Lymphomatoid Papulosis With T-cell Receptor-Gamma Delta Expression: A Clinicopathologic Case-series of 26 Patients of an Underrecognized Immunophenotypic Variant of Lymphomatoid Papulosis.

Lymphomatoid papulosis (LyP) has several histopathologic presentations. LyP featuring gamma-delta (γδ) T-cell receptor expression may masquerade as and may be misdiagnosed as aggressive cutaneous T-cell lymphoma, particularly primary cutaneous γδ T-cell lymphoma (PCGDTL) or γδ mycosis fungoides. We performed a clinicopathologic analysis of the largest series of LyP featuring γδ T-cell expression. We identified 26 patients with a diagnosis of LyP with γδ T cells from our institutions, as well as through a comprehensive review of the literature, and characterized these cases. Most cases were treated with topical steroids or not treated at all. The majority of cases showed a CD4 - CD8 + phenotype and featured at least one cytotoxic marker. Histopathologic features included an intraepidermal or dermal infiltrate with large cells and frequent angiotropism. One case was initially misdiagnosed as PCGDTL, requiring further therapy. Our case series, the largest international cohort of γδ T cell predominant LyP cases, confirms marked clinicopathologic heterogeneity that may contribute to misdiagnosis, reasserting the need to identify classic clinical features, CD30 + T-cell components, and markers of cytotoxicity when dealing with this differential diagnosis. A limitation of this study includes somewhat limited follow-up, histologic, and immunophenotypic information for some cases.

Primary cutaneous T-cell lymphoma: a review of the most common entities with focus on recent updates.

Cutaneous T-cell lymphomas are an heterogeneous group of uncommon lymphoid neoplasms that are challenging to diagnose and require close collaboration between dermatologists, pathologists and hematologists/oncologists. This article reviews the most common cutaneous T-cell lymphomas: mycosis fungoides (both classic and variant forms) as well as its leukemic counterpart Sézary syndrome, CD30+ T-cell lymphoproliferative disorders including the ever-expanding group of lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma, and primary cutaneous CD4+ small/medium lymphoproliferative disorder. We discuss the classic clinical and histopathologic features of these lymphomas and review how they can be distinguished from reactive entities. In particularly, updates to these diagnostic categories and current controversies in classification are highlighted. Moreover, we review the prognosis and treatment for each entity. These lymphomas exhibit variable prognosis, and therefore it is important to correctly classify atypical cutaneous T-cell infiltrates for appropriate patient treatment and prognosis. Cutaneous T-cell lymphomas are at the interface of several medical specialties; this review seeks to summarize key features of these lymphomas and highlight new and emerging insights into these lymphomas.

Primary cutaneous T-cell lymphoma: a review of the most common entities with focus on recent updates.

Cutaneous T-cell lymphomas are an heterogeneous group of uncommon lymphoid neoplasms that are challenging to diagnose and require close collaboration between dermatologists, pathologists and hematologists/oncologists. This article reviews the most common cutaneous T-cell lymphomas: mycosis fungoides (both classic and variant forms) as well as its leukemic counterpart Sézary syndrome, CD30+ T-cell lymphoproliferative disorders including the ever-expanding group of lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma, and primary cutaneous CD4+ small/medium lymphoproliferative disorder. We discuss the classic clinical and histopathologic features of these lymphomas and review how they can be distinguished from reactive entities. In particularly, updates to these diagnostic categories and current controversies in classification are highlighted. Moreover, we review the prognosis and treatment for each entity. These lymphomas exhibit variable prognosis, and therefore it is important to correctly classify atypical cutaneous T-cell infiltrates for appropriate patient treatment and prognosis. Cutaneous T-cell lymphomas are at the interface of several medical specialties; this review seeks to summarize key features of these lymphomas and highlight new and emerging insights into these lymphomas.

Appropriate use criteria for ancillary diagnostic testing in dermatopathology: New recommendations for 11 tests and 220 clinical scenarios from the American Society of Dermatopathology Appropriate Use Criteria Committee.

