Upregulation of the signal transducers and activators of transcription 3 (STAT3) pathway in lymphatic metastases of papillary thyroid cancer.

Papillary thyroid cancer (PTC) has an impressive propensity for lymphatic spread. Signal transducers and activators of transcription 3 (STAT3), constitutively activated in many different cancers, may play a role in PTC lymphatic metastases. We examined 49 patients with PTC, 22 with and 27 without lymphatic metastases. All patients had a total thyroidectomy with lymph node dissection to document true node negative cases. The level of STAT3 expression in benign, non-neoplastic thyroid tissue is barely detectable by immunohistochemistry. Only 11 of the 35 (31%) specimens exhibited weak immunostainingfor STAT3 and pSTAT3 was found weakly positive in 3 of 35 (9%) benign specimens. Expression of STAT3 in all PTC primary tumors was 98% (40/41) and thus significantly higher than corresponding benign thyroid tissue (p=0.0001). pSTAT3 was found in 37% of primary tumors (15/41) and this was significantly higher than pSTAT3 expression in benign tissue (p=0.006). Comparing node-positive and node-negative primary tumors, there was no difference in staining intensity for STAT3 where strong (2+) staining was seen 12/19 node-positive tumors and 13/22 node-negative tumors (p=1). Regarding pSTAT3 expression in primary PTC tumors, node negative cases (n=22) exhibited significantly less staining compared to node positive cases (n=19). Only 4 of 22 (18%) cases in the node-negative group were weakly (1+) positive for pSTAT3 while 12 of 19 (58%) cases in the node-positive group were positive (p=0.011) with 45% of these specimens exhibiting strong (2+) staining. Lymphatic metastases were highly positive (>93%) for both STAT3 and pSTAT3. The STAT3 pathway is ubiquitous in PTC and activated pSTAT3 is significantly upregulated in PTC tumors with metastatic disease. This study is the first to suggest a potential role for activated pSTAT3 in lymphatic metastases in thyroid cancer.