Hormone therapy (HT) to treat prostate cancer is reported to cause adverse changes in body composition. Clinically, interpatient body composition changes are heterogeneous, but the biological and clinical determinants of body composition toxicity are unknown. Herein, we test the hypothesis that inherited polymorphisms in steroidogenic genes are associated with differential changes in body composition after HT. Men with biochemically recurrent prostate cancer (BCR) who received 8 months of LHRH analog (LHRHa) +/- abiraterone acetate (AAP) were eligible if they had: i) CT imaging of L3 prior to and after treatment; and ii) nucleated cells collected. Cardiometabolic co-morbidities were retrospectively extracted. Body composition was measured using an AI-based segmentation tool. Germline DNA whole exome or genome sequencing was performed. In 162 men treated with 8 months of HT, median skeletal muscle mass (SMMi) loss was 6.6% and subcutaneous adipose gain was 12.3%. Men with type 2 diabetes had higher losses of SMMi after treatment (-11.1% vs -6.3%, P = 0.003). For the 150 men with germline NGS, SRD5A2 rs523349 genotype was associated with differential loss in skeletal muscle density after HT, (-1.3% vs -7.1%, P = 0.04). In addition, the HSD3B1 rs104703 genotype was associated with decreased baseline visceral adipose tissue (63.0 cm2/m2 vs 77.9, P = 0.05). In men with BCR, HT induced notable loss of skeletal muscle and increased subcutaneous adipose tissue. An inherited polymorphism in SRD5A2 and T2DM was associated with differential skeletal muscle toxicity. These findings suggest that inherited polymorphisms may contribute to the body composition toxicity observed with HT.

Differentiated thyroid cancer in older adults has been linked to alterations in the mutational landscape and tumor immune cell infiltration that create a tumor-permissive microenvironment. We sought to determine the impact of age on genomic alterations and immune cell composition in papillary thyroid cancer (PTC). Genomic alterations, immune cell composition, and clinical data were obtained using The Cancer Genome Atlas and computational immunogenomic analyses. Disease severity was recoded into three groups: Group A (T1-2N0M0), Group B (T1-3N1a-1bM0), and Group C (T4NxMx or TxNxM1). Histopathologic subtypes included conventional, follicular-variant, and tall cell variant PTC. Spearman's rank correlation, ANOVA, t-test, and multivariable linear regression were performed. A total of 470 PTC samples were retrieved from the TCGA portal with genomic alteration and immune cell composition data. TERT promoter alterations were more common in patients aged ≥65 years (26% vs 4%, P < 0.0001). Tumor mutational burden increased with increasing age (r = 0.463, P < 0.0001). Increasing age was associated with decreased CD8+ T cells (r = -0.15, P = 0.01) using CIBERSORT and decreased B cells (r = -0.13), CD8+ T cells (r = -0.19), and neutrophils (r = -0.14, P < 0.05) using TIMER. Multivariate regression found that increasing age was independently associated with increased resting NK cells and resting dendritic cells, and decreased naïve B cells and CD8+ T cells (P < 0.05). PTC tumors of older adults are characterized by increased TERT promoter alterations, increased tumor mutational burden, and a decreased cytotoxic CD8+ T cells and increased resting dendritic cell immune infiltrate. Further studies are needed to determine if these changes in immune cell infiltrate are associated with compromised outcomes.

