WHO Classification of Haematopoietic and Lymphoid Tumours, 5th Edition (2022) & ICC 2022 · Hematological Pathology Reference
Classification per WHO Classification of Haematopoietic and Lymphoid Tumours (5th ed., 2022) and ICC 2022. Click any entity card to jump to its immunophenotype.
| Entity | TCR / Lineage | Flow Cytometry Key Markers | IHC Key Markers | Critical Molecular / Genetics |
|---|---|---|---|---|
| Precursor T-cell Neoplasms | ||||
| T-ALL / T-LBL | Pre-T (variable maturation stage) | TdT+CD7+CD2+cCD3+CD34±CD1a±CD4/CD8 variablesCD3−/dimMPO− | TdT+CD99+CD3(cyt)+CD34±CD20− | NOTCH1 mut (>50%) · CDKN2A/B del · TAL1 · HOX fusions |
| ETP-ALL | Immature; stem cell-like | TdT+CD34+CD117+CD7+CD13±/CD33±CD1a−CD4−CD8−CD5 dim/− ⚑ Myeloid markers mimic AML — always test TdT+cCD3 |
TdT+CD117+CD34+CD1a− | DNMT3A · FLT3 · IDH1/2 · RUNX1 · worse prognosis than typical T-ALL |
| Mature — Leukemic / Disseminated | ||||
| T-PLL | αβ T-cell (CD4+ majority) | CD2+CD3+CD5+CD7+CD26+CD52+TCL1+CD4+ (~60%) or CD4/CD8 dp (~25%)TdT− | TCL1+CD3+CD5+Ki-67 highTdT− ★ TCL1 is the hallmark — most reliable IHC discriminator |
inv(14)(q11;q32) or t(14;14) → TCL1A overexpression · ATM mut/del · TP53 del(17p) · STAT5B/JAK3 |
| T-LGLL | αβ CD8+ cytotoxic T-cell | CD3+CD8+CD57+CD16+CD45RA+CD56−CD28−TCR αβ+ (clonal) ★ Clonality by TCR Vβ repertoire analysis is essential |
CD8+CD57+TIA1+Granzyme B+Perforin+ ★ BM: interstitial infiltrate — subtle, easily missed without IHC |
STAT3 mut (~40%) · STAT5B mut · TCR gene rearrangement (clonal) · Associated: RA, neutropenia, red cell aplasia |
| CLPD-NK / NK-LGLL | NK-cell (no TCR rearrangement) | sCD3−CD16+CD56+CD57±CD5− ⚑ No TCR rearrangement — clonality assessed by KIR restriction |
CD3ε (cyt)+sCD3−CD56+TIA1+EBV− | STAT3 mut (~30%) · KIR restriction (clonality marker) · No TCR rearrangement |
| ATLL (4 subtypes) | αβ CD4+ regulatory T-cell-like | CD2+CD3+CD4+CD5+CD25++ (IL-2Rα)CD7−CD8−CCR4+ | CD25+FOXP3+CCR4+CD4+CD7− ★ HTLV-1 serology + HTLV-1 proviral integration (clonal) is diagnostic |
HTLV-1 integrated provirus · CCR4 mut · TP53 mut · HBZ gene (viral) · Hypercalcemia (PTHrP) |
| ANKL | NK-cell | sCD3−CD56+CD16+CD2+HLA-DR+CD57− | CD3ε+CD56+TIA1+Granzyme B+EBER ISH+ | EBV+ (EBER ISH) · del(6q) · STAT3 · JAK-STAT activation · HLH · Fulminant |
| Sézary Syndrome | αβ CD4+ (skin-homing) | CD3+CD4+CD7−CD26−CD4:CD8 ratio >10KIR3DL2 (CD158k)+ ⚑ ≥1000 Sézary cells/μL or ≥10% Sézary cells required for diagnosis |
CD3+CD4+PD-1+CD7−FOXP3−CD26− | CDKN2A del · ZEB1 · TP53 · RB1 · Erythroderma + lymphadenopathy + peripheral blood involvement |
| Mature — Nodal T-cell Lymphomas | ||||
| AITL / nTFHL-AI | αβ TFH-cell | CD3+CD4+CD10+PD-1+CXCL13+BCL6+ICOS+CD8− | PD-1+CXCL13+CD10+BCL6+ICOS+CD21+ (FDC meshwork) ★ ≥2 TFH markers required (WHO 5). EBV+ B-blasts in background (not neoplastic cells) |
RHOA G17V (~70%) · TET2 (~80%) · DNMT3A · IDH2 R172 · CD28 fusions |
