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Background: Fluorine 18-labelled tetrafluoroborate ([ 18 F]TFB) is a substrate for the sodium/iodide symporter. In thyroid cancer, [ 18 F]TFB-PET/CT may be an alternative to iodine imaging to evaluate the extent of disease, eligibility for radioiodine treatment, and success of redifferentiation therapies. We report the results of a pilot study to determine tumor uptake of [ 18 F]TFB and compare its properties to [ 124 I]IodinePET/CT in patients with metastatic thyroid cancer., Methods: Five patients were included in a prospective study. All patients received PET/CT 1 h after injection of 356 ± 12 MBq [ 18 F]TFB and were given 230 ± 9 MBq [ 124 I]Iodine orally on the same day, followed by PET/CT after 48 h. Before redifferentiation therapy, patients underwent an additional baseline [ 124 I]Iodine PET/CT. Cases were analyzed by two board-certified specialists. Detection rates and Spearman correlation for [ 18 F]TFB and [ 124 I]Iodine were calculated., Results: Three patients had poorly differentiated thyroid cancer and received trametinib in a redifferentiation trial. Two patients had papillary thyroid cancer and did not receive redifferentiation therapy. Of the 33 lesions seen before/without redifferentiation therapy, 19 (58%) were visible on [ 18 F]TFB and 30 (91%) on [ 124 I]Iodine imaging. In the patients who underwent redifferentiation therapy, 48 lesions were newly seen on [ 124 I]Iodine PET/CT with a median SUV max of 3.3 (range, 0.4-285.0). All of these lesions were [ 18 F]TFB-negative., Conclusion: [ 18 F]TFB failed to predict radioactive iodine uptake in patients with poorly differentiated thyroid cancer who underwent redifferentiation therapy with trametinib. It is unclear whether such discrepancies may also occur in other redifferentiation therapies or may even be encountered in redifferentiation-naïve thyroid cancer., Trial Registration Number: NCT03196518, registered on June 22, 2017., (© 2024. The Author(s).)

While high-risk human papillomavirus (HPV) serves as an essential pathogen and an important prognostic and predictive biomarker for oropharyngeal squamous cell carcinoma, it occurs at low frequency (2.2-6%) in oral cavity squamous cell carcinoma (OCSCC). To date, the pathologic features of HPV-associated OCSCC (HPV( +)-OCSCC) have been sparsely reported and its prognosis is not well-defined. We herein described detailed clinicopathologic features and outcomes of a retrospective series of 27 HPV( +)-OCSCC, including 13 from Memorial Sloan Kettering Cancer Center (MSKCC) and 14 from The Cancer Genomic Atlas program (TCGA). The frequency of HPV positivity in OCSCC was 0.7% in MSKCC cohort and 4.9% in TCGA cohort. Although HPV( +)-OCSCC was predominantly non-keratinizing (in 81%) with various degree of maturation, its histologic spectrum was expanded to include keratinizing subtype (19%), adenosquamous carcinoma (7%), and papillary architecture (subtype, 7%). HPV( +)-OCSCC predominantly affected male patients (male:female ratio = 12.5:1) and (ex) smokers (77%). It might occur in mandibular mucosa, floor of mouth, tongue, retromolar trigone, buccal mucosa, maxillary mucosa, or hard palate. In oral cavity, positivity of HPV by RNA in situ hybridization was required, and p16 immunohistochemistry alone was insufficient to confirm the HPV + status. The positive predictive value of p16 immunopositivity in detecting HPV infection was 68%. HPV-positivity did not appear to affect outcomes, including disease specific survival and progression free survival in OCSCC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

EIF1AX mutation has been identified as a driver mutation for papillary thyroid carcinoma (PTC) by The Cancer Genome Atlas (TCGA) study. Subsequent studies confirmed this mutation in PTC and Anaplastic Thyroid Carcinoma (ATC) but also reported EIF1AX mutation in Follicular nodular disease (FND) and benign thyroid nodules. In this study, we review thyroid nodules with EIF1AX mutation from two institutions: a tertiary care hospital (YNHH, n = 22) and a major cancer referral center (MSKCC, n = 34) and report the varying histomorphology in the context of additional genetic abnormalities and institutional practices. Pathology diagnoses were reviewed according to the WHO 5th edition and correlated with the type of EIF1AX mutation and additional concurrent molecular alterations, if any. Most cases were splice site type mutations. Cases consisted of 9 FND, 7 follicular (FA) or oncocytic adenomas (OA), 2 non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) and 38 follicular-cell derived thyroid carcinomas. Of 8 cases with isolated EIF1AX mutation, 7 were FND, FA or OA (88%) and one was an oncocytic carcinoma (12%). Of 12 cases with EIF1AX and one additional molecular alteration, 9 (75%) were FND, FA or OA, 2 (17%) were NIFTPs and one (8%) was a poorly differentiated thyroid carcinoma. All 36 cases with EIF1AX mutation and ≥ 2 molecular alterations were malignant (100%) and included TP53 and TERT promoter mutations associated with ATC (n = 8) and high-grade follicular cell-derived non-anaplastic carcinoma (HGC, n = 2). Isolated EIF1AX mutation was noted only in thyroid nodules seen at YNHH and were predominantly encountered in benign thyroid nodules including FND. Accumulation of additional genetic abnormalities appears to be progressively associated with malignant tumors., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon-inclusion events included vinculin (VCL), tenascin C (TNC) and CD44. Knockdown of the VCL exon inclusion transcript in RBM10 -null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon-inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10 -null cells. Mouse Hras G12V /Rbm1O KO thyrocytes develop metastases that are reversed by RBM10 or by combined knockdown of VCL, CD44 and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusions in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFkB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers., Competing Interests: J.A.F. is a co-inventor of intellectual property focused on HRAS as a biomarker for treating cancer using tipifarnib which has been licensed by MSK to Kura Oncology. J.A.F. received prior research funding from Eisai and was a former consultant for LOXO Oncology, both unrelated to the current manuscript. B.R.U. and J.A.K are co-inventors of intellectual property (HRAS as a biomarker of tipifarnib efficacy) that has been licensed by MSK to Kura Oncology. O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder. O.A.-W. has received prior research funding from H3B Biomedicine, Nurix Therapeutics, Minovia Therapeutics, and LOXO Oncology unrelated to the current manuscript. R.K.B. is an inventor on patent applications filed by Fred Hutchinson Cancer Center related to modulating splicing for cancer therapy. R.K.B. and O.A.-W. are founders and scientific advisors of Codify Therapeutics, hold equity in this company and receive research support from this company unrelated to the current manuscript. R.K.B. is a founder and scientific advisor of Synthesize Bio and holds equity in this company. A.R.G is currently an Associate Professor of Surgery at the University of Sydney, Australia. M.S. is currently employed by Loxo Oncology.The remaining authors declare no competing interests.

Background: Craniofacial osteosarcomas (CFOS) are uncommon malignant neoplasms of the head and neck with different clinical presentation, biological behavior and prognosis from conventional osteosarcomas of long bones. Very limited genetic data have been published on CFOS., Methods: In the current study, we performed comprehensive genomic studies in 15 cases of high-grade CFOS by SNP array and targeted next generation sequencing., Result: Our study shows high-grade CFOS demonstrate highly complex and heterogenous genomic alterations and harbor frequently mutated tumor suppressor genes TP53, CDKN2A/B, and PTEN, similar to conventional osteosarcomas. Potentially actionable gene amplifications involving CCNE1, AKT2, MET, NTRK1, PDGFRA, KDR, KIT, MAP3K14, FGFR1, and AURKA were seen in 43% of cases. GNAS hotspot activating mutations were also identified in a subset of CFOS cases, with one case representing malignant transformation from fibrous dysplasia, suggesting a role for GNAS mutation in the development of CFOS., Conclusion: High-grade CFOS demonstrate highly complex and heterogenous genomic alterations, with amplification involving receptor tyrosine kinase genes, and frequent mutations involving tumor suppressor genes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The current edition of the World Health Organization (WHO) classification of endocrine tumors introduced grading for follicular cell-derived thyroid cancer. Tumors with necrosis and/or high mitotic count but not fulfilling the Turin criteria for poorly differentiated carcinoma will be reclassified as differentiated high-grade thyroid carcinoma (DHGTC). However, the impact of this reclassification has not been evaluated. In this study, we performed a systematic review and meta-analysis to estimate the prevalence of this new entry across thyroid tumor subtypes. Methods: In this systematic review and meta-analysis, studies reporting data on necrosis and/or mitoses in well-differentiated thyroid carcinoma (WDTC) were used to estimate the prevalence of DHGTC. Heterogeneity and potential publication bias were also evaluated. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed, and quality assessment was performed using a modification of the Newcastle-Ottawa scale. The study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO, ID: CRD42022378716). Results: In clinically unselected patients, the prevalence of DHGTC in WDTC was 0.072 [95% confidence interval, CI, = 0.045-0.113]. The proportion of high-grade tumors greatly varied across growth patterns and subtypes. Overall, the prevalence of DHGTC was higher in follicular thyroid carcinoma (FTC; 0.146 [CI = 0.101-0.205]) than in papillary thyroid carcinoma (PTC; 0.059 [CI = 0.036-0.097]). Diffuse sclerosing, follicular, and classic subtype PTC had the lowest rates of high-grade features (i.e., 0.018 [CI = 0.004-0.084]; 0.036 [CI = 0.010-0.124]; and 0.042 [CI = 0.027-0.066], respectively), while a greater proportion of solid trabecular and histologically aggressive PTC could be reclassified as DHGTC (i.e., 0.154 [CI = 0.067-0.314] and 0.168 [CI = 0.108-0.252], respectively). Similar proportions were obtained for minimally and widely invasive FTC (i.e., 0.136 [CI = 0.058-0.287] and 0.152 [CI = 0.086-0.254], respectively). Finally, in a cohort of patients with poor prognosis (i.e., fatal cases, metastatic and radioiodine resistant tumors, cases with biochemical recurrence), the proportion of DHGTC was 0.287 [CI = 0.155-0.469]. Conclusions: Following the current WHO indications, some tumors will be reclassified as DHGTC. The proportion of tumors with high-grade features is relevant in FTC, solid trabecular, and histologically aggressive PTC subtypes. A remarkable enrichment in DHGTC among patients with poor prognosis confirms the negative impact of high-grade features on outcome.

