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Lytic Lesions + Hypercalcemia in Hematological Conditions: Differentials

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1. Multiple Myeloma (PRIMARY and most common)

• Myeloma cells secrete MIP-1α (CCL3) and upregulate RANKL while simultaneously suppressing OPG - this shifts the RANKL/OPG ratio strongly toward osteoclast activation
• Myeloma cells also produce Wnt pathway inhibitors that block osteoblast function, creating a purely lytic pattern with no new bone formation
• Net result: massive uncoupled osteolysis, hypercalcemia, and pathologic fractures
• (Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 570; Goldman-Cecil Medicine, RANKL/OPG section)

• "Punched-out" lytic defects, classically 1-4 cm, with no surrounding sclerosis (the absence of reactive new bone is characteristic)
• "Moth-eaten" appearance in long bones; calvaria lesions are highly characteristic

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2. Adult T-Cell Leukemia/Lymphoma (ATLL) - HTLV-1 Associated

• Driven by HTLV-1 (most prevalent in Japan and the Caribbean basin)
• Patients present with circulating disease, bone marrow involvement, hypercalcemia, lytic bone lesions, lymphadenopathy, hepatosplenomegaly, skin lesions, and opportunistic infections
• Pathognomonic: "flower cell" (CD4+, CD25+, CD2+, CD3+, CD5+, CD7-)
• 4 variants: acute (worst, median survival 6 months), lymphomatous, chronic, smoldering
• (Harrison's Principles of Internal Medicine 22E, 2025)

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3. Non-Hodgkin Lymphoma (NHL)

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4. Leukemias (less common, but recognized)

• AML (acute myeloid leukemia) - rare but reported
• CLL - uncommon, but B-cell infiltration of bone can produce lytic change
• Mechanism involves locally produced osteoclast-activating cytokines including PTHrP, IL-1, IL-6, and IL-8
• (Brenner & Rector's The Kidney - Malignancy section)

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Summary Table: Hematological Differentials

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Key Differentiating Lab Workup

1. SPEP/UPEP + immunofixation - M-protein = myeloma/plasmacytoma
2. Serum free light chains - kappa/lambda ratio
3. PTH - suppressed in all malignancy-related hypercalcemia
4. PTHrP - elevated in ATLL, some NHL; low in myeloma
5. 1,25(OH)₂D (calcitriol) - elevated in lymphoma-related hypercalcemia
6. HTLV-1 serology - ATLL
7. Bone marrow biopsy - plasma cell % (myeloma), T-cell immunophenotype (ATLL)
8. Skeletal survey / Whole body low-dose CT - distribution and morphology of lytic lesions

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• CRAB = the four cardinal myeloma manifestations (Calcium, Renal, Anemia, Bone)
• The absence of bone scan uptake (cold lesions) in myeloma vs. hot lesions in metastatic carcinoma is a classic radiological differentiator

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Lytic Lesions + Hypercalcemia in Hematological Conditions: Complete Differential (Hematologist Level)

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TIER 1 - Plasma Cell Dyscrasias (Most Likely)

1. Multiple Myeloma

• Bone scan is characteristically cold (purely lytic, no reactive new bone = no osteoblast activity = no uptake) - use skeletal survey or PET/CT/whole-body low-dose CT instead
• RANKL↑ / OPG↓ ratio is the core pathophysiologic driver
• IgG (52%) > IgA (21%) > light chain only (16%) > IgD (2%) > IgE (rare) - IgD and IgE myelomas have disproportionately high rates of plasma cell leukemia transformation
• Bones affected descending: vertebrae > ribs > skull > pelvis > femur > clavicle > scapula
• Robbins, Cotran & Kumar; Harrison's 22E (2025)

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2. Solitary Plasmacytoma of Bone

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3. Plasma Cell Leukemia (PCL)

• Diagnostic threshold: >5% plasma cells in peripheral blood differential and/or absolute plasma cell count ≥500/µL
• Primary PCL (60%): de novo presentation in leukemic phase - younger patients, more hepatosplenomegaly, lymphadenopathy, higher platelet count, fewer bone lesions, smaller M-protein, but better survival than secondary PCL
• Secondary PCL (40%): leukemic transformation of known myeloma - older patients, more bone disease, rapidly fatal
• Immunophenotype: unlike typical myeloma, CD56 is often absent in PCL
• IgD (12%) and IgE (25%) myelomas are over-represented among PCL transformations
• Hypercalcemia present due to same RANKL/osteoclast mechanism
• Treatment: aggressive induction (VDT-PACE or daratumumab-VRd) → ASCT if response achieved
• Goldman-Cecil Medicine; Harrison's 22E; Robbins Cotran

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4. Nonsecretory Myeloma

• 3% of myeloma cases - no detectable M-protein in serum or urine by SPEP/UPEP/immunofixation
• Bone lesions and hypercalcemia are present and identical to secretory myeloma
• Diagnosis relies on bone marrow biopsy with immunoperoxidase/flow cytometry confirming clonal plasma cells
• Serum free light chain (sFLC) assay is abnormal in >60% - this is the key monitoring tool
• Pitfall: can be missed if sFLC not ordered; the clinician must have high suspicion when CRAB features present but standard protein studies are negative
• Goldman-Cecil Medicine

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5. POEMS Syndrome (Osteosclerotic Myeloma)

• Hypercalcemia and renal insufficiency are rare in POEMS (key differentiator from myeloma)
• Bone marrow usually has <5% plasma cells
• The diagnosis is confirmed by biopsy of a sclerotic lesion showing monoclonal plasma cells
• If lesions are limited: radiation therapy (>50% neuropathy improvement)
• If widespread: ASCT or systemic therapy
• Goldman-Cecil Medicine

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TIER 2 - Lymphoid Malignancies

6. Adult T-Cell Leukemia/Lymphoma (ATLL) - HTLV-1 Driven

• The hematologist must ask about origin: Japan, Caribbean basin, West Africa, Middle East - HTLV-1 endemic regions
• Hypercalcemia in ATLL is mediated by PTHrP secreted by malignant T-cells, often dramatically elevated, can reach severe levels (>14 mg/dL)
• Lytic lesions + hypercalcemia + flower cells on smear = pathognomonic triad
• CD4+, CD25+, CD2+, CD3+, CD5+, CD7- (the CD7 loss is a key negative)
• FOXP3+ (resembles regulatory T-cells - contributes to profound immunosuppression)
• Skin involvement: erythroderma, nodules, papules (not just rash - actual leukemic skin infiltration)
• Opportunistic infections mirror AIDS because CD4 cells are dysfunctional despite being numerous
• Acute form: survival 6 months; treatment with zidovudine + interferon-α ± arsenic, mogamulizumab (anti-CCR4)
• Harrison's Principles of Internal Medicine 22E (2025)

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7. Non-Hodgkin Lymphoma (NHL) with Bone Involvement

• Direct bone marrow infiltration → cytokine-mediated osteoclast activation (PTHrP, IL-1, IL-6, IL-8)
• Lytic lesions on imaging; PTH suppressed, PTHrP may be elevated
• Less commonly produces discrete punched-out defects (more permeative/infiltrative pattern)

• Malignant lymphocytes express 1α-hydroxylase (same enzyme as granulomatous macrophages)
• Converts 25(OH)D → active 1,25(OH)₂D without PTH regulation
• Lab pattern: PTH suppressed ↓, PTHrP normal, serum 1,25(OH)₂D elevated ↑
• This is the most important distinguishing lab from myeloma (where calcitriol is NOT elevated)
• Can occur even without direct bone involvement
• All types of lymphoma can cause this syndrome
• (Brenner & Rector's The Kidney; Frameworks for Internal Medicine)

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8. Hodgkin Lymphoma (HL)

• Lytic bone lesions and hypercalcemia occur but are less common than in NHL/myeloma
• Mechanism primarily ectopic 1,25(OH)₂D production (same as NHL above)
• Bone involvement in HL is usually part of stage IV disease
• Lytic lesions in HL can cause cord compression, pathologic fractures
• Key clinical point: HL is one of the few metastatic bone diseases that is potentially curable even with bone involvement - must not be mistaken for myeloma and written off as palliative
• (Harrison's 22E; Goldman-Cecil)

