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SummaryBackgroundThe four-stage American Joint Committee on Cancer (AJCC) staging system has been used for almost 50 years for assessing the risk of multiple cancers; the AJCC classification for papillary thyroid cancer is solely based on clinical parameters, and despite updated editions its accuracy remains suboptimal. We aimed to evaluate whether the performance of the AJCC system could be improved by integrating tumour genetic statuses of BRAF and TERT genes. MethodsThis retrospective multicentre cohort study used patient medical records from 15 medical centres across ten countries for patients (of all ages) with papillary thyroid cancer who had been surgically treated with total thyroidectomy or hemithyroidectomy with or without neck dissection, followed by postoperative radioiodine ablation and appropriate thyroid-stimulating hormone level targeting. Testing for BRAFV600E and TERT promotor ( TERTp) mutations was performed on genomic DNA isolated from surgical or cytological specimens of primary papillary thyroid cancer tumours at each centre. Data from all medical centres were pooled for aggregated analyses of the relationship between the genetic status and papillary thyroid cancer-specific mortality for each of the four classical stages of the 7th and 8th editions of the AJCC system (AJCC7E and AJCC8E). The primary endpoint was papillary thyroid cancer-specific mortality, characterised by mortality rates per 1000 person-years. FindingsUsing patients who were treated for papillary thyroid cancer between January 1979, to July 2023 at the 15 centres, our cohort comprised of 4746 patients (3612 [76·1%] females and 1134 [23·9%] males), with median age of 48 years (IQR 37–59; 89 [1·9%] patients aged ≤18 years). For the 4400 patients with available ethnicity data, the majority were Asian (2140 [48·6%]) and 2096 (47·6%) were White. For AJCC7E, compared with the original stages, the genetic duet of BRAFV600E and TERTp mutations was associated with increased mortality in all stages versus the corresponding original stages, although the HR for stage I did not reach statistical significance. Those with wildtype BRAFV600E and TERTp had flat survival curves for stages I–III with AJCC7E and stages I–II of AJCC8E. Patients with dual mutations had reductions in survival across all stages for the AJCC7E (stage I HR 5·96 [95% CI 0·73–48·66]; p=0·10; stage II 5·94 [95% CI 1·42–24·91]; p=0·015; stage III 4·04 [95% CI 1·87–8·70]; p=0·00037; and stage IV 1·79 [95% CI 1·15–2·76]; p=0·0092). TERTp mutation alone was also significantly associated with a significant increase in mortality for stage IV (3·57 [2·01–6·37]; p<0·0001). For AJCC8E, we observed a similar pattern of increased mortality when both mutations were present compared to mortality in the original staging, with significant differences in HR for stages I and II (stage I adjusted HR 10·30 [95% CI 3·43–30·93], p<0·0001; stage II HR 3·95 [95% CI 1·92–8·15]; p=0·00020). Stage III also showed increased mortality with dual mutations, but the increase was not statistically significant (HR 1·77 [0·95–3·31]; p=0·072). In contrast to AJCC7E, the dual mutations did not increase mortality compared with the original stage IV (HR 0·95 [0·47–1·92], p=0·89), but the TERTp mutation did significantly increase mortality in stage IV papillary thyroid cancer (HR 2·75 [1·36–5·58], p=0·0049). InterpretationIntegrating the genetic statuses of BRAF and TERTp into the AJCC system changes the original risk stages of the AJCC system and significantly improves the accuracy of its mortality risk classification for papillary thyroid cancer. FundingNational Institute on Aging, the Auburn Community Cancer Endowed Chair in Basic Research, the Heart, Breast, and Brain Health Equity Research program, National Institutes of Health, and the American Association for Cancer Research Fellowship 21–40–69-ESTR (USA); Ministry of Health (Czech Republic); Prémio Francisco Augusto da Fonseca Dias e Maria José Melenas da Fonseca para Jovens Investigadores (Portugal); Italian Ministry of Health-Ricerca Corrente (Italy); JSPS KAKENHI (Japan); MINCIENCIAS, L’OREAL-UNESCO-ICETEX-COLCIENCIAS, Universidad del Tolima (Colombia); STRATEGMED2/267398/4/NCBR/2015, the National Centre for Research and Development (Poland); RISBIN IPTEKDOK 2014, Ministry of Health (Indonesia); and the Information and Communications Technology and Future Planning of the Basic Science Research Program via the National Research Foundation of Korea (NRF) funded by the Ministry of Science (Korea).

