reveal Hedgehog pathway alterations, TP53 mutations, or a UV mutation signature in any case. In contrast, 3 cases demonstrated recurrent SLX4 mutations. In total, 18 unique mutations in 15 genes spanning an array of cellular functions including DNA repair and cell signaling were identified. Overall, the histomorphologic, clinical, and molecular features of TFI support its classification as a distinct and benign entity from BCC. In addition, the presence of recurrent SLX4 alterations suggests that TFI are likely not reactive but rather may represent a true neoplasm.
Am J Dermatopathol
· 2026 May · PMID 41417463
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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, including the breast. Immune-related RDD may be associated with increased plasma...Rosai-Dorfman disease (RDD) is a rare histiocytic disorder that most commonly affects lymph nodes but can also present in extranodal sites, including the breast. Immune-related RDD may be associated with increased plasma cells, with a significant proportion of the plasma cells expressing IgG4. These cases typically lack the other features of IgG4-related disease. We report a case of a 20-year-old woman who presented with a painless mass in the left breast. Prior biopsy was diagnosed as RDD with increased plasma cells. Ultrasound scan showed a well-circumscribed hypoechoic hypervascular solid subcutaneous mass with preservation of the surrounding breast parenchyma. Clinical assessment and imaging showed no evidence of regional lymphadenopathy or involvement of other organ systems. A wide local excision was performed. The excision showed a firm, unencapsulated fibrotic subcutaneous nodule. The histopathology revealed an expansion of the subcutaneous tissue, characterized by sheets of large histiocytes with round-to-oval nuclei and abundant pale to eosinophilic cytoplasm, set against a background of lymphoplasmacytic inflammation and stromal fibrosis. Several histiocytes demonstrated emperipolesis. The lesion was completely excised with clear margins. Immunohistochemistry showed that the histiocytes were positive for S100 and CD68, and negative for CD1a and AE1/AE3. The morphology and immunohistochemistry confirmed the diagnosis of extranodal RDD limited to the subcutaneous tissue of the breast. Extranodal RDD involving the breast is exceedingly rare and can mimic carcinoma both clinically and radiologically. Accurate diagnosis requires histologic and immunohistochemical confirmation.
Basomelanocytic tumors are rare cutaneous neoplasms characterized by an intimate admixture of basal cell carcinoma and melanoma. Although basal cell carcinoma (BCC) and melanoma are commonly encountered individually, onl...Basomelanocytic tumors are rare cutaneous neoplasms characterized by an intimate admixture of basal cell carcinoma and melanoma. Although basal cell carcinoma (BCC) and melanoma are commonly encountered individually, only a limited number of basomelanocytic tumors have been documented. We report the clinical and histologic features and molecular findings of 2 combined basomelanocytic tumors: 80-year-old man and 91-year-old-man, presented with lesions on the left upper lip and left forehead, respectively. The first tumor consisted of a close admixture of BCC, highlighted by p63 and keratin immunostains, and melanoma, highlighted by Melan-A and SOX10, with abundant melanoma in situ within the lobules of BCC. The second tumor exhibited 2 different neoplastic populations: 1 component of a nodular proliferation of basaloid epithelial nests with peripheral palisading, characteristic of BCC and stained positive for keratin 5/6, keratin 17, and p63. Scattered within these basaloid nests were melanocytes highlighted by Sox10, Melan-A, MiTF, and HMB-45. Molecular analyses of Case 1 show 11 identical variants with similar allelic frequencies detected in both the nodules of invasive melanoma and the remaining surrounding basal cell carcinoma with admixed melanoma cells. In addition, high-level NRAS amplification, and variants of KDR and TRAF7 variants were restricted to the nodules of invasive melanoma, possibly reflecting molecular progression. CDKN2A and PCTH1 mutations, frequently detected in melanoma and basal cell carcinoma, respectively, were detected in the second case. The presence of 2 components with distinct immunoprofile yet with some common genetic aberration suggests that basomelanocytic tumors may arise from a common progenitor.
Am J Dermatopathol
· 2025 Aug · PMID 41378810
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A 9-year-old boy with Gorlin syndrome (GS) developed asymptomatic palmar papules. Histopathologic examination of these lesions revealed angulated basaloid nests surrounded by sclerotic stroma in the upper dermis, with ov...A 9-year-old boy with Gorlin syndrome (GS) developed asymptomatic palmar papules. Histopathologic examination of these lesions revealed angulated basaloid nests surrounded by sclerotic stroma in the upper dermis, with overlying epidermal atrophy and hypogranulosis. These findings align with previously described basaloid proliferations in palmoplantar lesions of GS, distinct from the typical basal cell carcinomas found in other skin areas. Unlike basal cell carcinomas, these lesions remained stable during follow-up. This case highlights the unique histopathologic features of palmoplantar lesions in GS and raises questions about their pathogenesis and potential origin.
