What is anaplastic large cell lymphoma (ALCL)?

Anaplastic Large Cell Lymphoma (ALCL): Comprehensive Overview

Anaplastic Large Cell Lymphoma (ALCL) is a rare but aggressive CD30-expressing subtype of peripheral T-cell lymphoma with distinct clinical, pathological, and molecular characteristics that requires specific diagnostic and treatment approaches based on its subtype classification. 1

Classification and Subtypes

ALCL is classified into four distinct entities according to the WHO classification:

1. Systemic ALCL, ALK-positive

   • Characterized by overexpression of ALK-1 protein from chromosomal translocation t(2;5)
   • More common in children and young adults (median age ~35 years)
   • Better prognosis compared to other subtypes 2, 3

2. Systemic ALCL, ALK-negative

   • Further subdivided based on molecular features:
     • DUSP22 rearrangement (30% of cases) - relatively favorable prognosis
     • TP63 rearrangement (8% of cases) - poor prognosis (5-year OS rate of 17%)
     • Triple negative (lacking ALK, DUSP22, and TP63) - poor prognosis 2

3. Primary Cutaneous ALCL (pcALCL)

   • Excellent prognosis (10-year survival >90%)
   • Typically presents with solitary or localized skin lesions 2

4. Breast Implant-Associated ALCL (BIA-ALCL)

   • Distinct entity from systemic ALCL
   • Associated with textured breast implants
   • Most commonly presents as seroma around implant
   • Generally indolent when limited to effusion fluid 2

Pathological Features

ALCL is characterized by:

• Large pleomorphic lymphoid cells with abundant cytoplasm
• Distinctive "hallmark cells" with eccentric, horseshoe- or kidney-shaped nuclei
• Strong and uniform expression of CD30 on the cell membrane and in the Golgi region
• Variable loss of T-cell antigens (CD3, CD5, CD7)
• ALK+ ALCL shows ALK protein expression due to ALK gene rearrangement
• Cytotoxic granule proteins (TIA-1, granzyme B, perforin) often present 2, 3

Clinical Presentation

• Most patients with systemic ALCL present with advanced stage III or IV disease
• Frequently associated with systemic symptoms (B symptoms)
• Common sites of involvement:
  • Lymph nodes (most common)
  • Extranodal sites: skin, bone, soft tissues, lung, liver
  • Bone marrow involvement in 10-30% of cases 2, 1
• BIA-ALCL typically presents as seroma, mass, or hardening adjacent to breast implant, usually 8 years (median) after implant placement 2

Diagnosis

Diagnosis requires:

1. Excisional or incisional biopsy (preferred over core needle biopsy)
2. Immunophenotyping by immunohistochemistry:
   • Essential markers: CD30, ALK, CD3, CD2, CD4, CD8, CD5, CD7, CD45
   • Additional markers: EMA, cytotoxic markers (TIA-1, granzyme B, perforin)
3. Molecular/genetic testing:
   • ALK rearrangement
   • DUSP22 and TP63 rearrangements in ALK-negative cases
   • T-cell receptor gene rearrangement studies 2, 1
4. Staging workup:
   • Complete blood count and differential
   • Blood chemistries including LDH
   • PET/CT scan (preferred over CT alone)
   • Bone marrow biopsy
   • HIV and hepatitis B/C testing 2

Treatment Approaches

Treatment varies by subtype:

Systemic ALCL (ALK+ and ALK-)

• First-line therapy: CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) combined with brentuximab vedotin 1, 4
• Relapsed/refractory disease:
  • Brentuximab vedotin
  • Clinical trials
  • Salvage chemotherapy regimens (DHAP, ESHAP, GDP)
  • Consideration for stem cell transplantation 2, 1

Primary Cutaneous ALCL

• Localized disease: Surgical excision or radiotherapy (24-30 Gy)
• Multifocal disease: Low-dose methotrexate or brentuximab vedotin
• Systemic therapy only for extracutaneous spread 2, 1

Breast Implant-Associated ALCL

• Capsulectomy with implant removal for localized disease
• Systemic therapy for invasive or advanced disease 2

Prognosis

Prognosis varies significantly by subtype:

• ALK+ ALCL: Best prognosis (5-year OS ~70-80%)
• ALK- ALCL: Intermediate prognosis, varies by molecular subtype
• Primary Cutaneous ALCL: Excellent prognosis (5-year OS >90%)
• BIA-ALCL: Generally favorable when limited to effusion fluid 2, 1

Key Prognostic Factors

• ALK status: Most important prognostic factor in systemic ALCL
• International Prognostic Index (IPI): Predicts survival in patients with ALCL
• Molecular subtypes: DUSP22 and TP63 rearrangements in ALK-negative ALCL
• Disease extent: Localized vs. advanced disease 2, 1, 3

Recent Advances

• Targeted therapies: Brentuximab vedotin (anti-CD30 antibody-drug conjugate) has shown high response rates in CD30+ ALCL
• Molecular classification: Identification of DUSP22 and TP63 rearrangements has improved prognostication
• ALK inhibitors: Under investigation for ALK+ disease 1, 5

ALCL represents a heterogeneous group of lymphomas with distinct clinical and biological characteristics. Accurate diagnosis and classification are essential for optimal management and prediction of outcomes.