Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma that is most common in adolescents and young adults. Recent studies have reported that among T-cell diagnoses, the global incidence of HSTCL ranges from 1.4% to 2%. Unfortunately, HSTCL is typically rapidly progressing and refractory to conventional chemotherapy regimens; therefore, most patients with HSTCL have poor outcomes and die within 2 years of diagnosis.

In a recent review article published in Blood, Barbara Pro, MD, and Amir Behdad, MD, MBA, of Northwestern University in Chicago, Illinois, and Pamela Allen, MD, MS, of Emory University in Atlanta, Georgia, reviewed the clinical and pathologic features of HSTCL and summarized the latest results of molecular studies and potential novel therapeutic targets.1

Clinical and Pathologic Features of HSTCL

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“We know very little about the [biological] basis of hepatosplenic T-cell lymphoma,” said Matthew McKinney, MD, an assistant professor of medicine at the Duke University School of Medicine and the Duke Cancer Institute in Durham, North Carolina, who has been instrumental in mapping the genetic basis of the disease.2 “In general, work is very slow in the field due to the rarity of HSTCL, which makes it difficult to conduct clinical studies.”

In HSTCL, neoplastic T cells most commonly arise from small- to medium-sized, γδ T-cell receptor–expressing lymphocytes that infiltrate the sinusoids of the liver and spleen. These γδ T cells make up less than 5% of the circulating lymphocytes in healthy individuals; 30% of the T-cell population can be found in the spleen.

Because of its rarity and presentation of constitutional symptoms, HSTCL can be difficult to diagnose. Most cases of HSTCL arise de novo, and approximately 20% of the cases occur in the context of chronic immunosuppression and/or immune dysregulation. Some cases have been documented alongside inflammatory bowel disease and its therapies, including azathioprine, 6-mercaptopurine, and antitumor necrosis factor.

Although HSTCL can occur at any age, the median age of patients diagnosis is 34 years; approximately 70% of those diagnosed are men. Characteristic symptoms include splenomegaly (97%-100% of cases) and/or hepatomegaly (40%-80%), which may cause abdominal pain, and thrombocytopenia (45%-95%), which correlates with disease progression. Anemia (73%-84%) and neutropenia (36%-85%) are also common, and hemophagocytic syndrome may occur. Laboratory findings include elevated liver function tests (38%-43%) and lactate dehydrogenase (55%-62%). Conversely, lymphadenopathy, lymphocytosis, and leukemic presentations are not common.

According to the Dr Pro and colleagues, the differential diagnosis in HSTCL should include other T-cell lymphomas, including γδ T-cell large granular lymphocytic leukemia (γδ T-LGL), aggressive natural killer (NK)-cell leukemia, monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), and among non-neoplastic conditions, chronic active EBV disease (CAEBV); they also note that it is especially important for HSTCL to be included in the differential diagnosis of hemophagocytosis syndrome. These diagnoses can be differentiated based on age, morphological findings, immunohistochemical finding, and genetic/genomic findings. Compared with HSTCL, γδ T-LGL and MEITL tend to occur at later ages (median/mean age, 62 years and 59 years, respectively). Aggressive NK-cell leukemia typically involves medium-large atypical lymphoid cells instead of the small-intermediate atypical T-cells seen in HSTCL, and patients with CAEBV will typically be of younger age (median/mean, 19 years), EBV-positive, and with no genomic findings.