Waldenstrom Macroglobulinemia Involving Extramedullary Sites Morphologic and Immunophenotypic Findings in 44 Patients Pei Lin, M.D., Carlos Bueso-Ramos, M.D., Ph.D., Carla S. Wilson, M.D., Ph.D., Adnan Mansoor, M.D., and L. Jeffrey Medeiros, M.D. Waldenstrom macroglobulinemia (WM) is a clinicopathologic syndrome in which a B-cell neoplasm involving the bone mar- row, usually lymphoplasmacytic lymphoma (LPL), is associ- ated with immunoglobulin M paraprotein in the serum. Extra- medullary involvement occurs in a subset of patients and is infrequently examined histologically. The files of M.D. Anderson Cancer Center were searched for patients with WM who underwent biopsy of one or more extramedullary sites during the course of disease. Each biopsy specimen was clas- sified using the criteria of the World Health Organization clas- sification. The study group consisted of 44 patients (26 men and 18 women), with a total of 51 specimens obtained from lymph nodes (n  36), soft tissue (n  4), spleen (n  3), skin (n  2), lung (n  2), tonsils (n  1), colon (n  1), liver (n  1), and gallbladder (n  1). Lymphoplasmacytic lymphoma was the most common histologic type, in 40 (78%) samples. This category was morphologically heterogeneous and was fur- ther subclassified as lymphoplasmacytic (n  21), lymphoplas- macytoid (n  18), and polymorphous (n  1). Four of these LPL cases morphologically resembled marginal zone B-cell lymphoma. Four additional samples were involved by diffuse large B-cell lymphoma, probably transformed from LPL. Three more samples were involved by LPL with unusual features: two were CD5-positive and one was a composite tumor with clas- sical Hodgkin’s disease. Other categories of lymphoma in this group of patients with WM included small lymphocytic lymphoma/chronic lymphocytic leukemia (n  2), mantle cell lymphoma (n  1), and follicular lymphoma (n  1). Waldenstrom macroglobulinemia is most commonly associated with LPL but can rarely occur with other types of B-cell lym- phoma. Lymphoplasmacytic lymphoma in patients with WM is morphologically heterogeneous and can be indistinguishable from marginal zone B-cell lymphoma. CD5+ B-cell lympho- mas with features otherwise typical of LPL are rare, and we think these tumors are part of the spectrum of LPL. Key Words: Waldenstrom macroglobulinemia— Lymphoplasmacytic lymphoma—Extramedullary involvement— Immunophenotype. Am J Surg Pathol 27(8): 1104–1113, 2003. Waldenstrom macroglobulinemia (WM) is an uncom- mon clinical syndrome in which patients have a B-cell neoplasm associated with a monoclonal immunoglobulin M (IgM) paraprotein in serum. In the United States, the age-adjusted incidence rate per 1 million person-years at risk is 3.4 for men and 1.7 for women. 15 Patients with WM are elderly and have an indolent clinical course with a median survival of 5 years. The bone marrow is in- volved in almost all patients. Hepatomegaly, lymphade- nopathy, or splenomegaly occurs in 15–20% of the pa- tients. 12 Hyperviscosity syndrome also occurs in ap- proximately 15–20% of patients. 10,22 Because the diagnosis of WM is usually established by bone marrow evaluation with serum protein electrophoresis, histologic evaluation of extramedullary sites of disease is infre- quently performed. 6,27 According to the World Health Organization (WHO) classification, lymphoplasmacytic lymphoma (LPL)/WM includes most patients with the clinical syndrome of WM, although WM may occasionally be present in pa- tients with other types of B-cell non-Hodgkin’s lym- phoma. The authors of the WHO classification sug- gest that many cases diagnosed and reported as extra- nodal LPL in the literature are, in fact, examples of ex- tranodal marginal zone B-cell lymphoma (MZBCL). The purpose of this study was to assess the morpho- logic and immunophenotypic features of lymphomas in- volving extramedullary biopsy sites in 44 patients with From the Department of Hematopathology (P.L., C.B.-R., L.J.M.), University of Texas M.D. Anderson Cancer Center, Houston, Texas; and the Department of Pathology (C.S.W.), University of New Mexico at Albuquerque, Albuquerque, New Mexico, U.S.A. A.M. is currently at Department of Pathology and Laboratory Medicine University of Calgary/Calgary Laboratory Services, Calgary, Alberta, Canada. Address correspondence to Pei Lin, MD, Department of Hematopa- thology, Box 72, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, U.S.A.; e-mail: peilin@mdanderson.org The American Journal of Surgical Pathology 27(8): 1104–1113, 2003 © 2003 Lippincott Williams & Wilkins, Inc., Philadelphia 1104