RESUMEN
The diagnosis of cutaneous T-cell lymphoma (CTCL) remains challenging. Demonstration of a clonal T-cell population using T-cell receptor (TCR) gene rearrangement studies by next-generation sequencing (NGS) has been explored in several studies. This review summarizes the current literature on NGS-based sequencing methods for the assessment of TCR clonality in the evaluation of atypical cutaneous lymphoid infiltrates and CTCL on behalf of the American Society of Dermatopathology Appropriate Use Criteria Committee (lymphoproliferative subgroup). PubMed was searched for relevant articles, including CTCL and NGS, for clonality from 1967 to 2022. Thirteen studies were included in the analysis. The skin was the most commonly assayed compartment with TCR NGS. Sensitivity for TCR NGS in the skin ranged between 69% and 100%, compared to 44%-72% for polymerase chain reaction (PCR)-capillary electrophoresis. Specificity for TCR NGS in the skin ranged from 86% to 100%, compared to 77%-88% for PCR capillary electrophoresis. TCR NGS was also reported to have potential prognostic value in CTCL and can also be used to detect relapse and/or minimal residual disease after treatment.
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DISEASE OVERVIEW: Cutaneous T-cell lymphomas are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or the blood involvement are generally approached with systemic therapies, including biologic-response modifiers, histone deacetylase inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
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Linfoma Cutáneo de Células T , Micosis Fungoide , Síndrome de Sézary , Neoplasias Cutáneas , Humanos , Linfoma Cutáneo de Células T/diagnóstico , Linfoma Cutáneo de Células T/terapia , Micosis Fungoide/diagnóstico , Micosis Fungoide/terapia , Micosis Fungoide/patología , Estadificación de Neoplasias , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/terapia , Síndrome de Sézary/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/patologíaRESUMEN
DISEASE OVERVIEW: Approximately one-fourth of primary cutaneous lymphomas are B-cell derived and are generally classified into three distinct subgroups: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). DIAGNOSIS: Diagnosis and disease classification is based on histopathologic review and immunohistochemical staining of an appropriate skin biopsy. Pathologic review and an appropriate staging evaluation are necessary to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphomas with secondary skin involvement. RISK-STRATIFICATION: Disease histopathology remains the most important prognostic determinant in primary cutaneous B-cell lymphomas. Both PCFCL and PCMZL are indolent lymphomas that infrequently disseminate to extracutaneous sites and are associated with 5-year survival rates that exceed 95%. In contrast, PCDLBCL, LT is an aggressive lymphoma with an inferior prognosis. RISK-ADAPTED THERAPY: PCFCL and PCMZL patients with solitary or relatively few skin lesions may be effectively managed with local radiation therapy. While single-agent rituximab may be employed for patients with more widespread skin involvement, multiagent chemotherapy is rarely appropriate. In contrast, management of patients with PCDLBCL, LT is comparable to the management of patients with systemic DLBCL.
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Linfoma no Hodgkin , Neoplasias Cutáneas , Humanos , Linfocitos B , Biopsia , Rituximab/uso terapéutico , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapiaRESUMEN
COVID-19 infection and vaccination may be associated with a wide variety of cutaneous and immune manifestations. Here, we describe two patients who presented with monoclonal cutaneous T-cell infiltrates that showed cytologic and immunophenotypic features concerning for lymphoma shortly following COVID-19 vaccination. In one case, the eruption completely resolved. The second patient showed initial resolution, but her disease recurred and progressed following a breakthrough SARS-CoV-2 infection. These cases suggest that immune stimulation following exposure to SARS-Cov-2 protein(s) in vaccine or infection may facilitate the development of a lymphoma or lymphoproliferative disorder in susceptible individuals. Moreover, they show that separating these cases from pseudolymphomatous reactive conditions is often challenging and requires close clinical correlation.
