Non-Hodgkin lymphoma is a common lympho-proliferative disease. Liver involvement occurs in 10% of the patients and it means advanced disease (stage 4).
The first report of primary hepatic lymphoma was by Ata and Kamal in 1965 (4
). Primary hepatic lymphomas (PHL) are rare, with fewer than 100 cases reported in the world literature. PHL defines an extra-nodal lymphoma of the liver without involvement of any other organ. PHL is rare, representing <1% of all extra nodal lymphomas (5
). Most cases of PHL tend to be of B-cell origin with only a minority of them of T-cell origin (6
). The occurrence of primary hepatic anaplastic large cell lymphoma is extremely rare. In our review of the literature, we identified only eight other cases of primary hepatic ALCL (12
Clinical features of primary hepatic ALCL
The ALCL are a clinically heterogeneous group of T, B and indeterminate cell malignant lymphomas. In the general population, ALCL has T-cell phenotype in 50-70% of cases, and the remainders are mostly null (non- T, non-B) phenotype. Rare cases of ALCL with B-cell phenotype are currently separated from T-cell or null-cell ACLC.
ALCL is a subgroup of diffuse large-cell lymphoma with characteristic morphology and strong expression of CD-30 (Ki-1) antigen. The Ki-1 antibody is a monoclonal antibody against the Hodgkin cell line L428, and at first it was regarded as an antibody specific for Hodgkin and Reed-Sternberg cells of Hodgkin disease. However, the Ki-1 antigen was also discovered later in patients with diffuse large cell-type non-Hodgkin lymphoma. The most frequently involved extranodal sites are skin, bone, soft tissue, GI tract and lung (6
Most patients with PHL are middle-aged. Patients usually present with abdominal pain and constitutional symptoms. Hepatomegaly is found in the majority of patients (75-100%) and B symptoms (fever, drenching sweats and weight loss) appear in 37-86% of them (7
). Less common presentations include ascites, hepatic failure, thrombocytopenia and hypercalcaemia.
PHL may present as a solitary liver mass (42%) or as multiple lesions (50%); diffuse infiltration of the liver is rare in Caucasians and more common in Chinese patients, but the pattern of the liver infiltration has no prognostic value (8
The pathogenesis of PHL has not been established. An increasing number of cases are now being diagnosed in immuno-compromised patients, particularly patients with Human Immunodeficiency Virus. There is an association with hepatitis C (Hepatitis C infection is found in 60% of patients), which suggests that this virus may play a role in the pathogenesis of PHL, Epstein-Barr virus infection, immuno-suppression, organ transplantation, primary biliary cirrhosis and systemic lupus erythematosus.
Our patient neither virus infection nor signs of chronic liver disease were found.
Diagnosis of PHL requires the absence of lympho-proliferative disease outside the liver.
Liver biopsy of PHL may mimic poorly differentiated carcinoma, and in these cases, a high index of suspicion is needed. In our patient, liver biopsy did not confirm the diagnosis, and only the study of the surgical specimen gave the diagnosis of PHL.
Immuno-histochemical studies are required in order to distinguish between these tumours and poorly differentiated carcinomas. Sometimes further tests including cytogenetic studies, flow cytometry and gene rearrangement are necessary. However, detection of lymphomas by cytometry analysis is dependent of adequate sampling of the tissue, specimen viability and the ability of tumor cells to survive processing, and false negative results are common in large cell lymphomas (25% of large cell lymphomas are not detected by cytometry analysis). The main advantage of cytometry over immunohistochemical analysis in the initial diagnosis is speed, and may be helpful when the material for immunohistochemical analysis is not available, such as in the case of fine-needle aspiration (9
ALCL is a T-cell lymphoma immunophenotypically characterized by positive CD30 staining in a membranous and Golgi zone pattern. Approximately 60-85% ALCL cases are positive for ALK protein. The translocation [2;5] between the ALK gene on chromosome 5 is the most common cytogenetic abnormality that leads to upregulation of ALK protein. The majority of ALC cases will show one or more T-cell-associated antigens. However, there are cases of ALCL that are negative for all T-cell markers and they are known as null-cell type.
The optimal treatment is not yet defined due to the low incidence of this disease. Surgery, radiotherapy and chemotherapy were all reported as treatment modalities alone or in combination (11
). Only 17 patients, including our case, have been surgically treated. The importance of surgical resection for a cure or for a reduction of tumor burden cannot be assessed by this limited series. Whether or not systemic treatment with chemotherapy will give comparable results to surgery in resectable cases is also not currently known. Pescovitz et al
) noted that the disease-free survival rate for 5 patients treated with resection and combined chemotherapy was 80%, compared with 54% survival for chemotherapy alone. But Page et al
) reported complete remission in 83.3% of 24 cases evaluated with combination chemotherapy. Five year cause specific and failure free survival rates were 87.1% and 70.1% respectively. Outcomes are poorer in patients with AIDS, and in those with coexisting liver disease.
Currently, the most common treatment of PHL involves combination chemotherapy CHOP. Rituximab, an anti CD 20 monoclonal antibody, is added to this chemotherapy regimen if the histology confirms that the lymphoma is CD 20 antigen positive.
Massive liver infiltration, high index of proliferation, advanced age, elevated LDH levels, cirrhosis and increased levels of β2-microglobulin are the worst prognosis factors (12
This is, to our knowledge, the first reported case of primary hepatic anaplastic large cell Ki-1 non-hodgkin lymphoma in a setting of adult celiac disease. The only link between both diseases is a markedly increased incidence of gastrointestinal T-cell lymphoma in celiac disease.
In conclusion, PHL is a rare disease, but it should be considered in any patient at any age who presents liver mass or infiltration, and, although hepatoma or metastatic diseases are more common, the absence of elevated levels of CEA and AFP should indicate a search for PHL.
Our patient had none of the classic predisposing factors for hepatic lymphocytic proliferation, such as chronic viral hepatitis, HIV, EBV or autoimmune hepatic disease.
However, other mechanisms for the development of NHL in celiac disease may be implicated. It is also possible that this may be an entirely fortuitous association.