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Hepatosplenic T cell lymphoma. A review on 45 cases since the first report describing the disease as a distinct lymphoma entity in 1990

Abstract

Peripheral T cell lymphomas are a heterogeneous group of post-thymic, mature lymphoid malignancies, accounting for approximately 10–15% of all non-Hodgkin's lymphomas. A rare entity within this group is represented by hepatosplenic γδ T cell lymphoma, which is characterized by primary extranodal disease with typical sinusoidal or sinusal infiltration of the liver and the spleen, respectively, by expression of the T cell receptor γδ chain, and by a number of other frequent clinicopathological features including aggressive course of disease. In contrast to these common attributes some biologic characteristics such as expression of cytotoxic proteins and cytotoxic activity have been controversial. In this review, clinicopathological, immunophenotypical, molecular biological, cytogenetical and biological findings, and diagnostic and therapeutic difficulties in hepatosplenic γδ T cell lymphoma are discussed.

Introduction

In 1990, hepatosplenic γδ T cell lymphoma was recognized as a distinct lymphoma entity by Farcet et al1 who analyzed in detail two previously described peripheral γδ T cell lymphomas2 with predominant infiltration of the spleen and the liver. Since then, to our knowledge 44 cases have been described.1234567891011121314151617181920212223242526272829 Because of similar clinicopathological appearance, some additional cases have been discussed to represent hepatosplenic γδ T cell lymphomas, however, in these cases γδ T cell receptor studies were not available.30313233343536 A few more cases have been documented in studies on particular issues and are not available in detail.373839 Typical features are sinusoidal infiltration of the liver and sinusal infiltration of the spleen, no lymphadenopathy, an aggressive clinical course, and a predominance of young male adults.1529 Despite use of a variety of treatment regimens including bone marrow or peripheral stem cell transplantation it has not been possible to establish an effective treatment.29 Because of the above-mentioned clinicopathological features and the frequent presence of an isochromosome 7q often associated with trisomy 8, hepatosplenic γδ T cell lymphoma was recognized as a distinct lymphoma entity by the REAL classification in 1994.40 The present article intends to discuss clinical and biological features of the published cases, and an additional case in our institution.

Patients

Of the 45 cases reviewed, 41 were evaluable for age and sex. Two of the patients were under the age of 16 and three had exceeded the age of 50 years. The median age was 29 years (range 5–68 years) (Table 1). Thirty-four of the patients were male and seven female (Table 1). Nine patients developed the neoplasm following kidney transplantation (n = 6), heart transplantation (n = 1), Hodgkin's disease (n = 1) and AML (n = 1) (Table 1).

Table 1  Characteristics, condition for secondary lymphoma, treatment, response and survival of 45 patients with hepatosplenic γδ T cell lymphoma

Presentation and diagnosis

The majority of the patients presents with hepatosplenomegaly and systemic symptoms41 (Table 2). Other clinical features such as fatigue, jaundice due to hepatic involvement and Coombs negative hemolytic anemia, and purpura may occur. Lymphadenopathy has been reported only in a few patients at presentation of the disease.101823 The predominant laboratory findings are reduced peripheral blood cells ranging from isolated reduction of one lineage to pancytopenia, elevated lactate dehydrogenase, and pathologic liver parameters (Table 2). The finding of pancytopenia and normal bone marrow has generated the hypothesis that cytokines produced by the malignant γδ T cells may suppress bone marrow precursor cells,817 however, data providing strong evidence for this hypothesis are missing.

Table 2  Clinical symptoms, hematological and other laboratory findings at presentation of hepatosplenic γδ T cell lymphoma

Diagnosis of the disease has been complicated in some cases by misleading symptoms. For example, isolated thrombocytopenia which disappeared after splenectomy has been misinterpreted as idiopathic thrombocytopenic purpura,1516 circulating blast-like lymphoma cells were erroneously interpreted as acute lymphoblastic leukemia blasts,18 or presentation with hepatosplenomegaly, jaundice, elevated liver parameters, thrombocytopenia, and fever have led to the assumption of a virus infection, which has usually not been confirmed.5212629

Even more difficulties regarding the diagnosis of hepatosplenic γδ T cell lymphoma may result from not considering this rare entity as a differential diagnosis. In most of the cases splenectomy or liver biopsy should be sufficient to establish diagnosis. Furthermore, splenectomy has been reported to improve the patients’ condition for variable time (Refs 1, 4, 16, 21 and Table 1).

