Nguyen TT, Otsuki S, Ito H
… +4 more, Fujimoto M, Irie H, Hirata M, Haga H
Am J Dermatopathol
· 2026 Jun · PMID 42358018
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Cutaneous spindle cell squamous cell carcinoma (SCSCC) is known to mimic malignant spindle cell neoplasms. In the head and neck region, a deceptively bland, granulation tissue-like pattern has also been reported that may...Cutaneous spindle cell squamous cell carcinoma (SCSCC) is known to mimic malignant spindle cell neoplasms. In the head and neck region, a deceptively bland, granulation tissue-like pattern has also been reported that may simulate benign reactive processes; however, it has rarely been described in cutaneous SCSCC. Here, we report a case of cutaneous SCSCC with a granulation tissue-like spindle cell component arising from an upper arm burn scar in a 66-year-old woman. Histological examination of the punch biopsy specimen initially revealed a deceptively bland, yet atypical spindle cell proliferation with focal slit-like pseudovascular spaces, suggesting granulation tissue. Given the presence of a clinically ulcerated mass measuring 3.5 × 2.7 cm arising from a chronic scar, immunohistochemical analysis was performed, which supported the diagnosis of SCSCC, showing diffuse positivity for CK5 and p40 with p53 overexpression. Examination of the surgical specimen revealed morphological heterogeneity, with areas of conventional SCC and spindle cell components, including deceptively bland, granulation tissue-like areas and areas exhibiting myxoid change and overt cytologic atypia. This case highlights that cutaneous SCSCC may exhibit deceptively bland cytology closely mimicking granulation tissue, representing a potential diagnostic pitfall, particularly in limited biopsy specimens.
Takeuchi M, Kaku Y, Hashikawa K
… +4 more, Tominaga M, Nishikomori R, Tsutsumi Y, Koga H
Am J Dermatopathol
· 2026 May · PMID 42358014
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BACKGROUND: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by pathogenic variants in the Bruton tyrosine kinase (BTK) gene, leading to severe B-cell maturation defects and pan-hypogammaglobulinemi...BACKGROUND: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by pathogenic variants in the Bruton tyrosine kinase (BTK) gene, leading to severe B-cell maturation defects and pan-hypogammaglobulinemia. Botryomycosis is a rare chronic bacterial infection, typically caused by Staphylococcus aureus (S. aureus), characterized by suppurative and chronic inflammation and grape-like bacterial clusters in tissue. CASE PRESENTATION: We report 2 adult male siblings with previously undiagnosed XLA who presented with cutaneous botryomycosis. Case 1, aged 20 years, developed painless perianal nodules and plaques; laboratory tests revealed markedly decreased IgG, IgM, and IgA. Deep tissue cultures grew methicillin-resistant S. aureus, Streptococcus agalactiae, and Peptoniophilus species. Case 2, his elder brother, aged 21 years, had recurrent pneumonia and persistent verrucous nodules on both lower extremities; methicillin-resistant S. aureus was cultured from a localized abscess. Both siblings carried the same BTK pathogenic variant (c.1760T > C; p.Met587Thr). Skin lesions in both patients resolved with systemic antibiotics and subcutaneous immunoglobulin replacement therapy. HISTOPATHOLOGY: Biopsies revealed chronic inflammation with scattered neutrophils, fibrosis, and capillary proliferation centered on the hair follicle. Follicular infundibulum contained grape-like clusters of cocci, occasionally forming tetrads, without Splendore-Hoeppli phenomenon. The organisms were Gram-positive and nonspecifically Gomori methenamine silver-positive. Immunohistochemistry confirmed S. aureus as the causative pathogen. CONCLUSIONS: These sibling cases highlight cutaneous botryomycosis as an under-recognized but clinically relevant manifestation of XLA. Awareness of this association can facilitate earlier diagnosis of the underlying immunodeficiency through integration of clinical history, microbiology, immunohistochemistry, and histopathology.
Am J Dermatopathol
· 2026 Jun · PMID 42358012
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Genomic rearrangements resulting in ligand independent constitutive activation of anaplastic lymphoma kinase (ALK) gene have been shown to be a genomic driver in neoplasms of variable lineage, including mesenchymal tumor...Genomic rearrangements resulting in ligand independent constitutive activation of anaplastic lymphoma kinase (ALK) gene have been shown to be a genomic driver in neoplasms of variable lineage, including mesenchymal tumors. Inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma are typical well-described ALK-driven neoplasms in the skin and subcutis. However, recent literature has indicated additional ALK-rearranged mesenchymal tumors distinct from inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma, showing variable morphology, clinical presentation, and malignant potential. These tumors typically coexpress CD34 and S100, lack SOX10 expression, and are challenging to diagnose histologically owing to their morphological features being on a spectrum. This report describes a mesenchymal tumor with EML4-ALK fusion, displaying a unique histological pattern of compacted nested growth of uniform polygonal epithelioid cells with minimal stroma, nondescript vessels, low mitotic activity, and without necrosis. The features of this case do not exactly fit within the spectrum of cases described in the literature and expands the immunomorphological range of ALK-rearranged mesenchymal neoplasms.
