Lymphomas-B cell and Plasma Cell Neoplasms

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

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 gamma 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

T cells

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 / FCRIII 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+

Normal histology

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

Molecular analysis

Fluorescent in-situ hybridization (FISH)

To identify and count chromosomes / parts of chromosomes,

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

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

Early in normal lymphocyte differentiation within the bone marrow, the antigen receptor genes undergo recombination to create a variable region, 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

Grossing lymph nodes

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)

Features to report

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

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)

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

Classification Systems

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)

Cytogenetics

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%)

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)

Hemophagocytic syndrome

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 atypia

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

B cell disorders – general

Almost always surface Ig light chain positive

After rituximab therapy (anti-CD20 monoclonal antibody), bone marrow specimens contain aggregates of T cells that suggest relapse; thus, ordering immunostains is important (AJCP 1999;112:844)

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)

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

Histologic Types

Burkitt lymphoma

30% of childhood lymphomas, may present as B cell acute lymphoblastic leukemia FAB L3 (also called Burkitt leukemia)

Either endemic, sporadic or immunodeficiency-associated

In adults, often associated with immunodeficiency, including HIV; involves distal ileum, cecum, mesentery

In 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

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)

Positive stains: CD10, CD19, CD20, Ki-67 (almost 100%), surface immunoglobulin; also CD22, CD79a, bcl2, 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%)

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)

CD5+ Burkitt leukemia

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)

Chronic lymphocytic leukemia/small lymphocytic lymphoma [B cell type]

Also called CLL/SLL

Most common adult leukemia in Western countries, less common in Japan/Asia

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

Case reports: CLL with composite prolymphocytoid and Hodgkin’s transformation (Archives 2000;124:907), CLL with composite thymoma (Archives 2003;127:E76), 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)

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

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)

Positive stains: CD5, CD19, CD20 (dim), CD23, surface IgM (dim); also CD43, CD79a, CD79b (dim, in 20%), bcl2; variable CD11c

Negative stains: CD10, cyclin D1; also CD79b, FMC-7 (80% are negative)

Molecular: Trisomy 12 (30%, associated with atypical CLL and CD79b), deletion 13q14 (25-50%), deletion of 11q23 (worse prognosis, 10-20%)

DD: other low grade lymphomas with leukemic phase (mantle cell lymphoma, follicular lymphoma, rarely lymphoblastic lymphoma), 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), Mod Path 2002;15:1111 (resembles leukemic phase of mantle cell or follicular lymphoma)

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

Diffuse large B cell lymphoma

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

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); see also AIDS associated

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

Positive stains: CD19, CD20, CD22, CD79a; also CD10 (if follicular origin); variable CD45, variable surface Ig, variable bcl2; in Korea 1/3 are bcl6+/CD10+ (Hum Path 2001;32:954)

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

Breast

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

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

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

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

Follicular lymphoma

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)

Treatment: radiation, low dose chemotherapy when symptomatic, monoclonal antibodies to CD20; can monitor tumor burden and effects of therapy with real time PCR (Mod Path 2002;15:448)

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)

Micro: 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

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

Peripheral smear: cells have scant cytoplasm, cleaved nucleus; confirm neoplastic with flow cytometry

Bone marrow: usually paratrabecular involvement, usually positive for bcl2, CD10, CD20 (AJCP 2002;117:636); DD is benign lymphoid nodules, particularly in elderly; usually well delineated, not paratrabecular, CD10-, bcl2-, predominantly T cells (CD3+, CD5+, CD20-)

Positive stains: CD10, CD19, CD20 (strong), CD79a, bcl2 within follicles, bcl6; CD30+ in 30%; variable surface immunoglobulin

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

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)

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)

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

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)

Hairy cell leukemia

Rare; formerly known as leukemic reticuloendotheliosis

Older (mean age 50 years) white men (80% men) with pancytopenia (50%), massive splenomegaly with obliteration of white pulp and involvement of red pulp (common), infections (1/3)

Chronic leukemia with minimal lymphadenopathy; associated with frequent atypical mycobacterial infection with monocytopenia, weakness, weight loss

Treatment: 2-chlorodeoxyadenosine, interferon; cause apparent cures

Case reports: 42 year old man with WBC count of 98K (Archives 2003;127:253)

