Which paraneoplastic antibody is most classically associated with small cell lung cancer and autoimmune encephalitis?

• A. Anti-Yo (PCA-1)
• B. Anti-Ri (ANNA-2)
• C. Anti-Hu (ANNA-1)
• D. Anti-NMDA receptor antibodies

Answer: (C)

Paraneoplastic autoimmunity linking neurons to cancer shows patterns where specific antibodies point to particular tumors. Anti-Hu antibodies (ANNA-1) are the classic association with small cell lung cancer and autoimmune encephalitis, reflecting the immune system targeting neuronal Hu proteins in the setting of SCLC. This antibody commonly presents with encephalitis or limbic involvement, producing subacute cognitive changes, seizures, and behavioral symptoms in patients with SCLC. By contrast, anti-Yo (PCA-1) is more associated with cerebellar degeneration in breast or gynecologic cancers; anti-Ri (ANNA-2) often presents with opsoclonus–myoclonus syndrome, typically linked to breast cancer; and anti-NMDA receptor antibodies cause autoimmune encephalitis, usually in younger women with ovarian teratoma. Thus, anti-Hu is the best choice for the classic SCLC–paraneoplastic encephalitis connection.