Waldenström's macroglobulinemia differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Grammar Reviewer: Natalie Harpenau, B.S.[3]

Overview

Waldenstrom's macroglobulinemia must be differentiated from multiple myeloma, chronic lymphocytic leukemia/small lymphocytic lymphoma, b-cell prolymphocytic leukemia, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

Differentiating Lymphoplasmacytic lymphoma from other Diseases

Waldenstrom's macroglobulinemia must be differentiated from following other B cell lymphoid neoplasms:

Disease		Etiology (Genetic or other)	Clinical manifestations						Paraclinical findings		Associated findings
									Lab findings
			Symptoms				Signs		Immunochemistry	Histopathology
			Constitutional symptoms	Rash	Abdominal pain	Diarrhea	Mass	Other
Waldenström's macroglobulinemia		Mature B-cell Lymphoma Mutation of the MYD88 gene (L265P) Nonsense or frameshift mutations in the CXR4 gene	Weakness Anorexia Weight loss Fever	–	–	+	Generalized and local lymphadenopathy	Retinal hemorrhage with blurring of vision Vertigo Dizziness Headache Nystagmus Tinnitus Ataxia Bleeding	Expresses pan B-cell antigens: CD19 CD20 CD22 CD79a CD5 Variable expression of: CD11c CD43 CD25 Majority express: IgM surface immunoglobulin Fewer express: IgG or IgA Lack IgD Lack expression of: CD10 Cyclin D1	≥10 percent infiltration by small lymphocytes, plasmacytoid lymphocytes, and plasma cells Variable numbers of admixed immunoblasts Hyperplasia of mast cells in marrow (characteristic but not pathognomonic) Diffusely effaced lymph nodes Absence of proliferation centers and marginal zone type differentiation Russell bodies (intracytoplasmic inclusions) Dutcher bodies (intranuclear inclusions) Prominent epithelioid histiocytes	Diffuse large B-cell lymphoma Myelodysplastic syndrome/Acute myeloid leukemia Brain tumor Renal MALT lymphoma
B cell chronic lymphocytic leukemia/small lymphocytic lymphoma		Mature B-cell Lymphoma Chromosome 13 abnormalities Del13q Del11q Del17p Trisomy 12	33% of patients present with: Fever Weight loss Night sweats	–	–	–	Painless lymphadenopathy	May be asymptomatic Fatigue Recurrent infections Hepatosplenomegaly	Always expresses: CD5 CD38 Usually expresses: CD23 Dim expression of: CD20 Surface Ig	Monoclonal small well differentiated lymphocytes with a dense nucleus, partially aggregated chromatin, no discernible nucleoli, and a narrow border of clear to slightly basophilic cytoplasm Significant number of smudge cells or basket cells	Autoimmune hemolytic anemia Red cell aplasia Autoimmune thrombocytopenia
Follicular lymphoma		Mature B-cell Lymphoma Reciprocal translocation t(14;18) Overexpression of BCL2	20% of patients present with: Fever Weight loss Night sweats	+	+	±	Painless peripheral adenopathy in the cervical, axillary, inguinal, and/or femoral regions Asymptomatic large abdominal mass	Seizures Chest pain Bone pain Cough Dyspnea	Expresses: CD21 CD23 CD10 HLA-DR CD19 CD20 CD79a Expresses Surface: IgM IgG IgA	Nodular growth pattern	Most common clinically indolent NHL Peripheral nerve compression
Mantle cell lymphoma		Mature B-cell Lymphoma CD5 positive antigen in pre germinal center of B-cell Monomorphous small to medium sized B lymphocytes with irregular nuclei Chromosomal translocation at t(11:14)	Fatigue Night sweats Weight Loss	–	Abdominal distention	+	Palpable masses in skin, breast, and salivary glands Generalized lymphadenopathy	Extranodal involvement of GI tract, lungs, and CNS Mental Retardation	Positive for: CD5 B-cell antigen Cyclin D (overexpression) Co-express surface: IgM IgD Negative for: CD23-	Germinal centers filled by small-to-medium atypical lymphocytes Nodular appearance	_
Marginal zone lymphoma	Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type	Mature B-cell Lymphoma Recurrent translocations such as: t(1;14)(p22;q32) t(11;18)(q21;q21) t(14;18)(q32;q21) t(3;14)(p14.1;q32)	B symptoms may or may not be present	±	+	+	Painless or painfullymphadenopathy which can be gastric or non-gastric Lump in the superior lateral quadrant of the orbit, breast, neck, or salivary gland	Symptoms depend on the location of the tumor and may include: Fatigue Heartburn Fever Cough with blood in sputum Shortness of breath	B-cell associated antigens that co-express: BCL-2 CD19 CD20 CD22 CD79a Negative for: CD5 CD10 CD43 Cyclin D1	Presence of dense diffuse lymphoid infiltrate of marginal‐zone cells in lamina propria Prominent lymphoepithelial lesions and consisting of small atypical cells with monocytoid features	H. pylori infection Hashimoto's thyroiditis Sjogren’s syndrome Celiac disease
