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Journal of Clinical Oncology, Vol 25, No 27 (September 20), 2007: pp. 4312-4314 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.8876
Lymphoplasmacytic Lymphoma Arising in the Setting of Hepatitis C and Mixed CryoglobulinemiaDepartment of Pathology, Stanford University, Palo Alto, CA A 50-year-old man with a 5-year history of untreated hepatitis C virus (HCV) infection, progressive hepatosplenomegaly, and worsening pancytopenia was referred to our oncology clinic with a newly enlarging 3.0-cm left parotid nodule. On presentation, the patient appeared fatigued but otherwise well, with a temperature of 36.3°C, blood pressure of 121/71 mmHg, and heart rate of 86 bpm. CBC showed: WBC 3.1 K/µL, hemoglobin 8.5 g/dL, hematocrit 25.6%, mean corpuscular volume 78.5 fl, and mean corpuscular hemoglobin 26.0 pg. Serum lactate dehydrogenase was 216 U/L, while serum uric acid was 5.4 mg/dL. Iron studies showed: total iron 41 µg/dL, transferrin 500 mg/dL, and transferrin saturation 6%. The metabolic panel showed: sodium 137 mmol/L, potassium 4.1 mmol/L, chloride 111 mmol/L, glucose 104 mg/dL, serum creatinine 0.85 mg/dL, calcium 8.2 mg/dL, total protein 8.2 g/dL, albumin 2.2 g/dL, globulin 7.0 g/dL, total bilirubin 1.0 mg/dL, alkaline phosphatase 89 U/L, AST 43 U/L, and ALT 28 U/L. Coagulation testing revealed a prothrombin time of 20.2 seconds and an international normalized ratio of 1.7 units. Serum immunoglobulins (Igs) were: IgG 2,350 mg/dL, IgA 908 mg/dL, and IgM 4920 mg/dL. Serologic tests for hepatitis confirmed the presence of antibodies to hepatitis C and hepatitis A antigens, but not to hepatitis B surface antigen. Quantification of hepatitis C viral load by polymerase chain reaction showed no detectable HCV. A fine needle aspirate of the parotid nodule generated abundantly cellular aspirate smears comprised of small- to medium-sized lymphocytes, some with plasmacytoid features (Fig 1A; 40x Wright-Giemsa stain).
A bone marrow biopsy and aspirate showed a lymphoplasmacytic infiltrate composed of lymphocytes with basophilic cytoplasm and frank plasma cells (Fig 1B; 40x hematoxylin and eosin stain). Immunohistochemical studies showed CD20 positivity in the lymphocyte population and CD138 positivity in the plasma cell population. Flow cytometry was performed on both the marrow and parotid nodule aspirate material, and demonstrated a monoclonal B-cell lymphocyte population expressing CD19, CD20, with surface kappa light chain restriction, but lacking FMC7, CD10, and CD5. Gating on bright CD38+ events (plasma cells) showed a kappa light chain restricted plasma cell population. The histologic and flow immunophenotypic characterization was consistent with lymphoplasmacytic lymphoma. In situ hybridization (ISH) confirmed kappa light chain monotypia of plasmacytoid lymphocytes and plasma cells (Fig 1C; ISH kappa, eosin counterstain, 1 day; ISH lambda, eosin counterstain). Before identification of the patient's lymphoma, a serum protein electrophoregram (Fig 2A) demonstrated an abnormal M-spike. Subsequent protein immunofixation electrophoresis (PIE) confirmed that the abnormal protein was an IgM kappa paraprotein, along with coprecipitation of lesser amounts of IgG, IgA, and lambda light chain (Fig 2B). The pattern observed is consistent with rheumatoid factor activity seen in type II cryoglobulinemia, in patients infected with HCV. Evaluation of the patient's serum showed markedly elevated rheumatoid factor (RF) levels as confirmed by a turbidimetric assay for rheumatoid factor. The RF levels exceeded our upper limits of detection (> 1,600 kU/dL) despite 10- and 20-fold dilution of the sample. At discharge, the patient was diagnosed with mixed cryoglobulinemia and lymphoplasmacytic lymphoma associated with hepatitis C viral infection.