Micro: spleen - tumor cells larger than small lymphocytes, modest pale blue agranular cytoplasm with threadlike extensions seen with phase contrast microscope, round or folded nuclei, no distinct nucleoli; residual follicles often present; cells line pseudosinuses

Bone marrow: acellular aspirate due to reticulin fibers; hairy cells are bland with round or oval nuclei; distinct borders; extravasated red cells common

Positive stains: CD11c, CD19, CD20, CD22, CD25, CD79a, CD103, TRAP (tartrate resistant acid phosphatase), PCA-1 (plasma cell antigen-1), FMC7, surface IgH, DBA-44; variable TIA1

Negative stains: CD5, CD10, granzyme B, perforin

Molecular: no specific chromosomal anomalies

DD: nodal marginal zone B cell lymphoma, mastocytosis (tryptase+)

References: Mod Path 2004;17:840 (TIA1 expression)

Variant type

10% of cases, more aggressive; poor response to interferon

Mean age 70, often men with massive splenomegaly, marked lymphocytosis without infection, successful marrow aspirates

A Japanese variant also exists

Case reports: CD10+, CD25+, CD103-, poor response to interferon (Archives 2000;124:1710), 77 year old man, also with polycythemia vera (Archives 2003;127:e209)

Micro: medium/large leukemic cells, some with cytoplasmic projections; large, central nuclei with prominent nucleoli; fried egg appearance in bone marrow

Positive stains: CD11c (bright by flow), variable CD25, variable CD103, variable TRAP; also CD22

Negative stains: CD10

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)

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: 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)

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

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

Lymphomatoid granulomatosis

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)

Lymphoplasmacytic lymphoma

Also called plasmacytoid lymphoma, immunocytoma

Rare, 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 and hyperviscosity syndrome and associated with lymphoplasmacytic lymphoma, B-cell CLL/SLL, marginal zone B cell lymphoma (MALT type), myeloma

Hyperviscosity syndrome: in 90% 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)

Treatment: cannot cure; use plasmapheresis for hyperviscosity and hemolysis; median survival 5 years

May have poorer prognosis than other small B cell lymphomas (AJSP 2001;25:742)

May transform to diffuse large B cell lymphoma with Reed-Sternberg like cells or immunoblasts

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

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 0-50%, 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: 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)

Mantle cell lymphoma

Formerly known as centrocytic lymphoma

3-10% of non-Hodgkin lymphomas in Western countries

Usually 60+ years with stage III/IV disease; male predominant

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)

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)

Most patients relapse; complete remission in less than 35%

Case reports: indolent tumor for 12 years without treatment, with mutated immunoglobulin genes (Hum Path 2003;34:1030), 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), prolymphocytoid variant with leukostasis (Mod Path 2004;17:879)

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)

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, 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)

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

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)

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)

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

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

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

DD: diffuse large B cell lymphoma

References: Hum Path 2003;34:1022 (cytogenetics), Archives 2000;124:1457 (cell cycle markers), Archives 2001;125:513, AJCP 2002;117:246

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

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 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

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

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

Breast

Case reports: bilateral MALT with localized amyloidosis (Archives 2000;124:1233), collision tumor with invasive ductal carcinoma (Archives 2004;128:99)

Cervix

Case report presenting as endocervical polyp (Archives 2001;125:537)

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

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

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)

Gastric MALT patients often have coexisting GI or GU carcinomas

High grade gastric MALT lesions often demonstrate loss of alpha4beta7integrin compared to low grade lesions

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)

Case reports: with coexisting thymic MALToma (Archives 2000;124:770)

Micro: 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)

Positive stains: CD10 (variable)

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%

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

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

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

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-secondary

Similar to plasmablastic lymphoma with plasmacytic differentiation but associated with another plasma cell neoplasm

Positive stains: CD56 (in 75% of myeloma patients)

Negative stains: cyclin D1

Plasmablastic lymphoma associated with Castleman’s disease

Associated with multicentric Castleman’s disease

Lymph nodes, spleen, leukemic involvement

Micro: plasmablasts or immunoblasts

Positive stains: HHV8; CD20

Negative stains: CD30, EBV; no CD10 and bcl6 coexpression

Precursor B cell lymphoblastic leukemia/lymphoma

Usually children, presents with pancytopenia due to extensive marrow involvement, stormy onset of symptoms, bone pain due to marrow expansion, hepatosplenomegaly due to neoplastic infiltration, testicular involvement, CNS symptoms due to meningeal spread, frequent skin involvement