Abstract Context US papillary thyroid carcinoma (PTC) incidence recently declined for the first time in decades, for reasons that remain unclear. Objective This work aims to evaluate PTC incidence trends, including by histologic subtype and size, and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Design This descriptive study uses US Surveillance, Epidemiology, and End Results–18 cancer registry data (2000-2017). Patients Participants included individuals diagnosed with PTC (2000-2017) or NIFTP (2016-2017). Results During 2000 to 2015, PTC incidence increased an average 7.3% per year, (95% CI, 6.9% to 7.8%) during 2000 to 2009, and 3.7% per year (95% CI, 0.2% to 7.3%) during 2009 to 2012, before stabilizing in 2012 to 2015 (annual percentage change [APC] = 1.4% per year, 95% CI, –1.8% to 4.7%) and declining in 2015 to 2017 (APC = –4.6% per year, 95% CI, –7.6% to –1.4%). The recent declines were observed for all sizes of PTC at diagnosis. Incidence of follicular variant of PTC (FVPTC) sharply declined in 2015 to 2017, overall (APC = –21.1% per year; 95% CI, –26.5% to –15.2%) and for all tumor sizes. Observed increases in encapsulated papillary carcinoma (classical PTC subtype) and NIFTP each accounted for 10% of the decline in FVPTC. Classical PTC incidence continuously increased (2000-2009, APC = 8.7% per year, 95% CI, 8.1% to 9.4%; 2009-2017, APC = 1.0% per year, 95% CI, 0.4% to 1.5%), overall and for all sizes except smaller than 1 cm, as did incidence of other PTC variants combined (2000-2017, APC = 5.9% per year, 95% CI, 4.0% to 7.9%). Conclusion The reasons underlying PTC incidence trends were multifactorial. Sharp declines in FVPTC incidence during 2015 to 2017 coincided with clinical practice and diagnostic coding changes, including reclassification of noninvasive encapsulated FVPTC from a malignant to in situ neoplasm (NIFTP). Observed increases in NIFTP accounted for 10% of the decline in FVPTC.

- Proposed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs), formerly noninvasive encapsulated papillary carcinoma, follicular variant (PTC-FV), is an indolent tumor with follicular growth and frequent RAS mutations. - To detect histologic and molecular differences separating NIFTP from follicular adenomas (FAs) and invasive carcinomas, particularly papillary carcinomas with extensive follicular growth (PTC-EFGs) and invasive encapsulated PTC-FV (IE-PTC-FV). - Sixty-one tumors were reviewed histologically and reclassified into 32 NIFTPs (52%), 4 IE-PTC-FVs (7%), 14 PTC-EFGs (23%), and 11 FAs (18%). Next-generation sequencing for mutations in 50 genes was performed. Clinical outcomes were recorded. - The NIFTPs and FAs were well circumscribed and unencapsulated. The FAs had bland nuclei, whereas the NIFTPs showed at least 2 of 3 (67%; sufficient) nuclear features (enlargement, irregular contours, chromatin clearing). The IE-PTC-FVs had follicular growth, sufficient nuclear features, and extensive capsular invasion. The PTC-EFGs had a median of 5% papillae with intrathyroidal invasion (broad-based, sclerotic, or small follicle growth patterns); intranuclear pseudoinclusions were present only in PTC-EFGs (9 of 14; 64%). Mutations included RAS in 20 of the 32 NIFTPs (62%), 4 of the 11 FAs (36%), and 3 of the 4 IE-PTC-FVs (75%); BRAF K601E in 1 NIFTP (3%); BRAF V600E in 5 PTC-EFGs (36%). No NIFTPs or FAs recurred or metastasized. All 4 IE-PTC-FVs (100%) had hematogenous metastasis. Two PTC-EFGs (14%) had lymphatic metastasis. - The morphologic similarity and RAS mutations in FAs, NIFTPs, and IE-PTC-FVs supports the genetic similarity of those follicular neoplasms in contrast to the unique presence of BRAF V600E mutations in PTC-EFGs. Using strict diagnostic criteria supported by molecular testing, tumors with extensive follicular growth can be classified into follicular type or RAS-like (FA, NIFTP, IE-PTC-FV) versus papillary type or BRAF V600E-like (PTC-EFG).

