Lymphoma: B cell and plasma cell neoplasms
Last revised 11 December 2008
Last major update July 2004
Copyright (c) 2001-2008 PathologyOutlines.com, Inc.
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Lymph nodes: normal development, normal histology, molecular analysis, grossing lymph nodes, features to report
Non-Hodgkin’s lymphoma: general, classification, cytogenetics, staging, morphologic clues, hemophagocytic syndrome, chemotherapeutic atypia
B cell disorders: general, WHO classification
B cell lymphoma subtypes: Burkitt, Burkitt-like, CLL/SLL, diffuse large B cell, follicular, hairy cell leukemia, intravascular large B cell, lymphomatoid granulomatosis, lymphoplasmacytic, mantle cell, marginal zone-general, marginal zone-MALT, marginal zone-nodal, mediastinal (thymic), plasmablastic, pre B lymphoblastic leukemia/lymphoma, primary cutaneous B cell, primary cutaneous diffuse large B cell, primary effusion, prolymphocytic leukemia, pyothorax associated, splenic marginal zone, splenic lymphoma with villous lymphocytes
Plasma cell neoplasms: general, myeloma, plasmacytoma, heavy chain disease, primary amyloidosis, MGUS, cryoglobulinemia
Go to Lymphomas: non B cell
(T/NK cell disorders, Hodgkin Lymphoma, Post-transplantation/other, AIDS associated lymphoproliferative disorders, Other)
American Journal of Clinical Pathology (AJCP), Jan 1997 to Apr 2002 (no photos)
American Journal of Surgical Pathology (AJSP), Jan 1999 to July 2004
Archives of Pathology and Laboratory Medicine (Archives), Jan 1999 to July 2004
Human Pathology (Hum Path), Jan 2000 to June 2004
Modern Pathology (Mod Path), Jan 2001 to July 2004
Kjeldsberg, CR: Practical Diagnosis of Hematologic Disorders (3rd Edition); ASCP Press, 2000
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004, 728-45
Please refer to these primary references for more detailed discussions
Normal lymphoid cells undergo rearrangements within their antigen receptor genes, causing specificity for the immunoglobulin or T cell receptor that they produce
Monoclonal proliferations are presumed to be neoplastic; polyclonal populations are not
Lymphoid stem cell: TdT+, CD34+, HLA-DR+, then develops along B or T cell pathway
B cells
Develop from stem cells of yolk sac, fetal liver, spleen and bone marrow
In intersinusoidal bone marrow, hematopoeitic stem cells mature to early lymphoid progenitors, the pro-B, pre-B stages
Developmental stages are in close contact with slender CD10+ stromal cells or their extensions, which allows tightly regulated signaling (J Pathol 2005;205:311)
B cells express surface immunoglobulin (Ig), composed of 2 heavy (H) and 2 light (L) chains (either kappa or gamma)
B cell antigen receptor loci may have 4 types of modification - recombination of variable, diversity and joining regions (VDJ); somatic hypermutation of V segments; immunoglobulin heavy chain gene class switching; and receptor editing
Defects may cause chromosomal translocations
1-diagram of IgH gene rearrangement
References: Archives 2003;127:1148
Early B cell precursor is TdT+, CD34+, HLA-DR+, then undergoes heavy (H) chain rearrangement and adds CD19, then adds CD10, then adds IgM heavy chain; then adds light (L) chain rearrangement and adds cytoplasmic IgM with heavy and light chains, then B cells express IgM and IgD with the same binding site, then adds CD20 (now called preB cell); then adds surface Ig, then adds CD21 and CD22 and drops TdT (now called B cell)
If B cell encounters an antigen that interacts with its variable region, it becomes a plasma cell
Precursor B cells contain immunoglobulin related components but not immunoglobulin; express CD179a and CD179b (precursor to light chains) as part of their pre-B cell receptor, which disappears when replaced with conventional light chains
B cells express surface immunoglobulin, consisting of heavy chain and kappa or lambda light chains; immunoglobulin is associated with CD79a/CD79b complex to form a B cell antigen receptor complex
IgH (heavy chain of immunoglobulin): 14q32; variable portion coded by VDJ regions
IgL (light chain of immunoglobulin): kappa on 2p11, lambda on 22q11; no diversity region is present
Heavy chain isotype switch: determines if immunoglobulin is IgM, IgD, IgG1-4, IgA1-2 or IgE (9 constant regions); mediated by switch genes
B cell lymphomas: clonal light chain rearrangement is usually specific for the presence of a B cell neoplasm
Develop from bone marrow, become prothymocytes, then migrate to thymus gland, where self-recognizing T cells are eliminated
T cell receptors (TCR) are either alpha/beta (95%) or gamma/delta (5%) heterodimers
Precursor cell is TdT+, CD34+, HLA-DR+, then drops HLA-DR, then adds CD2, CD5, CD7 (early thymocyte) while undergoing gamma/beta chain rearrangement, then adds CD1 and drops CD34, now a common thymocyte, then undergoes beta/alpha chain rearrangement and adds CD4 and CD8, then splits into helper or cytotoxic T cell, without TdT, CD1, CD5 and CD7; has CD2, CD3, CD4 (helper) or CD8 (cytotoxic)
T alpha and delta are on 14q11; T beta is on 7q34; T gamma is on 7p15 (note: there are only 10 V regions, so a polyclonal population of cells can appear oligoclonal)
90% of peripheral T-cell lymphomas have rearrangements of T-alpha, beta and gamma, including all cases of mycosis fungoides and Sezary syndrome
T cell lymphomas: no distinct marker of clonality, but cells may express an abnormal immunophenotype
Note: T cell clonality is seen in AIDS and congenital immunodeficiency syndromes, but does NOT indicate malignancy
Note: rarely a clonal band may comigrate with the germline band; solution - use 2-3 restriction enzymes (HindIII, EcoRI, BamHI)
Note: T cells and NK cells arise from common progenitor that expresses CD3 epsilon and cannot develop into B cells
NK cells
Distinct group of non-T, non-B lymphocytes; large granular lymphocyte morphology on Wright-Giemsa stains; capable of lysing certain target cells without prior activation or major histocompatibility complex restriction; believed important in defense against viral and bacterial infections and cancers as well as immunomodulation and regulation of hematopoiesis; comprise 5-20% of peripheral blood lymphocytes
Positive stains: CD56 (adhesion molecule), CD57 (unknown function), CD16
(low affinity IgG Fc receptor / FC
RIII that is responsible for antibody
dependent cellular cytotoxicity in NK cells and also expressed on neutrophils
and monocyte subset); also cytoplasmic (not surface) CD3, CD2, CD7, CD8,
perforin, granzyme B, TIA-1
>90% are CD16+/CD56+
Centroblasts: large non-cleaved follicular center cells with moderate amounts of basophilic cytoplasm, round nuclei, open chromatin, multiple peripheral nucleoli
Centrocytes: small cleaved follicular center cells with scant cytoplasm
Leukemia: lymphoid neoplasms that present with widespread bone marrow involvement and large numbers of tumor cells in the peripheral blood
Mantle zone: Small unchallenged B cells surrounding pale staining germinal centers
Marginal zone: light zone surrounding follicles; contain post-follicular memory B cells derived after stimulation of recirculating cells from T cell dependent antigen
Germinal center: strong dense bcl6 expression and CD10 expression
TdT: terminal deoxynucleotidyl transferase; marker for premature B and T cells
Note: antigen stimulated B cells with the capacity to differentiate toward plasma cells express MUM1/IRF4 and CD138
Fluorescent in-situ hybridization (FISH)
To identify and count chromosomes / parts of chromosomes
Sources for testing (advertisements): Genzyme (FISH)
Northern blot
To detect mRNA
Polymerase chain reaction (PCR)
10,000 times more sensitive than Southern blot
Clones appear as 1-2 bands (if 1 or 2 alleles were rearranged); polyclonal cells appear as a smear since no amplification usually occurs due to wide separation of V and J regions
Faster than Southern blot and minimal tissue required
Helpful for determining clonality of lymphoid aggregates in bone marrow biopsies (Archives 2000;124:511)
Procedure: add sample DNA, 4 nucleotides, buffer with magnesium, primers and Taq DNA polymerase to test tube; use PCR cycler with 3 reactions (#1 - denature double stranded DNA, #2 - allow annealing of primers, #3 - allow DNA polymerase activity to extend primer); multiple cycles allow exponential expansion of amount of DNA; analyze products by gel electrophoresis, then stain gel with ethidium bromide OR transfer gel to nylon membrane by Southern blotting and hybridize membrane with labeled probe
False negatives due to imperfect consensus primers, inability to detect partial DJ rearrangements; mutations of Ig genes that prevent annealing of primers; lymphomas that arise from B cell precursors prior to rearrangement
PCR + temperature gradient gel electrophoresis
To analyze T cell receptor gene rearrangement (Archives 2001;125:202)
Reverse transcriptase PCR (RT-PCR)
To detect chimeric fusion mRNA transcripts translocations
Southern blot
Detects DNA via restriction endonucleases, electrophoresis and probes
For lymphoma, detects alterations of DNA restriction fragment length from rearrangement of immunoglobulin and T cell receptor genes
Rearrangement forms a distinct band if only 1% of total cells are affected, so very sensitive; only a single germline band is present if polyclonal or not clonal, image
Difficult and slow to perform
Procedure: extract DNA, cut into small fragments with restriction enzymes (EcoRI, HindIII, BamHI); run on electrophoretic gel (agarose); apply nylon membrane (blot) over gel to transfer DNA fragments onto membrane; denature the probe DNA and DNA fixed to the blot to allow hybridization and add probe DNA; detect the probe (xray if probe radioactive); usually analyze IgH and TCR-beta for clonality
Theory of molecular analysis
B cells express surface immunoglobulin (Ig), composed of 2 heavy (H) and 2 light (L) chains (either kappa or gamma)
T cell receptors (TCR) are either alpha/beta (95%) or gamma/delta (5%) heterodimers
Ig and TCR germline configuration contains Variable, Diversity, Joining and Constant region segments, IgH; TCR
Early in normal lymphocyte differentiation within the bone marrow, the antigen receptor genes undergo recombination to create a variable region, image, containing an antigen combining site and a constant region. Diversity occurs through recombination of segments plus imprecise V-D-J joining
Terminal deoxytransferase (TdT) adds or removes nucleotides, causing even more diversity
Point mutations in V and J regions occurs commonly within Ig genes, adding to diversity
An estimated 100 million different Ig and TCRs exist
Rearrangement forms a distinct band if multiple cells have the same rearrangement pattern, indicating clonality
80% of B or T cell lymphomas with characteristic immunologic and clinical features have clonal IgH or TCR-gamma rearrangement by PCR (Mod Path 2000;13:1269); 10% of B cell and T cell lymphomas have both clonal IgH and TCR-gamma rearrangement
DD of “clonality”: non-neoplastic tissue may be clonal, perhaps due to autoimmune diseases for B cell disorders or granulomatous diseases for T cell disorders; tissue with a small number of polyclonal B cells (skin, GI) may cause a pseudoclonal PCR profile; best to do multiple PCR and look for same rearranged band in every experiment
References: Archives 1999;123:1189
Best to obtain fresh and intact
Handle under sterile conditions for microbiology (depending on clinical history)
Use scrapes / cell suspension for flow cytometry, cytogenetics, molecular gene rearrangement studies, FISH
Obtain imprints for Wright stain or immunocytochemistry
Snap-freezing is best for research, some immunohistochemistry, future molecular studies
B5 (mercury containing fixative) provides best morphologic details
Formalin fixation is best for PCR
Use thin (2 mm) slices for proper fixation; cut perpendicular to long axis if possible
Include extranodal fat (infiltration implies malignant)
Clinical history (prior diagnoses of lymphoma, presence of lymphadenopathy or organomegaly, hematologic findings, constitutional symptoms, HIV status, prior immune abnormality, autoimmune disorders, other relevant serology, other related conditions such as H. pylori infection)
Anatomic site
Tumor type(s) (WHO classification), grade (if relevant)