Chromosomal instability (CIN), characterized by fluctuations in chromosome number or structure within cells, stands out as a hallmark of cancer, enabling tumors to thrive in hostile conditions. CIN serves as a driver of genetic diversity, giving rise to clonal heterogeneity (CH). Emerging evidence points to a potential correlation between CIN, CH, and the prognosis of breast cancer (BC) patients, especially in tumors exhibiting overexpression of the human epidermal growth factor receptor 2 (HER2+). However, our understanding of the role of CIN in other subtypes of BC is limited. Furthermore, it remains unclear whether CIN levels above a certain threshold in BC tumors could adversely affect tumor growth, or if lower to moderate levels of CIN might be associated with a more favorable prognosis for BC patients compared to elevated levels. Elucidating these relationships could significantly influence risk assessment and the formulation of future therapeutic approaches targeting CIN in BC. This study aimed to assess CIN and CH in tumor tissue samples obtained from Colombian patients diagnosed with luminal A, luminal B, HER2+, or triple-negative BC, and compare them with established clinicopathological parameters. The findings of this study indicate that BC patients exhibit intermediate CIN, high CH, and stable aneuploidy. All these characteristics were found to be related to clinicopathological features. Our results suggest that the identification of CIN, CH, and aneuploidy could improve cancer risk stratification, which could help to clarify the prediction of clinical outcomes and guide personalized therapeutic strategies for patients with different BC subtypes.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy characterized by diagnostic challenges, high recurrence rates, and poor prognosis. This study explored the role of miRNA processing genes in ACC and their potential role as diagnostic and prognostic biomarkers. We analyzed the mRNA expression levels of miRNA machinery components (DROSHA, DGCR8, XPO5, RAN, DICER, TARBP2, and AGO2) utilizing mRNA-Seq data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) projects. Additionally, protein levels were quantified in tissue samples from the Kolling Institute of Medical Research's tumor bank. Our results demonstrated that among all miRNA processing components, AGO2 exhibited significant overexpression in ACC compared to the normal adrenal cortex and benign adrenal adenoma (P < 0.001). Kaplan-Meier survival analysis indicated that higher AGO2 expression correlated with significantly worse overall survival in ACC patients (HR: 7.07, P < 0.001). Among 32 cancer types in TCGA, the prognostic significance of AGO2 was most prominent in ACC. This study is the first to report AGO2's potential as a diagnostic and prognostic biomarker in ACC, emphasizing its significance in ACC pathogenesis and potential application as a non-invasive liquid biopsy biomarker.

Measurement of thyroglobulin in fine-needle aspirates (FNA-Tg) is useful for the diagnosis of lymph node metastasis in thyroid carcinoma; however, the cutoff value remains unclear, particularly for the differential diagnosis of neck masses. To evaluate the cutoff value of FNA-Tg, we conducted a retrospective study of patients with neck masses outside the thyroid who pre-operatively underwent both FNAC and FNA-Tg, followed by pathological examination at our hospital from October 2015 to September 2020. The cutoff value of FNA-Tg was calculated using the receiver operating characteristic curve. Among 210 lesions, 57 were of thyroid origin and 153 lesions were not of thyroid origin. A high FNA-Tg value was observed in the lesions of thyroid origin (P: 0.001), and the cutoff value at the minimum point of 100% specificity was 32.2 ng/mL with a sensitivity of 87.7%. Regarding the effect of serum anti-Tg antibodies, FNA-Tg values were significantly lower or not significantly different depending on the grouping, warranting further studies. Among the cases with papillary thyroid carcinoma, the sensitivity of FNAC and FNA-Tg was 71.4% and 87.5%, respectively. The cutoff value of FNA-Tg for the differential diagnosis of neck masses was higher compared to previous reports because some metastatic lymph nodes of carcinomas and lesions, other than lymph nodes, exhibited higher FNA-Tg values. Therefore, if FNA-Tg is to be used as a screening test for the differential diagnosis of neck masses in patients without proven thyroid carcinoma, it is necessary to establish a higher cutoff value.

Inhibiting the activity of the androgen receptor (AR) is the cornerstone treatment for advanced prostate cancer. AR-targeted therapies are highly effective in slowing disease progression but are not curative and the resultant disease state, termed castration-resistant prostate cancer, is associated with significant patient morbidity and mortality. In most cases, resistance to these therapies arises due to alterations that reactivate the AR signalling axis. Interestingly, it has long been recognised that potent activation of AR with supraphysiological levels of androgens can suppress prostate cancer growth in both preclinical models and patients. This intriguing paradox - where both inhibition and activation of AR have anti-cancer effects - is now being harnessed clinically in the form of bipolar androgen therapy (BAT). This review describes mechanisms underlying the tumour-suppressive functions of AR in the context of potent androgenic stimulation and discusses how our maturing understanding of these mechanisms is influencing the clinical deployment of BAT.

Cancer is the second leading cause of death in the United States and among the most prevalent diseases globally, with an incidence expected to grow because of smoking, pollution, poor dietary habits, obesity, and the rise in the older population. Given their ability to reduce risk factors, albeit with varying efficacy, nutrition and fasting could help prevent cancer and other age-related disorders. Calorie restriction (CR), various forms of intermittent fasting (IF) or periodic fasting (PF), and fasting-mimicking diets (FMDs) have been shown to improve health span, increase lifespan, and prevent or postpone cancer in rodents. The effects of specific diets and fasting regimens on aging and cancer appear to be mediated in part by the reduction in the activity of the growth hormone (GH)/insulin-like-growth-factor-I (IGF-1) axis. Nevertheless, recent data indicate that the alternation of low and normal levels of these hormones and factors may be ideal for optimizing longevity and function. Here, we review the role of nutrition, CR, and fasting/FMD on cancer, focusing on the hypothesis that the modulation of GH, IGF-1, and insulin signaling partly mediates the effect of these dietary interventions on cancer prevention.

