Acute febrile neutrophilic dermatosis (Sweet syndrome) in acute myeloid leukemia patients: a 28-year institutional experience.

INTRODUCTION: Sweet syndrome (SS) is well-known to be associated with underlying hematologic malignancies. The incidence and qualities of SS among novel targeted therapies for acute myeloid leukemia (AML) have not yet been described. METHODS: Through retrospective review of 19432 patients diagnosed with acute/chronic leukemia or myelodysplastic syndromes/ myeloproliferative neoplasms (MDS+/-MPN) over 28 years, we calculated the incidence of SS in the setting of select hematologic malignancies and described the clinicopathologic characteristics of SS in patients with onset of SS after initiation of novel AML-targeted therapies. RESULTS: Overall incidence of SS was 0.36% (95% CI: 0.27% - 0.45%), which was significantly higher among patients with AML (50/5248, 0.94%; 95% CI: 0.71% - 1.25%). Nine AML patients were on 4 classes of novel targeted treatments - IDH1/2 inhibitor alone, FLT3 inhibitor, IDH2 and DOT1L inhibitor, and anti-CD33 therapy. In therapies inducing myeloid blast differentiation, SS occurred at later onset following treatment. CONCLUSIONS: In AML patients with fever and unusual skin lesions, physicians may consider SS earlier which may shorten time to diagnosis. Future assessments of SS among patients treated with novel therapies for AML and molecular studies of biopsies may help further explain this dermatologic adverse event with earlier diagnosis and management of neutrophilic dermatoses in these patients.

Aggressive Cutaneous Lymphomas and Their Mimics.

Cutaneous lymphomas encompass a heterogeneous group of neoplasms with a wide spectrum of clinical presentations, histopathologic features, and prognosis. Because there are overlapping pathologic features among indolent and aggressive forms and with systemic lymphomas that involve the skin, clinicopathologic correlation is essential. Herein, the clinical and histopathologic features of aggressive cutaneous B- and T-cell lymphomas are reviewed. Indolent cutaneous lymphomas/lymphoproliferative disorders, systemic lymphomas, and reactive processes that may mimic these entities are also discussed. This article highlights distinctive clinical and histopathologic features, increases awareness of rare entities, and presents new and evolving developments in the field.

Dermatologic adverse events associated with IDH inhibitors ivosidenib and enasidenib for the treatment of acute myeloid leukemia.

Two novel inhibitors of isocitrate dehydrogenase (IDHi), ivosidenib and enasidenib, significantly improve survival for AML patients with an IDH1 or IDH2 mutation, respectively; however, rash has been reported as a toxicity of IDHi. The objective of our study is to determine the incidence, grade, clinical, and histopathologic features of dermatologic adverse events (DAEs) secondary to IDHi. This study is a retrospective analysis of 169 patients who were treated with either ivosidenib or enasidenib as single agent or in combination with induction chemotherapy at Memorial Sloan Kettering Cancer Center from January 1, 2013 to April 1, 2021. DAEs thought to be possibly, probably, or definitely related to IDHi occurred in 55 of 169 patients [0.32, 95 % CI: 0.25 - 0.40]. Of a total 81 DAEs observed, the most common DAE types were inflammatory dermatoses (27 %); cutaneous vascular manifestations (8%); cutaneous infections (7%); and pruritus (2%). Notably, 50% of infections and 15.5% of rashes were high grade. Knowledge of these findings is critical to optimize the treatment and quality of life of patients with AML on IDHi.

Real-Time Reflectance Confocal Microscopy of Cutaneous Graft-versus-Host Disease Correlates with Histopathology.