Focal or complete involvement of lymph node or other structures
Specimen inadequacy
Results of ancillary studies
References: Hum Path 2002;33:1064; Mod Path 2004;17:131
Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma - general
Clonal lymphoproliferative disorder
Increasing incidence over past 40 years for unknown reasons
50,000 new cases in US per year, many HIV related
Heterogenous types of neoplasms; diagnosis of “NHL” gives far less information than type of NHL
Putative cell of origin known for most B cell NHLs but not most T cell NHLs
Often associated with a cytogenetic translocation that puts a proto-oncogene or apoptotic gene next to a gene that is constitutively active in lymphocytes
80% are B cell, NK are rare
All are monoclonal, as determined by antigen receptor gene rearrangement (immunoglobulin or T cell receptor)
Characteristic patterns of tissue involvement occur, such as follicular lymphomas in B cell areas, T cell lymphomas in paracortical zones
Most tumors are widely disseminated at diagnosis, requiring systemic therapy for cure; thus, staging is not as important as in Hodgkin lymphoma
In adults, most common subtypes are follicular lymphoma, diffuse large B cell lymphoma, CLL/SLL, multiple myeloma
Usually HER2 negative (Archives 2002;126:574)
Prognostic factors: see particular tumors; cyclin D3 overexpression identifies patients with indolent B cell lymphomas but adverse clinical features and poorer survival (AJCP 2001;115:404)
Risk factors: immunodeficiency (primary or secondary), autoimmune disorders (Sjogren’s, rheumatoid arthritis, Hashimoto’s thyroiditis), viruses (HIV, ATLV, KSHV/HHV8, HTLV-1), Helicobacter pylori infection, radiation, chemotherapy
Compared to Hodgkin lymphoma: more often extranodal, more often involve peripheral blood, bone marrow, GI, skin or CNS, more often disseminated, present with B symptoms less often (20% vs. 40%), less often mediastinal involvement (except for lymphoblastic and mediastinal large B cell lymphoma)
International Prognostic Index (IPI): poorer prognosis - age at diagnosis >60 years, presence of B symptoms, performance status 2-4 vs. 0-1, elevated serum LDH, more than 1 nodal or extranodal sites of disease, advanced vs. localized disease
Treatment: addition of rituximab (anti-CD20 antibody) to most regimens leads to improved survival
DD: florid immunoblastic proliferations seen in infectious mononucleosis or other viral infections, particularly in children; autoimmune lymphoproliferative syndromes in patients in Fas or FasL deficiency may develop giant lymphadenopathy resembling EBV+ post-transplant lymphoproliferative disease (AJSP 1999;23:829)
Sources for testing (advertisements): Genzyme (Flow cytometry), Genzyme (FISH)
Childhood NHL
Most common subtypes are Burkitt or Burkitt like, lymphoblastic leukemia/lymphoma, large cell lymphoma
Follicular and marginal zone lymphoma are uncommon
Usually extranodal, aggressive, often leukemic; better survival than adults
Fine needle aspiration
Sensitivity and specificity increase with flow cytometry; good in most lymphomas except marginal zone lymphoma and Hodgkin lymphoma
References: Archives 2000;124:1792
Rappaport classification: 1956, revised 1966
Lukes and Collins classification, 1974
Working Formulation: 1982; tumors classified as low, intermediate or high grade; nodular vs. diffuse; small, large or mixed tumor cell size
Kiel classification: European system used in 1980-1990’s
REAL (Revised European American Lymphoma) / World Health Organization (WHO): integrates clinical, morphologic, immunohistochemical and molecular characteristics
Includes NHL, lymphocytic leukemias, plasma cell neoplasms; excludes histiocytic neoplasms
Tumors are not classified as low grade / high grade since one entity could have both types
High concordance under REAL between diagnoses in community hospital and academia; discordances seen for diffuse large cell lymphoma vs. Burkitt-like lymphoma, marginal zone lymphoma vs. another subtype, follicle center lymphoma grade II vs. grade III, Hodgkin lymphoma-nodular sclerosis vs. mixed cellularity (AJCP 2001;115:650)
Relatively common translocations (more complete lists are listed with each tumor)
t(1;14)(p22;q32): bcl-10 and IgH; MALT lymphoma (% unknown)
t(1;14)(p32;q11): SCL (tal-1) and T cell receptor delta/alpha; precursor T acute lymphoblastic leukemia (15-30%)
t(1;14)(q21;q32); bcl-9 and IgH; preB ALL, mantle cell lymphoma
t(1;19)(q23;p13): PBX1 and E2A; precursor B acute lymphoblastic leukemia (30%)
t(2;5)(p23;q35): ALK and NPM; anaplastic large cell lymphoma, T/NK subtypes (40-70%)
t(2;8)(p12;q24): Ig Kappa and c-myc; Burkitt lymphoma (15%)
t(2;18)(p12;q21): Ig Kappa and bcl2; follicular lymphoma (<5%)
Trisomy 3: MALT lymphoma (% unknown)
t(3;14)(q27;q32): bcl6 and IgH; diffuse large B cell lymphoma (30%), follicular lymphoma (10%)
t(4;11)(q21;q23): AF4 and MLL; precursor B acute lymphoblastic leukemia (10%)
t(4;14)(p16.3;q32): FGFR3/mmset and IgH; multiple myeloma (25-30%)
t(5;14): preB ALL and peripheral eosinophilia; IL3 gene and IgH
t(6;14)(p25;q32) - mum/irf4 and IgH; multiple myeloma
7q isochromosome: protein unknown, hepatosplenic gamma/delta lymphoma (% unknown)
Trisomy 8: protein unknown, hepatosplenic gamma/delta lymphoma (% unknown)
t(8;13)(p11;q11-12): FGFR1 and ZNF 198; T cell lymphoblastic with eosinophilia (% unknown)
t(8;14)(q24;q32): c-myc and IgH; Burkitt lymphoma (75%), acute lymphocytic leukemia-type L3 (6%)
t(8;21): ETO gene and AML1 gene; AML-M2
t(8;22)(q24;q11): c-myc and Ig Lambda; Burkitt lymphoma (10%)
9p amplification: REL; primary mediastinal large B cell lymphoma (% unknown)
t(9;14)(p13;q32): PAX5 and IgH; lymphoplasmacytic lymphoma (% unknown)
t(9;22)(q34;q11): c-abl and bcr (Philadelphia chromosome); precursor B acute lymphoblastic leukemia
(5% of children, 25% of adults), chronic myelogenous leukemia (100%)
t(10;14)(q24;q11): HOX11 and T cell receptor delta/alpha; precursor T acute lymphoblastic leukemia (7%)
deletion of 11q23: CLL (10-20%)
t(11;14)(q13;q32): bcl-1/PRAD1 and IgH; mantle cell lymphoma (90%), B cell prolymphocytic leukemia (20%), myeloma (3%)
t(11;14): T-ALL; rhombotin 1/2 genes and IgH
t(11;18)(q21;q21): API2 and MLT; MALT lymphoma (50%)
Trisomy 12: protein unknown, B chronic lymphocytic leukemia (30%)
t(12;21)(p13;q22): ETV6-CBFA2 (TEL and AML1); Precursor B acute lymphoblastic leukemia (20%)
deletion 13q14: protein unknown; B cell CLL (25-50%)
inversion 14(q11;q32) or other #14 translocations: T cell prolymphocytic leukemia (75%)
t(14;15)(q32;q11-13); IgH and bcl-8; diffuse large B cell lymphoma (3%)
t(14;16)(q32;q23); IgH and c-maf; multiple myeloma
t(14;18)(q32;q21): IgH and bcl2; follicular lymphoma (90%), diffuse large B cell lymphoma (30%), image
t(14;19)(q32;q13): IgH and bcl-3; B cell CLL
t(15;17): retinoic acid receptor and PML gene; acute prolymphocytic leukemia, M3 (most)
t(16;22);(q23;q11): cmaf and Ig lambda; multiple myeloma
Trisomy 18: common in marginal zone lymphoma, MALT type
Staging of Non-Hodgkin lymphomas
I: one anatomic region or two contiguous regions on same side of diaphragm
II: two or more anatomic regions or noncontiguous regions on same side of diaphragm
III: both sides of diaphragm, but lymph nodes or spleen only
IV: any lymph node region plus liver, lung or bone marrow
National Cancer Institute Modified Staging for Intermediate and High Grade Lymphomas
I: Localized disease (nodal or extranodal)
II: Two or more nodal sites or a localized extranodal site plus draining sites plus either performance status <=70, B symptoms, any mass > 10 cm, serum LDH > 500, 3 or more extranodal sites of disease
III: Stage II and any poor prognostic factor
Morphologic clues to diagnosis
Small cells, round: CLL/SLL
Small / intermediate cells with atypia: Mantle cell lymphoma (irregular), MALT lymphoma (monocytoid)
Intermediate cells: follicular lymphoma (cleaved), Burkitt lymphoma (non-cleaved, prominent nucleoli), lymphoblastic lymphoma (fine chromatin)
Large cells: diffuse large B cell lymphoma, mycosis fungoides or Sezary syndrome (cerebriform), anaplastic large cell lymphoma (pleomorphic)
May be associated with non-Hodgkin lymphoma (most common: diffuse large B cell, T cell, NK)
Systemic presentation (fever, splenomegaly, jaundice), survival < 2 years, mild interstitial lymphoid infiltrate of bone marrow at presentation (AJSP 2001;25:865)
Treatment: cytotoxic chemotherapy if EBV related vs. treatment of infection in non-EBV infection
Gross: often no pronounced tumor mass
Micro: hemophagocytosis (phagocytosis by macrophages of white blood cells, red blood cells, platelets and precursors); in bone marrow, mild interstitial lymphoid infiltrate at presentation
Positive stains: depends on tumor type
Molecular: occasional HHV6 positive by PCR
Chemotherapeutic agents, particularly alkylating agents, can induce bizarre epithelial atypia
Observed in lower respiratory tract and sinonasal tract
Includes patients treated for leukemia, myeloma
Micro: striking nuclear enlargement, hyperchromasia and pleomorphism
DD: dysplasia, particularly in frozen sections (AJSP 2001;25:652)
B cell disorders
Almost always surface immunoglobulin light chain positive
Low grade tumors may have extensive sarcoid-like granulomas (Archives 2000;124:152)
B cell non-Hodgkin lymphomas rarely are CD2+, but behavior is similar to CD2- tumors; must differentiate from composite B, T cell lymphomas (AJCP 2001;115:396)
Micro images: granulomas in low grade lymphoma
Post-rituximab (anti-CD20 antibody)
Bone marrow specimens may contain aggregates of T cells that suggest relapse; so ordering immunostains is important (AJCP 1999;112:844)
CD79a and Pax-5 should be used as the first-line B lineage-specific markers for CD20 negative mature B-cell lymphomas; if negative, OCT.2 or BOB.1 may be useful (AJCP 2006;126:534)
B cell disorders - bone marrow biopsy
Overall incidence of marrow involvement at diagnosis of 40-55% in adults, varies from 20% (MALT lymphoma) to 80% (splenic marginal zone / mantle cell lymphoma)
Usually less than half of marrow is involved, particularly in SLL and follicular center cell lymphoma
Patterns of involvement are diffuse, focal paratrabecular, focal nonparatrabecular, interstitital intrasinusoidal
Rare patterns are intravascular or recapitulating nodal involvement by neoplasm
Focal paratrabecular: suggests follicular center cell lymphoma
Interstitial pattern: preservers marrow architecture but infiltrates interstitium of marrow; may appear normal on low power
Intrasinusoidal pattern: difficult to identify without special stains (CD20)
Predominant cell type in marrow usually is similar to that in lymph node, particularly for Burkitt’s lymphoma and T cell lymphoma; may be discordant for follicular lymphoma (marrow-small cleaved cells; lymph node-large cells or mixture of large and small cells)
Discordance of marrow and nodal lesions may be due to different clones, a benign lesion at one site or post-antibody therapy
Granulomas are common and non-specific
Note: presence of small, incidental, clonal B cell populations in peripheral blood or marrow often is NOT associated with subsequent lymphoma, at least within a few years (AJCP 2004;122:588)
Immunohistochemistry: important to define cell type involved, extent of involvement, post-treatment residual disease and whether it has same lineage as pre-treatment disease
WHO classification of B cell lymphoid neoplasms
Precursor B cell neoplasms:
Precursor B lymphoblastic leukemia/lymphoma
Mature (peripheral) B cell neoplasms:
Chronic lymphocytic leukemia/small lymphocytic lymphoma
B cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia
Splenic marginal zone B-cell lymphoma
Hairy cell leukemia
Extranodal marginal zone B-cell lymphoma of MALT type
Nodal marginal zone B-cell lymphoma
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B cell lymphoma
Mediastinal (thymic) large B cell lymphoma
Intravascular large B cell lymphoma
Primary effusion lymphoma
Burkitt lymphoma/leukemia
Lymphomatoid granulomatosis
B cell lymphoma subtypes
30% of childhood lymphomas, may present as B cell acute lymphoblastic leukemia FAB L3 (also called Burkitt’s leukemia)
Either endemic, sporadic or immunodeficiency-associated
In adults, often associated with immunodeficiency, including HIV; involves distal ileum, cecum, mesentery
