Hepatosplenic T-Cell Lymphoma

Definition

Hepatosplenic T-cell lymphoma (HSTL) is an aggressive subtype of extranodal lymphoma characterized by a hepatosplenic presentation without lymphadenopathy and a poor outcome. The neoplasm results from a proliferation of non-activated cytotoxic T cells, usually monomorphic and medium-sized, that exhibit a unique sinusoidal pattern of infiltration in the spleen, liver, and bone marrow. It is associated with a recurrent cytogenetic abnormality, the isochromosome 7q; has a distinct molecular signature; and displays frequent STAT5B mutations. Most cases are derived from the gamma-delta T-cell subset, and the gamma-delta T-cell phenotype has been part of the definition of the entity, which was initially named hepatosplenic gamma-delta T-cell lymphoma in the Revised European American Lymphoma (REAL) classification. Similar cases with an alpha-beta phenotype have been described, and the World Health Organization prefers the term hepatosplenic T-cell lymphoma in the current WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues .

Epidemiology

HSTL is rare, with cases reported in both Western and Asian countries. The disease represents 1% to 2% of all peripheral T-cell lymphomas. Its incidence might be underestimated, however, because the disease may mimic other conditions, and the diagnosis is sometimes difficult to establish. In some instances, there is also difficulty in assessing the gamma-delta T-cell origin on routine specimens. HSTL is characterized by a male predominance and occurs in young adults, with a median age around 35 years. Cases of HSTL in adolescents or children have been reported. However, HSTL is not restricted to these populations and can also occur in females and older adults.

Etiology

A number of cases have been reported in patients with immunologic manifestations or with a previous history of immune deficit, especially in patients receiving long-term immunosuppressive therapy for solid organ transplantation. In this context, HSTL is regarded as a late-onset posttransplantation lymphoproliferative disorder of host origin. Occasional cases have been observed following acute myeloid leukemia or Epstein-Barr virus (EBV)-positive lymphoproliferative disorders, in patients with falciparum malaria, or during pregnancy. Especially, several cases were recently reported in patients with Crohn's disease treated with azathioprine. The use of the anti–tumor necrosis factor agent infliximab along with azathioprine may increase the risk for HSTL in patients with inflammatory bowel disease, especially children. Other cases were reported in patients with psoriasis or rheumatoid arthritis receiving TNF-α inhibitors and immunomodulators. From these observations and in view of the functional properties of normal gamma-delta T cells, it has been postulated that chronic antigen stimulation in the setting of an underlying immune defect might play a role in the pathogenesis of the disease. As an example, expansion of gamma-delta T cells is observed in the peripheral blood of renal allograft recipients, and in vitro studies have shown that human gamma-delta T cells display an alloreactive response to various leukocyte antigen molecules. Infliximab has also been shown to induce clonal expansions of γδ-T cells in Crohn's disease.

To date, no association with human T-lymphotropic virus 1 or 2, human immunodeficiency virus, human herpesvirus 8, or hepatitis C virus has been reported. One case was reported in a patient positive for human herpesvirus 6, and another in a patient with parvoviral infection. The vast majority of cases do not show EBV association, with the exception of rare cases with cytologic features of transformation.

Clinical Features

The disease occurs mainly in young adults presenting with marked splenomegaly and most often hepatomegaly, but without lymphadenopathy. Most patients have B symptoms, including fatigue, fever, and weight loss, associated with abdominal pain, probably secondary to marked splenomegaly.

Thrombocytopenia is almost always present and is associated with anemia or leukopenia in about half of patients. A few cases have been reported in which features of idiopathic thrombocytopenic purpura or Coombs-negative hemolytic anemia were the first symptoms of HSTL. An overt leukemic picture is rare at presentation, and lymphocytosis is uncommon. However, with careful examination of blood smears, a minor population of atypical lymphoid cells can be identified in some patients. An association with hemophagocytic syndrome has occasionally been reported. Abnormal liver function tests are an inconstant finding at presentation.

Computed tomography shows an absence of mediastinal and retroperitoneal lymphadenopathy. Owing to bone marrow involvement (see later), almost all patients have Ann Arbor stage IV disease. They also frequently have elevated serum lactate dehydrogenase levels and a performance status greater than 1. As a consequence, the majority of patients present with two to three adverse risk factors of the age-adjusted International Prognostic Index and fall into its high-risk group.

Morphology

Histology

The diagnosis of HSTL is based on histopathologic and immunohistochemical findings. In the past, the diagnosis was often made by examination of the spleen or by liver biopsy obtained at the time of splenectomy; less often the diagnosis was made by bone marrow biopsy. Because the histologic features in the bone marrow are now recognized as highly characteristic, bone marrow biopsy is the recommended diagnostic strategy, thus avoiding splenectomy for diagnosis. In addition, to establish expression of the gamma-delta T-cell receptor (TCRγδ), flow cytometry on bone marrow cell suspensions is advised, even though monoclonal antibodies reactive with TCR γ in paraffin sections are now available and therefore can confirm γδ chain expression in most instances. The neoplastic cells are monomorphic and medium-sized and located preferentially in the sinusoids of the liver, cords and sinuses of the splenic red pulp, and sinuses of the bone marrow.

Spleen

In the spleen, the pattern of involvement is characterized by diffuse red pulp infiltration and preservation of the sinus and pulp cord architecture, whereas there is marked reduction or complete loss of the white pulp ( Fig. 34-1, A ). The red pulp contains a more or less dense infiltration consisting of usually monomorphic, medium-sized lymphoid cells with round to oval or slightly irregular nuclei, slightly dispersed chromatin, and inconspicuous nucleoli. The cytoplasm is pale and seldom exhibits azurophilic granules on smears or imprints. Mitotic figures are rare. Some pleomorphism is occasionally seen. The atypical cells are present within the cords and, to a variable extent from case to case, within the sinuses of the red pulp (see Fig. 34-1, B ). Dilated sinuses filled with sheets of neoplastic cells can be observed. A few small lymphocytes may be admixed, but plasma cells are rare. Histiocytes may be numerous. Rare cases show features of hemophagocytosis at presentation or during the course of the disease.

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