Multiple 3-tiered grading systems exist for mucoepidermoid carcinoma (MEC), leading to controversial results on the frequency and prognostic values of each grade. We aimed to identify prognostic histologic factors and to evaluate grading schemes in this retrospective study of 262 resected primary head and neck MECs. The rate of nodal metastasis was 8.4%. Large tumor size, tumor fibrosis, infiltrative border, lymphovascular invasion, perineural invasion, atypical mitosis, mitotic index (MI) ≥4/2 mm 2 (4/10 HPFs), necrosis, and pT4 stage were associated with increased risk of nodal metastasis. The 5-year recurrence-free survival (RFS) was 95%. Significant prognostic factors for RFS included infiltrative border, tumor-associated lymphoid stroma, architectural patterns (macrocystic, microcystic, and noncystic), anaplasia, atypical mitosis, MI, necrosis, lymphovascular invasion, margin, pT stage, and tumor size. Nuclear anaplasia, high mitotic rate, and ≥25% microcystic component were significant independent prognostic factors on multivariate survival analysis. There was no significant difference between low-grade (LG) and intermediate-grade (IG) MECs in terms of risk of nodal metastasis and outcomes using all 4 known grading systems. Rather, high-grade MEC was consistently associated with an increased risk of nodal metastasis at presentation and decreased RFS and distant metastasis-free survival (DMFS) compared with the LG/IG MECs. We therefore recommend simplifying MEC grading to a 2-tiered grading scheme using MI and/or tumor necrosis. Using a 2-tiered grading, high-grade histology independently predict RFS, and is associated with a 25% risk of nodal metastasis, a 5-year RFS of 76%, and a 5-year DMFS of 76%, whereas LG MEC has a nodal metastasis rate of 7.0%, 5-year RFS of 97% and 5-year DMFS of 99%., Competing Interests: Conflicts of Interest and Source of Funding: Supported in part by the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To introduce a biomarker-based dosimetry method for the rational selection of a treatment activity for patients undergoing radioactive iodine 131 I therapy (RAI) for metastatic differentiated thyroid cancer (mDTC) based on single-timepoint imaging of individual lesion uptake by 124 I PET., Methods: Patients referred for RAI therapy of mDTC were enrolled in institutionally approved protocols. A total of 208 mDTC lesions (in 21 patients) with SUV max  > 1 underwent quantitative PET scans at 24, 48, 72, and 120 h post-administration of 222 MBq of theranostic NaI- 124 I to determine the individual lesion radiation-absorbed dose. Using a general estimating equation, a prediction curve for biomarker development was generated in the form of a best-fit regression line and 95% prediction interval, correlating individual predicted lesion radiation dose metrics, with candidate biomarkers ("predictors") such as SUV max and activity in microcurie per gram, from a single imaging timepoint., Results: In the 169 lesions (in 15 patients) that received 131 I therapy, individual lesion cGy varied over 3 logs with a median of 22,000 cGy, confirming wide heterogeneity of lesion radiation dose. Initial findings from the prediction curve on all 208 lesions confirmed that a 48-h SUV max was the best predictor of lesion radiation dose and permitted calculation of the 131 I activity required to achieve a lesional threshold radiation dose (2000 cGy) within defined confidence intervals., Conclusions: Based on MIRD lesion-absorbed dose estimates and regression statistics, we report on the feasibility of a new single-timepoint 124 I-PET-based dosimetry biomarker for RAI in patients with mDTC. The approach provides clinicians with a tool to select personalized (precision) therapeutic administration of radioactivity (MBq) to achieve a desired target lesion-absorbed dose (cGy) for selected index lesions based on a single 48-h measurement 124 I-PET image, provided the selected activity does not exceed the maximum tolerated activity (MTA) of < 2 Gy to blood, as is standard of care at Memorial Sloan Kettering Cancer Center., Trial Registration: NCT04462471, Registered July 8, 2020. NCT03647358, Registered Aug 27, 2018., (© 2023. The Author(s).)

Background: The clinical behaviour and oncologic outcome of diffuse sclerosing papillary thyroid carcinoma (DS-PTC) is poorly understood. The objectives of this study were to compare the clinicopathological characteristics and oncological outcomes of DS-PTC to classic PTC (cPTC) and tall cell PTC (TC-PTC)., Methods: After institutional review board approval, 86 DS-PTC, 2,080 cPTC, and 701 TC-PTC patients treated at MSKCC between 1986 and 2021 were identified. Clinicopathological characteristics were compared by using chi-square test. Kaplan-Meier and log rank were used to compare recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). DS-PTC patients were propensity matched to cPTC and TC-PTC patients for further comparison., Results: DS-PTC patients were younger with more advanced disease than cPTC and TC-PTC (p < 0.05). Lymphovascular invasion (LVI), extranodal extension, and positive margins were more common in DS-PTC (p < 0.02). Propensity matching confirmed more aggressive histopathological features in DS-PTC. The median number of metastatic lymph nodes was significantly greater and DS-PTC metastases were RAI avid. DS-PTC 5-year RFS was 50.4% compared with 92.4% in cPTC and 88.4% in TC-PTC (p < 0.001). Multivariate analysis confirmed DS-PTC as an independent prognostic factor of recurrence. Ten-year DSS for DS-PTC was 100% compared with 97.1% in cPTC and 91.1% in TC-PTC. Differentiated high-grade, thyroid carcinoma DS had more advanced T-stage and worse 5-year RFS than DS-PTC., Conclusions: DS-PTC presents with more advanced clinicopathological features than cPTC and TC-PTC. Large-volume nodal metastases and LVI are characteristic features. Almost half of patients develop recurrence despite aggressive initial management. Despite this, with successful salvage surgery DSS is excellent., (© 2023. Society of Surgical Oncology.)

Acinic cell carcinoma (AciCC) is a rare salivary gland cancer with excellent prognosis in most cases. However, a subset of patients will develop distant metastasis and die of disease. Recently, a 2-tiered grading scheme in AciCC was proposed to recognize patients at risk of poor outcome. We performed a genetic analysis of AciCC to explore the underlying molecular correlates of the tumor grade and examined programmed death ligand 1 (PD-L1) expression to identify potential candidates for immunotherapy. A retrospective cohort of 55 patients included 34 high-grade (HG) and 21 low-grade AciCCs. Forty-three cases were subjected to targeted exome sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. PD-L1 immunohistochemistry was performed in 33 cases. Tumor mutation burden was low with a median of 1 and 2 mutations in low-grade and HG AciCCs, respectively. CDKN2A/B was the most frequently altered gene, and loss-of-function mutations were found only in HG but not in low-grade AciCCs (18/31 [58.1%] vs 0/12 [0%], P < .001). CDKN2A/B alterations were significantly associated with distant metastasis, which occurred in 16/18 (88.9%) CDKN2A/B mutants versus 11/25 (44%) wild-type cases (P = .004, Fisher exact test). Sequential profiling of multiple temporally distant samples from the same patient demonstrated intratumor heterogeneity, including the detection of CDKN2A/B deletion in the second, in HG metastasis only. ATM and PTEN mutations were detected in 6/31 (19.4%) and 5/31 (16.1%); ARID2, BIRC3, and FBXW7 mutations each in 4/31 (12.9%); and TP53, MTAP, and FAT1 each in 3/31 (9.7%) HG AciCC. PD-L1-positive labeling was more common in HG AciCC (9/17, 52.9% vs 3/16, 18.9%, P = .071). CDKN2A/B mutations in AciCC represent a molecular marker of HG histology and disease progression, providing a rationale for further studies to determine their prognostic and therapeutic significance in this salivary gland cancer. AciCC with ATM mutations may be amenable to targeted therapy. Immunotherapy can be considered to be a treatment option for a subset of patients with AciCC., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: The determinants of response or resistance to radioiodine (RAI) are unknown. We aimed to identify genomic and transcriptomic factors associated with structural responses to RAI treatment of metastatic thyroid cancer, which occur infrequently, and to test whether high MAPK pathway output was associated with RAI refractoriness., Experimental Design: Exceptional response to RAI was defined as reduction of tumor volume based on RECIST v1.1. We performed a retrospective case-control study of genomic and transcriptomic characteristics of exceptional responders (ER; n = 8) versus nonresponders (NR; n = 16) matched by histologic type and stage at presentation on a 1:2 ratio., Results: ER are enriched for mutations that activate MAPK through RAF dimerization (RAS, class 2 BRAF, RTK fusions), whereas NR are associated with BRAFV600E, which signals as a monomer and is unresponsive to negative feedback. ER have a lower MAPK transcriptional output and a higher thyroid differentiation score (TDS) than NR (P < 0.05). NR are enriched for 1q-gain (P < 0.05) and mutations of genes regulating mRNA splicing and the PI3K pathway. BRAFV600E tumors with 1q-gain have a lower TDS than BRAFV600E/1q-quiet tumors and transcriptomic signatures associated with metastatic propensity., Conclusions: ER tumors have a lower MAPK output and higher TDS than NR, whereas NR have a high frequency of BRAFV600E and 1q-gain. Molecular profiling of thyroid cancers and further functional validation of the key findings discriminating ER from NR may help predict response to RAI therapy., (©2023 American Association for Cancer Research.)