In tropical Africa, involves jaw or abdomen (endemic), 95% are EBV positive; malaria may facilitate EBV infection
Curable with aggressive therapy in 60%
Due to c-myc translocation that causes increased constitutive levels of c-myc
Marrow involvement of 15-30%
Leukemic cases were previously classified as FAB-L3;
Call Burkitt’s leukemia if tumor cells present in blood and diffuse marrow involvement at diagnosis
Leukemic cases associated with involvement of ileocecum
Gross images: contributed by Dr. Kaveh Naemi, Irvine, California - ileocecal valve tumor
Micro: diffuse infiltration of monomorphic, medium-sized (10-25 micron) cells with abundant basophilic cytoplasm, non-cleaved round nuclei with coarse chromatin and 2-5 distinct nucleoli; mitotically active with starry sky pattern (stars are tingible body macrophages)
Imprints demonstrate cytoplasmic lipid vacuoles; rarely granulomas (AJSP 2004;28:379)
bone marrow: usually diffuse infiltration of interstitium, with some preservation of adipose tissue; prominent mititoc figures; starry sky feature seen in lymph nodes is rare in marrow
Micro images: bone marrow shows medium sized cells with cytoplasmic vacuoles; starry sky pattern; A/B: Burkitt lymphoma; A-monotonous proliferation of medium sized cohesive cells; B-MIB1 staining of almost all cells; C/D: diffuse large B cell lymphoma with c-myc; C-coarse nuclear chromatin and central prominent nucleoli; D-MIB1+, but not in almost all cells; Ki-67 and bcl2 are strongly positive (uncommon for bcl2)
contributed by Dr. Kaveh Naemi, Irvine, California - ileocecal valve tumor - micro #1; #2; #3; #4; CD20; CD10; bcl2; Ki-67
Positive stains: CD10, CD19, CD20, Ki-67 (almost 100%), surface immunoglobulin; also CD22, CD79a, bcl6, surface IgM; EBV positive in endemic African cases and AIDS cases
Negative stains: CD5, CD23, TdT
Molecular: c-myc translocations:
t(8;14)(q24;q32): c-myc and IgH (75%); also reported in some diffuse large B cell lymphomas
t(2;8)(p12;q24): Ig Kappa and c-myc (15%)
t(8;22)(q24;q11): c-myc and Ig Lambda (10%)
Molecular images: t(8;14)
DD: diffuse large B cell lymphoma with c-myc translocation (Ki-67+ in 67% vs. 100% in Burkitt’s, Mod Path 2002;15:771)
References: Archives 2004;128:549 (EBV in endemic Burkitt)
Elderly patients with leukemic tumor cells resembling Burkitt lymphoma by morphology and immunostains
DD: blastoid variant of mantle cell lymphoma (c-myc neg, cyclin D1+, AJCP 1999;112:828)
Burkitt-like lymphoma (atypical Burkitt)
Usually adults
Micro: cellular pleomorphism and heterogeneity intermediate between Burkitt and diffuse large cell lymphoma
Positive stains: >95% Ki-67+
Negative stains: CD10, c-myc (usually)
Small lymphocytic lymphoma / Chronic lymphocytic leukemia
Almost all cases are B cell origin
Called CLL/chronic lymphocytic leukemia if leukemic involvement at diagnosis (5K/microliter or more of monoclonal B cell lymphocytosis)
SLL may progress to blood involvement, but usually less leukocytosis than cases with initial diagnosis of CLL
Usually older patients (median age 60), 2/3 male, with disease in bone marrow, lymph nodes, spleen, liver
Often presents with leukemia although patients may be asymptomatic
Median survival 4-6 years; indolent but incurable
Associated with hypogammaglobulinemia, monoclonal immunoglobulin spikes in some, infections, autoantibodies to red blood cells and platelets with resulting hemolytic anemia and thrombocytopenia
Often converts to high grade neoplasm via prolymphocytic transformation (20%) or Richter’s syndrome (10%)
Prolymphocytic transformation causes death within median 2 years
Richter syndrome with transformation to diffuse large cell lymphoma retains CLL phenotype (AJCP 2001;115:385) but causes death within median 5 months; Richter syndrome cases with EBV+ Hodgkin’s lymphoma features may have distinct clonal origin (AJSP 2004;28:679)
Primary digestive tract Richter’s syndrome is associated with longer survival (median 22 months) after chemotherapy (Mod Path 2001;14:452)
Rarely transforms to aggressive T cell or NK cell lymphoma with cytotoxic immunophenotype (AJSP 2004;28:849)
Diagnosis: absolute lymphocyte count of 4000 or more in peripheral blood is suggestive
Poor prognostic factors: 17p deletions, 11q22-23 deletion, non-mutated immunoglobulin genes, abherrant expression of CD2, CD7, CD10, CD13, CD33 or CD34 (AJCP 2003;119:824)
Case reports: CLL with composite prolymphocytoid and Hodgkin’s transformation (Archives 2000;124:907), CLL with composite thymoma (Archives 2003;127:E76), CLL with systemic mastocytosis (J Clin Pathol 2006;59:264), filamentous cytoplasm inclusions in peripheral blood due to dilated cisternae of rough endoplasmic reticulum containing IgG (Archives 2003;127:618), cases with t(14;18) (Archives 2002;126:1543), CLL with meningeal infiltration
Gross: nodes identified at prostatectomy are enlarged (mean 3.2 cm)
Micro: effacement of nodal architecture by pale staining pseudofollicles or proliferation centers with ill-defined borders, containing small round mature lymphocytes, prolymphocytes (larger than small lymphocytes, abundant basophilic cytoplasm, prominent nucleoli), paraimmunoblasts (larger cells with distinct nucleoli) and many smudge cells
Pseudofollicular centers are highlighted by decreasing light through the condenser at low power; cells have pale cytoplasm but resemble soccer balls or smudge cells on peripheral smear vs. bubbly cytoplasm in mantle cell lymphoma; may have plasmacytoid features
May have marginal zone, perifollicular or interfollicular patterns, but also proliferation centers (Mod Path 2000;13:1161)
bone marrow: small focal aggregates of variable size with irregular, poorly circumscribed outlines; lymphocytes are well differentiated, small, round with minimal atypia; may have foci of transformation; rarely has granulomas (J Clin Pathol 2005;58:815)
CLL cases with marrow involvement usually have interstitial, interstitial/focal or diffuse patterns; diffuse patterns associated with poor prognosis
marrow infiltrative patterns: also described as diffuse (unmutated IgH genes, ZAP-70+, more aggressive), nodular (associated with IgH hypermutation, ZAP-70 negative) or mixed (variable mutation of IgH, variable ZAP-70, Hum Path 2006;37:1153)
CLL/prolymphocytic leukemia: 10-55% prolymphocytes
Prolymphocytic leukemia: >55% prolymphocytes
Bone marrow involvement is interstitial, not paratrabecular
Other patterns are marginal zone, nodular, perifollicular and interfollicular (see below)
Micro images: increased numbers of mature lymphocytes in peripheral blood; 1-small cells with scant pale cytoplasm and condensed chromatin; 2-atypical CLL with lymphoplasmacytoid cells; 3-atypical CLL with irregular or clefted nuclei; 4-CD79b+ by flow cytometry; prolymphocytic and Hodgkin transformation #1; #2 (CD15, CD30, CD45RO); A-CLL with intracytoplasmic filamentous inclusion; B-anti-IgG lambda fluorescence; C/D-EM shows dilated rough ER; pseudofollicular growth; marginal zone growth; interfollicular growth #1; #2 (CD5+); #3 (CD23+)
Virtual slides: lymph node, bone marrow, liver and kidney; lymph node
Positive stains: CD5, CD19, CD20 (dim), CD23, surface Ig light chain, surface IgM (dim); also CD43, CD79a, CD79b (dim, in 20%), bcl2; variable CD11c, FMC7 (42%)
Negative stains: CD10, cyclin D1
Molecular: Trisomy 12 (30%, associated with atypical CLL and CD79b), deletion 13q14 (25-50%), deletion of 11q23 (worse prognosis, 10-20%)
Molecular images: IgH gene rearrangement
Sources for testing (advertisements): Genzyme (IgVH mutation analysis)
DD: other low grade lymphomas with leukemic phase (mantle cell lymphoma, follicular lymphoma, rarely lymphoblastic lymphoma, Mod Path 2002;15:1111), Hodgkin’s lymphoma, peripheral T cell lymphoma, reactive hyperplasia, persistent polyclonal B cell lymphocytosis (Mod Path 2004 May 14)
References: AJSP 2004;28:801 (new cyclin D1 antibody), Archives 2003;127:561 (CD79b), Archives 2003;127:567 (incidental findings at prostatectomy)
Chronic lymphocytic leukemia (features that differ from SLL)
Almost always B cell, rarely T cell disorder
Called CLL/chronic lymphocytic leukemia if leukemic involvement at diagnosis
Most common adult leukemia in Western countries, less common in Japan/Asia
Diagnosis: absolute lymphocytosis of 10K or more, but be suspicious if 5K or more in adults
Usually associated with lymphadenopathy or hepatosplenomegaly
5% have prolymphocytoid transformation with prolymphocytes (moderate basophilic cytoplasm, coarse chromatin, prominent single nucleoli) and paraimmunoblasts (larger cells with more abundant cytoplasm, disbursed chromatin, single prominent eosinophilic nuclei)
Cases with serum IgM paraprotein (3% of total) are otherwise similar (AJCP 2005;123:594)
Poor prognostic factors: high stage, high CD38 expression, p53 expression, lack of somatic mutations of immunoglobulin variable region (pre-germinal cell phenotype)
Molecular: 17p- (poor survival); 17p13 and 11q22-23 (associated with advanced disease); 12q trisomy, 13q14, 13q- (longest survival)
Rai staging of CLL:
0: lymphocytosis in blood and marrow
I: lymphocytosis and lymphadenopathy
II: lymphocytosis and hepatomegaly or splenomegaly
III: lymphocytosis and anemia
IV: lymphocytosis and thrombocytopenia
Binet staging of CLL:
A: no anemia, no thrombocytopenia, fewer than 3 lymphoid areas enlarged (cervical, axillary and inguinal lymphadenopathy, spleen, liver)
B: no anemia, no thrombocytopenia, 4 or more lymphoid areas enlarged
C: anemia (hemoglobin < 10 g/dl) or platelet count < 100 billion/L
Variants:
CD5 negative B-cell CLL
Probably is NOT CLL
Have adhesion molecular profiles resembling leukemic non-Hodgkin lymphoma but different from CD5+ B-cell CLL (Hum Path 2001;32:66)
Patients older with more advanced disease and lower absolute lymphocyte counts than CD5+ B-cell CLL (AJCP 1999;111:477)
Interfollicular pattern
Large, reactive germinal centers by definition
Resembles follicular lymphoma but germinal centers are bcl2 negative and tumor cells resemble CLL/SLL by histology (small round lymphoid cells with proliferation centers) and immunostains (CD5+, CD23+), AJCP 2000;114:41
Paraimmunoblastic variant
Rare, <30 reported cases
Usually multiple lymphadenopathies and rapid disease progression
Case report in 69 year old man (Hum Path 2002;33:1145)
Micro: diffuse proliferation of paraimmunoblasts (normally just in pseudoproliferation centers)
Molecular: consider as mantle cell lymphoma if t(11;14)(q13;q32) is present
DD: large cell variant of mantle cell lymphoma, CD5+ diffuse large B cell lymphoma
Progression from B-CLL or other low grade B cell lymphoproliferative disorder to pleomorphic lymphoma
Occurs in 1-10% of B-CLL
Apparently due to transformation or dedifferentiation of previously well differentiated tumor cells
Symptoms: abrupt onset of fever, weight loss, adenopathy, rapid clinical deterioration
Associated with lytic bone lesions
Peripheral blood smear usually normal
Micro: pleomorphic lymphoma with multinucleated giant cells; may have Reed-Sternberg like cells
Common in Western countries
Variants described separately are: intravascular, lymphomatoid granulosis, mediastinal, primary cutaneous, primary effusion
All ages, 30%-40% are extranodal (skin, bone, gastrointestinal, genitourinary, CNS); 50% are stage III/IV at diagnosis
Often single, rapidly growing mass; may be in liver, spleen; bone marrow involvement typically late
Fatal if untreated; remission in 70% after chemotherapy, 50% cure rate
Often difficult to diagnose on flow cytometry
Either germinal center B-like (bcl6+, CD10+, CD38+), activated B-like (IRF4+, FLIP+, bcl2+), or neither
1/3 arise from transformation of follicular lymphoma (germinal center like), detectable by bcl2 rearrangement or bcl6/CD10 coexpression with strong and uniform bcl6 expression
Overall 3 year survival ~ 78% in 2006 studies
Prognosis: Better if limited disease, favorable international prognostic index; better if germinal center gene expression profiles [documented as bcl6+ or (CD10+ or bcl6+ AND negative for MUM1/IRF4 and CD138) vs. activated B cell-like; poorer if p53 mutations present; poorer if CD10+ and bcl2+ by flow cytometry (AJCP 2001;116:183)
