Trovato M, Villari D, Bartolone L, Spinella S, Simone A, Violi M A, Trimarchi F, Batolo D, Benvenga S
Dipartimento di Patologia Umana, Universita' di Messina, Italy.
Thyroid. 1998 Feb;8(2):125-31. doi: 10.1089/thy.1998.8.125.
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.
我们检测了63例石蜡包埋的甲状腺标本及1例淋巴结转移标本中肝细胞生长因子（HGF）及其受体（HGF-R或c-met）的共表达情况。通过免疫细胞化学方法，我们发现在10例正常甲状腺组织和9例非乳头状恶性结节（5例滤泡癌、1例低分化（岛状）癌、3例未分化（间变性）癌）中，配体和受体均未检测到表达。在10例非肿瘤性结节（胶样结节）和17例良性肿瘤性结节中，10例胶样结节中的3例、10例滤泡性腺瘤中的2例以及7例嗜酸细胞腺瘤中的2例，在部分细胞（1%至3%）中显示出HGF和c-met的弱阳性但明显的染色（0至4+评分中的1+）。在这7例中，HGF的表达总是在间质中，而c-met的表达仅限于滤泡细胞的膜。在3例由滤泡旁C细胞异常生长形成的恶性结节（甲状腺髓样癌或MTC）中，2例呈阳性（占细胞的6%）。在这2例中，HGF（3+）的表达不是在间质中，而是在滤泡旁细胞的膜和细胞质中，而c-met（3+）的表达仅限于膜。与上述所有情况不同的是，在14例乳头状癌（PTC）中，包括5种组织学亚型（传统型；滤泡型；嗜酸细胞型；有实性生长灶型；弥漫硬化型）以及1例传统型PTC的颈部淋巴结转移灶，12例（86%）表达HGF，13例（93%）表达c-met。除2例阴性病例外，在15%至46%的细胞中检测到HGF。最高百分比（46%）见于伴有丰富肿瘤周围淋巴细胞浸润的传统型PTC病例，表明某些淋巴因子可能以旁分泌方式募集PTC细胞表达HGF。除1例阴性病例外，在43%至80%的细胞中发现了c-met，强度从强（3+）到极强（4+）。在PTC阳性病例中，25%的HGF免疫染色在间质中，8%在膜上，8%在细胞质中，59%在膜和细胞质中均有。在PTC阳性病例中，43%的c-met免疫染色在膜上，57%在膜和细胞质中均有。在淋巴结转移灶以及PTC的弥漫硬化型（最具侵袭性的亚型）中，HGF/c-met的共表达消失，因为在这两种情况下仅在膜上表达c-met。我们得出结论，在绝大多数PTC中，HGF/c-met系统被激活（通过两种成分的过表达）。在大多数PTC中，HGF及其受体（c-met）的相互作用是自分泌的，而非旁分泌的。