Poorly differentiated thyroid carcinoma (PDTC), defined by Turin criteria, comprises a subset of high-grade follicular-derived thyroid carcinomas with intermediate prognosis. While differentiated oncocytic thyroid carcinomas demonstrate clinicopathologic and genetic differences compared to their non-oncocytic counterparts, similar data is limited in oncocytic (Hurthle) PDTCs (OPDTCs). Here, we assessed the impact of various oncocytic cut-offs in PDTCs on clinical, histologic and survival parameters.Our bi-institutional cohort comprised 210 primary PDTCs with available slides reviewed by at least one pathologist. Histologic features, including oncocytic fraction, were recorded. Clinicopathologic data were obtained, including overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), locoregional recurrence free survival (LRRFS), and distant metastasis-free survival (DMFS). Radioactive iodine avidity data was available for 125 PDTCs based on postoperative whole-body scanning.Within our cohort, 39.0% PDTCs had any oncocytic component with 24.8% meeting the 75% World Health Organization (WHO) oncocytic definition. Any oncocytic component and > 25% oncocytic cut-off correlated with decreased DSS and LRRFS, respectively, compared to non-oncocytic PDTCs (NOPDTCs) on univariate and multivariate analysis. The 100% oncocytic cut-off was significant for DSS on univariate analysis but a non-significant trend on multivariate analysis. Any oncocytic cut-off (100%, > 75%, > 50%, > 25%, or > 0%) conferred higher radioactive iodine (RAI)-refractoriness to OPDTCs compared to NOPDTCs. NF1 and PTEN alterations were enriched in OPDTCs (40% vs. 0%, and 60% vs 8%, respectively), whereas NRAS mutations were frequent in NOPDTCs (47% vs. 7%).Among PDTCs, the presence of oncocytes led to downward trend in all outcome parameters, especially for DSS and LRRFS. OPDTCs were enriched in NF1 and PTEN mutations. Consistently, all oncocytic cut-offs were associated with RAI-refractoriness. Accordingly, additional studies are needed to reassess the current 75% cut-off used to define oncocytic thyroid lesions., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population., Methods: Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0-2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2-3 weeks of weekly paclitaxel (80 mg/m 2 ) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m 2 ), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete., Findings: The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002-4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0-12·8) in the pazopanib group versus 7·3 months (4·3-10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52-1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1-53·2) in the pazopanib group and 29·0% (13·2-44·8) in the placebo group. The incidence of grade 3-5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3-4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group)., Interpretation: To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated., Funding: National Cancer Institute and Novartis., Competing Interests: Declaration of interests KCB declares in the past 36 months an unpaid chair of the Americans Thyroid Association Anaplastic Thyroid Cancer Guidelines Task Force, now published. CHC declares in the past 36 months participation on a Data Safety Monitoring Board or Advisory Board for Bristol-Myers Squibb, Cue Biopharma, Sanofi, Mirati, Merck, Brooklyn ImmunoTherapuetics, and Exelixis. MFD declares in the past 36 months support for attending Radiation Oncologists (PA, USA), American Society for Radiation Oncology (ASTRO) Head and Neck Meeting (Scottsdaye, AZ, USA), 2020 ASTRO Annual Meeting (San Antonio, TX, USA); and reimbursement for travel, registration and food, Health Policy Committee Payer Relations for ASTRO. RLF declares in the past 36 months royalties from Bionix TruGuard oral stent, paid to the Mayo Clinic and to himself, honoria for lecture ITCCIR 2021, Elsevier royalties for providing content for sale textbook as Editor, and Hitachi-unrestricted use of research funds paid to the Mayo Clinic for named professorship (Hitachi Professor of Radiation Oncology Research). RAG declares in the past 36 months receipt of National Institutes of Health grant P30CA008748 to the Memorial Sloan Kettering Cancer Center. SAK declares in the past 36 months research support from Merck, Bristol Myers Squibb, and Castle BioSciences; consulting fees from Regeneron; Merck-paid advisory board; an unpaid advisory board role at Castle BioSciences; author for UpToDate; and a data safety monitoring board role at AlphaTau. NYL declares in the past 36 months advisory board roles at Pfizer, Merck, Merck EMD, Elsie, and Mirati. Q-TL declares in the past 36 months consultant roles for Nanobiotix, Roche, and Coherus; honoraria from Johns Hopkins Lecture and 2021 China International Exchange, and Promotive Association for Medical and Health Care Nasopharyngeal Cancer Branch Inaugural Conference and Minimally Invasive Surgery Training Course of Nasopharyngeal Cancer, paid flights or hotels Radiation Therapy Oncology Group (RTOG) foundation meetings or retreats, RTOG group chair (NRG Oncology), and stock or stock options exceeding US$1000 from Aldea. NR reports since the initial planning of the work research support from Pfizer, Repertoire, REPARE Therapuetics, and BMS, and in the past 36 months consulting fees from Illumina Paige.AI. MHS declares in the past 36 months grants from Merck and Eli-Lilly for clinical trials with payment made to his institution. EJS reports since the initial planning of the work support from GSK/Novartis (no payment) and in the past 36 months consulting fees from Eli Lilly, Roche, Regeneron, Eisai, and Elixis, advisory board roles (no compensation) with Eli Lilly, Novartis, and DSMB, and a Protocol Chair (unpaid) role with Eli Lilly and Novartis. PAT-S reports since the initial planning of the work NRG Oncology Statistics and Data Management Center grant from the National Cancer Institute (NCI). PX declares in past 36 months payment to his institution, research grants from AVO and Philips, and support from Philips to present at a Sun Nuclear QA meeting in 2019. SSY declares in past 36 months research support paid to his institution from Merck, Bristol-Myers Squibb, EMD Serono, Genentech, and BioMimetix; book chapter royalties from Springer and UpToDate; and service positions at ASTRO, Elsevier, and NRG Oncology. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In the upcoming World Health Organization fifth edition classification of endocrine tumors, there were several major changes related to high grade follicular-derived thyroid carcinoma (HGFCTC) and anaplastic thyroid carcinoma (ATC) based on emerging evidence about the diagnostic criteria clinical behavior, prognostic factors, and molecular signatures of these tumors. In this review, we aim to summarize the major evolutions of HGFCTC and ATC. HGFCTC is a nonanaplastic carcinoma with high grade features (High mitotic count, tumor necrosis). It is subdivided into poorly differentiated thyroid carcinoma diagnosed using the Turin proposal and differentiated high grade thyroid carcinoma. The latter is defined by the presence of the cytoarchitectutal features of well-differentiated thyroid carcinoma (eg, papillae) but harbors elevated mitotic activity and/or tumor necrosis. Poorly differentiated thyroid carcinoma is predominantly RAS -driven and associated with RAI avidity and high propensity for distant metastasis, whereas differentiated high grade thyroid carcinoma is mostly BRAFV600E -driven. ATC may show a wide range of histologic features. Carcinoma of pure squamous phenotype is associated with a high frequency of BRAF V600E mutations and is now considered as a subtype of ATC. There is a stepwise molecular progression from well-differentiated carcinoma to HGFCTC to ATC manifested by 1) early and persistent driver alteration in the MAPK pathway, particularly BRAF V600E and RAS mutations, and 2) gain of secondary aggressive molecular signatures (such as TERT promoter and TP53 mutations) when tumors progress from well-differentiated to high grade to anaplastic carcinoma., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The tall cell variant of papillary thyroid carcinoma has traditionally been treated more aggressively than classic papillary thyroid carcinoma. However, this may not be justified in patients with T1/T2 tall cell variant node-negative tumors., Methods: We evaluated well-differentiated thyroid cancers treated surgically between 1985 and 2015 at our institution. We compared patients undergoing lobectomy for node-negative T1/T2 tall cell variant tumors with the same cohort with classic papillary thyroid carcinoma. Patients who underwent early planned completion thyroidectomy were excluded. Tall cell variant tumors were defined as those with ≥30% tall cells. Survival and recurrence outcomes were determined by the Kaplan-Meier method and groups compared using the log-rank test., Results: Thyroid lobectomy was performed for T1/T2 N0X disease in 70 (15%) tall cell cases and 429 (23%) classic papillary thyroid carcinoma cases. There was no significant difference in 10-year overall survival (P = .56) or locoregional recurrence-free probability (P = .52). Disease-specific survival and local or central nodal recurrence-free probability were 100% in both groups. In 9 papillary thyroid carcinoma cases, subsequent contralateral lobe tumors developed, and in 5, lateral neck metastases developed. No recurrences were seen in the tall cell group., Conclusion: T1 node-negative tumors with tall cell histology can be satisfactorily managed with thyroid lobectomy, with equivalent oncological outcomes to classic papillary thyroid carcinoma., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Inactivation of the Hippo pathway promotes Yap nuclear translocation, enabling execution of a transcriptional program that induces tissue growth. Genetic lesions of Hippo intermediates only identify a minority of cancers with illegitimate YAP activation. Yap has been implicated in resistance to targeted therapies, but the mechanisms by which YAP may impact adaptive resistance to MAPK inhibitors are unknown., Methods: We screened 52 thyroid cancer cell lines for illegitimate nuclear YAP localization by immunofluorescence and fractionation of cell lysates. We engineered a doxycycline (dox)-inducible thyroid-specific mouse model expressing constitutively nuclear YAP S127A , alone or in combination with endogenous expression of either Hras G12V or Braf V600E . We also generated cell lines expressing dox-inducible sh-miR-E-YAP and/or YAP S127A . We used cell viability, invasion assays, immunofluorescence, Western blotting, qRT-PCRs, flow cytometry and cell sorting, high-throughput bulk RNA sequencing and in vivo tumorigenesis to investigate YAP dependency and response of BRAF-mutant cells to vemurafenib., Results: We found that 27/52 thyroid cancer cell lines had constitutively aberrant YAP nuclear localization when cultured at high density (NU-YAP), which rendered them dependent on YAP for viability, invasiveness and sensitivity to the YAP-TEAD complex inhibitor verteporfin, whereas cells with confluency-driven nuclear exclusion of YAP (CYT-YAP) were not. Treatment of BRAF-mutant thyroid cancer cells with RAF kinase inhibitors resulted in YAP nuclear translocation and activation of its transcriptional output. Resistance to vemurafenib in BRAF-mutant thyroid cells was driven by YAP-dependent NRG1, HER2 and HER3 activation across all isogenic human and mouse thyroid cell lines tested, which was abrogated by silencing YAP and relieved by pan-HER kinase inhibitors. YAP activation induced analogous changes in BRAF melanoma, but not colorectal cells., Conclusions: YAP activation in thyroid cancer generates a dependency on this transcription factor. YAP governs adaptive resistance to RAF kinase inhibitors and induces a gene expression program in BRAF V600E -mutant cells encompassing effectors in the NRG1 signaling pathway, which play a central role in the insensitivity to MAPK inhibitors in a lineage-dependent manner. HIPPO pathway inactivation serves as a lineage-dependent rheostat controlling the magnitude of the adaptive relief of feedback responses to MAPK inhibitors in BRAF- V600E cancers., (© 2022. The Author(s).)

