Low T3 syndrome as a predictor of poor prognosis in peripheral T-cell lymphomas.

PURPOSE: The purpose of the study was to evaluate the prognostic value of low T3 syndrome in peripheral T-cell lymphomas (PTCLs). METHODS: One hundred and seventy-four patients of newly diagnosed PTCLs were enrolled in the study. We performed statistical analysis based on the clinical data collected. RESULTS: Thirty-Six (20.69%) patients had low T3 syndrome at first admission. Results suggested that the patients with higher score of ECOG PS, International Prognostic Index (IPI) and Prognostic Index for T-cell lymphoma (PIT), bone marrow involvement and lower level of albumin tended to develop low T3 syndrome. The median progression-free survival (PFS) and overall survival (OS) were 10 months and 36 months, respectively, for all patients. Pre-existing low T3 syndrome was in correlation with worse PFS and OS. Patients with low T3 syndrome showed worse PFS (4 months vs 13 months, P = 0.0001) and OS (7 months vs 83 months, P < 0.0001) than patients without low T3 syndrome. IPI and PIT, respectively, combined with low T3 syndrome improved the ability to predict OS and PFS of PTCLs. CONCLUSIONS: The study indicated that low T3 syndrome may be a good candidate for predicting prognosis of peripheral T-cell lymphomas.

An Unexpected Presentation of a Maxillary Non-Hodgkin Lymphoma in an Elderly Hispanic Patient.

Extranodal NK/T-cell lymphoma (ENKTL), nasal type and aggressive NK cell leukemia are rare in Western World been less than 1% in USA to 8% in Asia among Non-Hodgkin's lymphomas. It is aggressive, with poor outcome and optimal treatment is unclear. A combination therapy that includes Peg-Asparaginase (SMILE) has been employed in young patients. An 85-year-old Puerto Rican male presented with anorexia, epistaxis, vertigo and involuntary facial movements. He was treated with injectable Onabotulinum toxin A due to suspicion of a hemifacial spasm. However, a CT scan demonstrated a left maxillary sinus lesion extending into the left middle turbinate with biopsy consistent with ENKTL. We adjusted therapy to patient's age and performance receiving Gemcitabine-Oxaliplatin (Gemox) with radiation obtaining a complete response with persistent negative Epstein Barr DNA titers. ENKTL is a rare disease initially misdiagnosed in our elderly patient, who demonstrated adequate response with a modified therapeutic regime.

Primary Cutaneous Anaplastic Large Cell Lymphoma-A Review of Clinical, Morphological, Immunohistochemical, and Molecular Features.

Primary cutaneous anaplastic large cell lymphoma (ALCL) is the second most common cutaneous T-cell lymphoma after mycosis fungoides and belongs to the spectrum of cutaneous CD30+ T-cell lymphoproliferative disorders. Although primary cutaneous ALCL usually presents as a localized nodule or papule with or without ulceration, multifocal lesions may occur in up to 20% of cases. Histologically, primary cutaneous ALCL consists of a diffuse dermal infiltrate of medium to large anaplastic/pleomorphic cells with abundant amphophilic-to-eosinophilic cytoplasm, horseshoe-shaped nuclei, strong and diffuse expression of CD30, and with focal or no epidermotropism. The neoplastic infiltrate may show angiocentric distribution and may extend to the subcutis. Patients with localized or multifocal disease have a similar prognosis with a 10-year overall survival rate of 90%. Approximately 30% of primary cutaneous ALCLs harbor a DUSP22 (6p25.3) gene rearrangement that results in decreased expression of this dual-specific phosphatase, decreased STAT3 activation, and decreased activity of immune and autoimmune-mediated mechanisms regulated by T-cells.

Tumor mutation burden involving epigenetic regulatory genes and the RhoA GTPase predicts overall survival in nodal mature T-cell lymphomas.

