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Thyroid cancer (TC) invariably remains the most prevalent endocrine cancer in the world. Major histological forms of TC include papillary (PTC), follicular (FTC), medullary (MTC), and anaplastic thyroid carcinoma (ATC), each of which has a unique clinical and molecular profile. The incidence rate of TC is higher in females, and unfortunately, it has tended to increase over the last several years. Yet the treatment of advanced or aggressive TC forms has improved recently because of developments in immunotherapy and targeted medicines, including PD-1 inhibitors and tyrosine kinase inhibitors (e.g., lenvatinib, sorafenib). Imaging, fine-needle aspiration biopsies, and molecular testing are implemented in the diagnostic process, e.g., in search of mutations that might affect prognosis and provide the most successful treatment option. Chemotherapy, immunotherapy, radioactive iodine therapy (RAI), surgery (such as a total thyroidectomy), and molecularly targeted therapies are currently standard treatment modalities in TC. Optimizing patient outcomes requires better diagnostic precision and individualized treatment regimens based on the genetic profile and tumor subtype. To improve survival and quality of life, it is critical to comprehend the complex etiology of TC and the changing therapeutic landscape.

Differentiated thyroid cancer (DTC) is a rare malignant disease, although its incidence has increased over the last few decades. It derives from follicular thyroid cells. Generally speaking, the prognosis is excellent. If treatment according to the current guidelines is given, cases of recurrence or persistence are rare. DTC requires special expertise by the treating physician. In recent years, new therapeutic options for these patients have become available. For this article we performed a systematic literature review with special focus on the guidelines of the American Thyroid Association, the European Association of Nuclear Medicine, and the German Society of Nuclear Medicine. For DTC, surgery and radioiodine therapy followed by levothyroxine substitution remain the established therapeutic procedures. Even metastasized tumors can be cured this way. However, in rare cases of radioiodine-refractory tumors, additional options are to be discussed. These include strict suppression of thyroid-stimulating hormone (also known as thyrotropin, TSH) and external local radiotherapy. Systemic cytostatic chemotherapy does not play a significant role. Recently, multikinase or tyrosine kinase inhibitors have been approved for the treatment of radioiodine-refractory DTC. Although a benefit for overall survival has not been shown yet, these new drugs can slow down tumor progression. However, they are frequently associated with severe side effects and should be reserved for patients with threatening symptoms only.

The most recent WHO classification of endocrine and neuroendocrine tumours has brought about significant changes in the diagnosis and grading of these lesions. For instance, pathologists now have the ability to stratify subsets of thyroid and adrenal neoplasms using various histological features and composite risk assessment models. Moreover, novel recommendations on how to approach endocrine neoplasia involve additional immunohistochemical analyses, and the recognition and implementation of these key markers is essential for modernising diagnostic capabilities. Additionally, an improved understanding of tumour origin has led to the renaming of several entities, resulting in the emergence of terminology not yet universally recognised. The adjustments in nomenclature and prognostication may pose a challenge for the clinical team, and care providers might be eager to engage in a dialogue with the diagnosing pathologist, as treatment guidelines have not fully caught up with these recent changes. Therefore, it is crucial for a surgical pathologist to be aware of the knowledge behind the implementation of changes in the WHO classification scheme. This review article will delve into the most significant diagnostic and prognostic changes related to lesions in the parathyroid, thyroid, adrenal glands and the gastroenteropancreatic neuroendocrine system. Additionally, the author will briefly share his personal reflections on the clinical implementation, drawing from a couple of years of experience with these new algorithms.

Thyroid carcinoma consists a group of phenotypically heterogeneous cancers. Recent advances in biological technologies have been advancing the delineation of genetic, epigenetic, and non-genetic factors that contribute to the heterogeneities of these cancers. In this review article, we discuss new findings that are greatly improving the understanding of thyroid cancer biology and facilitating the identification of novel targets for therapeutic intervention. We review the phenotypic features of different subtypes of thyroid cancers and their underlying biology. We discuss recent discoveries in thyroid cancer heterogeneities and the critical mechanisms contributing to the heterogeneity with emphases on genetic and epigenetic factors, cancer stemness traits, and tumor microenvironments. We also discuss the potential relevance of the intratumor heterogeneity in understanding therapeutic resistance and how new findings in tumor biology can facilitate designing novel targeting therapies for thyroid cancer.

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).

