EXPRESSION OF THE HEPATOCYTE GROWTH-FACTOR AND C-MET IN NORMAL THYROID, NONNEOPLASTIC, AND NEOPLASTIC NODULES

We have examined the coexpression of hepatocyte growth factor (HGF) an d its receptor (HGF-R or c-met) in an archivial series of 63 paraffin- embedded thyroid specimens plus one lymph node metastasis. By immunocy tochemistry, we found undetectable expression of both the ligand and t he receptor in 10 normal thyroids and 9 nonpapillary malignant nodules [5 follicular carcinomas, 1 poorly differentiated (insular) carcinoma , 3 undifferentiated (anaplastic) carcinomas]. Of 10 non-neoplastic no dules (colloid nodules) and 17 benign neoplastic nodules, 3 of 10 coll oid nodules, 2 of 10 follicular adenomas, and 2 of 7 oncocytic adenoma s showed a weak but distinct staining (1+ score in a scale from 0 to 4 +) of both HGF and c-met in a modest proportion of cells (1% to 3%). I n these 7 cases, expression of HGF was always stromal and expression o f c-met limited to the membrane of the follicular cells. Of 3 malignan t nodules derived from aberrant growth of the parafollicular C cells ( medullary thyroid cancer or MTC), 2 were positive (6% of cells). In th ese 2 cases, the expression of HGF (3+) was not stromal, but in both t he membrane and cytoplasm of the parafollicular cells, while that of c -met (3+) was restricted to the membrane. In contrast to all of the ab ove, of 14 papillary carcinomas (PTC) encompassing 5 histological vari ants (conventional; follicular; oncocytic; with foci of solid growth; diffuse sclerosing) plus 1 neck lymph node metastasis of 1 conventiona l PTC, 12 (86%) expressed HGF, and 13 (93%) expressed c-met. With the exception of 2 negative cases, HGF was detected in 15% to 46% of the c ells. The highest percentage (46%) pertained to conventional PTC cases with abundant peritumoral lymphocyte infiltration, indicating that so me lymphokine(s) may recruit PTC cells for HGF expression in a paracri ne fashion. With the exception of one negative case, c-met was found i n 43% to 80% of the cells, both at levels from intense (3+) to very in tense (4+). The immunostaining for HGF was stromal in 25%, membranous in 8%, cytoplasmic in 8%, and both membranous and cytoplasmic in 59% o f the PTC-positive cases. The immunostaining for c-met was membranous in 43% and both membranous and cytoplasmic in 57% of the PTC-positive cases. In the lymph node metastasis and in the diffuse sclerosing vari ant of PTC (the most aggressive variant), the coexpression of HGF/c-me t was lost, in that only c-met was expressed on membranes in both case s. We conclude that the HGF/c-met system is activated (by overexpressi on of both components) in the vast majority of PTC. In most PTC the in teraction of HGF and its receptor (c-met) is autocrine, not paracrine.