Primary biliary cirrhosis

* Primary lymphoma of the liver is rare. Recently, marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type have been described in the liver. Most of these cases occurred without known underlying liver disease, while others were seen in patients with chronic hepatitis. A case of primary hepatic MALT lymphoma in a patient with primary biliary cirrhosis was reported recently. Some authors have proposed that chronic persistent immunogenic stimulation causes development of acquired MALT and subsequently MALT lymphoma, based on the observation of MALT lymphoma in association with infectious agents, such as Helicobacter pylori and hepatitis C virus, and autoimmune diseases, such as Hashimoto thyroiditis and Sjogren syndrome. Primary biliary cirrhosis is a chronic, progressive, cholestatic liver disease characterized by destruction of intrahepatic small to medium-sized bile ducts; this disease is mediated by a cytotoxic T cell reaction. The prolonged immune activation in primary biliary cirrhosis may play a role in the lymphomagenesis of hepatic MALT lymphoma. We describe another case of primary hepatic MALT lymphoma, which was found incidentally in a patient with end-stage primary binary cirrhosis. This case further supports the role of immunogenic stimulation in the pathogenesis of this particular tow-grade Bcell lymphoma.

(Arch Pathol lab Med. 2000;'t 24:604-608)

Liver involvement in disseminated malignant lymphoma is a common condition. In contrast; primary hepatic lymphoma is rare and accounts for less than 1% of extranadal lymphomas.1.2 Similar to extranodal lymphomas of other anatomic regions, most primary hepatic lymphomas are of high-grade, large, B-cell type.3,4 A lymphoma of T cell lineage has also been described by Anthony et al5 in a series of 10 cases: Recently marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type (or MALT lymphoma) was recognized by Isaacson et al6 as a distinct entity of low-grade primary hepatic lymphoma. Eight cases have been reported to date, most of which were found incidentally without underlying liver disease.6-8 In one case, it was associated with primary biliary cirrhosis (PBC).9

Marginal zone B-cell lymphomas of MALT type occurring in the stomach were first described by Isaacson and Wright in 1983.10 Their characteristic clinical, biological, and pathologic features distinguish them from other lowgrade B-cell lymphomas in both the World Health Organization (WHO) classification and a revised EuropeanAmerican classification of lymphoid neoplasms.11,12 These classification systems recapitulate the morphology of Peyer patch and Waldeyer ring lymphoid tissue in the ileum and upper aerodigestive tract, respectively. Paradoxically extranodal marginal zone B-cell lymphomas of MALT type occur most frequently in organs devoid of indigenous MALT, such as the stomach, salivary gland, thyroid, and lungs.13 The list of sites of involvement is continuously growing, as this low-grade lymphoma can appear in virtually any site, including the liver.14 We report a case of marginal zone B-cell lymphoma of MALT type arising in a liver removed during transplantation for end-stage PBC, which had no evidence of extrahepatic involvement. The possible etiopathogenesis and treatment are discussed as well.

COMMENT

Our understanding of extranodal MALT lymphomas has been advancing constantly since they were first introduced more than a decade ago. These lesions are lowgrade lymphomas characterized by their indolent, prolonged, localized clinical course and potential curability with local amendments.15 They are separate from other conventional nodal-type small B-cell lymphomas with extranodal involvement, such as follicular lymphoma, mantle cell lymphoma, and small lymphocytic lymphoma/ Bcell chronic lymphocytic leukemia, which tend to progress rapidly to disseminated diseases and are incurable even with systemic treatment.15

Although they were originally observed in the stomach, which has remained the most common site of involvement, reports of MALT lymphomas have extended to diverse extranodal locations, both with and without mucosa. Furthermore, MALT lymphomas have been associated with various predisposing conditions related to an altered immune system. It was observed initially that Helicobacter gastritis invoked acquired MALT, which later gave rise to overt lymphoma, followed by a documented clinical regression after eradication of the organism by antimicrobial treatment.16,17 Infectious agents also have been found to be related to MALT lymphoma in diverse sites. Hepatitis C virus, Epstein-Barr virus, and Borrelia burgdorferi were demonstrated in association with MALT lymphoma in the liver, salivary glands, and skin.18-21 Similarly MALT lymphomas have been associated with autoimmune diseases, such as Hashimoto thyroiditis and lymphoepithelial sialadenitis/Sjogren syndrome, which account for 40- and 60fold increases in the risk for lymphoma, respectively.22-25 Sjogren syndrome is frequently observed in patients with PBC. It is therefore interesting that we have not seen more reports of MALT lymphomas in livers with PBC, since these 2 conditions actually share similar histopathologic features.