Sloan P, Husain A, Lye J
… +5 more, Best K, Walker L, Richardson G, Armstrong J, Lovat P
Am J Dermatopathol
· 2026 May · PMID 42358006
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BACKGROUND: The diagnosis of high-grade dysplastic nevus (HGDNs) can present a challenge for a pathologist. The utility of combined AMBRA1 and loricrin staining for the diagnosis of HGDN was evaluated using preferentiall...BACKGROUND: The diagnosis of high-grade dysplastic nevus (HGDNs) can present a challenge for a pathologist. The utility of combined AMBRA1 and loricrin staining for the diagnosis of HGDN was evaluated using preferentially expressed antigen in melanoma (PRAME) as a comparator. MATERIALS AND METHODS: A cohort of 145 cases of HGDN was selected from a consecutive series of 409 dysplastic nevi ascertained in a single pathology service between 2015 and 2019. Combined immunohistochemistry for AMBRA1 and loricrin expression in the epidermis overlying the HGDN was consensus scored by 2 experienced pathologists. PRAME immunohistochemistry was also consensus scored in the melanocyte population using a five-point scale (0-4+). RESULTS: All HGDNs showed maintenance of either 1 or both AMBRA1 and loricrin epidermal expression with 3 exceptions. In 1 instance, a focus of melanocytes within the HGDN was associated with loss of both markers in the overlying epidermis and the melanocytes in the focus were strongly positive (4+) for PRAME. On expert review, the diagnosis was changed to thin melanoma. In the other 2 cases showing loss of both markers, the absence of staining was focal and restricted to mounds of parakeratosis. Most HGDN were negative for PRAME although 48% were positive to some degree and 4% showed a 4+ expression. OBSERVATIONS: Clinical follow-up showed no evidence of progression or metastasis. We found that 23 patients (16%) had previous, concurrent, or subsequent early stage melanomas and 2 patients (1%) had previous melanoma in situ. One HGDN recurred after 3 years, and the further excision sample showed recurrent HGDN only. We observed that mild epidermal hyperplasia and parakeratosis were often found in HGDNs, suggesting an active melanocyte-epidermal interaction in the lesions. We speculate that epidermal hyperplasia resulted in some of the HGDN showing single-cell loricrin gaps or thinning of the loricrin band. AMBRA1, loricrin, and PRAME staining was additionally performed on 39 benign melanocytic nevi covering a range of types for comparison. Epidermal hyperplasia was generally not seen and almost all cases showed maintenance of both epidermal AMBRA1 and loricrin, with loricrin gaps and thinning seen only in 3 Meyerson nevi where there was parakeratosis (3/5 Meyerson nevi). CONCLUSION: This study suggests that AMBRA1 and loricrin staining is a useful biomarker to confirm the diagnosis and/or to signal low-risk behavior in HGDN, particularly in cases where 4+ PRAME staining could potentially point to a melanoma diagnosis.
Am J Dermatopathol
· 2026 May · PMID 42358005
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Desmoplastic trichilemmoma (DTM) is a rare and benign variant of conventional trichilemmoma which presents a diagnostic challenge. It closely mimics malignant neoplasms, particularly basal cell carcinoma (BCC), because o...Desmoplastic trichilemmoma (DTM) is a rare and benign variant of conventional trichilemmoma which presents a diagnostic challenge. It closely mimics malignant neoplasms, particularly basal cell carcinoma (BCC), because of overlapping clinical and histopathological features. Accurate differentiation is crucial to prevent misdiagnosis and management. The aim of this study was to synthesize the available clinical and histopathological data on DTM by presenting 2 new cases and conducting a systematic review of the literature. A retrospective query was conducted of database from 2012 to 2026 identifying 2 DTM cases. In addition, a systematic review of the PubMed database was performed for English language publications from 1990 to present day, yielding 29 publications for inclusion. The addition of 2 new cases brings the total number of DTMs in the compiled dataset to 94 cases. DTM typically presents as a solitary lesion on the head and neck of older adults, ranging in size from 0.3 to 7 cm, with rare cases reported on the chest, vulva, and lower extremities. Histopathologically, its lobular and cord-like growth pattern, peripheral palisading, and desmoplastic stroma closely mimic BCC. Immunohistochemically, the current cases showed immunoreactivity for CD34 and a concurrent negativity for BerEP4. Based on the current findings and review data, 8 CD34-positive/BerEP4-negative and 10 CD34-positive DTMs were identified. Accurate distinction between DTM and BCC requires careful histological examination, which is enhanced by the application of the proposed CD34-BerEP4 dual-marker approach. This diagnostic utility guides appropriate clinical management and prevents unnecessary or inadequate treatment.
