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A 37-year-old man presented with a 2-month history of unexplained fever and weight loss. He was noted to have pancytopenia, splenomegaly and hepatomegaly. HIV test was negative and no signs of infection were identified. Splenectomy yielded a 2050 gram spleen with diffuse red pulp expansion. Flow cytometric immunophenotypic studies demonstrated a population of medium to large cells expressing CD3 and gamma-delta T-cell receptors. The infiltrate was negative for EBV genomes by in situ hybridization.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 10 and is a hepatosplenic T-cell lymphoma.
Criteria for Diagnosis and Comments:
Hepatosplenic T cell lymphoma is an uncommon (0.5% of lymphomas), distinctive lymphoma with primary involvement of the spleen and liver. The spleen demonstrates marked enlargement due to uniform red pulp expansion by neoplastic cells. Similarly, hepatomegaly results from uniform sinusoidal infiltrates. Bone marrow is typically involved but the neoplastic cells are difficult to detect on routine morphologic review. Lymph nodes are not involved.
The neoplastic cells are best characterized as “moderate”. That is, they are of medium size with moderate cytologic atypia. The malignant cells typically have a rim of amphophilic to clear cytoplasm, the nucleus has moderate chromatin density and there is often a small nucleolus. Especially in the liver, the neoplastic cells can be difficult to differentiate morphologically from reactive sinusoidal cells seen in systemic inflammatory conditions. Increased cellularity and relative cytologic uniformity are clues to malignancy. Recognition of lymphoma in the spleen is usually easier due to the prominent splenomegaly.
Hepatosplenic T cell lymphoma is an aggressive lymphoma with many patients dying within 1-2 years of diagnosis. Initial descriptions identified all cases as expressing the gamma-delta T-cell receptor. In healthy individuals, nearly all mature T-cells express the alpha-beta T-cell receptor with only 1-2% of T-cells expressing the gamma-delta receptor. Hepatosplenic T-cell lymphomas with gamma-delta receptor expression occur disproportionately in young men. Subsequently, a smaller number of hepatosplenic T-cell lymphomas with alpha-beta receptor expression were identified. The alpha-beta expressing cases tended to have a broad age range and appear to demonstrate a female predominance.
In addition to surface T-cell markers and often gamma-delta receptor subtype expression, hepatosplenic T-cell lymphoma often demonstrates isochrome 7. This has been helpful in distinguishing this lymphoma from reactive sinusoidal lymphocytosis in some liver biopsies. Trisomy 8 is a less common finding.
Hepatosplenic T cell lymphoma is one of a family of extranodal T cell lymphomas with cytotoxic T-cell and/or natural killer cell differentiation. This family also includes extranodal NK/T cell lymphoma, nasal type, enteropathy-type T cell lymphoma and subcutaneous panniculitis-like T cell lymphoma. This family of lymphomas shares an aggressive, often rapidly fatal natural history. All of these lymphomas express cytoplasmic cytotoxic markers Tia-1 and granzyme B by immunohistochemistry. These markers are helpful in distinguishing these entities from other peripheral T-cell lymphomas, but should be used with caution, as systemic inflammatory processes will also have significant expression of these markers.
Extranodal NK/T cell lymphoma, nasal type occurs most commonly in the nasal cavity. In this location, it’s characteristic angioinvasion, necrosis and variably granulomatous response made it one of the entities included in the family of “lethal midline granulomas”. However, this entity can occur at extranodal sites throughout the body. In contrast to hepatosplenic T-cell lymphoma, it tends to be tumefactive and is uniformly positive for EBV genomes by in situ hybridization.
Diffuse large B-cell lymphoma (DLBCL) typically consists of larger, more atypical cells than hepatosplenic T-cell lymphoma, but the cytologic spectrums of the 2 entities certainly can overlap. DLBCL usually forms mass lesions when involving the spleen or liver. Immunophenotypic analysis, at least with CD20 and CD3 antibodies, is now requisite in lymphoma diagnosis, simplifying the distinction between these 2 entities.
Hairy cell leukemia is a cause of splenomegaly with red pulp expansion and accompanying cytopenias. The neoplastic cells are smaller and less atypical in hairy cell leukemia than hepatosplenic lymphoma. Again, a simple immunophenotypical evaluation will differentiate the B-cell differentiation of hairy cell leukemia from hepatosplenic T-cell lymphoma.
Hepatosplenic T-cell lymphoma can be differentiated from peripheral T-cell lymphoma, unspecified, by its characteristic disease distribution, cytotoxic marker expression and gamma-delta T cell receptor expression when present. Peripheral T-cell lymphoma, unspecified, will typically form discrete tumors when involving the liver or spleen.