Linfoma Hodgkin Clásico en el departamento de Anatomía Patológica del Hospital Nacional Edgardo Rebagliati Martins durante los años 2015 a 2019 / Classic Hodgkin Lymphoma at the Edgardo Rebagliati Martins National Hospital during 2015 to 2019

RESUMEN Introducción: Los Linfomas Hodgkin son neoplasias linfoides de células B, caracterizadas histológicamente por un contexto celular inflamatorio mixto mayoritario y escasas células neoplásicas de Hodgkin/ Reed- Sternberg. El Linfoma Hodgkin Clásico (LHC) representa el 10% de todos los casos de linfoma y el 85% de todos los Linfomas Hodgkin. De acuerdo con la vigente clasificación de la Organización Mundial de la Salud, el LHC se divide en 4 variantes: Esclerosis Nodular (EN), Celularidad Mixta (CM), Rico en Linfocitos (RL) y Depleción Linfocítica (DL). Objetivo: En este estudio revisamos todos los casos de Linfoma Hodgkin Clásico en el Departamento de Anatomía Patológica del Hospital Nacional Edgardo Rebagliati Martins durante los años 2015 a 2019, para determinar la variante más frecuente, la incidencia en cuanto a edad y sexo, características fenotípicas y relación con el Epstein Barr Virus (EBV). Materiales y Métodos: Se realizó un estudio descriptivo retrospectivo de la casuística de Linfoma Hodgkin Clásico en sus 4 variantes clínico - patológicas en el Departamento de Anatomía Patológica del Hospital Nacional Edgardo Rebagliati Martins durante los años 2015 a 2019. Se identificaron 72 pacientes con el diagnóstico de Linfoma Hodgkin Clásico, de los cuales únicamente se seleccionaron para el estudio 64. Los criterios de exclusión fueron la ausencia de pruebas de inmunohistoquímica confirmatoria y los casos de recidiva. Resultados: Se observó que la variante más frecuente correspondió a Esclerosis Nodular con 34 casos (53.12%) y la menos frecuente a la variante Rica en Linfocitos con 2 casos (3.12%). Así mismo se observó una predominancia en el sexo masculino con 42 casos, 20 de ellos con Esclerosis Nodular y 14 no clasificables, como las variantes más frecuentes, y una mayor incidencia entre los 41 y 50 años de edad, sin detectarse el pico bimodal referido en la literatura internacional. El perfil inmunohistoquímico más frecuente de las células Hodgkin/ Reed- Sternberg es CD15 y CD30 positivo, con CD45 negativo. El EBV estuvo presente en el 36% de los casos realizados y es más frecuente en las variedades Celularidad Mixta y Depleción Linfocítica. Conclusiones: El Linfoma Hodgkin Clásico es un grupo de neoplasias linfoides con características clínicas, histológicas y fenotípicas definidas. Es más frecuente en varones entre 41 y 50 años. Para un adecuado diagnóstico se requiere una completa información clínica y una buena biopsia, de preferencia excisional. La variante Esclerosis Nodular es la más frecuente y la Rica en Linfocitos la menos frecuente. Las células Hodgkin/ Reed- Sternberg suelen ser positivas para CD15 y CD30 y negativas para CD45. La positividad tenue del Pax-5 permite diferenciarlo de Linfomas no Hodgkin de Células B. El EBV es más frecuente en las variantes Celularidad Mixta y Depleción Linfocítica.