Purpose Our purposes were: 1) to estimate the prediction performance (PP) of cytology in identifying papillary thyroid carcinoma (PTC) subtypes; 2) to explore how the PTC subtypes distribute among the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) categories. Methods Nodules were included if both the histology with the PTC subtype report and the cytology report with the possible PTC subtype were available. The PP was calculated by making the proportion of True positives/False positives+false negatives. Results 309 cytologically “suspicious for malignancy” and “malignant” thyroid nodules with PTC histology were evaluated. ACR TI-RADS categorization for classical PTC was significantly different from non-classical PTC ( p- value 0.02). For the whole cohort the PP of cytologically classical cases was 0.74, while that of cytologically non classical cases was 0.41. ACR TI-RADS categorization was not significantly different for aggressive vs non-aggressive PTC subtypes ( p- value 0.1). When considering only aggressive or non-aggressive PTC subtypes, the PP of cytologically classical cases was respectively 0.86 and 0.87, while that of cytologically non classical cases was respectively 0.27 and 0.22. The PP of cytologically classical cases was 0.73 and 0.79, respectively for macroPTCs and microPTCs, while that of cytologically non classical cases was 0.55 and 0.33, respectively for macroPTCs and microPTCs. Conclusion Cytology examination reliably performed in predicting classical PTC versus non classical PTC subtypes. ACR TI-RADS categorization was significantly different among classical PTC versus non classical PTC subtypes.

Background Limited comprehensive evaluations have been conducted to date regarding the clinical behavior of papillary thyroid carcinoma (PTC) subtypes based on the 2022 World Health Organization (WHO) classification of thyroid neoplasms. Methods A total of 768 patients who underwent surgical treatment for PTC were retrospectively categorized into 12 subtypes according to the 2022 WHO classification system. Clinical and pathological variables including incidence rate, age at onset, sex, anatomical location of lesions, lesion size, presence of lymph node metastasis, capsular invasion, tumor microenvironmental features, familial predisposition, and gene mutations were comparatively analyzed across these subtypes. Results Among the 12 identified subtypes, the diffuse sclerosing subtype (DSS) demonstrated the highest incidence, followed by the encapsulated subtype (ES) and the subtype with fibromatosis/fasciitis-like stroma (WF/FLS). The spindle cell subtype (SCS) exhibited the lowest incidence. An annual increase in the incidence of WF/FLS subtypes was observed. Multifocal lesion occurrence was significantly more frequent in individuals with the DSS subtype compared to the overall PTC cohort ( p  < 0.05). Lymph node metastasis rates were notably elevated in the hobnail subtype (HS), tall cell subtype (TCS), DSS, and Warthin-like subtype (WLS). The prevalence of Hashimoto’s thyroiditis was significantly lower in the ES subtype ( p  < 0.05) and significantly higher in the WLS subtype ( p  < 0.001), relative to the broader PTC population. Subtypes including Solid subtype (SS), WF/FLS, HS, and WLS demonstrated higher frequencies of familial tumor history. Although gene mutation rates were elevated across all subtypes, no statistically significant differences were identified among them. Conclusion Papillary thyroid carcinoma subtypes defined by the 2022 WHO classification exhibit distinct demographic, pathological, and molecular profiles. Subtypes such as hobnail, tall cell, diffuse sclerosing, and Warthin-like show aggressive features, while encapsulated, infiltrative follicular, and oncocytic types follow indolent courses.The high familial rate and increasing trend of the WF/FLS subtype provide novel insight into its possible genetic and microenvironmental influences. Recognizing these subtype-based differences may refine surgical decision-making, risk stratification, and postoperative surveillance strategies.

