title: Co-expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) in thyroid nodules is associated with co-expression of CD30 ligand/CD30 receptor.
abstract: Data on the expression of interleukin 6 (IL-6)/interleukin 6 receptor (IL-6R) in thyroid nodules is scarce. Based on our recent data of CD30 ligand (CD30L)/CD30 receptor (CD30) in these nodules and on the knowledge that this signal stimulates IL-6 production in non-thyroid neoplasms, we wanted to evaluate the immunocytochemical expression of these 2 ligand/receptor systems in a large archival series of paraffin-embedded specimens. These specimens included 6 normal thyroids and 130 thyroid nodules. Co-expression of IL-6 and IL-6R in the epithelial (follicular) cells was observed solely in CD30L/CD30 positive nodules: 5/15 (33%) oncocytic adenomas; 6/30 (20%) follicular adenomas which belonged to 2 variants (4/4 microfollicular toxic and 2/2 hyalinizing trabecular); 9/30 (30%) papillary thyroid cancers (PTC), all belonging to the conventional variant. In PTC the proportion of tumor epithelial cells that were IL6 positive was inversely correlated with the pTNM staging (r=-0.549, p=0.01). All 15 follicular cancers (FTC), all 6 anaplastic cancers (ATC) were IL-6/lL-6R negative; 14/15 FTC and 5/6 ATC were CD30L/CD30 negative. In another oncocytic adenoma, another 4 conventional PTC and another 7 non-conventional PTC CD30L/CD30 expression was associated to expression of IL-6 only. IL-6 staining associated to absent expression of CD30L and CD30 was observed in 7 follicular adenomas (all belonging to variants different from toxic and hyalinizing trabecular), 2 oncocytic adenomas, 5 of the 30 colloid nodules and 2 normal thyroids. Of the 6 tumors arising from the parafollicular C cells (medullary thyroid cancer, MTC), all 3 that had metastasized were CD30L/CD30/IL-6 positive and IL-6R negative; only IL-6 expression was lost in both the local and distant metastases. This finding matched the loss of IL-6 expression in one PTC metastasis. All 3 non-metastasized MTC were IL-6/IL-6R negative, and 1/3 was CD30L positive/CD30 negative. We conclude that only in a subset of both benign and malignant thyroid nodules the IL-6/IL-6R signal could be induced by the CD30L/CD30. IL-6 expression is related with aggressiveness in both PTC and MTC. In the normal thyroid tissue, colloid nodules, and another subset of benign and malignant thyroid nodules, IL-6 expression is under control of signals other than CD30L/CD30.
authors.affiliation: Section of Endocrinology, Clinical/Experimental Department of Medicine and Pharmacology, University of Messina School of Medicine, Messina, Italy.
authors.forename: R M
authors.initials: RM
authors.lastname: Ruggeri
authors.forename: D
authors.initials: D
authors.lastname: Villari
authors.forename: A
authors.initials: A
authors.lastname: Simone
authors.forename: R
authors.initials: R
authors.lastname: Scarfi
authors.forename: M
authors.initials: M
authors.lastname: Attard
authors.forename: F
authors.initials: F
authors.lastname: Orlandi
authors.forename: G
authors.initials: G
authors.lastname: Barresi
authors.forename: F
authors.initials: F
authors.lastname: Trimarchi
authors.forename: M
authors.initials: M
authors.lastname: Trovato
authors.forename: S
authors.initials: S
authors.lastname: Benvenga
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000737:chemistry; D000236:Adenoma / Q000737:chemistry; D053285:CD30 Ligand; D018276:Carcinoma, Medullary / Q000737:chemistry; D002291:Carcinoma, Papillary / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000032:analysis*; D017730:Ki-1 Antigen / Q000032:analysis*; D008562:Membrane Glycoproteins / Q000032:analysis*; D009362:Neoplasm Metastasis; D019947:Receptors, Interleukin-6 / Q000032:analysis*; D013964:Thyroid Neoplasms / Q000737:chemistry; D016606:Thyroid Nodule / Q000737:chemistry*; D013967:Thyroiditis, Autoimmune / Q000378:metabolism
chemical_list: D053285:CD30 Ligand; D015850:Interleukin-6; D017730:Ki-1 Antigen; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; C505774:TNFSF8 protein, human