Case reports: associated with Hepatitis C (Archives 2000;124:1532), ALK+ but CD30- tumors (AJSP 2003;27:1473; Mod Path 2003;16:828); exhibiting Homer-Wright type rosettes (Archives 2003;127:e411); ovarian tumor with spindle cell morphology (Archives 2003;127:e169); composite tumor with Hodgkin’s lymphoma (AJCP 2006;126:222); distinctive patterns of splenic and bone marrow involvement (Mod Path 2005;18:495); see also AIDS associated diffuse B large cell lymphoma
Gross images: atrial mass #1; #2; lymph node
Micro: diffuse growth pattern with large cells (5 x normal lymphocytes) resembling immunoblasts (amphophilic cytoplasm, eccentric nuclei with one central nucleoli) or centroblasts (pale or basophilic cytoplasm, vesicular chromatin due to chromatin margination, 2-3 nucleoli, often near membrane), associated with neutrophils (Archives 2000;124:735); may have plasmacytic differentiation or epithelioid granulomas (Mod Path 2002;15:750)
ALK+: immunoblastic cells with intravascular growth pattern, ALK+, CD30-, often extensive necrosis
Anaplastic: resembles anaplastic large cell lymphoma or metastatic carcinoma
Microvillous: sinus growth pattern with surface villi by EM
T cell/histiocyte rich: see below
Micro images: typical histology; atrial mass; adrenal gland; paratesticular; ethmoid sinus; with neutrophils; CD45 (LCA); CD20; IgM; CD43 (T cells)
ovarian tumor with spindled morphology - 1-interlacing strands of spindle cells; 2-moderate cytoplasm, spindled nuclei, coarse chromatin; 3-CD20+; 4-CD3 negative
pelvic mass - A-CT scan; B-colonic wall; C-diffusely arranged round cells with rosettes and alveolar patterns, CD45+; D-EM
Micro images: starry sky pattern (unusual); bcl6+; CD10+; A-H&E; B-CD10+; C-CD10- with staining of granulocytes; D-no CD10 staining of granulocytes (staining failure); A/B-widespread epithelioid granulomas; C-tumor cells with large, round or indented nuclei and nucleoli; D-binucleated and epithelioid cells; E-CD10+; F-CD21+; spleen-involvement of red pulp cords and sinusoids; lymph node; bone marrow shows interstitial pattern (unusual)
Virtual slides: pre-sacral mass - H&E; CD20+; CD45+; CD3- (tumor cells); keratin-; mucicarmine-; vimentin-; lymph node
Positive stains: CD19, CD20, CD22, CD79a; also light chain restriction, CD10 (if follicular origin); variable CD45, variable surface Ig, variable bcl2; in Korea 1/3 are bcl6+/CD10+ (Hum Path 2001;32:954); CD3 (highlights infiltrating T cells, not tumor cells); CD68 (highlights infiltrating histiocytes, which may be prominent)
Negative stains: TdT, variable CD5, cytokeratin (rarely are positive, Archives 2001;125:1104)
Molecular: IgH and IgL are clonally rearranged, but may be difficult to document in T cell rich cases
t(14;18)(q32;q21): IgH and bcl2 in 30%, also in follicular lymphoma
t(3;14)(p27;q32): bcl6 and IgH in 30%, also in follicular lymphoma
Numerous other translocations involving bcl6 (3q27)
DD: carcinoma (including nasopharyngeal), melanoma, seminoma/dysgerminoma, granulocytic sarcoma, thymoma, infectious mononucleosis or other childhood viral infections
References: AJSP 2004;28:464 (stains as prognostic factors); Mod Path 2002;15:413 (CD10: flow vs. immunostains); Mod Path 2003;16:471 (bcl6 and CD10 and apoptosis/proliferation)
CD5+ diffuse large B cell lymphoma
5% of diffuse large B cell lymphomas, with diffuse splenic red pulp involvement, mantle cell like pattern (CD23-, FMC7+), or other
Overall, most do NOT appear related to CLL/SLL or mantle cell lymphoma (AJCP 2000;114:523)
T cell/histiocyte rich diffuse large B cell lymphoma
Usually older adults, often with advanced stage and involvement of lymph nodes, spleen, bone marrow
Morphologic variants include L&H like, centroblast/immunoblasts and Reed-Sternberg like
L&H like cases may be related to nodular lymphocyte predominant Hodgkin lymphoma
Case report of CD5+ tumor (Mod Path 2002;15:1051)
Micro: diffuse growth of neoplastic large B cells (<10% of cells) scattered within small reactive T cells and histiocytes, in fine fibrillary fibrous background
L&H like: pale and indistinct cytoplasm, lobated and vesicular nuclei resembling popcorn cells with small central nucleoli, background of small lymphocytes and often histiocytes, no granulomas
Centroblast like: pale eosinophilic cytoplasm, oval/round nuclei with vesicular chromatin and without nuclear atypia, small basophilic nucleoli adjacent to nuclear membrane
Reed-Sternberg like: large multinucleated cells with abundant amphophilic cytoplasm, pleomorphic nuclei with prominent eosinophilic or amphophilic round/central nucleoli, in background of small lymphocytes and histiocytes but without eosinophils, neutrophils or plasma cells
Positive stains: CD20, CD79a (weaker than CD20), bcl6, EMA (37%, associated with L&H), CD30 (30%, usually Reed-Sternberg like cells); rarely positive for bcl2 (13%), CD10 (10%)
References: AJSP 2002;26:1458
Primary sites of diffuse large B cell lymphoma (see also these chapters)
Bone
Must have no evidence of disease elsewhere for 6 months to be considered a bone primary
Usually good outcome; better prognosis if germinal center origin (AJSP 2003;27:1269)
75% male, median age 44 years
Sites: long bones, axial skeleton, limb girdles
Case reports: 70 year old man with iliac bone and rib lesions (Archives 2003;127:e323)
Micro: usually centroblastic, often with multilobated cells
Staining patterns: germinal center - bcl6+/CD10+ (48%), indeterminant - bcl6+/CD10- (31%), post-germinal center - bcl6-/CD10- (21%)
Positive stains: bcl2 (70%)
Negative stains: CD138
Most frequent morphologic type of lymphoma at this site (Archives 1999;123:1208)
CNS
By definition, arises exclusively in central nervous system with no obvious lymphoma outside CNS at diagnosis
5-10% of neoplasms in patients ages 75+ (Hum Path 2003;34:1137)
2-12% of AIDS patients at autopsy
Usually EBV- in immunocompetent patients vs. EBV+ in AIDS patients
Mean age: 10 years old if inherited immunodeficiency, 37 years for post-transplant, 39 years for AIDS
Favorable prognostic factors: single lesion, no periventricular or meningeal involvement, no immunodeficiency, age < 60 years, Karnofsky score > 70; also negative for p53, c-myc and bcl6 in one study (Archives 2003;127:208)
Median survival: 17-45 months if immunocompetent and chemoradiation therapy; 13.5 months with AIDS with multimodal therapy
Xray images: CT of dural mass
Case reports: cryoglobulin deposition within tumor bed in immunocompetent patient (Hum Path 2003;34:720), dural tumor presenting as intracranial mass (Archives 2000;124:1700)
Micro: dense cellular aggregates of atypical lymphoid cells with dense perivascular aggregates
Micro images: dural mass, 1-MRI shows brain stem and basal ganglia lesion; 2-tumor composed of large atypical cells with perivascular cell aggregation and necrosis; CD20
Positive stains: CD20, CD79a, monoclonal immunoglobulin
References: Archives 2004;128:595
Intestinal
CD10+ tumors may respond better to treatment (Archives 2002;126:956)
This subtype is rare in intestine; intestinal lymphomas are usually MALT-type
Micro images: 1/2-CD10; 3-bcl6
Peripheral nerve
Rare, <20 lymphomas reported of any subtype
Recent report describes primaries of sciatic nerve (n=2), radial nerve, sympathetic chain/spinal nerve (AJSP 2000;24:1257)
Mean age 55 years, no gender preference
Stains: CD56 negative, variable CDKN2A/p16
Spleen
Most frequent splenic lymphoma (50%), usually due to secondary dissemination from other sites
Histologic patterns are macronodular (60%, usually stage I, usually favorable outcome, bcl6+), micronodular (30%, advanced clinical stage and death due to disease, bcl6+, includes T cell rich B cell features), diffuse red pulp infiltration (10%, advanced clinical stage and death due to disease, bcl6+)
Micro: macronodular - homogenous compact masses of large lymphocytes effacing splenic architecture, usually necrosis, often sclerosis; tumor cells usually centroblasts, also immunoblasts and polylobated cells; often macrophages, occasional epithelioid histiocytes;
micronodular - uniform miliary pattern with focal coalescence of splenic white pulp micronodules; variable infiltration of red pulp; nodules composed of large B cells with occasional small T cells and histiocytes; no residual mantle zone, no follicular dendritic cell network; small areas of necrosis and macrophages occasionally seen; T cell/histiocyte rich B cell lymphoma
diffuse red pulp infiltration - diffuse tumor infiltration of red pulp cords and sinusoids with scattered residual white pulp islands; no pseudosinuses; tumor cells centroblastic, polylobated or pleomorphic; usually no necrosis
Positive stains: bcl6
DD: granulomas, Hodgkin lymphoma (CD15+, CD30+, prominent eosinophils, negative for B cell markers and bcl6), follicular lymphoma (nodular but different cytology, most cells are CD20+, CD10+), T cell lymphoma (T cells usually involve red pulp, are atypical, don’t form nodules)
References: AJSP 2003;27:895 (patterns), AJSP 2003; 27:903 (micronodular pattern)
Stomach
Defined as high grade B cell tumor without lymphoepithelial lesions or follicular colonization (which would make it high grade MALT)
Tonsil
In Japan/Korea, 50% are germinal center origin (bcl6+ in uniform pattern and CD10+) vs. MALT origin (Hum Path 2003;34:610)
Includes patients with focal follicular features that may represent follicular colonization of high grade tumor (Hum Path 2002;33:732)
Micro: involvement of pericryptal follicles in tonsils with adjacent dominant diffuse areas; tumor cells large, monomorphic, evenly spaced with clear cytoplasm, blastoid nuclei; residual germinal centers present
Positive stains: usually sporadic bcl6 (<50% of tumor cells)
Negative stains: CD10 (usually)
DD: follicular lymphoma with diffuse areas (strong bcl6+, CD10+)
Vagina
Uncommon site for either primary or secondary lymphoma
Mean age 42 for primary disease, range 26-66 years; symptoms of vaginal bleeding
All lymphomas at this site in one study were diffuse large B cell lymphoma (AJSP 2000;24:719)
Note: secondary cases are usually also diffuse large B cell lymphoma, present with vaginal bleeding at mean 65 years
Most common form of non-Hodgkin lymphoma in US (45% of all cases), rare in Asians, African-Americans
Median age 55 years; rare under age 20
Generalized painless lymphadenopathy and marrow involvement (85% have paratrabecular lymphoid aggregates), 10% with peripheral lymphocytosis; occasional involvement of splenic white pulp and hepatic portal triads
May have a history of waxing and waning lymphadenopathy
Indolent but incurable; median survival 8 years; 5 year survival is 72%
B cell lymphoma that originates from follicular center B cells
Transformation to diffuse large B cell lymphoma occurs in 22-30%, associated with poor prognosis (see below)
60-70% have marrow involvement at diagnosis
Of cases with marrow involvement, 40% have tumor cells in blood, which may resemble CLL
Case reports: 53 year old Japanese woman with crystals within tumor cells (Hum Path 2002;33:1141), grade 1 tumor with Burkitt translocations and aggressive clinical course (Archives 2004;128:210)
Treatment: radiation, low dose chemotherapy when symptomatic, rituximab; can monitor tumor burden and effects of therapy with real time PCR (Mod Path 2002;15:448)
Gross images: eyebrow lesion (Stage IV disease)
Micro (lymph node): nodal effacement by closely packed follicles containing small cleaved cells without nucleoli (centrocytes) and larger non-cleaved cells with moderate cytoplasm, open chromatin and multiple nucleoli (centroblasts); minimal or no apoptotic cells or tingible body macrophages; often is interfollicular involvement or capsular infiltration; rarely large areas of necrosis, dense fibrous bands; see also variants below
bone marrow: usually paratrabecular involvement by CD20+ CD10+ bcl2+ cells; rarely (5%) has follicular pattern (AJCP 2002;118:780)
bone marrow: focal paratrabecular (usually prominent) or focal nonparatrabecular patterns; may recapitulate neoplastic follicle or have “reverse germinal center” pattern with transforming cells on periphery of lymphoid cluster; pattern is usually does NOT resemble nodal pattern; may have foci of transformation resembling Reed-Sternberg cells; cells have cleaved nuclei
Grading: 1, 2 or 3 based on number of intrafollicular centroblasts in ten 40x fields to determine average (WHO); important to differentiate grades 1/2 vs. grade 3; based on high power field of 0.159 mm2 - grade 1: 0-5, 2: 6-15, 3: >15 centroblasts/HPF