NUT carcinoma (NC) is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT fusion oncoproteins (the most frequent fusion partner being BRD4 ) that carries a very poor prognosis, with most patients dying in under 1 year. Only rare primary thyroid NCs have been reported. Here, we evaluated a series of 14 cases. The median patient age at diagnosis was 38 years (range: 17 to 72 y). Eight of 13 cases with slides available for review (62%) showed a morphology typical of NC, whereas 5 (38%) had a non-NC-like morphology, some of which had areas of cribriform or fused follicular architecture resembling a follicular cell-derived thyroid carcinoma. For cases with immunohistochemistry results, 85% (11/13) were positive for NUT on biopsy or resection, though staining was significantly decreased on resection specimens due to fixation; 55% (6/11) were positive for PAX8, and 54% (7/13) for TTF-1. Tumors with a non-NC-like morphology were all positive for PAX8 and TTF-1. The fusion partner was known in 12 cases: 9 (75%) cases had a NSD3-NUTM1 fusion, and 3 (25%) had a BRD4-NUTM1 fusion. For our cohort, the 2-year overall survival (OS) was 69%, and the 5-year OS was 58%. Patients with NC-like tumors had a significantly worse OS compared with that of patients with tumors with a non-NC-like morphology ( P =0.0462). Our study shows that NC of the thyroid can mimic other thyroid primaries, has a high rate of NSD3 - NUTM1 fusions, and an overall more protracted clinical course compared with nonthyroid primary NC., Competing Interests: Conflicts of Interest and Source of Funding: Supported by a research grant from the National Institutes of Health (NCI, CA124633 to C.A.F.) and Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748 (R.A.G and B.X.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Pediatric thyroid carcinomas (TCs) are rare and mainly approached based on data extrapolated from adults. We retrospectively reviewed 222 pediatric TCs (patient age less than or equal to 21 y). Lymph node (LN) disease volume at presentation was considered high if the largest positive LN measured ≥1 cm and/or >5 LNs were positive. High-grade follicular cell-derived thyroid carcinoma (HGFCTC) were defined by the presence of marked mitotic count and/or tumor necrosis and considered as high-risk histology along with papillary thyroid carcinomas (PTC) diffuse sclerosing variant (DSV). Disease-free survival (DFS) was analyzed. LN involvement at presentation was significantly associated with male sex, larger tumor size, lymphatic invasion, positive surgical margins, and distant metastases at presentation. Five- and 10-year DFS was 84% and 77%, respectively. Only 1 patient with HGFCTC died of disease. Within PTC variants, PTC-DSV was associated with adverse histopathologic parameters and higher regional disease spread, unlike PTC tall cell variant which did not portend worse behavior. The presence of necrosis conferred worse DFS ( P =0.006), while increased mitotic activity did not. While the entire HGFCTC group did not correlate with outcome ( P =0.071), HGFCTC with necrosis imparted worse DFS ( P =0.006). When restricted to PTC-DSV and HGFCTC with necrosis, high-risk histologic classification emerged as an independent prognostic parameter of DFS ( P =0.020). The excellent prognosis of pediatric TCs differs from that of adult TCs showing similar histologic features. While neither increased mitotic activity nor PTC tall cell variant histology predict adverse outcome, PTC-DSV and tumors with necrosis constitute high-risk histologic variants with an increased risk of protracted disease., Competing Interests: Conflicts of Interest and Source of Funding: Supported in part by the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Extranodal extension (ENE) is a significant prognostic factor for human papilloma virus (HPV)-negative head and neck squamous cell carcinoma and is incorporated into AJCC 8th edition pN stage. It remains controversial whether ENE or the degree of ENE is prognostically relevant in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). A detailed clinicopathologic review was conducted in a large retrospective cohort of 232 surgically treated patients with HPV-positive OPSCC and nodal metastasis. Fifty-six patients (24%) had nodal metastasis with ENE. The median vertical extent of ENE was 2.9 mm (range 0.2-20.3 mm), and the median horizontal span of ENE was 2.5 mm (range: 0.3-14.0 mm). Comparing with patients without ENE, those with ENE were associated with a higher number of positive lymph nodes, lymphovascular invasion, perineural invasion, adjuvant chemotherapy, larger primary tumor size, and shorter follow up period. Patients with ENE had shortened overall survival (OS), disease specific survival (DSS), disease free survival (DFS), distant metastasis free survival (DMFS), and regional recurrence free survival (RRFS) on univariate survival analysis. The 5-year OS, DSS, and DFS were 95%, 97%, and 90% respectively for the group without ENE, and 64%, 71%, and 65% respectively for the group with ENE. On Multivariate survival analysis, the presence of ENE was an independent adverse prognostic factor for OS, DSS, and DFS. Additionally, major ENE defined as a vertical extent of ≥4 mm or irregular soft tissue deposit independently predicted shortened OS, DSS, and RFS. In conclusion, the presence of ENE, in particular major ENE, is an independent prognostic factor in HPV-positive OPSCC. Therefore, we propose to document the presence and extent of ENE for these tumors. Consideration may be given for AJCC 9th edition to include ENE into pN stage of HPV-positive OPSCC., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Secretory carcinoma (SC) is a rare form of salivary carcinoma that was first described in 2010 and is characterized by ETV6::NTRK3 fusion in most cases. In this large retrospective study, we aimed to identify adverse clinicopathologic factors and propose a prognostically relevant grading scheme for SC., Methods: A detailed clinicopathologic review was conducted on 90 SCs from the major and minor salivary glands., Results: The median age at presentation was 50 years (range: 7-93). Sixty-nine (77%) tumours originated from major salivary glands, whereas the remaining 21 involved minor salivary glands.Six cases (7%) had cervical nodal metastasis. Only lymphovascular invasion (LVI) was associated with a risk of nodal metastasis (P < 0.05). The 5-year disease-specific survival and disease-free survival (DFS) were 98% and 87%, respectively. On univariate survival analysis, adverse prognostic factors associated with decreased DFS included minor salivary gland origin, atypical mitosis, high mitotic index, high-grade transformation (HGT), necrosis, nuclear pleomorphism, infiltrative tumour border, fibrosis at the invasive front, LVI, positive margin, and advanced pT stage (P < 0.05). When adjusted for pT stage and margin status, mitotic index, LVI, nuclear pleomorphism, and HGT remained as independent prognostic factors., Conclusion: We therefore propose a two-tiered grading system for SC. The low-grade SC is defined as those with <5 mitoses /10 high-power fields and no tumour necrosis, and high-grade SC as those with ≥5 mitoses /10 high-power fields and/or necrosis. This proposed grading system can be useful to risk stratify patients with SC for appropriate clinical management., (© 2022 John Wiley & Sons Ltd.)

Importance: Methods of assessing final margin status in patients undergoing surgery for oral cavity squamous cell carcinoma, such as intraoperative frozen section histopathology (IFSH) taken from the tumor bed, may have limitations in accuracy., Objective: To evaluate the accuracy and implications of using IFSH samples to assess tumor bed margins in patients undergoing surgery for oral cavity squamous cell carcinoma (SCC)., Design, Setting, and Participants: This cross-sectional study included 1257 patients who underwent surgery for oral cavity SCC between January 1, 2000, and December 31, 2015, at an academic cancer center. A total of 4821 IFSH samples were examined from 1104 patients (87.8%) who had at least 1 IFSH sample. Institutional practice is to harvest margins for IFSH from the tumor bed. Statistical analysis was performed from August 1, 2021, to April 4, 2022., Main Outcomes and Measures: Sensitivity and specificity were calculated for IFSH samples of margins compared with the permanent pathology samples of the same tissue and for IFSH compared with the final tumor specimen histopathology (FTSH). Results were classified using a binary method, with histopathologic reports interpreted as either negative (including negative or atypia or dysplasia) or positive (including carcinoma in situ, suspicious, or positive)., Results: A total of 1257 patients met the inclusion criteria, including 709 men (56.4%), with a median age of 62 years (IQR, 52-73 years); 1104 patients (627 men [56.8%]; median age, 62 years [IQR, 52-72 years]) had IFHS samples. For IFSH relative to permanent sections of the IFSH tissue, sensitivity and specificity of IFSH were high (sensitivity, 76.5% [95% CI, 67.5%-85.5%]; specificity, 99.9% [95% CI, 99.8%-100%]), with discordant results in 24 of 4821 total specimens (0.5%). Final specimen margins were positive in 11.7% of patients (147 of 1257). Compared with FTSH, the sensitivity of IFSH for defining margin status was 10.8% (95% CI, 5.8%-15.8%), and the specificity was 99.1% (95% CI, 98.8%-99.4%). The rate of discordance was 4.0% (171 of 4284 specimens) between IFSH and FTSH., Conclusions and Relevance: The findings of this cross-sectional study suggest that IFSH is accurate compared with permanent pathologic characteristics of the same tissue, but less reliable at assessing final margin status on the tumor specimen. Despite a high specificity, the sensitivity of IFSH compared with FTSH is low, which may be associated with the inherent inability of tumor bed IFSH margin analysis to accurately account for the 3-dimensional association of tumor margins with the periphery of the specimen and the overall low rate of positive final tumor margins. Although tumor bed IFSH is widely used in the management of oral cavity cancer, this study suggests that there are limitations of this modality in assessing the final surgical margin status.

