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MATURE B CELL NEOPLASMS

CLL/SLL


MOST
: subclinical, if SLL no cytopenias, marrow neg >5000 lymphos CLL vs <5000 lymphos SLL. CLL nodes+, basket, 30% lymphos in BM. Strong: 23, 5, 43, 79a, BCL2. Weak or dim: 20, 19, sIgM or D. Neg: 10, cyclin D1, BCL-6

COMMON: spleen +, liver +, anemia, WAIHA, infections x hypogamma. Very low mitosis, < 2% prolymphos. Weak or negative: FMC7, cIg, 79b. Positive: 38 in advanced.


RARE: Young, genetic, chemicals?, conversion to DLBCL (Ritcher) or HL (EBV+). Irregular nucleus, paratrabecular in BM, cytopenia or < 5000 lymphos in CLL, aleukemic, 2-55% prolymphos (>55% = B-PLL), proliferation centers in BM, monoclonal spikes k or L. CD5-, 23- or dim, 79b+, 11c+, FMC7-, strong sIG, 10+ (1%), TRAP+. Cyclin D1 and MUM1 weak in proliferation centers

COMMENTS: May live as long as 20y. Incidental lymphocytosis may be small clones of unknown significance (do flow if lymphos > 5000 for 3 months or cytopenias, monoclonal lymphocytosis, symptomatic, even with < 5000 lymphos). If rituximat (antiCD20), use 79a or Pax-5 (both bright). 20 and Pax 5 are markers normally + in B cells prior to plasma cell. Low risk and good px: many mutations or del 13q. High risk or bad px: >2% prolymphos, few mutations or FISH panel with del 17p or 11q. Intermediate px: triso 12. 23+ no specific but favors CLL over MCL. 43 not specific (+ in other lymphomas or leukemias); sheets of 43+ B cells not seen in normal tissue other than tonsils, sialoadenitis, Peyer, T cells, plasma cells.
ZAP 70 is Flow cytometry test that may predict px in CLL. AZP 70 is a protien kinase that phosphorylate CD3 and the transmembrane protein LAT (Linker of Activated T Cells) allowing T cell to differentiate and secrete cytokines. If Flow shows ZAP 70 > 20%, disease is more advanced and aggresive.  

B-PLL (Prolymphocytic)


MOST
: Old, incurable, PB>55% prolymphos (larger than lymphos, big nucleoli), WBC>100K, BM + (interstitial or nodular), big spleen (both pulps). Strong 20, FMC7, sIgM/IgD, 79a, 79b, 22, 19. Neg 23 y 5


COMMON: decrease Hb and platelets. ZAP70+, 38+, clonal rearrangement Igs, del 17p, del 13q

RARE:  Nodes + (diffuse or nodular),5+, BCL-1+, 23+. Triso 12

PITFALLS: If proliferation centers consider transformed CLL (different entity). If psedofollicles consider blastoid leukemic MCL (cyclin D1 and t 11-14). MZL may show high # of prolymphos.  

 

MCL (Mantle)


MOST
: 60s, poor px. Small to intermediate size irregular cells, diffuse pattern in nodes. Strong: 5, 43, 20,19, 79a, FMC-7, BCL-2, cyclin D1. Other +: sIgD (also present in normal mantle cells), Pax5+, TRAP+. Weak (dim): 21, 23 (loosly arranged FDC meshworks). Negative: BCL-6, 10, MUM-1. PAS + vessels thickened.

COMMON: PB+, spleen+, BM+(interstitial or paratrabe), liver+, GI (multiple polyps), oropharyngeal.

RARE: Genetic ?. Clonality for sIgM or L. Blastoid variant may be 5-/10+/BCL6+/cyclin D1 neg, but cyclin D2+ and D3+.

PITFALLS: May look nodular with pseudofollicles. Do not confuse with SLL (centroblasts, paraimmunoblasts, proliferation centers). Starry sky possible (not = burkitt). Carefull: T cells, histios, endothelium, fibroblasts and normal mantle are cyclin D1+. Cyclin D1+ in some MM, HCL, in situ MCL.

