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Biology and Management of Rare Primary Extranodal T-cell Lymphomas

Biology and Management of Rare Primary Extranodal T-cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) are uncommonly encountered malignancies in the United States, and hepatosplenic T-cell lymphoma (HSTCL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and enteropathy-type T-cell lymphoma (ETTCL) are rare subtypes of PTCLs that often present with primarily extranodal disease. Despite the fact that these tumors have distinct clinical and pathologic features, they are often diagnosed after significant delay. The combination of delay in diagnosis with ineffective therapies has resulted in a poor prognosis in most cases. Techniques that identify T-cell receptor gene rearrangements and flow cytometry that can identify characteristic immunophenotypes have guided our understanding of the underlying cell of origin of these rare PTCLs. As knowledge regarding the biology of these lymphomas increases alongside the development of newer therapeutics with novel mechanisms, clinicians must accordingly improve their familiarity with the clinical settings in which these rare malignancies arise as well as the pathologic features that make them unique.


Distribution of PTCL Cases

Peripheral T-cell lymphomas (PTCLs) are uncommonly encountered malignancies that comprise only 5% to 10% of all non-Hodgkin lymphomas in the United States.[1] Hepatosplenic T-cell lymphoma (HSTCL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and enteropathy-type T-cell lymphoma (ETTCL) are rare subtypes that frequently present without any nodal involvement and make up only about 10% of all PTCLs with relative frequencies shown in Figure 1. Therefore, they can easily be misdiagnosed without proper clinical suspicion and familiarity with the clinical settings in which they arise.

PTCLs are malignancies of an immunologically mature T cell that has migrated from its site of differentiation in the thymus to a peripheral site of lymphoid tissue. In thymic development, immature thymocytes undergo sequential rearrangement of their TCR genes. Normal mature T cells express two mutually exclusive types of CD3-associated T-cell receptor heterodimers: the α/β T-cell heterodimer and the γ/δ T-cell heterodimer. It is now recognized that the majority of PTCLs arise from α/β T cells with only a minor subset that arise from cells expressing the γ/δ T-cell receptor.[2] γ/δ T cells, along with natural killer (NK) cells, are part of the innate immune system and exhibit preferential homing to the mucosa of the skin, the intestinal epithelium, and the sinusoidal areas of the spleen. Notably, it is these sites that are commonly affected by γ/δ T-cell lymphomas.[3]


Overall Survival in PTCL Patients

Primary extranodal PTCLs have disappointing outcomes when treated with conventional anthracycline-based chemotherapy regimens regardless of traditional prognostic variables such as those included in the International Prognostic Index (IPI).[1,4] The combination of frequent delays in diagnosis with the therapy-refractory nature of these tumors has led to a historically poor prognosis, as demonstrated in Figure 2. However, since these primary extranodal PTCLs have very distinctive clinical and pathologic presentations, improved understanding and recognition may lead to earlier diagnosis and earlier institution of proper therapy. Without improvements in recognition, however, the improved biologic understanding of these diseases and improved novel therapies will not lead to an overall improvement in outcomes.

Hepatosplenic T-cell Lymphoma

Hepatosplenic T-cell lymphoma (HSTCL) was first accurately described in 1990 by Farcet et al in two young adult males who presented with systemic symptoms, hepatosplenomegaly, thrombocytopenia, and an absence of lymphadenopathy.[5] Both patients achieved complete remissions to their initial therapy but quickly relapsed and subsequently died of their disease. Subsequent case reports confirmed it as a distinct clinicopathologic entity, and it was first provisionally recognized as a distinct lymphoma entity by the Revised European-American Lymphoma (REAL) classification in 1994.[6-11] In the current World Health Organization (WHO) classification, both the γ/δ-type as well as the α/β-type are included under the term hepatosplenic T-cell lymphoma, although epidemiologic and biologic differences may exist.[12]

HSTCL is a very rare form of PTCL as it represents only 1.4% of cases of peripheral T-cell and NK-cell lymphomas worldwide. Regionally, it represents a slightly higher percentage of all PTCLs in North America (3.0%) and Europe (2.3%) but is vanishingly rare in Asia (0.2%). Median age at time of diagnosis is 34 years, and 68% of cases are in male patients.[1]