| nTFHL-Follicular | αβ TFH-cell | CD3+CD4+PD-1+CD10+BCL6+ ★ Grows within follicles — must distinguish from FL with TFH infiltration |
PD-1+BCL6+CD10+CXCL13+CD3+ | TET2 · RHOA G17V (less frequent than AITL) |
| nTFHL-NOS | αβ TFH-cell | CD3+CD4+PD-1+CD10±CXCL13± | ≥2 TFH markers+CD3+CD4+ ★ No AITL morphology, no follicular pattern — diagnosis of exclusion within nTFHL group |
TET2 · DNMT3A · RHOA G17V (variable) |
| PTCL-NOS | αβ T-cell (usually CD4+) | CD3+/−CD4+ (most)Pan-T loss (CD5, CD7)CD30± ⚑ Diagnosis of exclusion — rule out all other PTCL entities first |
CD3±CD4+CD30± ★ GATA3+ (Th2-like) vs TBX21+ (Th1-like) subtyping has prognostic value |
GATA3 or TBX21 subgroups · TP53 · SETD2 · DNMT3A |
| ALCL ALK+ | T-cell (null cell phenotype often) | CD30++ (strong)ALK+EMA+CD3−/+CD4+/−CD8−CD43+ | CD30+ (strong membranous+Golgi)ALK+EMA+TIA1+CD3± ★ ALK pattern: nuclear+cytoplasmic = t(2;5); cytoplasmic only = variant fusion |
t(2;5)(p23;q35) → NPM1-ALK (~80%) · Other fusions: ATIC-ALK, TPM3-ALK · Best prognosis among ALCL |
| ALCL ALK− | T-cell (null cell phenotype common) | CD30++ (strong)ALK−CD3±EMA±CD4+/− | CD30+ strongALK−DUSP22+ (30%)TP63+ (8%)IRF4+ ★ DUSP22 rearr = good prognosis; TP63 rearr = poor prognosis |
DUSP22-IRF4 rearrangement 6p25.3 (~30%) · TP63 rearrangement (~8%) · JAK1/STAT3 |
| Nodal EBV+ T/NK lymphoma | T-cell or NK-cell | CD3±CD56±CD2+ ★ New WHO 5 entity — distinct from ENKTL (no nasal involvement required) |
EBER ISH+CD3+CD56±TIA1+ | EBV+ · Nodal-based · Must exclude ENKTL, ANKL |
| Mature — Extranodal T-cell & NK-cell Lymphomas | ||||
| ENKTL (nasal type) | NK-cell (majority) or cytotoxic T-cell | sCD3−cCD3ε+CD56+CD2+CD16±CD5−CD57− | EBER ISH+ (must)CD56+cCD3ε+TIA1+Granzyme B+Perforin+ ⚑ sCD3− on flow but cCD3ε+ on IHC — do not misclassify as B-cell! |
EBV+ (latency II) · del(6q) · DDX3X · STAT3/5 · JAK-STAT · P2RY8-CISH |
| HSTCL | γδ T-cell (majority); αβ rare | CD3+CD56+CD4−CD8−/dimCD16+TCR γδ+ (flow) ⚑ CD56+ mimics NK-cell lymphoma — confirm γδ TCR by flow or IHC |
CD3+TCRδ1+TIA1+Granzyme B dim/−EBV− | i(7q) · Trisomy 8 · SETD2 mut · STAT5B mut · Young males; IBD/immunosuppression |
| SPTCL | αβ CD8+ cytotoxic T-cell | CD3+CD8+CD4−CD56−TCR αβ+ | CD8+βF1+ (αβ TCR)TIA1+Granzyme B+CD56−EBV− ★ βF1+ distinguishes from pcGDTCL (TCRγδ+, βF1−) |
αβ TCR rearrangement (clonal) · HLH-associated mutations: UNC13D, PRF1 · Good prognosis if no HLH |
| Mycosis Fungoides | αβ CD4+ skin-homing T-cell | CD3+CD4+CD7−CD26−CD8−CD30± (transformed) ⚑ CD7/CD26 loss supports MF but not specific — correlate with morphology and clinical |
CD3+CD4+CD7−CD26−PD-1±CD30+ (transform)FOXP3− | CDKN2A del · TP53 mut (transformed) · DNMT3A · TCR gene rearrangement (clonal) |
| pcALCL | αβ CD4+ T-cell | CD30+ (>75% cells)ALK−CD4+CD3±EMA− | CD30+ALK−CD4+EMA−TIA1+IRF4/MUM1+ ★ EMA− and ALK− helps distinguish from systemic ALCL with skin involvement |
IRF4 rearrangement (6p25.3) in some cases · Excellent prognosis |
