Small B cell lymphoma is a morphological designation to a group of B cell lymphomas which are composed of a clonal population of small lymphoid cells. The subtypes of this category have diagnostically distinct characteristics and different clinical behaviors and treatment. Correct diagnosis and classification of these subsets depend on the integration of morphologic, immunophenotypic, and molecular genetic features. In this paper, differential diagnosis of this category of tumors and a practical approach based on biomarker evaluation are discussed. 1. Introduction Diagnosis of lymphoid neoplasms has been drastically changed during the last three decades. It had transitioned over the years from a purely morphology-based approach [1] to a system that integrates immunologic and molecular biology findings. The current World Health Organization (WHO) classification [2] is based on a constellation of clinical, morphologic, immunophenotypic, and molecular genetic features. In the WHO classification, lymphoid malignancies are categorized based on their ontogeny to B or T cells. In the B lymphocyte group, two major categories are recognized: precursor and mature B lymphocytes. Among mature B cell lymphoma neoplasms, those composed of small lymphoid cells are common and have overlapping features, thus definitive diagnosis may be challenging. Treatment and prognosis may vary from one subtype to the next, thus it is important to make the most definitive diagnosis as possible. In this paper we focus on the differential diagnosis of the common entities classified under the mature small B cell category which includes nodal, extranodal, and splenic marginal zone lymphoma (NMZL, ENMZL, SMZL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), lymphoplasmacytic lymphoma (LPL), and low grade follicular lymphoma (FL). Other small B cell neoplasms that predominantly involve the blood and bone marrow (prolymphocytic leukemia and hairy cell leukemia) are not discussed. The mature small B cell lymphomas comprise more than 30% of the non-Hodgkin lymphomas (FL grades I&II, 16%, ENMZL 8%, SLL 7%, MCL 6%, NMZL 2%, LPL 1%). Based on their clinical course, lymphomas can also be further classified as either an indolent or aggressive disease. Low grade FL, MZL, and CLL/SLL show indolent behavior; in contrast MCL and high grade follicular lymphoma have an aggressive course. Indolent lymphomas are generally incurable with current standard therapeutic approaches and have a chronic course with repeated relapses despite therapy. Nevertheless,
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