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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.

BACKGROUNDAdenoid cystic carcinoma (ACC) is a rare malignancy arising in salivary glands and other sites, characterized by high rates of relapse and distant spread. Recurrent/metastatic (R/M) ACCs are generally incurable, due to a lack of active systemic therapies. To improve outcomes, deeper understanding of genetic alterations and vulnerabilities in R/M tumors is needed.METHODSAn integrated genomic analysis of 1,045 ACCs (177 primary, 868 R/M) was performed to identify alterations associated with advanced and metastatic tumors. Intratumoral genetic heterogeneity, germline mutations, and therapeutic actionability were assessed.RESULTSCompared with primary tumors, R/M tumors were enriched for alterations in key Notch (NOTCH1, 26.3% vs. 8.5%; NOTCH2, 4.6% vs. 2.3%; NOTCH3, 5.7% vs. 2.3%; NOTCH4, 3.6% vs. 0.6%) and chromatin-remodeling (KDM6A, 15.2% vs. 3.4%; KMT2C/MLL3, 14.3% vs. 4.0%; ARID1B, 14.1% vs. 4.0%) genes. TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with both NOTCH1 mutations (q = 3.3 × 10-4) and MYB/MYBL1 fusions (q = 5.6 × 10-3), suggesting discrete, alternative mechanisms of tumorigenesis. This network of alterations defined 4 distinct ACC subgroups: MYB+NOTCH1+, MYB+/other, MYBWTNOTCH1+, and MYBWTTERT+. Despite low mutational load, we identified numerous samples with marked intratumoral genetic heterogeneity, including branching evolution across multiregion sequencing.CONCLUSIONThese observations collectively redefine the molecular underpinnings of ACC progression and identify further targets for precision therapies.FUNDINGAdenoid Cystic Carcinoma Research Foundation, Pershing Square Sohn Cancer Research grant, the PaineWebber Chair, Stand Up 2 Cancer, NIH R01 CA205426, the STARR Cancer Consortium, NCI R35 CA232097, the Frederick Adler Chair, Cycle for Survival, the Jayme Flowers Fund, The Sebastian Nativo Fund, NIH K08 DE024774 and R01 DE027738, and MSKCC through NIH/NCI Cancer Center Support Grant (P30 CA008748).

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: The comparative impact of histologic variants and grade has not been well described. Methods: Salivary cancer histologies were profiled using hospital and population‐based cancer registries. Multivariable models were employed to assess relationships between histology, grade, and survival. Results: On univariate analysis, histologic variants exhibited a wide spectrum of mortality risk (5‐year overall survival (OS): 86% (acinic cell carcinoma), 78% (mucoepidermoid carcinoma), 72% (adenoid cystic carcinoma), 64% (carcinoma ex‐pleomorphic adenoma), 52% (adenocarcinoma NOS), and 47% (salivary duct carcinoma) (p < 0.001). However, on multivariable analysis these differences largely vanished. Worsening grade corresponded with deteriorating survival (5‐year OS: 89% [low‐grade], 81% [intermediate‐grade], 45% [high‐grade]; p < 0.001), which was upheld on multivariable analysis and propensity score matching. Recursive partitioning analysis generated TNM + G schema (c‐index 0.75) superior to the existing system (c‐index 0.73). Conclusion: Grade represents a primary determinant of salivary cancer prognosis. Integrating grade into stage strengthens current staging systems. [ABSTRACT FROM AUTHOR]

Background: Elective neck dissection is a standard of care for pharynx and most larynx cancer patients undergoing surgery, based largely on historical series. It is unclear if this is necessary for all patients in the modern era. Methods: Patients with cN0 oropharynx, larynx, and hypopharynx cancers diagnosed from 2010–2015 undergoing primary surgery were identified in the National Cancer Data Base. Results: Inclusion criteria were met by 4117 cN0 patients. The presence of lymphovascular invasion (LVI) was the strongest independent predictor of pN+ (odds ratio [OR] = 4.19, 95% confidence interval [CI] 3.56–4.93, p < 0.001). Histologic grade strongly predicted pN+ (OR 2.58, 95% CI 1.88–3.59, p < 0.001). A nomogram predicted less than 10% of cN0 patients had pN+ risk <15%. Conclusion: LVI and grade are the strongest predictors of pN+ among patients with cN0 pharynx and larynx cancer. Even in the modern era, pN+ rates warrant neck dissection for cN0 patients. Level of Evidence: 3 Laryngoscope, 133:1660–1666, 2023 [ABSTRACT FROM AUTHOR]