—  SPECIALTY CONFERENCE  —

Surgical Pathology

Case 1 - Primary Hepatic Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma)

Lynne Abruzzo
M.D. Anderson Cancer Center
Houston, TX





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Clinical History
A 62-year-old woman was found to have elevated liver function tests on routine examination. She was otherwise well and her physical examination was unremarkable; she had no peripheral lymphadenopathy, palpable hepatosplenomegaly, or abdominal masses. Magnetic resonance imaging scan demonstrated a 5-cm mass in the left lateral segment of the liver. A needle biopsy of the mass was reported to show a periportal and parenchymal infiltrate composed of small lymphocytes, as well as fatty change. She underwent hepatic lobectomy three months after presentation. Following surgery, the patient declined to undergo a bone marrow biopsy and aspirate. Gastric endoscopy with biopsy performed 6 months later demonstrated chronic active gastritis with Helicobacter pylori, but no evidence of malignant lymphoma. The patient's past medical history was significant for autoimmune hemolytic anemia 12 years earlier, treated with splenectomy and blood transfusions, and toxic multinodular goiter 20 years earlier, treated with 135I.

During the month after presentation, laboratory examinations demonstrated the following: aspartate aminotransferase, 73 U/L (normal, 8-42 U/L); alanine aminotransferase, 71 U/L (normal, 1-55 U/L); alkaline phosphatase, 108 U/L (normal, 37-107 U/L); lactate dehydrogenase, 207 U/L (normal, 94-172 U/L); gamma-glutamyl transferase, 130 U/L (normal, 8-69 U/L); indirect bilirubin, 0.2 mg/dL (normal, 0.2-0.8 mg/dL); erythrocyte sedimentation rate, 58 mm/hr (normal, 0-20 mm/hr); and alpha-fetoprotein, 2.6 ng/mL (normal, 0-15 ng/mL). A complete blood count demonstrated slight anemia, hematocrit, 36.7% (normal, 38.0-47.0%) and thrombocytosis, platelet count, 465 x 109/L (normal, 150-450 x 109/L), with a normal white blood cell count. Serologic studies for rheumatoid factor antibodies, antinuclear antibodies, anti-smooth muscle antibodies, antimitochondrial antibodies, and hepatitis A, B, and C antigens were negative. At the time of the lobectomy, the antimitochondrial antibody titer was 1:160.


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Background
The MALT lymphoma concept emerged from the work of Isaacson and Wright, first published in 1983. [1] They showed that cases previously diagnosed as "pseudolymphoma" in stomach and bowel were actually extranodal low-grade B-cell lymphomas that recapitulated the morphology of Peyer patch marginal zone B cells, and typically arose in sites with no organized lymphoid tissue. They hypothesized that persistent antigen stimulation and chronic inflammation induced by infection with Helicobacter pylori organisms leads to the accumulation of extranodal lymphoid tissue, which forms the substrate for the development of extranodal MALT lymphoma.

Morphology and Immunophenotype
In the WHO classification, MALT lymphoma is defined as an extranodal lymphoma composed of a cytologically heterogeneous proliferation of small B lymphoid cells including marginal zone cells, cells resembling monocytoid cells, small lymphocytes, and scattered immunoblasts, and centroblast-like cells. [2] Marginal zone cells were previously described as "centrocyte-like cells" because their nuclei resemble those of small cleaved follicle center B cells, with slightly irregular nuclear contours, condensed chromatin, and inconspicuous nucleoli, but with more abundant pale cytoplasm. [3] Some cases show plasmacytic differentiation. [2] In extranodal sites the neoplastic cells surround and invade the mantle zones of reactive follicles, and form sheets that replace the reactive follicles and normal structures. In sites with epithelium, the neoplastic cells invade and destroy the epithelium to form lymphoepithelial lesions. In lymph nodes the neoplastic cells invade the marginal zones and expand the interfollicular region. They may form aggregates of monocytoid cells, most conspicuous in the parafollicular regions or adjacent to sinusoids. The neoplastic cells also invade and may colonize germinal centers (follicular colonization), which may be difficult to distinguish from follicular lymphoma without ancillary studies [2]. The postulated normal counterpart is a post-germinal center B cell.