	Splenic marginal zone lymphoma	Mature B-cell Lymphoma Clonal rearrangements of the immunoglobulin genes (heavy and light chains) Deletion 7q21-32 Translocations of the CDK6 gene located on 7q21	Fever Weight loss Night sweats	+	+	–	Painless swelling in the neck, axilla, groin, thorax, and abdomen.	Chest pain Bone pain	CD20 CD79a	Small lymphocytes Transformed blasts Epithelial histocytes Plasmacytic differentiation of neoplastic cells	Hepatitis C infection
	Nodal marginal zone B-cell lymphoma	Mature B-cell Lymphoma Stimulation of antigen receptor by autoantigen and co-stimulatory molecule CD40 Mutations in KMT2D, PTTPRD, NOTCH2, KLF2	Fever Weight loss Night sweats	+	–	–	Painless swelling in the neck, axilla, groin, thorax, and abdomen Generalized and local lymphadenopathy	Hemorrhage Dyspepsia	_	Follicular cells in reactive zone Centrocyte like cells in marginal zone lymphoma Centroblasts Plasma cells Immunoblasts	Hepatitis C infection Chronic infectious conditions or autoimmune processes, such as: H pylori gastritis Hashimoto thyroiditis Sjögren syndrome
Multiple Myeloma		Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells Clonal plasma cell proliferation	Constitutional symptoms may or may not be present Diffuse bone pain and tenderness with osteolytic lesions Worsens with activity Usually involves spine and ribs (axial skeleton) Hypercalcemia symptoms: Polyuria Polydipsia Constipation Loss of appetite Nausea and vomiting Lethary due to anemia Neurological symptoms: Numbness due to plasma cell infiltration of nerves or anti-neuronal glycoprotein antibodies Muscle weakness Confusion Dizziness Headache Paralysis Visual changes	–	Abdominal pain due to mesenteric venous thrombosis	No diarrhea Constipation due to hypercalcemia	Lymphadenopathy Hepatomegaly Splenomegaly Abdominal tenderness (if hypercalcemia is present)	Bone marrow failure-related symptoms, due to crowding out of normal bone marrow precursors by malignant plasma cells: Easy bruising, nosebleeds, bleeding gums due to thrombocytopenia Fatigue, weakness, shortness of breath, dizziness and paleness due to anemia Recurrent infections due to leukopenia Thrombotic symptoms, due to cancer-associated thrombosis and due to lenalidomide, which increases thrombotic risk: Shortness of breath due to pulmonary embolism Lower extremity edema due to deep vein thrombosis and renal involvement Abdominal pain due to mesenteric venous thrombosis Transient ischemic attack Retinal hemorrhage Pallor Ecchymoses Purpura Conjuctival pallor Visual defects Exudative retinal detachment Increased adipose deposition around the neck (if dexamethasone is used for therapy) Cotton-wool spots may be present Bony tenderness along cervical, thoracic, lumbar spine and in long bones Tinel's sign may be present Phalen sign may be present Dermatomal sensory loss Altered sensation Neuropathy Mood alterations (if hypercalcemia is present)	Expresses: CD138 CD38 CD79a VS38c Infrequently expresses CD19 CD56 (expressed by 70% of myeloma cells) Absent surface Ig	Infiltration of plasma cells in the bone marrow	Relevant history includes: Review of past medical history for other plasma cell diseases, hematologic malignancies, underlying renal disease, and underlying bone disease Review of family history for members with positive history of hematologic malignancies Review of occupational history related to farming, oil industry, or Agent Orange exposure
B-cell prolymphocytic leukemia		Deletion of chromosome 11 Chromosome 13	Anemia Weight loss Loss of appetite Fever	–	–	–	Massive splenomegaly Peripheral lymphadenopathy Hepatomegaly	Rapidly rising lymphocyte count Thrombocytopenia Pallor Petechiae Bruising Tachycardia Tachypnea	Expresses: Bright surface IgM IgD +/- CD20 CD19 CD22 CD79a FMC7 CD5 CD45 HLA-DR CD23+/- CD38 FMC7 Doesn't express: CD10	Prolymphocytes comprise >55% of the neoplastic cells Bone marrow has interstitial pattern of infiltration Lymph nodes may show vague nodularity, but proliferation centers are absent	t(11;14) must be excluded No associated paraproteinemia More common in white race and Ashkenazi jewish male