Nakazato S, Takakuwa E, Minagawa T
… +3 more, Anan T, Koga K, Goto K
Am J Dermatopathol
· 2026 Jun · PMID 42357999
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Malignant mixed tumor of the skin (MMTS) is an extremely rare malignant cutaneous adnexal neoplasm that arises through malignant transformation of a benign mixed tumor of the skin and exhibits a variety of histopathologi...Malignant mixed tumor of the skin (MMTS) is an extremely rare malignant cutaneous adnexal neoplasm that arises through malignant transformation of a benign mixed tumor of the skin and exhibits a variety of histopathological features. Benign mixed tumor of the skin is classified morphologically into apocrine and eccrine types; the former being characterized molecularly by PLAG1 rearrangement. To date, approximately 50 cases of MMTS have been reported, but most published case reports have not been supported by molecular pathological analysis. In this study we report the first documented case of MMTS in which a TRPS1::PLAG1 fusion gene was identified. Further accumulation of MMTS cases with detailed molecular analysis, focusing particularly on PLAG1 rearrangement and overexpression, is warranted.
Am J Dermatopathol
· 2026 May · PMID 42357996
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Kaposi sarcoma (KS) is a low-grade endothelial neoplasm whose definitive lineage-blood vascular versus lymphatic-remains controversial. This ambiguity stems from the tumor's known coexpression of both blood (eg, CD31 and...Kaposi sarcoma (KS) is a low-grade endothelial neoplasm whose definitive lineage-blood vascular versus lymphatic-remains controversial. This ambiguity stems from the tumor's known coexpression of both blood (eg, CD31 and CD34) and lymphatic (eg, podoplanin) endothelial markers. To clarify the phenotype of the neoplastic population, we developed novel dual immunohistochemistry protocols (HHV8/podoplanin and CD31/podoplanin) to specifically evaluate marker coexpression within HHV8-infected spindle cells. The assays were applied to a series of 13 KS lesions (from 12 patients). Coexpression of HHV8 (nuclear) with podoplanin or CD31 (cytoplasmic) was assessed using a semiquantitative scoring system (0: 0%; 1: 1%-10%; 2: 11%-50%; 3: 51%-100%). In all 9 cutaneous KS lesions, HHV8-positive cells demonstrated strong, uniform coexpression with the lymphatic marker podoplanin (mean score 3.0) across all histologic stages. By contrast, coexpression of HHV8 with the blood vascular marker CD31 was significantly weaker and more variable (mean score 1.0; P = 2.0E-07). Notably, this differential pattern was not observed in mucosal KS; the 3 mucosal lesions analyzed showed equally strong coexpression of HHV8 with both podoplanin and CD31 (mean scores 3.0 for both). These pilot findings indicate that the immunophenotype of KS is anatomic site-dependent because within cutaneous KS, the HHV8-infected neoplastic spindle cells exhibit a predominantly lymphatic immunophenotype, supporting a lymphatic endothelial differentiation in this context. By contrast, mucosal KS displays a hybrid blood vascular and lymphatic phenotype. This study provides a novel methodological framework for lineage assessment in vascular neoplasms and highlights the influence of microenvironment on KS tumor phenotype.