85% of acute lymphoblastic leukemias (ALL) are B cell, compared to 10-20% of lymphoblastic lymphomas (remainder are T cell)

Leukemia is defined as 20% or more lymphoblasts in bone marrow

Aggressive but 2/3 cured with chemotherapy

Derived from pre-germinal center naive B cells with nonmutated Vh region genes

Recommended to classify/manage B-ALL with mature phenotype, L1 morphology, and without c-myc translocations as pre-B lymphoblastic/lymphoma (not Burkitt lymphoma), Archives 2003;127:1340

Lymphoma cases: median age 20 years, 88% age 35 years or less; 2/3 female, usually extranodal (cutaneous nodules, bone or nodal involvement, NO marrow or mediastinal involvement); usually stage 1 or 2; prognosis better than leukemia, but 28% died after median 5 years; often 21q alterations, resembles blastoid variant of mantle cell lymphoma; rarely develop leukemia

Good prognostic factors: age 2-10 years, early pre-B phenotype, hyperploidy, t(12,21)

Poor prognostic factors (give bone marrow transplantation): under age 2 or teenager/young adult, t(9;22)

Micro: intermediate sized blast-like cells with scant cytoplasm, round or convoluted nuclei, fine chromatin, indistinct nucleoli, frequent mitosis; may have “starry sky” appearance (similar to Burkitt); usually no sclerosis

Positive stains: CD19 or CD20 or CD79a, TdT (rarely negative, Archives 2000;124:92); also CD99, CD179a and CD179b (light chain substitutes in precursor B cells, Mod Path 2004;17:423), variable CD10 (76%), CD20 (54%), CD22 and CD34

Negative stains: surface immunoglobulin, cytoplasmic IgM, T cell antigens, CD15, CD30, CD45

Note: may resemble Ewing’s sarcoma and be CD99+, CD45-, CD20-, CD3-, weakly positive for vimentin (AJCP 2001;115:11)

Molecular: t(1;19)(q23;p13): PBX1 and E2A (30%)

t(12,21)(p13;q22): ETV6-CBFA2 (TEL and AML1) (20%)

t(4;11)(q21;q23): AF4 and MLL (10%)

t(9;22)(q34;q11): bcr and c-abl [Philadelphia chromosome] (5-20%)

t(5;14)(q31;q32) - IL3 and IgH

t(1;14)(q25;q32) - IHX4 and IgH

Most tumors are hyperdiploid (>50 chromosomes), some are pseudodiploid

DD (based on morphology): Ewing’s sarcoma (negative for CD79a, CD43, TdT and immunoglobulin or T cell receptor rearrangement, strong/diffuse for vimentin), Burkitt lymphoma, granulocytic sarcoma, blastic variant of mantle cell lymphoma, Hodgkin lymphoma, AML (prominent nucleoli, delicate chromatin, fine azurophilic cytoplasmic granules)

Note: pre-T ALL, granulocytic sarcoma, Burkitt lymphoma, diffuse large B cell lymphoma and Ewing’s sarcoma are negative for CD179a/CD179b

References: AJCP 2001;115:868, AJSP 2000;24:1480

Primary cutaneous B cell lymphoma

Defined as arising in skin, without evidence of extracutaneous disease for 6 months from initial diagnosis

Usually follicular lymphoma, marginal zone lymphoma or diffuse large B cell lymphoma (Mod Path 2004;17:623)

Primary cutaneous diffuse large B-cell lymphoma

By definition, arises in skin with no known extracutaneous disease within 6 months of initial diagnosis

Represents 20% of primary cutaneous lymphomas; others are extranodal marginal zone lymphoma, diffuse large B cell lymphoma and follicular lymphoma

Usually men (85%), mean age 64 years (AJCP 2002;117:574)

Better outcome than other large B cell lymphomas; relapse common but death rare within 48 months

Primary cases have fewer features of follicular lymphoma than secondary cases (AJSP 2003;27:356)

CD10+ tumors in head and neck have increased risk of relapse

Can divide into follicular center type (CD10+, bcl6+, CD138- but without bcl2 translocations) and those with post-follicular center or activated B cell phenotype