COMMENT: Arise in naive B cells. In situ MCL is confined to mantle zone, good px. Bad px: Ki-67 > 60%, blastoid, pleomorphic, triso 12, p53 +, leukemic with nodes+ (better if nodes -). Cyclin D1 by IHC, confirm with ISH or PCR. CD5+ aggregates never normal 

 

FL (follicular)


MOST:
60s, subclinical, nodes+, spleen+, no zonation of centroblasts and centrocytes (mixed), no tingibles. Most low grade 1, 2 or 3a, indolent, with positive: 20, 79a, 19, 22, BCL2, Ki-67<20%. BCL-6+/10+ more intense in follicles; weak interfollicular positivity supports dx.Negative: MUM-1, 5, cyclinD1. t(14;18) and BCL-2 rearrangement by FISH. PCR clonal detection with primers to IGH(D-J)

COMMON: PB+, BM+ (paratrabe and interstitial). Sclerosis in diffuse areas. Weak 21/23 highlight follicles (absent in diffuse areas). sIg+(M, D or G). Pax5 + less intense than CLL of MCL ( Pax5 is intense in early proB/mature and preB/naive but weak in follicular and T cells, marginal zone, monocytoid and plasma cells)

RARE: GI+(duodenum), soft tissue+, eye+, breast+.

sIgA+. Grade 3B usually 10-/BCL2-/BCL6+/MUM1+/ Ki-67 > 20% and some 43+(43+ in B cells always suggest lymphoma). Some 3B pediatric cases testis+ or waldeyer+. In cases with 10 neg follicles, BCL-6 remains +. BCL6+/10- is either FL or DLBCL. Cases 5+/10+ may be FL floral variant. 30+ in 1/3 FLs.

PITFALLS: BCL2 normally neg in normal or reactive follicles but + in primary follicles, normal mantle, inmature B cells, inter and intrafollicular T cells (CD3+, 4+), marginal zone of spleen and abdominal nodes. Normal 10+ cells found in T cells (inter and intrafollicular), BM stromal cells, immature B cells. BCL-6 converts to negative when B cells exits follicle to become memory cell and plasma cells; some T cells interfollicular are BCL-6+.

COMMENTS: # centroblasts/HPF: grade 1(0-5), 2(6-15), 3A (>15), 3B (>15 and solid sheets). Only 3B aggresive. Pattern: folicular (>75% follicles), mixed (25-75%), diffuse or focally follicular (<25%). Diffuse with > 15 centroblasts = DLBCL. Follicular in situ = follicle partially colonized by BCL2+ cells (unknown significance, may predict early FL).

 

PCFCL (Primary cutaneous follicular)


MOST:
50s, skin, follicular or diffuse, good px even with recurrence (except in leg). Solitary plaques or nodules scalp, forehead or trunk. Perivascular or periadnexal, no tingibles, attenuated or absent mantle, epidermis neg, frequent reactive T cells. Positive: 20+, 79a+, 10+ if follicular pattern (negative if diffuse), BCL6+, 21 + in follicles meshwork. Weak or Neg: MUM-1, BCL2. Most no BCL2 rearrangement and neg t 14-18 (if strong BCL2 suspect nodal follicular with secondary skin involvement). Rearrangement Igs+.

RARE: Leg involvment, ulceration, extracutaneous dissemination, spindle pattern.

PITFALLS: If centroblasts predominating in diffuse pattern dx is PCDLBCL, leg type.

 

MZL (Marginal)


COMMON TO ALL MZL
: Postgerminal center memory cells. All common except splenic. 60s. Small B cell neo, pale monocytoid cells, centrocyte like lymphos, large transformed cells, immunoblasts, plasma cells. Good px.

Most 20+, 79a+, IgM (also A y G). 10-/BCL6-/BCL2+ (pattern also seen in LPL and DLBCL) .21+,35+, targetoid Ki-67 in follicles proving follicular colonization with disrupted meshwork.43+ common in allexcept in splenic. Numerous BCL2+ in follicle is abnormal and clue of colonization of follicle in MZL (BCL2 also + on marginal zone hyperplasia, abdominal nodes, ileum, mantle, some interfollicular lymphos and thymic medulla). Commonly negative: 23, 5. RARE : Scant BCL6+ in follicles, 10+, cyclin D1+, 5+. If 5+ expect relapse.