Cryoglobulins are complex molecular aggregates in the serum that precipitate at temperatures lower than 37°C, and redissolve on rewarming. Cryoglobulins are a heterogeneous mix of Igss, complement and nucleic acid fragments, and are a normal part of routine Ig clearance (along with rheumatoid factor) in healthy individuals. Dysregulation of this tightly controlled Ig clearance mechanism is often associated with autoimmune diseases and certain chronic infections.1-3 Both cryoglobulinemia and lymphoplasmacytic lymphoma have been independently associated with patients who have long standing hepatitis C infections. The modern classification of cryoglobulinemia was first proposed in 19744 and includes three types. Type I cryoglobulinemia is comprised of monoclonal Ig without rheumatoid factor. Type II, also known as mixed cryoglobulinemia, is comprised of heterogeneous Igs with strong monoclonal rheumatoid factor activity, and a monoclonal Ig (usually IgM) component. Type III is similar to type II cryoglobulinemia, though it lacks a monoclonal Ig component (Table 1), and displays polyclonal rheumatoid factor activity.1,5,7
The presence of increased levels of mixed cryoglobulins in the serum leads to various clinical manifestations, usually as a result of immune-complex deposition within the small vessels of the skin, peripheral nervous system, and kidneys. In the skin, this aberrant deposition leads to the classic findings of a lymphocytic vasculitis with resultant ischemia and purpura. It should be noted, however, that cryoglobulins do not always give rise to clinical symptoms. Though the initial proposal for cryoglobulinemia classification occurred in the late 1970s, the association of cryoglobulins with viral infection, specifically hepatitis C viral infection, was not discovered until the early 1990s.6,7 In patients with hepatitis C infection who develop a mixed cryoglobulinemia, viral proteins and nucleic acid fragments have been found to be components of the cryoprecipitate.2,8,9 While many patients with hepatitis C infection display mixed cryoglobulinemia, few subsequently develop a B-cell lymphoma. Recent studies have led to greater understanding of the etiologic role of chronic viral antigen exposure in the development of lymphoma. One model of lymphomagenesis proposes selective pressure on the B cell repertoire due to persistent hepatitis C antigen exposure, thus giving rise to a mono- or oligoclonal expansion of a subset of naïve B-cells. The B-cell receptor heavy and light chain Ig gene segments in patients with chronic HCV-associated non-Hodgkin's lymphoma have been examined. 10 They showed similar heavy and light chain gene-segment usage in B-cell receptors from the lymphomas of different HCV-positive patients, with high sequence similarity in the complementarity-determining regions. Some of the complementarity-determining regions exhibited sequence homology which showed projected specificity to a known HCV antigen, E2. These findings suggest a role for HCV in specific B-cell receptor activation and clonal expansion.10-12 In the case we present, the patient had a known history of untreated hepatitis C and presented with new onset anemia, fatigue, and hepatosplenomegaly. Review of his medical history showed no evidence of these symptoms in the past, nor were there any previous signs of cryoglobulinemia or lymphoma. The first indication for the presence of cryoglobulins was the abnormal serum protein immunofixation electrophoresis (serum PIE) following the patient's recent presentation (Fig 2). We noted the presence of a dominant band corresponding to IgM kappa (see Fig 2B, right panel) with unusual coprecipitation of other Ig components. This pattern is the hallmark of type II mixed cryoglobulinemia. Each lane of the immunofixation gel contains both abnormal cryoglobulin and normal Ig components. The antisera used to detect each Ig fraction are specific for the appropriate Ig light or heavy chain type. This patient's monoclonal IgM has rheumatoid factor activity and thus complexes with normal circulating polyclonal Igs, causing them to coprecipitate within the gel. These complexes then present Igs for detection by antisera and thus, result in the presence of smaller bands corresponding to the cryoglobulin-polyclonal Ig complexes. The identification of mixed (type II) cryoglobulins was accompanied by diagnosis of lymphoplasmacytic lymphoma with the same kappa light chain restriction seen on the serum PIE. Mixed cryoglobulinemia with subsequent progression to B-cell lymphoma in patients with hepatitis C is rare, though possibly under-reported. As our patient's case illustrates, new skin lesions, tissue swelling, or lymphadenopathy in patients with a history of hepatitis C infection should raise clinical suspicions and prompt evaluation by biopsy and protein electrophoresis.12-14 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Shihabi ZK: Cryoglobulins: An important but neglected clinical test. Ann Clin Lab Sci 36:395-408, 2006 2. Dammacco F, Sansonno D, Piccoli C, et al: The cryoglobulins: An overview. Eur J Clin Invest 31:628-638, 2001[CrossRef][Medline] 3. Kallemuchikkal U, Gorevic PD: Evaluation of cryoglobulins. Arch Pathol Lab Med 123:119-125, 1999[Medline] 4. Brouet JC, Clauvel JP, Danon F, et al: Biological and clinical significance of cryoglobulins: A report of 86 cases. Am J Med 57:775-788, 1974[CrossRef][Medline] 5. Trejo O, Ramos-Casals M, Lopez-Guillermo A, et al: Hematologic malignancies in patients with cryoglobulinemia: Association with autoimmune and chronic viral diseases. Semin Arthritis Rheum 33:19-28, 2003[CrossRef][Medline] 6. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 327:1490-1495, 1992[Abstract] 7. Dammacco F, Sansonno D: Antibodies to hepatitis C virus in essential mixed cryoglobulinemia. Clin Exp Immunol 87:352-356, 1992[Medline] 8. Weiner SM, Berg T, Berthold H, et al: A clinical and virological study of hepatitis C virus-related cryoglobulinemia in Germany. J Hepatol 29:375-384, 1998[CrossRef][Medline] 9. Trendelenburg M, Schifferli JA: Cryoglobulins in chronic hepatitis C virus infection. Clin Exp Immunol 133:153-155, 2003[CrossRef][Medline] 10. De Re V, De Vita S, Marzotto A, et al: Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia. Blood 96:3578-3584, 2000 11. Weng WK, Levy S: Hepatitis C virus (HCV) and lymphomagenesis. Leuk Lymphoma 44:1113-1120, 2003[CrossRef][Medline] 12. De Re V, De Vita S, Marzotto A, et al: Pre-malignant and malignant lymphoproliferations in an HCV-infected type II mixed cryoglobulinemic patient are sequential phases of an antigen-driven pathological process. Int J Cancer 87:211-216, 2000[CrossRef][Medline] 13. Neri S, Pulvirenti D, Mauceri B, et al: A case of progression from type II cryoglobulinaemia to Waldenstrom's macroglobulinaemia in a patient with chronic hepatitis C. Clin Exp Med 5:40-42, 2005[CrossRef][Medline] 14. Blanco P, Viallard JF, Rivel J, et al: Unusual manifestations of type II cryoglobulinaemia associated with Waldenstrom's macroglobulinaemia. J Clin Pathol 53:882-884, 2000
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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