A 49-Year-Old White Man With a Nodular Mass in the Liver.

A 49-year-old white man presented with a complaint of increased shortness of breath, which was progressive over 2 weeks. He also said he had a history of night sweats and chills, but no significant weight loss. His past medical history was significant for smoking 1 pack per day for 25 years and 30 years of occupational exposure to toxins, including asphalt and polyvinyl chloride.

Abdominal computed tomography showed a single low-density lesion, measuring 4 x 3 cm, in the right lower part of the liver (Figure 1 [view is looking toward the head, from below, taken at the level of the fourth lumbar vertebra]). On a chest computed tomographic scan, no mass lesion, infiltrate, consolidation, or pleural effusion was seen. No evidence of lymphadenopathy, organomegaly, or other pathology was found during the physical examination.

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Laboratory findings included elevated levels of alkaline phosphatase and lactate dehydrogenase. Serum carcinoembryonic antigen and [Alpha]-fetoprotein levels were within normal ranges. Representative cytopathologic features of fine-needle aspiration of the liver are shown in Figure 2. The patient also underwent an ultrasound-guided liver biopsy (Figure 3). Immunohistochemical study was positive for CD19, CD20, CD45, DR, FMC7, and [Kappa] light chain. Electron microscopy revealed cells with prominent nucleoli and abundant cytoplasmic polyribosomes (Figure 4).

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What is your diagnosis?

Pathologic Diagnosis: Primary B-Cell Non-Hodgkin Lymphoma of the Liver

Primary non-Hodgkin lymphoma of the liver is an extremely rare disease worldwide, accounting for 0.4% of all extranodal lymphomas.[1] Of the cases described in the literature, 74% are from western countries.

Both the etiology and the pathogenesis of primary hepatic lymphoma are not yet well understood, but multiple factors are believed to be involved (ie, genetic, infectious, and environmental). Primary hepatic lymphomas have been described against a background of impaired immune surveillance, such as acquired immunodeficiency syndrome (AIDS).[2] Simultaneous activation of other viral infections, most notably hepatitis C virus, Epstein-Barr virus, and cytomegalovirus, also may lead to B-cell activation and polyclonal proliferation in association with defective T-cell control.[3,4] Persistent hepatitis B virus infection played a role in the induction of both hepatocarcinogenic and hematopoietic tumor growth in organs with reticuloendothelial system. Hepatic lymphomas may be associated with autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, or autoimmune hemolytic anemia.[5] The evolution from a benign lymphoproliferative disorder, such as mixed cryoglobulinemia, to a B-cell lymphoma has been reported.[3] Exposure to chemicals and chemical fumes, as well as petroleum, chromium, and propane, was noted in 4 of 6 cases reported by DeMent et al in 1987.[6]

A growing number of cases of primary non-Hodgkin lymphoma of the liver have been reported in the literature recently. Most cases have been reported in adults, with only a few cases described in children.[7] Primary hepatic lymphoma occurs within a wide age range (5-87 years), but most commonly affects middle-aged individuals. The ratio of affected males to females varies among studies, ranging from 3 to 7.2.[5,8] Abdominal pain or discomfort, weight loss, and fever are the most frequent presenting symptoms. Ten percent of the patients were diagnosed incidentally without preceding symptoms,[9] as with our patient.

Primary lymphoma of the liver has been most commonly reported as a solitary mass, although multiple masses and diffuse lesions also have been described, frequently mimicking a hepatocellular carcinoma. Multifocality ranges from 30% to 35% and is more frequent in AIDS patients and in patients with an underlying liver disease. These lymphomas are characterized by a predominantly periportal infiltration of large lymphoid cells of the B-cell phenotype,[8] although they may rarely express a T-cell phenotype.[5] Diffuse large cell lymphoma is the most common subtype of non-Hodgkin lymphoma (46%). Other unfavorable histologic subtypes include diffuse mixed small and large cell (3%), lymphoblastic (3%), diffuse immunoblastic (2%), diffuse small noncleaved (1%), and diffuse histiocytic non-Hodgkin lymphomas (5%).[9] The immunoblastic subtype may have a slightly worse prognosis than the other subtypes of large cell lymphoma. Recently, another distinct primary lymphoma of the liver has been recognized as primary low-grade hepatic B-cell lymphoma of mucosa-associated lymphoid tissue. Interestingly, there has been an association of the t(3;14)(q27;q32) chromosome translocation involving the BCL6 gene, located at 3q27, introducing a potential predictive value.[10]

Liver enzymes usually demonstrate variably deranged liver functions, with elevation of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase. In contrast, serum carcinoembryonic antigen and [Alpha]-fetoprotein levels are invariably normal.