EXTRANODAL or MALT: Localized to orbit, gastric, skin. Possible: BM+, PB+. RARE: IPSID (see heavy chain diseases). If sheets of large cells dx is DLBCL arising in MALT. PITFALL: Normally MALT is IgD neg. IgD+ in gastric bipsy (probably normal mantle or MCL). Other immunostains: 50% 43+. ISH is better to determine clonality K or L in 138+. COMMENTS: t(1;18) resistant to H Pylori erradication. Other translocations: 1-14, 14-18, 3-14. Eye MZL related with clamidia, borrelia and Campy jejuni. If infection controled remission possible. Definition of lymphoepithelial lesion: aggregate of 3 or more cells destroying or degenerating the epithelium.

NODAL: generalized adenopathy. COMMON: marrow+(interstitial or nodular), BP+. Association with hashimoto or sjogren. Nodal is the only MZL BCL6+/-.Rare IgD+.

SPLENIC: Rare . Same as SLVL (with villous lymphos). Marked spleno and leucopenia. Initially whit pulp, then red. May involve splenic nodes, BM (interstitial or nodular), PB, liver. Nodes neg. Some autoimmune anemia or thrombocytopenia. 11c (50%), 5 (1/5), some sIgD+ or M. TRAP variable. Generally neg: 5, 10, 23, 103, 43. Many Ig heavy and light rearrangement. 7q21 common.  

 

HCL (Hairy)


MOST
: >50s. Long survival. Not every case need therapy. Dry marrow+ (increased reticulin), fry egg, no mitosis. Pancytopenia (infections, anemia, bleeding, monocytopenia). Spleen+ big (red pulp). PB+, cells with bean nucleus, no nucleoli, blue cyto and hairy projections, no polar.Positive: 25,103, BCL2, 20, 79a, FMC7, 22, 11c bright, sIg ( D, G or A), annexin 1, DBA.44 (negative in splenic villous lymphoma). Negative: 5, 10, cyclin D1.

COMMON: abdominal nodes+, liver+.

RARE: peripheral nodes+. 10+, 5+, cyclin D1.

PITFALLS: anexin also + in PMNs in BM, some CLL and mediastinal large B cell lymphomas. DBA.44 also + in other B cell lymphomas.

COMMENTS: arise from premarginal (activated B memory cells). TRAP in unfixed slides, only + if strong granular in cyto, non specific nor necessary.Best to monitor 20, TRAP, DBA.44 (annexin not good). Cytogenetics not practical. If treatment: splenectomy, antiCD22 or antiCD25. See vHCL in chapter Splenic B cell lymphoma unclassifiable. 

 

SPLEINC B CELL LYMPHOMA/LEUKEMIA UNCLASSIFIABLE


Splenic diffuse red pulp small B cell lymphoma
: Indolent but incurable. Rare. >40s. Arise from unknown peripheral B cells. Big spleen, red pulp + (cords and sinusoids). BM+ (interstitial and nodular), PB+ with small villous lymphos, some plasmocytoid but sIg and 38 neg. Skin may show plaques. Leucopenia, low lymphocytosis, decrease in platelets and some anemia. Nodes are neg. Diff dx: SMZL (follicular replacement in spleen and marrow). Positive: DBA.44, IgG, 20, Neg : annexin, 25, 103, 5, 11c, 10, 23, IgD, TRAP.

Hairy cell leukaemia variant (vHCL):Resistant to treatment. Indolent, good survival. Differences with HCL: leukocytosis, monocytes present, cells with big nucleoli resembling prolymphos with hairy projections, BM+ not dry (no reticulin fibrosis). Spleen+, PB+, liver+ but liver and nodes neg. Red pulp expanded with lakes, absent white pulp. Neg annexin A1, TRAP and 25. Positive DBA.44, 11c, 103 and panB.  

