[Primary effusion lymphoma with multisystemic extracavitary involvement in HIV negative diagnosed by autopsy] / Linfoma primario de las efusiones con afectación extracavitaria multisistémica en HIV negativo diagnosticado mediante autopsia.

Introduction: Primary effusion lymphoma is a low-frequency and high-grade non-Hodgkin lymphoma caused by the Human Herpes virus 8. It mainly affects individuals infected with the human immunodeficiency virus (HIV), although it has also been described in HIV-negative cases. It is characterized by the presence of a malignant lymphomatous effusion in the different serous cavities, the pleural cavity being the most affected. Involvement outside the serosae is very rare. Diagnosis is made by analysis of the fluid accumulated in the serosae or by biopsy of the same, demonstrating the presence of characteristic neoplastic lymphocytes. Treatment consists of different chemotherapy regimens associated with antiretroviral therapy in HIV-positive patients. The prognosis of this disease is poor, with a survival of a few months after diagnosis. Methodology: We present the case of an 83-year-old man, HIV negative, with left pleural effusion and ascites, observing a fluid with a predominance of mononuclear cells without the presence of malignant cells on cytological examination. Results: The patient died and the autopsy made the diagnosis of Primary effusion lymphoma, also observing multisystemic extracavitary involvement. Conclusion: Although Primary effusion lymphoma preferentially affects HIV-positive individuals, the absence of HIV infection should not rule out the disease. Extracavitary involvement should be sought even in asymptomatic patients.

Introducción: El Linfoma primario de las efusiones es un Linfoma no Hodgkin de alto grado y escasa frecuencia producido por el virus Herpes Humano 8. Afecta principalmente a individuos infectados por el virus de la inmunodeficiencia humana (HIV), aunque también se ha descripto en HIV negativos. Se caracteriza por la presencia de derrame linfomatoso maligno en las distintas cavidades serosas siendo la cavidad pleural la más afectada. La afectación fuera de las serosas es muy poco frecuente. El diagnóstico se realiza por análisis del líquido acumulado en las serosas o mediante biopsia de las mismas demostrando la presencia de linfocitos neoplásicos característicos. El tratamiento consiste en distintos regímenes de quimioterapia asociados a terapia antirretroviral en pacientes HIV positivos. El pronóstico de esta enfermedad es pobre, con una supervivencia de escasos meses posteriores al diagnóstico. Metodología: Presentamos el caso de un varón de 83 años, HIV negativo, con derrame pleural izquierdo y ascitis, observándose un líquido con predominio de mononucleares sin presencia de células malignas al examen citológico. Resultados: El paciente falleció y mediante la autopsia se llegó al diagnóstico de Linfoma primario de las efusiones, observándose además afectación extracavitaria multisistémica. Conclusión: Si bien el Linfoma primario de las efusiones afecta preferentemente a individuos HIV positivos, la ausencia de infección por HIV no debe descartar la enfermedad. El compromiso extracavitario debe ser buscado aún en pacientes asintomáticos.

Developing new ceramide analogs and identifying novel sphingolipid-controlled genes against a virus-associated lymphoma.

Primary effusion lymphoma (PEL) is an aggressive malignancy with poor prognosis even under chemotherapy. Kaposi sarcoma-associated herpesvirus (KSHV), one of the human oncogenic viruses, is the principal causative agent. Currently, there is no specific treatment for PEL; therefore, developing new therapies is of great importance. Sphingolipid metabolism plays an important role in determining the fate of tumor cells. Our previous studies have demonstrated that there is a correlation between sphingolipid metabolism and KSHV+ tumor cell survival. To further develop sphingolipid metabolism-targeted therapy, after screening a series of newly synthesized ceramide analogs, here, we have identified compounds with effective anti-PEL activity. These compounds induce significant PEL apoptosis, cell-cycle arrest, and intracellular ceramide production through regulation of ceramide synthesizing or ceramide metabolizing enzymes and dramatically suppress tumor progression without visible toxicity in vivo. These new compounds also increase viral lytic gene expression in PEL cells. Our comparative transcriptomic analysis revealed their mechanisms of action for inducing PEL cell death and identified a subset of novel cellular genes, including AURKA and CDCA3, controlled by sphingolipid metabolism, and required for PEL survival with functional validation. These data provide the framework for the development of promising sphingolipid-based therapies against this virus-associated malignancy.