Lymphoplasmacytic lymphoma differential diagnosis

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

Overview

Lymphoplasmacytic lymphoma 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

Lymphoplasmacytic lymphoma must be differentiated from other B cell lymphoid neoplasms including:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma:

• Always express CD5.
• Usually CD23 positive.

• B-cell prolymphocytic leukemia:

• Express bright surface IgM, CD20 and other B-cell antigens (CD19, CD22, CD79a, FMC7).

• Follicular lymphoma:

• Express CD10, HLA-DR, pan B-cell antigens (CD19, CD20, CD79a), CD21, and surface IgM, IgG, or IgA.
• Rearrangement of Bcl-2.

• Multiple myeloma:

• Express CD138, CD38, CD79a, VS38c and CD56 (70%)
• Presence of plasmacytic cell infiltration of bone marrow, osteolytic lesions, and renal insufficiency
• Translocation involving chromosome 11 (t11;14)

• Mantle cell lymphoma:

• Expresses CD5+ and CD23+
• Expresses surface IgM, IgD, and cyclin D1 in majority of cases
• Infiltration of bone marrow by monomorphous small lymphoid cells with irregular nuclei

• Marginal zone lymphoma:

• Expresses B cell markers CD19, CD20, and CD22.
• Infiltrates the bone marrow with a characteristic intertrabecular and intrasinusoidal pattern
• Most common cytogenetic abnormalities are loss of 7q (19%) along with +3q (19%) and +5q (10% )

Histopathology, immunophenotype, and genetic features of differential diagnosis of lymphoplasmacytic lymphoma

Disease entity	Histopathology	Immunophenotype	Genetic or other features
Lymphoplasmacytic lymphoma	≥10 percent infiltration by small lymphocytes, plasmacytoid lymphocytes, and plasma cells, with variable numbers of admixed immunoblasts. Characteristic (but not pathognomonic) hyperplasia of mast cells in marrow. Lymph nodes are usually diffusely effaced. Absence of proliferation centers and marginal zone type differentiation.	Expression of pan B-cell antigens (CD19, CD20, CD22, CD79a). Failure to express CD5 in mostly cases. Variable expression of CD11c, CD43, CD25. Mostly cases have IgM expression with only fewer expressing IgG or IgA. No CD10 and cyclin D1 expression.	Majority have a monoclonal IgM paraprotein. No specific chromosomal abnormalities.
Chronic lymphocytic leukemia/small lymphocytic lymphoma	"Typical" CLL/SLL cells are small mature appearing lymphocytes with a dense nucleus, partially aggregated chromatin, no discernible nucleoli, and a narrow border of clear to slightly basophilic cytoplasm.	Always express CD5. Usually CD23 positive. Dim expression of CD20 and surface Ig.	Del13q, del 11q, del17p, trisomy 12
B-cell prolymphocytic leukemia	Prolymphocytes comprise >55 percent of the neoplastic cells. Bone marrow has interstitial pattern of infiltration. Lymph nodes may show vague nodularity, but proliferation centers are absent.	Express bright surface IgM +/- IgD and bright CD20 as well as other B-cell antigens (CD19, CD22, CD79a, FMC7).	t(11;14) must be excluded. No associated paraproteinemia.
Follicular lymphoma	Nodular growth pattern of follicle center cells (centrocytes and centroblasts).	Typically express CD10, HLA-DR, pan B-cell antigens (CD19, CD20, CD79a), CD21, and surface IgM, IgG, or IgA.	t(14;18)
Multiple myeloma	Infiltration of plasma cells in the bone marrow.	Absent Surface Ig. Expresses CD138, CD38, CD79a, and VS38c. Infrequently expresses CD19. Approximately 70 percent of myeloma cells will express CD56.	Cytogenetics usually abnormal, although there is no specific cytogenetic abnormality.
Mantle cell lymphoma	Monomorphous small to medium-sized B lymphocytes with irregular nuclei.	CD5+ and CD23-. Typically co-express surface IgM and IgD. The vast majority over-express cyclin D1.	t(11;14)
Marginal zone lymphoma	Polymorphous infiltrate of small cells with paler-appearing marginal zone-type differentiation in lymph nodes.	Expresses B cell markers CD19, CD20, and CD22, and not CD5, CD10, and CD23.	Chromosomal abnormalities, usually trisomy 3 or t(11;18), are found in most cases. May demonstrate mixed cryoglobulinemia +/- hepatitis C infection.

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
Lymphoplasmacytic lymphoma (Waldenstrom’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	Express 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 abnormalties 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 express CD5 CD38 Usually express 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	Express CD21 CD23 CD10 HLA-DR CD19 CD20 CD79a Express 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	CD5+ CD23- B-cell antigen positive Overexpression of Cyclin D Co-express surface IgM IgD	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 translocation of s 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 painfull lymphadenopathy 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: 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	Diffuse bone pain and tenderness with osteolytic lesions Worsens with activity Usually involves spine and ribs (axial skeleton) Renal failure Hypercalcemia symptoms: Polyuria Polydispsia 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	_	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 Lower limb edema due to renal involvement 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 Abdominal pain due to mesenteric venous thrombosis Transient ischemic attack Retinal hemorrhage	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				–	–	–			Express bright surface IgM +/- IgD and bright CD20 as well as other B-cell antigens (CD19, CD22, CD79a, FMC7)	Prolymphocytes comprise >55 percent 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

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.