ABSTRACT Introduction: Hodgkin lymphomas are B-cell lymphoid neoplasms histologically characterized by a mixed inflammatory cellular component and few Hodgkin/Reed-Sternberg neoplastic cells. Classical Hodgkin Lymphoma (CHL) represents 10% of all lymphoma cases and 85% of all Hodgkin Lymphomas. According to the current World Health Organization classification, CHL is divided into 4 types: Nodular Sclerosing (NS), Mixed Cellularity (MC), Lymphocyte-Rich (LR), and Lymphocyte-Depleted (LD). Objective: We reviewed all cases of Classical Hodgkin Lymphoma in the Pathological Anatomy Department at Edgardo Rebagliati Martins National Hospital during 2015 to 2019, in order to determine the most frequent type, the incidence according to age and gender, phenotypical characteristics and relation to Epstein Barr Virus (EBV). Materials and Methods: We performed a retrospective descriptive case study of Classical Hodgkin Lymphoma and its 4 clinical-pathological types in the Pathological Anatomy Department at Edgardo Rebagliati Martins National Hospital during 2015 to 2019. 72 patients were identified with Classical Hodgkin Lymphoma diagnosis, of which only 64 were selected for the study. The exclusion criteria were the absence of confirmatory immunohistochemical tests and relapse cases. Results: The most frequent type observed was Nodular Sclerosing with 34 cases (53.12%) and the least frequent type was Lymphocyte-Rich with 2 cases (3.12%). Likewise, a predominance in the male gender was observed, with 42 cases, 20 of which were Nodular Sclerosing and 14 not classified, as the most frequent types, and a greater incidence among those 41 to 50 years of age, without detection of the bimodal peak referenced in international literature. The most frequent immunohistochemical profile of Hodgkin/ Reed- Sternberg was CD15 and CD30 positive, with CD45 negative. EBV was present in 36% of cases and is more frequent in the Mixed Cellularity and Lymphocyte-Depleted types. Conclusions: Classical Hodgkin Lymphoma is a group of lymphoid neoplasms with clinical, histological, and phenotypically defined characteristics. It is more frequent in men between 41 and 50 years of age. A complete clinical information and a good biopsy, preferably excisional, is required for an adequate diagnosis. The Nodular Sclerosing type is the most frequent and the Lymphocyte-Rich is the least frequent type. Hodgkin/ Reed- Sternberg cells are usually CD-15 and CD-30 positive and CD-45 negative. The Pax-5 mild positivity allows it to be differentiated from B-cell Non-Hodgkin Lymphomas. EBV is most frequent in Mixed Cellularity and Lymphocyte-Depleted types.

Linfoma de la zona gris con características intermedias entre un linfoma difuso de células B grandes y un linfoma Hodgkin clásico. Reporte de un caso y revisión de la literatura / Grey zone lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. Case report and literature review

Resumen Entre los linfomas de la zona gris (LZG) encontramos neoplasias con características compartidas entre un linfoma difuso de células B grandes (LDCBG) y un linfoma de Hodgkin clásico (LHC). Lo poco habitual de la patología combinado con la heterogenicidad de la enfermedad, su reciente descripción como entidad específica que conlleva a dificultad y reto diagnóstico, así como la falta de suficiente experiencia terapéutica hacen de la enfermedad una entidad compleja de difícil diagnóstico y reto terapéutico que justifica su descripción continua. Se presenta una paciente con fiebre de un mes sin respuesta al manejo inicial, se estudió y realizó biopsia de ganglio inguinal izquierdo con resultado diagnóstico de LZG con características intermedias entre LDCBG y LHC. Aunque no existen guías establecidas para el manejo de esta entidad, la evidencia actual sugiere mejor respuesta en tratamientos dirigidos a LDCBG, misma terapia empleada en esta paciente con la cual se obtuvo respuesta favorable.

Abstract In the grey zone lymphomas (GZL), there are overlapping characteristics between diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (CHL). The unusual nature of the pathology combined with the heterogeneity of the disease, its recent description as a specific entity, its diagnostic difficulty, and the lack of sufficient therapeutic experience justifies its continuous description. The case is presented of a patient with a fever of one month onset, with no response to initial management. A left inguinal lymph node biopsy reported a diagnosis of GZL with intermediate characteristics between DLBCL and CHL. Although there are no established guidelines for the management of this condition, the current evidence suggests a better response in treatments meant for diffuse large B-cell lymphoma. This same therapy was used in this patient, with a favourable clinical outcome.