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Vacunas contra la COVID-19 , COVID-19 , Linfoma , Papulosis Linfomatoide , Neoplasias Cutáneas , Femenino , Humanos , Vacunas contra la COVID-19/efectos adversos , Exantema , Linfoma/inducido químicamente , Linfoma/patología , Papulosis Linfomatoide/inducido químicamente , Papulosis Linfomatoide/patología , Recurrencia Local de Neoplasia , SARS-CoV-2 , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/patología , Vacunación/efectos adversos , Infección IrruptivaRESUMEN
INTRODUCTION: CD30 expression has been infrequently described in cutaneous B-cell lymphomas (CBCLs). We examined CD30 expression in reactive lymphoid hyperplasia (RLH) and CBCL and correlated expression with clinicopathologic features. METHODS: CD30 was examined in 82 CBCL patients and 10 RLH patients that had been evaluated in our cutaneous lymphoma clinics. The CBCL patients included: primary cutaneous follicle center lymphoma (PCFCL), Grade 1/2 systemic/nodal follicular lymphoma (SFL); primary cutaneous marginal zone lymphoma/lymphoproliferative disorder (PCMZL/LPD); systemic marginal zone lymphoma (SMZL); primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT); and extracutaneous/systemic diffuse large B-cell lymphoma (eDLBCL). We scored CD30 expression for intensity and extent and related CD30 expression to age at first diagnosis, sex, site of biopsy, clinical appearance, extracutaneous involvement, multiple cutaneous lesions, B-symptoms, lymphadenopathy, positive positron emission tomography/computed tomography (PET/CT), elevated lactate dehydrogenase (LDH), and positive bone marrow biopsy. RESULTS: CD30 expression was identified in 35% of CBCL, ranging from few, weak, scattered cells to strong and diffuse expression. It was most common in PCFCL and was not expressed in PCDLBCL-LT. Rare PCFCL expressed strong, diffuse CD30. Some cases of PCMZL/LPD, SMZL, FL, and RLH showed scattered, strongly positive cells. CD30 expression in CBCL was associated with favorable clinical features: younger age, negative PET/CT, and an LDH within normal limits. CONCLUSIONS: CD30 may be expressed in CBCL, possibly causing diagnostic confusion. CD30 expression was most commonly identified in PCFCL and is associated with favorable clinical features. In cases with strong and diffuse expression, CD30 could be a therapeutic target.
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Neoplasias Óseas , Linfoma de Células B de la Zona Marginal , Linfoma Folicular , Linfoma de Células B Grandes Difuso , Neoplasias Cutáneas , Humanos , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma Folicular/diagnóstico , Linfoma de Células B Grandes Difuso/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias Cutáneas/patología , Antígeno Ki-1/metabolismoRESUMEN
The DUSP22-IRF4 gene rearrangement results in downregulation of DUSP22, a presumed tumor suppressor in T-cell lymphomagenesis. It has been described in some cases of primary cutaneous and systemic anaplastic large-cell lymphoma, lymphomatoid papulosis, and transformed mycosis fungoides. Here we describe two patients with clinical lesions resembling patch/plaque mycosis fungoides that did not meet WHO criteria for large-cell transformation on histopathology yet showed a DUSP22 translocation. One patient who had a history of systemic anaplastic large-cell lymphoma with DUSP22 translocation presented with cutaneous involvement by his systemic lymphoma along with lymphomatoid papulosis and mycosis-fungoides-like lesions, all showing an identical immunophenotype and T-cell clone. These cases expand the spectrum of DUSP22-rearranged lymphomas to include mycosis-fungoides-like presentations without large-cell transformation.
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Fosfatasas de Especificidad Dual/genética , Linfoma Cutáneo de Células T/patología , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Neoplasias Cutáneas/patología , Adulto , Anciano , Femenino , Reordenamiento Génico , Humanos , Linfoma Cutáneo de Células T/genética , Masculino , Neoplasias Cutáneas/genética , Translocación GenéticaRESUMEN
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.
