A 55-year-old non-smoker woman presents with a peripheral lung adenocarcinoma. Molecular profiling reveals an EML4-ALK fusion gene (variant 1, E13:A20). Which pattern of ALK expression is seen on immunohistochemistry, and which targeted therapy is first-line?

• A Nuclear ALK staining; first-line therapy is crizotinib (1st generation ALK/MET/ROS1 inhibitor)
• B Membrane ALK staining similar to neuroblastoma; first-line therapy is lorlatinib (3rd generation ALK TKI)
• C No detectable ALK protein on IHC; FISH only is required for diagnosis; crizotinib is first-line
• D Strong granular cytoplasmic ALK staining in tumor cells; first-line therapy is alectinib (ALK TKI, 2nd generation) ✓

Explanation

EML4-ALK fusion results in constitutive, cytoplasmic ALK kinase activity; IHC using anti-ALK antibodies (D5F3 clone with signal amplification) shows strong granular cytoplasmic positivity in tumor cells. Based on randomized trials (ALEX, ALESIA), alectinib (2nd-generation ALK TKI) is the current first-line standard over crizotinib, demonstrating superior PFS and CNS penetration, critical because ALK-rearranged NSCLC has high brain metastasis frequency. Lorlatinib (3rd-generation) is used after 2nd-generation TKI failure.

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

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