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TIER 3 - Histiocytic Neoplasms

9. Langerhans Cell Histiocytosis (LCH)

• "Punched-out" lytic lesions of the skull - can resemble myeloma radiologically
• CT shows sharp, well-defined lytic defect with beveled edges (geographic lysis)
• Preferential involvement of the calvaria, mandible, and temporal bone (causes aural polyp, conductive hearing loss, postauricular swelling)
• Hypercalcemia occurs but is less prominent than in myeloma
• Key differentiator: age (children/young adults), Birbeck granules on EM, CD1a+ / CD207 (Langerin)+ / S100+ on IHC
• BRAF V600E mutation - has therapeutic implications (vemurafenib responsive)
• (Goldman-Cecil Medicine; Robbins & Kumar Basic Pathology; Grainger & Allison's Diagnostic Radiology)

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TIER 4 - Rare/Advanced Differentials (Complete the Hematologist's List)

10. Erdheim-Chester Disease (ECD)

• Non-Langerhans cell histiocytosis (CD68+, CD163+, CD1a-, S100-)
• BRAF V600E in ~54% of cases
• Bilateral and symmetrical long bone involvement (femora, tibiae, humeri) - the PET-CT pattern is distinctive (bilateral periosteal uptake)
• Lytic lesions less common than sclerotic lesions, but mixed patterns occur
• Hypercalcemia can occur
• Retroperitoneal fibrosis ("hairy kidney"), periaortic cuffing, diabetes insipidus, xanthelasma are hallmarks
• (Goldman-Cecil Medicine - described as a differential to LCH in the same section)

11. Hemophagocytic Lymphohistiocytosis (HLH) secondary to hematological malignancy

• Bone marrow infiltration by underlying lymphoma/leukemia triggers the syndrome
• Hypercalcemia via direct bony involvement + cytokine storm (IL-6, TNF-α)
• Context: ferritin >10,000, fever, splenomegaly, cytopenias, hypofibrinogenemia, elevated sCD25

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Master Comparison Table (Hematologist Reference)

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Diagnostic Algorithm - Hematologist Approach

Lytic lesion(s) + Hypercalcemia
│
├── Check PTH → Suppressed in ALL malignancy-related causes
│
├── SPEP/UPEP + Immunofixation + sFLC ratio
│   ├── M-protein present → Plasma cell dyscrasia spectrum
│   │   ├── Multiple lesions + CRAB → MULTIPLE MYELOMA
│   │   ├── Single lesion, no systemic disease → SOLITARY PLASMACYTOMA
│   │   ├── >5% plasma cells in blood → PLASMA CELL LEUKEMIA
│   │   ├── No M-protein on SPEP but sFLC abnormal → NONSECRETORY MYELOMA
│   │   └── Sclerotic lesions + neuropathy + λ-chain → POEMS
│   │
│   └── No M-protein → Consider lymphoid or histiocytic cause
│       ├── Check PTHrP elevated? → ATLL, some NHL
│       ├── Check 1,25(OH)₂D elevated? → NHL, Hodgkin lymphoma
│       ├── HTLV-1 serology positive + flower cells → ATLL
│       ├── Lymph node biopsy / PET-CT → NHL / Hodgkin
│       └── Young patient + skull/temporal lytic lesions → LCH (CD1a, BRAF)
│
└── Bone marrow biopsy in all cases

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Key Calcium Mechanism Summary for Exams & Boards

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L-Asparaginase Allergy: How to Proceed

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Step 1 - Classify the Reaction First

Key Pearl: Silent inactivation is more common than overt hypersensitivity and is associated with a negative clinical outcome in high-risk ALL because the enzyme appears to be given but is actually not working. Measuring serum asparaginase activity (SAA) is the only way to detect this.

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Step 2 - Immediate Management of the Acute Reaction

1. Stop the infusion immediately
2. Administer:
   • Epinephrine (for anaphylaxis: 0.01 mg/kg IM, max 0.5 mg)
   • IV antihistamines (diphenhydramine)
   • IV corticosteroids (hydrocortisone or methylprednisolone)
   • IV fluids; oxygen; bronchodilators as needed
3. Observe for minimum 1-2 hours post-reaction
4. Document the reaction grade per CTCAE criteria (Grade 1-4)
5. Check serum asparaginase activity level - if reaction occurred after a previous dose, retroactively check if prior doses had adequate activity

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Step 3 - The Formulation Switch Strategy

The Three Formulations

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The Decision Tree

Patient develops hypersensitivity or silent inactivation to:
│
├── NATIVE E. COLI asparaginase
│   └── Switch to PEGASPARGASE (PEG-asparaginase)
│       (PEG coating reduces immunogenicity: <20% develop antibodies)
│
├── PEGASPARGASE (first-line) → allergic reaction
│   └── Switch to ERWINIA asparaginase (Erwinaze / JZP458)
│       (Completely different bacterial source = no cross-reactivity)
│       - Dose: 25,000 IU/m² IM 3× per week (Mon/Wed/Fri)
│         OR 25,000 IU/m² IV over 1 hour 3× per week
│       - Activity window is SHORT (t½ ~16h), hence the 3×/week dosing
│
├── ERWINIA asparaginase → shortage/unavailable
│   └── JZP458 (recombinant Erwinia-derived, produced in Pseudomonas)
│       - Approved 2021; closes the "asparaginase allergy gap"
│       - Produced recombinantly, not dependent on bacterial fermentation → 
│         addresses supply shortage problem
│       [Blood, 2023 - PMID 36795447]
│
└── Allergic to ALL formulations (very rare)
    └── Asparaginase discontinuation as LAST RESORT
        - Intensify other components of regimen (consult protocol-specific guidance)
        - Do NOT simply omit without expert hematology/oncology discussion

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Step 4 - Why Cross-Reactivity Does NOT Occur Between Species

• Pegaspargase and native E. coli asparaginase: Both derived from E. coli - share the same protein epitopes. Antibodies raised against one will cross-react with the other. If pegaspargase causes hypersensitivity, switching to native E. coli asparaginase is not an option - both will be inactivated.
• Erwinia chrysanthemi asparaginase: Derived from a completely different organism with different protein structure and epitopes. Anti-E. coli asparaginase antibodies do not bind Erwinia enzyme. This is why the switch works.

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Step 5 - Key Additional Considerations

Premedication Before Subsequent Doses

• Antihistamines (cetirizine or diphenhydramine)
• Acetaminophen
• Low-dose corticosteroids

Therapeutic Drug Monitoring (TDM) - Asparaginase Activity Levels

• Target serum asparaginase activity (SAA): ≥0.1 IU/mL at nadir (trough)
• Check SAA ~72 hours after E. coli preparations, ~7 days after pegaspargase
• If SAA <0.1 IU/mL (even without clinical reaction) = silent inactivation = switch formulation immediately
• (Future Oncology, Burke & Zalewska-Szewczyk, 2022 - PMID 35107320)

Managing Other Asparaginase Toxicities (Not Allergy)

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Summary Algorithm

L-Asparaginase allergy/silent inactivation confirmed
         │
         ▼
    Measure SAA → if <0.1 IU/mL = inactivation confirmed
         │
         ▼
    Identify source: E. coli-derived (native or PEG)?
         │                          │
    Yes: SWITCH to              Already on Erwinia?
    ERWINIA asparaginase              │
         │                     Yes: Use JZP458 (recombinant Erwinia)
         ▼                          or asparaginase discontinuation
    Continue ALL protocol            as absolute last resort
    with Erwinia dosing
    (25,000 IU/m² 3×/week IM or IV)
         │
         ▼
    Monitor SAA 72h post-dose → target ≥0.1 IU/mL
    Continue TDM throughout course

---

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The Core Principle: E. coli Cross-Reactivity

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The Answer Depends on the Scenario

Scenario A: Patient reacted to native E. coli L-asparaginase

• The PEG conjugation significantly reduces immunogenicity
• Less than 20% of patients develop antibodies to pegaspargase vs. much higher rates with native E. coli form
• Goodman & Gilman explicitly states: "In hypersensitive patients [to native E. coli], pegaspargase is a safe and effective alternative"
• This switch is well-supported and widely practiced

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Scenario B: Patient reacted to pegaspargase itself