The neoplastic cells express pan-B-cell markers (CD19+, CD20+, CD22+, CD79a+) and monotypic surface immunoglobulin, usually IgM, but occasionally IgA or IgG. The neoplastic cells express bcl2, and may also express CD43 and CD11c. They are negative for CD10, CD23, and cyclin D1. [2, 4] Rare cases are positive for CD5. [5] Antibodies to the marginal zone cell-associated antigens CD21 and CD35 stain the neoplastic cells and also accentuate the disrupted follicular dendritic cell network of colonized lymphoid follicles. [2]

Clinical Features
MALT lymphoma, which comprises about 8% of all B-cell lymphomas, is the most common type of primary extranodal lymphoma. [6] It affects predominantly adults with a median age of 61 years, and women are affected slightly more often than men (male:female=1:1.2). [6] About half of all MALT lymphomas present in the gastrointestinal tract, the most common site of involvement. Within the gastrointestinal tract, the stomach is most frequently affected, accounting for 85% of all cases. [7] Other common sites of origin are salivary gland, lung, head and neck, ocular adnexae, skin, thyroid gland, and breast. [8] About two-thirds of patients present with localized disease (stage I or IIE) and about one-third present with stage III or stage IV disease. [9] MALT lymphoma is indolent and slow to disseminate. Regardless of the stage at presentation, about 80% of patients survive 10 years or more. Involvement of multiple extranodal sites at diagnosis, including bone marrow, does not confer worse prognosis. Recurrences, which are more common in extra-gastric MALT lymphomas, tend to occur after many years and to involve other extranodal sites. [9, 10]

Primary hepatic MALT lymphoma is rare, with about 50 cases reported to date. [11, 12, 13, 14] Like MALT lymphomas that arise in other sites, primary hepatic MALT lymphoma is a disease of older adults, with a mean age of about 61 years. [11] In most cases, the liver tumor was identified incidentally, either during surgical resection or imaging studies for another disease. [11] Because of the small number of reported cases, little is known about the clinical behavior of primary hepatic MALT lymphoma, nor is there a standard treatment. Patients with primary hepatic MALT lymphoma have been treated with resection of the mass, chemotherapy, or a combination of the two. Of 32 patients with clinical follow-up, 29 are still alive with a median follow-up of 2 years (range, 1 month to 8 years). [11] Thus, it seems likely that, similar to other MALT lymphomas, primary hepatic MALT lymphoma has an indolent clinical course.

Many patients with MALT lymphoma have a history of chronic inflammation, often in the setting of infection or autoimmune disease. In the stomach, the majority of cases (up to 90% in some studies) are associated with H. pylori infection. [2] In this setting, the development of MALT lymphoma is initiated by the malignant transformation and proliferation of neoplastic B cells that require the presence of H. pylori-antigen-specific activated T cells. [15] Of the cases that are associated with H. pylori infection, about 75% of cases are cured following treatment to eradicate the organisms. [16] Infectious agents also play a role in the development of MALT lymphoma at other sites. MALT lymphoma is associated with infection by Chlamydia psittaci in the ocular adnexae, [17, 18] by Borrelia burgdorferi in skin, [19] and by Campylobacter jejuni in the small intestine. [20] MALT lymphomas may also arise in the setting of autoimmune disease. Patients with Sjögren's syndrome or lymphoepithelial sialadenitis have a significantly increased risk of developing MALT lymphoma of the salivary gland. [2, 3] Similarly, patients with Hashimoto thyroiditis have a significantly increased risk of developing MALT lymphoma of the thyroid gland.

The inciting events(s) that lead to the development of primary hepatic MALT lymphoma are unknown. However, in a recent review of 46 patients with primary hepatic MALT lymphoma, pre-existing liver disease associated with chronic inflammation was documented in 16, including primary biliary cirrhosis (PBC) in four patients, viral hepatitis in six patients (five with chronic hepatitis B and one with hepatitis C), and "liver cirrhosis" in seven patients. [11] In total, only six cases of hepatic MALT lymphoma arising in the setting of PBC has been reported. [11, 12, 13, 14, 21, 22]

Primary biliary cirrhosis is a chronic, progressive inflammatory liver disease that affects primarily middle-aged women, reviewed by Kaplan [23] and Hohenester. [24] , that destroys small interlobular bile ducts and leads to cholestasis, scarring, and, eventually, cirrhosis. Most patients are asymptomatic at time of presentation, and come to medical attention either because of elevated serum alkaline phosphatase and/or serum cholesterol. They generally develop symptoms within a few years after presentation. Both environmental factors and inherited defects in immune regulation appear to contribute to its pathogenesis. Many patients with PBC have other autoimmune diseases, such as thyroiditis, scleroderma, rheumatoid arthritis, or Sjögren's syndrome. They can have many different kinds of circulating autoantibodies, the most important of which are the anti-mitochondrial antibodies (AMA). These autoantibodies are found in the vast majority of patients with PBC and are highly specific for the disease. The presence of elevated levels of serum alkaline phosphatase and gamma-glutamyl transferase in the presence of elevated AMA titers establish the diagnosis of PBC.