Background: Tumor grade is a new validated prognostic factor for medullary thyroid cancer (MTC). Calcitonin doubling time can predict MTC recurrence. We aimed to describe the association of tumor grade with calcitonin doubling and its effect on disease-specific outcomes times after resection. Methods: A retrospective analysis of MTC patients who underwent resection at a single tertiary-care cancer center between 1986 and 2017 were evaluated. Tumors were designated as high-grade MTC if two head and neck pathologists identified mitotic index ≥5 per 2 mm 2 , tumor necrosis, or a Ki67 proliferative index ≥5% within the tumor. Calcitonin doubling time was calculated using a validated calculator with at least three consecutive levels. Using Cox proportional hazards models, outcomes evaluated included locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS). Results: Among 117 patients, 95 were low grade and 22 high grade. Median follow-up was 70.2 months. High-grade patients demonstrated significantly faster calcitonin doubling times when compared with low-grade patients (8.51 ± 3.22 months vs. 38.42 ± 11.19 months; p  < 0.001). In addition, most high-grade patients (66.7%) had calcitonin doubling times less than 1 year compared with fewer low-grade patients (1.0%; p  < 0.001). High- and low-grade patients were further stratified by those who had calcitonin doubling times less than or greater than 2 years-a previously validated prognostic cutoff point. For patients with calcitonin doubling times less than 2 years, 70% were high grade, while 30% were low grade ( p  < 0.001). On multivariate analysis comparing grade and calcitonin doubling times, high-grade patients had significantly worse LRFS (hazards ratio [HR] 4.77 [confidence interval; CI 1.19-8.81]), DMFS (HR 7.25 [CI 2.36-22.28]), and OS (HR 6.04 [CI 1.85-19.72]; p  < 0.05 for all), while calcitonin doubling times less than 2 years had worse DMFS (HR 7.22 [CI 1.05-49.75]). High-grade patients with calcitonin doubling times less than 2 years had associated worse LRFS and OS (both p  < 0.05) compared with low-grade patients. Conclusions: The majority of high-grade MTC patients have calcitonin doubling times less than 2years. Close monitoring should be advocated for patients assessed to have high-grade tumors as they are at risk for poor disease-specific outcomes and structural recurrence.

Primary mesenchymal tumors of the thyroid gland are extremely rare, with only case reports and small case series documented in the English literature, many of which were published prior to the era of molecular pathology. In the current study, we aim to present a contemporary multi-centric cohort of thyroid mesenchymal tumors. Nineteen primary thyroid mesenchymal tumors were collected from three tertiary centers. Their clinicopathologic features, immunoprofile, molecular alterations, and outcome were described. Eight cases were classified as benign or intermediate with solitary fibrous tumor being the most common histotype (n = 3). The remaining 11 cases were malignant, including three angiosarcomas, one epithelioid hemangioendothelioma, one adamantinoma-like Ewing sarcoma, one biphasic synovial sarcoma, one malignant melanocytic peripheral nerve sheath tumor (melanotic schwannoma), one myxofibrosarcoma, and two undifferentiated pleomorphic/spindle sarcomas (one of which was radiation-induced). Six tumors showed characteristic diagnostic translocations. We herein also described the first case of thyroid malignant perivascular epithelioid cell tumor (PEComa) with RBM10-TFE3 fusion in a 35-year-old female patient. Thyroid mesenchymal tumors, benign or malignant, are rare with a broad spectrum of possible diagnoses. A comprehensive examination to include histology, immunohistochemistry, and molecular testing is essential for the correct diagnosis and to distinguish them from anaplastic thyroid carcinoma. PEComa may occur as a primary tumor of the thyroid gland, expanding the histologic spectrum of thyroid mesenchymal tumors., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: The definition of papillary thyroid carcinoma, solid variant (PTC-SV) varies from >50% to 100% of solid/trabecular/insular growth (STI). We aimed to identify prognostic factors and to establish an appropriate STI cutoff for PTC-SV in this multi-institutional study of 156 PTCs with STI., Results: Nodal metastases were seen in 18% and were associated with a higher percentage of papillary and STI. When substratified by infiltration/encapsulation status, the STI percentage did not impact the risk of nodal metastasis. pN1 stage was seen in 51% of infiltrative tumours and 1% of encapsulated lesions. Overall, PTC with STI had an excellent prognosis. The 10-year disease-free survival (DFS) was 87% in the entire cohort, 94% in encapsulated lesions, and 76% in infiltrative tumours. The STI percentage did not impact DFS. Fifty-four patients had noninvasive encapsulated lesions with 2-100% STI. None developed recurrence. Encapsulated lesions were enriched with RAS mutations (54%), whereas infiltrative lesions lacked RAS mutations (4%). The BRAF V600E mutation was an infrequent event, being seen in 11% of the entire cohort., Conclusion: In PTC with STI, the determining factor for nodal metastasis and DFS is the encapsulation/infiltration status rather than the STI percentage. Encapsulated noninvasive tumours with STI follow an indolent course with a very low risk of nodal metastasis and recurrence. Overall, PTC with STI has an excellent prognosis, with a 10-year disease-specific survival (DSS) and DFS of 96% and 87%, respectively. Therefore, the classification of SV-PTC as an aggressive PTC subtype may be reconsidered., (© 2022 John Wiley & Sons Ltd.)

Background: The development of systemic treatment options leveraging the molecular landscape of advanced thyroid cancer is a burgeoning field. This is a multidisciplinary evidence-based statement on the definition of advanced thyroid cancer and its targeted systemic treatment., Methods: An expert panel was assembled, a literature review was conducted, and best practice statements were developed. The modified Delphi method was applied to assess the degree of consensus for the statements developed by the author panel., Results: A review of the current understanding of thyroid oncogenesis at a molecular level is presented and characteristics of advanced thyroid cancer are defined. Twenty statements in topics including the multidisciplinary management, molecular evaluation, and targeted systemic treatment of advanced thyroid cancer are provided., Conclusions: With the growth in targeted treatment options for thyroid cancer, a consensus definition of advanced disease and statements regarding the utility of molecular testing and available targeted systemic therapy is warranted., (© 2022 Wiley Periodicals LLC.)

Context: The BRAFV600E mutation has been associated with more advanced clinical stage in papillary thyroid cancer (PTC) and decreased responsiveness to radioiodine (RAI). However, some BRAF mutant PTCs respond to RAI and have an indolent clinical behavior suggesting the presence of different subtypes of BRAF mutant tumors with distinct prognosis., Objective: To characterize the molecular and clinical features of 2 subtypes of BRAF-mutant PTCs defined by their degree of expression of iodine metabolism genes., Design: 227 BRAF-mutant PTCs from the Cancer Genome Atlas Thyroid Cancer study were divided into 2 subgroups based on their thyroid differentiation score (TDS): BRAF-TDShi and BRAF-TDSlo. Demographic, clinico-pathological, and molecular characteristics of the 2 subgroups were compared., Results: Compared to BRAF-TDShi tumors (17%), BRAF-TDSlo tumors (83%) were more frequent in blacks and Hispanics (6% vs 0%, P = 0.035 and 12% vs 0%, P = 0.05, respectively), they were larger (2.95 ± 1.7 vs 2.03 ± 1.5, P = 0.002), with more tumor-involved lymph nodes (3.9 ± 5.8 vs 2.0 ± 4.2, P = 0.042), and a higher frequency of distant metastases (3% vs 0%, P = 0.043). Gene set enrichment analysis showed positive enrichment for RAS signatures in the BRAF-TDShi cohort, with corresponding reciprocal changes in the BRAF-TDSlo group. Several microRNAs (miRs) targeting nodes in the transforming growth factor β (TGFβ)-SMAD pathway, miR-204, miR-205, and miR-144, were overexpressed in the BRAF-TDShi group. In the subset with follow-up data, BRAF-TDShi tumors had higher complete responses to therapy (94% vs 57%, P < 0.01) than BRAF-TDSlo tumors., Conclusion: Enrichment for RAS signatures, key genes involved in cell polarity and specific miRs targeting the TGFβ-SMAD pathway define 2 subtypes of BRAF-mutant PTCs with distinct clinical characteristics and prognosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This review summarizes the changes in the 5th edition of the WHO Classification of Endocrine and Neuroendocrine Tumors that relate to the thyroid gland. The new classification has divided thyroid tumors into several new categories that allow for a clearer understanding of the cell of origin, pathologic features (cytopathology and histopathology), molecular classification, and biological behavior. Follicular cell-derived tumors constitute the majority of thyroid neoplasms. In this new classification, they are divided into benign, low-risk, and malignant neoplasms. Benign tumors include not only follicular adenoma but also variants of adenoma that are of diagnostic and clinical significance, including the ones with papillary architecture, which are often hyperfunctional and oncocytic adenomas. For the first time, there is a detailed account of the multifocal hyperplastic/neoplastic lesions that commonly occur in the clinical setting of multinodular goiter; the term thyroid follicular nodular disease (FND) achieved consensus as the best to describe this enigmatic entity. Low-risk follicular cell-derived neoplasms include non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), thyroid tumors of uncertain malignant potential, and hyalinizing trabecular tumor. Malignant follicular cell-derived neoplasms are stratified based on molecular profiles and aggressiveness. Papillary thyroid carcinomas (PTCs), with many morphological subtypes, represent the BRAF-like malignancies, whereas invasive encapsulated follicular variant PTC and follicular thyroid carcinoma represent the RAS-like malignancies. This new classification requires detailed subtyping of papillary microcarcinomas similar to their counterparts that exceed 1.0 cm and recommends not designating them as a subtype of PTC. The criteria of the tall cell subtype of PTC have been revisited. Cribriform-morular thyroid carcinoma is no longer classified as a subtype of PTC. The term "Hürthle cell" is discouraged, since it is a misnomer. Oncocytic carcinoma is discussed as a distinct entity with the clear recognition that it refers to oncocytic follicular cell-derived neoplasms (composed of > 75% oncocytic cells) that lack characteristic nuclear features of PTC (those would be oncocytic PTCs) and high-grade features (necrosis and ≥ 5 mitoses per 2 mm 2 ). High-grade follicular cell-derived malignancies now include both the traditional poorly differentiated carcinoma as well as high-grade differentiated thyroid carcinomas, since both are characterized by increased mitotic activity and tumor necrosis without anaplastic histology and clinically behave in a similar manner. Anaplastic thyroid carcinoma remains the most undifferentiated form; squamous cell carcinoma of the thyroid is now considered as a subtype of anaplastic carcinoma. Medullary thyroid carcinomas derived from thyroid C cells retain their distinct section, and there is a separate section for mixed tumors composed of both C cells and any follicular cell-derived malignancy. A grading system for medullary thyroid carcinomas is also introduced based on mitotic count, tumor necrosis, and Ki67 labeling index. A number of unusual neoplasms that occur in the thyroid have been placed into new sections based on their cytogenesis. Mucoepidermoid carcinoma and secretory carcinoma of the salivary gland type are now included in one section classified as "salivary gland-type carcinomas of the thyroid." Thymomas, thymic carcinomas and spindle epithelial tumor with thymus-like elements are classified as "thymic tumors within the thyroid." There remain several tumors whose cell lineage is unclear, and they are listed as such; these include sclerosing mucoepidermoid carcinoma with eosinophilia and cribriform-morular thyroid carcinoma. Another important addition is thyroblastoma, an unusual embryonal tumor associated with DICER1 mutations. As in all the WHO books in the 5th edition, mesenchymal and stromal tumors, hematolymphoid neoplasms, germ cell tumors, and metastatic malignancies are discussed separately. The current classification also emphasizes the value of biomarkers that may aid diagnosis and provide prognostic information., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Oncogenic activation of mitogen-activated protein kinase (MAPK) signaling is associated with radioiodine refractory (RAIR) thyroid cancer. Preclinical models suggest that activation of the receptor tyrosine kinase erbB-3 (HER3) mitigates the MAPK pathway inhibition achieved by BRAF inhibitors in BRAF V600E mutant thyroid cancers. We hypothesized that combined inhibition of BRAF and HER3 using vemurafenib and the human monoclonal antibody CDX-3379, respectively, would potently inhibit MAPK activation and restore radioactive iodine (RAI) avidity in patients with BRAF- mutant RAIR thyroid cancer. Methods: Patients with BRAF V600E RAIR thyroid cancer were evaluated by thyrogen-stimulated iodine-124 ( 124 I) positron emission tomography-computed tomography (PET/CT) at baseline and after 5 weeks of treatment with oral vemurafenib 960 mg twice daily alone for 1 week, followed by vemurafenib in combination with 1000 mg of intravenous CDX-3379 every 2 weeks. Patients with adequate 124 I uptake on the second PET/CT then received therapeutic radioactive iodine ( 131 I) with vemurafenb+CDX-3379. All therapy was discontinued two days later. Treatment response was monitored by serum thyroglobulin measurements and imaging. The primary endpoints were safety and tolerability of vemurafenib+CDX-3379, as well as the proportion of patients after vemurafenb+CDX-3379 therapy with enhanced RAI incorporation warranting therapeutic 131 I. Results: Seven patients were enrolled; six were evaluable for the primary endpoints. No grade 3 or 4 toxicities related to CDX-3379 were observed. Five patients had increased RAI uptake after treatment; in 4 patients this increased uptake warranted therapeutic 131 I. At 6 months, 2 patients achieved partial response after 131 I and 2 progression of disease. Next-generation sequencing of 5 patients showed that all had co-occurring telomerase reverse transcriptase promoter alterations. A deleterious mutation in the SWItch/Sucrose Non-Fermentable (SWI/SNF) gene ARID2 was discovered in the patient without enhanced RAI avidity after therapy and an RAI-resistant tumor from another patient that was sampled off-study. Conclusions: The endpoints for success were met, providing preliminary evidence of vemurafenib+CDX-3379 safety and efficacy for enhancing RAI uptake. Preclinical data and genomic profiling in this small cohort suggest SWI/SNF gene mutations should be investigated as potential markers of resistance to redifferentiation strategies. Further evaluation of vemurafenib+CDX-3379 as a redifferentiation therapy in a larger trial is warranted (ClinicalTrials.gov: NCT02456701).