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Dermatología/normas , Patología Clínica/normas , Enfermedades de la Piel/patología , Medicina Basada en la Evidencia/normas , Humanos , Sociedades Médicas , Estados UnidosRESUMEN
DISEASE OVERVIEW: Cutaneous T-cell lymphomas are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with systemic therapies, including biologic-response modifiers, histone deacetylase inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
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Linfoma Cutáneo de Células T/diagnóstico , Linfoma Cutáneo de Células T/terapia , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapia , Antineoplásicos/uso terapéutico , Manejo de la Enfermedad , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Linfoma Cutáneo de Células T/etiología , Micosis Fungoide/diagnóstico , Micosis Fungoide/etiología , Micosis Fungoide/terapia , Estadificación de Neoplasias , Pronóstico , Medición de Riesgo , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/etiología , Síndrome de Sézary/terapia , Neoplasias Cutáneas/etiología , Trasplante de Células MadreRESUMEN
Primary cutaneous follicle center lymphoma (PCFCL) is the most common cutaneous B-cell lymphoma. The typical immunophenotype includes expression of both CD20 and BCL6, with the majority of cases lacking expression of CD10, BCL2, and the characteristic t(14;18)/IGH-BCL2 rearrangement seen in systemic follicular lymphoma (FL). Plasmacytic differentiation (PD) is an uncommon finding in both systemic and cutaneous FLs and presents a diagnostic challenge when present, leading to the potential for misdiagnosis as marginal zone lymphoma (MZL). Limited reports have described light chain restriction in the plasma cell component of FLs with PD, and rare cases of PCFCL with PD have been described. While the IGH-BCL2 translocation has been identified in a subset of FLs with PD, the presence of the BCL2 translocation in monotypic plasma cells of PCFCL has not been previously described to our knowledge. Here, we report a case of PCFCL with extensive PD in a 77-year-old woman that was favored to represent primary cutaneous MZL on an initial punch biopsy. Excisional biopsy, however, revealed that the atypical lymphocytes expressed CD10, BCL6, and BCL2, while the plasma cell component demonstrated light-chain lambda restriction. FISH studies showed the presence of an IGH-BCL2 translocation in both the lymphocytic and plasmacytic components.
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Linfocitos/patología , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma Folicular/diagnóstico , Células Plasmáticas/patología , Neoplasias Cutáneas/patología , Anciano , Biopsia con Aguja/métodos , Diferenciación Celular , Diagnóstico Diferencial , Femenino , Humanos , Cadenas lambda de Inmunoglobulina/metabolismo , Inmunohistoquímica/métodos , Inmunofenotipificación/métodos , Hibridación Fluorescente in Situ/métodos , Linfocitos/metabolismo , Linfoma de Células B de la Zona Marginal/patología , Linfoma Folicular/metabolismo , Neprilisina/metabolismo , Células Plasmáticas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Translocación GenéticaRESUMEN
Primary cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of neoplasms with variable clinical behavior. Immunophenotypic switch (IS) is a phenomenon that occurs during lymphoma progression and is defined by an alteration in the immunophenotypic expression of a tumor with retention of its genotypic signature. This has been well-recognized in hematopoietic neoplasms; however, it has been rarely reported in CTCL and its clinical implications are not well understood. We present the clinical, histopathologic, immunophenotypic, and genetic findings of three cases of CTCL that demonstrated IS post treatment with variable outcomes. We add our cases to the small number previously reported to increase awareness of this phenomenon and its diagnostic challenge.
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Transformación Celular Neoplásica/inmunología , Inmunofenotipificación/métodos , Linfoma Cutáneo de Células T/diagnóstico , Micosis Fungoide/patología , Neoplasias Cutáneas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Concienciación , Biopsia/métodos , Transformación Celular Neoplásica/patología , Preescolar , Diagnóstico Diferencial , Progresión de la Enfermedad , Resultado Fatal , Femenino , Reordenamiento Génico/genética , Genes Codificadores de los Receptores de Linfocitos T/genética , Genotipo , Humanos , Linfoma Cutáneo de Células T/genética , Linfoma Cutáneo de Células T/inmunología , Masculino , Persona de Mediana Edad , Micosis Fungoide/tratamiento farmacológico , Micosis Fungoide/metabolismo , Micosis Fungoide/radioterapia , Neoplasias Cutáneas/inmunología , Resultado del TratamientoRESUMEN
Follicle center lymphomas, including primary cutaneous follicle center lymphoma (PCFCL), may rarely show plasmacytic differentiation. Such cases can pose a diagnostic challenge and can be mistaken for other lymphomas that more commonly include plasma cells. Here, we report four cases of PCFCL and one case of systemic follicular lymphoma involving the skin with associated monotypic plasma cells, including the clinical, morphologic and immunophenotypic features.