Interest in MALT type lymphoma has created accumulating evidence for a role of chronic and persistent antigenic stimulation in lymphomagenesis. B-cell reaction related to foreign antigen or autoimmune conditions and exaggerated helper T cell response are believed to cause gene mutation of immunoglobulins and eventually overt malignant transformation.26,27 The concept was further manifested by the chromosome anomalies frequently seen in MALT lymphoma, such as trisomy 3 and t(11;18)(q21; q21).28-30 Another nonrandom translocation, t(3;14)(q27; q32), involving the bcl-6 gene also has been reported in this setting.31

Primary hepatic MALT lymphoma is obviously a rare event. Of the cases reported,6-9 all were incidental findings, with tumors ranging from 2 to 7.5 cm in diameter. Chronic hepatitis was found to be the underlying disease in several cases. The majority of cases were treated with local resecLion without adjuvant remedies. Prabhu et al8 recently reported a case of hepatic resection for MALT lymphoma in a patient who had PBC and history of autoimmune hemolytic anemia and toxic multinodular goiter of the thyroid.

Primary biliary cirrhosis is a chronic, progressive, cholestatic liver disease. It is characterized by cytotoxic T=cellmediated destructive cholangiopathy involving small to medium-sized intrahepatic bile ducts with nansuppurative chronic inflammation.32 Most patients demonstrate elevated titers of antimitochondrial antibodies and often suffer from other autoimmune diseases, such as progressive systemic sclerosis, rheumatoid arthritis, lupus erythematosus, thyroiditis, and Sjogren syndrome. Although the initiating immunogen(s) remain to be identified, both genetic and environmental factors are believed to be invalved in the altered immune reactivity. Similar to MALT lymphoma in other organs, chronic immune activation in PBC may contribute to lymphomagenesis in the liver.

The clinical presentation of our case was characteristic of MALT lymphoma; that is; it involved an extranodal site; the lesion was localized, and it was indolent. Studies have shown that localized MALT lymphomas are best managed by local radiation or surgical resection.33 Our patient had sufficient therapy for her primary hepatic MALT lymphoma; however, the effects of long-term immunosuppression on primary hepatic MALT lymphoma after liver transplantation remain to be elucidated.

In conclusion, our report brings up an interesting relationship between MALT lymphoma and PBC, which is an immune-mediated bile duct disease, and further supports the role of immunogenic stimulation in the pathogenesis of MALT lymphoma.

References

1. Freeman C. Berg IVs, Cutter St. Occurrence and prognosis of extranodal lymphomas. Cancer 1972;29:252-160.

2: )affe ES. Malignant Lymphoma: pathology of hepatic involvement. Semin Liver Dis. 1987:257-268:

3. Osborne BM, Butler )/, Guarda LA. Primary lymphoma of the liver: ten cases and a review of the literature. Cancer. 1985;56:2902-2910.

4. Ryan ), Straus DJ, Lange C, et al Primary lymphoma of the liver. Cancer. 1988;61:370-375:

S. Anthony PP, Sarsfield P, Clarke T. Primary lymphoma of the Liver: clinical and pathological features of 10 patients. I Clin Pathol. 1990;43:1007-1013.

6: Isaacson PG, Banks PM, Best PV, McLure SP, Muffler-Hermelink HK, Wyatt Ji. Primary low-grade hepatic S-cell lymphoma of mucosa-associated lymphoid tissue (MALTy type. Am ( Surg Pathol, 1995;19:571-575.

7. Maes M, Depardieu C, Dargent )-4, et al. Primary low-grade B-call lymphoma of MALT-type occurring in the liver: a study of tvo cases. / Hepatol. 1997; 27:922-927.

8. Prabhu R, Medeiros if, Kumar D, et al: Primary hepatic low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) associated with primary biliary cirrhosis. Mod Pathol. 1998; 1:404-410.

9. Ueda G, Oka K, Matsumoto T, et al. Primary hepatic marginal zone B-cell lymphoma with mantle cell lymphoma phenotype. Virchows Arch. 1996;4128: 311-314.

10. Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue: a distinctive type of B-cell lymphoma: Cancer. 1983;52:141(7-1416.

11. Jaffe ES, Harris NL, Diebold 1, Minter-Hermelink HK. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues, a progress report. Am / Clin Pathol. 1999;111:58-512,

12. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of tnphoid neoplasms: a proposal from the international Lymphoma Study Group. Blood. 1994;84:1367-1392.

13. Isaacson P, Wright DH. Extranodal malignant lymphoma arising from mucosa-associated lymphoid tissue. Cancer. 1984;53:2515-2524.

