Abstract
BACKGROUND: Cancer of unknown primary (CUP) is characterized by metastatic cancer cells with no identifiable primary tumor despite extensive diagnostics. This study investigates the epidemiologic, histopathological, and prognostic factors in 352 CUP cases in Iran. MATERIALS AND METHODS: This retrospective study reviewed the clinical documents of CUP patients registered in MACSA, a charity-based referral center in central Iran, Isfahan, within 2016-2021. The patients' data were analyzed, and survival associations were assessed using Cox proportional hazards regression models. RESULTS: Altogether 352 CUP patients were included in the study. The mean age at diagnosis was 65.9 ± 14.3 years, with 52.6% being male. Abdominal pain (32.1%) was the most common presentation. Metastatic adenocarcinoma (31.5%) was the most frequent histopathological type, with the liver (48.6%) as the most prevalent metastatic site. Single-site metastasis was seen in 55.4% of patients. Immunohistochemistry, conducted in 40.3% of patients, was inconclusive in identifying the primary site. The median overall survival was 5 months (95% confidence interval [CI]: 4.0-7.0). Multivariable Cox regression analysis showed older age increased risk of death (hazard ratio [HR]: 1.028, 95% CI: 1.019-1.037). Neuroendocrine tumors were linked to a lower risk (HR: 0.553, 95% CI: 0.313-0.978), while metastasis to the liver (HR: 1.382, 95% CI: 1.076-1.774) and pancreas (HR: 2.138, 95% CI: 1.094-4.176) increased mortality risk. CONCLUSION: This study provides large-scale evaluation of CUP in an Iranian population, revealing its poor prognosis and the limited diagnostic utility of IHC. The findings align with global data and highlight the urgent need for improved diagnosis and treatment to enhance patient outcomes.