GC-associated lymphoid clones infiltrating the BM osteoblastic niche exhibit mesenchymal features in common with SLO germinal centers.(A–D) Histological examination of B-cell non-Hodgkin lymphoma (B-NHL) patient specimens. (A) The frequency of para-trabecular/osteoblastic localization of lymphoid malignant clones in 197 cases of B-NHL with bone marrow (BM) infiltration. Lymphoid clones of germinal center (GC)-derivation exhibiting preferential tropism for the BM osteoblastic niche include: follicular lymphoma (FL), T-cell rich histiocyte rich diffuse large B-cell lymphoma (TCRBCL), and diffuse large B-cell lymphoma of GC type (DLBCL-GC). Non-GC-related lymphoid clones include: DLBCL- activated B-cell type (ABC); mantle-cell lymmphoma, (MCL); marginal-zone lymphoma, (MZL); lymphoplasmacytic lymphoma, (LPL). (B) Para-trabecular (left panel) and inter-trabecular (right panel) localization of two representative cases of FL with BM infiltration. The distribution of the lymphomatous infiltrates around bone trabeculae or in the inter-trabecular lacunae is highlighted by CD20 immunostaining (inserts). (C–D) FL lymphoid infiltrates localizing within the osteoblastic niche area (left panels) and inter-trabecular BM (right panels) display a stromal architecture reminiscent of that of secondary lymphoid organ (SLO) GCs and are characterized by the expression of BM-MSC markers SPARC (C) and CD146 (right D).Source: Sangaletti S. et al, Molecular Immunology Unit; Department of Experimental Oncology and Molecular Medicine; Fondazione IRCCS Istituto Nazionale Tumori; Milan, Italy.

Expression of CD19 and CD20 in B-cell lineage.Notes: Illustrative representation of B-cell differentiation, maturation, antigen expression and B-cell neoplasm associated with different stages of B-cell development. Cell lines used in the research study.47–51Abbreviations: GC, germinal center; ALL, acute lymphoblastic leukemia; MCL, Mantle cell lymphoma; FL, follicular lymphoma; BL, Burkitt lymphoma; DLBCL, Diffuse Large B-Cell Lymphoma; MZL, Marginal Zone Lymphoma; CLL/SLL, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; MALT, Mucosa-Associated lymphoid tissue; WM, Waldenstrom macroglobulinemia; MM, plasma cell myeloma; WSU-BL, Wayne State University-Burkitt lymphoma cell line; WSU-FSCCL, Wayne State University-follicular small cleaved cell lymphoma Cell line; WSU-NHL, Wayne State University-FL grade 3 Cell line; WSU-DLCL and WSU-DLCL2, Wayne State University-Diffuse large B-Cell lymphoma cell line; WSU-WM, Wayne State University-Waldenstrom macroglobulinemia Cell line.Source: Raufi A. et al, Lymphoma Research Laboratory, Wayne State University School of Medicine (WSU-SOM), Gordon Scott Hall for Basic Medical Sciences, Detroit, MI, USA.