Posted April 22, 2011

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Imaging studies revealed multiple lung nodules in a 42-year-old man. Received was an 8.7 x 3.0 x 2.5 cm wedge biopsy of peripheral lung tissue containing a 2.5 cm tumor mass. Flow cytometry revealed a monotypic kappa restricted B cell population lacking expression of CD5, CD10, or CD23.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, Case 12, and is extranodal marginal zone lymphoma, MALT type.

Criteria for Diagnosis and Comments: Sections of the lung show a lymphoid infiltrate with a lymphangitic pattern. The “lymphangitic pattern” is defined as preferential involvement of the bronchovascular bundles, interlobular septa and visceral pleura. Some sections also demonstrate confluent tumor masses that efface the normal pulmonary architecture. There is a background of sclerosis in foci of more advanced infiltration. The tumor cells include small, mature lymphocytes, “monocytoid” cells with abundant pale cytoplasm, plasmacytoid cells and mature plasma cells in varying proportions. Dutcher bodies are observed in foci of plasmacytoid differentiation. Lymphoepithelial lesions are conspicuous, involving bronchial and bronchiolar epithelium, focally forming intraluminal plugs and exhibiting partial destruction of the bronchial wall. The morphologic and immunophenotypic features of this lesion are characteristic of extranodal marginal zone lymphoma of Mucosa Associated Lymphoid Tissue (MALT) type (EMZL-MALT).

The lung is a relatively common site of primary extranodal lymphoma, following the gastrointestinal tract, skin and central nervous system. The most common primary pulmonary lymphoma is extranodal marginal zone lymphoma of MALT type. EMZL-MALT is seen almost exclusively in adult patients. Some patients are asymptomatic at presentation while others present with non-specific complaints such as cough, dyspnea, fever, or weight loss. Associated autoimmune conditions and monoclonal gammopathies are common in patients with pulmonary EMZL-MALT; however, in contrast to EMZL-MALT at other sites there is no consistent association with a specific infectious agent or autoimmune condition. The radiographic and macroscopic appearance, as in this case, is that of single or multiple pulmonary nodules that may be unilateral or, less commonly, bilateral.

Microscopically, the lymphangitic growth pattern described above is characteristic. Like EMZL-MALT at other sites, the neoplastic infiltrate in the lung characteristically exhibits a polymorphous cytology with a predominance of marginal zone (“monocytoid”) lymphocytes, variable numbers of admixed plasma cells and large transformed lymphocytes, lymphoepithelial lesions, and reactive germinal centers, often exhibiting infiltration of the germinal center by the neoplastic cells (“follicular colonization”). Destructive lymphoepithelial lesions are typically quite conspicuous in the lung, when compared to other sites. In paraffin sections, the neoplastic cells exhibit strong expression of B cell markers, including CD20, PAX5 (lymphoid cells and negative within plasma cells), and CD79a. Monotypic light chain expression is observed frequently due to the presence of relatively prominent plasmacytic differentiation seen in pulmonary EMZL-MALT. Aberrant expression of CD43 by the neoplastic cells may also be observed and is a helpful feature in confirming the neoplastic nature of the infiltrate in small biopsies. These lesions characteristically lack expression of CD5, CD10, CD23 and cyclin D1, allowing confident distinction from other small B cell lymphomas. The translocation t(11;18) involving the API2 and MALT1 genes is present in up to 40% of pulmonary EMZL-MALT and can be detected by FISH or RT-PCR. Treatment of pulmonary EMZL-MALT is typically with combination chemotherapy using standard regimens applied to low-grade B cell lymphomas. The prognosis is excellent, with most studies showing little or no difference in survival from age and gender-matched controls.

As in other sites, the principal differential diagnosis of EMZL-MALT in the lung is with other small B cell lymphomas and reactive lymphoid proliferations. As stated above, EMZL-MALT lacks CD5 in contrast to small lymphocytic lymphoma/chronic lymphocytic leukemia involving lung and mantle cell lymphoma. Absence of CD23 and cyclin D1 will further exclude SLL/CLL and mantle cell lymphoma respectively. In contrast to follicular lymphoma, with which EMZL-MALT may be confused on the basis of a nodular architecture, the cells of EMZL lack expression of CD10 and bcl-6. Florid reactive follicular lymphoid hyperplasia (FRFH) and lymphoid interstitial pneumonia (LIP) along with follicular bronchiolitis, a more localized form of FRFH, are part of a spectrum or reactive lymphoid hyperplasia in the lung that may substantially resemble EMZL-MALT. In comparison to EMZL-MALT, these proliferations are much more commonly associated with altered immune states, including HIV/AIDS, congenital immunodeficiency states, and autoimmune disease. FRFH can de distinguished from EMZL-MZLT on the basis of morphologic pattern (a relatively circumscribed nodular lesion effacing the normal architecture without significant lymphangitic pattern of infiltration, prominent germinal centers lacking colonization by monocytoid cells, absence of conspicuous lymphoepithelial lesions), cytomorphology (absence of cytologic atypia in the lymphocytes and absence of Dutcher bodies) and immunophenotype (T cell predominant outside of reactive germinal centers, B cells lack co-expression of CD43 or monotypia, germinal centers are bcl-2 negative, bcl-6 positive). LIP can be reliably distinguished from EMZL-MALT based on the diffuse interstitial pattern of the lymphoid infiltrate, with prominent involvement of the alveolar septa, the lack of cytologic atypia and the predominance of T lymphocytes with relatively few polytypic B cells and plasma cells. In difficult cases, immunoglobulin heavy chain (IGH) gene rearrangement studies may be performed to prove the monoclonal nature of EMZL-MALT compared to the polyclonal pattern expected in FRFH or LIP. Of note, IGH will not allow distinction of EMZL from other clonal lesions such as SLL, follicular or mantle cell lymphoma.