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Cadenas kappa de Inmunoglobulina/metabolismo , Linfoma de Células B/diagnóstico , Linfoma Folicular/diagnóstico , Células Plasmáticas/patología , Neoplasias Cutáneas/patología , Adulto , Anciano , Biopsia , Diferenciación Celular , Femenino , Humanos , Cadenas lambda de Inmunoglobulina/metabolismo , Inmunofenotipificación/métodos , Linfoma de Células B/patología , Linfoma Folicular/cirugía , Linfoma Folicular/ultraestructura , Masculino , Persona de Mediana Edad , Células Plasmáticas/metabolismo , Resultado del TratamientoRESUMEN
Increasingly, molecular methods are being utilized in the workup of melanocytic neoplasms. To this end, we sought to correlate data from a single nucleotide polymorphism (SNP) array platform based on molecular inversion probes with clinical data. Copy number variation (CNV) data were obtained on 95 melanocytic tumors (6 ordinary nevi, 15 atypical nevi, 34 ambiguous neoplasms, and 40 melanomas) from 92 patients. The average number of significant CNVs was 0 for nevi, 0.6 for atypical nevi (range 0-3), 2.8 for ambiguous neoplasms (range 0-17), and 18.1 for melanomas (range 0-69). Clinical follow-up data were available in 57 of 95 lesions (56 of 92 patients). Tumors from patients with adverse events demonstrated an average number of CNVs of 24.5 (range 6-69) as compared with 7.9 (range 0-35) among tumors without an associated adverse event (p ≤ 0.001). No adverse events were observed in nevi including atypical nevi. Adverse events were found in 2 of 19 ambiguous neoplasms and 10 of 32 melanomas with follow up. In these two latter groups of neoplasms, the correlation between adverse events and the average number of CNVs remained statistically significant even when controlled for Breslow depth (21.5 versus 8.7, p value = 0.036). No neoplasm with adverse events had ≤3 CNVs. These results provide further evidence that SNP array testing for CNVs may be helpful in the classification and prognostication of ambiguous neoplasms. Based on these results, an algorithmic approach to challenging melanocytic neoplasms using CNV data is suggested, using as cutoff of >3 CNVs with some caveats, as the threshold for a positive result. Future clinical validation, using a larger cohort of relevant tumors, will be necessary.
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Biomarcadores de Tumor/genética , Melanoma/genética , Melanoma/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Nevo Pigmentado/genética , Nevo Pigmentado/patología , Polimorfismo de Nucleótido Simple/genética , Adulto JovenRESUMEN
DISEASE OVERVIEW: Approximately one-fourth of primary cutaneous lymphomas are B-cell derived and are generally classified into three distinct subgroups: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). DIAGNOSIS: Diagnosis and disease classification is based on histopathologic review and immunohistochemical staining of an appropriate skin biopsy. Pathologic review and an appropriate staging evaluation are necessary to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphomas with secondary skin involvement. RISK-STRATIFICATION: Disease histopathology remains the most important prognostic determinant in primary cutaneous B-cell lymphomas. Both PCFCL and PCMZL are indolent lymphomas that infrequently disseminate to extracutaneous sites and are associated with 5-year survival rates that exceed 95%. In contrast, PCDLBCL, LT is an aggressive lymphoma with an inferior prognosis. RISK-ADAPTED THERAPY: Both PCFCL and PCMZL patients with solitary or relatively few skin lesions may be effectively managed with local radiation therapy. While single-agent rituximab may be employed for patients with more widespread skin involvement, multi-agent chemotherapy is rarely appropriate. In contrast, management of patients with PCDLBCL, LT is comparable to the management of patients with systemic DLBCL.