| Lymphomatoid Papulosis | Variable by type (CD4 or CD8) | CD4+ (type A,B,C)CD8+ (type D,E)CD30+ (types A,C,D,E) ★ Type D: CD8+CD30+ mimics aggressive lymphoma — self-healing behavior is key |
CD30+ (types A,C,D,E)ALK−DUSP22/IRF4 (type C,E) | 6p25.3 rearrangement (DUSP22-IRF4) in types C and E · Self-healing · 10-20% secondary lymphoma risk |
| pcGDTCL | γδ T-cell | CD3+CD56+CD4−CD8−TCR γδ+βF1− | TCRδ1+βF1−TIA1+Granzyme B+CD56+EBV− ⚑ Never shows fat-rimming (vs SPTCL) — epidermis and dermis+subcutis involved |
γδ TCR rearrangement (clonal) · Very aggressive prognosis · Chemotherapy refractory |
| pcCD4+ small/medium LPD | αβ CD4+ TFH-like | CD3+CD4+PD-1±CD10±CD30− | CD3+CD4+PD-1±CXCL13±CD30− ★ Solitary lesion, excellent prognosis — often resolves after biopsy |
No defining mutation · Clonal TCR in most but behaves indolently |
| pcCD8+ acral LPD | αβ CD8+ T-cell | CD3+CD8+CD4−CD30−CD56− | CD8+CD3+CD56−CD30− ★ Ear (acral) location · Indolent · New WHO 5 entity — don't over-treat |
No defining molecular alteration · Site-restricted (ear/acral) · Excellent prognosis · Clonal TCR |
| EATL | αβ CD8+/CD4− intraepithelial T-cell | CD3+CD4−CD8±CD103+CD5−CD30± | CD3+CD8±CD103+CD30+TIA1+Granzyme B+CD56− ★ Adjacent mucosa: villous atrophy + IEL expansion = celiac disease confirmation |
HLA-DQ2/DQ8 · JAK1/STAT3 · SETD2 mut · 9q31.3 gain · GNAI2 |
| MEITL | CD8+CD56+ (αβ or γδ) | CD3+CD8+CD56+CD4−CD30− ⚑ CD56+ in gut lymphoma: consider MEITL before ENKTL (check EBV!) |
CD3+CD8+CD56+MATK+CD30−EBV− ★ MATK IHC is a useful distinguishing marker for MEITL |
SETD2 mut · 8q gain · JAK-STAT · No celiac disease association · Asian populations |
| Indolent T-LPD of GI tract | CD8+ (intestinal) or CD4+ (oral/pharyngeal) | CD3+CD8+ (intestine)CD4+ (oral)CD56−CD30− ⚑ Do NOT mistake for MEITL or EATL — Ki-67 is the key: very low (<5%) |
CD3+CD8+ or CD4+Granzyme B−CD56−Ki-67 very low | No defining mutation · Clonal TCR · Watchful waiting often appropriate |
| Hydroa vacciniforme LPD | EBV+ T- or NK-cell | CD3+CD4+ or CD8+CD56± | EBER ISH+CD3+CD4+ or CD8+CD56± ★ EBER ISH is the key diagnostic marker — EBV drives the spectrum |
EBV+ (latency II/III) · Childhood onset · Spectrum from classic HV → systemic HV-LPD → lymphoma |
| Severe Mosquito Bite Allergy | EBV+ NK-cell | sCD3−CD56+CD16+ | EBER ISH+CD56+sCD3−cCD3ε+ | EBV+ NK-cells · Extreme local reaction to Aedes mosquito bite · May progress to ANKL |
Purple border = hallmark/discriminating marker · Green = positive · Red-orange = negative · Amber = variable/partial
| Entity | Architecture & Growth Pattern | Cytology (Cell Morphology) | Key Diagnostic Features | Pitfalls / Must Not Miss |
|---|---|---|---|---|
| Precursor Neoplasms | ||||
| T-ALL / T-LBL | Sheet-like growth, diffuse effacement · Starry-sky pattern · Thymic mass (LBL); BM involvement (>25% blasts = ALL) | Medium-sized blasts · Fine/stippled chromatin · Inconspicuous nucleoli · Scant agranular cytoplasm · High N:C ratio · Brisk mitoses · Karyorrhexis |