Nodal mature T-cell lymphomas (nMTCL) comprises a heterogeneous group of rare malignancies with aggressive biological behavior and poor prognosis. Epigenetic phenomena, including mutations in genes that control DNA methylation and histone deacetylation, in addition to inactivating mutations in the RhoA GTPase, play a central role in its pathogenesis and constitute potential new targets for therapeutic intervention. Tumor mutational burden (TMB) reflects the process of clonal evolution, predicts response to anti-cancer therapies and has emerged as a prognostic biomarker in several solid neoplasms; however, its potential prognostic impact remains unknown in nMTCL. In this study, we conducted Sanger sequencing of formalin-fixed paraffin-embedded (FFPE) diagnostic tumor samples using a target-panel to search for recurrent mutations involving the IDH-1/IDH-2, TET-2, DNMT3A and RhoA genes in 59 cases of nMTCL. For the first time, we demonstrated that high-TMB, defined by the presence of ≥ two mutations involving the aforementioned genes, was associated with decreased overall survival in nMTCL patients treated with CHOP-like regimens. Additionally, high-TMB was correlated with bulky disease, lower overall response rate, and higher mortality. Future studies using larger cohorts may validate our preliminary results that indicate TMB as a potential molecular biomarker associated with adverse prognosis in nMTCL.

TET-2 mutations predict poor outcomes and are associated with unfavorable clinical-biological features in PTCL, not otherwise specified and angioimmunoblastic T-cell lymphoma in Brazilian patients.

INTRODUCTION: Nodal peripheral T-cell lymphomas [nPTCL] constitute a heterogeneous group of rare malignancies with aggressive biological behavior and poor prognosis. Epigenetic phenomena involving genes that control DNA-methylation and histone deacetylation play a central role in their pathogenesis. However, the mutational landscape involving epigenetic regulators has never been reported in Latin American patients and their prognostic impact remains controversial. PATIENTS AND METHODS: From 2000 to 2019, 59-Brazilian patients with nPTCL were eligible for screening mutations in the IDH-1, IDH-2, RHOA, TET-2 and DNMT3A genes by Sanger sequencing at Formalin-Fixed Paraffin-Embedded samples [FFPE] of diagnosis. We reported the frequency, distribution and potential prognosis of these mutations. RESULTS: With a median follow-up of 3.70 years, estimate 2-year OS and PFS were 57.1% and 49.2%, respectively. Mutations in the IDH-1 gene were not found, mutations in the IDH-2 occurred in 3.4% (2/59), RHOA in 23.7% (14/59), TET-2 in 50.8% (30/59) and DNMT3A in 62.7% (37/59). RHOA gene mutations were more frequent in PTCL, NOS and AITL (p= 0.06). Almost half of the patients had more than one mutation in concomitance, particularly RHOA-mut and TET-2-mut. Mutations in RHOA (p= 0.030) and TET-2 (p= 0.046) were associated with high-tumor burden. In the non-ALCL subgroup (PTCL, NOS and AITL) TET-2 mutations were associated with decreased 2-year PFS [HR: 2.22, p= 0.048]. Likewise with lower overall response rate [ORR] (p= 0.048) and unfavorable clinical features, as bulky disease (p= 0.012), ECOG ⩾ 2 (p= 0.032), B-symptoms (p= 0.012), ⩾ 2 extranodal sites compromised (p= 0.022) and high-risk Prognostic Index for T-cell lymphoma (p= 0.005). CONCLUSION: Mutations in RHOA, TET-2 and DNMT3A were frequent in Brazilian patients with nPTCL. TET-2 mutations were associated with lower ORR for CHOP-like chemotherapy, decreased PFS and unfavorable clinical-biological characteristics in non-ALCL (PTCL, NOS and AITL). Further studies using a larger cohort may validate our findings.

Linfomas de células T/NK das regiões oral e maxilofacial: um estudo multicêntrico / T/NK cell lymphomas of the oral and maxillofacial regions: a multicenter study

