No abstract

EBV-associated lymphoproliferative disorders (LPD) include conditions of B, T, and NK cell derivation with a wide clinicopathological spectrum ranging from indolent, self-limiting, and localized conditions to highly aggressive lymphomas. Since the 2016 World Health Organization (WHO) lymphoma classification, progress has been made in understanding the biology of the EBV-associated LPDs. The diagnostic criteria of EBV+ mucocutaneous ulcer and lymphomatoid granulomatosis have been refined, and a new category of EBV-positive polymorphic B cell LPD was introduced to encompass the full spectrum of EBV-driven B cell disorders. The differential diagnosis of these conditions is challenging. This report will present criteria to assist the pathologist in diagnosis. Within the group of EBV-associated T and NK cell lymphomas, a new provisional entity is recognized, namely, primary nodal EBV+ T or NK cell lymphoma. The EBV + T and NK cell LPDs in children have undergone major revisions. In contrast to the 2016 WHO classification, now four major distinct groups are recognized: hydroa vacciniforme (HV) LPD, severe mosquito bite allergy, chronic active EBV (CAEBV) disease, and systemic EBV-positive T cell lymphoma of childhood. Two forms of HV LPD are recognized: the classic and the systemic forms with different epidemiology, clinical presentation, and prognosis. The subclassification of PTLD, not all of which are EBV-positive, remains unaltered from the 2016 WHO classification. This review article summarizes the conclusions and the recommendations of the Clinical Advisory Committee (CAC), which are summarized in the International Consensus Classification of Mature Lymphoid Neoplasms.

PURPOSE Peripheral T-cell lymphoma (PTCL) includes heterogeneous clinicopathologic entities with numerous diagnostic and treatment challenges. We previously defined robust transcriptomic signatures that distinguish common PTCL entities and identified two novel biologic and prognostic PTCL-not otherwise specified subtypes (PTCL-TBX21 and PTCL-GATA3). We aimed to consolidate a gene expression–based subclassification using formalin-fixed, paraffin-embedded (FFPE) tissues to improve the accuracy and precision in PTCL diagnosis. MATERIALS AND METHODS We assembled a well-characterized PTCL training cohort (n = 105) with gene expression profiling data to derive a diagnostic signature using fresh-frozen tissue on the HG-U133plus2.0 platform (Affymetrix, Inc, Santa Clara, CA) subsequently validated using matched FFPE tissues in a digital gene expression profiling platform (nCounter, NanoString Technologies, Inc, Seattle, WA). Statistical filtering approaches were applied to refine the transcriptomic signatures and then validated in another PTCL cohort (n = 140) with rigorous pathology review and ancillary assays. RESULTS In the training cohort, the refined transcriptomic classifier in FFPE tissues showed high sensitivity (> 80%), specificity (> 95%), and accuracy (> 94%) for PTCL subclassification compared with the fresh-frozen–derived diagnostic model and showed high reproducibility between three independent laboratories. In the validation cohort, the transcriptional classifier matched the pathology diagnosis rendered by three expert hematopathologists in 85% (n = 119) of the cases, showed borderline association with the molecular signatures in 6% (n = 8), and disagreed in 8% (n = 11). The classifier improved the pathology diagnosis in two cases, validated by clinical findings. Of the 11 cases with disagreements, four had a molecular classification that may provide an improvement over pathology diagnosis on the basis of overall transcriptomic and morphological features. The molecular subclassification provided a comprehensive molecular characterization of PTCL subtypes, including viral etiologic factors and translocation partners. CONCLUSION We developed a novel transcriptomic approach for PTCL subclassification that facilitates translation into clinical practice with higher precision and uniformity than conventional pathology diagnosis.