Aims: We aimed to study the clinicopathological and molecular features of high-grade non-anaplastic thyroid carcinomas (HGTCs), a carcinoma with a prognosis intermediate between those of well-differentiated carcinoma and anaplastic carcinoma., Methods and Results: This study included 364 HGTC patients: 200 patients (54.9%) were diagnosed with poorly differentiated thyroid carcinoma (PDTC), based on the Turin consensus (HGTC-PDTC), and 164 were diagnosed with high-grade features that did not meet the Turin criteria (HGTC-nonPDTC). HGTCs are aggressive: the 3-year, 5-year, 10-year and 20-year disease-specific survival (DSS) rates were 89%, 76%, 60%, and 35%, respectively. Although DSS was similar between HGTC-PDTC and HGTC-nonPDTC patients, HGTC-PDTC was associated with higher rate of radioactive iodine avidity, a higher frequency of RAS mutations, a lower frequency of BRAF V600E mutations and a higher propensity for distant metastasis (DM) than HGTC-nonPDTC. Independent clinicopathological markers of worse outcome were: older age, male sex, extensive necrosis and lack of encapsulation for DSS; older age, male sex and vascular invasion for DM-free survival; and older age, necrosis, positive margins and lymph node metastasis for locoregional recurrence-free survival. The frequencies of BRAF, RAS, TERT, TP53 and PTEN alterations were 28%, 40%, 55%, 11%, and 10%, respectively. TP53, PTEN and TERT were independent molecular markers associated with an unfavourable outcome, independently of clinicopathological parameters. The coexistence of BRAF V600E and TERT promoter mutation increased the risk of DM., Conclusions: The above data support the classification of HGTC as a single group with two distinct subtypes based on tumour differentiation: HGTC-PDTC and HGTC-nonPDTC., (© 2021 John Wiley & Sons Ltd.)

Purpose: Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC., Patients and Methods: Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm 2 , Ki67 proliferative index ≥ 5%, or tumor necrosis., Results: Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio [HR] = 11.490; 95% CI, 3.118 to 32.333; P < .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327; P = .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261; P = .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193; P = .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers., Conclusion: This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis., Competing Interests: Eric BaudinConsulting or Advisory Role: Ipsen, Novartis, AAA HealthCare, Pfizer, Hutchison MediPharmaResearch Funding: Pfizer (Inst), Novartis (Inst), HRA Pharma (Inst) James A. FaginConsulting or Advisory Role: Loxo OncologyPatents, Royalties, Other Intellectual Property: 3. MSK Ref. SK 2014-024-03 Title: Treatment of H-RAS-Driven Tumors. Application Number: 15/305,788 Dana HartlConsulting or Advisory Role: Medtronic Fedaa NajdawiEmployment: PathAINo other potential conflicts of interest were reported.

Background: Patients with medullary thyroid carcinoma (MTC) often receive lateral lymph node dissection with total thyroidectomy when calcitonin levels are elevated, even in the absence of structural disease, but the effect of this intervention on disease-specific outcomes is not known., Patients and Methods: We retrospectively reviewed patients from 1986 to 2017 who underwent thyroidectomy with curative intent for MTC at our institution. The association of disease-specific survival and clinicopathologic features was examined using univariate and multivariate Cox regression., Results: We identified 316 patients who underwent curative resection for MTC. Overall and disease-specific survival were 76% and 86%, respectively, at 10 years. To investigate the effect of prophylactic ipsilateral lateral lymph node dissection, we analyzed 89 patients without known structural disease in the neck lymph nodes at the time of resection and preoperative calcitonin > 200 pg/ml, of whom 45 had an ipsilateral lateral lymph node dissection (LND) and 44 did not. There were no differences in tumor size or preoperative calcitonin levels. There was no difference at 10 years in cumulative incidence of recurrence in the neck (20.9% LND vs. 30.4% no LND, p = 0.46), cumulative incidence of distant recurrence (18.3% vs. 18.4%, p = 0.97), disease-specific survival (86% vs. 93%, p = 0.53), or overall survival (82% vs. 90%, p = 0.6)., Conclusion: Lateral neck dissection in the absence of clinical or radiologic abnormal lymph nodes is not associated with improved survival in patients with MTC., (© 2021. Society of Surgical Oncology.)

Aims: The diagnosis of thyroid neoplasms relies upon the demonstration of histological parameters that can be focal and prone to subjective interpretation. We evaluated the utility of NRAS Q61R immunohistochemistry (IHC) in the diagnosis of thyroid lesions after determining its specificity and sensitivity as a surrogate marker for RAS Q61R mutation., Method and Results: NRAS Q61R IHC was performed on 282 primary or metastatic thyroid lesions from 256 patients. RAS mutation status was collected from patients' charts. Sensitivity and specificity of NRAS Q61R IHC for detecting a RAS Q61R mutation was calculated. IHC-positive cases were reviewed to determine the diagnostic utility of NRAS Q61R IHC. NRAS Q61R immunopositivity was seen in non-neoplastic, benign and malignant thyroid lesions. NRAS Q61R antibody cross-reactivity led to the detection of NRAS Q61R, KRAS Q61R and HRAS Q61R proteins. Among primary thyroid carcinomas, immunopositivity was most frequent in papillary thyroid carcinomas, follicular variant (48.0%). The sensitivity and specificity of NRAS Q61R IHC in detecting RAS Q61R mutation was 90.6% and 92.3%, respectively. When positive, the NRAS Q61R stain was determined to be helpful in demonstrating infiltration, tumour size, capsular and/or vascular invasion and multifocality., Conclusion: NRAS Q61R IHC is highly sensitive and specific for the detection of RAS Q61R mutations in thyroid pathology and is particularly relevant in follicular-patterned neoplasms. When evaluated alongside histological features, NRAS Q61R immunoreactivity can be instrumental in the diagnosis and classification of thyroid nodules., (© 2021 John Wiley & Sons Ltd.)