• The antibodies raised against pegaspargase will still recognize and neutralize any E. coli-derived asparaginase, including calaspargase pegol
• Giving pegaspargase again risks anaphylaxis or guaranteed silent inactivation
• The only correct move here is Erwinia asparaginase (Erwinaze / JZP458/crisantaspase) - completely different bacterial source, no cross-reactivity

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Decision Table

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Why This Distinction Matters Clinically

• The patient was started on native E. coli asparaginase (older protocol, resource-limited setting)
• The allergy occurred during the older native formulation phase before PEG was introduced

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One More Critical Point: Silent Inactivation

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Treatment of Secondary ITP due to SLE

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Step 1 - Confirm It IS SLE-ITP (Rule Out Mimics)

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Step 2 - When to Treat

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The Management Algorithm

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Structured Treatment by Line

FIRST-LINE: Glucocorticoids ± IVIG

• Active bleeding risk or ongoing significant hemorrhage
• Pre-surgical/procedural coverage (platelet count needs rapid rise)
• Contraindication to glucocorticoids (severe infection, uncontrolled diabetes)
• More rapid platelet increase required
• Dose: 1 g/kg/day × 1-2 days (or 0.4 g/kg/day × 5 days)

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CHRONIC/MAINTENANCE: Steroid-Sparing Immunosuppressants

Critical note: HCQ is not a primary ITP treatment, but it reduces overall SLE disease activity, prevents flares, and reduces the risk of progression. It should be the background agent in ALL SLE-ITP patients.

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SECOND-LINE: For Non-Response or Relapse After First-Line

• Chimeric anti-CD20 monoclonal antibody, depletes B-cells
• Dose: 375 mg/m² weekly × 4 doses (lymphoma protocol) OR 1000 mg × 2 doses 2 weeks apart (RA protocol)
• Response rate: 65-73% in SLE-related thrombocytopenia at 12 months
• Effective both for thrombocytopenia specifically and for overall SLE hematological domain
• Should be considered even before cyclophosphamide in most cases due to better safety profile
• Harrison's 22E (2025): "Anti-CD20 agents such as rituximab are used for lupus-related severe thrombocytopenia"

• IV pulse: 500-1000 mg/m² monthly
• Reserve due to toxicity (gonadotoxicity, hemorrhagic cystitis, malignancy risk)

• Third-line in some algorithms
• Addresses underlying SLE pathogenesis by reducing B-cell survival
• Growing evidence in SLE-related cytopenia; formally third-line

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THIRD-LINE / REFRACTORY: TPO Receptor Agonists and Splenectomy

• Response rate in ITP: 70-90% (primary ITP data); SLE-specific data from case reports and small series
• Currently considered experimental therapy in SLE-ITP per Rheumatology textbook (2022)
• Caution: theoretical concern about thrombosis risk in APS-positive patients (TPO-RAs can increase platelet count in a prothrombotic milieu)

• Dose: 200-1200 mg/day
• Historically used for refractory cases; also effective in Evans syndrome and AIHA
• Relatively well tolerated; does not increase infection risk
• Now less used due to availability of TPO-RAs and biologic options

• Not routinely recommended in SLE-ITP
• Concerns: less durable therapeutic effect than in primary ITP, high infection risk (SLE patients already immunocompromised), risk of thrombosis post-splenectomy especially if aPL-positive
• Reserve as absolute last resort if all medical management fails
• Pre-splenectomy vaccinations (pneumococcal, meningococcal, Hib) mandatory

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Structured Treatment Table (Rheumatology 2022 - Table 142.3)

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Special Clinical Scenarios

APS-Associated Thrombocytopenia within SLE

• Usually mild (rarely drops below 50,000)
• Does not typically require aggressive immunosuppression
• Hydroxychloroquine is particularly important - reduces thrombotic risk
• Anticoagulation is indicated for thrombotic events, but is not the treatment for thrombocytopenia itself
• Avoid aggressive platelet transfusion as it can fuel thrombosis

Evans Syndrome (SLE + ITP + AIHA)

• Combination of autoimmune hemolytic anemia AND thrombocytopenia
• More aggressive - treat both cytopenias simultaneously
• Rituximab particularly useful; danazol reported effective
• High-dose steroids + IVIG as bridge

Pregnancy-Associated SLE-ITP

• Avoid MMF (teratogenic - Category D/X)
• Safe options: prednisolone, AZA (low dose), HCQ, IVIG
• Rituximab: evidence of fetal B-cell depletion, avoid in pregnancy
• IVIG recommended pre-delivery if PLT <50,000 or planned cesarean/epidural

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Key Monitoring Parameters

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Summary Flow

SLE + PLT <20-30,000 or active bleeding
        ↓
Rule out TMA, CAPS, drug effect (smear!)
        ↓
FIRST LINE: IV MP pulse → oral prednisolone 0.5-0.6 mg/kg ± IVIG
(Add HCQ as background in ALL patients)
        ↓
PLT >50,000? → YES: Add AZA/MMF, taper steroids slowly
             → NO: Move to second line
        ↓
SECOND LINE: Rituximab (best evidence) ± CYC
        ↓
Still failing? → Belimumab / Danazol / TPO-RAs
        ↓
All medical therapy failed → Splenectomy (last resort)

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T-CELL LYMPHOMAS: THE COMPLETE HEMATOLOGIST'S GUIDE

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CHAPTER 1: INTRODUCTION & EPIDEMIOLOGY

---

CHAPTER 2: WHO CLASSIFICATION (2022 - 5th Edition)

MATURE T-CELL AND NK-CELL NEOPLASMS

1. Mycosis Fungoides (MF)
2. Sézary Syndrome (SS)
3. Primary Cutaneous CD4+ Small/Medium T-cell Lymphoproliferative Disorder
4. Primary Cutaneous Acral CD8+ T-cell Lymphoma
5. Subcutaneous Panniculitis-like T-cell Lymphoma (αβ type - indolent)
6. T-cell Large Granular Lymphocytic Leukemia (T-LGL)
7. NK-cell Large Granular Lymphocytic Leukemia (Chronic NK-cell lymphoproliferative disorder)
8. ATLL - Chronic and Smoldering subtypes

1. PTCL, Not Otherwise Specified (PTCL-NOS)
2. Angioimmunoblastic T-cell Lymphoma (AITL) / Nodal TFH lymphoma
3. Follicular T-cell Lymphoma
4. Anaplastic Large Cell Lymphoma, ALK+ (ALCL ALK+)
5. Anaplastic Large Cell Lymphoma, ALK- (ALCL ALK-)
6. Primary Cutaneous ALCL (pc-ALCL) — relatively indolent
7. Extranodal NK/T-cell Lymphoma, Nasal Type (ENKTL)
8. ATLL — Acute and Lymphomatous subtypes
9. Hepatosplenic T-cell Lymphoma (HSTCL)
10. Enteropathy-Associated T-cell Lymphoma (EATL, Type I)
11. Monomorphic Epitheliotropic Intestinal T-cell Lymphoma (MEITL, Type II)
12. Subcutaneous Panniculitis-like T-cell Lymphoma (γδ type — aggressive)
13. Primary Cutaneous γδ T-cell Lymphoma
14. T-cell Prolymphocytic Leukemia (T-PLL)
15. Adult T-cell Leukemia/Lymphoma, Acute/Lymphomatous

• AITL, follicular T-cell lymphoma, and nodal PTCL with TFH phenotype are grouped under "Nodal TFH-cell lymphomas"
• Breast implant-associated ALCL (BIA-ALCL) is now a distinct entity
• MEITL (Type II EATL) is definitively separated from EATL (Type I)

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CHAPTER 3: NORMAL T-CELL BIOLOGY & ONCOGENESIS

T-Cell Development

• Pre-T cells arise in bone marrow → migrate to thymus
• In thymus: TCR rearrangement → positive and negative selection → mature αβ or γδ T-cells
• CD4+ T-cells: T-helper functions (Th1, Th2, Th17, Tfh, Treg)
• CD8+ T-cells: cytotoxic functions
• NK cells: innate immune cytotoxicity, do NOT rearrange TCR

Oncogenic Mechanisms by Subtype

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CHAPTER 4: DIAGNOSTIC APPROACH TO T-CELL LYMPHOMA

Initial Workup (All T-cell lymphomas)

