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© 2002 American Society for Clinical Oncology
Unusual Presentations of LymphomaCase 2. Non-Hodgkin's Lymphoma Presenting as Liver DiseaseMater Misericordiae Hospital, Eccles Street, Dublin 7, Ireland Patient A: Obstructive jaundice secondary to a large liver mass. A 33-year-old man presented with a 3-month history of right upper-quadrant pain, malaise, and weight loss. Over the previous week he had become increasingly jaundiced and reported dark urine and pale stools. He had no relevant past medical history. Physical examination revealed jaundice and significant hepatomegaly, with an irregular liver palpable 5 cm below the right costal margin. There was no evidence of peripheral adenopathy or stigmata of chronic liver disease. His complete blood cell count and electrolyte levels were normal. His hepatic transaminase levels were mildly elevated at less than twice normal values. Total bilirubin was 7.5 mg/dL (normal, < 1.5 mg/dL), alkaline phosphatase was 851 U/L (normal, < 300 U/L), and lactate dehydrogenase was 2,936 U/L (normal, 230 to 460 U/L). Viral screen was negative and alpha-fetoprotein levels were normal. Contrast-enhanced computed tomography (CT) followed by T1-weighted magnetic resonance imaging (Fig 1) revealed a large, low-signal mass occupying the right lobe of the liver and causing obstruction of the common bile duct. Percutaneous needle biopsy showed a diffuse, large-cell B-cell lymphoma. Further staging, including bone marrow biopsy, failed to reveal evidence of disease elsewhere. In view of the size of the lesion, surgery was not considered and the patient was treated with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, with doxorubicin initially omitted because of the elevated bilirubin level. After two courses of treatment, the total bilirubin had normalized and treatment was intensified. The disease subsequently accelerated, however, leading to death 7 months after diagnosis.
Patient B: Fulminant hepatic lymphoma mimicking metastatic liver disease in a patient with hepatitis C. A 52-year-old man presented with a 1-month history of abdominal pain and vomiting. He had no past medical history of note apart from heavy alcohol use. No previous blood transfusions and no history of intravenous drug use were reported. On examination, he was unwell, with a Karnofsky performance status score of 30. He bore no stigmata of chronic liver disease. He had 3-cm irregular hepatomegaly with no evidence of splenomegaly. His hepatic transaminase levels were significantly elevated, with AST of 169 U/L and ALT of 148 U/L (normal, < 35 U/L for both). Bilirubin was 1.8 mg/dL (normal, < 1.5 mg/dL) and lactate dehydrogenase was 2,711 U/L (normal, < 460 U/L). His alpha-fetoprotein level was normal. He had hypercalcemia at 13.8 mg/dL (normal, < 10.6 mg/dL). Platelets were reduced at 70 x 109/L, circulating lymphocytes were elevated at 6.4 x 109/L (normal, 1.3 to 3.5 x 109/L), and his hemoglobin was 14 g. Anti–hepatitis C virus (HCV) antibodies were detected by immunoblot assay. Human immunodeficiency virus serology was negative. Ultrasound (Fig 2) demonstrated multiple hypoechoic liver lesions, and CT confirmed hepatomegaly and low attenuation lesions in both lobes of the liver consistent with metastatic malignancy. CT staging revealed no evidence of disease elsewhere. Percutaneous liver biopsy demonstrated infiltration with a high-grade tumor (Fig 3A) of lymphoid origin (CD45+, Fig 3B). Bone marrow biopsy demonstrated similar infiltration, confirming a diagnosis of diffuse large B-cell lymphoma with marrow involvement and hypercalcemia. The patient was treated with cyclophosphamide, doxorubicin, vincristine, and prednisone. On the 14th hospital day, he became acutely short of breath and pyrexial and developed evidence of cardiac and renal impairment. Despite transfer to intensive care, he had a rapidly deteriorating clinical course. The patient died 48 hours after chemotherapy was administered on the 17th hospital day.
