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Immunohistochemical Analysis of Phosphotyrosine Signal Transducer and Activator of Transcription 3 and Epidermal Growth Factor Receptor Autocrine Signaling Pathways in Head and Neck Cancers and Metastatic Lymph Nodes

Authors' Affiliations: Departments of ¹ Otolaryngology, ² Pathology, ³ Biostatistics, ⁴ Pharmacology, and ⁵ Oral Medicine and Pathology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Requests for reprints: Jennifer R. Grandis, Suite 500, Eye and Ear Institute, University of Pittsburgh, 203 Lothrop Street, Pittsburgh, PA 15213. Phone: 412-647-5280; Fax: 412-647-0108; E-mail: jgrandis{at}pitt.edu.

Purpose: To determine the effect of tyrosine-phosphorylated signal transducer and activator of transcription 3 (pSTAT3) immunoexpression on survival in two independent cohorts of patients with squamous cell carcinoma of the head and neck (SCCHN) and to evaluate pSTAT3, transforming growth factor- (TGF-), epidermal growth factor receptor (EGFR), and gastrin-releasing peptide receptor (GRPR) expression in matched tumor and lymph node metastases in one of these cohorts.

Experimental Technique: Immunostaining for pSTAT3, TGF-, EGFR, and GRPR was done in two SCCHN cohorts (cohort 1, 61 tumors; cohort 2, 69 paired primary tumors and lymph node metastases). Semiquantitative scores derived from the product of staining intensity (scale 0-3) score and percentage of positive tumor cells were correlated with clinical outcome.

Results: Immunoexpression of pSTAT3 did not correlate with clinical outcome in either cohort (cohort 1, P = 0.914; cohort 2, P = 0.312). In cohort 2, TGF- and EGFR expression in the primary tumors showed some association with decreased disease-free survival (P = 0.0306 and P = 0.0985, respectively). Both pSTAT3 and EGFR showed a correlation of expression between tumor and matched lymph node metastasis (P < 0.0001 and P = 0.0046, respectively). In addition, the expression of EGFR and GRPR in the primary tumors correlated with TGF- expression in paired nodal metastases (P = 0.0043 and P = 0.0268, respectively). In the nodal metastases, TGF- expression correlated with EGFR expression (P = 0.0069). In primary tumors, GRPR expression correlated with TGF- and EGFR expression (P = 0.0378 and P = 0.0026, respectively).

Conclusions: These findings support an autocrine signaling pathway involving TGF-, EGFR, and pSTAT3 in metastatic SCCHN as well as transactivation of EGFR by GRPR via TGF-, but fails to identify an independent prognostic role for pSTAT3 immunoexpression.