Restoration of the lost B-cell phenotype in classical Hodgkin lymphoma cells by all trans-retinoic acid treatment / 中国比较医学杂志

Objective To investigate the induction of B-cell specific phenotype in classical Hodgkin lymphoma (cHL)upon all-trans retinoic acid(ATRA)incubation. Methods To construct B-cell specific promoter(CD19, CD79a,CD79b)driven reporter plasmid with NEO cassette to realize stable transfection and selection of cHL reporter cells. To verify the intact integration by amplification of the promoter and luciferase sequences,and to functionally validate the B-cell specific promoter by ABF1 interference and luciferase assay. Repoter cells were incubated with various doses of ATRA and luciferase activity was detected at 24,48 and 72 hours. Reporter cells were treated alone or in combination with 5-Aza and ATRA followed by luciferase assay. Endogenous B-cell specific genes(CD19, CD20, CD79a and CD79b) transcription and expression levels were detected by real-time PCR and immunoblot, respectively. The expression level of CD30 antigen on Hodgkin lymphoma cell membrane upon ATRA was assessed by flow cytometry. Results ATRA treatment stimulated B-cell specific signature in cHL cells including CD19,CD79a and CD79b while down-regulated their CD30 expression. Conclusions ATRA induces B-cell phenotype deficient cHL cells to regain their B-cell transcriptional program while abolishes their Hodgkin-specific machinery.

Research progress in epigenetic aberrant in classic Hodgkin lymphoma / 实用肿瘤学杂志

The malignant phenotype of classical Hodgkin lymphoma ( cHL) is partly maintained by epige-netic aberrant ,of which consisted mainly abnormal histone methylation and deacetylation .Progress has been made in clinical trials related to the histone deacetylases inhibitors ( HDACis) in cHL.There is a close association noted between the epigenetic aberrants and the immune escape in cHL .DNA methyltransferase ( DNMT) inhibitors, HDACis and immune checkpoint blockade have shown synergistic effects .Further study to improve the cure rate in cHL by combination strategy is of significant importance .

Expression and clinical significance of p63 in nodular lymphocyte predominance Hodgkin lymphoma and classical Hodgkin lymphoma / 临床与实验病理学杂志

Purpose To investigate the expression and clinical significance of p63 in nodular lymphocyte predominant Hodgkin lym-phoma (NLPHL) and classical Hodgkin lymphoma (CHL). Methods 15 cases of NLPHL and 54 cases of CHL were stained for CD45, CD30, p63, PAX5, CD20, CD15, Oct-2, BOB1, MUM1, EMA, EBV-LMP1 and Ki-67 by immunohistochemical methods of EliVision. EBER were detected by in situ hybridization method in 12 cases of CHL. Results The expression of p63 in NLPHL (53. 3%, 8/15) was significantly higher than that in CHL (0, 0/54) (P<0. 05). Conclusions p63 protein is frequently expressed in NLPHL and helpful in the differential diagnosis between NLPHL and CHL.

Association between classical Hodgkin's lymphoma and Epstein-Barr virus infection in Northern Chinese Han population / 中国肿瘤临床

Objective:The occurrence of numerous tumors, particularly classical Hodgkin's lymphoma (CHL), is related with Ep-stein-Barr virus (EBV) infection. However, the incidence of CHL and its association with EBV varies significantly with ethnicity, geo-graphic location, sex, and age. This study investigated the association of EBV infection with CHL in Northern Chinese Han population. Methods:EBV-encoded small RNA (EBER) was detected in 136 cases of CHL through in situ hybridization. Results:A total of 37 cas-es were EBER positive (28%). The mixed cellularity (MC) subtype had the highest positive EBER rate of 49%(23/47;P<0.001), fol-lowed by lymphocyte-rich subtype with 30%(3/10), nodular sclerosis (NS) subtype with 14%(10/73), and 1ymphocyte depletion with 0%(0/2). Our study identified a single age distribution in the third decade. Moreover, NS subtype showed an evident single peak in the third decade. However, MC subtype had a lower peak in the fifth decade. The incidence of EBER showed a bimodal age distribution with two peaks in the first and fifth decades (21.6%and 24.3%, respectively). Conclusion:CHL in Northern Chinese Han population was associated with EBV infection, particularly the MC subtype.

Pathologic Characteristics and Differential Diagnosis of Hodgkin Lymphoma / 대한내과학회지

Recent advances in the understanding of the biology of Hodgkin lymphoma have led to a new classification. Hodgkin lymphoma is now recognized as a B-cell disorder of germinal center or post-germinal center origin. In the WHO classification, Hodgkin lymphoma consists of two categories, namely, nodular lymphocyte predominant Hodgkin lymphoma and classical Hodgkin lymphoma. Classical Hodgkin lymphoma encompasses not only nodular sclerosis, mixed cellularity, and lymphocyte depletion subtypes, but also lymphocyte-rich subtype, among which, nodular sclerosis stands out as a distinct entity. A borderline neoplasm with features intermediate between Hodgkin lymphoma and diffuse large B-cell lymphoma has also been recognized.