14. Burk JS. Are there site-specific differences among the MALT lymphomas: morphologic,clinical? Am jClin Pathol. 1993;171_St33-5143.

15. fisher RI, Dahlberg S, Nathwani BN; Banks PM, Miller TP, Grogan TM. A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal none lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study. Blood. 1995:85:1075-1082;

16: Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primary lowgrade 8-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet. 1993;342:575-577.

17. Wotherspoon AC , Oritz-Hidalgo C, Falzon MK, Isaacson PG. Helicol)acter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet. 1997; 338:1175-1176.

18: Luppi M; Longo G, Ferrari MG, et al. Additional neoplasms and HCV infection in low-grade lymphoma of MALT type. Br / HaematoL t. 1996;94:373375.

19. Ascoli V, Lo-Loco F, Artini M, Levrero h1, Martelli M, Negro F. Extranodal lymphomas associated with hepatitis C virus infection. Am ) Clin Pathol. 1998; 109:600-609.

20. Diss TC, Wotherspoon AC, Speight P, Pan L, isaacson PG. B-cell monoclonality, Epstein-Barr virus and t(14;181 in myoepithelial sialadenitis and lowgrade B-cell MALT lymphoma of the parotid gland: Ana ! Surg PathoL 1995;19: 531-536:

21. Cerroni L; Zochling N; Putt B, Kerl H. Infection by Borrelia burgdorteri and cutaneous B-cell lymphoma./ Cutan Pathol. 1997:24:457-461.

22. Holm LE, Blomgren H, Lowhagen T. Cancer risks in patients with chronic lymphocytic thyroiditis. N Engl / Med. 1985;312;601-604,

23. Hyjek E, Isaacson PG. Primary B-cell lymphoma of the thyroid and its relationship to Hashimoto`s thyroiditis. Hum Pathol. 1988;19:1315-1326.

24#. Hyjek E, Smith WI, Isaacson PG: Primary B-cell lymphoma of the salivary glands and its relationship to myoepithelial sialadenitis: Hum Pathol. 1988;19: 766--776.

25. Kassan SS; Thomas TL, Moutsopoulos tlM, et al. Increased risk of lymphoma in sicca syndrome. Ann Intern Med. 1978;89:888-892.

26. Du M, Diss TC, Xu C, Peng Li, Isaacson PG, Pan L. Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion. Leukemia. 1996;10:1190-1197.

27. Bahler DW, Miklos 1A, Swerdlow SH. Ongoing Ig gene hypermutation in salivary gland mucosa-associated lymphoid tissue-type lymphomas. Blood: 1997; 89:3335-3344.

28. Wotherspoon AC, Fin TM, Isaacson PG. Trisomy 3 in low-grade B-cell lymphomas of mucosa-associated lymphoid tissue. Blood. 1995;85:2000-2004. 29: Auer IA, Gascoyne RD, Connors IM, et al. T(11;18)(q21;q21) is the most

common translocation in MALT lymphomas. ,Ann Oncol. 1997; 8:979-985.

30: Ott G, Katzenberger T, Greiner A, et al The ti l-1;181(q21;q21 ) chromosome translocation is a frequent and specific aberration in low-grade but not high-grade malignant nan-Hodgkin's lymphomas of the mucosa-associated lymphoid tissue (MALT) type: Cancer Res. 1997;57:3944-3948.

31: fOieramm ), Pittaluga S, Stul M, et al. RCL6 gene rearrangements also occur in marginal zone B-cell lymphoma. Br! I Haematol. 1997;98:719-725.

32. Cornall Rt, Goodnow CC, Cyster IG: The regulation of self-reactive B cells: Curr Opin Immurral. 1995;7:804-811.

33. Schecter NR; Portlock CS, Yahalom [: Treatment of mucosa-associated Symphoid tissue lymphoma of stomach with radiation alone: ! Clin Oncol. 1998;16: 1916-1921.

Accepted for publication July 8, 1999.

From the Lillian and Henry M. Stratton-Hans Popper Department of Pathology (Drs Ye, Suriawinata, Black, Strauchen, and Thung) and the Division of Liver Diseases, Department of Medicine (Dr Min), Mount Sinai School of Medicine, City University of New York; New York, NY

Reprints: Swan N. Thung, MD, Department of Pathology; PO Box 1194, The Mount Sinai School of Medicine, One Gustave L. Levy PI, New York, NY 10029.

Copyright College of American Pathologists Apr 2000
Provided by ProQuest Information and Learning Company. All rights Reserved