BACKGROUND: Appropriate use criteria (AUC) provide patient-centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests. METHODS: RAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2. RESULTS: For 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid-Schiff, Gömöri methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated "usually appropriate" or "rarely appropriate" and 45 of 148 (30%), "appropriateness uncertain." LIMITATIONS: The study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded. CONCLUSIONS: AUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery.

Secondary skin involvement in classic Hodgkin lymphoma: Results of an international collaborative cutaneous lymphoma working group study of 25 patients.

BACKGROUND: Cutaneous involvement by classic Hodgkin lymphoma (CHL) is an extraordinarily rare phenomenon in the current era. To date, no single large case series of cutaneous involvement by Hodgkin lymphoma has ever been reported in the literature. METHODS: A comprehensive search for cases designated "skin" and "Hodgkin" was performed at different institutions between 1990 and 2020. Twenty-five cases were identified, and each case was independently reviewed by at least three board-certified dermatopathologists and/or hematopathologists. RESULTS: All cases represented examples of systemic CHL with secondary skin dissemination. A single lesion, usually a tumor, nodule or infiltrative plaque was observed in 56% of cases and multiple lesions were present in 28% of cases. Most patients (86%-12/14) had a diagnosis of stage IV disease at first diagnosis. The interval between the clinical (first) diagnosis of HL and the development of skin lesions ranged between 6 and 108 months (average 33.75 months). Comprehensive histopathologic evaluation of these cases (at the initial diagnosis) revealed a diagnosis of classic HL not otherwise specified (NOS) in 60% of cases (15/25), nodular sclerosis type in 24% (6/25), mixed cellularity in 12% (3/25), and lymphocyte depleted in 4% (1/25). CONCLUSIONS: We provide documentation of a large series of CHL with secondary skin involvement in association with CHL with additional clinical, morphologic, and immunophenotypic features.

Primary cutaneous lymphomas in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): A series of 12 cases.

BACKGROUND: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is associated with an increased risk of a second malignancy. METHODS: We conducted a retrospective clinicopathologic review of 12 patients with CLL/SLL who developed a second lymphoma in the skin. Demographic data, clinical information, and histopathology from 31 biopsies were recorded. Cases of secondary cutaneous involvement by CLL/SLL (leukemia cutis) and non-primary cutaneous lymphomas were excluded. RESULTS: A wide variety of primary cutaneous lymphomas was identified, including classic mycosis fungoides (3), cutaneous marginal zone lymphoma (2), primary cutaneous peripheral T-cell lymphoma unspecified (2), folliculotropic mycosis fungoides (1), Sézary syndrome (1), cutaneous gamma-delta T-cell lymphoma (1), cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (1), and cutaneous anaplastic large cell lymphoma (1). A male predominance was observed, and the average age was 74.1 years. In all patients, CLL/SLL predated the development of the second lymphoma, which was aggressive in the majority of cases (58%). Aggressive cytotoxic T-cell lymphomas, generally rare neoplasms, were relatively common (30%). CONCLUSIONS: CLL/SLL patients may develop a second lymphoma in the skin, which may be aggressive. Atypical cutaneous lymphoid infiltrates in this patient population should not be assumed to represent secondary CLL/SLL involvement and require thorough immunohistochemical analysis.

Cutaneous Involvement in Plasma Cell Myeloma.