Quantificação das citocinas séricas Th1/Th2 por citometria de fluxo no linfoma de Hodgkin clássico / Measurement of Th1/Th2 serum cytokines by flow cytometry in classical Hodgkin lymphoma

O linfoma de Hodgkin clássico (LHC) é uma neoplasia com distúrbio na produção de citocinas. Estudos demonstram que o padrão anormal das citocinas no linfonodo acometido pela lesão contribui não somente com a proliferação das células malignas H-RS, como também com o característico infiltrado hiper-reativo que compõe o tecido no LHC. Esta disfunção pode ser observada tanto no quadro clínico dos pacientes, como nas características histopatológicas: sintomas B, deficiência na resposta imune celular, bandas de colágeno e eosinofilia. As concentrações séricas das citocinas Th1 (IL-2, TNF, INF-γ) e Th2 (IL-4, IL-5, IL-10) foram estudadas em 45 pacientes com LHC, ao diagnóstico, e em 34 doadores saudáveis, por citometria de fluxo (CBA - cytometric beads array). Houve aumento das concentrações das citocinas TNF (p<0,01), INF-γ (p<0,01), IL-4 (p=0,01), IL-5 (p<0,01) e IL-10 (p<0,01) dos pacientes quando comparados com o grupo controle. Não foi evidenciada diferença em relação a IL-2. Ao correlacionarmos as concentrações das citocinas Th1/Th2 com as variáveis clínico-laboratoriais dos pacientes, observou-se que níveis elevados da IL-10 (Th2) estão correlacionados com as variáveis que implicam em pior prognóstico: estádios III/IV (p=0,01), presença de sintomas B (p=0,04), hemoglobina < 10,5g/dL (p=0+,01), linfócitos <600 mm³ (p=0,01) e, de acordo com o IPI, os pacientes de alto risco (p=0,01). Por outro lado, níveis séricos elevados da IL-2 (Th1) foram encontrados em estádio I/II, quando comparados com III/IV (p=0,03), o que indica que a IL-2 diminui com a progressão da doença. Os resultados sugerem que a IL-10 possa estar regulando negativamente a resposta imune citotóxica (Th1) pela inibição da IL-2. Há uma possível associação entre progressão da doença e níveis elevados da IL-10. Esse estudo evidenciou que a utilização do CBA é factível na detecção das citocinas, e que as alterações encontradas podem estar envolvidas na biologia do LHC.

Classical Hodgkin lymphoma (CHL) is a malignancy with an abnormal or unbalanced secretion/production of cytokines, which might support the growth of H-RS cells, their surrounding reactive bystander cells and may be responsible for the typical clinical and histopathologic features of CHL: systemic B symptoms, an apparent defect in cell-mediated immune response, tumor fibrosis and eosinophilic infiltrate. Serum concentrations of IL-2, IL-4, IL5, IL-10, TNF and IFN-γ (Th1/Th2) were measured in 45 patients at diagnosis of classical Hodgkin lymphoma and in 34 healthy controls by cytometric beads array (CBA). Levels of TNF (p<0.01), INF-γ(p<0.01), IL-4 (p=0.01), IL-5 (p<0.01) e IL-10 (p<0.01) were significantly higher in patients compared to the control group. No difference was observed for IL-2 between the two groups. On correlating Th1/Th2 cytokine concentrations with clinical risk factors, elevated IL-10 (Th2) levels are associated with variables that suggest worse prognoses including III/IV stage (p=0.01), B-symptoms (p=0.04), hemoglobin < 10.5g/dL (p=0.01), lymphocytes < 600/mm³ (p=0.01) and according to the seven-factored international prognostic score (IPI), a subset of patients with a particularly high risk of failure (p=0.01). Furthermore, the serum levels of IL-2 (Th1) were significantly higher in a group of I/II stage patients compared to III/IV patients (p=0.03) which implies that, the levels of IL-2 might decrease with disease progression. The elevated IL-10 levels in a subset of patients with poor clinical risk factors might down regulate a Th1 immune response by inhibiting IL-2 production causing survival disadvantage by suppression of the cytotoxic immune response against the tumor. This suggests an association between progression of CHL and higher levels of the IL-10 cytokine. This study showed that measurement of serum cytokines using the CBA methodology is highly reproducible, and that changes in concentrations...

