Oral Abstracts/Free Communications Presentations at the 28th Joint Meeting of the International Society of Dermatopathology, March 5–6, 2025, Orlando, Florida, USA

Direct Immunofluorescence Microscopy of Skin Biopsies in Children: A Retrospective Cohort Study of 986 DIF Studies Clint Christian Garbanzos ([email protected]) Background: Immune-mediated skin disorders are seen in children but biopsies for DIF are often reluctantly done with sparse literature supporting such practice. This study aims to identify common DIF patterns, assess concordance between DIF findings and clinical impressions, and evaluate how biopsy site impacts positive DIF results. Methods: We reviewed DIF data from all skin and mucosa specimens interpreted at our reference immunodermatology laboratory for patients aged 0–18 (August 22, 2017–November 30, 2023). DIF results were classified as positive if they showed characteristic patterns or negative if findings were absent or non-diagnostic. Results: Among 986 DIF studies, 153 (15.5%) were positive. The most frequent patterns were IgA-predominant vasculitis (55.5%), lichenoid tissue reaction (13.7%), pemphigoid disorders (7.2%), lupus (7.2%), dermatitis herpetiformis (5.2%), linear IgA bullous dermatosis (4.6%), pemphigus (3.3%), and non-IgA predominant vasculitis (3.3%). Linear IgA bullous dermatosis and dermatitis herpetiformis had the highest clinical concordance (100%), while pemphigus and non-IgA predominant vasculitis had the lowest (33.3%). Lower extremity biopsies were more likely to yield positive results (P < 0.05). Conclusion: IgA-predominant vasculitis was the most common DIF pattern in children, with lower extremity biopsies providing the highest diagnostic yield. This study demonstrates the utility of DIF in diagnosing certain immune-mediated dermatoses in children. Co-authors: Austin Todd, MS (Department of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN), Heather D. Hardway, PhD (Department of Dermatology, Mayo Clinic, Rochester, MN), Julia S. Lehman, MD (Department of Dermatology & Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN), Jorge A. Rios-Duarte, MD (Department of Dermatology, Mayo Clinic, Rochester, MN), and Dawn M.R. Davis, MD (Department of Dermatology and Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN) Evaluation of MTAP and P16 Immunohistochemistry and CDKN2A Deletion in Melanoma Kristine Cornejo ([email protected]) Background: Homozygous deletion of CDKN2A occurs in a subset of melanomas, resulting in loss of p16 expression by immunohistochemistry (IHC). MTAP resides near CDKN2A and are often co-deleted. The loss of MTAP/p16 expression as a surrogate marker for CDKN2A status in melanoma has not been explored. Methods: MTAP and p16 IHC was performed on a cohort of 35 melanomas cases with known CDKN2A copy number status previously determined by targeted DNA-based next-generation sequencing (NGS) using a multiplex PCR-based assay interrogating 97-genes. Concordance between IHC and NGS findings were evaluated. Results: MTAP loss was identified in 15/25 (60%) melanomas with and 0/10 (0%) without CDKN2A loss (P = 0.0016) (sensitivity: 60%; specificity: 100%). p16 loss was identified in 20/25 (80%) melanomas with and 4/10 (40%) without CDKN2A loss (P = 0.0413) (sensitivity: 80%; specificity: 60%). The positive predictive value (PPV) of MTAP and p16 loss for CDNK2A deletion were 100% and 83%, respectively. The combination of either MTAP/p16 loss was identified in 24/25 (96%) melanomas with and 4/10 (40%) without CDKN2A loss (P = 0.0008) (sensitivity: 96%; specificity: 60%; PPV: 86%). Conclusion: MTAP is a promising surrogate marker for CDKN2A status in melanoma with a high specificity, while the combination of p16/MTAP has the best sensitivity. Co-authors: Charlotte I. Wang (Massachusetts General Hospital), and Mai P. Hoang (Massachusetts General Hospital) Novel and Rare Gene Fusions in Melanoma: A Case Series Federico Repetto ([email protected]) Background: Melanoma is an aggressive malignancy with a complex molecular landscape. While common driver mutations are well-characterized, rare gene fusions remain underexplored, despite their diagnostic, prognostic, and therapeutic potential. We report 8 melanoma cases with unusual gene fusions, broadening the understanding of melanoma genomics and its clinicopathologic relevance. Methods: A total of 506 melanoma cases diagnosed between May 2022 and May 2024 were analyzed using next-generation sequencing (NGS). Of these, 353 cases underwent gene fusion testing. Public databases (COSMIC, TCGA) and literature (PubMed) were reviewed to contextualize identified fusions. Pathological and clinical data were also examined. Results: Rare or novel gene fusions were identified in 8 of 353 cases (2.3%), most frequently involving BRAF (3/8; 37.5%). Two fusions had been previously reported in melanoma—ANO10:RAF1 (once) and AGAP3:BRAF (twice). Two additional fusions were described in other malignancies but not melanoma: GOPC::ROS1 (glioma) and TPM3:ALK (anaplastic large cell lymphoma). Four novel fusions, not previously reported in any cancer, were identified: TERT::ZNFZ740, CCDC85A::BRAF, SGK3:BRAF, and FGFR1:MYO9B. Conclusions: This study highlights rare and novel gene fusions in melanoma, offering new insights into oncogenic mechanisms and potential therapeutic targets. These findings expand the molecular landscape of melanoma and warrant further investigation into their clinical significance. Co-authors: Federico Repetto, MD (1) Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA; 2) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA), Rosalynn M. Nazarian, MD (Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA), Anthony J. Iafrate, MD, PhD (Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA), Ruth K. Foreman, MD, PhD (Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA), Valentina Nardi, MD (Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA), Lyn M. Duncan, MD (Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA), Long P. Le, MD, PhD (Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA), Mai P. Hoang, MD (Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA), and Dora Dias-Santagata, PhD (Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA) CK17, SOX2, and GATA3 Immunostains Aid in Distinguishing HPV-Independent, p53 Wild-Type Penile Intraepithelial Neoplasia From Hyperplastic Non-Neoplastic Mimics Miranda Machacek ([email protected]) Background: HPV-independent, p53 wild-type penile intraepithelial neoplasia (PeIN) (verruciform acanthotic PeIN/vaPeIN) is rare and difficult to distinguish from hyperplastic non-neoplastic lesions given there is histologic overlap and currently lacks a confirmatory stain to identify its neoplastic nature akin to p53 for differentiated PeIN. Recently, CK17, SOX2, and GATA3 immunohistochemistry (IHC) has been proposed to aid in this distinction in the vulva. We thus assessed the utility of this panel in penile lesions. Methods: Candidate vaPeIN (negative for HPV and wild-type for p53 by IHC) were identified and the panel of IHC performed. CK17 was scored as 0/none; 1+/patchy/non-continuous; 2+/continuous/partial-thickness and 3+/continuous/full-thickness. SOX2 was scored as 0/none/weak in <10%; 1+/weak; 2+/moderate or 3+/strong in >10% of cells. GATA3 was scored as 0/staining in >75%; 1+/staining in 25%–75% or 2+/staining in <25% basal cells. Results: Immunohistochemistry revealed full-thickness/3+ CK17 staining in 3/3 (100%) vaPeIN versus 3/13 (23%) benign lesions. Moderate-strong/2–3+ SOX2 staining was seen in 3/3 (100%) vaPeIN versus 1/13 (8%) benign lesions. Loss of GATA3 (2+/<25% of basal cells) was identified in 1/3 (33%) vaPeIN versus 2/10 (20%) benign lesions. Conclusion: Our preliminary results support a potential role of CK17, SOX2, and GATA3 immunostains to distinguish vaPeIN from hyperplastic non-neoplastic mimics. Co-authors: Miranda Machacek (Massachusetts General Hospital), Chin-Lee Wu (Massachusetts General Hospital), Esther Oliva (Massachusetts General Hospital), Peter Sadow (Massachusetts General Hospital), Kyle Devins (Massachusetts General Hospital), Rosalynn Nazarian (Massachusetts General Hospital), and Kristine Cornejo (Massachusetts General Hospital) Direct Immunofluorescence Testing in Cutaneous Graft-Versus-Host Disease: Retrospective Single-Center Cohort Study of 121 Specimens Lindsey Wanberg ([email protected]) Objective: Our immunodermatology laboratory routinely receives skin biopsy specimens for direct immunofluorescence testing (DIF) for graft-versus-host disease (GVHD), despite the value of DIF for GVHD being unstudied This retrospective single-cohort study aims to characterize DIF utility in GVHD. Methods: We analyzed all DIF reports of specimens submitted for GVHD (8/22/2017–11/30/2023) and manually reviewed corresponding electronic medical records. Results: One hundred twenty-one DIFs were included. Mean duration from hematopoietic cell transplantation to skin biopsy was 419 days (6–4407). Frequent final diagnoses included acute GVHD (35, 28.9%), chronic GVHD (28, 23.1%), and drug rash (15, 12.4%). Of 121 DIFs, 107 (88.4%) were negative/non-diagnostic, 12 (9.9%) showed lichenoid tissue reaction (LTR), and 2 (1.7%; from the same patient) showed linear C3 deposition. Patients with LTR carried final diagnoses of acute GVHD (n = 2), chronic GVHD (n = 5), drug rash (n = 1), and uncertain GVHD versus drug rash (n = 4). The patient with linear C3 on DIF presented with erosions, and