Background: Visual inspection and biopsy is the current standard of care for oral cancer diagnosis, but is subject to misinterpretation and consequently to misdiagnosis. Topically applied PARPi-FL is a molecularly specific, fluorescent contrast-based approach that may fulfill the unmet need for a simple, in vivo, non-invasive, cost-effective, point-of-care method for the early diagnosis of oral cancer. Here, we present results from a phase I safety and feasibility study on fluorescent, topically applied PARPi-FL. Twelve patients with a histologically proven oral squamous cell carcinoma (OSCC) gargled a PARPi-FL solution for 60 s (15 mL, 100 nM, 250 nM, 500 nM, or 1000 nM), followed by gargling a clearing solution for 60 s. Fluorescence measurements of the lesion and surrounding oral mucosa were taken before PARPi-FL application, after PARPi-FL application, and after clearing. Blood pressure, oxygen levels, clinical chemistry, and CBC were obtained before and after tracer administration., Results: PARPi-FL was well-tolerated by all patients without any safety concerns. When analyzing the fluorescence signal, all malignant lesions showed a significant differential in contrast after administration of PARPi-FL, with the highest increase occurring at the highest dose level (1000 nM), where all patients had a tumor-to-margin fluorescence signal ratio of >3. A clearing step was essential to increase signal specificity, as it clears unbound PARPi-FL trapped in normal anatomical structures. PARPi-FL tumor cell specificity was confirmed by ex vivo tabletop confocal microscopy. We have demonstrated that the fluorescence signal arose from the nuclei of tumor cells, endorsing our macroscopic findings., Conclusions: A PARPi-FL swish & spit solution is a rapid and non-invasive diagnostic tool that preferentially localizes fluorescent contrast to OSCC. This technique holds promise for the early detection of OSCC based on in vivo optical evaluation and targeted biopsy of suspicious lesions in the oral cavity., Trial Registration: Clinicaltrials.gov -NCT03085147, registered on March 21st, 2017., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

IDH2 R172 mutations occur in sinonasal undifferentiated carcinoma (SNUC), large-cell neuroendocrine carcinoma (LCNEC), sinonasal adenocarcinomas, and olfactory neuroblastoma (ONB). We performed a clinical, pathologic, and genetic/epigenetic analysis of a large IDH2-mutated sinonasal tumor cohort to explore their distinct features. A total 165 sinonasal/skull base tumors included 40 IDH2 mutants studied by light microscopy, immunohistochemistry, and genome-wide DNA methylation, and 125 IDH2 wild-type tumors used for comparison. Methylation profiles were analyzed by unsupervised hierarchical clustering, t-distributed stochastic neighbor embedding dimensionality reduction and assessed for copy number alterations (CNA). Thirty-nine histologically assessable cases included 25 (64.1%) SNUC, 8 (20.5%) LCNEC, 2 (5.1%) poorly differentiated adenocarcinomas, 1 (2.7%) ONB, and 3 (7.7%) IDH2-mutated tumors with ONB features. All cases were high-grade showing necrosis (82.4%), prominent nucleoli (88.9%), and median 21 mitoses/10 HPFs. AE1/AE3 and/or CAM 5.2 were positive in all and insulinoma-associated protein 1 (INSM1) in 80% cases. All IDH2 mutants formed one distinct group by t-distributed stochastic neighbor embedding dimensionality reduction separating from all IDH2 wild-type tumors. There was no correlation between methylation clusters and histopathologic diagnoses. Recurrent CNA included 1q gain (79.3%), 17p loss (75.9%), and 17q gain (58.6%). No CNA differences were observed between SNUC and LCNEC. IDH2 mutants showed better disease-specific survival than SMARCB1-deficient (P=0.027) and IDH2 wild-type carcinomas overall (P=0.042). IDH2-mutated sinonasal tumors are remarkably homogeneous at the molecular level and distinct from IDH2 wild-type sinonasal malignancies. Biology of IDH2-mutated sinonasal tumors might be primarily defined by their unique molecular fingerprint rather than by their respective histopathologic diagnoses., Competing Interests: Conflicts of Interest and Source of Funding: Supported by the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748 (to MSKCC/S.D. and D.G.P.). Additional funding was provided by the German Cancer Consortium (DKTK), partner site Berlin (to D.C.). Berlin Institute of Health (BIH) (to S.G.). Charité Universitätsmedizin Berlin, BIH and the German Research Foundation (to P.J.). Friedberg Charitable Foundation (to M.S.), and German Cancer Aid and the Fördergemeinschaft Kinderkrebs-Zentrum, Hamburg (to U.S.). For the remaining authors none were declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objective: Nodal metastasis is one of the strongest predictors of outcomes in oral cavity squamous cell carcinomas (OSCC). The aim was to analyze the interplay of nodal characteristics in OSCC prognosis., Methods: In this retrospective cohort study we included OSCC patients treated with primary surgery including neck dissection between 2005 and 2015 (n = 619). Disease-specific survival (DSS) was the primary endpoint. Optimal cutoffs were identified using recursive-partitioning analysis (RPA). A novel characteristic-metastatic focus-to-lymph node size ratio (MLR)-was introduced. We compared the American Joint Committee on Cancer, Eighth Edition (AJCC8) pN categories to a new categorization., Results: Patients with higher neutrophil-to-lymphocyte ratio had more adverse nodal characteristics. All nodal characteristics were significant predictors of DSS in univariable analysis. In multivariable analysis, only number of positive nodes and MLR remained significant. An RPA including all nodal covariates confirmed the results. Compared with AJCC8, our RPA categorization had better hazard discrimination (0.681 vs. 0.598), but poorer balance value (0.783 vs. 0.708)., Conclusion: Patients with higher neutrophil-to-lymphocyte ratio had more adverse nodal characteristics. Total number of metastatic lymph nodes is the strongest predictor of outcomes in OSCC. MLR is a more powerful predictor than metastatic lymph node size or metastatic focus size alone., (© 2020 Wiley Periodicals LLC.)

Medullary thyroid carcinoma (MTC) is a rare nonfollicular cell-derived tumor. A robust grading system may help better stratify patients at risk for recurrence and death from disease. In total, 144 MTC between 1988 and 2018 were subjected to a detailed histopathologic evaluation. Clinical and pathologic data were correlated with disease specific survival (DSS), local recurrence free survival (LRFS)  and distant metastasis free survival (DMFS). Median age was 53 years (range: 3-88). Median tumor size was 1.8 cm (range: 0.2-11). Lymph node metastases were present in 84 (58%) cases while distant metastases at presentation were found in 9 (6%) patients. Seven (5%) had ≥5 mitoses/10 HPFs. Tumor necrosis was present in 30 cases (20%) while lymphovascular invasion occurred in 41 (28%) of tumors. Extra-thyroidal extension was found in 44 (31%) and positive margins were seen in 19 (14%). There was a strong correlation between increasing tumor size and tumor necrosis (p < 0.001). Median follow up was 39 months. In univariate analysis, male gender, higher American Joint Committee on Cancer (AJCC) stage group, larger tumor size, tumor necrosis, high mitotic index (≥5/10 HPF), nodal status, size of largest nodal metastasis, and elevated postoperative serum calcitonin predicted worse DSS, LRFS, and DMFS (p < 0.05). Extra-thyroidal extension correlated with DSS and DMFS while positive margins and distant metastasis at presentation imparted worse DSS (p < 0.05). In multivariate analysis, tumor necrosis and mitotic activity (5 mitosis/10 HPFs as the cutoff) were the only independent predictors for DSS (p = 0.008 and 0.026, respectively). Tumor necrosis was the sole independent prognostic factor for LRFS and DMFS (p = 0.001 and 0.003, respectively). The presence of tumor necrosis and high mitotic rate are powerful independent prognostic factors in MTC and outperform serum calcitonin and stage. We propose a grading system based on tumor necrosis and mitotic activity to better stratify MTC patients for counseling, post-resection surveillance, and therapy.

Complete removal and negative margins are the goal of any surgical resection of primary oral cavity carcinoma. Current approaches to determine tumor boundaries rely heavily on surgeons' expertise, and final histopathological reports are usually only available days after surgery, precluding contemporaneous re-assessment of positive margins. Intraoperative optical imaging could address this unmet clinical need. Using mouse models of oral cavity carcinoma, we demonstrated that PARPi-FL, a fluorescent PARP inhibitor targeting the enzyme PARP1/2, can delineate oral cancer and accurately identify positive margins, both macroscopically and at cellular resolution. PARPi-FL also allowed identification of compromised margins based on fluorescence hotspots, which were not seen in margin-negative resections and control tongues. PARPi-FL was further able to differentiate tumor from low-grade dysplasia. Intravenous injection of PARPi-FL has significant potential for clinical translation and could aid surgeons in assessing oral cancer margins in vivo.

Introduction: Aggressive variants of papillary thyroid cancer (PTC) have been described with increasing frequency. These variants include diffuse sclerosing variant, tall cell variant, columnar cell variant, solid variant, and hobnail variant., Methods: We have performed a review of the more aggressive variants of PTC with respect to main characteristics, histological and molecular features, and the consequences that the knowledge of these variants should have in the treatment of the patients., Results: At the present time, we do not know the prognostic value of these aggressive PTC variants. The extent of the surgical treatment and adjuvant therapy necessary should be decided on the basis of the extent of the tumor at presentation and the opinion of experienced clinicians., Conclusion: These aggressive variants should be known by clinicians, to avoid underdiagnosis, and treated according to the latest recommendations in the literature.

Purpose: We performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with 18 F-PARPi in patients with head and neck cancer., Patients and Methods: Eleven patients with newly diagnosed or recurrent oral and oropharyngeal cancer were injected with 18 F-PARPi (331 ± 42 MBq), and dynamic PET/CT imaging was performed between 0 and 25 minutes postinjection. Static PET/CT scans were obtained at 30, 60, and 120 minutes postinjection. Blood samples for tracer concentration and metabolite analysis were collected. Blood pressure, ECG, oxygen levels, clinical chemistry, and complete blood count were obtained before and after tracer administration., Results: 18 F-PARPi was well-tolerated by all patients without any safety concerns. Of the 11 patients included in the analysis, 18 F-PARPi had focal uptake in all primary lesions ( n = 10, SUV max = 2.8 ± 1.2) and all 18 F-FDG-positive lymph nodes ( n = 34). 18 F-PARPi uptake was seen in 18 F-FDG-negative lymph nodes of 3 patients ( n = 6). Focal uptake of tracer in primary and metastatic lesions was corroborated by CT alone or in combination with 18 F-FDG. The overall effective dose with 18 F-PARPi PET was 3.9 mSv - 5.2 mSv, contrast was high [SUV max (lesion)/SUV max (trapezius muscle) = 4.5] and less variable than 18 F-FDG when compared with the genioglossus muscle (1.3 vs. 6.0, P = 0.001)., Conclusions: Imaging of head and neck cancer with 18 F-PARPi is feasible and safe. 18 F-PARPi detects primary and metastatic lesions, and retention in tumors is longer than in healthy tissues., (©2020 American Association for Cancer Research.)