Con el objetivo de describir las características clínico-patológicas de los casos de porocarcinoma ecrino (PE) registrados en el Instituto Nacional de Enfermedades Neoplásicas (INEN), se realizó un estudio trasversal que incluyó todos los casos entre 1998-2009. Para ello se realizó una revisión de fichas clínico-patológicas y una nueva lectura de las láminas de patología de los casos encontrados. Se hallaron 19 casos de PE; la mediana de edad fue de 64 años (rango: 37-98); con mayor frecuencia en el sexo masculino (57,9%); la localización más frecuente fue en el pie (21,1%), seguida de cabeza, tórax y muslo (15,8%, en todos los casos). Se describe un caso de localización glútea que cursó con una conducta inusualmente invasiva y con compromiso rectal. Se concluye que el PE es una entidad poco frecuente en el Perú, su localización más común es en el pie, y afecta predominantemente al sexo masculino.

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL. Significance: Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85

OBJETIVOS: Estudiar la incidencia, características clinicopatológicas e inmunofenotípicas de los linfomas extraganglionares (LEG) en el área hospitalaria de Lima Metropolitana. MATERIALES Y MÉTODOS: Se estudió todos los casos de LEG con diagnóstico anatomopatológico durante 1998 en cuatro hospitales generales y el Instituto de Enfermedades Neoplásicas. Se recogió datos de las historias clínicas. Dos patólogos revisaron las muestras histológicas, usando la clasificación REAL. RESULTADOS: Se diagnosticó 616 linfomas no Hodgkin, de los cuales 308 (50,0%) fueron primarios extraganglionares, y 88 linfomas de Hodgkin. La localización más frecuente de los LEG fue estómago (70 casos) y piel (49 casos). Los linfomas primarios de estómago, orofaringe, intestino y glándulas salivares fueron a predominio de inmunofenotipo B, los linfomas de la nasofaringe y piel fueron a predominio de células T. En el tracto digestivo fueron más frecuentes los linfomas de la zona marginal MALT. En linfomas de células T predominó el T periférico. CONCLUSIONES: La mayor frecuencia de LEG en órganos como el estómago, intestino, piel y orofaringe, coincide con lo reportado en otras latitudes. El número de LEG con relación a linfomas ganglionares fue más elevado que lo encontrado por otros autores.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common variant of non-Hodgkin lymphoma (NHL) accounting for approximately 30% of the NHL cases worldwide. Previous reports have associated certain viral infections with the development of DLBCL such as HIV and EBV, both infections related with an aggressive clinical course and worse outcome. The human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus regarded as the pathogenic agent for adult T-cell lymphoma/leukemia. HTLV-1 is endemic in Japan, the Caribbean basin, South America, and parts of Africa. In Peru, up to 3% of the healthy adult population carries HTLV-1. As data on the impact of HTLV-1 infection in DLBCL outcomes is scarce, we aim to describe the clinical features and outcomes of HTLV-1-positive patients with a pathological diagnosis of DLBCL. Methods: We retrospectively reviewed medical records of patients diagnosed and managed for DLBCL at the National Institute of Neoplastic Diseases in Lima-Peru between 2007 and 2019. Patients were evaluated for HTLV-1 infection at the time of diagnosis. Positive HTLV-1 cases were matched to negative HTLV-1 controls based on age, sex, and cancer staging. Treatment responses were assessed according to the Lugano criteria. Overall survival (OS) and event-free survival (EFS) curves were estimated using the Kaplan-Meier method and compared with the Log-rank test to determine the impact of HTLV-1 infection. Multivariate Cox regression models were reported with adjusted Hazar Ratios (aHR) with a 95% confidence interval (95% CI). Results: A total of 192 patients with DLBCL were identified and had sufficient data for analysis. Seventy (37%) cases were positive for HTLV-1 infection and 122 (63%) were not. Table 1 summarizes the clinical features and outcomes of DLBCL patients according to HTLV-1 status. Overall, the majority of patients were ≥65 years (59%), had ECOG performance status ≤2 (95%) and were stage III-IV (51%) at diagnosis. One third (n=64) of patients had extranodal involvement with 71 affected sites of which bone marrow involvement was frequently found in HTLV-1-negative DLBCL cases (55% vs. 7%, p<0.001) and liver/gastrointestinal tract in HTLV-1-positive cases (48% vs. 9%, p<0.001). There was no difference among DLBCL groups regarding risk stratification based on NCCN-IPI score (p=0.394). With a median follow-up of 6.5 years, we found that in DLBCL patients, HTLV-1 infection had no significant impact in 5-year OS (HTLV-1-positive 40% versus HTLV-1-negative 42%, p=0.930) and EFS rates (HTLV-1-positive 33% versus HTLV-1-negative 32%; p=0.890) (Figure 1). Multivariate cox regression analysis could not identify HTLV-1 infection as a risk factor for higher mortality or disease progression (Figure 1). Conclusion: To the best of our knowledge, this is the largest case series describing the clinical characteristics and outcome of HTLV-1-positive DLBCL patients. A study from Japan on early stage localized (head and neck) B-cell-NHL (n=198, HTLV-1 seropositive n=21 and with DLBCL n=12) treated with radiotherapy and/or multi-agent chemotherapy found poorer prognosis on HTLV-1 carriers compared to non-carriers (5-year OS: HTLV-1-positive n=21, 49% vs. HTLV-1-negative n=177, 78%, p=0.007; Hiroaki et al BJH 2003). In this study, we included DLBCL patients with both early and advanced stage disease along with localized and extranodal involvement. We found that HTLV-1 infection had no significant impact on 5-year OS and EFS rates when using conventional therapy for DLBCL. Moreover, we did not find differences in relapsed and mortality rates. Further investigation is needed to confirm the potential impact of HTLV-1 infection in DLBCL outcome. Disclosures No relevant conflicts of interest to declare.

