The Role of Molecular Markers in Thyroid Cancer Diagnostics and Treatment.

Molecular testing for cytologically indeterminate thyroid nodules has demonstrated benefit by reducing the need for diagnostic thyroidectomies and reducing costs. Its use is currently recommended in practice guidelines from the American Thyroid Association and the American Association of Endocrine Surgeons when clinically appropriate. Moreover, there is growing evidence that molecular testing may provide prognostic information and can detect targetable genetic alterations which may expand treatment options for refractory advanced thyroid cancers.

Molecular-derived risk of malignancy and the related positive call rate of indeterminate thyroid cytology diagnoses as quality metrics for individual cytopathologists.

BACKGROUND: Indeterminate thyroid cytopathology diagnoses represent differing degrees of risk that are corroborated by follow-up studies. However, traditional cytologic-histologic correlation may overestimate the risk of malignancy (ROM) because only a subset of cases undergo resection. Alternatively, some molecular tests provide probability of malignancy data to calculate the molecular-derived risk of malignancy (MDROM) and the positive call rate (PCR). The authors investigated MDROMs and PCRs of indeterminate diagnoses for individual cytopathologists as quality metrics. METHODS: This study was approved by the Department of Pathology Quality Improvement Program. Thyroid cytopathology diagnoses and ThyroSeq v3 results were retrieved for each cytopathologist for a 2-year period with at least 3 years of follow-up for the atypia of undetermined significance (AUS), follicular neoplasia (FN), and follicular neoplasia, oncocytic-type (ONC) cytopathologic diagnoses. MDROMs and PCRs were compared with reference ROMs and cytologic-histologic correlation outcomes. RESULTS: The overall MDROMs (and ranges for cytopathologists) for the AUS, FN, and ONC categories were 13.4% (range, 5.8%-20.8%), 28.1% (range, 22.1%-36.7%), and 27.0% (range, 19.5%-41.5%), respectively, and most individual cytopathologists' MDROMs were within reference ROM ranges. However, PCRs more effectively parsed the differences in cytopathologists' ROM performance. Although the overall PCRs were not significantly different across cytopathologists (p = .06), the AUS PCRs were quite different (p = .002). By cytologic-histologic correlation, six of 55 resected cases (10.9%) were falsely negative, and there were no false-positive cases. CONCLUSIONS: MDROMs and PCRs evaluate concordance with reference ROMs and with one another and provide individual feedback, which potentially facilitates quality improvement.

Outcomes of subtotal parathyroidectomy for renal hyperparathyroidism.

BACKGROUND: Renal hyperparathyroidism due to end-stage kidney disease is associated with considerable morbidity, and when refractory is treated with parathyroidectomy. Recurrent renal hyperparathyroidism is a major surgical complication, yet initial target parathyroid remnant size and outcomes, including rates of recurrence are not well elucidated. METHODS: This is a single-institution retrospective cohort study of patients who underwent initial subtotal parathyroidectomy for renal hyperparathyroidism on dialysis, from 1990-2022. The subtotal parathyroidectomy was defined as resection of 3 parathyroid glands ± partial resection of the fourth gland leaving a remnant of ∼75-100 mg, and postresection intraoperative parathyroid hormone goal was 150-250 pg/mL. Clinical data were examined for outcomes. RESULTS: Among 204 patients who met inclusion criteria, 139 (68%) had follow-up data; 58% (80/139) were women and median age was 45 years. Surgical complications included 2 hematomas (1.4%), 1 recurrent laryngeal nerve injury (<1%), and no patient required readmission for intravenous calcium. Using a target remnant size of 75-100 mg, recurrent renal hyperparathyroidism was uncommon (14/139, 10%) and arose at a median interval of 58.6 months (range, 8-180). In cases of recurrence, the postresection intraoperative parathyroid hormone level was less likely to drop <250 pg/mL (40%, 4/10 vs nonrecurrence 65%, 80/123; P = .11) with a slightly lower median decrease (70% vs 81% in nonrecurrence, P = .8); however, neither were significant. Recurrence did not occur in the 19 patients who later received kidney transplantation (P = .2). CONCLUSION: In subtotal parathyroidectomy for renal hyperparathyroidism, use of a target 75-100 mg remnant size results in low complication rates. Durable cure appears to be more likely with renal transplantation.

Sex differences in patients with primary hyperparathyroidism.