Liver involvement in disseminated non-Hodgkin’s lymphoma (NHL) is not uncommon,1 but it is rarely the presenting organ. Less than 1% of extra nodal lymphomas are thought to arise in the liver,2 and fewer than 100 cases have been reported.3 While the classical description of primary hepatic lymphoma refers to a high-grade large-cell lymphoma of B-cell origin characterized by a single large liver mass,4 presentation as multiple nodules or as a low-grade diffuse process involving the entire liver5 has also been described. In a review of published cases of aggressive primary hepatic lymphoma, presentation as single lesions and multiple masses was noted to occur with approximately equal frequency.3 Most cases develop in middle-aged men, who often present with abdominal pain, weight loss, and fever. Pre-existing liver disease may be present in a minority of cases. It seems to be an aggressive disease with several poor prognostic characteristics, including bulky tumor volume and unfavorable histology, resulting in a median survival of only 6 months in patients treated with chemotherapy. Given this heterogenosity, it is not surprising that there are few clinical, laboratory, or radiologic features specific to this disease. Although regional lymph nodes are occasionally involved, the absence of peripheral lymph nodes and the lack of clues allowing distinction from other primary or metastatic tumors results in frequent misdiagnosis.4,6 Because the normal approach to patients with solid tumors affecting the liver is either surgical or palliative in nature, it is essential that patients with chemosensitive diseases are identified. In this context, needle biopsy may provide insufficient material for diagnostic purposes, leading to a requirement for laparotomy and wedge resection.3 Chronic hepatitis C infection has been associated with both hepatocellular carcinoma7 and B-cell malignancy.8 Essential mixed cryoglobulinemia type II, an indolent clonal B-cell lymphoproliferative disorder, is largely limited to carriers of the HCV and is associated with a low-grade NHL of the bone marrow.9 Moreover, HCV has been localized from both these types of B-cell lymphoproliferative lesions.10 Given that lymphoid stimulation by exogenous antigens has been related to NHL development in other extranodal sites, a role of HCV as an exogenous trigger of B-cell proliferation has therefore been suggested. High-grade NHL, frequently of large-cell type, is also overrepresented in these patients. These typically occur in patients without a preceding history of cryoglobulinemia or low-grade NHL and are more likely to be extranodal in origin, with the liver or spleen often involved.8,11,12 In one case-control study, patients with hepatitis C were estimated to have a 50-fold increase in risk of lymphoma involving the liver.13 Interestingly, HCV has not been isolated from the tumors of these high-grade patients. The current case is similar to one reported by Gil et al14 involving a hepatitis C carrier with a fulminant lymphoma primarily affecting the hepatosplenic area but with concomitant bone lesions and hypercalcemia. REFERENCES 1. Chabner BA, Johnson RE, Young RC, et al: Sequential nonsurgical and surgical staging of non-Hodgkin’s lymphoma. Ann Intern Med 85: 149-154, 1976 2. Freeman C, Berg JW, Cutler SJ: Occurrence and prognosis of extranodal lymphoma. Cancer 29: 252-260, 1971 3. Ieng-Kit Lei K: Primary non-Hodgkin’s lymphoma of the liver. Leuk Lymphoma 29: 293-299, 1998[Medline] 4. Osborne BM, Butler JJ, Guarda LA: Primary lymphoma of the liver: Ten cases and a review of the literature. Cancer 56: 2902-2910, 1985[CrossRef][Medline] 5. Harris AC, Ben-Ezra JM, Contos MJ, et al: Malignant lymphoma can present as hepatobiliary disease. Cancer 78: 2011-2019, 1996[CrossRef][Medline] 6. Rodriguez J, Rawls D, Speights VO: Primary lymphoma of the liver mimicking metastatic liver disease. South Med J 88: 677-680, 1995[Medline] 7. Simonetti RG, Camma C, Fiorella F, et al: Hepatitis C virus infection as a risk factor for hepatocellular carcinoma in patients with cirrhosis: A case-control study. Ann Intern Med 116: 97-102, 1992
8.
De Vita S, Sacco C, Sansonno D, et al: Characterization of overt B-cell lymphomas in patients with hepatitis c virus infection. Blood 90: 776-782, 1997
9.
Pozzato G, Mazzaro C, Crovatto et al: Low-grade malignant lymphoma, hepatitis C virus infection and mixed cryoglobulinemia. Blood 84: 3047-3053, 1994
10.
Sansomo S, De Vita S, Cornacchiulo V, et al: Detection and distribution of hepatitis C virus related proteins in lymph nodes of patients with type II mixed cryoglobulinaemia and neoplastic and non-neoplastic lymphoproliferation. Blood 88: 4638-4645, 1996 11. Hussell T, Isaacson PG, Crabtree JE, et al: The response of cells from low grade B-cell gastric lymphomas of mucosal associated lymphoid tissue to Helicobacter pylori. Lancet 342: 571-574, 1993[CrossRef][Medline] 12. Satoh T, Yamada T, Nakano S, et al: The relationship between primary splenic malignant lymphoma and chronic liver disease associated with hepatitis C virus infection. Cancer 80: 1981-1988, 1997[CrossRef][Medline] 13. De Vita S, Zagonel V, Russo A, et al: Hepatitis C virus, non-Hodgkin’s lymphoma and hepatocellular carcinoma. Br J Cancer 77: 2032-2035, 1998[Medline] 14. Gil J, Rodriguez C, del Toro J, et al: Fulminant hepatosplenic B cell lymphoma in a young patient with HCV-chronic hepatitis. Leukemia 12: 1005-1006, 1998[Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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