WHO recommends to report as follicular (>75% follicular), follicular and diffuse (25-75% follicular) or focally follicular (<25% follicular)
Note: grade 3 with diffuse areas should be reported as diffuse large B cell lymphoma
Flow cytometry: CD10+ cells with high bcl2 predicts follicular lymphoma vs. reactive hyperplasia, but may occur in some diffuse large B cell lymphomas (AJCP 2003;119:145)
Micro images: follicular lymphoma; bone marrow involvement and bcl2+; paratrabecular infiltrate; pleomorphic CD30+ cells #1, #2; various stains
Virtual slides: grade 1 tumor of lymph node; grade 2 tumor of lymph node; bone marrow tumor
Peripheral smear: cells have scant cytoplasm, cleaved nucleus; confirm neoplastic with flow cytometry
Positive stains: CD10, CD19, CD20 (strong), CD79a, bcl2 within follicles, bcl6; CD30+ in 30%; variable surface immunoglobulin (intense in bone marrow)
Note: CD10 frequently weak/negative in interfollicular infiltrates and in grade III follicular lymphomas (AJCP 2001;115:862)
Note: CD10 sensitive and specific for follicular lymphoma among small B cell lymphomas in multiparameter flow cytometry (AJCP 2002;117:291)
Note: may contain pleomorphic, CD30+ cells (Archives 2001;125:1036)
Negative stains: CD5 (although mixed T cells are often present), cyclin D1; also variable CD11c, CD23, CD25, CD43
Molecular: t(14;18)(q32;q21): IgH and bcl2 (90%, also present in diffuse large B cell lymphoma), causes overexpression of bcl2, which prevents cells in follicular center from undergoing apoptosis (but bcl2 is not specific for follicular lymphoma and often occurs in marginal zone hyperplasia in spleen, abdominal lymph nodes and ileal lymphoid tissue, AJSP 2003;27:888)
All cases have clonal rearranged immunoglobulin genes
DD: reactive hyperplasia: normal nodal architecture, follicles vary considerably in size and shape, have sharply defined margins, surrounded by a mantle zone, follicle contains mixture of centrocytes and centroblasts, cleaved cells are restricted to follicles, numerous mitoses and tingible body macrophages are present; bcl2 is not within follicles, typically are CD20+ bcl2 negative/dim by flow cytometry, AJCP 2000;114:258; also, CD10 and bcl6 are restricted to germinal centers
DD: mantle cell lymphoma with diffuse pattern (CD5+, CD43+, CD10-), marginal zone B cell lymphoma (CD10-), peripheral T cell lymphoma (rarely contains sharply demarcated follicles with abundant follicular dendritic cells, CD4+, bcl6+, CD10+, T cell receptor rearrangements), follicular colonization by other low grade lymphomas, SLL/CLL (in bone marrow, no cleaved nuclei, CD5+, weak surface Ig-, CD10-)
References: AJSP 2000;24:846 (CD10 and bcl6)
Childhood tumors
Commonly present as localized disease of head and neck lymph nodes and tonsils
Good response to therapy with complete remission and excellent prognosis
High grade cytology
Negative for bcl2 expression and t(14;18)
Diffuse histology
Rare, composed of diffuse infiltration of centrocyte-like cells; follicular areas may be seen in larger biopsy specimens
Same staining pattern and molecular findings
DD: mantle cell lymphoma
Floral
Nodules are surrounded and infiltrated by small lymphocytes of the follicular mantle, resulting in an unusual serrated configuration. Resembles progressive transformation of germinal centers and lymphocyte predominance Hodgkin lymphoma; occasionally CD5 positive, but usually CD10 positive with bcl2 rearrangement (AJCP 2000;114:912)
Focal marginal zone differentiation
Tumors are primary follicular cell (not primary marginal zone) since bcl2 immunoreactive, have t(14;18) and are same clone as follicular center cell (Mod Path 2001;14:191)
Incipient
Monoclonal proliferation of germinal center cells within a lymph node follicle
Case report at Hum Path 2001;32:1410
Must meet criteria for follicular lymphoma (positive for B cell antigens, CD10, bcl6, bcl2; IgH rearrangement)
Transformation
Transforms to diffuse-large cell lymphoma in 20-30%, rarely to Burkitt/Burkitt like lymphoma/ALL
Survival < 1 year for either type of transformation
Associated with overexpression of cyclin D3 and downregulation of caspase 3 (Mod Path 2004;17:670)
Rarely, blastic/blastoid transformation (AJSP 2000;24:525)
Due to additional but inconsistent chromosomal abnormalities, including +7p, +10p1, +12, +20p13, 9q- (Hum Path 2003;34:915)
Primary sites for follicular lymphoma
Cutaneous
Mean 64 years; localized papulonodular lesions, often in head, neck and trunk, with excellent prognosis
By definition, arises in skin with no known extracutaneous disease within 6 months of initial diagnosis; has follicular growth pattern and germinal center cytology (AJSP 2001;25:875)
In Scottish Highlands, cutaneous B cell lymphomas (all subtypes) are associated with Borrelia burgdorferi (Lyme disease, AJSP 2000;24:1279)
One study-similar relapse rate as stage 1 nodal follicular lymphoma, but more likely to attain complete remission (AJSP 2002;26:733)
Micro images: disseminated disease including skin
Positive stains: bcl6+ and usually CD10+ centrocytes and centroblasts, usually bcl2+ in follicular and interfollicular/diffuse areas (AJSP 2001;25:732); similar to follicular lymphoma otherwise
Molecular: t(14;18)+ in only 20-30% by PCR (Mod Path 2001;14:913; Mod Path 2001;14:828, AJSP 2000;24:694); FISH may be more specific than PCR due to bystander cell positivity for t(14;18) (AJSP 2004;28:748)
DD: cutaneous MALT lymphoma (negative for bcl6 and CD10, positive for bcl2, although colonized follicles [CD21+] are bcl6 and bcl2 positive, AJSP 2001;25:732), disseminated follicular lymphoma involving skin (usually t(14;18)+, Mod Path 2001;14:913)
Duodenal
Higher incidence of follicular lymphoma in duodenum compared to remainder of GI tract (AJSP 2000;24:688)
All women in one series
Often nodal involvement even with low stage disease
Micro: associated with lymphomatous polyposis; surrounds Ampulla of Vater; composed of neoplastic follicles with small cleaved cells
Positive stains: CD10, CD20, CD75, CD79, bcl2
Negative stains: CD3, CD5, CD23, CD45RO, cyclin D1
Gastrointestinal (other than duodenum)
Uncommon, most are stage 1E (62%) or 2E (38%), no gender preference, median 54.5 years (range, 26-81 years)
5 year survival estimated at 62% (no deaths of lymphoma), median disease free survival of 69 months
Gross: nodular mucosal surface, usually of small bowel (85%), colorectum or ileocecal valve
Micro: often transmural involvement, usually grade 1 or 2 of 3; predominantly follicular growth pattern, occasionally mixed with diffuse, rarely entirely diffuse
Micro images: 1-CD10+ germinal center; 2-CD10+ tumor cells; 3-bcl6+ tumor cells
Positive stains: CD20, bcl2, CD10
Negative stains: T cell markers, CD43, cyclin D1
Molecular: usually t(14;18) is present
Reference: AJSP 2002;26:216, Archives 2002;126:956
Testicular in a child
Rare, <10 cases
Case report of 6 year old boy with bcl2-, t(14-18) negative tumor (Archives 2001;125:551)
Rare chronic leukemia; formerly known as leukemic reticuloendotheliosis
Mean age 52 years, range 20-80 years; 80% men
Commonly present with massive splenomegaly with obliteration of white pulp and involvement of red pulp, pancytopenia (50%), marrow fibrosis, monocytopenia, infections in 1/3; frequently atypical mycobacterial infections with weakness and weight loss; minimal lymphadenopathy
Bone marrow aspiration biopsies unsuccessful in 30-50% due to marrow fibrosis
Treatment: purine analogs 2-deoxycoformycin and 2-chlorodeoxyadenosine and interferon cause complete remission in 76-85% and markedly improve disease free survival (Hematol Oncol Clin North Am 2006;20:1153).
Case reports: Case of the Week #95, 42 year old man with WBC count of 98K (Archives 2003;127:253), with blastic transformation (Archives 1997;121:707), with transformation to large cell lymphoma (Hum Path 2004;35:1423)
Peripheral blood: monocytopenia, leukopenia, often no/rare leukemic cells; 5-10% have WBC > 10 billion/L, usually due to tumor cells
Micro: spleen - tumor cells larger than small lymphocytes, modest pale blue agranular cytoplasm with circumferential threadlike extensions seen with phase contrast microscope, round or folded (oval) nuclei, no distinct nucleoli; residual follicles often present; cells line pseudosinuses; often blood lakes
bone marrow - diffuse or focal involvement with irregular, poorly demarcated infiltrates; cells may be loosely spaced; hairy cell is 10-14 microns with abundant, clear to lightly basophic or eosinophilic cytoplasm with surface circumferential delicate and broad projections; may have cytoplasmic vacuoles and azurophilic granules; oval / folded / indented nuclei with variable chromatin and no prominent nucleoli; may be perinuclear halo in formalin fixed tissue due to abundant cytoplasm; marked marrow fibrosis and increased mast cells are common; no/rare mitotic figures
stromal variant - leukemic cells are spindled
Cytology: small/intermediate sized cells with moderate pale-gray cytoplasm, has circumferential hair-like and short, blunt cytoplasmic projections, round/oval nuclei with smooth nuclear borders, stippled chromatin, occasional nucleoli (Cytojournal 2006;3:1)
Micro images: bone marrow aspirate #1; #2; bone marrow trephine biopsy (figures A-F);
1-large lymphocytes with abundant cytoplasm, eccentric nuclei, often cytoplasmic projections; 2-TRAP+; 3-hypercellular bone marrow with “fried egg” lymphocytes that are monotonous with abundant cytoplasm; minimal residual disease is DBA.44+ (figure 1B); CD11c+; CD20+; CD25+; DBA-44+; TIA1+
Cecal lesion - image #1; #2; immunostain for DBA.44
Cytology images (endoscopic ultrasound/EUS): Diff Quik #1; #2
Positive stains: CD19, CD20, CD22, DBA.44, CD79a, PAX5, TRAP (tartrate resistant acid phosphatase); also CD11c, CD25, CD103, HC2, FMC7; reticulin shows thickened fibers that may circle individual cells and infiltrate normal appearing areas; TIA1 in 56% (Mod Path 2004;17:840); flow cytometry with CD11c, CD20, CD25 and CD103 is useful (Archives 2007;131:383);
Combined TRAP and DBA44 is sensitive but not specific (AJSP 2005;29:474); variable staining for cyclin D1/bcl1 (Mod Path 2000;13:1308); atypical immunophenotyping in 34% (AJCP 2006;125:251),
Negative stains: CD79b, CD5, CD23, CD10
DD: splenic marginal zone lymphoma (cytoplasmic processes are polar, not circumferential; nodular involvement, not obliteration, of splenic white pulp; negative for DBA.44, TRAP, CD103), nodal marginal zone B cell lymphoma, mastocytosis (tryptase+, CD117+, Giemsa+, toluidine blue+, negative for B cell markers)
References: Mod Path 2004;17:840 (TIA1 expression), eMedicine
Hairy cell leukemia variant type
Very rare, older individuals
More aggressive than classic type; poor response to standard treatments
Mean age 70, often men with massive splenomegaly, marked lymphocytosis without infection, successful marrow aspirates
No neutropenia, no monocytopenia
A Japanese variant also exists
Case reports: CD10+, CD25+, CD103- with poor response to interferon (Archives 2000;124:1710), 77 year old man with polycythemia vera (Archives 2003;127:e209), with biclonal paraproteinemia (Archives 1997;121:150)
Micro: bone marrow - diffuse interstitial or sinusoidal (Archives 2005;129:395) patterns; morphologic features intermediate between hairy cells and prolymphocytes; cells are large with abundant basophilic cytoplasm, circumferential stellate projections, round, occasionally bilobed nucleus and prominent nucleolus
spleen - expansion of red pulp with no / atrophic white pulp; lymphoid cells in sinusoids
Micro images: 1A-abundant slightly basophilic cytoplasm with projections, round/oval nuclei with central nucleoli; 1B-TRAP+; 1C-fried egg appearance in bone marrow; 1D-CD20+; intrasinusoidal pattern
Flow cytometry images: A-CD20 (bright) and CD22+; B-CD11c+ and CD22+; C-CD103+ and CD25 negative; D-CD19+ and FMC7+; E-kappa+; F-lambda negative; CD103+ but CD25 negative
Positive stains: CD11c (bright by flow), CD19, CD22, FMC7, variable CD25, CD103 (60%), TRAP (60%)
Negative stains: CD10, CD23, CD5
DD: B cell prolymphocytic leukemia (no cytoplasmic projections), splenic marginal zone lymphoma (smaller cells may have short cytoplasmic projections, clumpy chromatin, indistinct nucleoli, different staining pattern, splenic white pulp is infiltrated by tumor)