|
⚑ Mimics B-ALL — sCD3− on flow; always check cCD3 and TdT ⚑ ETP-ALL: no thymic mass; myeloid markers → mimics AML |
| Leukemic / Disseminated | ||||
| T-PLL | Diffuse BM infiltrate · Spleen: red pulp infiltration · Lymph nodes: diffuse paracortical/sinusoidal · Skin involvement common | Small-to-medium lymphocytes · Irregular/oval nuclei · Prominent nucleolus · Moderate pale cytoplasm · Cytoplasmic blebs/protrusions (characteristic) · Rare cerebriform nuclei |
|
⚑ Can mimic MF (cerebriform cells) — skin involvement + TCL1+ helps ⚑ Subtle BM infiltrate early — use CD3/TCL1 IHC |
| T-LGLL / CLPD-NK | BM: interstitial infiltrate (subtle!) · Spleen: red pulp cords and sinuses · Peripheral blood: large granular lymphocytes | Large lymphocytes · Abundant pale cytoplasm · Kidney-shaped nucleus · Prominent azurophilic cytoplasmic granules (LGL morphology) |
|
⚑ BM cellularity can appear normal or hypocellular — always do IHC panel ⚑ Associated cytopenias may dominate clinical picture masking lymphoma |
| ATLL | Diffuse lymph node effacement · BM: diffuse to interstitial · Skin: dermal band-like infiltrate ± epidermotropism | "Flower cells" = multilobated/clover-leaf nuclei (pathognomonic!) · Highly pleomorphic · Condensed chromatin · Prominent nucleoli |
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⚑ Smoldering/chronic subtypes have subtle morphology — check HTLV-1 in endemic area patients ⚑ Skin lesion mimics MF — HTLV-1 and CD25 discriminate |
| Sézary Syndrome | BM: interstitial · Lymph nodes: dermatopathic or effaced · Skin: band-like epidermotropic infiltrate | Cerebriform cells: deeply convoluted/folded nuclei ("brain-like") · Small-to-medium size · Scant cytoplasm · Convoluted nuclear grooves |
|
⚑ Cerebriform cells also in T-PLL and MF — clinical context mandatory ⚑ Low-level Sézary cells can appear in reactive erythroderma — quantify carefully |
| Cutaneous T-cell Lymphomas | ||||
| Mycosis Fungoides | Epidermotropism · Pautrier microabscesses · Papillary dermis: "wiry"/"lamellar" fibrosis · Band-like superficial dermal infiltrate · Tumor stage: nodular/diffuse dermal | Cerebriform (convoluted) nuclei · Disproportionately large nuclei for cell size · Aligned lymphocytes along DEJ · Halos around intraepidermal lymphocytes · Transformed MF: large cells (>25%), RS-like cells |
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⚑ Patch stage MF can be inflammatory/non-specific — need multiple biopsies ⚑ Spongiosis and epidermotropism overlap with eczema — serial biopsies + clonality essential ⚑ Transformed MF: CD30+ can mimic LyP/pcALCL — clinical stage is key |
| SPTCL | Lobular panniculitis · No septal involvement · Subcutaneous fat predominant · No epidermal/dermal involvement (in pure SPTCL) | "Fat-rimming": lymphocytes wrapping individual fat cells in "lace-like" pattern = CLASSIC · Karyorrhexis and fat necrosis · Bean-bag macrophages if HLH present |
|