Os linfomas representam um grupo importante, complexo e heterogêneo de distúrbios proliferativos malignos originados a partir das células do tecido linfoide. Os linfomas de células T/NK maduras representam 12,7% a 26,2% dos linfomas não-Hodgkin, são condições relativamente raras, e a incidência da maioria das neoplasias aumenta com a idade. Portanto, o objetivo desse estudo é avaliar as características clinicopatológicas e imunoistoquímicas de uma série de linfomas de células T/NK maduras que acometem as regiões oral e maxilofacial e fornecer uma revisão atualizada da literatura sobre as bases biológicas desse grupo de doenças malignas. Casos diagnosticados como linfomas maduros de células T/NK afetando a região oral e maxilofacial foram recuperados retrospectivamente de seis centros de patologia oral e maxilofacial, e seus diagnósticos foram confirmados por meio de lâminas coradas com hematoxilina e eosina, reações imuno-histoquímicas e hibridização in situ para detecção do vírus Epstein-Barr (EBV). Um total de 22 casos foram incluídos neste estudo. Onze (50%) consistiam em linfomas extranodais de células T/NK, tipo nasal; oito (36,4%) eram linfomas periféricos de células T, sem outra especificação; dois (9,1%) eram leucemia/linfomas de células T, tipo adulto e um (4,5%) era um linfoma anaplásico de grandes células ALK-positivo. No geral, houve predomínio do sexo masculino, com média de idade de 55 anos. O palato foi o local mais acometido (50%), e os tumores geralmente se apresentavam como úlceras destrutivas e dolorosas. O EBV estava presente em todos os casos de linfoma de células T/NK extranodal tipo nasal, mas estava ausente nos outros subtipos.

Lymphomas represent an important, complex, and heterogeneous group of malignant proliferative disorders arising from lymphoid tissue cells. Mature T/NK cell lymphomas represent 12.7% to 26.2% of non-Hodgkin lymphomas, are relatively rare conditions, and the incidence of most neoplasms increases with age. Therefore, the aim of this study is to evaluate the clinicopathological and immunohistochemical characteristics of a series of mature T/NK cell lymphomas that affect the oral and maxillofacial regions and to provide an updated review of the literature on the biological basis of this group of malignancies. Cases diagnosed as mature T/NK cell lymphomas affecting the oral and maxillofacial region were retrospectively retrieved from six oral and maxillofacial pathology centers, and their diagnoses were confirmed by hematoxylin-and-eosinstained slides, immunohistochemical reactions, and in situ hybridization for detection of Epstein-Barr virus (EBV). A total of 22 cases were included in this study. Eleven (50%) consisted of extranodal T/NK cell lymphomas, nasal type; eight (36.4%) were peripheral T-cell lymphomas, not otherwise specified; two (9.1%) were T-cell leukemia/lymphomas, adult type and one (4.5%) was an ALK-positive anaplastic large cell lymphoma. Overall, there was a predominance of males, with a mean age of 55 years. The palate was the most affected site (50%), and the tumors usually presented as destructive and painful ulcers. EBV was present in all cases of nasal type extranodal T/NK cell lymphoma but was absent in the other subtypes.

Total skin electron beam therapy for primary cutaneous T-cell lymphomas: clinical characteristics and outcomes in a Mexican reference center.

AIM: The aim of this study was to assess treatment modalities, treatment response, toxicity profile, disease progression and outcomes in 14 patients with a confirmed diagnosis of primary cutaneous T-cell lymphoma (PCTCL) treated with total skin electron beam therapy (TSEBT). BACKGROUND: Primary cutaneous lymphomas (PCLs) are extranodal non-Hodgkin lymphomas originating in the skin without evidence of extracutaneous disease at diagnosis. Despite advances in systemic and local therapy options, the management of advanced stages remains mostly palliative. MATERIALS AND METHODS: This is a retrospective study of patients with PCTCL, diagnosed and treated in a reference center in Mexico City, analyzing treatment modalities, response to treatment, long-term outcome, and mortality. RESULTS: Eight males (57%) and 6 (43%) females were identified. Most patients were stage IVA (n = 5, 36%) followed by stage IB and IIB (28.5% and 21.4%, respectively). Eleven patients received the low-dose RT scheme (12 Gy), 1 patient, the intermediate-dose RT scheme (24 Gy), and 2 patients, the conventional-dose RT scheme (36 Gy). Mean follow-up time was 4.6 years. At first follow-up examination, 6-8 weeks after radiotherapy, the overall response rate (ORR) for the cohort was 85%. The median PFS for the whole cohort was 6 months. CONCLUSION: This study reinforces the role of TSEBT when compared with other treatment modalities and novel agents. Low-dose TSEBT is now widely used because of the opportunity for retreatment.