Histopathology

The most common feature present in almost all patients with hepatosplenic γδ T cell lymphoma is infiltration by malignant cells of the spleen and frequently of the liver (Table 2). Bone marrow involvement is seen in approximately two-thirds of the patients at diagnosis, more often in progressive course of disease, lymphadenopathy is rare1018 and sometimes associated with infiltration of other organs by malignant cells in the terminal stage of disease.56 In the spleen, the red pulp is generally diffusely invaded and expanded by malignant γδ T cells315 resulting in an increased mass, whereas the white pulp can appear from normal to reduced to small residual areas. Normal γδ T cells have been shown to be also localized in the splenic sinuses, probably due to special homing receptors.42 Therefore, and because of the sometimes sole involvement of the spleen it seems likely that hepatosplenic γδ T cell lymphoma originates in the splenic red pulp.15 A known phenomenon in peripheral T cell lymphomas and also documented in areas invaded by malignant hepatosplenic γδ T cells is erythrophagocytosis.123818222326 Besides peripheral cytopenia, this feature may be another indicator for active cytokine production by the tumor.18 Tumor necrosis factor α has been presumed to be responsible for histiocyte activation and subsequent erythrophagocytosis in EBV transformed T cell lymphomas.43 However, hepatosplenic γδ T cell lymphoma is generally not EBV associated. In the liver, the typical site of infiltration is the sinusoids, but marked or even exclusive portal infiltration has been reported in some cases (Figure 1).12528 Bone marrow, if affected, is usually hypercellular with a sinusoidal distribution of the T cells.1516171820

Figure 1
figure1

 Histology and immunohistochemistry of a fine needle liver biopsy performed after the first cycle of chemotherapy in case 45 (see Table 1). Following chemotherapy peripheral γδ T cells were markedly reduced and hepatosplenomegaly decreased. (a) Hematoxylin and eosin staining; (b) staining with anti-CD3; and (c) staining with anti-CD20 antibodies (all ×200). In this case, as in a few others, main infiltration of the liver by the lymphoma cells was noted in the portal areas. Sinusoidal infiltration was present but negligible.

Malignant hepatosplenic γδ T cells are usually of small to medium size with relatively regular or folded nuclei, mostly inconspicuous nucleoli, and with a mature dispersed chromatin and a pale blue, not granulated, somewhat abundant cytoplasm. Blast-like appearance at diagnosis is rare,18 however, terminal transformation to blast-like cells with large nucleoli has been reported several times (Refs 6, 9, 11, 20 and case 45).

Immunophenotype

A phenotype which has been accepted to be common in hepatosplenic γδ T cell lymphoma is CD2+CD3+CD4 CD5CD7+CD8TCRγδ+. TCR-Vδ expression seems to be restricted to Vδ1. NK-related antigens CD16 and CD56 are frequently expressed (Table 3). As may be expected, there are many exceptions to this ‘common phenotype’ since expression of CD5, CD7, CD8, CD16 and CD56 is variable (Table 3). Even expression of CD3 and TCR-γδ has been lost in one case at presentation of relapse,1 and CD7 in another patient after chemotherapy.15 Additionally, weak to strong expression of CD8 as in some populations of normal γδ T cells,42 which are usually CD4 and CD8 negative, has been described. Absence of common T cell antigens as CD5 or CD7 has been associated with peripheral T cell lymphomas.15 CD7, a molecule which acts as an activator of various NK and T cell populations including normal γδ T cells4445 was expressed in two-thirds of the cases (Table 3). Other molecules associated with activation but not strictly restricted to T cells such as CD11b, CD11c, CD38, CD43, and Fas ligand are frequently expressed (Table 3). B cell markers (CD19, CD20, CD21, CD22), immunoglobulins, TCR-αβ chain, TdT, CD10, CD15, CD25, CD33, CD34, CD41, and CD68 were consistently negative (data not shown). Ki67 was studied in one patient: at diagnoses it was not detectable, but in blast transformation it turned out to be strongly positive8 (data not shown).