Reflectance confocal microscopy (RCM) allows noninvasive, real-time evaluation of the skin at a resolution akin to histopathology (HP), but its application in cutaneous graft-versus-host disease (GVHD) has not been extensively assessed. We describe RCM features of cutaneous GVHD including acute (aGVHD), late acute, chronic (cGVHD; sclerotic and nonsclerotic subtypes), and inactive GVHD and correlate RCM with same-site HP for a subset of patients. Thirty-two adult and pediatric allogeneic hematopoietic cell transplantation (allo-HCT) recipients with cutaneous GVHD received RCM imaging of ≥1 lesions (n = 44), 13 of which necessitated skin biopsy. RCM images were deidentified and assessed by 2 RCM experts blinded to clinical and HP findings to reach a consensus on the features and patterns of the inflammatory dermatoses. Major RCM features (present in ≥65% of lesional sites) and patterns were reported. To determine the correlation between RCM and HP, detection of cellular features and patterns of inflammatory dermatoses were compared using percent agreement and prevalence-adjusted, bias-adjusted kappa estimates. Seven patients with early or late aGVHD (7 lesions) had irregular honeycombing, spongiosis, dermoepidermal junction (DEJ) and dermal inflammation, and melanophages; those with early aGVHD also had hyperkeratosis, dilated vessels, and coarse connective tissue. Both groups had an interface dermatitis pattern. Eighteen patients with nonsclerotic cGVHD (24 lesions) had irregular honeycombing, spongiosis, DEJ and dermal inflammation, dilated vessels, coarse connective tissue, and interface and spongiotic dermatitis patterns. Three sclerotic patients with cGVHD (7 lesions) had irregular honeycombing, DEJ and dermal inflammation with an interface dermatitis pattern. Four patients with inactive GVHD (6 lesions) showed minimal inflammation. RCM and HP had similar detection rates for 6 of 13 features and overall patterns important for diagnosis in 2 patients with late aGVHD (2 lesions; 15%) and 10 with nonsclerotic cGVHD (11 lesions; 85%) necessitating skin biopsy. RCM can detect features commonly reported in cutaneous GVHD and is comparable to HP. Additional characterization of cutaneous GVHD by RCM may enable future use in diagnosing, monitoring, or predicting disease in real time.

Sézary syndrome and mycosis fungoides: An overview, including the role of immunophenotyping.

This review discusses the definition and major categories of cutaneous T-cell lymphoma, Sézary syndrome and mycosis fungoides, and the role of immunophenotyping in their diagnosis. The following key points are raised: (a) Sézary syndrome and mycosis fungoides cells most often have a characteristic CD3+ CD4+ CD7- and/or CD26- immunophenotype. (b) This immunophenotype is not specific, but can assist in the distinction from non-neoplastic T cells and other subtypes of mature T-cell neoplasm. (c) However, small subsets of normal and reactive T-cells can have an overlapping immunophenotype, and can be distinguished by evaluating for additional changes in antigen expression.

Outcomes and prognostic factors in African American and black patients with mycosis fungoides/Sézary syndrome: Retrospective analysis of 157 patients from a referral cancer center.

BACKGROUND: The prevalence of mycosis fungoides/Sézary syndrome (MF/SS) is higher in the black population than in the white population in the United States and worse outcomes have been observed in black patients. OBJECTIVE: To describe the outcomes and to identify prognostic factors in African American and black patients with MF/SS. METHODS: Clinical features and follow-up data were analyzed in 157 self-identified African American or black patients seen during 1994-2018. RESULTS: We included 122 patients with early stage MF and 35 patients with advanced-stage disease (median follow-up of 25 months). Overall, >80% of the patients who died from disease or progressed had erythema or hyperpigmentation without hypopigmentation. Patients with hypopigmentation, either as the sole manifestation or in combination with other lesions, had better overall survival (P = .002) and progression-free survival (P = .014). Clinical stage, TNMB classification, plaque disease, and elevated serum lactate dehydrogenase were also significantly associated with outcomes. Demographic and socioeconomic parameters were not associated with prognosis. LIMITATIONS: A retrospective study at a single cancer center. CONCLUSION: MF/SS manifestations and outcomes in African American and black patients are heterogeneous. Demographic and socioeconomic factors do not seem to have a prognostic role, while clinical characteristics might help in the stratification of risk of progression and shorter survival, allowing for individually tailored therapeutic interventions.

Scleromyxedematous Changes in a Patient With Long-Standing Mycosis Fungoides Who Progressed to Sézary Syndrome.

Mycosis fungoides (MF) variants with different clinicopathologic and immunohistochemical features have been well-delineated. We report a case of scleromyxedematous changes arising in a patient with long-standing MF who progressed to Sézary syndrome (SS) shortly afterward. Total-skin electron-beam radiation therapy resulted in an excellent response, controlling both the MF/SS and the scleromyxedematous lesions; however, the patient died few months later. Although mucin deposition has been described in association with MF/SS (mainly follicular mucinosis in folliculotropic MF), there are limited reports in the literature on dermal mucinosis and scleromyxedematous changes in MF/SS. The mechanism of this association and its prognostic implications requires further investigation.

Immunohistochemical Detection of γ/δ T Lymphocytes in Formalin-fixed Paraffin-embedded Tissues.

