46  T-Cell Lymphomas

Key Points
  • TCL comprise ~12% of NHL; indolent cutaneous (MF/SS) common; nodal PTCL-NOS/AITL/ALCL aggressive
  • PTCL-NOS: unspecified diagnosis, mixed histology; 5-y OS ~30%; CHOP-based 1st-line; pralatrexate or HDAC-i for R/R
  • AITL: CD4+ TFH origin; TET2, DNMT3A, IDH2 mutations; stage III–IV at dx; similar prognosis & tx as PTCL-NOS
  • ALCL: CD30+; ALK+ (better, ~50% 5-y OS) vs ALK− (worse); BV-CHOP or BV-CHP 1st-line; consider upfront autologous tx
  • Cutaneous TCL (MF/SS): indolent; skin-only → topical steroids, UVB, PUVA; advanced → bexarotene, HDAC-i, mogamulizumab
  • ENKL: EBV+, aggressive, extranodal; limited-stage → RT (>50 Gy) ± chemo; advanced → asparaginase-based (SMILE); 5-y OS ~35%
  • Hepatosplenic TCL: rare, very aggressive, young men; poor prognosis; allogeneic tx considered

46.1 PTCL-NOS (Peripheral T-Cell Lymphoma, Unspecified)

46.1.1 Dx & Prognosis

  • CD4+ T-cells w/ mixed small & large cells, epidermotropism variable
  • Provisional dx; heterogeneous group; 5-y OS ~30–40%
  • No single defining genetic hit; TET2, DNMT3A, RHOA, TP53 ↑ in subset
  • Poor prognosis factors: high IPI, B symptoms, LDH ↑

46.1.2 Tx

  • Frontline: CHOP or CHOP-like (q21d × 6–8 cycles)
  • Consider upfront autologous tx in good-risk pts a/w favorable genomics
  • Relapsed/refractory:
    • Pralatrexate (MTX analog; ~30% ORR)
    • Romidepsin or vorinostat (HDAC inhibitors; ~25–30% ORR)
    • Brentuximab vedotin for CD30+ cases

46.2 AITL (Angioimmunoblastic T-Cell Lymphoma)

46.2.1 Dx

  • CD4+ T-cells; TFH phenotype (CD10+, CXCL13+, PD1+, ICOS+)
  • Genetic: TET2 (60–80%), DNMT3A, IDH2 mutations
  • Hyperplastic follicles, atypical TFH cells; infiltrate B-cells (may co-exist a/w B-cell lymphoma)
  • Clonal B-cell population frequent
  • Median age ~60 y; stage III–IV at dx; B symptoms, ↑ LDH

46.2.2 Disease Course & Prognosis

  • 5-y OS ~25–30% (similar to PTCL-NOS)
  • Indolent or aggressive course; watch-&-wait acceptable if asymptomatic
  • Hemolytic anemia (Coombs+) in ~10%

46.2.3 Tx

  • Frontline: CHOP or CHOP-like (like PTCL-NOS)
  • Upfront autologous tx for good-risk pts or unfavorable genetics
  • Relapsed/refractory: pralatrexate, romidepsin, brentuximab vedotin

46.3 ALCL (Systemic Anaplastic Large-Cell Lymphoma)

46.3.1 Dx

  • Uniformly CD30+ large T-cells a/w hallmark cells (eccentric nucleus, stalky vasculature)
  • ALK+ (40% of systemic ALCL):
    • NPM-ALK fusion [t(2;5)(p23;q35)]; median age 35 y
    • Better prognosis (~80–90% 5-y OS w/ anthracyclines)
  • ALK− (60%):
    • Older pts (median ~60 y); worse prognosis (~50% 5-y OS)
    • Overlaps w/ PTCL-NOS; must rule out primary cutaneous ALCL
  • Early stage (I–II) much better than III–IV

46.3.2 Tx

  • Frontline for all:
    • Brentuximab vedotin (anti-CD30) + CHOP or CHP (BV-CHOP/BV-CHP)
    • ECHELON-2: BV-CHP superior to CHOP alone in CD30+ PTCL
  • Consider upfront autologous tx for ALK− or high-risk features
  • Relapsed/refractory: brentuximab vedotin, ALK inhibitors (ALK+), pralatrexate, HDAC-i
  • Alt for ALK+: ALK inhibitors (crizotinib, alectinib)

46.4 Cutaneous T-Cell Lymphomas

46.4.1 Mycosis Fungoides (MF) & Sézary Syndrome (SS)

46.4.1.1 Dx

  • MF: CD4+ infiltrate epidermotropic, small atypical cells, ± microabscesses
    • Early patches/plaques (stage IA–IIA); bathing-suit distribution; often pruritic
    • Advanced: diffuse erythroderma (stage IIB+), lymphadenopathy, visceral involvement
  • SS: leukemic variant; ↑ circulating Sézary cells (>1000/μL or clonal TCR)
  • TCR clonality assists dx; biopsy essential

