American Journal of Dermatopathology最新文献

Abstract: The development of a mature histiocytic neoplasm after an immature lymphoproliferative disorder is rare but well documented. Previous studies have demonstrated clonal relationships between these entities-often through T- and B-cell receptor clonality analyses-supporting the concept of transdifferentiation. We report a unique case of a solitary, subtle xanthogranuloma identified during routine comprehensive skin examination in a patient with a history of T-cell acute lymphoblastic lymphoma, postallogeneic stem cell transplant. Next-generation sequencing of the skin lesion revealed the presence of a DNMT3A mutation identical to that found in the patient's prior lymphoma, despite the patient being in both morphologic and molecular remission in the peripheral blood and bone marrow. This case underscores the importance of vigilant surveillance and highlights a potential mechanistic link through clonal evolution or transdifferentiation.

Abstract: Superficial ALK- rearranged myxoid spindle cell neoplasms/epithelioid fibrous histiocytoma (SAMS/EFH) are newly defined hybrid soft tissue tumors within the broader class of S100 and CD34 coexpressing spindle cell tumors that harbor receptor tyrosine kinase fusions. Several research groups have contributed to describing and characterizing the morphologic and immunophenotypic spectrum of SAMS/EFH and exploring its relationship with other similar appearing and molecularly driven neoplasms. To further expand the knowledge of this entity, we present a unique hybrid case of superficial ALK- rearranged myxoid spindle cell neoplasm/EFH with novel aberrant cytokeratin expression and rare ALK::PRKAR1A fusion, thus, adding to the spectrum of such unique and newly emerging tumors.

Background: Dermatologic adverse events (dAEs) are prevalent with BCR-ABL tyrosine kinase inhibitors (TKIs), affecting quality of life and treatment adherence. Despite their prevalence, underlying mechanisms of toxicity remain unclear. We sought to characterize dAEs across TKI generations to elucidate mechanisms driving toxicities.

Methods: Retrospective cohort study of patients receiving imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and asciminib at Memorial Sloan Kettering Cancer Center between 2001 and 2023 with dermatologic biopsy for TKI-related dAEs. Clinical and histopathologic characteristics were analyzed. Fisher exact test, with Freeman-Halton extension, was used to determine statistically significant differences.

Results: Among 28 patients with 32 unique dAEs, imatinib was implicated in 32.1% of patients, second-generation TKIs in 57.1%, and ponatinib in 10.7%. Imatinib-induced dAEs exhibited significantly higher rates of papular/plaque morphology ( P = 0.02) with acanthosis ( P = 0.001) and eosinophilic infiltrates ( P = 0.02). Second-generation TKIs frequently caused folliculocentric eruptions with adnexal involvement. Ponatinib-related dAEs demonstrated significantly higher rates of ichthyosiform ( P = 0.002) and pityriasiform ( P = 0.02) morphologies with hyperkeratosis and fibrosis. No biopsy-confirmed asciminib dAEs were available.

Conclusions: dAE pathogenesis varies across TKI generations, suggesting distinct patterns of inflammation and keratinocyte dysregulation. Imatinib-related dAEs demonstrated epidermal hyperplasia and eosinophilic inflammation, suggesting immune-mediated hypersensitivity as an important mechanism of toxicity. Second-generation TKI dAEs demonstrated prominent adnexal and perivascular involvement, possibly driven by off-target inhibition and proinflammatory mechanisms. Ponatinib dAEs reflected chronic epidermal alterations, possibly driven by off-target vascular endothelial growth factor receptor, fibroblast growth factor receptor, and Src-family kinase inhibition. Limited sample size, particularly for third-generation TKIs, limits generalizability. Understanding these differences may improve management strategies, optimizing patient quality of life and treatment continuation.