This study provides a comprehensive analysis of global, continental, and national trends in the prevalence and mortality of prostate cancer (PC), breast cancer (BC), and thyroid cancer (TC). Utilizing 2021 Global Burden of Diseases (GBD2021) data, prevalence and death rates for 2021 were examined, with temporal trends from 1990 to 2021 analyzed via Joinpoint regression. Annual percentage change (APC) and average APC (AAPC) were calculated with 95% CI. Distributive inequalities were quantified using the slope index of inequality and concentration index. In 2021, PC, BC, and TC showed higher global age-standardized prevalence rates (ASPR) in Europe and America compared to Africa and Asia, while higher age-standardized death rates (ASDR) for PC and BC were noted in Africa. Over the study period, significant global increases in ASPR were observed for PC (AAPC = 0.78, 95% CI: 0.67 to 0.89), BC (AAPC = 0.31, 95% CI: 0.24 to 0.37), and TC (AAPC = 1.42, 95% CI: 1.31 to 1.52). Conversely, ASDR significantly decreased for PC (AAPC = -0.83, 95% CI: -0.92 to -0.74), BC (AAPC = -0.48, 95% CI: -0.56 to -0.39), and TC (AAPC = -0.23, 95% CI: -0.29 to -0.17). Variations were observed across continents and time periods, affecting 204 countries and territories. Higher Social Development Index (SDI) levels were associated with a more pronounced burden of these cancers. The findings highlight significant global heterogeneity in prevalence, death rates, and temporal trends of endocrine cancers, with important implications for epidemiology and public health policies.

Telomerase reverse transcriptase promoter mutation (pTERT MT) promotes human carcinogenesis via aberrant expression of telomerase reverse transcriptase (TERT). However, the tumorigenic impact of TERT expression independent of pTERT MT remains unclear despite numerous mechanisms of TERT being suggested. To tackle this issue, we employed comprehensive bioinformatics to assess biological variations noticed among different TERT expression mechanisms. Papillary thyroid cancer (PTC) with pTERT MT (pTERT MT PTC) presented aggressive clinical behavior and exhibited biological profiles associated with cellular immortality and genomic instability. PTC with TERT expression but without pTERT MT (TERT (+) PTC), also exhibited poor clinicopathological characteristics and was enriched with immune responses. In accordance, c-MYC/E2F and nuclear factor kappa B (NFκB) were dominant transcription factors in pTERT MT PTC and TERT (+) PTC, respectively. Notably, we revealed TERT hypermethylated oncological region (THOR) as a potential TERT expressing mechanism in TERT (+) PTC patients. Furthermore, three unique subtypes of papillary thyroid cancer were deciphered using a combination of machine learning-based scoring systems. Our proposed scoring system was clinically significant, especially in microcarcinoma, predicting survival outcomes and inferring therapeutic responses to radioactive iodine therapy. Finally, our analysis was expanded to endocrine-related cancers, unveiling various regulatory mechanisms of TERT with poor clinical outcomes and biological behaviors.

Immune checkpoint inhibitors (ICIs) can trigger immune-related adverse events (irAEs). The appearance pattern of irAEs, who is prone to them, and their mechanisms are still uncertain. In this study, we aimed to monitor patients initiated on ICIs for endocrinological aspects and to investigate the potential predictive markers in the development of endocrine-irAEs. The study prospectively included 43 patients with metastatic disease scheduled for anti-PD-1/L1 therapy. Endocrinological follow-up was conducted at specified intervals as well as in response to any additional reported complaints. Serum concentrations of CXCL10, IL-1beta, and IL-17A were measured prior to ICI and during the endocrine-irAEs. A total of 39.5% of the patients experienced endocrine-irAEs, with a median onset time of 3 months. Among patients, 34.9% developed thyroid-related adverse events, and 4.6% experienced hypophysitis. Thyroid autoantibodies were associated with a higher incidence of thyroid-related irAEs (P = 0.004). In the irAE group, median pre-ICI CXCL10 and baseline thyroid stimulating hormone (TSH) levels were significantly higher, baseline total testosterone level in men was lower than in the non-irAE group (P < 0.05), whereas IL-1beta and IL-17A levels did not differ (P > 0.05). Serum CXCL10, IL-1beta, and IL-17A concentrations did not differ significantly pre-ICI and during adverse events (P > 0.05). Pre-ICI CXCL10 concentration was correlated positively with anti-TPO levels in patients with at least one thyroid autoantibody positivity (r = 0.706, P = 0.01) and negatively with baseline total testosterone level of men (r = 0.509, P = 0.002). Our results suggest that higher pre-ICI serum CXCL10 and TSH levels might have a predictive role in the development of endocrinopathies. Besides, baseline thyroid antibody measurements could be beneficial in predicting thyroid dysfunction.

Adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas are rare neuroendocrine tumors that co-secrete excess catecholamines and adrenocorticotropic hormone, resulting in Cushing syndrome (CS). This review aims to summarize important patient characteristics, investigations, and outcomes in all cases reported in the English literature. A literature search was conducted to identify all English-language case reports and case series describing adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas. Relevant characteristics were systematically recorded. Cases that did not provide definitive evidence of an adrenocorticotropin (ACTH)-producing pheochromocytoma/paraganglioma were excluded. Our search strategy identified 93 published cases that met the inclusion criteria. We additionally reported one patient for a total of 94 cases. Details related to patient characteristics, laboratory data, and outcomes were commonly underreported. The median age was 47 years, and females accounted for 72% of cases. A cushingoid appearance was reported in 82% of patients, and hypertension in 86%. Infections were reported in 23% of patients. Urinary metanephrines were elevated at least three-fold above normal in 74% of cases. ACTH levels were high in 88% of patients and inappropriately normal in 12%. The median 24-hour urinary cortisol was 21-fold the upper limit of normal. Adrenalectomy was performed in nearly all patients, with 88% achieving a cure for both catecholamine and glucocorticoid excess. A total of 11 patients died. Metastases were uncommon (6%). Adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas are associated with considerable morbidity and mortality. It should be considered in the diagnostic workup of all patients with ectopic CS. Surgical cure is achieved in most patients, and infections are the leading cause of peri-operative mortality.

Pembrolizumab-related thyroid dysfunction has been associated with better outcomes in metastatic cancer patients. This study aims to examine the outcomes (pathological complete response (pCR) and event-free survival (EFS)) in early-stage triple-negative breast cancer (TNBC) patients receiving preoperative therapy who developed pembrolizumab-related thyroid dysfunction. Patients were divided into four groups based on the occurrence or not of pembrolizumab-related thyroid dysfunction (group A and D, respectively) and, in case of pre-existing thyroid disorder, based on the need for levothyroxine start/adjustment or not (group B and C, respectively). pCR and EFS in groups A, B, and C were compared to the ones in group D. Sixty-four early-stage TNBC patients were included, and the median follow-up was 16.5 months (IQR 12.0-23.8). Multiple patterns of thyroid irAEs were observed (overt hypothyroidism in 56.3%, subclinical thyrotoxicosis in 28.1%, overt thyrotoxicosis and subclinical hypothyroidism in 21.9%, and 21.9% of patients). No statistical difference was found in pCR (chi-square test, P = 0.611) comparing groups A, B, and C to group D. The median EFS in groups A, B, and C and in group D were 16.5 (IQR 12.0-24.0) and 16.0 (IQR 12.0-22.3) months, respectively (log-rank test, P = 0.671). The percentage of patients obtaining pCR was 85.7% in patients developing pembrolizumab-related overt thyrotoxicosis and 42.1% in remaining patients (chi-square test, P = 0.036). The EFS was 16.0 months (IQR 12.0-25.0) in patients developing pembrolizumab-related overt thyrotoxicosis and 16.0 months (IQR 12.0-23.5) in the remaining patients (log-rank test, P = 0.494). In conclusion, multiple patterns of pembrolizumab-related thyroid dysfunction occur in early-stage TNBC. Patients developing pembrolizumab-related overt thyrotoxicosis are more likely to achieve pCR.