46.4.1.2 Disease Course & Prognosis

  • Indolent compared to nodal PTCL; 10–15% progress to advanced stage
  • Limited disease (<10% skin) → good outcomes
  • Extensive disease → risk of transformation
  • Median survival: stage IA ~20 y; stage IV ~5 y

46.4.1.3 Tx: Skin-Directed (Early-Stage)

  • Topical steroids: 1st-line; excellent response rates (45–65% CR)
  • Topical retinoids (bexarotene): 67–75% PR
  • Topical nitrogen mustard: 72–93% PR, 24–65% CR
  • Phototherapy:
    • Narrowband UVB: 72–93% PR, 24–65% CR
    • PUVA: 28–92% PR, 35–80% CR
    • TSEBT (total skin electron-beam): 73–92% PR, 14–50% CR

46.4.1.4 Tx: Systemic (Advanced-Stage/SS)

  • Bexarotene (retinoid): ~30% ORR, well-tolerated
  • Romidepsin (HDAC-i): 34% CR, 25% ORR; cytopenias common
  • Vorinostat (HDAC-i): 30% CR; low ORR but durable
  • Pralatrexate: 45% CR; active in R/R
  • Mogamulizumab (CCR4 antibody): 28% CR; neutropenia, thrombocytopenia
  • Interferon-α: IFN + TSEBT; modest activity
  • Gemcitabine, liposomal doxorubicin: limited role
  • Pembrolizumab: emerging; activity reported
  • Combine agents to limit cumulative toxicity

46.4.1.5 Allogeneic Transplant

  • Curative option for selected pts; 3-y OS ~55%, 3-y EFS ~52%
  • RIC or standard conditioning; graft-vs-CTCL effect observed
  • High GVHD; careful pt selection

46.5 Primary Cutaneous ALCL

46.5.1 Dx

  • Uniformly CD30+ large T-cells; similar histology to systemic ALCL
  • Must distinguish from systemic ALCL → full staging (CT, bone marrow, peripheral blood)
  • Second most common CTCL; indolent course

46.5.2 Prognosis

  • Excellent; >90% 5-y OS w/ complete surgical excision alone
  • Limited to dermis/subcutis; rarely involves lymph nodes or viscera

46.5.3 Tx

  • Localized: observation or topical/local RT
  • Multifocal: topical steroids, phototherapy, TSEBT
  • Advanced/disseminated: systemic agents; brentuximab vedotin considered

46.6 Subcutaneous Panniculitis-Like TCL (SCPTCL)

46.6.1 Dx

  • CD8+ (sometimes CD4+) infiltrate in subcutaneous fat; tender nodules; ± waxing/waning
  • Autoimmune disease co-exists in 20%
  • Distinguish from T-cell panniculitis (benign)

46.6.2 Prognosis

  • Generally indolent; median survival ~9 y
  • Complicated by infection, autoimmune flares

46.6.3 Tx

  • No standard regimen
  • Oral corticosteroids trial
  • Systemic chemo if aggressive

46.7 ENKL (Extranodal NK/T-Cell Lymphoma)

46.7.1 Epidemiology & Dx

  • ~5% of TCL in Asia; <1% in US; aggressive, EBV+
  • Most common site: nasopharynx (“midline granuloma”); also skin, GI, bone, soft tissue
  • Histology: CD3+, CD4/CD8−, CD56+, cytotoxic (TIA-1+, granzyme B+)
  • EBV+ clonal by in situ hybridization
  • Circulating EBV DNA useful for prognosis

46.7.2 Prognosis

  • Limited-stage (I–III): 50–80% OS w/ combined modality
  • Advanced (IV): 5-y OS ~35%; 1-y OS varies by risk (81–28%)
  • Poor: age >60, stage III–IV, distant nodes, high IPI

46.7.3 Tx

  • Limited-stage (I–III) (single RT field):
    • Sequential: upfront chemo → consolidation RT (>50 Gy)
    • Concurrent: RT (40 Gy) + concurrent chemo
    • RT alone: selected cases only
    • Preferred regimen: asparaginase-based (SMILE: dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) ± concurrent RT
  • Advanced (IV):
    • L-asparaginase–based (SMILE)
    • Concurrent cisplatin + RT (40 Gy) → VIDL × 3 (etoposide, ifosfamide, doxorubicin, cisplatin, dexamethasone)
  • RT dose: 40–54 Gy a/w better outcomes than <40 Gy

46.8 NK/T-Cell Lymphoma, NOS

46.8.1 Dx

  • Anaplastic or pleomorphic CD3+, CD56+, NK or T-phenotype
  • Cytotoxic (TIA-1+, granzyme B+); EBV±
  • Extranodal predilection
  • Heterogeneous group; rarer than ENKL