Table 3  Immunophenotype, and rearrangements of T cell receptor and immunoglobulin genes in hepatosplenic γδ T cell lymphoma

Regarding expression of cytotoxic granule-associated proteins, the data are somewhat conflicting. A study by Boulland and coworkers37 revealed presence of TIA, and absence of granzyme B and perforin in all their cases with hepatosplenic γδ T cell lymphoma. Since sole expression of TIA is a marker for more immature cytotoxic cells and granzyme B and perforin are associated with functional cytotoxic cells,46 they concluded that hepatosplenic γδ T cell lymphomas represent tumors of non-activated cytotoxic γδ T cells. In contrast, other investigators demonstrated expression of granzyme B and perforin in the malignant γδ T cells (Refs 15, 18, 19, 28 and Table 3). The latter may be supported by the demonstration of cytotoxicity by malignant γδ T cells in three cases as described below.

Molecular rearrangement studies

In the initial report of hepatosplenic γδ T cell lymphoma Southern analysis of the T cell receptor (TCR) β and δ chain genes demonstrated clonality of the cells.1 Vδ1 associated with different Vγ regions has been identified to be the predominant Vδ region (Refs 7, 15, 22, 24, 28 and Table 3). Non-productive TCR β-chain rearrangements have been confirmed frequently (Refs 6, 7, 10, 22, 24, 28 and Table 3).

Garcia-Sanchez et al1112 utilized TCR rearrangements for monitoring of disease follow-up. They sequenced a TCR-δ VDJ product and designed a clone-specific probe by which they were able to detect the malignant clone in spleen, bone marrow, peripheral blood and liver. After treatment, only a liver specimen was still positive.11 Weirich and coworkers25 amplified DNA from fixed decalcified bone marrow and demonstrated invasion of the spleen by the identical γδ T cell clone, although the splenic population appeared as a ‘high-grade’ lymphoma and the γδ T cells in the bone marrow as ‘low-grade’ lymphoma cells. These data suggested a common precursor cell for both forms of the lymphoma cells.25

Cytogenetics

In 19 of the reviewed cases, karyotypes of γδ-lymphoma cells were available (Table 4). Earlier studies showed the presence of an isochromosome 7q, often associated with trisomy 8,9131415 inspiring the discussion that isochromosome 7q may represent the primary chromosomal aberration accompanied by trisomy 8 as a secondary change.9 Meanwhile isochromosome 7q has been detected in 13 of the patients, all of them male, and associated with trisomy 8 in 10 cases, however, trisomy 8 without isochromosome 7 has not been reported (Table 4). Although isochromosome 7q and trisomy 8 by themselves are known cytogenetic abnormalities in a number of hematological malignancies and solid tumors47 the combination of both seems to be unique in hepatosplenic γδ T cell lymphoma. On the other hand in some patients with clear clinicopathological criteria of hepatosplenic γδ T cell lymphoma different karyotypes of the malignant cells were shown (Table 4), suggesting that although the combination of isochromosome 7q and trisomy 8 has been proposed to classify hepatosplenic γδ T cell lymphoma as a distinct entity41 the karyotype alone is not sufficient to define the disease. Earlier studies suggested isochromosome 7q to be an adverse prognostic factor.18 The present evaluation of karyotypes does not support this hypothesis. The median survival in patients with isochromosome 7q was 7.5 months as compared to 10 months in the total population and 5 months in patients with other aberrations. Consequently, the prognostic value of chromosomal aberrations in hepatosplenic γδ T cell lymphoma remains undetermined.

