The Implications of a Dermatopathologist's Report on Melanoma Diagnosis and Treatment.

An accurate and comprehensive histopathology report is essential for cutaneous melanoma management, providing critical information for accurate staging and risk estimation and determining the optimal surgical approach. In many institutions, a review of melanoma biopsy specimens by expert dermatopathologists is considered a necessary step. This study examined these reviews to determine the critical primary histopathology Breslow score in which a histopathology review would be most beneficial. Histopathology reports of patients referred to our institute between January 2011 and September 2019 were compared with our in-house review conducted by an expert dermatopathologist. The review focused on assessing fundamental histologic and clinical prognostic features. A total of 177 specimens underwent histopathology review. Significant changes in the Breslow index were identified in 103 cases (58.2%). Notably, in many of these cases (73.2%), the revised Breslow was higher than the initially reported score. Consequently, the T-stage was modified in 51 lesions (28.8%). Substantial discordance rates were observed in Tis (57%), T1b (59%), T3a (67%) and T4a (50%) classifications. The revised histopathology reports resulted in alterations to the surgical plan in 15.3% of the cases. These findings emphasize the importance of having all routine pathologies of pigmented lesions referred to a dedicated cancer center and reviewed by an experienced dermatopathologist. This recommendation is particularly crucial in instances where the histopathology review can potentially alter the diagnosis and treatment plan, such as in melanoma in situ and thinner melanomas measuring 0.6-2.2 mm in thickness. Our study highlights the significant impact of histopathology reviews in cutaneous melanoma cases. The observed changes in Breslow scores and subsequent modifications in T-stage classification underline the need for thorough evaluation by an expert dermatopathologist, especially in cases of melanoma in situ and thin melanomas. Incorporating such reviews into routine practice within dedicated cancer centers can improve diagnostic accuracy and guide appropriate treatment decisions, ultimately leading to better patient outcomes.

White epidermal nevus as an early sign of tuberous sclerosis complex-A case series.

Tuberous sclerosis complex (TSC) is a rare genetic disease with neurocutaneous manifestations, often presenting initially to the dermatology clinic. We report a cohort of neonates who presented with a novel finding of white epidermal nevus and were eventually diagnosed with TSC. White epidermal nevus may be yet another dermatological finding that may aid in the early diagnosis of TSC.

MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2.

Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower IFNγ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays, under the control of JAK2 promoter, demonstrated reduced activity in MYC-overexpressing cells, which was partly reversible upon mutagenesis of a MYC E-box binding site in the JAK2 promoter. Moreover, silencing of MYC or its cofactor MAX with siRNA increased JAK2 expression and IFNγ responsiveness of melanomas, while concomitantly enhancing the effector functions of T cells coincubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.

Adenosine-Deaminase-Acting-on-RNA-1 Facilitates T-cell Migration toward Human Melanoma Cells.

The effect of tumor/T-cell interactions on subsequent immune infiltration is undefined. Here, we report that preexposure of melanoma cells to cognate T cells enhanced the chemotaxis of new T cells in vitro. The effect was HLA class I-restricted and IFNγ-dependent, as it was abolished by ß2M-knockdown, MHC-blocking antibodies, JAK1 inhibitors, JAK1-silencing and IFNgR1-blocking antibodies. RNA sequencing (RNA-seq) of 73 melanoma metastases showed a significant correlation between the interferon-inducible p150 isoform of adenosine-deaminase-acting-on-RNA-1 (ADAR1) enzyme and immune infiltration. Consistent with this, cocultures of cognate melanoma/T-cell pairs led to IFNγ-dependent induction of ADAR1-p150 in the melanoma cells, as visualized in situ using dynamic cell blocks, in ovo using fertilized chick eggs, and in vitro with Western blots. ADAR1 staining and RNA-seq in patient-derived biopsies following immunotherapy showed a rise in ADAR1-p150 expression concurrently with CD8+ cell infiltration and clinical response. Silencing ADAR1-p150 abolished the IFNγ-driven enhanced T-cell migration, confirming its mechanistic role. Silencing and overexpression of the constitutive isoform of ADAR1, ADAR1-p110, decreased and increased T-cell migration, respectively. Chemokine arrays showed that ADAR1 controls the secretion of multiple chemokines from melanoma cells, probably through microRNA-mediated regulation. Chemokine receptor blockade eliminated the IFNγ-driven T-cell chemotaxis. We propose that the constitutive ADAR1 downregulation observed in melanoma contributes to immune exclusion, whereas antigen-specific T cells induce ADAR1-p150 by releasing IFNγ, which can drive T-cell infiltration.