• H&E morphology
• Immunohistochemistry panel: CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD20, CD25, CD30, CD45, CD56, ALK, TIA-1, granzyme B, perforin, BCL6, CXCL13, PD-1, EBV-LMP1, EBER-ISH
• Flow cytometry: aberrant loss of pan-T markers (CD5, CD7 loss most sensitive)
• TCR gene rearrangement (PCR for TCRβ and TCRγ): confirms clonality
• Cytogenetics (FISH): ALK rearrangement, i(7q), 6q deletion

• CT chest/abdomen/pelvis with contrast
• PET-CT (FDG-avid in most aggressive subtypes)
• Bone marrow biopsy (bilateral trephine + aspirate)
• Lumbar puncture: CNS involvement in blastic variants, ENKTL, HSTCL
• HTLV-1 serology (all patients in endemic regions / clinical suspicion of ATLL)
• EBV serology + EBER-ISH on tissue

Prognostic Scoring - IPI for T-cell lymphoma

• Age >60
• LDH > normal
• ECOG PS ≥ 2
• Stage III-IV

• 1 extranodal site

• Age >60, LDH elevation, ECOG PS ≥2, bone marrow involvement
• Better discriminatory power than IPI in PTCL-NOS

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CHAPTER 5: AGGRESSIVE T-CELL LYMPHOMAS (IN DETAIL)

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5.1 PTCL, Not Otherwise Specified (PTCL-NOS)

• Diffuse effacement of lymph node architecture by pleomorphic T-cells (small, medium, and large)
• High mitotic index; prominent inflammatory background (eosinophils, plasma cells, histiocytes)
• Immunophenotype: CD4+ (most common); loss of CD5 and/or CD7 (aberrant T-cell phenotype)
• CD30 expression variable (20-30% of cases — relevant for BV eligibility)
• EBV negative

• GATA3+ subgroup (~40%): GATA3, CCR4, IL18RA expression; worse prognosis; associated with copy number alterations in 7q
• TBX21+ subgroup (~35%): T-bet, CXCR3, IFN-γ expression; somewhat better outcome; associated with cytotoxic gene expression
• Neither subgroup changes standard therapy yet, but trials are ongoing

• Peripheral lymphadenopathy (most common)
• B symptoms (fever, night sweats, >10% weight loss) in ~50%
• Extranodal involvement: skin, liver, spleen, bone marrow, GI tract
• Advanced stage (III-IV) at diagnosis in >70%
• Elevated LDH in ~60%

• CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) q21 days × 6 cycles: historically standard; ORR ~70%, but CR rate only 40-50%; 5-year OS ~32%
• CHOEP (CHOP + etoposide): superior to CHOP in patients <60 years based on German NHL-B1 trial; NOT recommended in elderly due to excess toxicity
• BV-CHP (brentuximab vedotin + CHP): FDA-approved for CD30+ PTCL (≥1% expression) based on ECHELON-2 (see landmark trials); vincristine replaced by BV

• Autologous stem cell transplantation (ASCT) in CR1 is recommended for eligible patients — improves PFS in retrospective analyses
• Prospective data limited but ASCT in CR1 is guideline standard in most centers (NCCN, ESMO)

• Romidepsin (HDAC inhibitor): ORR ~25-35%; FDA-approved for relapsed PTCL
• Belinostat (HDAC inhibitor): ORR ~26%; FDA-approved
• Pralatrexate (antifolate): ORR ~29%; FDA-approved (first drug specifically approved for PTCL)
• Brentuximab vedotin (anti-CD30 ADC): ORR ~33-41% in CD30+ PTCL
• Alisertib (Aurora A kinase inhibitor): ORR ~30% in PTCL; Phase III LUMIERE trial ongoing
• Duvelisib (PI3K-δ/γ inhibitor): ORR ~32% in R/R PTCL
• Salvage chemotherapy (GDP, ICE, DHAP) followed by allogeneic SCT for eligible patients

• 5-year OS: 25-32% with CHOP-based therapy
• Median OS: ~18-24 months

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5.2 Angioimmunoblastic T-cell Lymphoma (AITL) / Nodal TFH Lymphoma

• Arises in germinal center microenvironment
• EBV-positive B-immunoblasts are commonly present (not the neoplastic clone, but a bystander population)
• These EBV+ cells can give rise to secondary EBV+ B-cell lymphomas (occurs in ~5% of cases)
• Polyclonal hypergammaglobulinemia is almost universal

• Generalized lymphadenopathy (virtually all patients)
• Hepatosplenomegaly (~50%)
• Skin rash (morbilliform, pruritic) — very characteristic
• B symptoms: fever, weight loss, night sweats
• Polyarthritis (~30%)
• Pleural effusions, ascites
• Polyclonal hypergammaglobulinemia (near-universal)
• Positive Coombs test / autoimmune hemolytic anemia (~30%)
• Eosinophilia
• Elevated LDH
• Advanced stage (III-IV) in >80%
• Opportunistic infections (due to immune dysregulation)

• Partial or complete effacement of lymph node architecture
• Prominent high endothelial venules (HEV)
• Expanded follicular dendritic cell (FDC) meshwork around vessels
• Polymorphous infiltrate: neoplastic TFH cells (pale cytoplasm), plus reactive eosinophils, plasma cells, histiocytes, B-immunoblasts
• EBV+ large B-immunoblasts present
• Neoplastic cells: CD3+, CD4+, CD10+, BCL6+, CXCL13+, PD-1+, ICOS+ — these TFH markers are required for diagnosis

• Similar to PTCL-NOS in general
• A subset (~15-20%) may respond to immunosuppression alone (glucocorticoids, cyclosporine, methotrexate) — especially for "inflammatory" presentations
• Standard: CHOP or BV-CHP for CD30+ cases
• IDH2-mutant AITL: enasidenib (IDH2 inhibitor) has shown activity in pilot studies
• Romidepsin has been combined with CHOP in ongoing trials
• ASCT in CR1 recommended for eligible patients
• PRISM-CRC trial: Romidepsin + CHOP (RomCHOP) showed no benefit over CHOP alone in a Phase III trial — negative result but important to know

• Median OS: 15-36 months (Harrison's 22E)
• 5-year OS: ~32%
• Complete remissions are uncommon and short-lived
• Worse than PTCL-NOS in some series despite "inflammatory" appearance

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5.3 Anaplastic Large Cell Lymphoma (ALCL)

5.3a ALCL, ALK-Positive (sALCL ALK+)

• Other ALK translocations: t(1;2) → TPM3-ALK; t(2;3) → TFG-ALK; inv(2) → ATIC-ALK; t(2;17) → CLTC-ALK
• All result in constitutive ALK kinase activation → JAK/STAT3, PI3K/Akt, RAS/ERK pathway activation

• 40-60% of all ALCL cases
• Younger patients: median age 34 years; most common in children/adolescents (up to 10-15% of pediatric NHL)
• Male predominance (male:female ~3:1)

• Characteristic "hallmark cells": large pleomorphic cells with horseshoe- or kidney-shaped (reniform) nuclei with prominent nucleoli and perinuclear eosinophilic cytoplasm
• Sinusoidal (intrasinusoidal) pattern of growth in lymph nodes — cells pack the sinuses
• Immunophenotype: CD30+ (strong, uniform), ALK+, EMA+
• Variable: CD3+/-, CD4+, CD43+, CD25+, CD45+ (weak)
• CD15 negative (distinguishes from Hodgkin lymphoma)
• Hallmark cell + CD30+ + ALK+ = diagnosis
• Cytotoxic markers (TIA-1, granzyme B): variable

• Rapidly growing peripheral and/or mediastinal lymphadenopathy
• Extranodal involvement (skin, bone, soft tissue, liver) in ~60%
• B symptoms common
• Less CNS involvement than B-cell counterparts
• Occasionally presents with "soft tissue masses"

• CHOP × 6 cycles (standard)
• BV-CHP (brentuximab vedotin + CHP): ECHELON-2 showed superior PFS and OS vs CHOP in CD30+ PTCL including sALCL; now preferred for eligible patients
• CHOEP: may benefit younger patients (ALK+); add etoposide to CHOP