Am J Dermatopathol
· 2025 Aug · PMID 41378809
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Tinea nigra, a rare superficial fungal infection caused by Hortaea werneckii, is often mistaken for a melanocytic lesion. We report a case in Shenzhen, a city in southern China, involving a 31-year-old woman with slowly...Tinea nigra, a rare superficial fungal infection caused by Hortaea werneckii, is often mistaken for a melanocytic lesion. We report a case in Shenzhen, a city in southern China, involving a 31-year-old woman with slowly enlarging brown patches on her left palm over 15 years. The patches were smooth, asymptomatic, and without scaling or travel history to tropical regions. Dermatological examination revealed a 30 mm × 25-mm brown macule with distinct borders. Dermoscopic analysis showed brownish-gray pigmented strands parallel to skin ridges, differing from the pattern in melanoma. Histopathological examination confirmed fungal hyphae in the upper stratum corneum. The fungus was identified as H. werneckii using metagenomic next-generation sequencing. The lesion resolved completely after an 8-week course of 1% butenafine cream. Accurate diagnosis is crucial to prevent misdiagnosis as malignant melanoma. Dermoscopy and fungal microscopy are key diagnostic tools. Treatment with topical antifungal agents is effective, with symptoms resolving within weeks.
Am J Dermatopathol
· 2025 Aug · PMID 41378808
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Recent studies have proposed the use of the polydactyly nail unit model as a tool for the study of the molecular basis of onychogenesis. However, the histological and immunohistochemical description of this model is stil...Recent studies have proposed the use of the polydactyly nail unit model as a tool for the study of the molecular basis of onychogenesis. However, the histological and immunohistochemical description of this model is still a matter of debate in the literature, and the validity of the concept of the onychodermis used in the histological interpretation of both polydactyly and the adult nail unit has been challenged on the basis of detailed histological studies of adult fingernail units. The aim of this study was to provide new histological and immunohistochemical data on both the adult toenail unit and polydactyly nail unit to test the onychodermis/onychofibroblasts hypothesis. A histological study was performed on a series of 20 normal adult toenails from 10 cadavers and 10 polydactyly nail units. This study supported a strong analogy between the finger and toe dermis of the adult nail. The telocyte population is relatively sparse compared with the fibroblast (fibrocyte) population of the nail mesenchyme as a whole. The dynamic immunohistochemical profile of the nail telocytes was present in both fingers and toes, with the CD34+/CD10+ profile correlating with the onychogenic epithelial region, and the CD34-/CD10+ profile correlating with the spatial rearrangement of the epidermal ridges of the nail bed that are aligned longitudinally and almost parallel to each other. The main differences resulted from more consistently well-formed adipose tissue, a more discrete mucinous component at the level of the distal hypodermis of the hallux, and a thicker nail bed dermis. Previous studies of polydactyly have not taken into account the stage of development of the distal phalanx. Morphological variations of the developing phalanx have been classified into 2 types with 4 subtypes. In all but 1 type, the nail mesenchyme had 2 compartments: a matrical dermis devoid of onychofibroblasts and a CD10+ loose connective tissue with onychofibroblasts. In all cases, the onychofibroblasts interact closely with the thick periosteal/perichondrial layer of the developing bone. By contrast, in the adult nail unit, the matrix apex is independent of the distal interphalangeal (DIP) joint synovioentheseal complex and has only focal and lateral connection to the periosteum through a lateral fenestrated fascia. Moving proximally to distally the quiescent periosteum is separated from the matrix epithelium by a thick matrical dermis and its hypodermis, whereas the nail bed dermis shows a definite and stable anchorage to the periosteum. The oversimplified concept of onychodermis does not allow us to analyze the complex microanatomy of the adult nail unit with major misunderstanding of the matrical hypodermis and the hypodermal channel of the nail bed. The polydactyly nail unit is a good model for studying early nail morphogenesis and hereditary and congenital nail disorders, but not a histological model for analyzing the normal nail unit, in particular the role of telocytes versus onychofibroblasts as nail mesenchymal stem cells. The classification of morphological variations of the polydactyly nail unit is essential for the future interpretation of molecular studies using this model.