No well-defined relationship between site and prognosis (Mod Path 2001;14:10)

Treatment: less aggressive (surgery and radiotherapy)

Case reports: t(14;18)(q32;q21) involving IgH and MALT1 (not bcl2, distinguish MALT1 vs. bcl2 by FISH, Hum Path 2003; 34:1212)

Gross: solitary or grouped papules, plaques or tumors, usually in head, neck and trunk of older patients

Micro: 3 groups: (a) large and small B cells, (b) grade 3 follicular lymphomas (usually in head/neck and CD10+) and (c) monomorphous (AJSP 2001;25:307)

Positive stains (tumor cells): CD20; variable bcl2, variable bcl6

Negative stains (tumor cells): CD3 (positive in background cells), CD10 (usually)

Flow cytometry: T cells are 65-90% of cells (Archives 1999;123:1236)

Leg

5-10% of primary cutaneous diffuse large B cell lymphomas cases

Usually elderly patients

May have poorer prognosis (AJSP 2003;27:1538), although somewhat controversial (Hum Path 2002;33:937)

Gross: solitary or grouped red/blue nodules

Micro: dense, diffuse large cells infiltrating entire dermis; usually thin grenz zone; cells resemble immunoblasts (large oval vesicular nuclei with prominent nucleoli) or centroblasts (large noncleaved nuclei, prominent nucleoli)

Primary effusion lymphoma (PEL)

Also called body cavity lymphoma

Rare type of diffuse large B cell lymphoma with lymphomatous effusions in pleural, pericardial and abdominal cavities but no tumor mass

Strongly associated with HHV8 and advanced HIV; usually EBV+; also in non immunosuppressed patients, often elderly

Survival usually only months

Case reports: HIV negative patient (Archives 2000;124:753), patient with coexisting small bowel mass (AJSP 2002;26:1363), 42 year old HIV+ man with pleural cavity and lingual tumor; both HHV8+ and solid with plasmablastic features (Hum Path 2004;35:632)

Micro: large Reed-Sternberg like cells (immunoblastic or anaplastic) with abundant basophilic cytoplasm, round nucleus, single prominent nucleoli, perinuclear halo, variable nuclear pleomorphism with binucleated cells; rarely is solid with plasmablastic features (see below)

Positive stains: CD30, CD138, EMA, HHV8; also HLA-DR, variable CD3, CD45

Negative stains: CD5, CD19, CD20, CD22, CD23, CD43, CD79a, immunoglobulins, p53, bcl6

Molecular: often required for diagnosis since negative B cell stains; clonal rearrangements and somatic mutations of Ig heavy chain; clonal Epstein-Barr virus and HHV-8 genetic sequences; also gain of sequences in chromosomes 12 and X (Archives 2000;124:824)

DD: plasmablastic lymphoma (not an effusion), pyothorax associated lymphoma (different clinical history)

References: Mod Path 2002;15:944 (reverse transcriptase in situ PCR to detect HHV8)

Solid variant

Very rare; GI tract, skin, lung, cerebrum; rarely nodal (AJSP 2004;28:693)

May represent a heterogeneous group of disorders

Case reports: HHV8+, HIV+, EBV+ primary bowel lymphomas (B cell and null cell) without primary effusion lymphoma (Hum Path 2002;33:846)

Micro: large pleomorphic cells; nodal case resembled anaplastic large cell lymphoma

Positive stains: HHV8, CD30, variable EBV

Negative stains: B and T cell markers, immunoglobulin expression

DD: diffuse large B cell lymphoma with plasmablastic features (HHV8-)

T cell primary effusion lymphoma

Case report of 87 year old man, HHV8+, HIV- (Archives 2001;125:1246)

Prolymphocytic leukemia

Elderly men with peripheral blood lymphocytosis > 100,000, marked splenomegaly, pancytopenia

Classify as mantle cell lymphoma if t(11;14) positive (AJCP 2001;115:571)

Diagnosis: prolymphocytes comprise >55% of leukemic infiltrate

Micro: prolymphocytes in peripheral blood with moderate pale blue agranular cytoplasm, round nuclei, prominent central nucleoli; involves red and white pulp of spleen

Positive stains: bright surface immunoglobulin, CD5, CD19, CD20 (bright), CD22, FMC7