The classification and management of neuroendocrine neoplasms (NENs) arising in the tubular gastrointestinal (GI) tract and pancreas have significantly evolved over the last decades. In the latest WHO classification published in 2022, NENs are separated regardless of their primary origin into two main groups: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The substantial changes in the grading system changed the definition of grade 3 to include high-grade well-differentiated NETs (G3-NETs), and poorly differentiated NECs (-NECs). Although these two subgroups are considered high grades with Ki-67 >20%, they have different genomic profiles, prognosis, and clinical behavior, which critically influence their treatment strategies. The available clinical trial data to guide therapy of these high-grade subgroups are extremely limited, which impacts their management. In this review, we will summarize the current advances in the multidisciplinary approach for the management of high-grade gastroenteropancreatic NENs (GEP-NENs) including G3-NETs and NECs.

REarranged during Transfection (RET) is a developmentally important receptor tyrosine kinase that has been identified as an oncogenic driver in a number of cancers. Activating RET point-mutations give rise to the inherited cancer syndrome Multiple Endocrine Neoplasia type 2 (MEN2), characterized by medullary thyroid carcinoma. There are two MEN2 subtypes, MEN2A and MEN2B, that differ in tumour aggressiveness and the associated constellation of other disease features, which are caused by distinct patterns of RET amino acid substitution mutations. MEN2A-RET mutations affecting extracellular cysteine residues promote ligand independent dimerization and constitutive RET activity, while MEN2B is caused by a single amino acid change in the tyrosine kinase domain of RET, releasing autoinhibition and producing a more active MEN2B-RET kinase that can promote signalling as monomers or dimers in the absence of ligand. These mutations cause intrinsic biochemical changes in RET structure and activation but also trigger extrinsic effects that alter RET cellular location, interactions and mechanisms of downregulation that can prolong or mislocate RET activity, changing or enhancing functional outcomes. Together, changes in specific combinations of RET-mediated effects associated with different mutations give rise to the distinct MEN2 disease phenotypes. Here, we discuss the current understanding of the intrinsic and extrinsic characteristics of RET MEN2A cysteine and MEN2B mutants and how these contribute to transforming cellular processes and to differences in tumour progression and disease aggressiveness.

Multiple endocrine neoplasia type 2 (MEN2) is the collective term for 2 distinct types of autosomal dominantly inherited neuroendocrine neoplasm (NEN) syndromes (Barakat, 2004); MEN2A and MEN 2B (or MEN3). MEN2 is characterised by medullary thyroid cancer (99%) and phaeochromocytoma (50%) but also other conditions according to specific genotype. MEN2A also includes a 25% risk of developing parathyroid hyperplasia and is now recognised as 4 separate syndromes: Classic MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung's disease (HD) and Familial MTC (Wells, 2015). MEN2B accounts for around 5% of all MEN2 cases and predisposes patients to diffuse intestinal ganglioneuromatosis (Goncharova, 2020), mucosal neuromas, and musculoskeletal abnormalities (Henderson, 2022). MEN2 is autosomal dominantly inherited meaning that several generations in a single family may be affected by the same syndrome. We present a mini review of 4 case studies (x2 MEN2A, x2 MEN2B) that illustrate the advantages of RET testing, as well as some of the likely obstacles that must be overcome to receive a diagnosis of MEN2A or MEN2B. In addition, despite improved genotype/phenotype correlation in MEN2, we highlight that not all cases are 'typical' which emphasises the need for all MEN2 patients to be cared for in a centre of expertise and experience. Some of our case study patients or parents also took this opportunity to personally tell us more about their lives with MEN2, illustrating the need for more research into the psychosocial impact of these hereditary diseases.

The molecular biology of pituitary neuroendocrine tumors (PitNETs) revealed few recurrent mutations and extensive chromosomal alterations, with the latter being the driving force in a subset of these lesions. Addressing the need for an easily applicable diagnostic tool, we conducted a retrospective study of 61 PitNETs operated at a tertiary care center. All cases were subtyped according to the 2022 WHO classification of endocrine tumors. A genome wide NGS panel targeting 1500 single-nucleotide polymorphisms (SNP) was used to classify chromosomal imbalances, loss of heterozygosity and copy number variations in DNA from formalin fixed paraffin embedded tissues. We identified four distinct chromosomal patterns, with varying distribution among different tumor lineages. Forty-two of 61 (69%) PitNETs showed chromosomal alterations. Gonadotroph PitNETs showed mostly quiet genomes. The majority of lactotroph PitNETs (19/20, 95%) were altered, exhibiting a gained genome and a remarkably low recurrence rate. Nine of ten (90%) corticotroph PitNETs harbored chromosomal alterations, of which two aggressive corticotroph tumors and one metastatic corticotroph PitNET showed massive chromosomal losses leading to near haploid/near homozygous genomes. The comparison of the molecular profile of primary and recurrent PitNETs of five patients showed no significant accumulation of alterations over time. A simple genome wide 1500 SNP test can be used in the identification of outspoken aggressive subsets of PitNET by the occurrence of a near haploid/near homozygous genome. Furthermore, the presence of neoplastic tissue in resected material can be potentially confirmed for non-gonadotroph PitNETs in suboptimal histological assessment conditions.

