A comprehensive effort to assess the prevalence of microsatellite instability in a large series of malignant thyroid tumors comprising all major histologic subtypes has found that the overall prevalence of MSI in follicular thyroid cancer is 2.5%. The study also found that MSI is either entirely absent or rare in other histology subtypes of thyroid carcinoma.
A comprehensive effort to assess the prevalence of microsatellite instability (MSI) in a large series of malignant thyroid tumors comprising all major histologic subtypes has found that the overall prevalence of MSI in follicular thyroid cancer is 2.5%. The study also found that MSI is either entirely absent or rare in other histology subtypes of thyroid carcinoma.
“Tumor MSI status has become more clinically relevant because of the remarkable response of patients with MSI-high (MSI-H) cancers to treatment with PD-1/PD-L1 immune checkpoint inhibitors such as nivolumab and pembrolizumab,” the authors, led by Luke K. Genutis, BS, of The Ohio State University, wrote inThyroid. “Our results…suggest that in some instances, clinical MSI testing and potential use of checkpoint inhibitor therapy should not be overlooked for follicular thyroid cancer patients.”
The authors recruited 301 patients with thyroid cancer at Ohio State University to create an initial sample set. All tumors were histologically confirmed as either papillary, follicular, medullary, or anaplastic thyroid cancer. They assessed these samples for MSI using polymerase chain reaction (PCR)-based detection, and immunohistochemistry of a tissue microarray (TMA).
At The University of Texas MD Anderson Cancer Center, investigators created a validation set of 188 tumor samples from 184 advanced thyroid carcinoma patients. These samples were analyzed by targeted next-generation sequencing (NGS). The authors compared each tumor with matched normal tissue or paired blood, which allowed for germline sequence variants to be excluded in the analysis. They then assessed the tumor samples for MSI using NGS-based detection programs.
In all, the authors screened a total of 485 patients with thyroid cancer for MSI and mismatch repair (MMR) deficiency, using a combination of PCR-based detection, immunohistochemistry, and next-generation sequencing. The samples included all major histologic subtypes, as follows: 195 papillary, 156 follicular, 50 anaplastic, 65 medullary, and 17 poorly differentiated thyroid carcinomas.
In examining a set of 35 follicular thyroid carcinomas, Genutis et al found 2 samples that showed clear instability at multiple microsatellites. No other tumor samples displayed MSI, although 2 anaplastic samples had single base pair insertions or deletion mutations for BAT26.
The investigators assembled an additional 110 follicular thyroid carcinomas tumor samples from a different cohort of patients into a TMA to determine the overall frequency of MSI in follicular thyroid cancer. They then performed immunohistochemistry microscopy for the 4 MMR proteins. They found that 2 of the 110 samples were MMR-deficient. Both samples lacked expression of MSH2 and MSH6.
Genutis et al then turned to the validation set from MD Anderson. Of those 188 thyroid carcinomas, 74 were papillary, 45 were medullary, 37 were anaplastic, 18 were poorly differentiated, 11 were follicular and 3 were Hürthle cell carcinomas. They used their MonoSeq variant caller to determine MSI status in these tumors.
The authors identified 10 samples that they deemed most likely to be MSI-H. Of these, 3 each were papillary and follicular, 2 were anaplastic, and 1 each was medullary and poorly differentiated. “Five of these cases had available paired tumor and normal DNA, and PCR-based MSI detection was performed using the five Bethesda panel microsatellites,” they wrote. “None of these cases showed MSI for any of the assessed markers, making it unlikely that any of the samples in this cohort were MSI-H.”
Thus, out of a total of 156 follicular thyroid carcinomas, 4 (2.5%) showed MSI. No cases of MSI were found in any of the other 327 samples representing other thyroid cancer subtypes. “The MSI-H FTC cases were evaluated for expression of MMR proteins using IHC, and three were deficient in MSH2/MSH6 while the remaining case showed equivocal expression of MLH1/PMS2,” Genutis et al wrote. “Additionally, we show that one of these cases harbored a somatic hemizygous loss-of-function mutation inMSH2.”
Genuti et al closed by noting that their study emphasizes the importance of examining molecular phenotypes in uncommon subtypes of cancers that are not represented well in large datasets.
Genutis LK, Tomsic J, Bundschuh RA, et al. Microsatellite Instability Occurs in a Subset of Follicular Thyroid Cancers.Thyroid. 2019. DOI: 10.1089/thy.2018.0655 [Epub ahead of print]