ALK gene rearrangements in non-small cell lung carcinoma are most commonly found in which histological subtype, and what is the characteristic oncogenic mechanism?

• A Squamous cell carcinoma; ALK amplification driving ERK phosphorylation
• B Small cell carcinoma; ALK point mutation activating EGFR pathway
• C Large cell carcinoma; ALK translocation to chromosome 2p23 creating a secreted kinase
• D Adenocarcinoma; EML4-ALK inversion creates a constitutively active ALK fusion kinase ✓

Explanation

ALK rearrangements occur almost exclusively in adenocarcinoma of the lung (specifically the acinar and solid subtypes), are more common in younger patients and non-smokers, and the most common rearrangement is an inversion on chromosome 2p creating the EML4-ALK fusion. This produces a constitutively active ALK tyrosine kinase that drives RAS-MAPK, PI3K-AKT, and JAK-STAT signaling. Squamous cell carcinoma typically harbors FGFR1 amplification, EGFR mutations, or CDKN2A loss.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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