Non-Hodgkin's lymphoma is a common malignant disease. Liver involvement occurs in 10% of patients and is a sign of advanced disease. PHL refers to an extra-nodal lymphoma of the liver without involvement of any other organ (e.g., lymph node, spleen, etc) [3
]. The vast majority (67%) of PHL patients are middle-aged men who usually present with abdominal pain, nausea and constitutional symptoms [4
]. PHL is notably rare, representing <1% of all extra-nodal lymphoma [4
]. One Chinese study reported that in 446 cases of non-Hodgkin's lymphoma, 45 developed liver involvement, of which only one had PHL [5
]. Limited experience showed that PHL had non-specific clinical manifestations. Hepatomegaly is found in most patients, constitutional symptoms (e.g., fever, night sweats and weight loss) appear in 37%, fever in 86%, weight loss in 57% and jaundice in 4% [3
]. In liver, PHL may present as a solitary mass (42%) or as multiple lesions (50%). Patients with PHL have abnormal liver function tests (cholestasis and cytolysis) [7
], mostly elevated LDH and alkaline phosphatase (ALP) [6
]. Additionally, hypercalcemia is found in 40% of the patients. The cause of PHL is not entirely clear, but may be related to viral hepatitis [10
]. Hepatitis C virus (HCV) infection is found in 20%-60% of patients with PHL. The frequent association with HCV suggests that this virus may play a role in the pathogenesis of PHL [7
]. PHL is also seen in immunocompromised patients, but the relationship between PHL occurrence and immune deficiency has not yet been reported. Our patient had neither hepatitis C infection nor signs of immunodeficiency. Therefore, we speculated that PHL also could occur in patients without any prior liver disease. Diagnosis of PHL requires a liver biopsy compatible with lymphoma and absence of lymphoproliferative disease outside the liver. Through analyzing 90 patients with hepatic lymphoma, Lei Ki [4
] proposed the following criteria for the diagnosis of primary hepatic lymphoma: 1) the symptoms are mainly caused by liver involvement at presentation; 2) no clear evidence of superficial lymph node enlargement and distant lymph node metastasis; 3) no abnormalities in peripheral blood cells in blood smears, including spleen, lymph node and bone marrow. Some other studies also reported that the dynamic change of serum LDH could be used as a diagnostic marker [12
]. However, the value of LDH for the diagnosis of PHL is limited because of its poor specificity. Therefore, a definite diagnosis of PHL is difficult to establish solely based on clinical signs and symptoms. The imaging presentation of PHL is variable and can be a solitary intrahepatic lesion, multiple nodules and diffuse infiltration of the liver. In the imaging reports of 12 patients with PHL provided by Elsayes KM, et al [13
], there were three cases of solitary nodules, one with diffuse damage, and eight with multiple nodular liver lesions. Multiple nodular lesions in liver accounted for the majority of these cases, while diffuse infiltration was rare. Imaging of our patient showed diffuse nodular lesions, and the presentation varied in ultrasound, CT or MRI. Therefore, there is no pathognomonic imaging pattern to confirm the diagnosis.
Hepatoma and metastasis from gastro-intestinal (mostly colon) carcinoma present very similarly and are much more common. Normal levels of the tumor markers, AFP and CEA are found in almost 100% of patients with PHL facilitating the differential diagnosis [3
]. The examination of the colon to exclude primary colon carcinoma may be indicated. Thus, a definite diagnosis of PHL should include histological and marker studies of the biopsy sample. Our patient presented with clinical and laboratory features which were suggestive for PHL; liver biopsy stained with specific immuno-histochemical stains and flowcytometric studies also confirmed the diagnosis of PHL. There is no consensus on the optimal treatment for PHL. Surgical treatment, radiotherapy and chemotherapy were all reported as treatment modalities alone or in combination. The prognosis of PHL is considered very poor with a median survival as low as six months for patients treated with chemotherapy alone. With the availability of rituximab (a monoclonal chimeric antibody directed against CD20 B cell antigen), chemotherapy protocols for the treatment of PHL have dramatically changed in the last decade. R-CHOP protocol increased the complete-response rate and prolonged the survival significantly. Unfortunately, our patient was died of complications of chemotherapy. Our report indicated that complications caused by chemotherapy still would be a major problem.
In conclusion, PHL is a rare disease, lacking specific imaging and clinical manifestations and biochemical indicators. Its diagnosis is difficult, needing to exclude organs or tissues lymphoma outside of the liver. When multiple space-occupying lesions are found in liver but there is no any other organ or tissue invasion, PHL should be suspected and liver biopsy should be done. If the diagnosis is made, chemotherapy should be started immediately, and adverse reactions and complications should be closely monitored.