Original contributionClonal analysis of bilateral, recurrent, and metastatic papillary thyroid carcinomas☆
Introduction
Papillary thyroid carcinoma (PTC) is the most common histotype of thyroid cancer and accounts for about 1% of human malignancies [1]. Patients with PTC generally have a good prognosis, especially in those younger than 45 years at the time of diagnosis [2]. However, about 5% of patients with PTC experience a recurrence within 5 years after the initial treatment [3], [4]. In patients with local or distant recurrence after lobectomy, a tumor is found in more than 60% of the time in the resected contralateral lobe [5], [6]. In addition, PTC is often multifocal, with a reported frequency varying widely from 18% to 87%, among which 61% are bilateral [7], [8].
The clonal origin of multifocal PTC is still under debate. There are 2 different theories to address this issue. One is that these tumors are of monoclonal origin, arising from intrathyroidal metastasis of a clonal population of cells. The other is that the multiple foci are of independent origin and arise separately in a background of field cancerization. Distinguishing between these 2 theories will improve our understanding of both the biological mechanisms of multifocal PTC, as well as the possible reasons why PTC recurs. Several studies have been performed to investigate the clonality of tumors located in the same thyroid lobe with varied results [9], [10], [11], [12], [13]. The clonality of tumors occurring simultaneously in both thyroid lobes or that of recurrent tumors in the contralateral lobe remains unknown.
Previous studies have shown that PTC displays several highly prevalent genetic alterations, like mutations in BRAF or RAS, and rearrangements of the RET or NTRK1; among these alterations, mutations in the BRAF gene (exon 15-BRAFV600E) is the most common [14], [15], [16], [17], [18]. Because of its high prevalence and presumed early place as a genetic event in thyroid carcinogenesis [19], BRAFV600E mutation has been used as a marker for clonality analysis and has shown some advantage in evaluating the clonal origin of multifocal PTCs [12], [13]. However, few studied have combined this mutation with other methods based on changes established early enough to assess the clonality of tumors.
Determination of X-chromosome inactivation (XCI) has also been used to study clonality in many human tumors, including thyroid cancers [20]. According to the Lyon [21] hypothesis, 1 of the 2 X-chromosomes in all female somatic cells is randomly deactivated by the DNA methylation at CpG islands during early embryogenesis. Once established, the inactivated X-chromosome is stably transmitted from a parent cell to its progeny. Therefore, a given group of cells resulting from clonal expansion of a single progenitor shows the same pattern of XCI. Distinguishing the patterns of XCI permits investigators to determine whether multiple tumors in female subjects arise from one or more progenitors.
In this study, we investigated the clonality of bilateral PTCs (synchronous or metachronous) and metastatic lymph nodes by assaying for the presence or absence of the BRAF mutation. We also examined the XCI status in separate tumors in female patients. By combining the 2 strategies, genotypic clonality (BRAF mutations, involved in the malignant transformation) and phenotypic clonality (XCI, established in early embryogenesis), we reasoned that we could provide more definitive answers as to clonality in multifocal or recurrent PTCs.
Section snippets
Case selection and tumor specimen collection
A computer-based database comprising 809 patients was established to select eligible cases. These patients were admitted to the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China), from 1997 to 2006 and underwent thyroidectomy for the treatment of thyroid carcinoma, with or without neck lymph node dissection. A list of cases was generated according to the following criteria: (a) bilateral or recurrent PTCs (including both primary and recurrent tumors) were
Clinical features of the study group
A total of 66 tumors from 25 patients (female, 18; male, 7) were analyzed in this study, among which 51 were bilateral tumors and 15 were metastatic lymph nodes. Twenty-two pairs were synchronous, whereas 3 pairs were metachronous (ie, recurrent, shown in Table 1). The mean age at diagnosis was 42.2 years (range, 14-75 years), and the median diameter of the studied tumors was 2.2 cm (range, 0.3-9.4 cm). Of the 3 recurrent PTCs, both the primary and recurrent tumors were studied; and the
Discussion
Multifocality is frequently observed in patients of PTC, with an increased risk of lymph node metastases and regional recurrence [7], [30]. However, as a specific subtype of multifocal PTCs, bilateral PTC has not been widely investigated. Studies of this subtype were just restricted to clinical observations [5], [6], [30], and the clonal origin of bilateral tumors remains unknown.
Most clonality studies on PTCs were done on multiple tumors located in one thyroid lobe [10], [12]. Only a few
Acknowledgment
We thank Ruokuo Han, Ruopeng Weng, and Zonglin Lin for patients' clinical follow-up, and Qixing Chen and Feng Zhang for technical assistance. We are also grateful to Dr Robert Wohlhueter (Centers for Disease Control and Prevention, Atlanta, GA; retired) for his contributions to the preparation of the manuscript.
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Funding support: This study was supported by National Basic Research Program of China (973 Program, No. 2009CB521704) from the Ministry of Science and Technology of the People's Republic of China (Beijing, China).