Germinal Center Cells Turning to the Dark Side: Neoplasms of B Cells, Follicular Helper T Cells, and Follicular Dendritic Cells.

Gaining knowledge of the neoplastic side of the three main cells-B cells, Follicular Helper T (Tfh) cells, and follicular dendritic cells (FDCs) -involved in the germinal center (GC) reaction can shed light toward further understanding the microuniverse that is the GC, opening the possibility of better treatments. This paper gives a review of the more complex underlying mechanisms involved in the malignant transformations that take place in the GC. Whilst our understanding of the biology of the GC-related B cell lymphomas has increased-this is not reviewed in detail here-the dark side involving neoplasms of Tfh cells and FDCs are poorly studied, in great part, due to their low incidence. The aggressive behavior of Tfh lymphomas and the metastatic potential of FDCs sarcomas make them clinically relevant, merit further attention and are the main focus of this review. Tfh cells and FDCs malignancies can often be misdiagnosed. The better understanding of these entities linked to their molecular and genetic characterization will lead to prediction of high-risk patients, better diagnosis, prognosis, and treatments based on molecular profiles.

Renal intravascular lymphoma in a dog / Linfoma intravascular renal em um cão

A 10-year-old male large mixed breed dog was presented with skin ulcers and fracture on the right hind limb caused by vehicle collision. Given required limb amputation, and as being a shelter senior dog, euthanasia was requested by the owner and a complete post-mortem examination was conducted immediately after death. Gross changes were consistent with marked bilateral nephromegaly. Histopathological examination of the kidneys revealed round cells filling blood vessels. Immunohistochemically, the round cells were positive for CD3 antibody. Based on these findings, in absence of involvement of the bone marrow and peripheral blood, and inexistence of primary extravascular masses, the tumor was classified as T-cell intravascular lymphoma. To the authors knowledge, this is the first report describing intravascular lymphoma involving the kidneys alone in a dog.(AU)

Um canino, macho, de 10 anos, sem raça definida (SRD), e grande porte, chegou para atendimento apresentando fratura em membro pélvico direito devido a atropelamento por veículo automotivo. Adicionalmente, foram observadas úlceras cutâneas ao nível da fratura. Devido à necessidade de amputação do membro e, por ser um cão idoso, o proprietário optou pela eutanásia, realizando-se necropsia imediatamente após a morte do paciente. Os achados macroscópicos foram consistentes com acentuada nefromegalia bilateral. A avaliação histopatológica dos rins revelou células redondas neoplásicas obliterando vasos sanguíneos. Imunohistoquimicamente, essas células foram positivas para CD3. Baseando-se nos achados histopatológicos, na ausência de envolvimento da medula óssea e do sangue periférico e, na inexistência de massas primárias extravasculares, o tumor foi classificado como linfoma intravascular de células T. Possivelmente, este é o primeiro relato de linfoma intravascular envolvendo unicamente os rins de um cão.(AU)

Renal intravascular lymphoma in a dog / Linfoma intravascular renal em um cão

ABSTRACT: A 10-year-old male large mixed breed dog was presented with skin ulcers and fracture on the right hind limb caused by vehicle collision. Given required limb amputation, and as being a shelter senior dog, euthanasia was requested by the owner and a complete post-mortem examination was conducted immediately after death. Gross changes were consistent with marked bilateral nephromegaly. Histopathological examination of the kidneys revealed round cells filling blood vessels. Immunohistochemically, the round cells were positive for CD3 antibody. Based on these findings, in absence of involvement of the bone marrow and peripheral blood, and inexistence of primary extravascular masses, the tumor was classified as T-cell intravascular lymphoma. To the author's knowledge, this is the first report describing intravascular lymphoma involving the kidneys alone in a dog.