OBJECTIVES: Plasma cell myeloma (PCM) involving skin is rare and occurs in 1% to 4% of patients with PCM. We evaluated the clinicopathologic features, cytogenetic findings and clinical follow-up in a series of PCM cases with cutaneous involvement. METHODS: Cases of PCM with cutaneous involvement were retrospectively reviewed with clinical data. RESULTS: Skin involvement in PCM occurred in older individuals (mean, 75 years) and was more frequent in men (7/10 patients). All cases showed bone marrow involvement preceding the cutaneous lesions. Histopathologically, the infiltrate was plasmacytic (n = 5) or primitive or plasmablastic (n = 4), and 1 case showed predominantly lymphoplasmacytic features with cyclin D1 immunoreactivity and CCND1 gene rearrangement. Concurrent amyloid deposition was seen in one biopsy, and another case demonstrated coexisting squamous cell carcinoma. The most common immunophenotype was CD138+, CD20-, and CD56+ with light chain restriction. Cytogenetic analysis (available for 7 cases) showed multiple hyperdiploid abnormalities. Follow-up was available for 8 cases (mean, 42 months; range, 11-156 months) and showed short-term disease-related death in 7 of 8 patients. CONCLUSIONS: Cutaneous involvement in PCM demonstrates a diverse cytomorphologic spectrum with plasmacytic, plasmablastic, or lymphoplasmacytic features and may show concurrent amyloid deposition or neoplasms such as squamous cell carcinoma. Cutaneous involvement typically occurs late in the course of the disease and likely portends poor outcome.

Secondary cutaneous involvement by direct extension in high-grade B-cell lymphomas.

Cutaneous involvement by a systemic lymphoma via direct extension is a very rare phenomenon, historically described in patients who had advanced-stage disease with bulky lymphadenopathy. Since its original description, most cases of cutaneous lymphomatous spread via direct extension are attributable to Hodgkin disease. Here, we report the occurrence of direct cutaneous dissemination in the setting of nodal high-grade B-cell lymphomas, specifically diffuse large B-cell lymphoma (DLBCL) and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (also called gray-zone lymphoma). Both cases are adequately documented with clinical, histopathologic, and immunophenotypic data, as well as additional cytogenetic analysis.

Spindle-cell (Sarcomatoid) Variant of Cutaneous Anaplastic Large-cell Lymphoma (C-ALCL): An Unusual Mimicker of Cutaneous Malignant Mesenchymal Tumors-A Series of 11 Cases.

Cutaneous anaplastic large-cell lymphoma (C-ALCL) represents one of the entities within the group of CD30-positive lymphoproliferative disorders of the skin. Most cases are ALK-negative, though isolated cases of ALK-positive C-ALCL have also been reported. By definition, the diagnosis of C-ALCL requires the expression of CD30 in >75% of the cells. Histopathologically, C-ALCL shows a dermal-based nodular and circumscribed proliferation of large pleomorphic cells with vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm, including hallmark cells. Since 1990, isolated case reports of a so-called "sarcomatoid" variant have been published in the literature. Herein, we present a series of 11 cases of spindle (sarcomatoid) C-ALCL, with comprehensive histopathologic, immunophenotypic, and molecular data. Spindle C-ALCL represents a potential mimicker of malignant mesenchymal or hematopoietic tumors in the skin and should always be considered in the differential diagnosis when assessing cutaneous pleomorphic spindle cell neoplasms.

Cutaneous Involvement by Mantle Cell Lymphoma: Expanding the Spectrum of Histopathologic Findings in a Series of 9 Cases.

Mantle cell lymphoma (MCL) is an aggressive B-cell neoplasm with cutaneous involvement in ∼1% of cases. We present a single institutional series of nine patients (12 specimens) with cutaneous involvement by systemic MCL and review the clinicopathologic features. Six males and 3 females (age range 55-87 years) were included. Sites of involvement were head and neck (n = 3), trunk (n = 5), and extremities (n = 4). Histopathologically, 3 showed classic cytomorphology, 2 were blastoid, 3 pleomorphic, and 1 showed features resembling marginal zone lymphoma. Two cases presented with cutaneous lesions as the first tissue manifestation of the disease. A second malignancy was identified in 3/9 cases (2 melanomas and 1 papillary thyroid carcinoma). In one patient, MCL was juxtaposed with metastatic melanoma within the same biopsy specimen. Fluorescence in situ hybridization studies, when available, demonstrated the characteristic t(11,14) translocation. Direct immunofluorescence was performed on one case and showed immunoglobulin M (IgM) expression on the tumor cells. Follow-up was available in 7 cases (mean 42 months, range 6-78 months) and revealed death from disease for 6 patients that occurred within 1 week to 11 months (mean 4 months) after cutaneous involvement. In our series, 6/9 cases demonstrated blastoid, pleomorphic, or marginal zone lymphoma-like morphologies that could potentially mimic other hematolymphoid neoplasms. MCL may show surface IgM expression on DIF or may occur in association with other solid tumors. Immunohistochemistry for cyclin D1 and/or SOX-11 may be helpful for diagnosis, and imaging studies may be necessary to detect systemic involvement when cutaneous involvement is the first manifestation of the disease.