Table 4  Cytogenetic findings in hepatosplenic γδ T cell lymphoma

Cytotoxicity

Functional data of malignant γδ T cells have been obtained in three cases with hepatosplenic γδ T cell lymphoma. Falcao and coworkers4 were the first to demonstrate NK activity of γδ T cells in their case by lysis of K562 cells. Salhany et al18 studied cytotoxic activity of γδ T cells against the P815 cell line in two of their patients. Spontaneous cytotoxicity was not observed, however, after incubation with anti-CD3 or anti-CD16 the γδ T cells from one patient were able to mediate some lytic activity.18 In our case (case 45) the lymphoma cells exhibited strong cytotoxicity against K562 cells and moderate lysis of Daudi cells. Altogether the data indicate that at least some hepatosplenic γδ T cell lymphomas consist of mature cytotoxic γδ T cells. Specific T cell receptor-mediated cytotoxic activity by the tumor cells seems unlikely.48

Treatment and outcome

Of the patients available for treatment and response, four were alive at the time when the reports were finished, one in CR after m-BACOP, two in CR after allogeneic bone marrow transplantation, and one patient alive with a 6 year history of untreated hepatosplenic γδ T cell lymphoma followed by CHOP because of disease progression (Table 1). One patient died in CR from sepsis due to aplastic anemia without evidence of disease (case 28, Table 1). 36 patients were dead from disease at the time when their cases were reported. Of these, the median survival was 8 months (range 0–42 months, Table 1). Treatment included splenectomy, steroids, alkylating agents, CHOP or CHOP-like therapies, second or third generation regimens for high-grade lymphomas, purine analogues, multiagent therapy approaches, and autologous and allogeneic bone marrow or peripheral stem cell transplantation (Table 1). Complete remissions were reported only in five of these 36 patients (cases 1–3, 34, and 45; Table 1). Considering that the observation time after allogeneic transplantation was short, that – although many approaches have been attempted – induction of CR has been rare, and that relapses are common and occur early, one has to conclude that curative treatment is not available in hepatosplenic γδ T cell lymphoma.

Initial improvement has been observed in the majority of cases, no matter whether splenectomy, oral treatment with steroids or alkylating agents, or aggressive approaches have been attempted. Thus, the question of whether aggressive treatment improves the overall survival is unresolved. Possibly transplantation after a short attempt to induce remission might be a suggestion, however, the data do not provide enough evidence to give general recommendations.

Concluding remarks

Because of a variety of common features hepatosplenic T cell lymphoma is generally considered a distinct lymphoma entity. It can be distinguished from most other lymphoma types by the combination of TCR-γδ gene rearrangement and expression, primary involvement of the spleen and the liver with a typical sinusal or sinusoidal infiltration pattern, respectively, extranodal disease, and some other rather common features as presentation with hepatosplenomegaly and peripheral cytopenia, a typical immunophenotype, and the frequent presence of isochromosome 7q and trisomy 8. Differential diagnoses include T-lymphoblastic lymphomas expressing TCR γδ,49 peripheral cytotoxic T cell lymphomas,505152 and unusual forms of T-chronic lymphocytic/promyelocytic leukemias with CD8 phenotype.5354 TCR γδ T-lymphoblastic lymphomas may be excluded by expression of TdT.4149 Clinicopathological and immunological overlaps with cytotoxic T cell lymphomas, unusual CD8+ T-CLL/PLL and so called ‘S100-positive T-chronic lymphoproliferative disease (T-CLPD)’ are possible, because hepatosplenomegaly, an aggressive clinical course, lack of azurophilic granules, and expression of CD8 are common. Especially in S100 T-CLPD hepatosplenic infiltration is sinusoidal or sinusal, respectively. However, all of these entities usually express the TCR-αβ chains.5051525354 In cases which can not be clarified by clinicopathology, immunology, and standard molecular biology more sophisticated molecular approaches as indicated above should be involved. As the disease is rare its biology is not yet well understood. However, because of the dilemma of an aggressive clinical course and an unsatisfactory response to treatment, more insight in the biology of the malignant γδ T cells may hopefully contribute to develop new therapeutic concepts.

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Acknowledgements

Figure 1 was kindly provided by Prof ML Hansmann, Department of Pathology, JW Goethe University, Frankfurt am Main, Germany

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Correspondence to E Weidmann.

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Weidmann, E. Hepatosplenic T cell lymphoma. A review on 45 cases since the first report describing the disease as a distinct lymphoma entity in 1990. Leukemia 14, 991–997 (2000). https://doi.org/10.1038/sj.leu.2401784

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Keywords

  • hepatosplenic γδ
  • T cell lymphoma
  • clinicopathology
  • biology and molecular biology
  • aggressive course of disease
  • treatment

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