De Novo CD3 Negative Hepatosplenic T-cell Lymphoma: Diagnostic Challenges and Pitfalls

Abstract

Hepatosplenic T-cell lymphoma is a rare and aggressive peripheral T-cell malignancy that is distinctively characterized by sinusoidal infiltration of mature medium-sized T lymphocytes in the spleen and liver. The neoplastic cells are classically surface CD3(+), CD2(+), CD5(-), CD4(-), and CD8(+/-) and manifest variable expression of markers associated with natural killer (NK) cells such as CD16 and CD56. In this article, we report the first case to date of a newly diagnosed de novo surface CD3(-) hepatosplenic T-cell lymphoma with circulating blastlike neoplastic cells expressing NK-cell-associated markers. The lack of surface CD3 expression, together with the expression of NK-cell-associated markers and the leukemic presentation, leads to significant diagnostic challenges in differentiating this CD3(-) hepatosplenic T-cell lymphoma from NK-cell neoplasms, in particular aggressive NK-cell leukemia. The related literature is reviewed, and the approaches for adequate diagnosis of this novel situation are described.

EBV-negative Aggressive NK-cell Leukemia/Lymphoma

“…Interestingly, five of our patients were White (not of Hispanic heritage), providing further epidemiological contrast with ANKL EBV-positive. Similar to EBV-positive ANKL, our patients presented acutely with fever, splenomegaly, and cytopenias 2, 4, 5 . Besides, bone marrow and peripheral blood involvement, lymphadenopathy was a common feature observed in 57% of cases, similar to what has been reported for EBV-positive disease 1, 2, 4 .…”

“…Similar to EBV-positive ANKL, our patients presented acutely with fever, splenomegaly, and cytopenias 2, 4, 5 . Besides, bone marrow and peripheral blood involvement, lymphadenopathy was a common feature observed in 57% of cases, similar to what has been reported for EBV-positive disease 1, 2, 4 . Historically, the terminology of “leukemia/lymphoma” has been used for this disease, 17 reflecting its systemic nature and extensive multi-organ involvement 8, 17 .…”

“…ANKL is an extremely rare entity with less than 200 cases published to date 2, 4, 5 . It has a strong association with EBV infection, which is considered part of disease definition.…”

“…However, patients with EBV-negative disease tend to be older (median age 63 years) compared to patients with EBV-positive ANKL (median age approximately 36–38 years) 2, 4, 16 . The older age at onset might correlate with other epidemiological features.…”

“…Patients present acutely with fever, cytopenias, liver failure, coagulopathy and fulminant clinical course with < 2 months survival 4–6 . Although a highly complex karyotype, with unbalanced chromosomal abnormalities has been reported, no specific recurrent alterations have been identified 4, 7, 8 .…”