T lymphocytes can be distinguished based on the composition of the T-cell receptor (TCR) chain in α/ß T cells and γ/δ T cells. Correspondingly, α/ß lymphomas can be distinguished from γ/δ lymphomas. The latter are rare neoplasms, which are usually confined to particular organs and tissues and carry a dismal prognosis. Until recently, monoclonal antibody (mAb) clone g3.20 to the TCR γ-chain was the reagent of choice for the immunohistochemical detection of γ/δ T cells and lymphomas in standard formalin-fixed paraffin-embedded tissues. However, due to technical problems, mAb g3.20 became recently unavailable. Our attempts to identify another commercially available clone to the TCR γ-chain were unsuccessful. However, we were able to identify a mAb (clone H-41, SC-100289; Santa Cruz, Dallas, TX) to the TCR δ-chain. H-41 works well in immunohistochemistry on paraffin-embedded tissue and comparison with previously stained cases, shows superior immunolabeling to mAb g3.20. H-41 to the TCR δ-chain appears to be a suitable reagent for the replacement of mAb g3.20.

Unrelated immunodeficiency states may impact outcomes and immune checkpoint molecule expression in patients with mycosis fungoides: A clinicopathologic case-control study.

BACKGROUND: Immunodeficiency (ID) correlates with worse outcomes and decreased immune checkpoint molecule expression in melanoma. The impact of ID in mycosis fungoides (MF) is unknown. OBJECTIVE: Our goal was to evaluate the impact of ID in MF. METHODS: We conducted a case-control study of 17 patients with MF and ID versus age-, stage-, and race-matched controls as a subset of a comparative analysis of 23 patients with MF with ID (prior lymphoma, recent/current pregnancy, HIV, hypogammaglobulinemia, and prior chemotherapy) versus without ID. Programmed cell death 1 (PD1), programmed death ligand 1 (PDL1), forkhead box p3, and interleukin 17 immunohistochemistry was performed on 12 patients with ID and 10 controls. RESULTS: Patients with ID had more treatment failure (14 of 23 vs 5 of 17 [P = .028]), more treatment failure within 3 years of diagnosis (12 of 23 vs 4 of 17 [P = .050]), more angiocentrism (6 of 12 vs 0 of 10 [P = .005]), larger cells (1.92 ± 0.51 out of 3 vs 1.30 ± 0.48 out of 3 [P = .009]), more cases with at least 10% PD1 positivity (9 of 11 vs 4 of 10 [P = .031]) and at least 10% PDL1 positivity (7 of 12 vs 2 of 10 [P = .042]), and a higher average percentage of PD1+ cells (43.27 ± 40.22 vs 11.2 ± 13.62 [P = .028]). No differences in survival, forkhead box p3 expression, interleukin 17 expression, histologic depth, ulceration, granulomatous changes, or syringotropism were seen. LIMITATIONS: This was a small single-center study with heterogeneous immunodeficiencies. CONCLUSION: ID correlated with worse outcomes and increased PD1 and PDL1 expression in MF. Patients with MF and ID may be candidates for immune checkpoint inhibitor therapy, pending further investigation.

In vivo intraoral reflectance confocal microscopy of an amalgam tattoo.

The majority of oral pigmentations are benign lesions such as nevi, melanotic macules, melanoacanthomas or amalgam tattoos. Conversely, mucosal melanomas are rare but often lethal; therefore, excluding oral melanomas in this setting is crucial. Reflectance confocal microscopy is a non-invasive, in vivo imaging system with cellular resolution that has been used to distinguish benign from malignant pigmented lesions in the skin, and more recently in the mucosa. However, lesions located posteriorly in the oral cavity are difficult to assess visually and difficult to biopsy due to their location. Herein we present a patient with previous multiple melanomas presenting with an oral amalgam tattoo in the buccal mucosa, which was imaged using an intraoral telescopic probe attached to a commercially available handheld RCM. In this case report we describe this novel probe, the first RCM description of an amalgam tattoo and we discuss its differences with the findings described in oral melanomas.

Handheld Reflectance Confocal Microscopy for the Detection of Recurrent Extramammary Paget Disease.

