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NKX3.1 CUP Prostate — SCE Medical Oncology MCQ

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ModerateCancer of Unknown PrimaryNKX3.1 CUP ProstateSCE Medical Oncology

A 62-year-old man with cancer of unknown primary has multiple bone metastases. PSA is 2.1 ng/mL (low). Biopsy shows poorly differentiated adenocarcinoma. IHC: NKX3.1 positive, PSA negative, CDX2 negative, TTF-1 negative. What is the likely primary?

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Correct answer: D — Prostate — NKX3.1 is a highly sensitive and specific marker for prostate origin even when PSA IHC is negative; serum PSA may be low in poorly differentiated/neuroendocrine prostate cancers

NKX3.1 is a prostate-specific homeobox transcription factor with higher sensitivity (~98%) than PSA IHC (~70-80%) for detecting prostate origin, particularly in poorly differentiated and neuroendocrine variants where PSA may be lost. In CUP with bone metastases, NKX3.1 positivity should prompt prostate cancer-directed treatment (ADT) even when serum PSA is not markedly elevated. Poorly differentiated prostate cancers may have low serum PSA despite extensive metastatic disease.

Reference: NICE NG36 CUP; ESMO CUP; Gurel et al Am J Surg Pathol 2010