Primary hepatic lymphoma (PHL) is a rare form of non-Hodgkin lymphoma (NHL) which primarily involves the liver, as opposed to a predominant lymph nodal or splenic involvement in other subtypes of NHL. The liver is the major reticuloendothelial organ, and hepatic involvement secondary to systemic NHL is common, such that 40% of patients with NHL posses liver involvement. The majority of the patients with PHL report vague symptoms such as nausea, vomiting, upper abdominal pain or discomfort, and approximately one-third report constitutional symptoms including fever, myalgias, and weight loss. However, due to the low incidence with characteristically vague symptoms at the outset, patients with PHL often undergo extensive investigations before reaching up to a definitive diagnosis. Diagnosis of PHL depends on a liver biopsy which should be compatible with the lymphoma and with the absence of extrahepatic lymphoproliferative involvement.
Primary hepatic lymphoma may often confound with other space-occupying liver lesions namely the hepatocellular carcinoma, hepatic adenoma, focal hyperplasia of the liver, and hepatic hemangioma. At times it is crucial for a hepatologist to address the rare possibility of PHL besides the common notably, the hepatocellular carcinoma while approaching the space-occupying lesions of the liver.
Certain viruses such as hepatotropic and non-hepatotropic viruses share links with the causation of the PHL. Of note, the common hepatotropic viruses linked with the causation of PHL are HCV and HBV infection. Some uncommon non-hepatotrophic viruses such as HIV, HEV, and CMV also have reports in the literature. Certain autoimmune diseases, namely systemic lupus erythematosus (SLE) may also have links with PHL.
In a large case series of over 69 patients with PHL, the prevalence of seropositive HBV infections was 20%; however, the majority of the patient population was from the western world. In contrast to this, one author reported only 4% of cases of PHL harboring HBV infection out of 90 individuals. The majority of the patient population was of Asian origin, which was then considered as an endemic region of HBV infection. Another study from China showed the presence of positive HBV surface antigen among 21/35 (60%) of Chinese patients. However, considering the high prevalence of HBsAg positivity of around 10% among the Chinese population suggests that the association of HBV with PHL may be coincidental rather directly involved in the causation of PHL. A common hepatotrophic virus such as HCV was positive among 6 of 28 (21%) of immune competent PHL patients. Most of these HCV infected patients have had a high-grade B-cell lymphoma.
Considering the rarity of primary hepatic lymphoma, its exact incidence remains undetermined. However, in literature, it is reported to be 0.4% of all cases of extranodal non-Hodgkin lymphoma and 0.016% of all cases of non-Hodgkin lymphoma. The mean age of occurrence of PHL is 50 years; males are more prone to develop PHL in comparison to females (1.7 to 1.0).
Despite a well established underlying pathophysiology in the pathogenesis of other forms of lymphoma; both non-Hodgkin and Hodgkin lymphoma, the pathophysiology underlying primary hepatic lymphoma is largely underdetermined. An exception to this is the association of primary hepatic lymphoma with some viruses, notably the hepatitis C virus (HCV) where the virus is thought to stimulate B cells which initially leads to polyclonal and then to monoclonal B cell expression. Hepatitis C virus has been proposed to cause translocation and hence overexpression of the anti-apoptotic factors, bcl2, and monoclonal IgH rearrangement. Additionally, HCV alters in the transcriptional regulation of genes like p21, p53, and H-ras by the viral core and/ or NS35 proteins. Similarly, hepatitis B virus infection is thought to produce B cell antigenic stimulation resulting in the monoclonal B cell proliferation.
Despite all non-invasive methods to detect liver lymphoma, the histopathological examination is required to confirm the diagnosis. Histopathologically, primary hepatic lymphoma can be of various types including non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL) or T cell lymphoma, and in some instances non-B non-T cell lymphoma. Diffuse large B-cell lymphoma is the most prevalent compared to other variants of non-Hodgkin lymphoma.
In one case series over 41 patients, 34 (83%) of patients had B cell lymphoma, predominantly of diffuse large B-cell lymphoma (27/34) (79.41%). However, there were also rare reports of other cell types, such as T-cell lymphoma, precursor T-cell lymphoblastic lymphoma, and Burkitt lymphoma. In a case series of 10 patients, eight patients had diffuse large B cell lymphoma, one had Burkitt lymphoma, and one had T cell type lymphoma. In yet another case series, MALToma has been reported to be the second most common variant of lymphoma after diffuse large B-cell lymphoma, affecting 8/20 (40%) of patients with primary hepatic lymphoma.
Histopathologic features of the commonly reported diffuse large B-cell lymphoma are the abundant mitotically active large and atypical cells in the wall of the mass with pale to clear cytoplasm and vague cell membranes associated with granular, eosinophilic necrotic debris. The nuclei are large with condensed or open chromatin with prominent nucleoli. On Immunohistochemical analysis, positive pan B markers such as CD 20, negative epithelial tumor markers namely the cytokeratin AE1/AE3, positive pan T cell markers CD3 and Tdt, and the absence of Hep Par 1 coincides with the diagnosis of diffuse large B-cell lymphoma.
