Sequential triple primary malignancies in the larynx, lung, and liver with discordant p53 expression patterns: a case report.

Sequential triple primary malignancies are very uncommon. Distinguishing new primary tumors from metastases in cancer survivors is a diagnostic challenge. This case illustrates how comprehensive immunohistochemistry (IHC), particularly p53 expression patterns as a surrogate for TP53 gene status, can determine clonal independence. A 71-year-old male ex-smoker presented with three malignancies over 4 years. First, laryngeal squamous cell carcinoma (pT1bN0M0) showed complete loss of p53 staining (null pattern, truncating mutation). Four years later, lung adenocarcinoma (pT1bN1M0; TTF-1+/Napsin A+) showed strong, diffuse p53 nuclear positivity (missense mutation pattern). One month later, intrahepatic cholangiocarcinoma (pT1N0M0; CK7+/CK19+/TTF-1-) showed wild-type p53 (scattered weak positivity). Divergent p53 IHC patterns (two mutant phenotypes and one wild-type) indicated three independent primaries. The patient recovered well after each curative-intent surgery. Meticulous IHC profiling and careful interpretation of p53 staining patterns are crucial for distinguishing multiple primary cancers from metastatic disease.