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Thymidylate Synthase Expression in Gastroenteropancreatic and Pulmonary Neuroendocrine Tumors

Authors' Affiliations: ¹ Thoracic Oncology Unit, ² Pathology Division, and ³ Division of Medical Oncology, Department of Clinical and Biological Sciences, University of Torino, San Luigi Hospital, Torino, Italy

Requests for reprints: Paolo Ceppi, Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital Regione Gonzole 10, 10043 Orbassano, Torino, Italy. Phone: 39-011-9026644; Fax: 39-011-9026753; E-mail: paolo.ceppi{at}unito.it.

Purpose: The predictive role of the quantification of thymidylate synthase (TS) in tumors treated with antifolate drugs, such as 5-fluorouracil (5-FU), has been extensively reported in a variety of human tumors. Neuroendocrine tumors (NET) represent potential targets of antifolate agents, but no data on TS expression level in these tumors are currently available.

Experimental Design: A series of 116 NETs were collected, including 58 gastroenteropancreatic (GEP) and 58 lung NETs. In 24 well-differentiated GEP neuroendocrine carcinomas (WD-NEC), a 5-FU–based treatment was given. Total RNA was extracted from microdissected paraffin blocks. TS mRNA quantification was done by real-time PCR, whereas protein expression was evaluated by immunohistochemistry.

Results: By means of both quantification by real-time PCR and immunohistochemistry, a higher TS expression in pulmonary small cell lung cancer and large cell NEC compared with typical and atypical carcinoids was observed (P < 0.01). Similarly, in GEP tumors, a higher TS expression in poorly differentiated carcinomas than both WD-NEC and benign tumors (P < 0.01) was found. In patients with WD-NEC treated with 5-FU, high TS mRNA levels were associated with shorter time to progression (P = 0.002) and overall survival (P = 0.04). This negative prognostic role was confirmed in multivariate analysis adjusting for major prognostic variables (P = 0.01). No association between TS mRNA and survival was observed in WD-NEC patients not receiving 5-FU.

Conclusions: This study, for the first time, (a) reports the differential TS expression in the spectrum of NETs and (b) indicates TS as a possible predictive marker of treatment efficacy in WD-NEC patients treated with 5-FU.