Marginal zone lymphoma of extranodal sites: A review with an emphasis on diagnostic pitfalls and differential diagnosis with reactive conditions

Marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) represents 8% of all B-cell lymphomas and it is the most common small B-cell lymphoma arising at extranodal sites. The gold-standard test to establish a diagnosis of MALT lymphoma remains histopathologic analysis with the aid of immunohistochemistry (IHC) and/or flow cytometry immunophenotypic analysis. MALT lymphoma represents a progression from a persistent chronic inflammatory process, and therefore distinguishing MALT lymphoma from chronic inflammation by histopathology may be challenging in some cases. Despite recent trends to consider IGH rearrangement/clonality as a confirmatory diagnostic test of MALT lymphoma, this method is far from ideal for this purpose since a positive or a negative result does not necessarily confirm or exclude that a process is lymphoma or reactive. This test must be correlated with the morphologic findings. Moreover, MALT lymphoma may arise in association with underlying autoimmune conditions where clonal lymphoid populations are not uncommonly detected. Therefore, we believe that an integrated approach including detailed morphologic review in combination with IHC and/or flow cytometry is best to establish a diagnosis of MALT lymphoma in most cases. We present helpful morphologic tips to avoid potential diagnostic pitfalls at some of the most common extranodal sites, including the stomach, ocular adnexa/conjunctiva, salivary gland, lung, thymus, breast, thyroid, small and large intestine and the dura. The differential diagnosis of MALT lymphoma with IgG4-related disease is also discussed.