The classic clinical presentation of HSTCL is a young male who presents with systemic symptoms, jaundice, abdominal pain, significant thrombocytopenia with or without anemia, and marked hepatosplenomegaly without associated lymphadenopathy. Involvement of the peripheral blood with circulating lymphocytes, erythrophagocytosis, and involved lymph nodes are not common features early in the disease but may occur in late stages of illness. Bone marrow involvement is an almost constant feature. Often there is evidence of diffuse hepatic enlargement in the absence of gross lesions.[6-11]

Approximately 10% to 20% of HSTCL patients have a history of immunocompromise, including solid organ transplantation, inflammatory bowel disease, systemic lupus, Hodgkin lymphoma, and malarial infection.[9,13,14] All of these conditions are known to be associated with the expansion of γ/δ T cells as a result of chronic antigen stimulation, but there is no known association with viral infection and almost every described case is Epstein-Barr virus (EBV)-negative. It has been described as a late complication posttransplant lymphoproliferative disorder occurring up to 10 years after transplantation.[13,14]


Sinusoidal Infiltration of Spleen in Hepatosplenic T-cell Lymphoma

Without an experienced hematopathologist, the diagnosis of HSTCL can be missed, and interobserver agreement on diagnosis from expert hematopathologists in the International Peripheral T-cell Lymphoma Project was only 72%.[1] Normally, lymphomas invade the portal tracts of the liver and are seen mainly in the white pulp of the spleen. HSTCL, in contrast, is characterized by marked sinusoidal infiltration of spleen with resultant atrophy of the white pulp (Figure 3). Liver involvement is characterized by marked sinusoid expansion and sparing of the portal triads without hepatocyte destruction.[5-11] Morphologically, small clusters of a monomorphic population of medium-sized lymphoid cells are typically seen, with moderately clumped chromatin and a rime of pale eosinophilic cytoplasm.[3]


Immunohistochemical Stain of Hepatosplenic T-cell Lymphoma

The bone marrow is characteristically hypercellular and the diagnosis is greatly facilitated by use of proper immunohistochemical stains, since the lymphoma cells may be difficult to identify with light microscopy alone (Figure 4). The neoplastic cells have a phenotype resembling immature cytotoxic T cells and are typically CD2+, CD3+, CD4–, CD5–, CD7+, CD8–, with either TCR-γ/δ+ o r TCR-α/β+.[3, 7-9] Many variations exist, however, and some cases may be CD8+. Other antigens that are frequently positive are NK-related antigens such as CD16 and CD56.[7-9]

The neoplastic cells have rearranged TCR genes, and the diagnosis of HSTCL occasionally may rely solely on T-cell receptor rearrangement. Unfortunately, there are no available monoclonal antibodies against the γ/δ T-cell receptor for use with paraffin-embedded tissue. The majority of cases of HSTCL are of the γ/δ-type, but cases that express the α/β-type receptor are considered immunophenotypic variants of the same disease.[10,11]

HSTCL is associated with recurrent cytogenetic chromosomal abnormalities such as isochromosome 7q translocations, which frequently occur in association with trisomy 8.[7,8,11-15] Cases of trisomy 8 without isochromosome 7q translocations, however, have not been reported. Available data from gene-expression profiling also supports the notion that hepatosplenic T-cell lymphoma is a distinct entity as it has a characteristic signature that is distinct from other PTCLs.[16]

HSTCL has the worst prognosis of all PTCLs, with 5-year failure-free survival and overall survival rates of 0% and 7%, respectively.[1] There is no reliable biomarker to predict prognosis, and the IPI score is not helpful in risk stratification. Since this disease was first reported in the early 1990s, most patients reported have survived less than 1 year despite aggressive combinations of chemotherapy.[6-13]

Reduction of immunosuppression is ineffective for HSTCLs that arise in the posttransplant setting, and all cases should be treated with chemotherapy at diagnosis. Although most patients are refractory to anthracycline-based therapy or have only brief responses, limited evidence suggests that some patients may respond to a platinum/cytarabine-based induction regimen.[8] All patients remain at significant risk of relapse, as the durations of response are very short. Consolidation with allogeneic stem cell transplantation should be offered to all eligible patients since there has been a demonstrable graft-vs-lymphoma effect and it is likely that stem cell transplantation from an allogeneic donor offers the only chance for durable remission in this disease.[17-20]


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