Clinical manifestations, pathologic features, and diagnosis of hepatosplenic T cell lymphoma

INTRODUCTION — The peripheral T cell lymphomas (PTCLs) are a heterogeneous group of generally aggressive neoplasms that constitute <15 percent of all non-Hodgkin lymphomas in adults. (See "Classification of hematopoietic neoplasms".)

Among these, in decreasing frequency of occurrence, are:

●Peripheral T cell lymphoma, not otherwise specified (NOS)

●Anaplastic large cell lymphoma, primary systemic type

●Angioimmunoblastic T cell lymphoma

●Extranodal NK/T cell lymphoma, nasal type

●Subcutaneous panniculitis-like T cell lymphoma

●Enteropathy associated T cell lymphoma

●Hepatosplenic T cell lymphoma

Hepatosplenic T cell lymphoma (HSTL) was initially described as a neoplasm of mature gamma/delta T cells that infiltrate the sinusoids of the spleen, liver, and bone marrow. Originally called hepatosplenic gamma/delta T cell lymphoma, the preferred nomenclature was changed to hepatosplenic T cell lymphoma when cases were identified with the clinicopathologic features of HSTL that expressed the alpha/beta T cell receptor [1-3].

The clinical presentation, pathologic features, and diagnosis of HSTL will be discussed here. The other NK/T cell lymphomas and the treatment of the PTCL are discussed separately. (See "Initial treatment of peripheral T cell lymphoma".)

EPIDEMIOLOGY — Hepatosplenic T cell lymphoma (HSTL) is a very rare neoplasm accounting for less than 1 percent of non-Hodgkin lymphomas [1]. The exact incidence is unknown and only a few hundred patients have been reported in the literature [4]. The median age at diagnosis is approximately 35 years and there is a male predominance.

Up to 40 percent of patients have a history of chronic immune suppression, such as that associated with treatment for a prior solid organ transplantation, lymphoproliferative disorder, or inflammatory bowel disease [4-7]. Regarding the latter, there has been an association between the development of HSTL with the use of tumor necrosis factor (TNF) blockers, thiopurine, and the anti-TNF monoclonal antibodies infliximab and adalimumab in young patients with Crohn disease [8].

PATHOGENESIS — The pathogenesis of HSTL is largely unknown. One proposed mechanism is chronic immune suppression [1]. Up to 20 percent of HSTLs occur in patients who are immunosuppressed, such as solid organ transplant recipients. As such, some cases of HSTL may represent a post-transplantation lymphoproliferative disorder of host origin. Also important is isochromosome 7q, which is found in up to 80 percent of cases, and trisomy 8, which is found in up to 50 percent of cases [9]. The genes that are dysregulated by these genetic aberrations are unknown. (See "Treatment and prevention of post-transplant lymphoproliferative disorders" and "Secondary cancers after hematopoietic cell transplantation".)

Gene expression profiling (GEP) studies may shed some light on the pathogenesis of this disorder. As an example, an unsupervised analysis in one GEP study found that HSTLs clustered together, while other T cell lymphomas with gamma-delta expression were scattered throughout the alpha beta T cell lymphoma cluster, suggesting that HSTL is a unique entity [10]. (See 'Genetic features' below.)

CLINICAL FEATURES — Most patients with HSTL present with marked hepatosplenomegaly and thrombocytopenia without lymphadenopathy. Common signs and symptoms at presentation include [5,11-13]:

●Splenomegaly (100 percent)

●Hepatomegaly (40 to 71 percent)

●Systemic B symptoms of fever, night sweats, or weight loss (67 to 80 percent)

●Thrombocytopenia (64 to 100 percent)

●Anemia (57 to 73 percent)

●Neutropenia (36 to 57 percent)

●Abnormal liver function tests (38 to 57 percent)

●Abnormal lymphocytes in the peripheral blood (10 to 27 percent)

●Adenopathy (0 to 13 percent)

Although circulating neoplastic cells are not usually prominent, subtle bone marrow involvement can be detected in almost all cases [5,11,12,14-16].

PATHOLOGY

Patterns of involvement — HSTL characteristically involves the sinusoids of the spleen, liver, and bone marrow (image 1). As described above, peripheral blood involvement may be identified in up to 30 percent of cases but is often subtle. The circulating cells are usually bland, resemble monocytes or atypical lymphocytes, and require flow immunophenotyping for positive recognition.

Spleen — Gross examination of the spleen reveals an enlarged red spleen without nodules, which reflects red pulp expansion and white pulp effacement by the tumor [11]. Atypical lymphoid cells infiltrate the cords and sinuses of the red pulp (picture 1). These neoplastic cells may form clusters within the sinuses and there may be admixed macrophages exhibiting erythrophagocytosis. (See 'Morphology' below.)