Toussaint AL, Sánchez-Cárdenas C, Fuentes-García R
… +2 more, Charli-Joseph Y, Toussaint-Caire S
Am J Dermatopathol
· 2026 May · PMID 42357995
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Acral cutaneous melanoma is a highly aggressive form of skin cancer that develops in palms, soles, and/or the nail unit. PReferentially expressed Antigen in MElanoma (PRAME) is an immunohistochemical marker that has show...Acral cutaneous melanoma is a highly aggressive form of skin cancer that develops in palms, soles, and/or the nail unit. PReferentially expressed Antigen in MElanoma (PRAME) is an immunohistochemical marker that has shown a high degree of expression in cutaneous melanomas. However, no meta-analysis has previously focused on acral melanocytic proliferations. Herein, we performed the first meta-analysis to objectify the utility of PRAME immunohistochemistry, focusing on this understudied subtype of melanocytic proliferations involving acral sites. Thirteen studies were identified, which included 930 lesions (557 malignant and 373 benign). A random-effects model was used to calculate sensitivity, specificity, and likelihood ratios. Summary receiver operating characteristic curves and forest plots were created, and heterogeneity was assessed using Cochran Q and I2 statistics. PRAME expression in acral melanoma showed the highest diagnostic accuracy at a cutoff value of 3+/50%, pertaining to the optimal balance between sensitivity and specificity (78% and 92%, respectively). Although PRAME immunostaining enhances the accurate diagnosis of acral melanocytic proliferations, its expression in atypical and borderline melanocytic proliferations remains controversial and shows considerable variability. Thus, the definitive diagnosis of acral melanoma still relies on careful clinicopathologic assessment and, occasionally, molecular correlation.
Am J Dermatopathol
· 2026 Jun · PMID 42357990
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Fibrofolliculomas, benign adnexal tumors often associated with Birt-Hogg-Dubé syndrome, exhibit characteristic perifollicular epithelial and stromal proliferation. Although their clinicopathologic features are well estab...Fibrofolliculomas, benign adnexal tumors often associated with Birt-Hogg-Dubé syndrome, exhibit characteristic perifollicular epithelial and stromal proliferation. Although their clinicopathologic features are well established, the molecular and metabolic drivers of stromal remodeling remain poorly understood, particularly in sporadic cases. We investigate the presence of dermal interstitial glycogenosis (DIG) and stromal senescence in fibrofolliculomas, exploring potential mechanistic parallels with pulmonary interstitial glycogenosis and mammalian target of rapamycin (mTOR)-driven cutaneous lesions. Archival skin biopsy specimens diagnosed as fibrofolliculoma between 2015 and 2025 (n = 13) were analyzed using Periodic acid-Schiff ± diastase staining and immunohistochemistry for p53, GLB1 (β-galactosidase), CD68, and phospho-S6 and compared with age-matched, sex-matched, and site-matched controls (n = 3). Clinical data, including imaging and genetic testing, were reviewed in cases of fibrofolliculoma. All fibrofolliculomas exhibited diastase-sensitive Periodic acid-Schiff-positive stromal granules consistent with glycogen accumulation. Stromal cells demonstrated immunoreactivity for GLB1, p53, and phospho-S6 in the absence of CD68 expression, indicating nonhistiocytic stromal senescence and mTOR activation. Birt-Hogg-Dubé syndrome was suspected in 4 of 10 patients but unconfirmed; DIG and senescence markers were present regardless of clinical context. Glycogenosis and cellular senescence markers were absent in controls. These findings identify DIG and stromal senescence as conserved features of fibrofolliculomas, suggesting a metabolic-senescence axis driven by mTOR signaling, and provide a rationale for mTOR-targeted therapies, including topical rapamycin, in the treatment of fibrofolliculomas.
Am J Dermatopathol
· 2026 Jun · PMID 42339859
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Cutaneous squamous cell carcinoma in situ is characterized by well-established architectural and cytological abnormalities that are readily appreciated at both low and high magnification. We have encountered a subset of...Cutaneous squamous cell carcinoma in situ is characterized by well-established architectural and cytological abnormalities that are readily appreciated at both low and high magnification. We have encountered a subset of lesions with a deceptively bland appearance at scanning magnification that demonstrated unequivocal malignant features on closer examination, which we term "stealth pigmented squamous cell carcinoma in situ." In this study, we describe 51 cases of this entity and compare its clinical, histological, and immunohistochemical features with those of its closest morphologic mimickers. These stealth lesions are most often found on the lower extremities and pigmented, thus clinically suspected to be melanocytic lesions or pigmented keratoses, not atypical squamous proliferations. At low magnification, they typically seem flat and orthokeratotic with basal hyperpigmentation above minimal solar elastosis. At higher magnification, keratinocyte atypia, dysmaturation, and numerous mitotic figures are evident throughout the epidermis. This stealth variant is as proliferative as conventional squamous cell carcinoma in situ by Ki67 but significantly less likely to overexpress p16. We believe stealth pigmented squamous cell carcinoma in situ represents a distinct variant of squamous cell carcinoma in situ. Although prognostic significance remains to be studied, recognition of this pigmented entity is important to avoid misdiagnosis and undertreatment as a benign epidermal lesion.
