Introduction Hepatosplenic T cell lymphoma HSTCL

Introduction Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of peripheral T-cell lymphoma, which is derived from cytotoxic T-cells typically expressing γδ T-cell receptor (TCR). It usually occurs in young men and is characterized by B symptoms such as a fever, weight loss and night sweats, hepatosplenomegaly, thrombocytopenia, and anemia. The patient\'s prognosis is typically poor [1]. Approximately 20% of all HSTCL cases are associated with immunodeficiency which include chronic immunosuppressive therapies after solid-organ transplantation and collagen diseases such as SLE, HIV, malaria infection, AML, Hodgkin\'s lymphoma, and inflammatory bowel diseases [2], suggesting that the immunodeficient status may contribute to the development of HSTCL. Histologically, the lymphoma sirtuin activators have medium-sized nuclei and a rim of pale cytoplasm, and homogeneous medium-sized CD3-positive lymphoma cells infiltrate the cords and sinuses in the red pulp of the spleen, sinusoids of the liver and the bone marrow [1]. Immunohistochemistry analyses generally show CD3(+), CD4(−), CD5(−), CD8(−/+), CD56(+/−), TCRδ1(+), TIA-1(+), and granzyme B(−). HSTCL accounts for only 3% of all T-cell lymphomas in the United States and 2.3% in Europe. Notably, it occurs less frequently in Eastern and South-eastern Asian countries (0.2%) [3]. Because HSTCL is especially rare in Asia, its actual characteristics in Asia have not been well-documented [4]. We experienced 4 cases of HSTCL out of 292 cases (1.3%) of T cell lymphoma according to the clinical and pathological records between 1998 and 2014 in our institution. Surprisingly, 3 out of the 4 cases were middle-aged to elderly patients (cases 1–3), and only one case was an adolescent male [5].
Case presentation The clinical and laboratory features of these 4 cases are summarized in Table 1 (cases 1–4). None of the patients had previous illness that was related to immunodeficiency, immunosuppression or an abnormal immunological status. All of the patients had B symptoms, hepatosplenomegaly and cytopenias at diagnosis, resulting in a high or high-intermediate International Prognostic Index (IPI). Case 1 was a 74-year-old female. A liver biopsy demonstrated the infiltration of small to medium-sized lymphoma cells in the sinusoids and portal area, and these cells were CD3(+), CD4(−), CD5(−), CD8(−), CD56(+), TIA-1(+), granzyme B(−) and Epstein–Barr virus-encoded RNA (EBER) in situ hybridization(−) (Fig. 1). The patient had a CR by treatment with 6 cycles of CHOP, and has remained alive for more than 12 months after achieving a CR. Case 4 was a 23-year-old male. A bone marrow biopsy demonstrated hypercellular bone marrow with medium- to large-sized lymphoma cells that were CD3(+), CD4(−), CD5(−), CD8(−), CD56(−), TIA-1(+), granzyme B(−) and EBER(−), as previously reported [5]. He was treated with 1 cycle of CHOP followed by 3 cycles of IVAC (ifosfamide, etoposide and cytarabine), resulting in a PR. Allogeneic bone marrow transplantation from an unrelated donor preceded by a preparative regimen composed of etoposide, cyclophosphamide and total body irradiation provided a CR. He relapsed 3 months post-transplant and died 19 months after the diagnosis.
Discussion HSTCL predominantly occurs in young men, with a median age of 34 years. There have been few reports showing its frequency separated by age, but only 4 out of 90 cases (4.4%) undergoing stem cell transplantation have been reported as patients over 60 years of age [1]. In addition, HSTCL is believed to be related to immunodeficiency. In our institution, 3 out of the 4 HSTCL cases developed HSTCL after middle age, including an aged case at 74 years of age. All of these 4 cases had no previous illness. However, other disease phenotypes and their inferior prognoses were similar to the typical HSTCL cases. Six HSTCL over 65 years of age have been reported in detail to date. The clinical and histopathological characteristics of the patients are summarized in Table 2 (cases 5–10) [6–10]. These characteristics, as well as our aged cases (Case 1) (Table 1), were also compatible with the typical HSTCL cases. Notably, three of these 7 aged HSTCL cases including our Case 1 were from Japan. A possible mechanism of the initiation of HSTCL is a prolonged immunosuppressive status which generates the expansion of γδ T-cells recognizing multiple pathogens through excessive antigenic stimulation. Our cases did not have any previous illness related to immunosuppression, recurrent infectious episodes or laboratory evidence of HTLV-1 infection which has the potential of causing immunosuppression as well as a T-cell malignancy. The cause of their immunocompromised status was therefore unknown; an age-related decline in the immune function might be responsible for the lymphomagenesis of HSTCL in these cases. In addition, both of the two previous aged Japanese cases (cases 5 and 6) were positive for EBER (Table 2). In Eastern Asia, EBV infection and reactivation are thought to contribute to the tumorigenesis of T-cell or natural killer (NK)-cell posttransplant lymphoproliferative disorder (T-PTLD) and non-hepatosplenic/non-cutaneous γδ peripheral T-cell lymphomas [7]. Although EBER was undetectable in our cases, there might be a potential contribution of EBV infection and reactivation to the development of HSTCL in aged patients as well as other lymphoid malignancies [6,7].