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BACKGROUND: Atypical cutaneous lymphoid infiltrates are challenging lesions in dermatopathology. We present a summary of the literature regarding kappa and lambda immunohistochemistry (IHC) and in situ hybridization (ISH) in the evaluation of atypical cutaneous or mucosal lymphoid infiltrates. METHODS: Relevant articles from 1967 to 2018 in the English language were identified and summarized. In the absence of larger studies, case series of n ≥ 3 were included. RESULTS: Sixty-three articles assessing kappa and lambda IHC and/or ISH were identified. Most focused on marginal zone lymphomas. Other lymphomas included follicle center lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma, plasmablastic lymphoma, multiple myeloma, monoclonal gammopathy of undetermined significance, and polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS). Non-neoplastic lesions included reactive lymphoid hyperplasia, cutaneous plasmacytosis, connective tissue disease, IgG4-related disease, acrodermatitis chronic atrophicans, Zoon balanitis, dermatitides, and infiltrates around epithelial dysplasias/neoplasias. CONCLUSION: Kappa and lambda IHC and ISH are useful tools in the evaluation of cutaneous B-cell lymphomas and plasma cell neoplasms. The literature supports that the detection of light-chain restriction by IHC and ISH is one of the most useful findings in the differential diagnosis of reactive lymphoid hyperplasia vs B-cell lymphoma with plasmacytic differentiation.
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Cadenas kappa de Inmunoglobulina/análisis , Cadenas lambda de Inmunoglobulina/análisis , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Enfermedades de la Piel/diagnóstico , Humanos , Linfocitos/patologíaRESUMEN
AIMS: Histopathological overlap between lupus erythematosus and certain types of cutaneous T cell lymphoma (CTCL) is well documented. CD123+ plasmacytoid dendritic cells (PDCs) are typically increased in lupus erythematosus, but have not been well studied in CTCL. We aimed to compare CD123 immunostaining and histopathological features in these conditions. METHODS AND RESULTS: Skin biopsies of cutaneous lupus erythematosus (CLE, n = 18), lupus erythematosus panniculitis (LEP, n = 17), mycosis fungoides (MF, n = 25) and subcutaneous panniculitis-like T cell lymphoma (SPTCL, n = 9) were retrospectively reviewed and immunostained with CD123. Percentage, distribution and clustering of CD123+ cells were compared between CLE and MF and between LEP and SPTCL using χ2 and two-tailed t-tests. A higher percentage of CD123+ cells was observed in CLE than MF (P < 0.01), more frequently comprising ≥20% of the entire infiltrate (P < 0.01) and forming clusters (P < 0.01). Similarly, LEP showed a higher percentage of CD123+ cells than SPTCL (P = 0.01), more frequently comprising ≥20% of the infiltrate (P = 0.04) and forming clusters (P = 0.01). Basal vacuolar change or dyskeratosis was observed in all CLE cases and in 48% cases of MF cases (P = 0.05). Plasma cells were readily identified in 76% cases of LEP but in none of the SPTCL cases (P = 0.01). Adipocyte rimming by lymphocytes, hyaline fat necrosis and fibrinoid/grungy necrosis did not significantly differ between LEP and SPTCL. Dermal mucin also failed to distinguish between groups. CONCLUSIONS: CD123 immunostaining is helpful in differentiating CLE from MF and LEP from SPTCL, but should be interpreted in conjunction with clinicopathological features and other ancillary studies to ensure accurate diagnosis.
