TTF-1, CDX-2, and PAX-8 Immunoexpression in a Large Serie of Extrapulmonary Small Cell Neuroendocrine Carcinomas: A Study of 138 Cases

Background: Extrapulmonary small cell neuroendocrine carcinoma (EP-SC) is a rare malignancy with a poor prognosis. In our study, one hundred and thirty-eight EP-SCNC tissue samples underwent a complex analysis. Method: We studied the possible benefit of TTF-1, CDX-2, and PAX-8 immunohistochemical analyses for determining the primary site of EP-SCNC origin. Results: The median survival of our cohort was 11.5 months. Patients younger than 70 years had significantly better overall survival (p=0.024). Across the full cohort, CDX-2 positivity was found in 19 tumors (13.9%), TTF-1 in 35 tumors (25.7%), and PAX-8 in 63 tumors (46.3%), regardless of tumor origin. The expression of CDX-2 and PAX-8 did not differ significantly among different organ systems (p=0.2 and 0.3), respectively. The expression of TTF-1 differed significantly in tumors from various sites of origin (p=0.009), expressed more often in breast, pancreatic, and genitourinary tumors. Interestingly, TTF-1 expression proved to have a negative prognostic impact relative to patient survival (age-adjusted Cox regression analysis, HR=1.62, 95%CI:1.06-2.47, p=0.021). Conclusion: As most patients with EP-SCNC had a metastatic presentation, finding the primary tumor origin, which is important for patient prognoses, is both challenging and important at the same time. Only TTF-1 immunohistochemical analysis proved to be helpful with this task. Moreover, a diagnosis of primary lung small cell carcinoma cannot be established based on TTF-1 positivity, since only 25.7% of EP-SCNC in our study displayed TTF-1 positivity.