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Background: Cytopathological evaluation of thyroid fine-needle aspiration biopsy (FNAB) specimens can fail to raise preoperative suspicion of medullary thyroid carcinoma (MTC). The Afirma RNA-sequencing MTC classifier identifies MTC among FNA samples that are cytologically indeterminate, suspicious, or malignant (Bethesda categories III-VI). In this study we report the development and clinical performance of this MTC classifier. Methods: Algorithm training was performed with a set of 483 FNAB specimens (21 MTC and 462 non-MTC). A support vector machine classifier was developed using 108 differentially expressed genes, which includes the 5 genes in the prior Afirma microarray-based MTC cassette. Results: The final MTC classifier was blindly tested on 211 preoperative FNAB specimens with subsequent surgical pathology, including 21 MTC and 190 non-MTC specimens from benign and malignant thyroid nodules independent from those used in training. The classifier had 100% sensitivity (21/21 MTC FNAB specimens correctly called positive; 95% confidence interval [CI] = 83.9-100%) and 100% specificity (190/190 non-MTC FNAs correctly called negative; CI = 98.1-100%). All positive samples had pathological confirmation of MTC, while all negative samples were negative for MTC on surgical pathology. Conclusions: The RNA-sequencing MTC classifier accurately identified MTC from preoperative thyroid nodule FNAB specimens in an independent validation cohort. This identification may facilitate an MTC-specific preoperative evaluation and resulting treatment.

Objective: To characterize malpractice trends related to active surveillance (AS) as a treatment strategy across cancers. Background: Active surveillance is increasingly considered a viable management strategy for low-risk cancers. Since a subset of AS cases will progress, metastasize, or exhibit cancer-related mortality, a significant barrier to implementation is the perceived risk of litigation from missing the window for cure. Data on malpractice trends across cancers are lacking. Methods: Westlaw Edge and LexisNexis Advance databases were searched from 1990 to 2022 for malpractice cases involving active surveillance in conjunction with thyroid cancer, prostate cancer, kidney cancer, breast cancer, or lymphoma. Queries included unpublished cases, trial orders, jury verdicts, and administrative decisions. Data were compiled on legal allegations, procedures performed, and verdicts or settlements rendered. Results: Five prostate cancer cases were identified that pertained to active surveillance. Two cases involved alleged deliberate indifference from AS as a management strategy but were ruled as following the appropriate standard of care. In contrast, 3 cases involved alleged physician negligence for not explicitly recommending AS as a treatment option after complications from surgery occurred. All cases showed documented informed consent for AS, leading to defense verdicts in favor of the physicians. No cases of AS-related malpractice were identified for other cancer types. Conclusions: To date, no evidence of successful malpractice litigation for active surveillance in cancer has been identified. Given the legal precedent detailed in the identified cases and increasing support across national guidelines, active surveillance represents a sound management option in appropriate low-risk cancers, with no increased risk of medicolegal exposure. [ABSTRACT FROM AUTHOR]

Background: With innovative treatment options such as radiofrequency ablation (RFA) for thyroid nodules, new complications are being identified. It is important to define and delineate complications in order to counsel patients appropriately about treatment options and their associated risks and benefits. Methods: A 46‐year‐old male presented with a left thyroid nodule (6.5 cm). Fine needle aspiration results were benign. He started to develop intermittent dyspnea and underwent one RFA procedure. Approximately 6 days post‐RFA, the neck area was raised and red with blister. The skin overlying the blister underwent eventual dehiscence with fluid spillage. Several months later, MRI imaging showed substernal extension with tracheal deviation. Results: A left thyroid lobectomy was performed with cutaneous excision and successful closure of a fistula. Conclusions: This is the first reported case of a thyroid nodule rupture following RFA which manifested into a thyro‐cutaneous fistula and required surgical intervention. [ABSTRACT FROM AUTHOR]