Artificial intelligence applications in oncology imaging often struggle with diagnosing rare tumors. We identify significant gaps in detecting uncommon thyroid cancer types with ultrasound, where scarce data leads to frequent misdiagnosis. Traditional augmentation strategies do not capture the unique disease variations, hindering model training and performance. To overcome this, we propose a text-driven generative method that fuses clinical insights with image generation, producing synthetic samples that realistically reflect rare subtypes. In rigorous evaluations, our approach achieves substantial gains in diagnostic metrics, surpasses existing methods in authenticity and diversity measures, and generalizes effectively to other private and public datasets with various rare cancers. In this work, we demonstrate that text-guided image augmentation substantially enhances model accuracy and robustness for rare tumor detection, offering a promising avenue for more reliable and widespread clinical adoption. Artificial intelligence (AI) is becoming increasingly relevant to assist with oncology imaging, but diagnosing rare tumours remains challenging. Here, the authors develop an AI approach to detect rare thyroid cancer subtypes by integrating clinical knowledge with image generation based on ultrasound imaging data from large patient cohorts.

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.

Background Renaming encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently suggested to prevent the overtreatment, cost and stigma associated with this low-risk entity. The purpose of this study is to document the incidence and further assess the clinical outcomes of reclassifying EFVPTC to NIFTP. Methods We searched synoptic pathologic reports from a high-volume academic endocrine surgery hospital from 2004 to 2013. The standard of surgical pathology practice was based on complete submission of malignant thyroid nodules along with the nontumorous thyroid parenchyma. Rigid morphological criteria were used for the diagnosis of noninvasive EFVPTC, currently known as NIFTP. A retrospective chart review was conducted looking for evidence of malignant behavior. Results One hundred and two patients met the strict inclusion criteria of NIFTP. The incidence of NIFTP in our cohort was 2.1% of papillary thyroid cancer cases during the studied time period. Mean follow-up was 5.7 years (range 0–11). Five patients were identified with nodal metastasis and one patient with distant metastasis. Overall, six patients showed evidence of malignant behavior representing 6% of patients with NIFTP. Conclusion Our study demonstrates that the incidence of NIFTP is significantly lower than previously thought. Furthermore, evidence of malignant behavior was seen in a significant number of NIFTP patients. Although the authors fully support the de-escalation of aggressive treatment for low-risk thyroid cancers, NIFTP behaves as a low-risk thyroid cancer rather than a benign entity and ongoing surveillance is warranted.

This review provides historical context to recent developments in the classification of the follicular variant of papillary thyroid carcinoma (FVPTC). The evolution of the diagnostic criteria for papillary thyroid carcinoma is described, clarifying the role of molecular analysis and the impact on patient management. A PubMed search using the terms \"follicular variant\" and \"papillary thyroid carcinoma\" covering the years 1960 to 2016 was performed. Additional references were identified through review of the citations of the retrieved articles. The encapsulated/well-demarcated, noninvasive form of FVPTC that occurs annually in 45,000 patients worldwide was thought for 30 years to be a carcinoma. Many studies have shown almost no recurrence in these noninvasive tumors, even in patients treated by surgery alone without radioactive iodine therapy. The categorization of the tumor as outright cancer has led to aggressive forms of treatment, with their side effects, financial costs, and the psychological and social impacts of a cancer diagnosis. Recently, the encapsulated/well-demarcated, noninvasive FVPTC was renamed as noninvasive follicular thyroid neoplasm with papillary-like nuclear features. The new terminology lacks the carcinoma label, enabling clinicians to avoid aggressive therapy. By understanding the history of FVPTC, future classification of tumors will be greatly improved.

In recent years, the incidence of thyroid cancer has rapidly increased. To address the issue of the inefficient diagnosis of thyroid cancer during surgery, we propose a rapid method for the diagnosis of benign and malignant thyroid nodules based on hyperspectral technology. Firstly, using our self-developed thyroid nodule hyperspectral acquisition system, data for a large number of diverse thyroid nodule samples were obtained, providing a foundation for subsequent diagnosis. Secondly, to better meet clinical practical needs, we address the current situation of medical hyperspectral image classification research being mainly focused on pixel-based region segmentation, by proposing a method for nodule classification as benign or malignant based on thyroid nodule hyperspectral data blocks. Using 3D CNN and VGG16 networks as a basis, we designed a neural network algorithm (V3Dnet) for classification based on three-dimensional hyperspectral data blocks. In the case of a dataset with a block size of 50 × 50 × 196, the classification accuracy for benign and malignant samples reaches 84.63%. We also investigated the impact of data block size on the classification performance and constructed a classification model that includes thyroid nodule sample acquisition, hyperspectral data preprocessing, and an algorithm for thyroid nodule classification as benign and malignant based on hyperspectral data blocks. The proposed model for thyroid nodule classification is expected to be applied in thyroid surgery, thereby improving surgical accuracy and providing strong support for scientific research in related fields.