Molecular: 14q+ is most common; cytogenetic abnormalities are complex, suggesting clonal evaluation and genomic instability

Pyothorax associated lymphoma

Rare, associated with history of chronic pyothorax or chronic pleuritis due to therapeutic artificial pneumothorax for pleuropulmonary tuberculosis (AJSP 2002;26:724)

Presents with pleural mass, occasional liver involvement

Tumor cells derive from late germinal center or post-germinal center cells (negative for CD10 and bcl6, positive for MUM1 and CD138)

Median survival is 5 months

Micro: diffuse proliferation of large lymphoid cells with frequent plasmacytoid differentiation

Positive stains: CD20, CD79a, EBV LMP, EBV EBNA, occasionally CD138, CD2, CD3, CD4

Negative stains: HHV-8, CD10, bcl6

Molecular: immunoglobulin light chain restriction, clonal B cell population in six cases, EBV genome

Splenic marginal zone B cell lymphoma

Also called splenic lymphoma with villous lymphocytes

Rare low grade B cell lymphoma of middle aged and elderly patients

Usually disseminated (as opposed to MALT lymphoma) with splenomegaly and left upper quadrant pain, paratrabecular marrow involvement in 75% causing anemia, involvement of peripheral blood, liver and often splenic hilar lymph nodes, but no peripheral nodal involvement unless it transforms

Usually indolent but 13% transform, possibly related to 7q deletion (AJSP 2001;25:1268)

Note: cases with plasmacytic differentiation often present with monoclonal serum disorders and autoimmune disorders, including hemolytic anemia; may have Waldenstrom’s macroglobulinemia; are similar otherwise to non-plasmacytic cases (AJSP 2000;24:1581)

Case reports: blastic transformation (Archives 2000;124:748), 22 year woman (Archives 2002;126:214), associated with Gaucher’s disease with transformation to diffuse large B cell lymphoma (Archives 2003;127:e242)

Marginal zone: light zone surrounding splenic follicles; contains post-follicular memory B cells derived after stimulation of recirculating cells from T cell dependent antigen

Gross: multiple small, grey-white nodules

Micro: infiltration of small atypical lymphocytes in mantle zone and medium lymphocytes with pale cytoplasm and oval clear nucleus in marginal zone, leading to mixed mantle-zone and marginal-zone involvement pattern; variable follicular colonization but definite increase in white pulp; cells are centrocyte-like, monocytoid (easily recognized with imprints) or lymphoplasmacytic; < 20% immunoblasts; involves red pulp also; intrasinusoidal infiltration of bone marrow relatively specific finding

Peripheral smear: scant cytoplasm and cleaved nucleus; confirm neoplastic with flow cytometry

Positive stains: CD19, CD20, CD22, CD45 RA, CD79a, bcl2; tumor cells are IgM+ and IgD (dim), but there is no IgD positive mantle area

Negative stains: CD3, CD5, bcl-1/cyclin D1, CD10, CD23; also CD43, CD25

Molecular: clonal rearrangements of IgH and IgL are common; often gains in chromosomes X, 3, 18 and losses in 6q and 7q31-32 (Mod Path 2003;16:1210)

DD: lymphoplasmacytic lymphoma (no pale corona surrounding reactive or colonized germinal centers and no monocytoid B cells in marginal zone), B-CLL (CD5+), persistent polyclonal B cell lymphocytosis (Mod Path 2004 May 14)

Plasma cell neoplasms

General

Various disorders characterized by monoclonal proliferation of immunoglobulin producing cells resembling lymphocytes or plasma cells

Monoclonal immunoglobulin (Ig) is also referred to as “M” component

Detect as monoclonal peak on serum or urine electrophoresis

Bence Jones proteins: free light chains without attached heavy chains

WHO classification of plasma cell neoplasms:

Plasma cell myeloma

Plasmacytoma

Monoclonal immunoglobulin deposition diseases

Heavy chain diseases

Plasma cell myeloma (multiple myeloma)

Neoplastic proliferation of plasma cells with multifocal skeletal involvement

Usually middle-aged to elderly patients with widespread skeletal lytic lesions, bone marrow plasmacytosis and monoclonal gammopathy; also pathologic fractures and back pain; also weakness, anemia, pallor, hepatosplenomegaly, hypercalcemia, primary amyloidosis (AL type) and renal insufficiency due to toxicity of light chains (Bence Jones proteins) to renal epithelium