Background: While numerous factors determine prognosis in papillary thyroid carcinoma (PTC), distant metastasis (M1) represents one of the most dire. Escalating nodal burden and aggressive histology may contribute to higher metastatic risk, but this relationship is poorly defined and challenging to anticipate. We evaluate the predictive impact of these histological features on predicting distant metastases at initial presentation. Methods: Univariate and multivariable logistic regression models of conventional and aggressive thyroid cancer variants (well-differentiated papillary thyroid carcinoma [WDPTC], diffuse sclerosing variant [DSV], tall cell variant [TCV], poorly differentiated thyroid cancer [PDTC], and anaplastic thyroid carcinoma [ATC]) identified via U.S. cancer registry data were constructed to determine associations between M1 status and quantitative nodal burden. Associations between metastatic lymph node (LN) number and M1 disease were modeled using univariate and multivariable logistic regression with interaction terms, as well as a linear continuous probability model. Results: Overall, M1 prevalence at disease presentation was 3.6% (n = 1717). When stratified by subtype, M1 prevalence varied significantly by histology (WDPTC [1.0%], DSV [2.3%], TCV [4.1%], PDTC [17.4%], ATC [38.4%] [p < 0.001]). For WDPTC, M1 prevalence escalated with metastatic LN number (0 LN+ [0.5%], 1–5 LN+ [2.0%], 6–10 LN+ [3.4%], >10 LN+ [5.5%] [p < 0.001]) and LN ratio (p < 0.001). A statistically significant interaction was observed between histology and increasing nodal burden for M1 risk. On multivariable analysis, each successive metastatic LN conferred increased M1 risk for WDPTC (odds ratio [OR] 1.06 [1.05–1.08], p < 0.001) and TCVs (OR 1.04 [1.02–1.07], p < 0.001). In contrast, other aggressive variants had a higher baseline M1 risk, but this did not vary based on the number of positive LN (DSV, OR 1.02 [0.95–1.10], p = 0.52; PDTC, OR 1.00 [0.98–1.02], p = 0.66; ATC, 1.00 [0.98–1.02], p = 0.97). Conclusions: Progressive nodal burden independently escalates the risk of distant metastasis in WDPTC and TCVs of PTC. Conversely, aggressive variants such as PDTC and ATC have substantial M1 risk at baseline and appear to be minimally affected by metastatic nodal burden. Consideration of these factors after surgery may help tailor clinical decision-making for treatment and surveillance. Further studies are warranted to calibrate the ideal management approach for these higher risk patient groups. [ABSTRACT FROM AUTHOR]

Background: Flexible fiberoptic laryngoscopy is performed prior to thyroid surgery to evaluate the function of the recurrent laryngeal nerve. We assess the cost‐effectiveness of preoperative laryngoscopy prior to total thyroidectomy for a low‐risk thyroid cancer patient without dysphonia. Methods: A decision tree analysis was performed from a third‐party payer perspective. We assessed the cost‐effectiveness of fiberoptic laryngoscopy prior to total thyroidectomy for T2N0M0 papillary thyroid carcinoma, such that an ipsilateral vocal fold paralysis alters the surgical plan to hemi‐thyroidectomy, when permissible, to avoid the risk of bilateral vocal fold paralysis. Results: Performing preoperative laryngoscopy to assess vocal fold function has an incremental cost‐effectiveness ratio (ICER) of 45 193 USD/QALY compared to no laryngoscopy. At a willingness‐to‐pay of 100 K/QALY, the intervention is cost‐effective if the incidence of vocal fold paralysis is at least 0.57%, or when the permissible rate of hemithyroidectomy in cases of incidental paralysis is at least 41%. Probabilistic sensitivity analysis shows that laryngoscopy is cost‐effective in 90.9% of cases. Conclusions: Fiberoptic laryngoscopy is a cost‐effective prior to total thyroidectomy in asymptomatic, low‐risk thyroid cancer patients. [ABSTRACT FROM AUTHOR]