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Biomarcadores de Tumor/análisis , Subunidad alfa del Receptor de Interleucina-3/análisis , Linfoma Cutáneo de Células T/diagnóstico , Paniculitis de Lupus Eritematoso/diagnóstico , Adulto , Anciano , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Lupus Eritematoso Sistémico/diagnóstico , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
DISEASE OVERVIEW: Cutaneous T-cell lymphomas (CTCL) are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, skin-directed therapies are preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with systemic therapies. These include biologic-response modifiers, histone deacetylase (HDAC) inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
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Antineoplásicos Inmunológicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Inhibidores de Histona Desacetilasas/uso terapéutico , Micosis Fungoide , Síndrome de Sézary , Neoplasias Cutáneas , Aloinjertos , Humanos , Micosis Fungoide/diagnóstico , Micosis Fungoide/patología , Micosis Fungoide/terapia , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/patología , Síndrome de Sézary/terapia , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapiaRESUMEN
Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma with increased prevalence in patients with immunosuppression or B-cell neoplasms. To the best of our knowledge, an association with cutaneous T-cell lymphoma (CTCL) has not been previously described. In this report, we present two cases of MCC arising in the setting of CTCL. The first case was a female during her 70s with previously diagnosed stage IVA1 Sezary syndrome. Biopsy of a scaly patch showed two distinct abnormal cell populations. The first population consisted of hyperchromatic dermal and epidermotropic lymphocytes, expressing CD3 and CD4 with diminished CD7. The second population consisted of intraepidermal clusters of larger atypical cells that expressed synaptophysin, neurofilament, CK20, and Merkel cell polyomavirus transcript. The combination of findings was consistent with intraepidermal MCC in a background of CTCL. Excision showed residual intraepidermal MCC without dermal involvement. The second case was a male during his 50s with a longstanding history of mycosis fungoides, who presented with a new lesion on his right thigh. Biopsy and excision showed dermal MCC without secondary involvement by CTCL. Our cases show that MCC may rarely occur in the setting of T-cell lymphoma, and that intraepidermal MCC may mimic epidermotropic T-cells.
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Carcinoma de Células de Merkel/patología , Linfoma Cutáneo de Células T/patología , Neoplasias Primarias Múltiples/patología , Neoplasias Cutáneas/patología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The transcription factor GATA-3, highly expressed in many cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphomas (PTCL), confers resistance to chemotherapy in a cell-autonomous manner. As GATA-3 is transcriptionally regulated by NF-κB, we sought to determine the extent to which proteasomal inhibition impairs NF-κB activation and GATA-3 expression and cell viability in malignant T cells. Proteasome inhibition, NF-κB activity, GATA-3 expression, and cell viability were examined in patient-derived cell lines and primary T-cell lymphoma specimens ex vivo treated with the oral proteasome inhibitor ixazomib. Significant reductions in cell viability, NF-κB activation, and GATA-3 expression were observed preclinically in ixazomib-treated cells. Therefore, an investigator-initiated, single-center, phase II study with this agent in patients with relapsed/refractory CTCL/PTCL was conducted. Concordant with our preclinical observations, a significant reduction in NF-κB activation and GATA-3 expression was observed in an exceptional responder following one month of treatment with ixazomib. While ixazomib had limited activity in this small and heterogeneous cohort of patients, inhibition of the NF-κB/GATA-3 axis in a single exceptional responder suggests that ixazomib may have utility in appropriately selected patients or in combination with other agents.
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Compuestos de Boro/uso terapéutico , Glicina/análogos & derivados , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma de Células T Periférico/tratamiento farmacológico , Terapia Recuperativa/métodos , Anciano , Compuestos de Boro/farmacología , Línea Celular Tumoral , Femenino , Factor de Transcripción GATA3/efectos de los fármacos , Factor de Transcripción GATA3/farmacología , Glicina/farmacología , Glicina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , FN-kappa B/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/uso terapéutico , Células Tumorales CultivadasRESUMEN
The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations.
Asunto(s)
Antígeno Ki-1/genética , Linfoma Anaplásico Cutáneo Primario de Células Grandes/genética , Papulosis Linfomatoide/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias Cutáneas/genética , TYK2 Quinasa/genética , Western Blotting , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Hibridación Fluorescente in Situ , Antígeno Ki-1/metabolismo , Linfoma Anaplásico Cutáneo Primario de Células Grandes/metabolismo , Linfoma Anaplásico Cutáneo Primario de Células Grandes/patología , Papulosis Linfomatoide/metabolismo , Papulosis Linfomatoide/patología , Mutación , Proteínas Nucleares/metabolismo , Nucleofosmina , Fusión de Oncogenes , Proteínas de Fusión Oncogénica/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/genética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , TYK2 Quinasa/metabolismo , Transcriptoma/genéticaRESUMEN
The cell of origin and the tumor microenvironment's role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment's pathogenic role in these aggressive lymphomas.