 

PCM (Myeloma)


MOST:
Incurable, months to 7 years, symptomatic, multifocal lytic bones or fx , high Ca, anemia (low erythropoietin), renal+ (tubular damage x light chains + infections), infections (decrease in polyclonal Igs), M protein >30g of IgG, 25 of A or 1gr/24h urine light chain

COMMON : amyloidosis. Positive: 79a, 38, 138 (also + in normal plasma cells), 56 + (except in PCL). CD19 neg (positive in normal plasma cells). BCL-2, 43 and MUM-1 may be +. Other aberrant + markers: 20, 117, 10. If cyclin D1 + t(11;14) +

RARE : Plasmablastic with prominent nucleoli (bad px). Smoldering: asymptomatic, no organ involvement, only M protein and/or >10% plasma cells in marrow. IgE or D common in PCL. Also possible light chain only, biclonal or non secretory. In nonsecretory no serum M protein but IHC shows cytoplasmic M protein (produced but not secreted). Sometimes Igs not detected in serum or by IHC. Rare circulating plasma cells are possible in classic PCM but >20% plasmocytoid lymphos CD56 neg is dx of PCL (evolve to PCM or show spleen+, liver+, nodes +, cavity or CSF effusions. POEMS is an osteoslcerotic PCM in middle age japanese with paratrabe marrow fibrosis (sclerotic bone), few plasma cells trapped in fibrosis (<5%), neuropathy, endocrinopathy, liver+, spleen+, skin+, nodes + resembling plasma cell Calstleman and gammopathy IgG or A, most L.

PITFALLS: Dif dx PCM vs plasmocytoma based in pathology + clinic + radiology.

COMMENTS : If PCM < 10% plasma cells may be due to suboptimal aspirate (check bx for clusters and count 138+ plasma cells monoclonal for K or L). Plasma cells mature, bluish cyto, perinuclear hof, bi or multinucleation, morulas, flame (IgA), gaucher like, crystaline rods, russell, pleomorphism. BM: interstitial clusters, nodules or diffuse sheets with spared areas (reason for suboptimal aspirate). Extramarrow lesions in advanced PCM. FISH pannel available (see Molecular Genetic notes). Stage based in M protein level, bone lesions, Hb, Ca, creatinine, serum B2 microglobulin and albumin.  

 

OTHER PLASMA CELL NEOPLASMAS


SOLITARY PLASMOCYTOMA OF BONE
: All bones above knee or elbow. Pain or fx. 1/3 patients M protein in serum or urine. No symptoms of PCM or other bone lesions with MRI. Morphology and IHC same than PCM. 2/3 evolve to PCM.

EXTRAOSEOUS PLASMOCYTOMA: Upper respiratory tract, GI, nodes, skin, breast, thyroid, testis, parothyroid. No symptoms of PCM or other bone lesions with MRI. 1/3 serum or urine M protein (most IgA). Morphology and IHC same than PCM. Differential with MALT challenging (CD20+ favor lymphoma). More indolent y better px than bone plasmocytoma (only 15% evolving to PCM).

MGUS: 3% > 50s. Asymptomatic. May be related with neuropathy, endocrinopathy, liver or skin disease and transplant. M protein < 30g/L (Most IgG, others M, A or biclonal), <10% 138+ mature plasma cell in marrow(interstitial or small clusters), rule out organ damage or lymphoma. 1% per year evolve to PCM (more chance in M protein > 25g/L, monoclonal IgM, A or aneuploidy). May progress to amyloidosis; IgM clone can evolve to LPL/WM. Flow shows normal clone of plasma cells (38+, 19+, 56-) mixed with abnormal clone (weak 38, 19- and 56 +/-). FISH same genetic abnormalities than PCM.

MONOCLONAL IMMUNOGLOBULIN DEPOSITION DISEASES (MIDD):
Light chain deposition disease (LCDD)
poor px, associated to PCM, MGUS or LPL(WM), no fibrilary (no amyloidogenic) electron dense periendotelial deposits, K light chains, nephrosis with mesangial changes similar to KW, cardiac/ liver failure and perivascular changes in other organs (lung, spleen, marrow, CNS, intestine, polineuropathy, joints). 1/4 monoclonal gammopathy not demostrated in serum or urine; monoclonal plasma cells demostrated by IHC in the vecinity of deposits and marrow. LCDD deposits are not Beta pleated with no avidity for congo red, different to amyloid where EM deposits are fibrilar (amyloidogenic). HCDD (heavy chain deposition disease) has similar presentation and labs that LCDD. HCDD isotype IgG1 or IgG3 related with hypocomplementemia. AL 1/5 ssociated to PCM or LPL. Most MGUS with M protein. Light chains generally L detected by SPE and IFE (rarely heavy chain). Light chains glicosylation lead to perivascular amyloidogenic deposits. Involve same organs that LCDD. Organ replacement or masses are possible (amyloidomas). Monoclonal plasma cells demostrated by IHC in the vecinity of deposits or BM. Px poor due to cardiac failure. Common: nephrotic, heptomegaly, macroglosia, hemorrhage, purpura, malabsorption, bone pain, neuropathy, carpal tunel. For dx use comercially available anti L chain serum specific for variable regions (V) that are included in the L chain amyloidogenic fragments. Regular comercial anti L not useful. For bx: abdominal fat pad, rectum or BM. 
 