• Crizotinib (ALK inhibitor): ORR ~90% in heavily pretreated ALK+ ALCL; remarkable responses but not curative
• Alectinib, brigatinib, lorlatinib (next-gen ALK inhibitors): active in crizotinib-resistant cases
• Brentuximab vedotin (anti-CD30): ORR ~86% in relapsed sALCL — landmark SG035-0004 trial
• Salvage chemo → autologous SCT for chemo-sensitive relapse
• Allogeneic SCT for multiply relapsed disease

• 5-year OS: 70-80% with CHOP
• 8-year OS: 82% (Harrison's 22E data)
• IPI-Low risk: 5-year OS >90%
• Favorable prognostic factors: ALK+, young age, complete remission

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5.3b ALCL, ALK-Negative (sALCL ALK-)

• DUSP22-IRF4 rearrangement (~30%): associated with relatively favorable prognosis (closer to ALK+ ALCL)
• TP63 rearrangement (~8%): associated with very poor prognosis
• JAK1/STAT3 mutations (~18-20%): potentially targetable
• No ALK rearrangement

• Older patients: median age 58 years
• Male predominance
• Accounts for ~60% of all ALCL in adults

• CD30+, ALK-, EMA variable
• Must exclude ALK+ by FISH (not just IHC, as some ALK rearrangements show weak staining)
• Must exclude Hodgkin lymphoma (CD15-, CD20-)

• BV-CHP: now standard first-line for CD30+ disease (ECHELON-2)
• CHOP remains an option
• ASCT in CR1 strongly recommended (worse prognosis requires consolidation)
• Relapsed: Brentuximab vedotin (ORR ~56-86%); crizotinib has no role (ALK-negative)
• Duvelisib, romidepsin, belinostat for multiply relapsed disease
• Allogeneic SCT for eligible multiply relapsed patients

• Significantly worse than ALK+
• 5-year OS: ~49% with CHOP (Harrison's 22E)
• DUSP22+ subgroup: ~90% 5-year OS (excellent)
• TP63+ subgroup: ~17% 5-year OS (devastating)

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5.3c Primary Cutaneous ALCL (pc-ALCL)

• Related to lymphomatoid papulosis (LyP) — both are in the CD30+ lymphoproliferative disease spectrum

• Solitary or grouped skin nodules/tumors, often with ulceration
• Usually on trunk or extremities
• May wax and wane (spontaneous regression possible)
• Regional lymph node involvement does NOT change the diagnosis (still pc-ALCL, not sALCL) unless generalized
• Rarely disseminates systemically

• Solitary/localized: Radiotherapy (curative intent, ~95% response rate) OR surgical excision
• Multiple lesions: Brentuximab vedotin — ALCANZA trial showed superior response to physician's choice
• Low-dose methotrexate (weekly oral) for multiple/recurring lesions
• Spontaneous regression observed — watchful waiting is appropriate for regressing lesions
• Systemic chemotherapy rarely needed

• 5-year OS: ~90-95%
• Disease-specific survival approaches that of the general population

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5.3d Breast Implant-Associated ALCL (BIA-ALCL)

• Estimated incidence: 1 in 3,000-30,000 women with textured implants (varies with implant type)
• Textured implants >> smooth implants
• Median time from implantation to diagnosis: ~10 years (range 2-28 years)

• Late-onset periprosthetic seroma (most common — in 90%)
• Capsular mass (less common but worse prognosis)
• Usually confined to the capsule without lymph node involvement
• Rarely disseminates

• Complete surgical removal of implant + total capsulectomy = curative in most cases (seroma-type)
• If capsular mass or node+ disease: BV-CHP chemotherapy
• Radiotherapy for residual disease after surgery

• Disease-specific OS ~95% with complete capsulectomy
• Mass-forming/nodal disease: worse (similar to sALCL ALK-)

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5.4 Extranodal NK/T-cell Lymphoma, Nasal Type (ENKTL)

• EBV latency type II (LMP1+, EBNA2-)
• EBV causes constitutive NF-κB activation, anti-apoptotic signaling (BCL2↑), immune evasion (CD274/PD-L1↑)

• 6q deletion (del 6q21-q25) — loss of PRDM1, ATG5 tumor suppressors
• JAK3 mutations (~35%)
• STAT3/STAT5B mutations
• TP53 mutations (~30%)
• DDX3X mutations
• RAS/MAPK pathway mutations

• Angiocentric and angioinvasive growth — tumor cells infiltrate and destroy blood vessel walls
• Coagulative necrosis (often extensive)
• Pleomorphic lymphoid cells admixed with inflammatory cells
• Immunophenotype: CD2+, CD56+, cytoplasmic CD3ε+ (surface CD3-), TIA-1+, granzyme B+, perforin+
• CD4-, CD8-, CD5- (NK-cell phenotype)
• EBER-ISH+ (mandatory for diagnosis)
• EBV DNA in plasma (very useful for monitoring)

• Nasal obstruction, epistaxis, nasal discharge — early symptoms
• Facial swelling, proptosis
• "Lethal midline granuloma" appearance — destruction of nasal cartilage/bone, perforation of palate, massive facial destruction in advanced disease
• Fever, B symptoms
• Other sites: skin, GI tract, testis, orbit, salivary gland (extranasal ENKTL — worse prognosis)

• Stage I: Single site, localized (e.g., nasal cavity)
• Stage II: Local extension with or without regional lymph nodes
• Stage III/IV: Disseminated disease (rare at presentation but rapidly fatal)
• EBV DNA levels (plasma) correlate with disease burden, response, and relapse

• Age >60
• Stage III/IV
• Distant lymph node involvement
• Non-nasal type
• Low/high risk based on score

• Elevated EBV DNA adds prognostic value to PINK score

• L-asparaginase-containing regimens + concurrent or sequential radiotherapy = standard of care
• SMILE regimen: Steroid (dexamethasone), Methotrexate, Ifosfamide, L-asparaginase, Etoposide — landmark regimen for ENKTL
  • ORR: 80% in newly diagnosed; 79% in relapsed
• P-GEMOX: Pegaspargase + gemcitabine + oxaliplatin — another effective regimen, less toxic than SMILE
• DDGP: Cisplatin + dexamethasone + gemcitabine + pegaspargase — Chinese protocol with excellent results (ORR >90% in early stage)
• Radiotherapy dose: 50-54 Gy to involved field
• Concurrent chemoradiation (e.g., DeVIC + RT) is an option for Stage IE

• NK cells (unlike normal tissue) lack asparagine synthetase → dependent on exogenous asparagine
• L-asparaginase depletes asparagine → selective death of NK/T cells
• MDR (P-glycoprotein) overexpression makes ENKTL resistant to anthracyclines — this is why CHOP does NOT work

• Allogeneic SCT (only curative option for relapsed)
• Pembrolizumab / nivolumab (PD-1 inhibitors): ORR ~35-68% in R/R ENKTL; EBV+ tumors upregulate PD-L1 (LMP1 induces PD-L1) → rationale for checkpoint inhibition
• BV: limited activity (often CD30-)
• CAR-T targeting CD30 or CD7 under investigation

• Stage I-II with L-ASP + RT: 5-year OS ~70-80% (dramatically improved over CHOP era)
• Stage III-IV: 5-year OS ~10-20%; median OS <12 months
• Previously (CHOP era): 5-year OS <30% even for early stage → L-ASP changed everything
• EBV DNA clearance after treatment = CR and favorable outcome; persistent EBV = relapse

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5.5 Hepatosplenic T-cell Lymphoma (HSTCL)

• Young men (median age 35 years); male:female ~9:1
• Strong association with chronic immunosuppression:
  • IBD patients on azathioprine + infliximab (anti-TNF) combination — highest risk group
  • Post-solid organ transplant (renal, hepatic)
  • HIV infection
  • Other immunosuppressive conditions

• Isochromosome 7q [i(7q)] — cardinal genetic alteration; gain of 7q22-q31
• Trisomy 8
• Ring chromosome 7
• JAK3 mutations; STAT5B mutations; TET3, SETD2 mutations
• PI3K/mTOR pathway activation