RESUMO: Um canino, macho, de 10 anos, sem raça definida (SRD), e grande porte, chegou para atendimento apresentando fratura em membro pélvico direito devido a atropelamento por veículo automotivo. Adicionalmente, foram observadas úlceras cutâneas ao nível da fratura. Devido à necessidade de amputação do membro e, por ser um cão idoso, o proprietário optou pela eutanásia, realizando-se necropsia imediatamente após a morte do paciente. Os achados macroscópicos foram consistentes com acentuada nefromegalia bilateral. A avaliação histopatológica dos rins revelou células redondas neoplásicas obliterando vasos sanguíneos. Imunohistoquimicamente, essas células foram positivas para CD3. Baseando-se nos achados histopatológicos, na ausência de envolvimento da medula óssea e do sangue periférico e, na inexistência de massas primárias extravasculares, o tumor foi classificado como linfoma intravascular de células T. Possivelmente, este é o primeiro relato de linfoma intravascular envolvendo unicamente os rins de um cão.

Primary cutaneous T cell lymphomas: photochemotherapy immunomodulation with analysis of the inflammatory-expansive cellular dynamic.

Primary cutaneous T cell lymphomas (CTCLs) are characterized by hyperproliferation of malignant CD4+ T cells with primary localization on the skin. The common characteristics are the migration of the malignant mature T-lymphocytes into the epidermis, with hyperproliferation of malignant CD4+ T cells and epidermotropism. Sézary syndrome (SS) is the leukemic variant. It was established that CTCLs arise from a clonal expansion of CD4+ T cells with an identical rearrangement of the T cell receptor. The purpose of this study was to evaluate the immunomodulation effect of photochemotherapy-A (psoralen plus ultraviolet A (PUVA)). Pre- and post-PUVA punch skin biopsies of nine patients were stained immunohistochemically for CD34+, CD8+, CD7+, CD16+, CD56+, CD1a+, Bcl2+, p53+, CD45RA+, and CD45RO+ cells. The results showed a pre-PUVA cells/mm(2) without significant difference among expansive or reactive cells. Post-PUVA analysis showed a significant decrease in the mean of expansive-reactive cells. PUVA immunomodulated decreasing cellular infiltrate. These findings could contribute to the comprehension of how PUVA acts. We achieved ectoscopic clearance of the lesions, although post-PUVA, there still was a mononuclear pathological infiltrate. This result demonstrates that the PUVA treatment should only be withheld when the histological analysis is normal.

Aplicación de la citometría de flujo en el diagnóstico inmunológico de los linfomas cutáneos T / Application of flow cytometry in the immunological diagnosis of cutaneous T-cell lymphomas

Se comunican las características inmunofenotípicas de 7 pacientes (5 del sexo masculino y 2 del femenino) con el diagnóstico clínico-morfológico de linfomas cutáneos de células T, atendidos en la consulta de Hematología del Instituto de Hematología e Inmunología. La edad de los pacientes osciló entre 17 y 88 años. El inmunodiagnóstico se realizó por inmunofluorescencia directa, con un panel de anticuerpos monoclonales que incluyó marcadores linfoides B y T: CD2, CD3, CD4, CD5, CD7, CD8, CD19, CD22 y CD25. La lectura se realizó en un clitómetro de flujo FaCScan (Becton-Dickinson). Cada marcador se consideró positivo si un porcentaje mayor al 20 % de los linfocitos expresaba el antígeno. Nuestros resultados mostraron que en la mayoría de los pacientes predominó el patrón general de los linfocitos T con función auxiliadora (CD3+, CD4+, CD8-). Se corrobora que la citometría de flujo es un procedimiento más rápido y menos laborioso que otros métodos de inmunofenotipaje celular, que nos permite un diagnóstico de certeza y la aplicación de una terapia efectiva.

The immunophenotypic characteristics of 7 patients (5 males and 2 females) with the clinical-morphological diagnosis of cutaneous T-cell lymphoma that received attention at the Hematology service of the Institute of Hematology and Immunology were reported. The patients were between 17 and 88 years old. The immunodiagnosis was made by direct immunofluorescence with a panel of monoclonal antibodies that included B and T lymphoid markers: CD2, CD3, CD4; CD5, CCD7, CD8, CD19, CD22 and CD25. The reading was obtained in a FaCScan (Becton-Dickinson) flow cytometer. Every marker was considered positive if a percentage over 20 % expressed the antigen. Our results showed the prevalence of the general pattern of T lymphocytes with auxiliary function (CD3+, CD4+, CD8-). It was proved that flow cytometry is a faster and less laborious than other methods of cellular phenotyping, allowing an accurate diagnosis and the application of an effective therapy.