Background: Active surveillance is established as an alternative to surgery for papillary thyroid microcarcinomas, but inclusion criteria and mortality risk for pursuing a nonsurgical approach have not been clearly defined. To gauge the feasibility of expanding active surveillance thresholds, we investigated the effects of increasing size and age on disease-specific survival (DSS) in a large nonoperative thyroid cancer cohort, compared against a matched group of surgical patients. Methods: Papillary thyroid carcinoma patients staged T1-4N0M0 were identified in the Surveillance, Epidemiology, and End Results (SEER) database between 1975 and 2015, stratified by nonsurgical and surgical management. Propensity score matching was performed to adjust for imbalances in covariates. Multivariable models were constructed using restricted cubic splines to model nonlinear relationships of age and tumor size with DSS. Results: Overall, 1453 nonoperative patients and 54,718 surgical patients met the inclusion criteria. Collectively, increasing age and size after certain thresholds independently led to greater differences in DSS between nonsurgical and surgical patients. For younger ages (14–55 years), surgical approach compared with nonsurgical approach was not associated with any difference in the 10-year DSS among 0–4 cm cancers (99.8% vs. 100%, p = 0.470), 4.1–6 cm cancers (98.8% vs. 100%, p = 0.599), or >6 cm cancers (97.3% vs. 100%, p = 0.718). Older patients with larger tumors (>75 years, >6 cm) demonstrated the greatest difference in DSS (48.1% vs. 91.3%, p < 0.001). Similar results were found when applying propensity score matching. For age, restricted cubic spline plots showed minimal relative survival hazard in nonoperative cases beginning after age 60 years, with a change point illustrating acceleration in relative hazard beyond age 72 years. For size, relative survival hazard was observed after 2.0 cm and increased slowly with nodule growth up to an inflection point of 4.5 cm. Beyond this, mortality risk escalated with each additional year without plateau. Conclusions: Increasing age and size lead to progressively greater mortality risk without surgery, but only beyond certain thresholds. We define escalating gradients at which a nonsurgical approach may be deemed appropriate, and beyond which survival benefits from surgery become apparent. Such findings reconcile controversial observations regarding age and size in active surveillance and further reshape evolving treatment paradigms in thyroid cancer. [ABSTRACT FROM AUTHOR]

It begs the question that physicians and patients increasingly face for many of their low-risk patients: is surgery needed at all? Perhaps one of the most controversial topics in thyroid cancer is the extent of surgery. Perhaps most encouragingly, it is important to acknowledge that progression is not a surrogate indicator for death, but merely a proxy for surgery: all patients who went on to delayed surgery did well. [Extracted from the article]