• Characteristic sinusoidal infiltration without destroying architecture
• Spleen: Red pulp infiltrated; white pulp relatively spared
• Liver: Sinusoidal infiltration (hepatic sinuses packed with neoplastic cells)
• Bone marrow: Sinusoidal infiltration; BM almost always involved
• Lymphadenopathy is ABSENT — this is a key clinical feature
• Cells: Small to medium-sized lymphocytes with moderate pale cytoplasm, slightly irregular nuclei
• Immunophenotype: CD3+, TCRδ1+, CD4-, CD8- (double negative), CD56+/-, CD5-, CD7+/-
• Granzyme B- and perforin- in most cases (despite being "cytotoxic" lineage — represents an immature NK-like cytotoxic cell)
• TCRβ negative (confirms γδ phenotype)
• EBV negative

• Massive splenomegaly — the dominant finding
• Hepatomegaly
• Cytopenias (thrombocytopenia, anemia, neutropenia) — from splenic sequestration and marrow involvement
• NO lymphadenopathy (absent in virtually all cases)
• Constitutional symptoms (fever, weight loss, fatigue)
• Leukocytosis or lymphocytosis occasionally (circulating tumor cells)
• Often misdiagnosed as infection/inflammatory disease initially

• Bone marrow biopsy with sinusoidal pattern + γδ phenotype = diagnostic
• Splenectomy/splenic biopsy if BM non-diagnostic
• PET-CT: spleen and liver FDG-avid; no significant nodal involvement

• No standard of care — very rare disease with no RCTs
• CHOP-based regimens: ORR ~60% but responses brief; median OS only 10-16 months
• ICE, IVAC, FLAG-Ida as second-line options
• Pentostatin (purine analog): some responses in case series
• Allogeneic SCT is the only potentially curative approach — should be pursued in all eligible patients achieving remission
• For patients with IBD + immunosuppression-related HSTCL: discontinue azathioprine and anti-TNF immediately
• Splenectomy: may improve cytopenias (not a curative measure but useful for palliation)

• Median OS: 10-16 months even with treatment
• Nearly uniformly fatal without allogeneic SCT
• Even with allogeneic SCT: long-term DFS ~25-35%

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5.6 Enteropathy-Associated T-cell Lymphoma (EATL) — Type I

• ~65-95% of EATL patients have celiac disease (current or historical)
• Only 1 in 10,000 celiac patients develops EATL (rare complication)
• Refractory celiac disease type II (RCD II) is a precursor state — clonal proliferation of aberrant intraepithelial lymphocytes → may transform to EATL over years
• Risk can be reduced (but not eliminated) by strict gluten-free diet

• Gain of chromosome 9q (MYC amplification) common
• Gain of 1q
• Loss of 8p, 13q
• JAK1/STAT3 mutations

• Large, pleomorphic T-cells with prominent nucleoli
• Ulceration and necrosis of small bowel
• Adjacent mucosa shows villous atrophy (celiac-type changes)
• Background inflammation (histiocytes, eosinophils)
• Immunophenotype: CD3+, CD7+, CD8+/-, CD4-, CD103+, CD30+, TIA-1+, granzyme B+
• Most cases are CD56-

• Abdominal pain, weight loss, diarrhea (often in a celiac patient whose symptoms have changed)
• Small bowel obstruction or perforation (presenting emergency in ~50%)
• Malabsorption
• B symptoms
• Often diagnosed at emergency laparotomy
• May present with new diagnosis of celiac disease in elderly

• Surgical resection (mandatory for perforation/obstruction)
• CHOP or CHOEP: ORR ~60% but brief responses
• IVE/MTX protocol (ifosfamide, vincristine, etoposide + high-dose methotrexate): used in UK (LATTE study); ORR ~50%
• ASCT in CR1 — recommended for eligible patients; only curative option aside from allogeneic
• Nutritional support critical (often severely malnourished)

• 5-year OS: ~10-20% with conventional therapy
• Most patients are elderly, malnourished, and PS-poor → cannot tolerate intensive therapy
• Median OS: 7-10 months

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5.7 Monomorphic Epitheliotropic Intestinal T-cell Lymphoma (MEITL) — Type II

• Monotonous small to medium lymphoid cells (NOT large/pleomorphic like EATL)
• "Monomorphic" appearance
• CD3+, CD8+, CD56+, CD103+, TIA-1+ — the CD56+ is a key distinguisher from EATL
• MATK (HCK) overexpression — characteristic molecular finding
• JAK1 and STAT5B mutations common
• EBV negative

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5.8 Adult T-cell Leukemia/Lymphoma (ATLL) — Acute & Lymphomatous Subtypes

• Endemic: Japan (southwest), Caribbean, West Africa, South America
• Transmission: breast milk (most important), sexual contact, blood transfusion
• Latency: 20-60 years from infection to malignancy; <5% of infected develop ATLL

• CD4+, CD25+, CD2+, CD3+, CD5+ but CD7- and FOXP3+
• CCR4 overexpression (targetable by mogamulizumab)

• VCAP-AMP-VECP (LSG15 regimen, Japan): standard in Japan; complex 8-drug regimen
• CHOP (Western centers — limited efficacy)
• Zidovudine (AZT) + interferon-α: effective particularly for chronic/smoldering; also used in acute
• Mogamulizumab (anti-CCR4 mAb): approved in Japan; ORR ~50% in relapsed ATLL; ADCP mechanism
• Allogeneic SCT: only curative approach; recommended for all eligible patients achieving remission
• Lenalidomide: activity in R/R ATLL
• Valemetostat (EZH1/2 dual inhibitor): recent approval in Japan for R/R ATLL (2021); first epigenetic drug for ATLL

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5.9 T-cell Prolymphocytic Leukemia (T-PLL)

• ATM deletion/mutation (del 11q22.3) — cardinal alteration; seen in >75%
• TCL1 overexpression: inv(14)(q11q32) or t(14;14)(q11;q32) in ~80%; activates AKT signaling
• JAK3 mutations: ~30%; constitutive JAK/STAT activation
• STAT5B mutations: activating mutations
• Trisomy 8q, gains of 8q24 (MYC)

• Small to medium lymphocytes with round/irregular nuclei and distinct nucleolus
• Prominent cytoplasmic protrusions (blebs/knobs) visible by EM
• CD3+, CD7+, CD5+, CD52 (strongly, important for therapy), CD4+CD8- in 60%, CD4+CD8+ in 25%, CD4-CD8+ in 15%
• TCL1 IHC positive

• Marked lymphocytosis (often >100 × 10⁹/L)
• Splenomegaly, hepatomegaly
• Lymphadenopathy
• Skin infiltration (~25%)
• Serosal effusions
• Rare CNS involvement

• Alemtuzumab (anti-CD52 mAb): ORR ~70-80%; CR ~60% — the most active agent; this was the drug that transformed T-PLL outcomes
• IV alemtuzumab superior to SC for T-PLL
• Alemtuzumab induction → allogeneic SCT = only curative strategy; mandatory for eligible patients achieving CR
• Ibrutinib: active in some cases (TCL1-driven cases activate BTK); used in combination strategies
• Venetoclax: BCL2 overexpressed in T-PLL; clinical trials ongoing
• Pentostatin + mitoxantrone + cyclophosphamide (PMitCEBO): some activity

• Median OS without treatment: ~7 months
• With alemtuzumab: median OS ~21 months
• With alemtuzumab + allogeneic SCT: median OS ~3-4 years; some long-term survivors

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CHAPTER 6: INDOLENT T-CELL LYMPHOMAS (IN DETAIL)

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6.1 Mycosis Fungoides (MF)

• Annual incidence: ~0.5 per 100,000
• Median age at diagnosis: 50-60 years (but can occur at any age)
• Male:female ~2:1; higher incidence in Black individuals

• Flat, non-indurated, erythematous patches (resembling eczema, psoriasis, or tinea)
• Fine wrinkling of skin within the patch ("cigarette paper" texture)
• Predilection for non-sun-exposed areas: buttocks, lower trunk, breast, inner thigh (the "bathing trunk distribution")
• May persist for years to decades before progressing
• Histology: atypical lymphocytes in epidermis (epidermotropism); Pautrier's microabscesses may be absent at this stage

• Indurated, raised, variably erythematous plaques
• Often pruritic
• Well-demarcated borders
• Histology: dense band-like infiltrate in upper dermis; Pautrier's microabscesses (collections of atypical T-cells within the epidermis — pathognomonic)
• Epidermotropism well established