References: AJCP 2005;123:132
Intravascular large B cell lymphoma
Also called angiotropic lymphoma, but a confusing term
A type of diffuse large B cell lymphoma with intravascular growth in skin, CNS, other sites
Rare; complex signs and symptoms (fever of unknown origin, skin rash, mental status changes, rapidly progressive dementia); often diagnosed at autopsy with involvement of most organs
Median age 71 years, often fatal
May be a heterogeneous group of tumors, with some cases a transformation from other lymphomas (Mod Path 2001;14:1147),
Treatment: combination chemotherapy may be effective if detected early
Case reports: in bone marrow (Archives 1999;123:952), with renal cell carcinoma (Archives 2001; 125:1239), with Kaposi’s sarcoma and HHV-8 (AJSP 1999;23:482), in renal biopsy (Archives 2003;127:1380), myeloperoxidase+ tumor (Archives 2001;125:948), presenting with DIC (J Clin Pathol 2003;56:468)
Micro: large centroblast-like lymphoid cells with prominent nucleoli within small vessel lumina (often capillaries) except in lymph nodes; frequent mitotic figures; often fibrin thrombi
1B: renal cell carcinoma; 1C: intravascular tumor; 1D: CD20+; myeloperoxidase+ tumor
Stains: similar to diffuse large B cell lymphoma (positive for CD19, CD20, CD22, CD79a); usually bcl2 positive; rarely are T cell lymphomas
Negative stains: CD29 and CD54 (adhesion molecules, Hum Path 2000;31:220), EBV
Molecular: often immunoglobulin gene rearrangement, rarely T cell receptor gene rearrangements
DD: granulocytic sarcoma
Also called polymorphic reticulosis
Rare EBV associated lymphoproliferative disorder, varies from indolent process to an aggressive disorder
Clinical: usually men 40+ years; involves lung with bilateral nodules, skin, kidney, CNS; tends to spare lymphoid tissue
May have fever of unknown origin, hemoptysis, history of multiple skin or other biopsies without diagnosis
Second most common pulmonary lymphoma after SLL
Skin is extrapulmonary organ most commonly involved (40-50% of patients)
85% of patients with skin lesions had multiple erythematous dermal papules or subcutaneous nodules with an angiocentric lymphohistiocytic infiltrate of CD4+ T cells and angiodestruction, necrosis, panniculitis, atypia; some EBV+, occasionally clonal IgH; 1/3 progress; 2/3 resolve with chemotherapy / immunomodulation therapy,
15% of patients with skin lesions had indurated and atrophic plaques (AJSP 2001;25:1111)
Poor prognosis if constitutional symptoms or multiple organ involvement (2/3 die within a year of pulmonary disease and infection)
Gross: lung nodules up to 10 cm with central necrosis and cavitation
Micro: nodular and diffuse lymphoid infiltrates along lymphatics and bronchovascular bundles (in lung); centers of nodules have large vessels with lymphatic infiltration; usually high grade; small lymphocytes, plasma cells, histiocytes are also seen, rarely accompanied by neutrophils, granulomas
Positive stains: CD19, CD20, CD3, EBV positive by in-situ hybridization
Molecular: B cells are clonal (IgH rearrangements), but T cells are not
DD: inflammatory lesions (have neutrophils), granulomatous inflammation, varicella-zoster virus pneumonia (have prominent lymphocytic reaction), Wegener’s granulomatosis (giant cells, microabscesses), necrotizing sarcoidosis (few lymphocytes), bronchocentric granulomatosis (eosinophils, bronchocentric, few lymphocytes, history of asthma and allergic bronchopulmonary aspergillosis)
Also called plasmacytoid lymphoma, immunocytoma
Rare (2% of hematopoietic neoplasms), older patients (50-69 years) with involvement of bone marrow, lymph node, spleen and liver
May affect nerve roots, meninges and rarely brain or small intestine (Archives 2001;125:677)
No masses causing bony erosions as seen with multiple myeloma
Most patients have monoclonal IgM and Waldenstrom’s macroglobulinemia with hyperviscosity symptoms
10% have autoimmune hemolysis due to cold agglutinins (IgM antibodies that bind at < 37C)
Waldenström's macroglobulinemia: clinical syndrome defined by serum IgM monoclonal gammopathy, monoclonal Ig light chains (Bence-Jones protein) in urine, hyperviscosity syndrome and B cell neoplasm involving marrow, including lymphoplasmacytic lymphoma, B-cell CLL/SLL, marginal zone B cell lymphoma (MALT type), myeloma
Diagnostic criteria for Waldenström's recommended by Second International Workshop:
• IgM monoclonal gammopathy of any concentration
• Bone marrow infiltration by small lymphocytes showing plasmacytoid or plasma cell differentiation
• Intertrabecular pattern of bone marrow infiltration
• Immunophenotype is surface IgM+, CD19+, CD20+, CD22+, CD25+, CD27+, FMC7+, CD5 variable, CD10-, CD23-, CD103-, CD108-
Hyperviscosity syndrome: due to IgM’s large size and number; symptoms are visual impairment (distended and tortuous retinal veins with hemorrhage and exudates), neurologic symptoms due to sluggish blood flow, bleeding due to IgM binding of clotting factors and cryoglobulinemia causing Raynaud’s phenomena and cold urticaria
Laboratory: moderate to severe normochromic anemia with marked rouleaux formation (like partially stacked coins); 30% have leukemia composed of lymphocytes and lymphoplasmacytoid cells; also features of Waldenstrom’s macroglobulinemia (above)
Prognosis: median survival is 5 years, 40% survive 10 years or more or die of unrelated causes
May transform to diffuse large B cell lymphoma with Reed-Sternberg like cells or immunoblasts
May have poorer prognosis than other small B cell lymphomas (AJSP 2001;25:742)
Case reports: with peliosis hepatis (Archives 2004;128:1283)
Treatment: cannot cure; use plasmapheresis for hyperviscosity and hemolysis
Micro: partial or complete effacement by small B cells with plasmacytic differentiation in 3 architectural patterns (a) open sinuses with small follicles and hemosiderosis, (b) hyperplastic follicles, (c) diffuse plasma cells, lymphocytes, “plymphyocytes”
By definition, excludes other small B cell lymphomas
Often with reactive mast cells, epithelioid histiocytes, cytoplasmic (Russell) and nuclear (Dutcher) PAS positive inclusions; inclusions are cytoplasmic immunoglobulin
bone marrow: focal or diffuse involvement by small B cells with plasmacytic differentiation and cytoplasmic (Russell) and nuclear (Dutcher) PAS positive inclusions; inclusions are cytoplasmic immunoglobulin and are nonspecific; diffuse involvement associated with decrease in normal hematopoietic cells;
Often with reactive mast cells, epithelioid histiocytes, mature plasma cells
Micro images: 1-sheets of small lymphocytes, plasmacytoid lymphocytes and plasma cells; 2-occasional PAS+ nuclear inclusions (Dutcher bodies); 3-extracellular PAS+ material; with peliosis hepatis; H&E and bcl-10
Positive stains: CD19, CD79a, surface and cytoplasmic immunoglobulin (IgM, IgD); also variable CD20, CD22, CD38, variable CD43, strong cytoplasmic immunoglobulin in plasma cell component (monoclonal kappa or lambda, not both)
Negative stains: CD5 (usually), CD10, CD23, bcl2
Molecular: t(9;14)(p13;q32): PAX5 and IgH in 0% (Hum Path 2004;35:447) to 50%, may be more common in nodal tumors; PAX5 encodes B cell specific activator protein (transcription factor); no t(1;14)(p22;q32) or t(11;18)(q21;q21) of MALT lymphoma (Mod Path 2004 May 14)
Cytogenetic abnormalities are associated with polymorphous subtype and poor prognosis (AJCP 2001;116:543)
DD: myeloma (CD20 negative, strong CD138+), serum hyperviscosity also seen in CLL/SLL, marginal zone B cell lymphoma-MALT type (AJCP 2001;116:683)
DD: serum hyperviscosity also seen in CLL/SLL, marginal zone B cell lymphoma-MALT type (AJCP 2001;116:683); rarely in myeloma of IgM, IgA, IgG
References: Hum Path 2004;35:447 (translocation less common than previously reported), AJSP 2003;27:1104 (extranodal tumors)
Formerly known as centrocytic lymphoma
3-10% of non-Hodgkin lymphomas in Western countries
Usually 60+ years with stage III/IV disease; 80% men
Lymphadenopathy, bone marrow involvement in 2/3 (lymphoid aggregates, often paratrabecular), splenomegaly in 50% with white pulp involvement, periportal hepatic infiltration, lymphomatoid polyposis of small bowel and other extranodal involvement; CNS involvement in 10% (Mod Path 2002;15:1073); B symptoms (fever, night sweaters, weight loss) in 1/3
Peripheral blood involvement (leukemic phase): in 20-60% at diagnosis; usually <20,000 absolute lymphocytes, associated with worse outcome
More aggressive than SLL/CLL or marginal zone lymphoma; median survival ~3 years, may transform to blastoid variant, but blastic transformation is uncommon
Cell of origin appears to be naïve pregerminal center B lymphocytes present in primary lymphoid follicles and mantle zones of secondary follicles with nonmutated Vh region genes
Prognostic features: nodular or mantle zone pattern have longer survival (5 years); blastic variant has shorter survival (3 years); International Prognostic Index not useful because most patients present with high stage disease with multiple foci of extranodal involvement
Most patients relapse; complete remission in less than 35%
Case reports: chronic indolent tumors with mutated immunoglobulin genes (Hum Path 2003;34:1030, Hum Path 2005;36:1232), two cases with prominent intrasinusoidal bone marrow infiltrate (Hum Path 2003;34:789), cases with composite Hodgkin lymphoma (AJSP 2003;27:1577, AJSP 2003;27:1483), multiple lymphomatous polyposis throughout GI tract (Archives 2003;127:1028), colonic tumor with synchronous adenocarcinoma (Archives 2003;127:E64), presenting as breast mass (J Clin Pathol 2001;54:883), prolymphocytoid variant with leukostasis (Mod Path 2004;17:879)
Treatment: no standard or curative treatment as of 2007; various chemotherapy regiments are used; rituximab is effective with chemotherapy; proteasome inhibitor bortezomib may be helpful
Micro: three patterns of tumor infiltration: (1) diffuse replacement of entire lymph node, (2) into expanded mantle zone, or (3) nodular; tumor cells are monotonous small lymphocytes resembling mantle cells with scant cytoplasm, cleaved, slightly irregular or round nuclei; condensed chromatin, no nucleoli; no large cells, no proliferation centers; may have prominent hyalinized vessels or scattered epithelioid histiocytes; rarely platelet satellitism around atypical lymphocytes (AJCP 2001;115:567); blastoid variant (below), prominent nucleoli resemble AML-M3 (AJCP 2002;117:246)
bone marrow: focal paratrabecular and nonparatrabecular patterns; may have benign germinal centers; cells are pleomorphic with variation in size and irregular nuclear contours; blastic variant may resemble ALL
Micro images: presenting as breast mass
73 year old woman with enlarged axillary lymph node - diffuse architectural effacement by a predominantly nodular infiltrate #1; #2; tumor cells have scant cytoplasm, irregular nuclei, small nucleoli
with synchronous colonic adenocarcinoma - 1-low power; 2-lymphoma nodules; 3A-H&E; 3B-CD20+; 3C-cyclin D1+; 3D-CD5+
CD20+; cyclin D1+ (nuclear staining); CD43+ (cytoplasmic staining);
various images; H&E, stains, FISH (see legend); ISH for cyclin D1; CSF with lymphoid cells with moderate cytoplasm and irregular nuclear contours #1; #2 with prominent cytoplasmic granules; CSF with lymphoid cells displaying scant cytoplasm, prominent nucleoli and immature chromatin in blastoid variant; peripheral smear and bone marrow resembling CLL #1; #2;
Virtual slides: lymph node; cyclin D1
Peripheral smear: cells (if present) have scant cytoplasm and cleaved nuclei; confirm neoplastic with flow cytometry; differential diagnosis is SLL/CLL, prolymphocytic leukemia, follicular lymphoma
Positive stains: CD5, CD19 (strong), CD20 (strong), cyclin D1/bcl1 (variable nuclear staining since cells are at different stages of cell cycle); also CD22, CD43, CD79a, FMC7, surface IgM or IgD, kappa or lambda, bcl2
In-situ hybridization for bcl-1 is more sensitive/specific than immunostains (Mod Path 2001; 14:62)
Negative stains: CD23, usually CD10; also bcl6, CD11c, TdT, T cell antigens; usually p27(kip1) negative [B-CLL, follicular and marginal zone lymphomas are p27 positive, hairy cell leukemia is p27 weak/negative, Mod Path 2001;14:1022)
May have dim CD23 expression by flow cytometry (AJCP 2001;116:893, AJCP 2003;120:760)