Am J Dermatopathol
· 2026 Jun · PMID 42333526
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The Paget disease represents a form of adenocarcinoma arising in epidermis; it can be distinguished in mammary (when involves the nipple areolar epidermis) and extramammary Paget disease (uncommon form that involves apoc...The Paget disease represents a form of adenocarcinoma arising in epidermis; it can be distinguished in mammary (when involves the nipple areolar epidermis) and extramammary Paget disease (uncommon form that involves apocrine gland-rich areas); they present significant diagnostic challenges because of its nonspecific clinical appearance and frequent misidentification as benign, inflammatory skin conditions. Line-field confocal optical coherence tomography (LC-OCT) is a novel, noninvasive imaging modality that enables in vivo, real-time visualization of the skin with near-histological resolution. The objective of this study was to evaluate the diagnostic performance and clinical applicability of LC-OCT as a noninvasive imaging tool for the in vivo assessment of both mammary and extramammary Paget disease, and to establish their correspondence with conventional histopathological findings. This retrospective study included 4 patients with histopathologically confirmed diagnoses of mammary and extramammary Paget disease. All lesions were imaged in vivo with LC-OCT before biopsy. In both mammary Paget disease and extramammary Paget disease, LC-OCT identified intraepidermal clusters and single hypo-reflective Paget cells correlating with histological findings. LC-OCT represents a valuable adjunct in dermatologic diagnostics, offering near-histological, real-time visualization of cutaneous architecture. It can enhance diagnostic accuracy, guide biopsy site selection, improve preoperative margin assessment, and support follow-up after nonsurgical therapy.
Hamilton L, Bourgeois JC, Johnson K
… +3 more, Jimenez A, Wilson JM, Goodwin BP
Am J Dermatopathol
· 2026 Jun · PMID 42333525
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Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis that most commonly presents with nodal disease but may involve extranodal sites, including the skin. Purely cutaneous Rosai-Dorfman disease (CRDD) i...Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis that most commonly presents with nodal disease but may involve extranodal sites, including the skin. Purely cutaneous Rosai-Dorfman disease (CRDD) is uncommon and demonstrates a wide range of clinical and histopathologic features, frequently resulting in diagnostic delay. We report a case of a 64-year-old woman with an 18-month history of a progressively enlarging, pruritic nasal mass encompassing the entire nasal dorsum and bilateral nasal sidewalls refractory to multiple therapies and repeatedly misdiagnosed as granulomatous rosacea. Deep biopsy revealed a dense lymphoplasmacytic infiltrate with storiform fibrosis involving the dermis, subcutis, and skeletal muscle. Scattered large histiocytes demonstrated emperipolesis and expressed S100, OCT2, and CD68, whereas CD1a was negative. Extensive ancillary studies excluded infection and hematolymphoid malignancy. This case highlights a rare and underrecognized presentation of CRDD with histopathologically confirmed skeletal muscle involvement and underscores key diagnostic pitfalls relevant to dermatologists and dermatopathologists.
Fukuda K, Mitsui Y, Ogawa K
… +5 more, Morita K, Ochi A, Fukumoto T, Yoshizawa A, Shinkuma S
Am J Dermatopathol
· 2026 Jun · PMID 42333518
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We present the case of a 75-year-old woman with a vulvar collision tumor consisting of basal cell carcinoma (BCC) and primary extramammary Paget disease (EMPD). The patient presented for evaluation of a pigmented nodule...We present the case of a 75-year-old woman with a vulvar collision tumor consisting of basal cell carcinoma (BCC) and primary extramammary Paget disease (EMPD). The patient presented for evaluation of a pigmented nodule on the right labium majus identified 1 year ago. The nodule was excised, and histopathology revealed nests of basaloid cells with nuclear palisading surrounded by myxoid stroma, consistent with nodular BCC. In addition, scattered intraepidermal cells with clear amphophilic cytoplasm at the periphery of the specimen raised suspicion for EMPD coexistence. Further visual inspection revealed bilateral hypopigmented patches on the labia majora. Gynecological and urological examination showed no abnormal findings. The hypopigmented lesion was excised with a 1-cm margin. Histopathology showed an intraepidermal pagetoid spread of tumor cells with atypical nuclei and abundant amphophilic cytoplasm. A diagnosis of a collision tumor comprising BCC and primary EMPD was made. A BCC-EMPD collision is rarely reported. This case highlights that coexisting EMPD can be overlooked, particularly when evaluating vulvar BCC, underscoring the diagnostic challenge posed by basaloid proliferation and pagetoid spread. Furthermore, our review of the literature elucidated the unique clinicopathological features of BCC-EMPD collision and discussed its differentiation from secondary EMPD with Pinkus-like changes and BCC with pagetoid spread.