 

LPL(Waldestrom)


MOST
: Small postfollicular B cells, indolent, mixed with plasma cells, 60s. IgM clone = WM. BM+ paratrabecular (nodular, diffuse or interstitial). Positive: IgM or A, 20, 22, 79a, 19, 138 (plasma cells). Negative: 103, 5, 10, 23, IgD

COMMON: IgG+. Anemia, hyperviscosity, spleen + (nodules red pulp), liver+,nodes + with normal architecture and sinusoidal PAS+ ( Dutcher). PB+ with low count or cytopenias. 25+, 38+

RARE: IgA+ or combination of IgM + IgG. Presentation with MGUS and/or amyloidosis. Skin+, neuropathy, GI+ (diarrhea). Nodes+ with pseudofollicular architecture (no proliferation centers). IgH/Pax5 t(9;14), del 6q and some triso. Transformation to DLBCL

PITFALLS: Difficult diff dx with MZL with plasmocytoid differentiation.

COMMENTS: Some HCV related with cryoglobulinemia.  

 

HEAVY CHAIN DISEASES


COMMON TO ALL HEAVY CHAIN DISEASES
: postgerminal B. Truncated Igs , very rare and 60s except alpha (more common, young poor mediterranean). All 20+, 79a+, 138+ and 20- in plasma cells, CD5- and 10-.

GAMMA HEAVY CHAIN DISEASES: abnormal IgG. Common: BM (increase in plasma cells IgG monotypic), PB, spleen, liver, nodes, waldeyer, GI, skin, thyroid, salivary, eosinophilia, preceded by autoimmune (RA, lupus, sjogren, hashi, myasthenia etc). No amyloid. Bones neg. SPE OK. Dx:IgG without light chains by IFE in PB or urine. Polymorphic with lymphos, many plasma cells, eos, immunoblasts, histiocytes. Dif dx: HL, AILT, CLL, plasmocytoma. Survival months to years.

Mu HEAVY CHAIN DISEASE: heavy chain with no variable region. Common: BM (small lymphos similar to CLL and vacuolated plasma cells), PB, spleen, liver. Nodes neg. SPE normal. Dx: antimu polymers in urine by IEF, Bence Jones K in urine. Long survival.

ALPHA HEAVY CHAIN DISEASE: Campy jejuni? Abnormal alpha (igA) in serum. Same as Immunoproliferative small intestinal disease (IPSID), MALT variant, malaabsorption, fever, low Ca. SPE OK or hypogamma. Dx :aberrant antiA by IFE. May reverse or remitt for years with antibiotics (antracycline) or progress to DLBCL. Small intestine +, mesenteric nodes +. BM and other organs neg. Bx similar to MALT with lymphoplasmocytic infiltrate and lymphoepithelial lesions.

 

DLBCL NOS (Diffuse Large B cell)


MOST
: Asymptomatic with mass, cells twice size lymphos, all ages, nodal or extranodal (any organ possible). Positive: 20,19, 22, 79a, cIg (M, G or A). Non germinal center or activated (postgerminal) phenotype MUM-1+, BCL6+/-, CD10-, (14;18 neg) and bad px. Germinal center phenotype BCL6+, MUM1-, t(14;18)/CD10+/- and better px.

COMMON: EBER in situ hybridization+ if immunodeficiency (worse px), 1/4 PB+ and BM+ (commonly discordant with low grade lymphoma). CD30+ in anaplastic variant, Ki-67 >40 (never 100%), p53+.