Background The tall cell variant of papillary thyroid carcinoma (PTC) is as an aggressive histological variant. The proportion of tall cells needed to influence prognosis is debated. Methods Patients with PTC and tall cells, defined as having a height-to-width ratio of ≥ 3:1, seen at a high-volume center between 2001 and 2015, were reviewed. Specimens were classified as (1) focal tall cell change, containing < 30% of tall cells; (2) tall cell variant, ≥ 30% of tall cells; and (3) control cases selected from infiltrative classical PTCs without adverse cytologic features. Univariate, sensitivity, and multivariate analyses were performed with persistent/recurrent disease as the primary outcome. Results We identified 96 PTCs with focal tall cell change, 35 with the tall cell variant and 104 control cases. Factors associated with poor clinical prognosis were significantly greater in those with focal tall cell change and tall cell variants. Regarding primary outcome, hazard ratios were 2.3 (95% confidence interval [CI] 1.0–5.7) for focal tall cell change, and 3.4 (95% CI 1.2–8.7) for tall cell variants compared with controls. Five-year disease-free survival was higher for the control group (92.7%, CI 87.4–98.0) compared with focal tall cell change (76.3%, CI 66.1–86.5) and the tall cell variant (62.2%, CI 43.2–81.2). When stratified in groups consisting of tall cell proportions (< 10%, 10–19%, 20–29% and ≥ 30%), identification of ≥ 10% tall cell change was associated with worse outcome ( p  = 0.002). Conclusions PTCs with ≥ 10% tall cell change have worse prognosis than those without tall cells. Our data indicate that thyroid cancer management guidelines should consider PTCs with focal tall cell change outside of the low-risk classification.

Purpose This study aims to develop a deep learning–based computer-aided diagnosis (CAD) system for the automatic detection and classification of lateral cervical lymph nodes (LNs) on original ultrasound images of papillary thyroid carcinoma (PTC) patients. Methods A retrospective data set of 1801 cervical LN ultrasound images from 1675 patients with PTC and a prospective test set including 185 images from 160 patients were collected. Four different deep leaning models were trained and validated in the retrospective data set. The best model was selected for CAD system development and compared with three sonographers in the retrospective and prospective test sets. Results The Deformable Detection Transformer (DETR) model showed the highest diagnostic efficacy, with a mean average precision score of 86.3% in the retrospective test set, and was therefore used in constructing the CAD system. The detection performance of the CAD system was superior to the junior sonographer and intermediate sonographer with accuracies of 86.3% and 92.4% in the retrospective and prospective test sets, respectively. The classification performance of the CAD system was better than all sonographers with the areas under the curve (AUCs) of 94.4% and 95.2% in the retrospective and prospective test sets, respectively. Conclusions This study developed a Deformable DETR model-based CAD system for automatically detecting and classifying lateral cervical LNs on original ultrasound images, which showed excellent diagnostic efficacy and clinical utility. It can be an important tool for assisting sonographers in the diagnosis process.

The incidence of thyroid cancer has shown marked increases globally over recent decades. This study investigated how the incidence of papillary thyroid carcinoma (PTC) subtypes and World Health Organisation (WHO) endocrine tumour classification changes have affected overall thyroid cancer incidence recorded in Australia. Using incidence data from the Australian Institute of Health and Welfare cancer registry (spanning 1982 to 2019), this descriptive epidemiological study employed joinpoint regression analysis to assess temporal trends in thyroid carcinoma incidence, focusing on PTC. Results were then compared with WHO endocrine tumour classification changes over the same period. The results showed increasing trends for the classic PTC subtype over the entire 38-year period and for thyroid microcarcinomas post-2003, while a declining trend for the follicular variant of PTC was observed commencing in 2015. Examination of PTC incidence also revealed distinct changes in trends that align with the WHO classification of papillary microcarcinoma as a subtype in 2004 and the reclassification of some encapsulated follicular variant of PTCs to non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) in 2016/17. Even when taking these WHO classification changes into account, significant increases in PTC over the last three decades are observed. These findings underscore the shifts in classification driven by improving diagnostic clarity influencing thyroid carcinoma incidence patterns. However, thyroid carcinoma cases in Australia have dramatically increased over the last three decades independent of WHO classification changes, suggesting a genuine increase rather than simply being a direct consequence of improved reporting and diagnostics.