The majority of patients with primary hepatic lymphoma present with vague symptoms such as nausea, vomiting, upper abdominal discomfort, and jaundice. Hepatomegaly may also be present and can range from moderate to severe resulting in patient abdominal discomfort. Similar to non-Hodgkin lymphoma, with few exceptions; notably the Burkitt lymphoma, the disease course is indolent among the majority of the patients with primary hepatic lymphoma. Many patients fail to realize that a subtle right-sided pain or lump is significant until the tumor size is sufficiently enlarged to disturb the liver capsule. Some rare presentations of primary hepatic lymphoma include acute liver failure and chronic hepatitis. Congestive splenomegaly can also occur in primary hepatic lymphoma due to hepatic dysfunction and portal hypertension.
Following a history and comprehensive physical examination to rule out features of systemic lymphoma including generalized superficial lymphadenopathy, evaluation is mostly dependent on excluding the common causes of space-occupying liver lesions; notably hepatocellular carcinoma, metastatic liver disease, hepatic adenoma, hemangioma, and hydatid cyst. A thorough workup is helpful including HBsAg, HCV antibodies, EBV IgM or PCR, and HIV serology. A range of other biochemical and tumor markers such as serum LDH, B-2 microglobulin, alpha-fetoprotein (AFP), serum carcinoembryonic antigen (CEA), CA 19-9, and CA-125 are required to prognosticate the tumor and to differentiate between the primary vs. metastatic liver disease.
Imaging studies, such as triphasic CT scan of the liver, are helpful to define characteristics of the liver lesion and can also help to determine the underlying co-existent liver cirrhosis and associated organ involvement. In contrast to hepatocellular carcinoma which shows arterial as well as portovenous and delayed phase enhancement, the lesion of lymphoma may only show arterial phase enhancement. The lesions are mostly hypodense with heterogeneous patterns, which is suggestive of tumor-related infarction and necrosis within the lesion.
Radiologically, primary hepatic lymphoma can present in three forms:
Since the primary hepatic lymphoma is rare, the majority of evidence regarding treatment and tumor response comes from case series. Furthermore, the response to different strategies, i.e., surgery vs. chemotherapy, is again drawn from discrete case series.
In one case series by Yang XW et al. demonstrated the prognosis of eight patients who have had surgical resection of the tumor. They reported that out of eight patients, one patient did not survive due to the postoperative complication and died on the eighth postoperative day. The cumulative six months, 1-year, and 2-year survival rates were 77.8%, 66.7%, and 55.6% respectively, with a median survival of 23 months. Only one patient remained alive and tumor-free after five years following tumor resection. Additionally, they also noted that postoperative chemotherapy was a significant prognostic factor for survival (P = 0.006).
In contrast to the above study, Page et al. determined that the combination chemotherapy helped achieve complete remission among 83.3% of patients and 5 years cause-specific and failure-free survival rates were 87.1% and 70.1% respectively. In addition to the above study, Peng Y et al. found 70% of their patients did respond to the combination chemotherapy.
Prognosis and treatment response further depends on the size of the tumor; notably, tumors of greater than 7 cm in size, serum lactate dehydrogenase levels over 10% of the upper limit of the normal, raised beta-2 microglobulin levels in excess of 3 mg/dl, and presence of constitutional symptoms.
Among patients with no high-risk factors, treatment with combination chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is usually effective in achieving remission. Among patients with the presence of at least one or more than one pre-treatment risk factors requires consideration of using altering triple combination. Alternate regimens consist of doxorubicin, methylprednisolone, cytosine arabinoside, and cisplatin, alternating with methotrexate, bleomycin, cyclophosphamide, doxorubicin, vincristine, and methylprednisolone.
The common differentials of primary hepatic lymphoma are the other space-occupying lesions of the liver; notably the:
However, in the majority of the cases imaging followed by a targeted biopsy of the lesion helps to confirm the diagnosis.
Primary hepatic lymphoma is sensitive to combination chemotherapy with complete remission can be achieved among more than 80% of the patients. The 5-yeas cause-specific survival approaches 87.1%. Prognosis after surgical resection is highly variable, and the significant risk of postoperative bleeding due to the vascular nature of the tumor further increase the morbidity and mortality rates after surgical intervention.
Some patients with primary hepatic lymphoma can develop acute liver failure which itself carries a significant risk of mortality. Tumor bleeding and hematological spread to other locoregional lymph nodes have also been documented.
Patients with chronic viral hepatitis, deranged liver function tests, the presence of indolent non-resolving upper abdominal symptoms, and space-occupying liver lesions should seek consultation for further evaluations by a hepatologist. A CT scan in the majority of cases is diagnostic; however, a biopsy is often necessary for an absolute diagnosis in suspicious cases. A hematologist is always required to guide and institute further therapy, notably the combination of chemotherapy. Most patients with primary hepatic lymphoma are responsive to combination chemotherapy, and the 5-year survival exceeds more than 80%.
Primary hepatic lymphoma is an uncommon problem, which requires a high level of suspicion for diagnosis since the presentation of PHL, commonly resembles other space-occupying liver lesions; notably hepatocellular carcinoma, which is less chemoresponsive and requires an entirely different approach to treatment. Furthermore, around 10% of patients with primary hepatic lymphoma have features of the pre-existing liver disease, that could further add in the risk of developing hepatocellular carcinoma in post cirrhotic liver among such patients. A hepatologist, interventional radiologist, hematologist, primary care provider, nurse practitioner and finally the patients are the key components of a multidisciplinary team, including physicians, nurses, mid-level practitioners, and pharmacists working together to diagnose and formulate therapy to improve rates of remission, disease-free survival, and cure.
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