Causes 1% of cancer deaths in Western countries, males > females, African Americans > Whites

Infections common (due to impaired humoral immunity) with Streptococcus pneumoniae, Staphylococcus aureus, E coli; cellular immunity is normal

Most commonly affects vertebral column, ribs, skull, pelvis; begins in medulla, then erodes cortical bone

Can spread to skin (0.5%), lymph nodes

Hyperviscosity syndrome present in 7%, usually due to IgA or IgG3

Cell of origin is less differentiated than plasma cells; expresses antigens associated with myelomonocytes (CD33), megakaryocytes (Gp IIb/IIIa), erythroid cells (glycophorin)

On Xray, lesions appear as punched out defects, associated with generalized osteoporosis

Prognosis: poor; < 1 year if multiple lesions and no treatment; many years if indolent

Median survival is 3 years with chemotherapy; 10% survive 10 years; death due to uncontrolled disease or marrow failure

Laboratory: Monoclonal secretion of immunoglobulins > 3g/dl in serum or 6 mg/dl in urine of Bence Jones proteins, usually IgG (55%) or IgA (25%), appears as monoclonal spike in serum or urine electrophoresis; may create falsely positive elevated hemoglobin (Archives 2000;124:616); usually elevated serum IL-6; frequently infected with HHV8

In 20% of cases, only monoclonal light chains (Kappa or Lambda) are present, usually in urine

Occasionally light chains deposit in renal proximal tubules, thyroid follicular or gallbladder surface epithelial cells (Hum Path 2003;34:270)

Rouleaux formation occurs in peripheral blood (erythrocytes resemble stacked coins) due to protein present, parallels erythrocyte sedimentation rate

M component: monoclonal immunoglobulin (M-myeloma), up to 160kd, restricted to plasma and extracellular fluid

Treatment: alkylating agent chemotherapy, bone marrow transplantation, anti-topoisomerase II alpha agents

Note: highly proliferative tumors usually are topo II alpha positive and sensitive to anti-topo II alpha agents

Poor prognostic factors: cyclin D1+ (associated with advanced stage, grade, AJCP 2001;116:535), IgD form (see below), high IL-6 levels, plasmablastic morphology, CD10+

Case reports: plasmablastic transformation resembling acute leukemia (Hum Path 2003;34:710), coexisting acute monocytic leukemia (Archives 2003;127:1506), presentation with subcutaneous nodules and mediastinal mass simulating hemangioma (Archives 2000;124:628), after diagnosis of sarcoidosis (Archives 2002;126:365)

Gross: Multiple masses of neoplastic plasma cells throughout the skeletal system; generalized osteoporosis

Micro: sheets or aggregates of plasma cells or plasmablasts; all cells have large nuclei, may be multinucleated; often with prominent nucleoli, perinuclear hof (due to prominent Golgi apparatus), Mott Cells (blue grapelike inclusions), Russell bodies (cytoplasmic crystalline rods), Dutcher bodies (intranuclear crystalline rods)

“Flaming” plasma cells: fiery fringes formed by pseudopodic cytoplasmic projections that are carmine red after Wright-Giemsa staining; peripheral cytoplasm has numerous dilated endoplasmic reticulum cisterns distended with immunoglobulin that may fragment and appear around the cell; associated with IgA myeloma (Archives 2001;125:1394)

Bone marrow biopsies should have >10% plasma cells

Positive stains: kappa or lambda light chains (usually one markedly more than the other), CD38 (plasma cells), CD79a, CD117, CD138, EMA (70%); also vimentin (70%), CD33 (myelomonocytes), GP IIb/IIIa, glycophorin

Note: cutaneous plasmacytomas uniformly express CD117 (Archives 2003;127:1596)

Negative stains: CD19, CD20

Molecular: 13q-, 14q, rearrangements common

t(4;14)(p16;q32) in 25-30% of cases, causing increased expression of FGFR3 (fibroblast growth factor receptor 3) and IgH

t(11;14)(q13;q32) [cyclin D1 and ? IgH]: usually part of complex karyotype; may be missed by routine cytogenetics, particularly if the proliferative rate is low (AJCP 2000;113:831)

