TTF-1, CDX-2, PAX-8 and GATA-3 immunoexpression in a large serie of extrapulmonary small cell neuroendocrine carcinomas: a study of 138 cases

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. Multicentric study included 138 high-grade small cell carcinomas exhibiting neuroendocrine morphology without known pulmonary involvement. Using TMA, we studied the possible benefit of TTF-1 (DAKO, clone 8G7G3/1, dilution 1:200), CDX-2 (DAKO, ready to use kit DAK-CDX2), PAX-8 (Cell Marque, polyclonal, dilution 1:50) and GATA-3 (Cell Marque, clone L50-823, 1:200) immunohistochemical analyses for determining the primary site of EP-SCNC origin. For statistical analyses, the Kaplan-Meier, the Cox regressions analyses, the Pearson chi-square test and the Fisher’s exact test were used. 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%), PAX-8 in 63 tumors (46.3%) and GATA-3 in 8 tumors (6.5%), regardless of tumor origin. The expression of CDX-2, PAX-8 and GATA-3 did not differ significantly among different organ systems (p = 0.2; 0.3 and 0.12), 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). 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.