The breast epithelium, vital for mammary gland function, is influenced by oestrogen through the ER signalling pathway. Luminal breast cancer, characterised by ER expression, comprises the majority of all breast cancers and presents significant clinical challenges due to therapy resistance and recurrence. Despite advancements in understanding luminal disease, improving long-term survival and reducing relapse of breast cancer patients by predicting therapy efficacy and understanding resistance mechanisms remain critical challenges. This review discusses luminal breast cancer biology, focusing on molecular classification of the primary disease, metastatic spread, and experimental models.

The RET receptor tyrosine kinase is physiologically stimulated by growth factors belonging to the glial cell line-derived neurotrophic factor (GDNF) family (GFLs) and by the growth differentiation factor-15 (GDF15) cytokine. RET plays a critical role in normal development as well as in various human tumors and developmental disorders. This review focuses on mechanisms of RET signaling and their alterations in human diseases.

Multiple endocrine neoplasia type 2 (MEN 2) is a rare hereditary endocrine tumour syndrome caused by mutations in the rearranged during transfection (RET) gene. MEN 2 is divided into two main entities, MEN 2A and MEN2B, both of which present with medullary thyroid cancer (MTC) in approximately 100% of cases and pheochromocytoma in 50% of cases. Specific RET mutations are associated with a risk of early onset of MTC, from 1 year of age (highest risk) to 5 years of age (high risk). This risk defines the optimal timing for thyroidectomy, ideally at an age when the disease has not spread. This is the most important genotype-phenotype correlation observed in MEN 2. Specific RET mutations also define the penetrance of pheochromocytoma. However, despite the presence of these highest/high risk variants, some patients unexpectedly present with non-aggressive MTC or never present with pheochromocytoma, suggesting that factors other than the major RET variant may modify the natural history and genotype-phenotype correlations. Improving our understanding of the genotype-phenotype correlations would allow individualizing the management and follow-up of patients with MEN 2. The aim of this brief review is to discuss the main genotype-phenotype correlations in MEN 2 and the potential factors that might influence these correlations.

BRAFK601E is an uncommon mutation typically found in encapsulated follicular-patterned thyroid tumors. Previous studies on BRAFK601E-positive thyroid tumors were conducted before implementation of the non-invasive follicular neoplasm with papillary-like nuclear features (NIFTP) diagnosis. This study aimed to characterize BRAFK601E-positive tumors and evaluate changes in diagnosis and management of these patients after introduction of NIFTP. We evaluated 25 thyroid tumors that were positive for BRAFK601E and diagnosed considering the NIFTP criteria. Clinicopathologic characteristics and recurrence rates of these tumors were compared to 29 BRAFK601E-positive tumors diagnosed prior to the acceptance of NIFTP diagnosis. RNA-seq analysis was performed on 10 BRAFK601E-positive tumors. In the current study, 72% of BRAFK601E-positive tumors were diagnosed as non-invasive tumors on resection, with NIFTP (48% of all tumors) being the most common diagnosis. BRAFK601E-positive tumors exhibited a RAS-like gene expression profile with BRAF-RAS score (BRS) and thyroid differentiation score (TDS) distinct from BRAFV600E-positive tumors (P<0.001). Since 2016, patients with BRAFK601E-positive tumors less frequently underwent total thyroidectomy (41% vs 100%, P<0.001) and received radioiodine (7% vs 75%, P<0.001). None of the tumors positive for an isolated BRAFK601E mutation from the current or 2016 studies showed recurrences on follow-up. Our study demonstrates that most BRAFK601E-positive tumors are low risk, RAS-like tumors, which were diagnosed as NIFTP in half of all study cases. Since 2016, patients with BRAFK601E-positive nodules receive less aggressive treatment. The risk of recurrence of BRAFK601E-positive tumors without other, high-risk features appears to be low, and lobectomy without radioiodine is likely sufficient treatment for these patients.