Based on evidence accumulated over the past three decades showing that noninvasive encapsulated follicular variant of papillary thyroid carcinoma has an indolent clinical behavior and a RAS-like molecular profile similar to follicular adenoma, the Endocrine Pathology Society working group in 2016 proposed to rename this entity as "noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)" in order to eliminate the term "carcinoma" from the diagnosis. It is a major evidence-based attempt initiated by an international group of endocrine pathologists to tackle the epidemic of thyroid cancer overdiagnosis and overtreatment. However, its creation and continuous existence are not without controversies. NIFTP has sparked a wave of follow up studies aiming to decipher the exact nature of this new entity. In this review, we summarize the rationale, diagnostic criteria, controversies and subsequent changes to the NIFTP concept, and their impact on patient care and pathology practice.

For oral, oropharyngeal and oesophageal cancer, the early detection of tumours and of residual tumour after surgery are prognostic factors of recurrence rates and patient survival. Here, we report the validation, in animal models and a human, of the use of a previously described fluorescently labelled small-molecule inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP1) for the detection of cancers of the oral cavity, pharynx and oesophagus. We show that the fluorescent contrast agent can be used to quantify the expression levels of PARP1 and to detect oral, oropharyngeal and oesophageal tumours in mice, pigs and fresh human biospecimens when delivered topically or intravenously. The fluorescent PARP1 inhibitor can also detect oral carcinoma in a patient when applied as a mouthwash, and discriminate between fresh biopsied samples of the oral tumour and the surgical resection margin with more than 95% sensitivity and specificity. The PARP1 inhibitor could serve as the basis of a rapid and sensitive assay for the early detection and for the surgical-margin assessment of epithelial cancers of the upper intestinal tract.

Polymorphous adenocarcinoma (PAC) and cribriform adenocarcinoma of (minor) salivary gland (CASG) are salivary gland tumors with overlapping spectrum of morphology. Whether these represent distinct entities or a histologic spectrum of the same tumor remains contentious. PACs harbor recurrent PRKD1 E710D hotspot mutations in >70% of cases, whereas 80% of CASGs display rearrangements involving PRKD1, PRKD2, or PRKD3 (PRKD1/2/3). We studied the molecular and morphologic features of 37 PACs/CASGs, seeking to identify the associations among genotype, histologic phenotype, and classification. DNA was subjected to Sanger sequencing analysis of the PRKD1 hotspot locus. Fluorescence in situ hybridization (FISH) analysis for PRKD1/2/3 was performed using dual-color break-apart probes. Tumors were classified into four categories as described previously: PAC, CASG, tumor with indeterminate features (TIF), and tumor with a predominant papillary pattern (TPPP). PRKD1 E710D hotspot mutations were identified in 56%, 20%, 43% and 0% of PACs, CASGs, TIFs, and TPPPs, respectively. FISH demonstrated PRKD1/2/3 rearrangements in 13%, 78%, 36%, and 75% of PACs, CASGs, TIFs, and TPPPs, respectively. Histologically, fusion-positive tumors were associated with a high percentage of papillary growth, low percentage of single filing arrangement, a propensity of base of tongue location, and frequent (50%) lymph node metastasis, compared with the mutation-related tumors which had negligible nodal metastasis risk. Our results demonstrated that (1) PACs/CASGs are underpinned by genetic alterations affecting PRKD genes; (2) despite the associations between PAC and PRKD1 hotspot mutations and CASG and PRKD1/2/3 fusion, such distinction is not absolute; and (3) there is of a novel genotypic-phenotypic association whereby fusion-positive tumors are usually located in the base of the tongue, show papillary architecture and have a high risk of nodal metastasis. Genetic analysis of PRKD genes appears to be useful characterizing this spectrum of tumors, not only histologically but also clinically identifying those tumors with high risk of nodal metastasis.

Introduction: Long-term outcomes after curative resection in patients with germline RET mutations and medullary thyroid cancer (MTC) are highly variable and mutation-specific oncologic outcomes are not well-described., Methods: Sixty-six patients identified from 1986 to 2017 from a single-institution cancer database were assessed for recurrence and survival using Kaplan-Meier estimates, and correlated with clinicopathologic features using log-rank or Cox proportional hazards., Results: Median follow-up was 9.3 years (range 0.3-31.5), median tumor diameter was 1.5 cm (range 0.1-7.5), and preoperative calcitonin was known in 41 patients [median 636 (range 0-9600)]. Overall survival (OS) of the cohort was 94% at 10 years, the cumulative incidence of locoregional recurrence was 38% at 10 years, and 19/24 (79%) patients underwent repeat neck operation. The cumulative incidence of distant recurrence was 27% at 10 years. Predictors of distant recurrence were tumor size, positive lymph nodes, and pre- and postoperative carcinoembryonic antigen, but not calcitonin. M918T mutation-bearing patients had 10-year distant recurrence-free survival of 0%, compared with 83% in all other patients (p < 0.001), and equivalent 10-year OS (100% vs. 92%; p = 0.49)., Conclusions: Structural and metastatic recurrence is common in patients with germline RET mutations, and MTC and can occur 20 years after initial treatment, however survival remains high. Management should focus on optimal surveillance strategies and long-term control of structural disease.

Sinonasal undifferentiated carcinoma (SNUC) is an aggressive malignancy harboring IDH2 R172 mutations in >80% cases. We explored the potential of genome-wide DNA methylation profiling to elucidate tumor biology and improve the diagnosis of sinonasal undifferentiated carcinoma and its histologic mimics. Forty-two cases, including sinonasal undifferentiated, large cell neuroendocrine, small cell neuroendocrine, and SMARCB1-deficient carcinomas and olfactory neuroblastoma, were profiled by Illumina Infinium Methylation EPIC array interrogating >850,000 CpG sites. The data were analyzed using a custom bioinformatics pipeline. IDH2 mutation status was determined by the targeted exome sequencing (MSK-IMPACT TM ) in most cases. H3K27 methylation level was assessed by the immunohistochemistry-based H-score. DNA methylation-based semi-supervised hierarchical clustering analysis segregated IDH2 mutants, mostly sinonasal undifferentiated (n = 10) and large cell neuroendocrine carcinomas (n = 4), from other sinonasal tumors, and formed a single cluster irrespective of the histologic type. t-distributed stochastic neighbor embedding dimensionality reduction analysis showed no overlap between IDH2 mutants, SMARCB1-deficient carcinoma and olfactory neuroblastoma. IDH2 mutants demonstrated a global methylation phenotype and an increase in repressive trimethylation of H3K27 in comparison to IDH2 wild-type tumors (p < 0.001). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed no difference in pathway activation between IDH2-mutated sinonasal undifferentiated and large cell neuroendocrine carcinomas. In comparison to SMARCB1-deficient, IDH2-mutated carcinomas were associated with better disease-free survival (p = 0.034) and lower propensity for lung metastasis (p = 0.002). ARID1A mutations were common in small cell neuroendocrine carcinoma but not among IDH2 mutants (3/3 versus 0/18 and p < 0.001). IDH2 mutations in sinonasal carcinomas induce a hypermethylator phenotype and define a molecular subgroup of tumors arising in this location. IDH2-mutated sinonasal undifferentiated carcinoma and large cell neuroendocrine carcinoma likely represent a phenotypic spectrum of the same entity, which is distinct from small cell neuroendocrine and SMARCB1-deficient sinonasal carcinomas. DNA methylation-based analysis of the sinonasal tumors has potential to improve the diagnostic accuracy and classification of tumors arising in this location.

Background: Several multitargeted tyrosine kinase inhibitors (TKIs) have demonstrated activity in patients with thyroid cancer that is refractory to radioactive iodine (RAI). The antitumor effect is attributed at least in part to the ability of these TKIs to inhibit angiogenesis in these vascular tumors. Vascular endothelial growth factor (VEGF) Trap (VT) is a recombinantly produced fusion protein consisting solely of human sequences for VEGF receptors 1 and 2 extracellular domains and human immunoglobulin 1. Evaluating VT in patients with thyroid cancer is reasonable considering the activity observed with TKIs targeting VEGF., Methods: The current study was a single-institution, phase 2, Simon 2-stage design (21 to >41 patients) study based on the objective response rate and/or 6-month progression-free survival as the primary endpoints. Eligible patients were required to have progressive, RAI-refractory and/or [ 18 F]fludeoxyglucose-avid, recurrent and/or metastatic, nonmedullary, nonanaplastic thyroid cancer; disease that was measurable using Response Evaluation Criteria In Solid Tumors (RECIST) criteria; and adequate organ and bone marrow function. VT at a dose of 4 mg/kg intravenously was administered every 14 days., Results: A total of 40 patients were included in the analysis. Of these patients, 24 had papillary thyroid cancer, 2 had follicular thyroid cancer, and 11 had Hurthle cell thyroid cancer. The final 3 tumors were classified as poorly differentiated. There were no complete and/or partial responses noted; 34 patients achieved stable disease and 6 patients experienced disease progression as their best response. Of the 34 patients with stable disease, 16 remained on the study for >6 months and 6 patients remained on the study for >12 months. The median duration on treatment was 4.1 months (range, 0.6-30.8 months)., Conclusions: Unlike TKIs, which have shown responses in this setting, to the authors' knowledge there have been no responses observed with the use of single-agent VT to date. It does not appear to be a promising drug for the treatment of patients with thyroid cancer., (© 2019 American Cancer Society.)

Context: BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI)., Objectives: To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR)., Design: This was a pilot trial that enrolled from June 2014 to January 2016., Setting: Academic cancer center., Patients: Patients with RAIR, BRAF mutant thyroid cancer., Intervention: Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation., Main Outcome Measure: The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I., Results: Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048)., Conclusions: Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit., (Copyright © 2019 Endocrine Society.)