Importance: Extramammary Paget disease (EMPD) is commonly refractory to surgical and nonsurgical therapies. Identifying recurrent or persistent EMPD is challenging because the disease is multifocal, and multiple blind scouting biopsies are usually performed in this setting. Handheld reflectance confocal microscopy (HRCM) has been used to diagnose and map primary EMPD and therefore may be used to identify EMPD recurrences. Objective: To evaluate HRCM's diagnostic accuracy in the setting of recurrent or persistent EMPD as well as its potential diagnostic pitfalls. Design, Setting, and Participants: This prospective case series study included patients referred to the Dermatology Service at Memorial Sloan Kettering Cancer Center between January 1, 2014, and December 31, 2016, with biopsy-proven EMPD in whom HRCM was used to monitor treatment response. Five patients were included, and 22 sites clinically concerning for recurrent or persistent disease were evaluated using HRCM and histopathologic examination. In 2 patients, video mosaics were created to evaluate large areas. Main Outcomes and Measures: Sensitivity and specificity of HRCM in identifying recurrent or persistent EMPD; causes for false-negative results according to their location, histopathologic findings, and previous treatments. Results: Of the 22 clinically suspicious sites evaluated in 5 patients (4 men, 1 woman; median [range] age, 70 [56-77] years), 9 (40.9%) were positive for recurrent disease on HRCM and histopathologically confirmed, and 13 (59.1%) sites were negative on HRCM, but 3 of the 13 were positive for EMPD on histopathological examination. In general, HRCM had a sensitivity of 75% and a specificity of 100% in identifying recurrent or persistent EMPD. False-negative results were found in 2 patients and occurred at the margins of EMPD, close to previous biopsy sites. Creating video mosaics (or video mosaicking) seemed to improve the detection of EMPD. Conclusions and Relevance: Handheld reflectance confocal microscopy is a useful auxiliary tool for diagnosing EMPD recurrences and can be used to guide scouting biopsies, thus reducing the number of biopsies needed to render a correct diagnosis.

Ocular Argyrosis Mimicking Conjunctival Melanoma.

PURPOSE: To present a novel case of ocular argyrosis mimicking conjunctival melanoma. METHODS: A 48-year-old man who is a jewelry manufacturer presented with raised pigmented lesions in the inferior fornices of both eyes. Brown-black colored, follicle-like, masses were observed in both fornices. RESULTS: An incisional biopsy confirmed the presence of silver and the diagnosis of ocular argyrosis. CONCLUSIONS: Despite its limited negative health effects, ocular argyrosis should be considered in the differential diagnosis of conjunctival pigmented lesions because of the potential for misidentification of neoplastic growth.

Reduced H3K27me3 expression in Merkel cell polyoma virus-positive tumors.

Merkel cell carcinoma is a primary cutaneous neuroendocrine carcinoma, which once metastatic is difficult to treat. Recent mutation analyses of Merkel cell carcinoma revealed a low number of mutations in Merkel cell polyomavirus-associated tumors, and a high number of mutations in virus-negative combined squamous cell and neuroendocrine carcinomas of chronically sun-damaged skin. We speculated that the paucity of mutations in virus-positive Merkel cell carcinoma may reflect a pathomechanism that depends on derangements of chromatin without alterations in the DNA sequence (epigenetic dysregulation). One central epigenetic regulator is the Polycomb repressive complex 2 (PRC2), which silences genomic regions by trimethylating (me3) lysine (K) 27 of histone H3, and thereby establishes the histone mark H3K27me3. Recent experimental research data demonstrated that PRC2 loss in mice skin results in the formation of Merkel cells. Prompted by these findings, we explored a possible contribution of PRC2 loss in human Merkel cell carcinoma. We examined the immunohistochemical expression of H3K27me3 in 35 Merkel cell carcinomas with pure histological features (22 primary and 13 metastatic lesions) and in 5 combined squamous and neuroendocrine carcinomas of the skin. We found a strong reduction of H3K27me3 staining in tumors with pure histologic features and virus-positive Merkel cell carcinomas. Combined neuroendocrine carcinomas had no or only minimal loss of H3K27me3 labeling. Our findings suggest that a PRC2-mediated epigenetic deregulation may play a role in the pathogenesis of virus-positive Merkel cell carcinomas and in tumors with pure histologic features.

Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas.

Primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the latest 2016 World Health Organization Classification of Cutaneous lymphomas. We sought to better characterize and provide diagnostic and therapeutic guidance of this rare cutaneous lymphoma. Thirty-four patients with a median age of 77 years (range 19-89 years) presented primarily with extensive annular necrotic plaques or tumor lesions with frequent mucous membrane involvement. The 5-year survival was 32% with a median survival of 12 months. A subset of 17 patients had a prodrome of chronic patches prior to the development of aggressive ulcerative lesions. We identified cases with lack of CD8 or αß T-cell receptor expression yet with similar clinical and pathological presentation. Allogeneic stem cell transplantation provided partial or complete remissions in 5/6 patients. We recommend the term primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma as this more broad designation better describes this clinical-pathologic presentation, which allows the inclusion of cases with CD8 negative and/or αß/γδ T-cell receptor chain double-positive or double-negative expression. We have identified early skin signs of chronic patch/plaque lesions that are often misdiagnosed as eczema, psoriasis, or mycosis fungoides. Our experience confirms the poor prognosis of this entity and highlights the inefficacy of our standard therapies with the exception of allogeneic stem cell transplantation in selected cases.