RARE: Unusual morphologies: spindle, signet ring. Coexpresion of 38 and 138 in CD20+ cells, CD5+(cyclin D1 neg).

PITFALLS: Burkitt, blastic MCL, plasmablastic lymphoma or immature PCM in immunoblastic variant.

COMMENTS: In normal germinal center MUM1 and BCL6 never + at the same time. Lymphomas that may transform to DLBCL: CLL, NLPHL, MZL, FL. Histologic variants: Centroblastic, immunoblastic and anaplastic (ALK neg). Px determined by IPI. Bad px if BCL2+, old, BM+, high stage, high Ki-67. If BCL6+ better px. Treatment: antiCD20 and chemo

 

T CELL/HISTIOCYTE RICH LARE B CELL LYMPHOMA


MOST
: 40s, aggresive with poor px, arise in germinal B cells, diffuse or vaguely nodular, scatterd single large B cells (no aggregates) in background of CD3/5 + T cells and CD68+ histio. Advanced with nodes+, BM+, liver+ (portal), spleen+(white pulp). Positive: pan B, BCL6. Negative: 15, 30, 138, EVB.

COMMON: May recur as DLBCL. BCL2+, EMA+

PITFALLS: Difficult diff dx with NLPHL ( IgD +, present follicular dendritic meshwork, eos and plasma cells favor HL) , if clusters or large B cells call DLBCL, NOS.

COMMENTS: If EBV + classify as EBV+ DLBCL.  

 

PRIMARY DLBCL OF CNS


MOST
: Rare. 60s. Intraocular and/or solitary supratentorial not invading dura. Headache, focal neurologic or psicosis. No systemic involvement. Tumoral cells like centroblasts, perivascular and intraluminal (angiocentric) mixed with reactive CD3. Positive: Pan B, MUM-1, concentric vascular lamellae of reticulum around perivascular tumoral cells.

COMMON: BCL-6+, MIB-1 > 50%, BCL-2 + (not related to 14-18 and with worse px). Negative CD10.

RARE: Meningeal involvement. Multiple masses (suspect HIV/EBV driven). CD10+ and EBV-LMP (20%).

COMMENTS: almost all CNC lymphomas are non Hodgkin B cell . Diff radiologic with glioblastoma (central necrosis). Butterly infiltrate common. Only necrosis with foamy histiocytes present if steroids. Px improving in recent years.

 

PRIMARY CUTANEOUS DLBCL, LEG TYPE


MOST
: Rare. Older women. One or both legs. Morphology similar to DLBCL. Positive: pan B, BCL2, MUM-1, BCL6. Neg: CD10.

COMMON: Systemic dissemination.

RARE: Involvement of sites different to legs.

PITFALLS: Confusion with follicular cutaneous (BCL2 neg)

COMMENTS: Worse px if multiple skin lesions or systemic. 

 

EBV + DLBCL OF ELDERLY


MOST
: >50, bad px, elderly x deterioration of immunity but no really immune deficiency, extranodal + (skin, lung, tonsil, stomach). 20+, 79a+, LMP-1+. Neg: 10, 15, BCL6

COMMON: necrosis, high IPI, MUM1+ (postgerminal center), CD30+/-, EBNA-2+, light chain restriction difficult to demostrate.

RARE: 1/3 nodes + only. If immunoblastic CD20 neg with cIg+

PITFALLS: Confusion with other EBV + lymphomas like plasmablastic, primary effusion and chronic inflamation related

COMMENTS: 2 subtypes: Large cell type and polymorphic with plasma cells, histio and Hodgkin like cells. 

 

DLBCL RELATED WITH CHRONIC INFLAMMATION


MOST:
aggresive, EBV+ (LMP1 and EBNA-2), > 50s, Japan, big painful thoracic mass involving pleura, sometimes lung, plerual effusion after long history of pyothorax (10 years) post Tb treatment with pneumothorax. Morphology similar to DLBCL. 20+, 79a+.

