IVLBCL has been described in an increasing number of reports, mostly single case report and small series. It primarily affects elderly individuals with a slight predominance in men, and can progressively involve any organ without involvement of lymphoid tissues and peripheral blood [5, 6]. Patients with IVLBCL usually present with a wide range of clinical manifestations that are generalized and nonspecific, or localized and related to the involved organ [4]. Most of the symptoms and signs might be related to organ dysfunction caused by occlusion of small vessels or capillaries. Due to the absence of significant mass lesions or lymphadenopathy, the clinical picture is further complicated and a timely diagnosis is very challenging.
Previously, one-half of IVLBCL cases were made by post-mortem [2]. With the improvement of awareness of this entity, most patients were diagnosed by bone marrow biopsy and skin biopsy from positive skin lesions or random skin biopsy [4, 7]. In our case, bone marrow biopsy revealed no evidence of lymphoma infiltration, and random skin biopsy was not performed because of a low index of suspicion of IVLBCL. Therefore, a biopsy from an affected organ is necessary. Significantly, PET-CT is a powerful tool for the early diagnosis of IVLBCL by identifying indicated sites for biopsy because these patients usually show high FDG uptake in involved organs [8, 9]. With the review of literature, liver biopsies can be performed using percutaneous, transjugular, or laparoscopic approaches, and each method has advantages and disadvantages [10]. Because of the absence of severe coagulopathy, ultrasonography-guided percutaneous liver biopsy was performed in our patient. Up to present, only 12 cases of IVLBCL diagnosed by liver biopsies have been described in the literature [10-21]. The clinical and immunohistochemical features of the reported cases and our case are summarized in Table 2 [See Additional File 1].
The patients with hepatic involvement of IVLBCL were predominantly men (11/13, 84.6%). The age of the patients ranged from 42 to 79 years, with a mean age of 61 years. With the exception of 2 cases from the West [14, 18], the remaining 11 cases were reported from Asia. Due to the limited number of reported cases, whether IVLBCL of liver is more prevalent among Asian populations is unclear. Lymphoma infiltration of bone marrow was detected in 4/13 patients (30.8%). The common clinical presentations were fever (7/12, 58.3%), anemia (7/12, 58.3%), thrombocytopenia (6/12, 50.0%), hepatomegaly and/or splenomegaly (8/12, 66.7%), and high levels of serum LDH (9/12, 75.0%). The ferritin and liver enzymes levels were elevated in 6 of 12 cases tested (50.0%). The clinical manifestations were variable and nonspecific, but indicative for suspected IVLBCL of the liver. The definitive diagnosis was mainly based on its typical morphologic and immunohistochemical features.
The histopathological findings presented in our case were consistent with those described in previous reports. IVLBCL of the liver was characterized by the infiltration of large atypical lymphocytes cells in the hepatic sinusoids. The neoplastic cells are typically positive for B-cell markers as CD20 and PAX-5, and a subset of cases may co-express the T-cell marker CD5 [22]. According to the algorithm of Hans et al. [23], our case was classified as the non-germinal center B-cell-like subtype (positive for BCL-6 and MUM-1, negative for CD10). Notably, EBER-positive nuclear signals were detected by in situ hybridization in our case. Although EBV-positive diffuse large B-cell lymphoma was listed as a distinct subtype of DLBCL in the revised World Health Organization (WHO) classification [1], no study focusing on EBV expression in IVLBCL has been reported. In addition, data for EBV-expression was not available in 11/12 previously reported cases, and only a case showed EBV-negativity detected by in situ hybridization [12]. The EBV-positivity rate might be higher than actual, as negative cases were less likely to be reported. It has been well established that latent EBV infection is causative of B-cell lymphoma [24]. Our case implied that EBV infection might be an important risk factor for poor prognosis of IVLBCL, like as the DLBCL. In the previously reported cases of hepatic IVLBCL, molecular characteristics of the tumor cells were not mentioned and need further investigation.
IVLBCL usually shows an aggressive clinical course with a poor prognosis. Specifically, a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone with the recombinant anti-CD20 antibody rituximab (R-CHOP) is the most commonly used regimen to improve the outcome of IVLBCL [25]. Unfortunately, our patient died before treatment could be administered because of rapid disease progression.