Grossly, the tumor in our case appeared as a firm mass that was tan-white on cut section with areas of necrosis inside; calcification was rare. Microscopically, the tumor was composed of diffuse sheets of large malignant cells with pleomorphic, sometimes vesicular nuclei containing prominent nucleoli and scant eosinophilic cytoplasm forming no apparent organoid pattern.

Due to the rarity of primary hepatic lymphoma, the working diagnosis before liver biopsy is invariably one of metastatic carcinoma versus hepatocellular carcinoma or cholangiocarcinoma. Preoperative diagnosis of primary lymphoma of the liver is difficult. Symptoms and the findings of diagnostic imaging are not specific for primary hepatic lymphoma and cannot be distinguished from those of a primary liver cancer or other metastatic tumor. A confident diagnosis can be established only after histologic examination of the liver tissue obtained by a fine-needle aspiration or surgical biopsy. Microscopic section would show classic dissociated large lymphoid cells with pleomorphic, somewhat vesicular nuclei containing prominent nucleoli and a small amount of basophilic cytoplasm. As with any poorly differentiated tumor, special studies, including electron microscopy, immunohistochemical analysis, and lymphocyte surface markers, are especially useful not only to differentiate lymphoma from other malignant tumors, but also to identify the immunophenotype of the lymphoma.

The prognosis of the primary hepatic lymphoma is usually poor, particularly in those patients presenting with liver failure. Despite their usual high grade of malignancy, these lymphomas have a relatively good prognosis in localized disease after early treatment. Therapy includes surgical resection and radiotherapy, chemotherapy, or both.

References

[1.] Freeman C, Berg JW, Culter SJ. Occurrence and prognosis of extranodal lymphomas. Cancer. 1972;29:252-260.

[2.] Scerpella EG, Villareal AA, Casanova PF, et al. Primary lymphoma of the liver in AIDS: report of one new case and review of the literature. J Clin Gastroenterol. 1996;22:51-53.

[3.] Pozzato G, Mazzaro C, Crovatto M, et al. Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia. Blood. 1994;84:3047-3053.

[4.] Mitterer M, Pescosta N, McQuain C, et al. Epstein-Barr virus related hemophagocytic syndrome in a T-cell rich B-cell lymphoma. Ann Oncol. 1999;10: 231-234.

[5.] Pouderoux P, Gris JC, Pignodel C, et al. Primary sinusoidal lymphoma of the liver revealed by autoimmune hemolytic anemia. Gastroenterol Clin Biol. 1997;21:514-518.

[6.] DeMent SH, Mann RB, Staal SP, et al. Primary lymphomas of the liver: report of six cases and review of the literature. Am J Clin Pathol. 1987;88:255-263.

[7.] Miller ST, Wollner N, Meyers PA, et al. Primary hepatic or hepatosplenic non-Hodgkin's lymphoma in children. Cancer. 1983;52:2285-2288.

[8.] Pescovitz MD, Snover DC, Orchard P, et al. Primary hepatic lymphoma in an adolescent treated with hepatic lobectomy and chemotherapy. Cancer. 1990; 65:2222-2226.

[9.] Lei KI. Primary non-Hodgkin's lymphoma of the liver. Leuk Lymphoma. 1998;29:293-299.

[10.] Maes M, Depardieu C, Dargent JL, et al. Primary low-grade B-cell lymphoma of MALT-type occurring in the liver: a study of two cases. J Hepatol. 1997; 27:922-927.

Accepted for publication August 8, 2000.

From the Department of Pathology, Medical College of Ohio, School of Medicine, Toledo, Ohio.

Reprints not available from the author.