correlation of DIF results with serologic findings led to a diagnosis of concurrent bullous pemphigoid and GVHD. Conclusions: DIF results are unlikely to change management when GVHD is a clinical consideration. However, the presence of certain findings (eg, erosions, bullae) may justify DIF to evaluate for immunobullous diseases. Co-authors: Heather D. Hardway, PhD (Department of Dermatology, Mayo Clinic, Rochester, MN), and Julia S. Lehman, MD (Mayo School of Graduate Medical Education, Department of Dermatology, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN) Augmenting Error Detection in Dermatopathology Reports With GPT-4o: Balancing AI Assistance and Human Expertise Josh Del Papa ([email protected]) Objective: Artificial intelligence (AI) tools, including large language models (LLMs), are becoming integrated into everyday technologies. Their thoughtful application in pathology offers opportunities to enhance workflows and improve accuracy. This study explores the potential of GPT-4o to support error detection in dermatopathology reports. Methods: A dataset of 250 synthetic reports was created, with 25 errors randomly embedded, including reused microscopic descriptions, spelling mistakes, and laterality errors. A dermatopathology expert reviewed 100 reports to establish a ground-truth error key. A non-expert staff member without dermatopathology fellowship training then reviewed 150 reports, first unaided and then, after a two-week washout, with error flags generated by GPT-4o. Results: GPT-4o greatly improved error detection sensitivity for the non-expert reviewer, largely driven by dermatopathology-specific errors such as margin status. Excluding this category, sensitivity increased from 23% to 77% using the AI tool. Specificity remained high (100% for the reviewer, 92% for GPT-4o). Using GPT-4o reduced response times by 1.8x (P < 0.001). Conclusions: LLM-based tools like GPT-4o hold promise to enhance error detection and efficiency in pathology workflows, improving sensitivity while maintaining specificity. However, human expertise remains essential to refine AI models and ensure accuracy. A human-in-the-loop approach is critical for successful AI integration into pathology practice. Co-authors: Josh Del Papa (1. Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; 2. Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON, Canada), Sherman Lin (1. Schulich School of Medicine & Dentistry, Western University, London, ON, Canada; 2. Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON, Canada), Kyla Trinh (1. Western University, London, ON, Canada; 2. Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON, Canada), Lisa Bi (1. Western University, London, ON, Canada; 2. Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON, Canada), Rajendra Singh (Director of Dermatopathology and Digital Pathology, Summit Health, Woodland Park, NJ), and Matthew J. Cecchini (1. Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; 2. Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON, Canada) Acral Hemorrhagic Darier Disease Johanna Brito-Luna ([email protected]) Darier-White disease (DWD), also known as follicular keratosis, is a genetic skin disorder caused by mutations in the ATP2A2 gene, which encodes the SERCA2 protein. This protein regulates intracellular calcium in epidermal cells. The mutation leads to cell adhesion defects, resulting in acantholysis and abnormal keratinization. Clinically, it manifests as rough, warty papules and plaques, primarily affecting areas like the face, scalp, chest, back, groin, and armpits. A rare hemorrhagic acral variant involves vesicles or blisters on the hands and feet. We present 3 patients, 2 of whom are consanguineous, diagnosed with DWD since childhood and exhibiting hemorrhagic lesions on the dorsal and palmar surfaces of the hands. Histopathology revealed ortho and parakeratosis, extensive suprabasal blistering containing abundant erythrocytes and neutrophils, dyskeratotic cells in the blister roof, and acantholytic cells at the base. The hemorrhagic acral DWD variant was first reported by Jones in 1964 in 4 patients, including 2 relatives. It is characterized by hemorrhagic papulovesicles in acral regions, triggered by minimal trauma. Studies suggest this variant may involve mutations distinct from ATP2A2 exon 15, though the genotype–phenotype correlation remains unclear. Co-authors: Fabián Cruz-Murillo (Carlos Andrade Marin Hospital, Department of Dermatology), Patricio Freire-Murgueytio (Carlos Andrade Marin Hospital, Department of Dermatology), Myriam Ortega (Carlos Andrade Marin Hospital, Department of Dermatology), and Santiago Palacios (CEPI (Skin Center), Department of Dermatology)

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