⚑ Mimics lupus panniculitis — CD8 clonal T-cells favor SPTCL; plasma cells favor lupus ⚑ pcGDTCL involves dermis and epidermis — fat-rimming ABSENT |
| pcALCL | Nodular dermal infiltrate · May extend to subcutis · Epidermis usually uninvolved · Ulceration common | Large cells with pleomorphic or horseshoe-shaped nuclei · Prominent eosinophilic nucleolus · Abundant pale cytoplasm · Hallmark cells · Background: mixed inflammation |
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⚑ Must exclude systemic ALCL-ALK− with skin involvement — clinical staging mandatory ⚑ LyP type C can be morphologically identical — clinical (waxing/waning) is the discriminator |
| LyP (Types A–F) | Wedge-shaped dermal infiltrate · Perivascular · Self-healing papules · Multiple lesions in different stages | Type A: large CD30+ cells + mixed infiltrate · Type B: epidermotropic small cerebriform cells (MF-like) · Type C: sheets of CD30+ large cells (pcALCL-like) · Type D: CD8+ epidermotropic · Type E: angioinvasive CD8+ |
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⚑ Type D and Type E are morphologically alarming but clinically indolent ⚑ Type C = pcALCL morphology — clinical correlation (self-healing) resolves distinction |
| pcGDTCL | Epidermotropic AND dermal AND subcutaneous · No fat-rimming · Necrosis prominent · Ulceration | Medium-to-large pleomorphic cells · Irregular nuclei · Prominent nucleoli · Coarse chromatin · Angioinvasion can occur |
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⚑ SPTCL vs pcGDTCL: fat-rimming (SPTCL) absent here; βF1 negative confirms γδ ⚑ Can mimic lupus panniculitis or fasciitis clinically |
| Nodal T-cell Lymphomas | ||||
| AITL / nTFHL-AI | Diffuse effacement with residual "burned-out" follicles · Expanded FDC meshworks (CD21/CD23+) · Prominent HEV proliferation · Capsular fibrosis ± extension | Atypical medium cells with clear cytoplasm (TFH cells) · Irregular nuclei · Small nucleoli · Background: eosinophils, plasma cells, histiocytes · EBV+ B-blasts in background (not neoplastic cells) |
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⚑ EBV+ B-blasts can obscure neoplastic T-cells — can mimic EBV+ DLBCL if numerous ⚑ FDC expansion can simulate follicular lymphoma at low power ⚑ TET2+DNMT3A+RHOA mutations may be detectable in blood/BM before nodal disease |
| PTCL-NOS | Diffuse effacement · Paracortical expansion · Variable residual follicles · High endothelial venules may be present | Medium-to-large pleomorphic cells · Irregular vesicular nuclei · Prominent nucleoli · Abundant pale cytoplasm · Mixed inflammatory background · High mitotic rate |
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⚑ Never diagnose PTCL-NOS without ruling out AITL (TFH markers), ALCL (CD30), and other entities ⚑ Pan-T antigen loss (CD3, CD5, CD7) is characteristic but not specific |
