Interinstitutional variation in predictive value of the ThyroSeq v2 genomic classifier for cytologically indeterminate thyroid nodules.

BACKGROUND: The ThyroSeq v2 next-generation sequencing assay estimates the probability of malignancy in indeterminate thyroid nodules. Its diagnostic accuracy in different practice settings and patient populations is not well understood. METHODS: We analyzed 273 Bethesda III/IV indeterminate thyroid nodules evaluated with ThyroSeq at 4 institutions: 2 comprehensive cancer centers (n = 98 and 102), a multicenter health care system (n = 60), and an academic medical center (n = 13). The positive and negative predictive values of ThyroSeq and distribution of final pathologic diagnoses were analyzed and compared with values predicted by Bayes theorem. RESULTS: Across 4 institutions, the positive predictive value was 35% (22%-43%) and negative predictive value was 93% (88%-100%). Predictive values correlated closely with Bayes theorem estimates (r2 = 0.84), although positive predictive values were lower than expected. RAS mutations were the most common molecular alteration. Among 84 RAS-mutated nodules, malignancy risk was variable (25%, range 10%-37%) and distribution of benign diagnoses differed across institutions (adenoma/hyperplasia 12%-85%, noninvasive follicular thyroid neoplasm with papillary-like nuclear features 5%-46%). CONCLUSION: In a multi-institutional analysis, ThyroSeq positive predictive values were variable and lower than expected. This is attributable to differences in the prevalence of malignancy and variability in pathologist interpretations of noninvasive tumors. It is important that clinicians understand ThyroSeq performance in their practice setting when evaluating these results.

Crucial parameters in thyroid carcinoma reporting - challenges, controversies and clinical implications.

In the modern era, a pathology report of thyroid carcinoma requires the inclusion of numerous prognostically relevant histopathological features, e.g. the presence and extent of vascular and capsular invasion, extrathyroidal extension, the surgical margin status and the characteristics of nodal metastasis. These pathological features are crucial components of the initial risk stratification to determine the need for completion thyroidectomy and/or postoperative radioactive iodine ablation therapy. The current review aims to summarise the diagnostic criteria, the controversies, the prognostic impacts and the challenges of these pathological characteristics, focusing specifically on the parameters that are incorporated into the American Joint Committee on Cancer (AJCC) staging system, the College of American Pathologists (CAP) reporting template, the American Thyroid Association (ATA) and the National Comprehensive Cancer Network (NCCN) guidelines.

Phase 2 study evaluating the combination of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory thyroid cancer.

BACKGROUND: Patients with recurrent and/or metastatic, radioactive iodine-refractory thyroid carcinoma have limited treatment options. Sorafenib, an oral kinase inhibitor, is approved by the US Food and Drug Administration for the treatment of radioactive iodine-refractory thyroid carcinoma, although it demonstrated low response rates (12.2%) as a single agent in the first-line setting. The objective of the current study was to determine whether adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results. METHODS: In this single-institution, phase 2 study, 36 patients with metastatic, radioactive iodine-refractory thyroid carcinoma of follicular origin received treatment with the combination of oral sorafenib (200 mg twice daily) and intravenous temsirolimus (25 mg weekly). The receipt of prior systemic treatment with cytotoxic chemotherapy and targeted therapy, including sorafenib, was permitted. The primary endpoint was the radiographic response rate. RESULTS: The best response was a partial response in 8 patients (22%), stable disease in 21 (58%), and progressive disease in 1 (3%). Six patients were not evaluable for a response. Patients who had received any prior systemic treatment had a response rate of 10% compared with 38% of those who had not received prior systemic treatment. One of 2 patients with anaplastic thyroid cancer had an objective response. The progression-free survival rate at 1 year was 30.5%. The most common grade 3 and 4 toxicities associated with sorafenib and temsirolimus included hyperglycemia, fatigue, anemia, and oral mucositis. CONCLUSIONS: Sorafenib and temsirolimus appear to be an active combination in patients with radioactive iodine-refractory thyroid carcinoma, especially in patients who received no prior treatment compared with historic data from single-agent sorafenib. Activity is also observed in patients who previously received sorafenib. This regimen warrants further investigation. Cancer 2017;123:4114-4121. © 2017 American Cancer Society.

Higher administered activities of radioactive iodine are associated with less structural persistent response in older, but not younger, papillary thyroid cancer patients with lateral neck lymph node metastases.

BACKGROUND: While radioactive iodine (RAI) adjuvant therapy is commonly recommended for most papillary thyroid cancer patients presenting with large volume nodal involvement, it remains unclear if such therapy impacts the disease-specific recurrence rate and overall survival. In this study, we compared the risk of achieving a structural persistent response after low administered activity (100 mCi), intermediate administered activity (150 mCi), and high administered activity (>200 mCi) RAI adjuvant therapy in patients presenting with pathologic N1b disease. METHODS: This was a retrospective review of 181 papillary thyroid cancer patients with N1b disease treated with total thyroidectomy, neck dissection, and RAI remnant ablation. Dose-response relationships were determined between the administered activity of (131)I and the best response to initial therapy. RESULTS: Out of the 181 patients, only 39% achieved no clinical evidence of disease (NED) after initial therapy. Young patients (Stage I) had a statistically nonsignificant trend toward higher rates of NED with increasing dose (34% low activity, 36% intermediate activity, 46% high activity), but there was no evidence of dose-response effect with regard to the likelihood of having a structural persistent response to initial therapy or the likelihood of having persistent biochemical evidence of disease. However, analysis of the older patients (Stage IVa) did reveal a trend toward statistically significant dose-response relationships with increasing administered activities being associated with lower rates of structural persistent response (46% low activity, 23% intermediate activity, 17% high dose). Unfortunately, the lower rate of structural persistent response only modestly increased the likelihood that patients would be NED but was instead associated with a higher proportion of patients being classified as having biochemical persistent disease at 12-18 months. CONCLUSIONS: It appears that administering more than 100 mCi of RAI as adjuvant therapy in N1b disease is unlikely to improve the initial response to therapy. This is especially true for the younger (Stage I) patients. It is plausible that administered activities of 150-260 mCi may be associated with an improved response to initial therapy in older patients (Stage IVa) who are probably at highest risk of having poor outcomes, but the potential benefit from RAI should be balanced against potential adverse effects in those patients.