Influência do CD 20 na refratariedade do linfoma de Hodgkin clássico ao tratamento inicial com o esquema ABVD, no Ceará, Brasil / Influence of CD 20 antigen expression in the refractoriness of classical Hodgkin lymphoma in the first line treatment with ABVD protocol in Ceará state, Brazil

INTRODUÇÃO: A significância prognóstica do marcador imunológico CD 20 no linfoma de Hodgkin clássico (LHc) ainda é incerta, particularmente no que se refere à refratariedade ao tratamento inicial. OBJETIVOS: Avaliar a influência da positividade do marcador CD 20 na refratariedade do LHc ao tratamento poliquimioterápico inicial, com o esquema doxorubicina 25 mg/m², bleomicina 10 mg/m², vinblastina 6 mg/m² e dacarbazina 375 mg/m² (ABVD), no Ceará, Brasil. MATERIAL E MÉTODOS: Estudo analítico incluindo 97 pacientes com diagnóstico de LHc firmado entre janeiro de 2000 e dezembro de 2004. A análise foi realizada avaliando variáveis demográficas, clínicas e laboratoriais. RESULTADOS: Foi evidenciada uma positividade do CD 20 em 38,1 por cento dos pacientes. Na análise bivariada, CD 20 positivo (razão de chance [RC] = 4,02; intervalo de confiança [IC] = 1,09 - 8,54; p = 0,02), a presença de sintomas B (RC = 4,02; IC = 1,18-17,51; p = 0,01) e a elevação da desidrogenase lática (mediana não-refratários 248,5 [200,5 - 389,5]; mediana refratários 356 [208,5 - 545]; p = 0,03) apresentaram relação de pior prognóstico quanto à refratariedade. Na regressão logística, o CD 20 positivo (RC ajustada = 3,6; IC = 0,99 - 13,09; p = 0,05) e a presença de sintomas B (RC ajustada = 5,41; IC = 1,16 - 25,34; p = 0,03) continuaram apresentando pior prognóstico. DISCUSSÃO: Esses dados coincidem com a literatura, em que a positividade do marcador CD 20 está relacionada com pior resposta ao tratamento com ABVD. CONCLUSÃO: Os nossos dados indicam que o tratamento com ABVD não é completamente adequado para a abordagem terapêutica inicial deste subgrupo de pacientes e novas pesquisas precisam ser realizadas no sentido de aperfeiçoar o tratamento destes pacientes.

INTRODUCTION: The prognostic value of CD20 antigen expression in classical Hodgkin lymphoma (cHL) is uncertain, particularly regarding the refractoriness to first-line treatment. OBJECTIVES: To assess the influence of CD20 positiveness on the refractoriness of cHL to first-line chemotherapy with ABVD protocol in Ceará State, Brazil. MATERIAL AND METHODS: Analytical study including 97 patients diagnosed with cHL between January/2000 and December/2004. The analysis was performed evaluating demographic, clinical and laboratory variables. RESULTS: CD20 antigen expression was positive in 38.1 percent of the patients. In the bivariate analysis, CD20 antigen expression (OR = 4.02; CI = 1.09 - 8.54; p = 0.02), the presence of B-symptoms (OR = 4.02; CI = 1.18-17.51; p = 0.01) and an elevated lactate dehydrogenase level (median not refractory 248.5 [200.5 - 389.5]; median refractory 356 [208.5-545]; p = 0.03) showed worse prognosis as to refractoriness. In the logistic regression analysis, the presence of CD 20 (OR = 3.6; CI = 0.99-13.09; p = 0.05) and B-symptoms (OR = 5.41; CI = 1.16-25.34; p = 0.03) continued to show worse prognosis. DISCUSSION: These findings coincide with literature data indicating that CD 20 antigen expression is associated with low response to treatment with ABVD. CONCLUSION: Our data show that the treatment with ABVD is not totally appropriate for the initial therapeutic approach in this subgroup of patients and that further studies are required to optimize their treatment.