e19541 Background: Primary central nervous system lymphoma (PCNSL) is an aggressive and rare extranodal non-Hodgkin lymphoma with a dismal prognosis in most patients. Outcomes in Latin population is unknown. Methods: We present a retrospective cohort of fifty-five and six newly diagnosed Peruvian patients treated at the Instituto Nacional de Enfermedades Neoplasicas from 2000-2020 and at Oncosalud from 2014-2020, respectively. Inclusion criteria were (1) histologic diagnosis of diffuse large B-cell lymphoma by two pathologists; (2) disease localized exclusively in the brain, cranial nerves, meninges, or eyes; and (3) no evidence of human immunodeficiency virus infection. Results: Median age at diagnosis was 52 years old [range 21-76]. Sixty-one percent were men. Eastern Cooperative Oncology Group performance status was ≥2 in 68% of patients. Clinical presentation was characterized by intracranial hypertension symptoms (67%), focal deficit (64%), visual disturbance (18%), and seizures (9%). elevated LDH was present in 26/46 (57%) patients, multiple lesions in 19/56 (34%) patients, and involvement of deep structures 21/62 (34%) patients. Seven patients were treated by surgery only (3, subtotal and 4, total resection), three patients received radiotherapy only, and six patients did not receive any treatment. Forty-two patients received the following chemotherapy protocols: DeAngelis (26%), high-dose methotrexate (HD-MTX) (17%), HD-MTX + high-dose ARAC (HD-ARAC) (36%) and HD- MTX + HD-ARAC + Rituximab (9%), HD-MTX + Rituximab + Temozolomide (TMZ) as induction and consolidation with etoposide (VP16) + HD-ARAC (12%), the latter was used in the private center. Clinical outcomes are described in Table. The median follow-up time was 9m (0.03-248). The median overall survival (OS) was 9.9m, 5y OS was 41.7% (95% CI, 29.2-53.9). The median OS were 6.6m and 67.3m for the public and the private institution, respectively (p=0.02). 5y OS was 34% and 100% in the public and the private center, respectively. Conclusions: Peruvian patients are 15 years younger than those reported in the literature. OS in our cohort is dismal, being poorer in those patients treated at the public center reflecting treatment disparities between the public and private health system. All patients who received HD-MTX+HD-ARAC+TMZ as induction and VP16 +HD-ARAC as consolidation achieved complete response and the median OS was not reached although this can be explained due to a short follow-up time compared to those who received DeAngelis regimen. A longer follow-up is needed to demonstrate if polychemotherapy without radiotherapy is the best treatment in this group of patients.[Table: see text]