• Ulcerating skin tumors, often >1 cm diameter
• Rapid progression
• Extracutaneous spread begins (lymph nodes, viscera)
• Histology: loss of epidermotropism; large transformed cells may predominate (large cell transformation — 20% risk; associated with poor prognosis, median OS <2 years)

• T1: Patches/plaques <10% body surface area (BSA); T1a = patches only, T1b = plaques ± patches
• T2: Patches/plaques ≥10% BSA; T2a/b as above
• T3: Skin tumors (≥1 tumor ≥1cm diameter)
• T4: Erythroderma (≥80% BSA involvement)

• N0: No clinical abnormality
• N1: Clinically abnormal but histologically normal (Dutch grade 1/NCI LN0-2)
• N2: Clinically abnormal, dermatopathic changes with clusters (Dutch grade 2/NCI LN3)
• N3: Histologically involved (Dutch grade 3-4/NCI LN4)
• NX: Clinically abnormal, not biopsied

• M0: No visceral organ involvement
• M1: Visceral involvement

• B0: <5% Sézary cells; B0a <250/µL clone, B0b ≥250/µL clone
• B1: >5% Sézary cells but not B2
• B2: ≥1000/µL Sézary cells with positive clone (Sézary syndrome criterion)

• Stage IA: 5-year OS >95% (near-normal life expectancy)
• Stage IB-IIA: 5-year OS ~60-80%
• Stage IIB: 5-year OS ~40-50%
• Stage IV: 5-year OS <20%

• Pautrier's microabscesses: Collections of atypical T-cells within the epidermis (pathognomonic; seen in ~30-50% of biopsies)
• Epidermotropism: lymphocytes aligning along the dermal-epidermal junction and infiltrating into epidermis
• Cerebriform nuclei (highly irregular, convoluted) — Lutzner cells
• Dense band-like (lichenoid) infiltrate in papillary dermis

• CD3+, CD4+, CD45RO+
• Aberrant loss of CD7 (most sensitive marker) and/or CD5
• CD8- (in most cases; rare CD8+ variant exists)
• CCR4+ (targeted by mogamulizumab)

1. Clinical appearance
2. Histopathology (minimum 2 biopsies from different sites)
3. Immunophenotype (aberrant CD4+ T-cells)
4. TCR gene rearrangement (clonal T-cell population)
5. Blood involvement assessment (B staging)

• Topical corticosteroids (Class I-II): First-line for limited disease; ORR ~90% for T1, ~60% for T2
• Topical mechlorethamine (HN2/nitrogen mustard) (Valchlor gel): ORR ~60-70% in early MF; approved
• Topical bexarotene (retinoid): ORR ~40-60% in T1-T2
• Topical imiquimod (TLR7 agonist): For limited patches
• Narrowband UVB (NB-UVB): For patch-stage MF without skin thickening; ORR ~80% for Stage IA; CR possible
• PUVA (psoralen + UVA): Superior to UVB for plaque-stage disease; ORR ~90% for Stage IA-IIA; photochemotherapy
• Localized radiotherapy: Single plaques/tumors; MF is extremely radiosensitive; doses of 20-36 Gy effective
• Total Skin Electron Beam Therapy (TSEBT): Electrons to entire skin surface (4-36 Gy); ORR >90%; CR ~50-75%; used for T3-T4 or extensive T2 disease; modern low-dose TSEBT (12 Gy) effective with fewer toxicities (ACE-LY-004 trial framework)

• Bexarotene (oral RXR-retinoid): ORR ~55%; FDA-approved; causes hypertriglyceridemia + central hypothyroidism (prophylactic fenofibrate + levothyroxine required)
• HDAC inhibitors:
  • Vorinostat (SAHA): ORR ~30%; FDA-approved; first HDAC inhibitor for MF/SS
  • Romidepsin: ORR ~34-38%; FDA-approved
• Mogamulizumab (anti-CCR4 mAb): ORR ~28% (skin), ~37% (blood); FDA-approved 2018 for relapsed MF/SS; MAVORIC Phase III trial: mogamulizumab superior to vorinostat in PFS (7.7 vs 3.1 months; p<0.0001) [PMID 30100375] — landmark trial
• Brentuximab vedotin (anti-CD30 ADC): ORR ~73% in CD30+ MF/SS; ALCANZA Phase III trial: BV superior to physician's choice (MTX or bexarotene) in CD30+ CTCL; ORR 56.3% vs 12.5%; median PFS 16.7 vs 3.5 months [PMID 34507350] — landmark trial
• Extracorporeal photopheresis (ECP): For erythrodermic MF/SS (T4, B0-1); blood removed, treated with UVA + psoralen, returned; immunomodulatory; ORR ~60% for blood; response in skin ~40%
• Alemtuzumab (anti-CD52): Activity in erythrodermic MF/SS; significant infection risk
• Pralatrexate: ORR ~54% in relapsed CTCL (PROPEL study)
• Duvelisib (PI3Kδ/γ inhibitor): Active in R/R CTCL
• Pembrolizumab (PD-1 inhibitor): Activity in MF; caution — PD-1 is expressed on neoplastic cells; rare paradoxical skin flare

• Multi-agent chemotherapy (CHOP, ICE)
• Consider allogeneic SCT for eligible patients (only curative)
• Autologous SCT: short responses, not generally recommended

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6.2 Sézary Syndrome (SS)

1. Erythroderma (T4 skin involvement)
2. Lymphadenopathy
3. Sézary cells in peripheral blood (≥1000/µL Sézary cells with clonal TCR)

• MF: upregulation of PD-1, TOX2
• SS: higher expression of CCR4, CCR10; different cytokine milieu (Th2-skewed)
• SS has more chromosomal complexity than MF

• Erythroderma: Total body erythema, warmth, scaling, pruritus (often severe, intractable)
• Leonine facies: Thickened, furrowed facial skin
• Ectropion: Eversion of eyelids
• Alopecia, onychodystrophy (nail changes)
• Profound pruritus (most debilitating symptom)
• Palpable lymphadenopathy
• Marked immune impairment: recurrent bacterial/viral/fungal infections
• Hypereosinophilia common
• Elevated IgE

• Sézary cells: lymphocytes with cerebriform (convoluted) nuclei — looks like a brain on EM
• Clonal TCR rearrangement in blood (mandatory criterion)
• CD4:CD8 ratio >10 (due to expansion of CD4+ Sézary clone)
• Loss of CD7 on circulating T-cells (most sensitive blood marker)
• Low NK cell counts → susceptibility to viral infections (especially herpes)

• ECP + bexarotene or interferon = most common backbone for blood control
• Mogamulizumab: Highly effective at clearing blood disease (B2 → B0); ORR in blood ~47%; MAVORIC trial landmark
• ECP + mogamulizumab: synergistic
• Skin-directed: TSEBT, PUVA
• Note: mogamulizumab depletes Tregs — must be cautious before allogeneic SCT (increased GvHD risk)

• Median OS: 2-4 years
• Worse than patch/plaque MF due to systemic involvement
• CD4:CD8 ratio, blood disease burden, LDH are prognostic factors

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6.3 T-cell Large Granular Lymphocytic Leukemia (T-LGL)

• Rheumatoid arthritis (~30% of T-LGL patients; strong association)
• Other autoimmune diseases (Sjögren, SLE, vasculitis)
• Post-HSCT (clonal expansion of donor T-cells)
• Felty's syndrome = RA + splenomegaly + neutropenia — often driven by T-LGL

• STAT3 mutations (~40%): Y640F most common; gain-of-function → constitutive JAK/STAT signaling
• STAT5B mutations (~5-10%): associated with more aggressive disease
• BCL2 overexpression (STAT3-driven)
• Survival signals: FasL dysregulation; Mcl-1 overexpression

• Large lymphocytes with abundant pale cytoplasm and azurophilic granules (visible on Wright-Giemsa)
• Immunophenotype: CD3+, CD8+, CD57+, CD16+/-, NK markers variable
• CD4-; CD56-/+
• TCR gene rearrangement (clonal)
• PB count: Usually 2,000-20,000 LGL/µL (may be <500 — "aleukemic LGL")