Liver — Gross examination of the liver reveals diffuse enlargement with no masses. Atypical lymphoid cells infiltrate dilated sinusoids, but the portal tracts and hepatocytes are generally uninvolved (picture 2 and picture 3 and picture 4) [11,12]. (See 'Morphology' below.)

Bone marrow — Bone marrow biopsy typically demonstrates a hypercellular marrow with trilineage hyperplasia and large hyperlobulated megakaryocytes [17]. Infiltration of variably dilated sinuses by atypical lymphoid cells is frequently subtle and may only be appreciated by staining for T cell antigens, such as CD3 (picture 5) [11]. Erythrophagocytosis may be prominent. (See 'Morphology' below.)

Morphology — The morphology of the infiltrating atypical lymphoid cells in HSTL is similar regardless of tissue site. They are monotonous, medium-sized lymphoid cells with round or slightly irregular nuclei, loosely condensed chromatin, and a moderate amount of pale cytoplasm [1]. Nucleoli are small and distinct. Mitotic activity is generally low [18]. Histologic transformation to large cell or blastic morphology may occur with disease progression [1].

Immunophenotype — The tumor cells express CD2, surface CD3, CD7, and CD16 (picture 6 and picture 7). CD56 expression is variable. In most cases, CD4, CD5, and CD8 are not expressed. B cell surface markers (eg, CD20) are negative. Most cases of HSTL express the gamma/delta T cell receptor (TCR delta positive), but a subset of cases expresses the alpha/beta T cell receptor (TCR beta positive). The cytotoxic granule protein TIA-1 is expressed, but perforin and granzyme B are absent [11,12,19-21].

Genetic features — T cell receptor (TCR) gene studies demonstrate clonal rearrangements. The gamma and delta genes are most frequently rearranged. The TCR beta gene is rearranged in alpha/beta variants and may be involved in nonproductive rearrangement in some cases of gamma/delta HSTL.

Conventional cytogenetics or fluorescence in situ hybridization (FISH) demonstrate isochromosome 7q or other chromosome 7 abnormalities in the majority of cases [1,6,11,22,23]. Other cytogenetic changes that have been reported include trisomy 8 and the loss of a sex chromosome [1]. The tumor cells are Epstein-Barr virus (EBV) negative.

Driver mutations involving several oncogenic pathways have been identified [24,25]. These include mutations in STAT3 (and, rarely in STAT5B) that lead to activation of the JAK/STAT pathway, and mutations involving SETD2, IN080, TET3, and SMARCA2, which may produce epigenetic changes that lead to aberrant gene expression.

DIAGNOSIS — The diagnosis of HSTL is usually made based on core needle biopsies of the liver or bone marrow, which show accumulation of malignant cells within the sinusoids (table 1 and picture 4). Patients presenting primarily with splenic enlargement may be diagnosed by splenectomy.

The diagnosis is principally made based upon the demonstration of infiltrating atypical lymphocytes that are positive for CD2, surface CD3, CD7, and CD16, and negative for CD4, CD5, CD8 or B cell surface markers (eg, CD20) (picture 7). The atypical lymphocytes express gamma/delta T cell receptors and/or alpha/beta T cell receptors. Demonstration of isochromosome 7q by cytogenetic testing is not essential, but, if identified, strongly supports the diagnosis of HSTL.

Disagreements among hematopathology groups have led to two main competing classification systems, the International Consensus Classification (ICC) [26] and the World Health Organization (WHO) classification, 5^th edition (WHO5) [27]. Both classifications maintain HSTL as a distinct entity.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of HSTL includes other types of T cell lymphomas and B cell disorders that present with splenomegaly.

Splenic marginal zone lymphoma — Splenic marginal zone lymphoma (SMZL) typically presents with splenomegaly, lymphocytosis, and cytopenias. Unlike HSTL, which only involves the red pulp, pathologic examination of the spleen in SMZL demonstrates involvement of both the white and red pulp in practically all cases. In addition, SMZL is a B cell tumor that expresses surface immunoglobulin (eg, IgM+, IgD+) and B cell antigens (CD19, CD20, CD22) and is negative for T cell markers such as CD3. (See "Splenic marginal zone lymphoma".)

