Specialty Thyroid Laboratory: Carole Spencer’s University of Southern California Thyroid Cancer Laboratory

Thyroid cancer: TERT promoter mutations negatively impact survival

TERT is one of the markers included in the ThyroSeq2 molecular marker test for indeterminate thyroid needle biopsy results.

Telomerase reverse transcriptase (TERT) promoter mutations are associated with decreased survival of patients with thyroid cancer.

Key results
TERT promoter mutations were associated with extrathyroidal invasion (P=.01), higher stage (P<.001), and histological type (P=.001).
TERT promoter mutations were associated with decreased 10 y OS of patients with differentiated thyroid cancer (66.2% vs 98.3%, HR, 7.18; 95% CI, 2.77-18.59; P<.001) and patients with papillary thyroid cancer (74.2% vs 99.3%, HR, 14.20; 95% CI, 3.03-66.68; P=.001).
TERT promoter mutations were associated with decreased 10y overall survival in patients with BRAF mutations (82.6% vs 99.4%, HR, 5.62; 95% CI, 1.85-17.09; P=.002).

Study design: 409 patients with thyroid cancer were analyzed for associations betweenTERT mutation status, clinicopathologic features, and survival

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GENE CLASSIFIER

A gene expression classifier test has a poor positive predictive value for malignancy in thyroid nodules with atypia of undetermined significance; however, a second consecutive gene expression classifier test yielded a higher positive predictive value.

Repeat fine-needle aspiration (FNA) for thyroid nodules with atypia of undetermined significance (AUS) is recommended instead of moving directly to gene expression classifier (GEC) testing, according to researchers.

Carmen V. Villabona, MD, of the department of endocrinology, Cleveland Clinic Florida in Weston, Florida, and colleagues evaluated 119 patients who underwent FNA of thyroid nodules larger than 1 cm with AUS identified from 2012 to 2014. Researchers sought to determine the clinical validity and utility of GEC for evaluation of AUS cytology as well as the performance of ultrasound for predicting malignancy when a nodule is identified as AUS.

Based on initial cytopathology, 48 nodules were sent for GEC, and 27 were classified as GEC suspicious for malignancy. Surgery was performed in 21 of the cases, and had thyroid cancer on histopathology. In 71 cases with AUS cytology on initial FNA, GEC was not performed and patients were sent for a second FNA; 19 of nodule were identified as benign and 52, ranging from 1 to 4 cm in size, were still reported as AUS.

Fourteen (27%) of the cases with reported AUS after second FNA were classified as GEC benign; four had surgical follow-up and three of those were confirmed benign and one malignant. Thirty-eight (73%) of the cases were reported as GEC suspicious for malignancy; 35 underwent, and 32 were confirmed as malignant. A sensitivity of 96% was yielded with GEC correctly identifying 32 of the 35 malignant samples.

There was a positive predictive value of 92% for malignancy for nodules designated AUS on second evaluation that were hypoechoic and solid on ultrasound.

“Our data suggests that proceeding directly to surgery after two AUS cytologies for nodules that are solid and hypoechoic is a reasonable practice given a high yield for malignancy,” the researchers wrote. “Additional assessment with GEC would be helpful in nodules not having these ultrasound characteristics to better exclude malignancy. Also being more cost effective, we suggest repeating a biopsy rather than conducting GEC.

This study also yielded another clinically important finding that thus far has only been reported once previously: the fact that GEC testing was far less specific in the 31 Hurthle-cell predominant nodules (HCNs) identified (13% of the total).

The presence of Hurthle-cell predominance was the only clinical factor that influenced GEC test performance and was associated with an increased rate of GEC-suspicious results despite a relatively low malignancy rate: 77.4% of HCNs had GEC-suspicious results vs just 54.0% of non-HCNs (P < .01), but the actual malignancy rate was 22.6%, similar to the 25.6% in non-HCNs.

These findings confirm those of one prior study of GEC test performance in 72 patients with HCNs, finding that a suspicious GEC did not increase the probability of malignancy in HCNs, with a specificity of only 7.5%.

In that study and the current one, a GEC benign result was almost always a true negative and could allow the patient to avoid surgery, but that was of minimal help because most GEC results for HCNs were suspicious.

So although the majority of HCNs test suspicious on GEC, most turn out to be benign.

This suggests that GEC testing may not be cost-effective in nodules identified as HCN on biopsy, Dr Wu and colleagues say.

“This is important for clinicians to know, so when we get the results we can more appropriately counsel the patient. . . . I can’t imagine that [routine] GEC [testing] can be cost-effective in Hurthle cells. The test is quite expensive and probably doesn’t add that much,” Dr Livhits commented.

The size of a thyroid nodule does not appear to affect gene expression classifier (GEC) test performance, a new study suggests.

GEC, or molecular, testing is a relatively new technology introduced to try to characterize the risk of malignancy in thyroid nodules that are deemed ‘indeterminate’ following ultrasound and biopsy.

And there has been a concern, from prior studies, suggesting potential sampling error with use of GEC tests in nodules larger than 4 cm, explain James X Wu, MD, and colleagues at the University of California, Los Angeles (UCLA) David Geffen School of Medicine, in their article published in the July 2016 issue of Thyroid.

But in the 231 patients with 245 indeterminate nodules that they studied, all from a single tertiary referral center, the negative predictive value of GEC testing did not differ by nodule size.

“I think this is somewhat reassuring that if you have a patient with a larger nodule with a negative molecular test and the patient prefers to avoid surgery and has no other risk factors, it’s something you can discuss with them,” senior investigator Masha J Livhits, MD, told Medscape Medical News.

She stressed, however, that although the study shows that a benign GEC test provides some reassurance regardless of nodule size, other factors still need to be considered in deciding whether to send the patient for surgery.

“There’s still a lot of clinical judgement based on what the ultrasound looks like. If it looks suspicious, it doesn’t matter what the molecular testing result is, or if it’s a rapidly enlarging nodule or a patient with personal risk factors. . . . The clinical judgement is very important, maybe more important even than the molecular testing results.”

Even Benign thyroid nodules by cytology have a chance to still be cancer.

780 cytology benign nodules were tested for molecular markers. 73 had molecular markers BRAF (39) RAS (33) RET/PTC (1). 52 cancers were removed, and 24 had markers. Only 50% had markers but all that had markers had cancer. It is strongly pointed to cancer when positive but can be less valuable if negative as 50% of the cancers had no markers.

52/780 (6.6 %) nodules first thought to be cytologically benign had cancer, of which half had molecular markers for cancer.

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