Evaluation of the polymerase chain reaction-based T-cell receptor ß clonality test in the diagnosis of early mycosis fungoides.

BACKGROUND: T-cell receptor (TCR) clonality may help establish a diagnosis of mycosis fungoides (MF). Routine clonality analysis is performed by using a polymerase chain reaction TCR- gamma assay, yet with this method, 10% to 50% of T-cell lymphomas escape detection. TCR- beta gene rearrangement is an additional assay. Data about its efficacy are controversial. OBJECTIVE: To evaluate the role of TCR-ß assay in the diagnosis of early MF. METHODS: A retrospective study of 61 skin biopsies, 20 from patients with MF, 30 from patients suspected to have early MF, and 11 from patients with chronic inflammatory skin disease. RESULTS: Monoclonality was detected in 16 of 20 (80%) MF cases: 15 (75%) with TCR-ß and 12 (60%) with TCR-γ assay. Of the 30 suspected cases of early MF, 14 showed monoclonality with TCR-ß, and only 5 of 14 showed monoclonality with TCR-γ assay. None of the chronic inflammatory condition samples showed monoclonality. Therefore, TCR-ß clonality assay was more sensitive than TCR-γ in early MF (83% vs 43%; P = .002). LIMITATIONS: This was a retrospective, relatively small study. CONCLUSION: TCR-ß showed a higher sensitivity rate compared with TCR-γ in early-stage MF. The combined use of the TCR-ß and TCR-γ clonality tests can significantly improve the diagnosis rate of early-stage MF.

Basal cell carcinoma induced by therapeutic radiation for tinea capitis-clinicopathological study.

AIMS: An increased prevalence of aggressive histological subtypes, such as micronodular and morpheaform, has been seen, irrespective of the clinical course, in basal cell carcinoma (BCC) following irradiation for tinea capitis. The aim of this study was to assess the histopathological features of BCCs among patients irradiated for tinea capitis and correlate them with the clinical course. METHODS AND RESULTS: The medical records and BCC biopsy specimens of individuals who were previously irradiated for tinea capitis were reviewed. Demographic data and clinical characteristics were retrieved. Biopsy specimens were evaluated for histological subtype classification and additional histopathological features. A telephone survey was conducted to assess the clinical behaviour of the tumours. Thirty-one patients (17 male; 14 female) were included. The average age at time of first biopsy was 56 years. The total number of lesions was 185, with 80% of subjects showing multiple lesions. The nodular subtype was the most prevalent, followed by superficial, micronodular and mixed tumours. One-third of the BCCs could be classified as aggressive histologically. Stromal fibroplasia and melanin deposits were common. There was no mortality related to BCC. None of the 17 patients who completed the survey had evidence of local invasiveness or metastases. CONCLUSIONS: BCCs following radiation therapy for tinea capitis show unique histological characteristics related to aggressive behaviour. These aggressive features did not reflect the clinical behaviour in the current cohort.

Efficacy of Dapsone in the Treatment of Pemphigus Vulgaris: A Single-Center Case Study.

BACKGROUND: Pemphigus vulgaris (PV) is a chronic autoimmune blistering disease. Most patients require long-term therapy with systemic steroids, and a steroid-sparing agent is usually also utilized. Dapsone is a chemotherapeutic agent with anti-inflammatory properties that is used as a steroid-sparing agent in PV. OBJECTIVE: The aim of the present study was to evaluate the efficacy of dapsone as an adjuvant therapy in patients with PV. METHODS: A retrospective analysis of patients' files was performed. All 26 patients included in the study group were treated with dapsone as an adjuvant to systemic steroids for at least 3 consecutive months and were followed up during their dapsone treatment period. RESULTS: After 3 months of treatment with dapsone, 13 patients were in the consolidation phase, 4 patients demonstrated partial remission on minimal therapy, 7 patients demonstrated complete remission on minimal therapy, and 2 patients were defined as treatment failures. The trend of clinical improvement continued after 6 months of treatment and at the study end point. CONCLUSION: This retrospective case series, one of the largest reported, indicates that dapsone is efficacious and safe for patients with PV in whom it is well tolerated soon after the initiation of treatment.