title: Multicentric occurrence of multiple papillary thyroid carcinomas--HUMARA and BRAF mutation analysis.
abstract: Papillary thyroid carcinomas (PTCs) occasionally form multiple tumor foci in different sites of the same thyroid gland. However, it is controversial whether discrete nodules of PTC arise independently (multicentric occurrence) or are seeded from a single tumor via lymphatic channels (intraglandular metastasis). In order to determine the clonal origin of multiple PTCs, we examined X-chromosome inactivation patterns using a human androgen receptor gene-based assay (HUMARA) and the BRAF mutation using allele-specific PCR (AS-PCR) in 32 microdissected cancerous tissues from 14 Japanese women with multifocal PTC. All tumor foci were greater than 3 mm in size and met the criteria for microscopic classical PTC. Samples from 13 of the 14 patients were informative based on HUMARA. Tumor foci from two cases (15.4%) displayed a discordant X-chromosome inactivation pattern. Foci from the other 11 cases (84.6%) showed a concordant inactivation pattern of the X-chromosome. AS-PCR indicated that BRAF mutational status between the tumor foci was discordant in three (25%) and concordant in nine (75%) of 12 available cases. When the results of these two molecular analyses were combined, 28.6% of the cases were discordant in X-chromosome inactivation pattern and/or BRAF mutation, suggesting multicentric origin. Some of the remaining concordant cases also may be of multicentric origin. These results support a hypothesis that multicentric occurrence in multiple PTCs may be common, possibly greater than 30%. Although the exact mechanism of multicentric occurrence is still unclear, our findings contribute to the understanding the histogenesis of papillary thyroid carcinoma.
authors.affiliation: Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Nakazawa
authors.affiliation: Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Tahara
authors.affiliation: Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Kasai
authors.affiliation: Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Oishi
authors.affiliation: Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Mochizuki
authors.affiliation: Department of Epigenetic Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katoh
mesh_terms: D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D002291:Carcinoma, Papillary; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D047368:Tumor Burden; D049951:X Chromosome Inactivation
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF mutation; HUMARA; X-chromosome inactivation pattern; clonal analysis; intraglandular metastasis; multicentric occurrence; multiple papillary thyroid carcinoma