Multifocal pleomorphic dermal sarcoma and the role of inflammation and immunosuppression in a lung transplant patient: a case report.

BACKGROUND: Pleomorphic dermal sarcoma is the cutaneous variant of undifferentiated pleomorphic sarcoma. It is a rare malignancy of unclear histogenesis; it is a diagnosis of exclusion that requires extensive use of immunohistochemistry to rule out other malignancies. Pleomorphic dermal sarcoma typically presents as a solitary tumor in sun-exposed areas and may have unpredictable clinical behavior, with some tumors associated with metastasis and death. CASE PRESENTATION: We present an unusual case of multifocal pleomorphic dermal sarcoma arising in the areas of alpha-1-antitrypsin deficiency panniculitis in a lung transplant patient. Our patient was a 58-year-old white woman whose initial presentation was consistent with alpha-1-antitrypsin deficiency panniculitis. She then developed extensive multifocal, bleeding, and ulcerated nodules in the areas of the panniculitis. A skin biopsy was consistent with a diagnosis of pleomorphic dermal sarcoma. Her immunosuppressive regimen was decreased, and she was treated with liposomal doxorubicin 40 mg/m2 every 3 weeks with some initial improvement in the size of her tumors. However, soon after beginning therapy, she developed pneumonia and septic shock and ultimately died from multi-organ failure. CONCLUSIONS: We hypothesize that chronic, multifocal inflammation in the skin in the setting of immunosuppression led to simultaneous, malignant transformation in numerous skin lesions. We discuss the challenges of diagnosing pleomorphic dermal sarcoma, therapeutic options, and stress the need for multidisciplinary management of these cases.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy, and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience, and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate" and 52 (25%) "rarely appropriate" and 43 (20%) having "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision to order specific tests rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-the AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate," 52 (25%) "rarely appropriate" and 43 (20%) "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Transplantation in the Treatment of Primary Cutaneous Aggressive Epidermotropic Cytotoxic CD8-Positive T-Cell Lymphoma.

BACKGROUND: Primary cutaneous aggressive epidermotropic cytotoxic CD8 positive T-cell lymphoma (CD8+ PCAETL) is a rare subtype of peripheral T-cell lymphoma with poor outcomes and without a standardized treatment strategy. Allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested as a potential curative therapy. PATIENTS AND METHODS: We conducted a retrospective case series. We identified 8 patients with the diagnosis of CD8+ PCAETL, 4 of whom also underwent allogeneic HSCT. RESULTS: Eight patients were treated at our center with combination chemotherapy and several novel agents, including histone deacetylase inhibitors, brentuximab, and pralatrexate. Patients underwent a median of 8.5 treatments before HSCT. Six of the 8 patients examined, including all 4 who received an HSCT, were alive at their last follow-up. CONCLUSION: Allogeneic HSCT is a promising treatment modality for CD8+ PCAETL. Because of the aggressive nature of this disease and lack of sustained remission with currently available therapies, HSCT should be considered early in the course of treatment. Two novel agents, brentuximab and pralatrexate, showed significant activity against CD8+ PCAETL, and may be incorporated earlier in the treatment course.

Bullous systemic lupus erythematosus in a 6-year-old boy.

Bullous systemic lupus erythematosus (BSLE) is a rare subepidermal blistering disorder characterized by an acute vesiculobullous eruption in a subset of individuals with systemic lupus erythematosus. BSLE most commonly affects young women and only rarely affects children. Herein we report a rare case of BSLE in a 6-year-old boy.