The recently adopted terminology of “Noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP) reflects the indolent behavior of these tumors. In contrast to conventional papillary thyroid carcinomas, NIFTP can be managed conservatively. The purpose of this study was to investigate changes in surgical and pathologic practice patterns at our institution since the introduction of the NIFTP diagnosis in 2016. A retrospective analysis of all thyroid specimens received in our laboratory between January 2015 and April 2017 was performed. The final cohort consisted of 1508 thyroidectomy specimens from 1508 patients (1153 (76.5%) women and 355 (23.5%) men), of which 1011 (67%) were total thyroidectomies and 497 (33%) were partial thyroidectomies. There were 558 (69.2%) total thyroidectomies and 248 (30.8%) partial thyroidectomies performed prior to introduction of the NIFTP diagnosis and 453 (64.5%) and 249 (35.5%) total and partial thyroidectomies, respectively, after the change in nomenclature. Within a year following the initial use of this diagnosis, 67 NIFTP cases were identified (9.5% of all thyroidectomies), whereas compared with the year preceding it, malignant diagnoses decreased from 54.5 (439) to 44.6% (313), and the benign category remained unchanged from 44.5 (367) to 45.9% (322). For the entirely submitted 67 NIFTP cases, the mean number of blocks submitted was 14.7 (0.98 blocks/g); for malignant lesions 17.7 (0.92 blocks/g); and for benign lesions 16.6 (0.75 blocks/g). The results of our study suggest that NIFTP are encountered in almost 10% of thyroidectomies at our institution with expected shifts in cytology and surgical pathology diagnoses as a result of the change in nomenclature. During this time period, significant shifts towards less aggressive surgical management were not observed. All 67 NIFTP nodules were submitted entirely with no significant difference in the number of cassettes submitted for NIFTP nodules as compared with follicular variant papillary thyroid carcinoma (PTC), classic variant PTC, or follicular adenoma.

Glucose metabolism-related genes play an important role in the development and immunotherapy of many tumours, but their role in thyroid cancer is ambiguous. To investigate the role of glucose metabolism-related genes in the development of papillary thyroid cancer (PTC) and their correlation with the clinical outcome of PTC, we collected transcriptomic data from 501 PTC patients in the Cancer Genome Atlas (TCGA). We performed nonnegative matrix decomposition clustering of 2752 glucose metabolism-related genes from transcriptome data and classified PTC patients into three subgroups (C1 for high activation of glucose metabolism, C2 for low activation of glucose metabolism and C3 for moderate activation of glucose metabolism) based on the activation of different glucose metabolism-related genes in 10 glucose metabolism-related pathways. We found a positive correlation between the activation level of glucose metabolism and the tumour mutation burden (TMB), neoantigen number, mRNA stemness index (mRNAsi), age, and tumour stage in PTC patients. Next, we constructed a prognostic prediction model for PTC using six glucose metabolism-related genes (PGBD5, TPO, IGFBPL1, TMEM171, SOD3, TDRD9) and constructed a nomogram based on the risk score and clinical parameters of PTC patients. Both the prognostic risk prediction model and nomogram had high stability and accuracy for predicting the progression-free interval (PFI) in PTC patients. Patients were then divided into high-risk and low-risk groups by risk score. The high-risk group was sensitive to paclitaxel and anti-PD-1 treatment, and the low-risk group was sensitive to sorafenib treatment. We found that the high-risk group was enriched in inflammatory response pathways and associated with high level of immune cell infiltration. To verify the accuracy of the prognostic prediction model, we knocked down PGBD5 in PTC cells and found that the proliferation ability of PTC cells was significantly reduced. This suggests that PGBD5 may be a relatively important oncogene in PTC. Our study constructed a prognostic prediction model and classification of PTC by glucose metabolism-related genes, which provides a new perspective on the role of glucose metabolism in the development and immune microenvironment of PTC and in guiding chemotherapy, targeted therapy and immune checkpoint blockade therapy of PTC.