Also t(14;16)(q32;q23) - IgH and c-maf; t(16;22)(q23;q11) - c-maf and Ig lambda; t(6;14)(p25;q32) - mum/irf4 and IgH

DD: reactive synovitis with Dutcher bodies (Archives 2002;126:199; 1A-H&E; 1B-PAS; 2A-kappa; 2B-lambda)

References: Archives 2004;128:645 (detecting clonality in cutaneous plasmacytomas with light chain restriction)

Variants:

Immunoglobulin D multiple myeloma

Rare subtype (1% of cases)

More aggressive than other forms with survival of 12-17 months; 70% have azotemia

Only 60% have an M spike, often less than 2000 mg/dl

Gamma light chain present

Case reports: 2 Chinese patients with spectral karyotyping (Hum Path 2001;32:1016), 81 year old woman with compression fracture and renal failure (Archives 2003;127:1383)

Indolent multiple myeloma: similar to smoldering but with a few bone lesions and mild anemia; most develop overt multiple myeloma within 3 years

Multilobated nuclei: <20 cases reported through 1998; associated with light-chain disease

Aggressive with shorter survival, more renal failure, lytic bone disease, hypercalcemia, amyloidosis

Micro: either mature plasma cells, multinucleated plasma cells or cells with multilobated, cleaved, or monocytoid nuclei; markedly irregular nuclear contours or nuclear lobulation similar to neutrophils

DD: metastatic carcinoma, T-cell lymphoma, myelomonocytic leukemia, megakaryocytes, neutrophils, histiocytes

Nonsecretory multiple myeloma: rare, defined as no monoclonal protein in serum or urine, but do have typical myeloma osteolytic lesions and bone marrow plasmacytosis; no renal failure or hypercalcemia; diagnose based on monoclonal protein in plasma cells via immunostaining

Osteosclerotic multiple myeloma: component of rare POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin lesions)

Plasma cell leukemia: primary if initial diagnosis is based on leukemic phase of myeloma, otherwise secondary; peripheral blood has >20% plasma cells with absolute count of 2000/ml or more; primary plasma cell leukemia associated with younger age, hepatosplenomegaly, lymphadenopathy, fewer lytic bone lesions but poorer prognosis than secondary

Smoldering multiple myeloma: myeloma patients with stable disease for months/years; no anemia, bone lesions, renal insufficiency or hypercalcemia; have >10% plasma cells in bone marrow and monoclonal serum protein

Plasmacytoma

Isolated plasma cell neoplasm, usually of bone or soft tissue (oropharynx) composed of terminally differentiated B cells

Types: solitary plasmacytoma of bone, extramedullary plasmacytoma, primary lymph node plasmacytoma

DD: myeloma (plasma cells usually more anaplastic), plasmacytosis (no light chain restriction)

Solitary plasmacytoma of bone

An infrequent (3-5%) variant of myeloma

Bone lesion with monoclonal plasma cell infiltrate; no other lytic bone lesions; no plasma cell infiltrates in random bone marrow biopsies

Rarely involves lymph nodes or peripheral blood

Causes local bony destruction, pathologic bone fractures at same sites as myeloma (spine, long bones, pelvis)

Usually progresses to myeloma, but may take 10-20 years

Laboratory: expansion of a single clone of immunoglobulin secreting plasma cells, increase in serum levels of single homogeneous immunoglobulin (monoclonal spike on serum electrophoresis)

Case report with anaplastic cytology (Archives 2004;128:237)

Extramedullary plasmacytoma

Arises outside bone marrow; often in nasal cavity, nasopharynx, sinuses, lung

May recur locally, but less likely to progress to multiple myeloma than solitary plasmacytomas of bone

Case reports: associated with amyloidoma (Archives 2002;126:969), in breast (Archives 2001;125:1078), metastatic to myocardium (Archives 2000;124:910

Primary lymph node plasmacytoma

Rare, must exclude metastatic multiple myeloma (40% of high stage myelomas metastasize to lymph nodes), metastatic upper respiratory tract plasmacytomas (15% metastasize to cervical lymph nodes) and Castleman’s disease

Often involves cervical nodes, mean 5 cm, 40% had serum monoclonal proteins, most patients had localized disease and were cured after local excision or radiation, similar to other extramedullary plasmacytomas (AJCP 2001;115:119)

