title: Expression of the hepatocyte growth factor and c-met in normal thyroid, non-neoplastic, and neoplastic nodules.
abstract: We have examined the coexpression of hepatocyte growth factor (HGF) and its receptor (HGF-R or c-met) in an archival series of 63 paraffin-embedded thyroid specimens plus one lymph node metastasis. By immunocytochemistry, we found undetectable expression of both the ligand and the 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 nodules (colloid nodules) and 17 benign neoplastic nodules, 3 of 10 colloid nodules, 2 of 10 follicular adenomas, and 2 of 7 oncocytic adenomas 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%). In these 7 cases, expression of HGF was always stromal and expression of c-met limited to the membrane of the follicular cells. Of 3 malignant nodules derived from aberrant growth of the parafollicular C cells (medullary thyroid cancer or MTC), 2 were positive (6% of cells). In these 2 cases, the expression of HGF (3+) was not stromal, but in both the membrane and cytoplasm of the parafollicular cells, while that of c-met (3+) was restricted to the membrane. In contrast to all of the above, of 14 papillary carcinomas (PTC) encompassing 5 histological variants (conventional; follicular; oncocytic; with foci of solid growth; diffuse sclerosing) plus 1 neck lymph node metastasis of 1 conventional 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 cells. The highest percentage (46%) pertained to conventional PTC cases with abundant peritumoral lymphocyte infiltration, indicating that some lymphokine(s) may recruit PTC cells for HGF expression in a paracrine fashion. With the exception of one negative case, c-met was found in 43% to 80% of the cells, both at levels from intense (3+) to very intense (4+). The immunostaining for HGF was stromal in 25%, membranous in 8%, cytoplasmic in 8%, and both membranous and cytoplasmic in 59% of 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 variant of PTC (the most aggressive variant), the coexpression of HGF/c-met was lost, in that only c-met was expressed on membranes in both cases. We conclude that the HGF/c-met system is activated (by overexpression of both components) in the vast majority of PTC. In most PTC the interaction of HGF and its receptor (c-met) is autocrine, not paracrine.
authors.affiliation: Dipartimento di Patologia Umana, Universita' di Messina, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Trovato
authors.forename: D
authors.initials: D
authors.lastname: Villari
authors.forename: L
authors.initials: L
authors.lastname: Bartolone
authors.forename: S
authors.initials: S
authors.lastname: Spinella
authors.forename: A
authors.initials: A
authors.lastname: Simone
authors.forename: M A
authors.initials: MA
authors.lastname: Violi
authors.forename: F
authors.initials: F
authors.lastname: Trimarchi
authors.forename: D
authors.initials: D
authors.lastname: Batolo
authors.forename: S
authors.initials: S
authors.lastname: Benvenga
mesh_terms: D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012016:Reference Values; D013961:Thyroid Gland / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D016606:Thyroid Nodule / Q000378:metabolism* / Q000473:pathology
chemical_list: D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met