COMMON: If immunoblastic CD20 neg, 79a neg. MUM+, 138+. CD30 may be +

RARE: associated with chronic osteomyelitis, bone metallic implants or skin ulcers. May express T markers

 

LYMPHOMATOID GRANULOMATOSIS


MOST
: adult, rare, aggresive, necrotic, cavitated lung nodules. Angiocentric/angiodestructive. ScantEBV+ B cells (sometimes immunoblastic or multinucleated HL cells CD15 neg) mixed with inflammatory background with predominating T cells (most CD3+, 4+), plasma cells, histio, immunoblasts. PMNs and eos absent.

COMMON: Immunodeficiency or reduced immunity. kidney+, brain +(nodules), skin plaques or subcutaneous nodules,CD30+. Clonality of Igs in grade 2 and 3.

RARE: immunodeficient children, upper respiratory+, GI +, nodes+, spleen+. Granulomas only in skin.

PITFALLS: Don't evaluate EBER+ cells in areas of necrosis, classical RS CD15+ cells always favor HL, extranodal NK/T cells lymphoma nasal type is also angiodestructive

COMMENTS: Grade 1: polymorphic infiltrate with focal necrosis, no atypia, simulate inflammation with < 5 EBER + cells/hpf by ISH.Grade 2: More large lymphid cells CD20+ sometimes in clusters and common necrosis with5-50 EBER+ cells. Grade 3: Marked necrosis and large atypical pleomorphic HL CD20+ cells, common ly in aggregates with > 50 EBER+ cells frequently LMP-1+. 

 

PRIMARY MEDIASTINAL (THYMIC) LARGE B CELL LYMPHOMA


MOST
: Rare. Arise in thymic medullary cells in 30s or 40s. Thymic mass with alveolar fibrosis, fever. BM and nodes negative (except neck and supraclavicular). Pos: 20, 79a, 19, 22, MAL (golgi+). Neg: Ig always neg.

COMMON: Clear cell morphology or pleomorphic with HL cells. Positive: CD30+ (weaker than HL), 15, MUM1, 23, BCL2, BCL6, high Ki-67. Invasion pleura and pericardium possible with worse px. Few reactive perivascular T cells present. If progression disseminate to liver, CNS, kidney, adrenal but BM continues neg.

RARE: Composite combining CHL.CD10+.

COMMENTS: Many respond to chemo and radio better than conventional DLBCL

 

INTRAVASCULAR LARGE B CELL LYMPHOMA


MOST
: Any age, any organ (common CNS, skin, BM, liver, spleen). Nodes negative. Most 60s. Due to lack of adhesion molecules neoplastic cells deposit in lumen of capillaries or sinusal in BM, liver and spleen (hemophagocytic). Positive: PanB.

COMMON: 1/3 coexpress CD5 and 10. If CD10 neg MUM1+.

RARE: lumen of arteries or veins, PB +.

COMMENTS: Agresive with poor px. If only skin + better px. 

 

ALK POSITIVE LARGE B CELL LYMPHOMA


MOST
: Rare, all age, advanced, poor px, large immunoblastic cells, sinusoidal, neg t(2;5), nodes+ or mediastinal mass. Pos: cyto ALK granular, 38, 138, cIgA. Neg: 20, 79a, 3, 30. CD45 weak or neg.

COMMON: Plasmablastic differentiation or multinucleated cells

RARE: Oral cavity, stomach, soft tissues.Positive cIgG, 4, 57, MUM-1, 43.

PITFALLS: T cell anaplastic is 30+. HIV + immunoblastic lymphoma oral cavity is ALK neg. Careful Dif dx with Ca (some cases keratin+, EMA+ and neg CD45). 

 

PLASMABLASTIC LYMPHOMA


MOST
: Rare, aggresive and advanced. 50s with immunodeficiency or HIV+. B immunoblasts or plasmocytoid cells. Plasma cell phenotype with pos: 38, 138, MUM1, 79a, 30, EMA. Neg: 45, 20, PAX5, K or L restriction. Oral cavity. EBV+.

COMMON: Other paranasal, GI, skin, bone, soft tissues. cIgG+, clonal Ig rearrengement.

RARE: Nodes +. Elderly due to deterioration of immune system.