Note: occasionally is discordance between results in peripheral blood and bone marrow (AJCP 2002;118:758)
Molecular: t(11;14)(q13;q32): cyclinD1 (also called bcl-1, PRAD1, CCND1) and IgH in 90% (same translocation present in some B cell prolymphocytic leukemia, myeloma and CLL); cyclin D1 regulates G1 to S phase transition
Note: t(11;14) may also be found in normal patients; is not sufficient for malignancy by itself
Leukemic cases often have chromosome 17 abnormalities associated with p53; also additional cytogenetic breakpoints at 8q24, 9p22-24 and 16q24 (AJCP 2001;116:886)
Clonal IgH rearrangements present in 100% of cases by PCR
Real time RT-PCR for quantifying cyclin D1 may be useful for diagnosis (Mod Path 2002;15:556)
Insertion of CCDN1 gene at IgH locus may be microscopic, causing fusion gene with bcl1 overexpression on an apparently normal chromosome 14 (J Clin Pathol 2003;56:798)
FISH: 57%-90% of interphase nuclei have 3 or more 11q13 signals (AJCP 2000;114:248); may be more sensitive than immunostains (Mod Path 2002;15:517)
Molecular images: PCR/Southern blot image; peripheral blood single and double fusion of cyclin D1-IgH cells
DD: SLL/CLL (CD5+, CD23+, cyclin D1-, weak CD19 and CD20 staining, usually no atypical nuclei, p27 negative), prolymphocyte transformation of CLL with t(11;14) [Hum Path 2003;34:330], follicular lymphoma (CD5-, CD10+, cyclin D1-), marginal zone lymphoma (CD5-, CD10-, cyclin D1-), hairy cell leukemia (also cyclin D1+), myeloma (cyclin D1+)
References: AJSP 2004;28:801 (new cyclin D1 antibody), Mod Path 2004;17:553 (fusion transcripts in peripheral blood), Hum Path 2002;33:7 (review), Mod Path 2003;16:161 (catalyzed signal amplification of cyclin D1), Univ of Pittsburgh case of the month
Variants of mantle cell lymphoma
Blastoid variant of mantle cell lymphoma
Median age 63 years, range 40-79 years; 80% men
Moderate to marked leukocytosis
Aggressive behavior
Case reports: leukemic mantle cell lymphoma with classic and blastoid components with different immunophenotypes (AJCP 2004;122:122)
Micro: diffuse, nodular or mantle zone pattern; higher grade histologic features; either lymphoblastic with intermediate size cells containing round nuclei and finely disbursed chromatin with marked mitotic activity and leukemic involvement, resembling CLL/SLL or AML; or pleomorphic with heterogeneous larger cells with deeply indented, pleomorphic nuclei and variably prominent nucleoli, also with high proliferation rate, and often with striking staining of chromatin due to tetraploid clones, resembling diffuse large B cell lymphoma
Micro images: cases with prominent nucleoli; various images; large tumor cells with immature chromatin and prominent nucleoli; peripheral smear shows irregular nuclei with immature chromatin; A-starry sky pattern; B-immature chromatin and high mitotic rate
Positive stains: CD19, CD20, CD5, surface immunoglobulin
Negative stains: CD34, TdT, CD23 (or weak)
Molecular: t(11;14); blastoid variant associated with c-myc and 8q24 abnormalities (Mod Path 2002;15:1266); usually complex karyotypes with 3+ additional chromosomal abnormalities, most commonly chromosome 13; also 18, 17, 8 and 3
Molecular images: bcl1 by PCR; cyclin D1 mRNA by RT-PCR
DD: diffuse large B cell lymphoma; transformation of CLL (clinical history, CLL cases resemble ALL-L3, CD23+, Mod Path 1997;10:818), transformation of B-PLL (variable CD5+, background of CLL type cells, lower N/C ratio, prominent nucleoli
References: Hum Path 2003;34:1022 (cytogenetics), Archives 2000;124:1457 (cell cycle markers), Archives 2001;125:513, AJCP 2002;117:246, Mod Path 2000;13:825
Cutaneous mantle cell lymphoma
Associated with disseminated disease at diagnosis or shortly thereafter
Micro: dermal and subcutaneous aggregates of small to medium lymphocytes, often perivascular or periadnexal; Grenz zone present with sparing of the epidermis; often blastoid
Reference: AJSP 2002;26:1312
Marginal zone B cell lymphoma-general
3 types of lymphomas with overlapping characteristics: MALT lymphoma, nodal margin zone lymphoma and splenic marginal zone lymphoma (all described separately, “splenic” after pyothorax associated lymphomas)
All thought to derive from cells in the nodal or splenic marginal zone, perhaps from B memory cells that are post-germinal center and IgM+, IgD-, based on a low sequence homology between their IgH variable genes and germline genes
All feature perifollicular proliferation of centrocyte or monocyte-like, irregular small B cells, mixed with larger centroblast or immunoblast-like cells; may have plasmacytoid features
All usually have bone marrow involvement (AJCP 2002;117:698)
Cells resemble monocytoid B cells in lymph node sinuses in toxoplasmosis, cat-scratch disease, AIDS, infectious mononucleosis, autoimmune disorders and other reactive disorders
Plasmacytoid cells may be negative for B cell markers but are strongly immunoreactive for kappa or lambda
Extranodal marginal zone lymphomas have similar features in children/young adults and older adults (AJSP 2003;27:762)
Marginal zone lymphoma, MALT type
Most common primary extranodal lymphoma; slightly more common in women
B cell neoplasm of mucosal and non-mucosal extranodal sites that interacts with epithelium and reactive germinal centers; by definition, emulates Peyer’s patches in terminal ileum
Common sites: stomach, bowel, salivary glands, lung, thyroid, lacrimal gland, conjunctiva, bladder, kidney, skin, soft tissue, thymus, breast; occasionally bone marrow (20%) and spleen
Usually localized (70%) and possibly curable by surgery, radiation or antibiotics
Disseminated disease is usually refractory to chemotherapy
Rare transformation to large cell lymphoma, which may have Reed-Sternberg like cells
Median survival 8 years; late relapse in 30% at same site or other extranodal sites
Includes cases previously designated "pseudolymphoma" or extranodal lymphoid hyperplasia
May be associated with Waldenström macroglobulinemia (AJCP 2001;116:683)
Risk factors: Sjogren's syndrome (possibly other chronic inflammatory diseases of salivary gland, AJSP 2001;25:1546), Hashimoto's thyroiditis, Helicobacter pylori gastritis, possibly Hepatitis C virus or Borrelia burgdorferi infection
Case reports: benign morphology but clonal band by immunoglobulin gene rearrangement, later developed marginal zone B-cell lymphoma of liver, spleen, marrow (AJCP 2001;116:550); systemic Whipple’s disease with monoclonal B cell proliferation [resembling MALT lymphoma] and lymphadenopathy (Archives 2003;127:1619)
Gross: Multiple lesions common
Gross images: liver tumor
Micro: Architectural effacement by atypical centrocyte-like cells (small cleaved follicular cells with abundant cytoplasm), that infiltrate around reactive B cell follicles in a marginal zone distribution; in stomach, may invade epithelial structures to form lymphoepithelial lesions; cells are at various stages of B cell differentiation including monocytoid B cells, small lymphocytes, plasma cells; may have follicular colonization of neoplastic cells
Micro images: low grade; high grade #1; high grade #2; high grade #3; low grade with transformation and crystalline inclusions
Positive stains: CD19, CD20, CD22, CD79a, surface Ig, cytoplasmic Ig in plasma cell component, bcl-10; variable CD11c, variable bcl2
Note: Plasmacytoid cells may be negative for B cell markers but are strongly immunoreactive for kappa or lambda
Negative stains: IgD, CD5, CD10, CD23, variable CD43, bcl-1
Molecular: t(11;18)(q21;q21): API2 and MALT1 (50%); associated with aggressive disease and poor response to antibiotics
t(14;18)(q32;q21): IgH and MALT1 - described in nongastric extranodal MALT lymphomas; indistinguishable from IgH-bcl2 by cytogenetics; associated with other karyotypic abnormalities including various trisomies
t(1;14)(p22;q32): bcl-10 and IgH (% unknown): inactivates the “pro-apoptotic” bcl-10 protein; associated with advanced MALT
t(1;2)(p22;p12): bcl-10 and Ig Kappa
Trisomy 18 is also common; trisomy 3 present, whole or partial in 26-55%
Multiple lesions often have 1-3 neoplastic clones (Mod Path 2001;14:957)
Low grade lesions often are bcl6 negative, but have bcl6 mutations by PCR
DD: CLL/SLL (CD5+, CD23+), follicular lymphoma (CD10+), mantle cell lymphoma (CD5+), inflammatory pseudotumor, rhabdomyomas (if tumors contain crystalline inclusions, Archives 2000;124:460)
Variants of MALT lymphoma
CD5+ MALT
Associated with disseminated lymphoma, often in head and neck, responding poorly to treatment
Must rigorously exclude other B cell lymphomas
Case reports: 87 year old woman with CD5+ tumor of breast (Hum Path 2003;34:1065)
Primary sites of MALT lymphoma (see also these Chapters)
Bladder
Case report (4 cases) at Archives 2001;125:332
<100 cases reported, usually not confirmed by immunoglobulin gene rearrangement studies
Patients >60 years old, 3 female, 1 male; all had chronic cystitis
Treatment: radiotherapy for limited low grade disease apparently gives long-term control
Micro: centrocyte-like cells, plasmacytoid B cells or both
Micro images: 1-involvement of lamina propria; 2-lymphoepithelial lesion in cystitis glandularis
Molecular: gene rearrangement studies
Breast
Case reports: bilateral MALT with localized amyloidosis (Archives 2000;124:1233), collision tumor with invasive ductal carcinoma (Archives 2004;128:99)
Micro images: 1-Congo red+ amyloid; 2 and 4-small lymphoid cells and lymphoepithelial lesions; 3 and 5-CD20+; 1-ductal carcinoma and MALT lymphoma; 2-carcinoma-white arrow, MALT-black arrow; 3-carcinoma-arrow, lymphoma at bottom; 4- monocytoid lymphocytes; 5-CD20+ lymphocytes; 6-metastatic carcinoma in lymph node
Cervix
Case report presenting as endocervical polyp (Archives 2001;125:537)
Micro images: endocervical polyp - H&E, CD20, CD45RA and CD10
Colon
Usually indolent
API2-MALT1 fusion gene due to t(11;18)(q21;q21), associated with MALT lymphoma
API2-MALT1 positive tumors are usually males with larger tumors with more advanced stage
API2-MALT1 negative tumors are usually female
References: Mod Path 2003;16:1232
Cutaneous
Resembles cutaneous lymphoid hyperplasia (both F > M, mean age 50’s) and cutaneous follicular lymphoma; most patients relapse to skin or subcutaneous site
In Scottish Highlands, cutaneous B cell lymphomas are associated with Borrelia burgdorferi/Lyme disease (AJSP 2000;24:1279); usually marginal zone, also follicular center or diffuse large B cell lymphomas; case report in Switzerland of tumor associated with B. burgdorferi infection that regressed after bacterial eradication (Hum Path 2000;31:263); case report in Germany of MALT lymphoma associated with B. burgdorferi outside classical endemic zones, with lesions on nipple (AJSP 2003;27:702)
Asian cases were not associated with Borrelia DNA, API2-MALT1 fusion nor bcl10 mutation (AJSP 2003;27:1061)
Micro: diffuse proliferation of marginal zone cells outside reactive lymphoid follicles; cells are centrocyte-like or monocytoid B cells with plasmacytic differentiation; no epidermal change or diffuse pattern of dermal or subcutaneous infiltration; light chains are monotypic; B cell / T cell often 3:1 or more (hyperplasia is usually T > B, AJSP 1999;23:88)
Positive stains: bcl2
Negative stains: CD1a, CD10, bcl6
CD21+ follicles may be reactive germinal centers (CD10+, CD20+, bcl6+, bcl2-), MALT lymphoma colonized follicles (CD10-, CD20+, bcl6 variable, bcl2 variable), follicular lymphoma (CD10+, CD20+, bcl6+, bcl2+) or expanded follicular dendritic cell meshworks (bcl6-, bcl2+), AJSP 2001;25:732
Kidney
Rare, discussed at Archives 2000;124:919
Liver
Rare, case reports at Archives 2000;124:604, Archives 1999;123:716
Associated with chronic hepatitis, primary biliary cirrhosis or no liver disease
Gross images: liver tumor
Micro images: tumor cells mixed with hepatocytes; bile ducts infiltrated by tumor cells; CD20+; 1-tumor cells invade liver in serpiginous pattern entrapping nodules of normal liver; 2A-reactive follicle surrounded by pale, intermediate sized lymphocytes with mildly irregular nuclei; 2B-bcl2+ tumor cells (reactive follicles are bcl2 negative); 3A-pale tumor cells invade bile duct; 3B-lymphoepithelial lesions are AE1/AE3+
Lung
Also called lymphoma of bronchial associated lymphoid tissue (BALT)