• Usually asymptomatic or discovered incidentally
• Neutropenia (most common clinically significant finding) → recurrent bacterial infections
• Anemia (sometimes pure red cell aplasia — PRCA)
• Splenomegaly (moderate)
• Associated autoimmune features (RA, others)
• Lymphadenopathy uncommon

1. Clonal LGL expansion in blood (>2 months duration; LGL count usually >500/µL)
2. CD3+CD8+CD57+ immunophenotype
3. Clonal TCR gene rearrangement
4. Compatible bone marrow histology (interstitial infiltration)

• Severe neutropenia (ANC <500) causing recurrent infections
• Transfusion-dependent anemia/PRCA
• Symptomatic splenomegaly
• Associated with comorbid autoimmune disease requiring LGL treatment

• Methotrexate (MTX) 10 mg/m² weekly: ORR ~50-60%; response in 3-6 months; first-line in most centers
• Cyclosporine A (CsA) 5-10 mg/kg/day: ORR ~50%; particularly useful for PRCA; faster response than MTX
• Cyclophosphamide (oral low-dose 50-100 mg/day): ORR ~50%; particularly for autoimmune manifestations
• Choice depends on: neutropenia → MTX; PRCA → CsA; RA coexisting → MTX

• Alemtuzumab: Active but high infection risk
• Pentostatin: Active in T-LGL (purine analog)
• JAK inhibitors (ruxolitinib, tofacitinib): Rationale based on STAT3 mutations; clinical trials ongoing; responses reported
• Anti-CD52 strategies

• 10-year OS: ~70%
• Most patients live near-normal lifespan
• Transformation to aggressive lymphoma is rare (<5%)
• STAT5B-mutated T-LGL: more aggressive (worse OS)

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6.4 Primary Cutaneous CD4+ Small/Medium T-cell Lymphoproliferative Disorder

• Usually presents as a solitary skin papule or nodule (face, neck, trunk)
• Indolent; often self-limiting
• Immunophenotype: CD4+, CD8-, PD-1+, CD10+, BCL6+/- (TFH-like)
• Clonal TCR rearrangement present
• No systemic disease
• Treatment: Excision or observation; rarely needs systemic treatment
• Excellent prognosis: 5-year OS >95%; spontaneous regression can occur

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6.5 Primary Cutaneous Acral CD8+ T-cell Lymphoma

• Rare, indolent
• Presents as solitary nodule on ear (most characteristic) or acral sites (feet, hands, nose)
• CD3+, CD8+, TIA-1+, granzyme B-
• Indolent clinical course; no systemic spread
• Treatment: Radiotherapy or surgery
• 5-year OS >95%

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6.6 Subcutaneous Panniculitis-like T-cell Lymphoma (SPTCL)

• CD3+, CD8+, αβ TCR+, TIA-1+, granzyme B+
• Usually presents as multiple subcutaneous nodules (trunk, extremities)
• NO hemophagocytic syndrome (HPS) typically — when HPS absent, prognosis excellent
• Treatment: Immunosuppression (cyclosporine, steroids); avoid chemotherapy if possible
• 5-year OS: >80% (excellent without HPS)

• CD3+, CD56+, γδ TCR+, TIA-1+
• More aggressive; often accompanied by HPS
• Systemic chemotherapy required
• Worse prognosis: 5-year OS <30%
• HPS in SPTCL: 5-year OS drops to <15%

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CHAPTER 7: EXTRANODAL NK/T-CELL LYMPHOMA — SPECIAL TOPICS

"Aggressive NK-cell Leukemia" (ANKL)

• Fulminant NK-cell neoplasm; distinct from chronic NK-cell LPD
• EBV+ in >95%
• Rapid multi-organ failure; HPS nearly universal
• Peripheral blood: large granular lymphocytes flooding the blood
• Median OS: weeks to months
• Treatment: L-ASP-based regimens (SMILE); allogeneic SCT if achievable

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CHAPTER 8: LANDMARK CLINICAL TRIALS

Trial 1: ECHELON-2 (Horwitz et al., Lancet 2019; 5-year update Ann Oncol 2022 [PMID 34921960])

• 5-year PFS: 51.4% (BV-CHP) vs 43.0% (CHOP); HR 0.70 (p = 0.0098)
• 5-year OS: 70.1% (BV-CHP) vs 61.0% (CHOP); HR 0.72 (p = 0.0244)
• Subgroup analysis: Benefit greatest in sALCL subtype; also seen in CD30+ PTCL-NOS and AITL
• Peripheral neuropathy: 67% (BV-CHP) vs 52% (CHOP); resolved/improved in 72-78%
• Retreatment with BV after BV-CHP: ORR 59% (still active)

• Benefit was primarily driven by sALCL subgroup
• CD30 threshold: ≥1% expression required (FDA label); real-world patients with <10% CD30 may have less benefit
• Vincristine is replaced — concerns about loss of vincristine efficacy
• ASCT post-BV-CHP data analyzed in companion paper [PMID 35470385]

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Trial 2: MAVORIC (Kim et al., Lancet Oncol 2018 [PMID 30100375])

• Median PFS: 7.7 months (mogamulizumab) vs 3.1 months (vorinostat); HR 0.53 (p<0.0001)
• ORR: 28% vs 5%
• Blood response: 37% vs 7%
• Skin response: 42% vs 24%
• Grade ≥3 AEs: 41% vs 61% (mogamulizumab better tolerated)
• Characteristic mogamulizumab rash (drug eruption) in ~24%

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Trial 3: ALCANZA (Prince et al., Lancet 2017; final data Blood Adv 2021 [PMID 34507350])

• ORR lasting ≥4 months: 56.3% (BV) vs 12.5% (physician's choice); p<0.0001
• Median PFS: 16.7 months (BV) vs 3.5 months (PC); HR 0.27
• CR rate: 16% (BV) vs 2% (PC)
• 5-year OS: 43% (BV) vs 33% (PC) — long-term benefit
• Subgroup analysis: Benefit in both MF and pc-ALCL

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Trial 4: SG035-0004 (Pro et al., J Clin Oncol 2012; updated 2014)

• ORR: 86% (highest single-agent ORR in any lymphoma trial at that time)
• CR rate: 57%
• Durable responses in a subset
• Median OS: not reached at initial analysis

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Trial 5: PROPEL (O'Connor et al., J Clin Oncol 2011)

• ORR: 29%; CR rate: 11%
• Median duration of response: 10.1 months

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Trial 6: RomCHOP (Bachy et al., Lancet Oncol 2022 — NEGATIVE TRIAL)

• No improvement in PFS or OS with romidepsin + CHOP vs CHOP
• Increased toxicity with combination

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Trial 7: LUMIERE (Phase III, AITL-specific — ongoing as of 2024)

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Trial 8: BELIV (IDH2 inhibitor in AITL — early phase)

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Trial 9: ACE-LY-004 (Brentuximab + TSEB in MF)

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Trial 10: HTLV-1 / AZT + IFN (Bazarbachi et al.)

• For chronic and smoldering ATLL: AZT/IFN superior to chemotherapy (OS benefit)
• For acute/lymphomatous ATLL: AZT/IFN + chemotherapy appears superior to chemotherapy alone
• First randomized-level evidence supporting antiviral approach in ATLL

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CHAPTER 9: TARGETED THERAPIES AND NOVEL AGENTS

Antibody-Drug Conjugates (ADCs)

HDAC Inhibitors

Monoclonal Antibodies

Targeted Pathway Inhibitors

CAR-T Cell Therapy in T-cell Lymphoma

• Allogeneic "off-the-shelf" CAR-T using gene-edited cells (knock-out of CD7 in donor T-cells before engineering)
• CD7 CAR-T with CD7 knocked out (CRISPR-edited): Phase I data showing ORR ~64% in R/R T-ALL/PTCL
• CD5-directed CAR-T: Under investigation
• CD30 CAR-T: Active in ALCL and other CD30+ PTCL (Phase I ongoing)

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CHAPTER 10: PROGNOSIS COMPARISON TABLE

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CHAPTER 11: KEY IMMUNOPHENOTYPE QUICK REFERENCE

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CHAPTER 12: BOARD EXAM HIGH-YIELD MNEMONICS & PEARLS

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