| ALCL ALK+ / ALK− | Sinusoidal/paracortical growth pattern · Cohesive tumor cell aggregates · Partial nodal involvement possible · Skin, soft tissue, BM involvement | "Hallmark cells": horseshoe/embryo-shaped nucleus · Prominent eosinophilic nucleolus juxtaposed to nuclear membrane · Abundant pale cytoplasm · Large cell size · Variants: small cell, lymphohistiocytic (ALK+ only) |
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⚑ Small cell variant (ALK+): predominant small cells can look reactive — look for hallmark cells ⚑ Lymphohistiocytic variant: histiocytes can obscure large cells ⚑ CD30 single + = not ALCL; must be strong and diffuse (>75%) |
| Extranodal T-cell & NK-cell Lymphomas | ||||
| ENKTL (nasal type) | Angiocentric: tumor cells surround and invade vessel walls · Angiodestructive: vessel wall necrosis · Coagulative necrosis (often extensive) · Geographic necrosis | Polymorphic: small, medium AND large cells admixed · Irregular nuclei · Condensed chromatin · Pale-to-clear cytoplasm · Azurophilic cytoplasmic granules · Mitoses + apoptosis · Karyorrhexis |
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⚑ Extensive necrosis can destroy tissue — multiple biopsies needed; submit entire specimen ⚑ EBV LMP1 can be negative (latency II) — always use EBER ISH, not LMP1 alone ⚑ Granulomatous reaction can mask lymphoma cells |
| HSTCL | Sinusoidal infiltration of spleen (red pulp), liver (hepatic sinusoids), BM (sinusoidal) · White pulp atrophy · No nodule formation · Subtle at low power | Medium-sized cells · Round-to-oval pale/clear nuclei · Moderate pale cytoplasm · Inconspicuous nucleoli · Low mitotic rate early · Azurophilic granules · Can appear monotonous |
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⚑ Morphologically subtle — cells look "normal" early; sinusoidal pattern is the giveaway ⚑ Can mimic hairy cell leukemia (sinusoidal spleen) — use CD3/TIA1/TCRγδ ⚑ BM infiltrate requires CD3/TIA1 IHC — H&E alone will miss it |
| EATL | Ulcerating mass in small intestine · Adjacent mucosa: villous atrophy + increased IEL · Necrosis ± perforation · Mixed inflammatory background | Medium-to-large pleomorphic cells · Irregular nuclei · Prominent nucleoli · Abundant pale cytoplasm · High mitotic rate · CD30+ large cells |
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⚑ EATL vs MEITL: EATL is pleomorphic/inflammatory; MEITL is monomorphic/CD56+ ⚑ Perforation can be the presenting event |
| MEITL | Monomorphic intraepithelial pattern · Small intestine predominant · Dense intraepithelial infiltrate · Less necrosis and inflammation than EATL | Monomorphic small-to-medium cells · Round, uniform nuclei · Condensed chromatin · Scant cytoplasm · Intraepithelial predominance · Minimal pleomorphism · Low-power: "packed" enterocytes |
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⚑ Can mimic indolent T-LPD of GI — Ki-67 >50% in MEITL vs <5% in indolent ⚑ ENKTL enters differential if CD56+ — check EBER ISH (negative in MEITL) |
⚑ = diagnostic pitfall requiring active exclusion · ★ = high-yield discriminating feature