Background: The Afirma gene expression classifier (GEC) assesses malignancy risk in patients with indeterminate thyroid nodules. Afirma putatively reduces costs by classifying certain nodules as benign and thereby avoiding unnecessary surgery. Prior studies have evaluated its impact exclusively on GEC-tested nodules. The objective of the current study was to analyze the effect of Afirma on 1) cytopathology diagnosis, 2) the rate of surgery, and 3) the rate of malignancy on all indeterminate nodules at a high-volume thyroid center.Methods: A retrospective cohort analysis of indeterminate (Bethesda III/IV) thyroid nodules from 2012 through 2014 was performed. Cases were evaluated from January 2012 to July 2013 (pre-Afirma), and from July 2013 to December 2014 (post-Afirma).Results: Of 4292 fine-needle aspirations (FNAs) performed, 13.2% were classified as indeterminate. The GEC was used in 45.3% of post-Afirma cases, with the GEC-Benign call rate at 37.1%. In comparing pre-Afirma and post-Afirma cohorts, a significant increase in Bethesda III (10.7% vs 13.4%; P<.005) and Bethesda IV (1.8% vs 2.9%; P<.01) rates were observed. Conversely, the incidence of Bethesda II was found to be significantly decreased (74.6% vs 68.8%; P<.001). The rate of surgery did not change significantly between pre-Afirma and post-Afirma cohorts (37.7% vs 45.1%; P = .11), nor did the malignancy rate (25.3% vs 36.0%; P = .12).Conclusions: The incidence of indeterminate FNA diagnoses significantly increased after Afirma became routinely available, whereas the incidence of benign diagnoses significantly decreased. These data suggest that Afirma may shift FNA interpretation toward Bethesda III/IV, in which molecular testing is used. Moreover, the institutional rates of surgery and malignancy did not appear to change, raising uncertainty regarding the benefits of molecular assay risk stratification. Afirma may produce unintended collateral effects, increasing the number of indeterminate FNA diagnoses while not affecting the institutional thyroidectomy rate or malignancy yield. Cancer Cytopathol 2016;124:722-8. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Survival rates are commonly used to measure success in treating cancer, but can be misleading. Modern diagnostic practices can lead to the appearance of improving cancer survival, as tumors are diagnosed earlier (lead-time bias) or as an increasing proportion are slow-growing (length bias), whereas the actual burden of cancer deaths is unchanged. Increasingly, more subclinical thyroid cancers are being diagnosed. The objective of the current study was to determine whether thyroid cancer survival rates have been affected by this phenomenon. METHODS The authors analyzed survival data from patients with thyroid cancer who were treated at Memorial Sloan Kettering Cancer Center (MSKCC) from 1950 to 2005, and United States population-based incidence, prevalence, and survival data from 1973 to 2009 in the Surveillance, Epidemiology, and End Results data set. RESULTS US thyroid cancer incidence has increased 3-fold from 1975 to 2009. Over time, the proportion of thyroid cancers that are subcentimeter in size has increased from 23% (1983) to 36% (2009). At MSKCC, this percentage rose from 20% (1950) to 35% (2005). The incidence rates of large tumors (>6 cm) and distant metastasis have not changed. In the United States, 10-year relative survival improved from 95.4% to 98.6% (1983-1999). At MSKCC, 10-year disease-specific survival improved from 91.1% to 96.1% (1950-2005). However, when stratified by tumor size and stage, no changes in survival outcomes were observed. US thyroid cancer mortality rates have remained stable (1975-2009). CONCLUSIONS Modern medical practices increasingly uncover small, asymptomatic thyroid cancers. Survival rates appear improved, but this finding is spurious, attributable instead to shifts in the characteristics of disease being diagnosed. Relying on survival rates to measure success in treating thyroid cancer may reinforce inappropriately aggressive management. Treatment decisions in thyroid cancer should be made based on mortality, not survival data. Cancer 2015;121:1793-1799. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The Bethesda System for Reporting Thyroid Cytopathology is the standard for interpreting fine needle aspiration (FNA) specimens. The 'atypia of undetermined significance/follicular lesion of undetermined significance' (AUS/FLUS) category, known as Bethesda Category III, has been ascribed a malignancy risk of 5-15%, but the probability of malignancy in AUS/FLUS specimens remains unclear. Our objective was to determine the risk of malignancy in thyroid FNAs categorized as AUS/FLUS at a comprehensive cancer center. Methods: The management of 541 AUS/FLUS thyroid nodule patients treated at Memorial Sloan-Kettering Cancer Center between 2008 and 2011 was analyzed. Clinical and radiologic features were examined as predictors for surgery. Target AUS/FLUS nodules were correlated with surgical pathology. Results: Of patients with an FNA initially categorized as AUS/FLUS, 64.7% (350/541) underwent immediate surgery, 17.7% (96/541) had repeat FNA, and 17.6% (95/541) were observed. Repeat FNA cytology was unsatisfactory in 5.2% (5/96), benign in 42.7% (41/96), AUS/FLUS in 38.5% (37/96), suspicious for follicular neoplasm in 5.2% (5/96), suspicious for malignancy in 4.2% (4/96), and malignant in 4.2% (4/96). Of nodules with two consecutive AUS/FLUS diagnoses that were resected, 26.3% (5/19) were malignant. Among all index AUS/FLUS nodules (triaged to surgery, repeat FNA, or observation), malignancy was confirmed on surgical pathology in 26.6% [CI 22.4-31.3]. Among AUS/FLUS nodules triaged to surgery, the malignancy rate was 37.8% [CI 33.1-42.8]. Incidental cancers were found in 22.3% of patients. On univariate logistic regression analysis, factors associated with triage to surgery were younger patient age ( p<0.0001), increasing nodule size ( p<0.0001), and nodule hypervascularity ( p=0.032). Conclusions: In patients presenting to a comprehensive cancer center, malignancy rates in nodules with AUS/FLUS cytology are higher than previously estimated, with 26.6-37.8% of AUS/FLUS nodules harboring cancer. These data imply that Bethesda Category III nodules in some practice settings may have a higher risk of malignancy than traditionally believed, and that guidelines recommending repeat FNA or observation merit reconsideration. [ABSTRACT FROM AUTHOR]