This category includes:

• ALK- positive ALCL
• ALK- negative ALCL
• Breast implant associated ALCL

ALK- Positive Anaplastic Large Cell Lymphoma

Epidemiology:

• Account for 3% of adult NHL
• 10-30% of childhood lymphoma
• Bimodal age presentation
• Median age- 30 years
• Male predominance

Pathogenesis:

t(2;5)(p23;q35) 

↓

Fusion of ALK on chromosome 2p23 and NPM1on chromosome 5

↓

Production of a chimeric oncoprotein-NPM1::ALK fusion protein- which is constitutive expressed (has kinase function)

↓

Triggering of numerous cellular signalling pathways including the PLC-γ, PI3K/AKT, Cdc42/Rac1, JNK/cJun RAS/ERK/MAPK, mTOR, JAK/STAT3 and STAT5B pathways

↓

Enhanced cell survival, inhibition of apoptosis, Promoting tumour dissemination and evasion the immune surveillance mechanisms

Note: Various other chromosomal rearrangements with different partner genes are noted.

Translocation-  Partner gene

t(1;2)- TPM3

Inv(2)-  ATIC 

t(2;3)-   TFG 

t(2;17)-  CLTC 

t(2;X)- MSN 

t(2;19)-  TPM4 

t(2;22)-  MYH9 

t(2;9)-  TRAF1 

t(2;11)-  EEF1G 

t(2;17)-  RNF213/ALO17

Clinical Features:

• B symptoms
• Generalized lymphadenopathy
• Extranodal disease- skin, bone, soft, tissue, lung etc

Investigations:

• Lymph node biopsy
  • Paracortical, sinusoidal, perifollicular, intravascular and diffuse patterns of growth
  • Tumor cells are large with pleomorphic / horseshoe shaped nuclei and abundant cytoplasm. (Hallmark cells)
  • Doughnut cells – Due to plane of sectioning, nuclei of some cells appear to contain cytoplasmic inclusions (These are not true inclusions but invaginations of nuclear membrane)
  • When lymph node architecture is partially effaced, the tumor characteristically grows within the sinuses (Resembling metastatic tumor)
• Immunophenotyping
  • Positive – CD30(Hallmark of this lymphoma), Pan T markers (CD3, CD4), TCR alpha beta, Cytotoxic granule associated proteins (TIA-1, Granzyme B, Perforin), EMA, One / More T-cell antigen CD2, CD4, CD25, IL2 – receptor, Clusterin, Cadherin, galectin 3
  • Negative- CD5, CD7, CD8, CD15 – (differentiates from RS Cell), BCL-2
  • ALK (Anaplastic large cell lymphoma kinase protein)- Very important prognostic marker
• Molecular studies
  • Clonal rearrangements of TCR genes
  • EBV sequences absent
  • Abnormalities of ALK locus and Chr. 2
• Cytogenetics: Mentioned above

Prognosis:

• 5-year survival
  • ALK positive ALCL and ALK negative ALCL with DUSP22-IRF4 rearrangements- 80%
  • ALK negative ALCL- 40%
• Markers of poor prognosis – 
  • ALK negativity
  • B Symptoms
  • High IPI score
  • Small cell variant on histology
  • CD56 or survivin expression
  • Mediastinal or visceral involvement

Pretreatment Work-up:

• Same as PTCL-NOS

Treatment Plan:

• For both ALK- Positive and ALK- Negative cases- 6 cycles of any one following chemotherapies (Better to do repeat PET-CT after 2 cycles of chemotherapy)
  • Brentuximab +CHP- Preferred
  • CHOP
  • CHOEP
  • DA-EPOCH
• For ALK-Negative ALCL: Once PET-CT is in CR, HDT followed by ASCR needs to be done.
• For refractory or relapsed cases: Treat like relapsed/ refractory PTCL-NOS

Other treatment options:

• Crizotinib
  • Inhibitor of both ALK and c-met
  • Used in relapse/ refractory cases
  • Dose: 165-280mg/m2-BD until disease progression/ unacceptable toxicity
  • ORR- 88%

Primary ALCL associated with breast implants

• Present with effusion associated with implant
• Median time of development of lymphoma- 7 years after implant
• Present with unilateral effusion around the implant
• IHC: Similar to ALK- Negative ALCL
• Treatment
  • Surgical removal of implant along with capsule is curative in most of the patients (if disease is limited to breast)
  • For patients with disease beyond capsule or involvement of axillary lymph node: Chemotherapy +/- radiotherapy is needed

Note:

• Primary cutaneous ALCL- Refer to “Primary cutaneous T-cell lymphomas” section