Micro: lymph node effacement by mature plasma cells, with no/rare lymphocytes or immunoblasts

Heavy chain disease

Rare malignant disorders (100 cases reported) with secretion of IgH fragments (not complete immunoglobulin)

Types - CLL/SLL-like, lymphoplasmacytic lymphoma-like, Mediterranean lymphoma-like (small bowel lymphoma in malnourished populations)

Gamma, alpha, mu types

25% associated with autoimmune diseases

Laboratory: localized band in beta1 or beta2 regions in 60%; 40% have no detectable protein by electrophoresis

Case reports: Hodgkin’s lymphoma with gamma heavy-chain disease (Archives 2001;125:803), 59 year old woman with immunotactoid glomerulopathy, follicular lymphoma and gamma heavy-chain disease (Archives 2004;128:689)

Primary amyloidosis

Monoclonal proliferation of plasma cells secreting free light chains (usually lambda), which are deposited as amyloid

Amyloid: fibrillary protein, 95% composed of non-branching fibrils 7.5 to 10 nm thick with variable length in beta pleated sheet conformation; 5% is serum amyloid P component, proteoglycans and highly sulfated glycosaminoglycans; deposited in various tissues causing local damage; due to primary amyloidosis (AL), secondary amyloidosis (AA) or familial amyloidosis (AF); only primary amyloidosis is associated with plasma cell dyscrasias

Clinical: due to overt multiple myeloma (20%) or plasmacytomas of bone marrow or minor population of plasma cells

Rare (2,000 cases/year in US), usually ages 60-70 years, 2/3 are men

Symptoms: weight loss, fatigue, heart failure, peripheral neuropathy, nephrotic syndrome (1/3), bleeding (acquired factor X deficiency due to its binding to amyloid protein)

80% have serum or urine monoclonal protein, although electrophoretic spike may be small; detect with immunofixation of serum or urine if amyloidosis suspected

Biopsy is 80% sensitive in rectum and fat, 50% in bone marrow (may be confined to blood vessel walls only)

Median survival 1-2 years; death due to cardiac disease, renal failure, infection, hemorrhage

Case reports: subcutaneous nodular amyloidosis due to lambda light chains (Hum Path 2001;32:346), amyloidosis and extramedullary plasmacytoma in larynx of child (Hum Path 2001; 32:132), monoclonal immunoglobulin deposition disease associated with nephrotic syndrome and subsequent heavy chain disease with amyloidosis (AJSP 2003;27:1477)

Treatment: alkylating agent chemotherapy

Micro: pale pink amorphous tissue, apple-green birefringence with Congo red stain and polarized light microscopy; check vessel walls in bone marrow biopsies

EM: fine, linear, nonbranching fibrils

Monoclonal gammopathy of undetermined significance (MGUS)

Monoclonal immunoglobulin in serum or urine without diagnostic features of multiple myeloma or macroglobulinemia

Clinical: more common than multiple myeloma (1 million vs. 13,000/year in US)

Higher prevalence in African-Americans

Incidence increases with age (mean age 64 years): 1% of healthy people age 50 years+ vs. 3% at 70 years+

Paraprotein is usually IgG, also IgA, IgM; may be multiple paraproteins

Serum immunoglobulin level less than 3g/dl.

Micro: fewer plasma cells than multiple myeloma, plasma cells lack nucleoli (AJCP 2001;115:127)

Treatment: follow with serial measurements of monoclonal protein but no specific treatment

In one study, 26% progressed to overt malignant plasma cell disorder over median of 10 years

Cryoglobulinemia

Cryoglobulins: proteins that precipitate as serum is cooled but before 37C, redissolve upon warming

Simple/type I (monoclonal) or mixed /type II (two types of monoclonal immunoglobulin, usually IgG and IgM) or mixed/type III (like type II but polyclonal)

Type I: associated with multiple myeloma, lymphoplasmacytic lymphoma

Type II: associated with chronic active hepatitis C infection, autoimmune disease, non-Hodgkin lymphomas, lymphoplasmacytic lymphoma

Type III: associated with chronic infections and autoimmune diseases

Symptoms: often none; also Raynaud’s phenomenon, ulceration, purpura

Treatment: corticosteroids, plasmapheresis

Go to Lymphomas: non B cell

End of Lymphomas: B cell and plasma cell neoplasms chapter / outline

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