Abstract: Mycosis fungoides bullosa is a rare clinical subtype of mycosis fungoides, with less than 40 cases reported in the literature. We report a case of a 66-year-old female with a history of stage IIB folliculotrophic mycosis fungoides with large cell transformation, currently being treated with romidepsin and gemcitabine, transferred to our institution due to worsening cutaneous involvement. On exam, there were large, erythematous, crusted and eroded plaques of the neck, trunk, and bilateral upper and lower extremities, some with overlying tense bullae. Punch biopsy showed a marked infiltrate of atypical CD3+ lymphocytes with epidermotropism of predominantly CD4+ cells (CD4:CD8 ratio of 8:1), loss of CD5 and CD7, and scattered CD30+ cells. Direct immunofluorescence showed a non-diagnostic staining pattern. Blood cultures were negative. Given the clinical and histopathologic findings, a diagnosis of mycosis fungoides bullosa was made. Mycosis fungoides is the most common type of cutaneous T-cell lymphoma. Mycosis fungoides bullosa, a vesiculobullous presentation of mycosis fungoides, is a rare variant first described by Dr. Moritz Kaposi in 1887. Proposed mechanisms of bullae formation include confluence of Pautrier's microabscesses or loss of keratinocyte cohesion due to proliferation of atypical lymphocytes. Diagnosis is based on the presence of vesiculobullous lesions among typical lesions of mycosis fungoides, histopathologic features consistent with mycosis fungoides, and negative evaluation for other causes of vesiculobullous lesions such as infection and autoimmune blistering diseases. Recognition is important as mycosis fungoides bullosa carries poor prognosis, with 50% of reported patients expiring within 1 year of bullae appearance.

Abstract: Homozygous deletion of CDKN2A in melanoma is common, but loss of p16 expression by immunohistochemistry is an imperfect surrogate marker for CDKN2A deletion. Methylthioadenosine phosphorylase ( MTAP ), located at the same chromosomal locus as CDKN2A (9p21.3), is frequently codeleted. Recently, protein arginine methyltransferase 5 (PRMT5), a downstream effector of MTAP, has emerged as a therapeutic target, and loss of MTAP expression may both inform and enhance the use of PRMT5 inhibitors. We evaluate the expression of MTAP in nevi and melanomas, comparing it with p16 as a diagnostic surrogate for CDKN2A deletion, and evaluating its utility as a marker for MTAP locus deletion. We included 45 nevi and 70 melanomas, with correlation of p16 and MTAP expression to CDKN2A and MTAP locus status in 63 melanoma cases. Most nevi (71%) showed a mosaic pattern of p16 expression, whereas 100% of nevi showed retained expression of MTAP. In melanoma, 59% of cases showed loss of p16, and 10% showed loss of MTAP. p16 had a moderate sensitivity (82%) and negative predictive value (NPV; 87%) and low specificity (43%) and positive predictive value (PPV; 35%) for detection of CDKN2A homozygous deletion. In contrast, MTAP loss was 100% specific for homozygous deletion of CDKN2A , with a PPV of 100%, sensitivity of 41%, and NPV of 82%. Complete loss of p16 expression was seen in 90% of melanomas with single copy CDKN2A deletion, whereas MTAP showed retained or mosaic expression in 100% of these cases. These findings support the use of MTAP as a surrogate marker for the homozygous deletion of CDKN2A in melanoma. Furthermore, loss of MTAP expression also strongly correlates with homozygous deletion of the MTAP locus with 100% specificity, 70% sensitivity, and a PPV of 100% and NPV of 93%. This finding may have implications for the susceptibility of melanoma to PRMT5 and related inhibitors. Methylthioadenosine Phosphorylase (MTAP) and p16 Expression in Melanocytic Nevi and Melanoma with Molecular Correlation.

Abstract: Onychocytic matricoma (OCM) is an acquired benign onychogenic tumor producing a localized thickening of the nail plate that usually presents as longitudinal pachymelanonychia. However, longitudinal pachyleukonychia as the presenting sign of OCM is increasingly recognized in clinical practice. To our knowledge, polydactylous OCM has not previously been reported in the literature. This study aims to describe a new nail genodermatosis presenting as polydactylous longitudinal leukonychia with histology typical of OCM. Four cases were identified. The previously unreported familial nail abnormality occurred in at least 2 first-degree relatives. Longitudinal white bands located exclusively on the fingernails were the only characteristic of this disease. The longitudinal bands varied in number from 2 to 4 per nail. Nail changes may appear during childhood, but most cases were observed between the ages of 20 and 50 years. The multiple longitudinal bands corresponded histologically to multiple OCM. Three cases in this series had no relevant personal of family history of neoplasm, but only 2 generations were analyzed. In 1 family, polydactylous OCM was associated with a family history of melanoma and renal cell carcinoma. The genomic profile of this single family allowed a diagnosis of OCM associated with BRCA1-associated protein (BAP1) tumor predisposition syndrome (TPDS). Our results are limited by incomplete follow-up and the small size of this retrospective case series. As such tumors are rare, additional cases need to be collected to clarify the role of onychocytic hamartoma as an early indicator of BAP1 TPDS.