46.8.2 Tx & Prognosis

  • Similar to ENKL; asparaginase-based preferred
  • Prognosis poor; RT + systemic chemo for limited-stage
  • Early allogeneic tx referral for fit candidates

46.9 Hepatosplenic TCL

46.9.1 Dx & Epidemiology

  • Rare (~1–2% of PTCL); very aggressive
  • Young men (median ~14–25 y); γδ T-cell type
  • Hepatosplenomegaly, bone marrow involvement (sinusoidal infiltration)
  • Cytopenias, coagulopathy; often systemic at dx

46.9.2 Prognosis

  • Very poor; median OS <2 y
  • No cure w/ standard chemo

46.9.3 Tx

  • Allogeneic transplant strongly considered; only curative option
  • Induction: platinum-based (e.g., VAC: cyclophosphamide, doxorubicin, cisplatin, etoposide)
  • Early allogeneic tx referral essential

46.10 Adult T-Cell Leukemia/Lymphoma (ATLL)

46.10.1 Epidemiology & Dx

  • HTLV-1–associated; endemic Caribbean, Japan, Brazil
  • Transmitted: breast milk, blood products, sexual contact
  • Follows decades-long asymptomatic HTLV-1 infection
  • CD4+ T-cells; convoluted “flower-like” nuclei
  • HTLV-1 serology required for dx; high viral load, clonal integration

46.10.2 Clinical Subtypes

  • Acute: rapidly progressive; B symptoms, lytic bone lesions, hypercalcemia, skin, nodal, marrow involvement
  • Lymphoma: nodal dominant; slower progression
  • Chronic: ↑ circulating cells; skin involvement; may progress to acute form
  • Smoldering: low tumor burden; skin/marrow involvement; progresses to acute

46.10.3 Prognosis

  • Acute/lymphoma: median OS ~1 y
  • Chronic/smoldering: median OS ~5 y (if untreated)
  • Transformation to acute: variable; poor prognosis

46.10.4 Tx

  • Induction: azacitidine, platinum-based (VAC), arsenic trioxide (ATO), interferon + zidovudine
  • Upfront allogeneic transplant recommended; only potential cure
  • Early transplant referral critical
  • No standard regimen established for this rare disease

46.11 Breast Implant–Associated ALCL (BIA-ALCL)

46.11.1 Epidemiology & Dx

  • Rare; textured implant association; ~1264 cases reported
  • Typically late (median 8–10 y post-implantation)
  • Presentation: seroma, capsular thickening, mass around implant
  • Histology: CD30+ ALCL; similar to ALK− systemic ALCL
  • Most localized to implant pocket; rarely systemic

46.11.2 Prognosis

  • Localized (seroma only, completely resected): 5-y DFS ~95%
  • Advanced (beyond capsule, node/organ involvement): much worse; prognosis like ALK− systemic ALCL

46.11.3 Tx

  • Localized: surgical excision (implant + capsule) = curative; observation alone for completely excised
  • Advanced/disseminated: brentuximab vedotin ± chemo; adjuvant RT considered
  • Prognosis far better than systemic ALCL a/w complete resection

46.12 Treatment Summary Tables

Relapsed/refractory PTCL agents
Agent N CR (%) ORR (%) mPFS (mo) mDOR (mo) Toxicity
Pralatrexate (PTCL) 111 29 11 10.1 3.5 Mucositis, cyto
Brentuximab vedotin (ALCL) 58 86 57 25.6 20 Neuropathy, cyto
Romidepsin (PTCL) 69 29 14 9 — Cytopenias, fatigue

ORR, overall response rate; mPFS, median progression-free survival; mDOR, median duration of response; CR, complete remission.

46.13 Clinical Pearls

Tip

Pearl 1: PTCL-NOS & AITL remain treatment challenges (5-y OS ~30%); CHOP-based 1st-line; pralatrexate, romidepsin, BV for R/R. Upfront autologous tx improves ALK− ALCL outcomes; select on risk factors.

Tip

Pearl 2: Cutaneous TCL (MF/SS) indolent a/w prolonged survival but incurable; skin-directed (topical, phototherapy, RT, retinoids) preferred early to minimize toxicity. Advanced → bexarotene, HDAC-i, mogamulizumab; allogeneic tx curative in select.

Tip

Pearl 3: ENKL & hepatosplenic TCL aggressive & rare; RT cornerstone limited-stage (>50 Gy); asparaginase-based chemo for systemic. Prognosis poor; early allogeneic tx referral critical for fit candidates.

Tip

Pearl 4: ATLL HTLV-1–associated; decades-long latency; acute/lymphoma subtypes poor prognosis (median ~1 y); allogeneic tx only curative option. Early transplant referral essential.