The patient that we describe had a history of autoimmune disease, as well as evidence of a nonsuppurative destructive cholangitis in areas of liver uninvolved by MALT-type lymphoma. [13] Although there was no evidence of chronic cholestasis, the histologic features were those of early PBC and the AMA titers were positive. In approximately one-third of patients with PBC, the disease has an indolent clinical course, and it persists in the early stages of many years. [23] Thus, this patient's PBC may have remained at a low but immunologically stimulating stage for a long time. Since MALT-type lymphomas appear to evolve slowly from acquired lymphoid tissue, [1, 2] it is plausible that this patient's lymphoma arose from the chronic inflammation associated with PBC.

Differential Diagnosis
The differential diagnosis of primary hepatic MALT lymphoma includes hepatic involvement by nodal marginal zone lymphoma or MALT lymphoma from a primary site other than liver, which must be excluded by careful clinical staging. In addition, three different chromosomal translocations have been shown to be specific for MALT lymphomas: the t(11;18)(q21;q21) involving the API2 and MALT1 genes, the t(14;18)(q32;q21) involving the IgH and MALT1 genes, and the t(1;14)(p22;q32) involving the BCL10 and IgH genes. [3, 25] Their incidence varies depending upon the site of origin of the MALT lymphoma, but none have been identified in the few cases of primary hepatic MALT lymphomas that have been studied. Thus, identification of one of these translocations by conventional cytogenetic or FISH studies suggests a possible primary site for further evaluation.

The differential diagnosis also includes hepatic involvement by other B-cell lymphomas composed of predominantly small lymphoid cells, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). Features that help to distinguish between MALT lymphoma and these other entities include the heterogeneity of the cellular infiltrate, the presence of reactive germinal centers and lymphoepithelial lesions, the lack of expression of CD10 and cyclin D1, and the lack of expression of CD5 in the vast majority of cases. In all cases the neoplastic cells demonstrate monotypic surface immunoglobulin expression by flow cytometry. Molecular diagnostic studies demonstrate clonal immunoglobulin heavy chain gene rearrangements. Conventional cytogenetic and FISH studies may demonstrate characteristic translocations associated with follicular lymphoma (the t(14;18) involving the IgH and BCL2 genes) or mantle cell lymphoma (the t(11;14) involving the CCND1 and IgH genes).

MALT CLL/SLL Follicular MCL
sIg + + (weak) + +
CD5 ? + ? +
CD10 ? ? + ?
CD20 + + (weak) + +
CD23 ?/+ +/? ?/+ ?
BCL2 + + + +
CyclinD1 ? ? ? +

Finally, the differential diagnosis also includes hepatic reactive lymphoid hyperplasia or "pseudolymphoma", a rare or controversial entity. [26, 27] There are only about 30 cases of hepatic pseudolymphoma reported in the literature, the majority from Japan. Because most patients have a history of autoimmune disease, malignancy, or hepatitis, this disorder is believed to be a reactive immunologic response to chronic infection or inflammation. Macroscopically the tumors range from less than 1 cm up to 5.5 cm. Histologically this lesion is characterized by a nodular infiltrate of generally small lymphoid cells with well-formed germinal centers, scattered histiocytes and immunoblasts, but no atypical cells. Broad bands of lymphocytes divide the hepatic parenchyma and extend into the perinodular portal tracts. The lymphoid infiltrate entraps bile ducts, especially at the periphery of the lesions, but lymphoepithelial lesions are not seen. In situ hybridization or immunohistochemical stains for immunoglobulin light chains show that the plasma cells are polyclonal. The few cases tested have failed to show clonal immunoglobulin gene rearrangements. Following needle biopsy, a few cases have regressed spontaneously.

References
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