In pediatric HIV patients with lymphoid interstitial pneumonitis, chemokines and cytokines may recruit inflammatory cells, either representing an early stage of MALT or providing a microenvironment for the evolution of a monoclonal B-cell population (Mod Path 2001;14:929)
In adults, lung MALT is usually low-grade, median age 68 years (range 34-88), often associated with autoimmune disorders, monoclonal gammopathies, hepatitis C, H. pylori gastritis; 44% involve mediastinal nodes
Usually indolent with good prognosis; disease specific 10 year survival is 72%
Treatment: local resection for limited disease, chemoradiotherapy for advanced disease
Case reports: 41 year old woman with multiple lung nodules, negative flow cytometry but clonal IgH gene rearrangement (Archives 2003;127:115)
Positive stains: CD20, CD43
DD: reactive disorder (flow cytometry or gene rearrangement studies may be necessary to differentiate)
References: AJSP 2001;25:997, AJSP 2002;26:76
Stomach MALT - B cell lymphoma chapter
Indolent; when it spreads, tends to involve other mucosal sites such as Waldmeyer’s ring
Pathophysiology: H. pylori chronic infection produces H. pylori reactive T cells, => activation of polyclonal B cells => (over time) emergence of monoclonal B cell population(s), still dependent on T cell activation (now still reversible), => T cell independence (similar to EBV, HTLV-1 models)
Rarely post-transplant (usually low grade, EBV-, mean 7 years after transplant, AJSP 2000;24:100)
Arises from post-germinal center memory B cells (usually bcl6 and CD10 negative)
May arise as oligoclonal proliferations with separate lesions composed of different clones, dominant clones then appear and may disseminate to other lesions (Mod Path 2001;14:957)
Gastric MALT patients often have coexisting GI or GU carcinomas
Note: clonality is not specific for lymphoma as lymphoid follicles in gastritis may also be monoclonal (AJSP 2003;27:882)
5 year cause-specific survival: low grade-94%, diffuse large B cell with areas of MALT-type lymphoma-84%, diffuse large B cell without areas of MALT-type lymphoma-64%
Prognostic factors: Poor – compact clusters of large cells; Favorable – in high grade lymphomas, presence of a low grade component or lymphoepithelial lesions; irrelevant - scattered large cells making up 5-10% of tumor cells (AJSP 2001;25:95)
Survival worse for patients with pure diffuse large B cell lymphoma than high grade MALToma or CD10+ diffuse large B cell lymphoma (AJSP 2000;24:1641)
Stomach - MALT - B cell lymphoma chapter (continued)
Case reports: Case of the Week #127, MALT and histiocytic lymphoma of stomach (AJSP 1996;20:1406), gastric MALT, thymic MALT and Sjogren’s syndrome (Archives 2000;124:770), simultaneous gastric MALT and carcinoma (AJSP 1997;21:505)
Treatment: treat H. pylori gastritis (note: may have positive serology even if H. pylori negative by histology, Mod Path 1999;12:1148); H. pylori eradication therapy produces a long term favorable outcome (Tohoku J Exp Med 2008;214:79); also radiation therapy
Gross images: image1
Micro: dense, monotonous population of centrocyte-like cells, often with residual germinal centers and lymphoepithelial lesions; may have plasmacytoid differentiation; commonly lymphoepithelial lesions (infiltration of glandular epithelium by lymphocytes) or follicular colonization
Signet-ring epithelial cells present in 1/3 in superficial lamina propria associated with lymphoid areas, may represent lymphoepithelial lesions (AJSP 1996;20:588); adjacent mucosa has epithelial erosion (61%), intestinal metaplasia (59%), H. pylori (57%), lymphoid follicles (39%), atrophy (37%), atypical regenerative changes (19%), dysplasia (4%, Archives 2000;124:1628)
High grade lesions should have lymphoepithelial lesions or follicular colonization to be classified as MALT (AJSP 2003;27:790)
Micro images: lymphoepithelial lesion; monoclonal light chain staining; various images
case of the week #127 - stomach nodule - #1; #2; #3; #4; CD20; CD3; CD43; modified Steiner stain of other areas of stomach
Stomach - MALT - B cell lymphoma chapter (continued)
Positive stains: B cell markers (CD19, CD20, CD79a), bcl10, bcl6 (some high grade tumors, but <75% of cells, AJSP 2003;27:790), CD10 (variable), CD43 (variable); monoclonal light chain restriction
Negative stains: bcl6 (low grade tumors)
Molecular: trisomy 3 by FISH (Hum Path 1999;30:706); PCR has false positives as gastritis contains monoclonal B cells (Mod Path 1999;12:885)
DD: benign lymphocytic proliferation (no lymphoepithelial lesions, no Dutcher bodies, no atypia, no monoclonality by PCR)
References: AJSP 1992;16:130, AJSP 2000;24:1641
Thymus
Early MALT in patients with thymic lymphofollicular hyperplasia and myasthenia gravis or connective tissue disease has ill-defined lymphoid follicles with sheets of centrocyte-like B cells disrupting the medullary epithelial cytokeratin network; CD20+, CD79a+, bcl2+; monoclonal IgH rearrangement present; negative for CD5, CD10, CD23, bcl6 (AJCP 2002;117:51)
Case reports: with coexisting gastric MALToma (Archives 2000;124:770), in 63 year old woman resembling thymoma (Hum Path 2000;31:255)
Thyroid
Virtually all primary thyroid lymphomas are MALT-type arising in the setting of lymphocytic thyroiditis in older patients (mean age 64 years), F/M = 2.5:1, AJSP 2000;24:623
May also contain diffuse large B cell lymphoma
Favorable outcome with appropriate therapy
Prognosis: excellent - pure MALT-type and stage IE; poor - large cell component or higher stage
Positive stains: survivin (Hum Path 2002;33:524)
Marginal zone lymphoma - nodal
Uncommon; 2/3 women; mean age 61 years (range 26-92 years)
Usually associated with Sjogren’s syndrome
Usually localized lymphadenopathy (59% stage I-II at diagnosis); marrow and blood involvement are rare
Usually indolent; may have longer survival than extranodal marginal cell lymphoma; 5 year survival of 57%-79%
May be preceeding by marginal zone hyperplasia with clear cells (AJCP 2001;116:550)
Case reports: biclonal disease (Archives 2000;124:1816)
Micro: interfollicular infiltrate of monocytoid, centrocyte-like B cells that are 2-3x larger than small lymphocytes, have moderately abundant pale cytoplasm, round/irregular nuclei with clumped chromatin; similar morphology to MALT lymphoma or splenic marginal zone B cell lymphoma; also has benign follicular centers; 30% have neoplastic plasma cells
Micro images: axillary node - A/B-H&E; C-CD20
Positive stains: CD19, CD79a, bcl2; also CD22, IgM, IgD; variable CD11c
Negative stains: CD5, CD10, CD23, CD25, bcl10, cyclin D1; variable CD43 and bcl6
Molecular: clonal rearrangements of IgH and light chains; trisomy 18 and 3; 1q21 or 1q34 abnormalities
DD: follicular lymphoma (CD10+, bcl6+, t(14,18) present), lymphoid hyperplasia (has reactive follicles and normal appearing cells, no destructive changes, no lymphoepithelial features), CLL/SLL (CD5+, CD23+), mantle cell lymphoma (CD5+, cyclin D1+), hairy cell leukemia (CD103+, CD11c+, CD25+), mastocytosis (tryptase+), lymphoplasmacytic lymphoma, lymphocyte predominance Hodgkin’s lymphoma, acute monocytic leukemia, toxoplasmic lymphadenitis
References: AJSP 2003;27:762
Tumors in children/young adults
67% of marginal zone B cell lymphomas in children / young adults (up to age 29 years) are nodal
80% male, usually no underlying disease
Excellent prognosis with low risk of recurrence
Micro: partial to total effacement of lymph nodes with obliteration of sinuses by atypical cells with predominantly interfollicular distribution and marked expansion of marginal zones; 2/3 had disruption of residual follicles resembling progressive transformation of germinal centers; cells are polymorphic, small to medium size, some with moderate cytoplasm and round nuclei and others with scant cytoplasm and irregular nuclei; frequent plasma cells and larger transformed cells, few/rare blast cells
References: AJSP 2003;27:522
MALT subtype of nodal marginal zone lymphoma
Perisinusoidal, perivascular infiltration of monocytoid / centrocytic cells and residual germinal centers with well-preserved mantle cuff; negative for IgD, cyclin D1, CD5; 44% had masses in salivary gland, soft tissue, skin or breast suggestive of extranodal lymphoma, AJSP 1999;23:59
Splenic subtype of nodal marginal zone lymphoma
Polymorphic infiltrate surrounding residual germinal centers, no or attenuated mantle cuff; bcl2+ (83%); IgD+ (100%), CD5-, CD23-, cyclinD1-; resembles follicular lymphoma, but residual germinal centers were bcl2-, no t(14;18); no splenomegaly, AJSP 1999;23:59
Mediastinal (thymic) large B cell lymphoma subtype
Young adults, 2/3 female
A type of diffuse large B cell lymphoma, often thymic (mediastinal) mass, superior vena cava syndrome or tracheobronchial compression
Aggressive but curable; 50% present with stage 1 or 2 disease; usually no bone marrow involvement
5 year survival is 50%, with relapses to kidney, breast, adrenal cortex, ovary, liver, pancreas, GI
May derive from thymic medullary B cells or from germinal center (AJSP 2001;25:1277)
Gross: large, bulky, locally invasive, often fibrotic
Micro: pleomorphic large cells including centroblasts and immunoblasts with abundant cytoplasm and distinct cell borders; oval, cleaved or multilobated nuclei; also histiocytes, small lymphocytes, sclerosis; variable residual thymic tissue
Positive stains: CD19, CD20, CD45, CD79a; also CD22, bcl6, surface immunoglobulin; variable CD10 (33%), CD23, CD30, CD45, TdT; rarely beta-hCG (AJSP 1999;23:717)
Negative stains: CD3, CD5, CD15, CD21
Molecular: clonal IgH and IgL rearrangements, 9p amplification involving REL gene
DD: Hodgkin’s lymphoma, lymphoblastic lymphoma, germ cell tumors, thymoma
Plasmablastic lymphoma of oral mucosa type
Usually mucosa of oral cavity and jaw with local invasion and rapid dissemination to extraoral sites; also nasal cavity, paranasal sinuses, eyelid, orbit or occasionally other sites with similar morphology
No serum monoclonal protein, no significant bone marrow involvement
Usually HIV+ (73%), EBV+; occasionally HIV- but immunosuppressed or elderly patients without known immunodeficiency
More common than non oral mucosal type; usually male, median age 48 years (range 11-86 years)
Aggressive with poor prognosis (survival 1-16 months)
Case reports: 82 year old, HIV- man with cervical nodal tumor (Archives 2004;128:581); tumors with immunoblastic features in HIV+ patients with Kaposi’s sarcoma (Mod Path 2003;16:424); presentation as lung tumor (Archives 2001;125:282)
Micro: monotonous proliferation of large lymphoid cells with immunoblastic features (abundant basophilic cytoplasm with occasional paranuclear hofs, open chromatin, prominent central nucleoli), cohesive tumor cells may resemble plasmablasts; tumor cells infiltrate in large cohesive masses with relatively well defined advancing edge; frequent mitotic figures, apoptotic cells, occasional tingible body macrophages, cells with plasmacytic features
Micro images: HIV negative case history above - 1: loose tumor cell clusters with dense basophilic cytoplasm and slightly eccentric nuclei; 2: high grade tumor with plasmacytic features; 3: CD138+; 4: CD30+; 5: lysozyme+; 6: EBER ISH positive
Micro images: lung tumor in case history above - H&E; VS38c+; EBER ISH positive
Positive stains: CD38, CD45, CD138, MUM1, EMA, EBER; variable cytoplasmic light or heavy chain expression, variable HHV8; CD10, CD43, CD45RO, bcl2, bcl6
Negative stains: CD3, CD19, CD20, CD79a; usually CD30-, ALK-
Molecular: monoclonal immunoglobulin heavy chain gene rearrangement
Molecular image: PCR of IgH gene rearrangement
DD: plasma cell myeloma (fewer blast-type cells, fewer mitotic figures), Burkitt lymphoma (CD20+)
References: AJSP 2004;28:736 (HHV8-), AJSP 2004;28:41 (HHV8+)
Variants
Plasmablastic lymphoma with plasmacytic differentiation
No gender predominance; median age 55 years (range 30-86 years)
Nodal or extranodal; may occur in oral cavity
33% HIV+
Aggressive; most patients die in first year after diagnosis
Micro: predominance of immunoblasts and plasmablasts (rounded nuclei, coarse chromatin, smaller nuclei); also small cells with plasmacytic differentiation, and occasional binucleated cells with typical plasma cell cartwheel chromatin
Positive stains: MUM1, CD38, CD138; EBV ISH (62%), monoclonal light chain expression; variable CD56 and CD79a
Negative stains: CD20, bcl6, HHV8
Plasmablastic lymphoma-seco