Single thyroid tumour showing multiple differentiated morphological patterns and intramorphological molecular genetic heterogeneity

Schopper, Heather K.; Stence, Aaron A.; Ma, Deqin; Pagedar, Nitin A.; Robinson, Robert A.

doi:10.1136/jclinpath-2016-203821

Cited by 15 publications

(19 citation statements)

References 14 publications

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“…Similar conclusions were made in the report on a case with simultaneous independent papillary and medullary carcinomas [24]. Moreover, distinct morphological components of a composite thyroid carcinoma also had highly different mutational profiles, indicating divergent growth and no clonal association despite the close spatial relationship [28].…”

Section: Discussionsupporting

confidence: 87%

High Genetic Diversity and No Evidence of Clonal Relation in Synchronous Thyroid Carcinomas Associated with Hashimoto’s Thyroiditis: A Next-Generation Sequencing Analysis

et al. 2020

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The close association between pre-existing Hashimoto’s thyroiditis and thyroid cancer is well established. The simultaneous occurrence of multiple neoplastic foci within the same organ suggests a common genotoxic effect potentially contributing to carcinogenesis, the nature of which is still not clear. Next-generation sequencing (NGS) provides a potent tool to demonstrate and compare the mutational profile of the independent neoplastic foci. Our collection of 47 cases with thyroid carcinoma and Hashimoto’s thyroiditis included 14 with at least two tumorous foci. Detailed histological analysis highlighted differences in histomorphology, immunoprofile, and biological characteristics. Further, a 67-gene NGS panel was applied to demonstrate the mutational diversity of the synchronic tumors. Significant differences could be detected with a wide spectrum of pathogenic gene variants involved (ranging between 5 and 18, cutoff >5.0 variant allele frequencies (VAF)). Identical gene variants represented in both synchronous tumors of the same thyroid gland were found in only two cases (BRAF and JAK3 genes). An additional set of major driver mutations was identified at variable allele frequencies in a highly individual setup suggesting a clear clonal independence. The different BRAF statuses in coincident thyroid carcinoma foci within the same organ outline a special challenge for molecular follow-up and therapeutic decision-making.

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Section: Discussionsupporting

confidence: 87%

High Genetic Diversity and No Evidence of Clonal Relation in Synchronous Thyroid Carcinomas Associated with Hashimoto’s Thyroiditis: A Next-Generation Sequencing Analysis

et al. 2020

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“…These discrepancies may be due to the large number of patients in our cohort who had PTC components, as characterised by the presence of BRAF mutations . Because tumour histology can greatly affect intratumour molecular heterogeneity, it is imperative to sample multiple tumour sites for mutational profiling to obtain a conclusive and comprehensive genetic landscape of the tumour …”

Section: Discussionmentioning

confidence: 99%

Mutational profiling of poorly differentiated and anaplastic thyroid carcinoma by the use of targeted next‐generation sequencing

Duan

et al. 2019

Histopathology

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Aims To characterise the mutational profiles of poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) and to identify markers with potential diagnostic, prognostic and therapeutic significance. Methods and results Targeted next‐generation sequencing with a panel of 18 thyroid carcinoma‐related genes was performed on tissue samples from 41 PDTC and 25 ATC patients. Genetic alterations and their correlations with clinicopathological factors, including survival outcomes, were also analysed. Our results showed that ATC had significantly higher mutation rates of BRAF, TP53, TERT and PIK3CA than PDTC (P = 0.005, P = 0.007, P = 0.005, and P = 0.033, respectively). Nine (69%) ATC cases with papillary thyroid carcinoma (PTC) components harboured BRAF mutations, all of which coexisted with a late mutation event (TP53, TERT, or PIK3CA). Nine cases with oncogenic fusion (six RET cases, one NTRK1 case, one ALK case, and one PPARG case) were identified in 41 PDTCs, whereas only one case with oncogenic fusion (NTRK1) was found among 25 ATCs. Moreover, all six cases of RET fusion were found in PDTC with PTC components, accounting for 33%. In PDTC/ATC patients, concurrent TERT and PIK3CA mutations were associated with poor overall survival after adjustment for TNM stage (P = 0.001). Conclusions ATC with PTC components is typically characterised by a BRAF mutation with a late mutation event, whereas PDTC with PTC components is more closely correlated with RET fusion. TERT and concurrent PIK3CA mutations predict worse overall survival in PDTC/ATC patients.

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“…Nevertheless, such heterogeneity detected at the microscopic level does not necessarily reflect the degree of heterogeneity present at the molecular level. Indeed, several studies have confirmed the high intratumour variation in the PTC dissimilarity of each single tumour [25, 26]. …”

Section: Phenotypic and Molecular Heterogeneity Of Tc Subtypesmentioning

confidence: 99%

“…The possible explanations for this variation proposed by the authors included a multiclonal origin of the tumour and that RET rearrangements may constitute a later subclonal event. An interesting case was reported by Schopper et al [26], who analysed a single thyroid tumour that showed a combination of conventional PTC, the follicular variant of PTC, clear-cell PTC, columnar-cell carcinoma, and PDTC. The authors used massively parallel next-generation sequencing (NGS) using a laboratory-developed NGS panel of 8 cancer-related genes ( BRAF , KRAS , HRAS , NRAS , EGFR , PIK3CA , KIT, and PDGFRA ) to analyse each morphological component and metastasis.…”

Section: Phenotypic and Molecular Heterogeneity Of Tc Subtypesmentioning

confidence: 99%

Heterogeneity of Thyroid Cancer

et al. 2018

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There are 5 main histological types of thyroid cancers (TCs): papillary, follicular (also known as differentiated), poorly differentiated, anaplastic (the most aggressive form), and medullary TC, and only the latter arises from thyroid C cells. These different forms of TCs show significant variability, both among and within tumours. This great variation is particularly notable among the first 4 types, which all originate from thyroid follicular cells. Importantly, this heterogeneity is not limited to histopathological diversity only but is also manifested as variation in several genetic and/or epigenetic alterations, the numbers of interactions between the tumour and surrounding microenvironment, and interpatient differences, for example. All these factors contribute to the great complexity in the development of a tumour from cancer cells. In the present review, we summarise the knowledge accumulated about the heterogeneity of TCs. Further research in this direction should help to gain a better understanding of the underlying mechanisms contributing to the development and diversity of TCs, paving the way toward more effective treatment strategies.

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Single thyroid tumour showing multiple differentiated morphological patterns and intramorphological molecular genetic heterogeneity

Cited by 15 publications

References 14 publications

High Genetic Diversity and No Evidence of Clonal Relation in Synchronous Thyroid Carcinomas Associated with Hashimoto’s Thyroiditis: A Next-Generation Sequencing Analysis

High Genetic Diversity and No Evidence of Clonal Relation in Synchronous Thyroid Carcinomas Associated with Hashimoto’s Thyroiditis: A Next-Generation Sequencing Analysis

Mutational profiling of poorly differentiated and anaplastic thyroid carcinoma by the use of targeted next‐generation sequencing

Heterogeneity of Thyroid Cancer

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