PITFALLS: Df dx with PCM with plasmablastic transformation. Pure plasmablastic lymphoma Ki-67>90% , common mitosis, EBER ISH +, immunodeficiency.CD56+ favor PCM

 

LARGE B CELL LYMPHOMA ARISING IN HHV8 ASSOCIATED MULTICENTRIC CASTLEMAN


MOST
: Aggresive. Spleen+ (may be big), nodes+ with hialynized follicles with plamablasts (isolated or in clusters) in germinal zone, mantle and interfollicular. HHV8 latent nuclear antigen 1 (LANA-1) +, cIgM+, L restriction, 20+. Neg: 79a, 138, EBER. Plasma cells interfollicular are non clonal, IgA+, LANA neg. CD38+/-

COMMON: HIV+, liver+, lung+, GI+.

RARE: HHV8+ african or mediterranean patients HIV negative . Leukemic cells.

PITFALLS: Plasmablastic and PEL shows IgH hypermutation (not seen in lymphoma arising in HHV8). HHV PEL is EBER +, cIgG neg.

COMMENTS: HHV8 same as KSHV.

 

PEL (Primary effusion)


MOST
: Aggresive, poor px, young male HIV+, immunosupressed, old mediterranean. Serous effussion, no mass, nodes-, spleen-, liver-,HHV8+ (KSHV), EBER ISH+, EBV LMP neg. Immunoblastic, plasmablastic or plasmocytoid morphology with some RS like cells. Pos: 45, HHV8+ associated latent protein (LANA). Neg: 19, 79a, 20, sIg, cIg, BCL6

COMMON: 38+, 138+, 30+, EMA+

RARE: Aberrant T markers with T cell rearrengement. Old mediterranean HHV8+ and EBV-. Castleman. Extranodal variant with same morphology and phenotype.

PITFALLS: If solid pleural , pericardial or peritoneal mass = extracavitary PEL. Pyothorax associated lymphomas is EBV+, HHV8 neg, PanB+.  

 

BURKITT


MOST
: Advanced, aggresive but curable. Diffuse pattern and starry sky with nucleus same size of histyocyte , multiple small paranuclear nucleoli and cytoplasmic vacuoles. Ki-67 close to 100%. Myc translocation 8-14 + (not 100% specific and only + in 90% by FISH). Pos: sIgM, 10, 22, 19, 20, 43, 38, BCL6. Neg: TdT, BCL2, 5, MUM-1.

COMMON: EBV+. Jaw and orbit in endemic, abdomen in sporadic (ileum, ovary, kidney, gonad, salivary, bone, thyroid, breast). Nodes+ more in adults and HIV+.

RARE: t(2;8) or t(8;22). Leukemic (L3) with BM +, PB+ and CNS+, bad px. Plasmocytoid cells with solitary central nucleoli suggest HIV. Nuclear pleomorphism with BCL2+ seen in Burkitt like (same entity).

PITFALLS: DLBC lymphoma Ki-67 is at the most 90%

COMMENTS: 3 variants: endemic (Kids Africa and New Guinea), sporadic (kids and young in rest of the world with abdominal mass) and HIV or immunosuprresed associated. In Africa most EBV+, malaria may be related. EBV+ in 30% sporadic and 40% immunosupressed. A tumor CD10- and BCL6+ is probably a DLBCL or FL but is not Burkitt. 

 

UNCLASSIFIABLE


Between DLBCL and Burkitt
: Morphology and immunophenotype difficult to classify. Many are doble hit lymphomas with MYC and BCL2 traslocation (BCL2+). If MYC+ classify as Burkitt. If MYC neg don't call Burkitt. TdT + favor lymphoblastic lymphoma.

Between DLBCL(mediastinal) and CHL: Complicated morphology with some fibrosis, eos and HL cells. Some EBV+ and may express 30+, 15+. May spread to liver, spleen or BM. CD20+ strong and uniform suggest primary mediastinal B cell lymphoma.

Last reviwed 5/05/2010 Back to CONTENTS

 

Main References:
-Wikipedia
-eMedicine
-WHO classification of tumors of hematopoietic and lymphoid tissues
-Russell A.Higgins, MD; Jennifer E Blankenship, MD; Marsha C Kinney, MD. Application of Immunohistochemistry in the Diagnosis of Non Hodgkin and Hodgkin Lymphoma. Arch Pathol Lab Med. 2008; 132: 441-462