T cell large granular lymphocyte leukemia — T cell large granular lymphocyte (LGL) leukemia typically presents in older adults with neutropenia and/or anemia along with a subtle chronic peripheral blood lymphocytosis. Up to 50 percent of cases are associated with splenomegaly. The great majority of T cell LGL leukemias express CD3, CD8, CD16, and CD57, and do not express CD4. T cell receptor genes are rearranged and some cases have mutations in STAT signaling genes [28]. Although most cases of LGL leukemia have an alpha/beta TCR phenotype, a subset exhibits a gamma/delta TCR phenotype. The clinical setting, immunophenotype, and the presence of large intracytoplasmic granules in the tumor cells of T cell LGL leukemia help to distinguish it from HSTL. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia".)

Aggressive NK leukemia/lymphoma — Aggressive natural killer (NK) leukemia/lymphoma can present with marked hepatosplenomegaly and demonstrates a similar immunophenotype to HSTL with expression of CD2, CD16, and CD56. However, unlike HSTL, aggressive NK leukemia/lymphoma lacks expression of both T cell receptors and CD3; typically demonstrates azurophilic granules in the cytoplasm; expresses all the cytotoxic protein markers (granzyme B, TIA-1, and perforin); and is frequently EBV associated. (See "Natural killer (NK) cell large granular lymphocyte leukemia".)

Acute lymphoblastic leukemia — Like HSTL, precursor T-lymphoblastic leukemia/lymphoma typically presents in older children and young adults. Blasts are present in the peripheral blood, bone marrow, or tissue biopsy and can be identified by their positivity for TdT, which is negative in HSTL. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

Other gamma/delta lymphomas — Neoplasms of gamma/delta T cells may occur in other sites, particularly mucosal or cutaneous tissues; these appear to behave similarly to primary extranodal alpha/beta T cell or NK cell neoplasms of the same sites, and do not show the same proclivity to involve the sinuses of the liver, spleen, and bone marrow [29-32]. Thus, as with certain other NK/T cell lymphomas, the site of presentation and pattern of tissue involvement are important defining criteria for the diagnosis of HSTL.

Intravascular large cell lymphoma — Intravascular large cell lymphoma (ILCL) also preferentially involves sinusoids and may mimic the appearance of HSTL, particularly in the bone marrow. However, liver and spleen enlargement is rare in ILCL, and most cases of ILCL are of B cell origin and easily distinguishable by immunohistochemistry.

TREATMENT — The treatment of HSTL is discussed separately. (See "Initial treatment of peripheral T cell lymphoma".)

PROGNOSIS — Despite the relatively bland appearance of the cells, this is an aggressive tumor with a median survival of less than two years. While patients typically respond to initial chemotherapy, relapses are common. There are case reports of long-term survival after allogeneic hematopoietic cell transplantation.

Prognostic models used for other types of non-Hodgkin lymphoma have limited applicability to patients with HSTL. Most patients fall into the low risk category when assessed with either the International Prognostic Index (IPI) or the similar Prognostic Index for T cell lymphomas (PIT) (table 2) [33,34].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging".)

SUMMARY

●Description - Hepatosplenic T cell lymphoma (HSTL) is a neoplasm of mature T cells that infiltrate the sinusoids of the spleen, liver, and bone marrow. Initially called hepatosplenic gamma/delta T cell lymphoma, the preferred nomenclature was changed to hepatosplenic T cell lymphoma when cases were identified with the clinicopathologic features of HSTL that expressed the alpha/beta T cell receptor.

●Epidemiology - HSTL is a rare neoplasm accounting for <1 percent of non-Hodgkin lymphomas. It most commonly presents in young men with a median age at diagnosis of 35 years. Ten to 20 percent of patients have a history of chronic immune suppression related to treatment for solid organ transplantation, lymphoma, or inflammatory bowel disease. (See 'Epidemiology' above.)

●Clinical presentation - Most patients with HSTL present with marked hepatosplenomegaly and thrombocytopenia without lymphadenopathy. Other common findings include systemic B symptoms (fever, night sweats, or weight loss), anemia, neutropenia, and abnormal liver function tests. (See 'Clinical features' above.)

●Diagnosis - The diagnosis of HSTL is based on evaluation of a biopsy specimen of the liver, bone marrow, or spleen (table 1). These biopsies demonstrate the accumulation of malignant cells within the sinusoids of the liver and bone marrow and within the red pulp of the spleen (picture 4). The infiltrating atypical lymphocytes express CD2, surface CD3, CD7, and CD16, but do not express CD4, CD5, CD8 or B cell surface markers (eg, CD20) (picture 7). In addition, the atypical lymphocytes usually express gamma/delta T cell receptors or alpha/beta T cell receptors. (See 'Pathology' above.)

●Differential diagnosis - The differential diagnosis of HSTL includes other types of T cell lymphomas and B cell disorders that present with splenomegaly. (See 'Differential diagnosis' above.)