BACKGROUND: Differences in presenting symptoms of primary hyperparathyroidism and outcomes of parathyroidectomy between sexes have been described, but whether these can be assessed by perioperative use of a validated tool, such as the Pasieka Parathyroidectomy Assessment Score, is unknown. METHOD: All patients with primary hyperparathyroidism were asked to complete symptom assessment at the preoperative and postoperative visits. The assessment included a query for 13 Pasieka Parathyroidectomy Assessment Score parameters evaluated using a visual analog scale as described by Pasieka (summative score 0-1,300), and general quality of life and wellness. A review of a prospectively maintained database of primary hyperparathyroidism patients (January 2016-December 2019) was performed, and those who had a 6-month cure after initial parathyroidectomy were included. RESULTS: The study cohort was mostly women (77%, 541/701). The median preoperative Pasieka Parathyroidectomy Assessment Score was higher in women (155, 0-1,190) than in men (80.5, 0-855, P < .001), although there were similar rates of asymptomatic primary hyperparathyroidism (Pasieka Parathyroidectomy Assessment Score = 0, 12.5% vs 7%, P = .042). After curative parathyroidectomy, women reported a substantial reduction in symptomatology, with Pasieka Parathyroidectomy Assessment Score declining by 35% at initial postoperative visit (median, 155 vs 100, P < .001), further decreasing to 48% by 6 months (155 vs 80, P < .001). The Pasieka Parathyroidectomy Assessment Score in men did change but to a much smaller degree at both the initial postoperative visit (80.5 vs 70; P = .036) and at 6 months (80.5 vs 57.5; P = .048). CONCLUSION: When assessed with the Pasieka Parathyroidectomy Assessment Score, improvement in symptoms was clearly demonstrated for women after curative parathyroidectomy. Whether symptom improvement also occurs in men is less apparent but may be due to disparities in the development and validation of outcomes tools in general.

Normocalcemic hyperparathyroidism: Intervention to differentiate primary from secondary hyperparathyroidism.

BACKGROUND: Normocalcemic hyperparathyroidism can occur, but surgery should not be considered until common etiologies for secondary hyperparathyroidism are comprehensively excluded. Calcium deficiency is an underrecognized cause of normocalcemic parathyroid hormone elevation, and we aim to determine if the implementation of a preoperative calcium challenge can be used to reduce unnecessary parathyroidectomy. METHODS: Consecutive patients referred for parathyroidectomy (1/21-6/22) with normocalcemia (serum calcium <10 mg/dL) and concurrently elevated parathyroid hormone levels were routinely treated with supplemental calcium and vitamin D3, and follow-up laboratory studies were assessed. RESULTS: A total of 29/314 (9%) patients had normocalcemic parathyroid hormone elevation with mean calcium, parathyroid hormone, and vitamin D 25OH levels of 9.5 ± 0.3 mg/dL, 109.9 ± 34.9 pg/mL, and 42.7 ± 23.8 ng/mL respectively. Confounding factors included estimated glomerular filtration rate <60 in 2, loop diuretic use in 4, and prior gastric bypass or gastric sleeve surgery in 4. Follow-up biochemical evaluation was available in 27 (92%); results were unchanged in 7 patients (26%); normalization of parathyroid hormone levels with persistently normal calcium levels occurred in 15 (55%), thus confirming secondary hyperparathyroidism and hypercalcemia with elevated parathyroid hormone levels (classic primary hyperparathyroidism) was diagnosed in 5 (19%). Parathyroid exploration has been completed for 3 of 5 patients with classic primary hyperparathyroidism to date. CONCLUSION: A preoperative calcium challenge was prospectively initiated in normocalcemic patients with parathyroid hormone elevation, and there was high compliance (92%). Short-interval calcium supplementation revealed ∼50% to have resolved secondary hyperparathyroidism due to insufficient calcium intake, which avoided unnecessary surgery. In contrast, classic patients were unveiled in 20%, allowing for prompt and correct surgical intervention.

Molecular Profiling of 50 734 Bethesda III-VI Thyroid Nodules by ThyroSeq v3: Implications for Personalized Management.

CONTEXT: Comprehensive genomic analysis of thyroid nodules for multiple classes of molecular alterations detected in a large series of fine needle aspiration (FNA) samples has not been reported. OBJECTIVE: To determine the prevalence of clinically relevant molecular alterations in Bethesda categories III-VI (BCIII-VI) thyroid nodules. METHODS: This retrospective analysis of FNA samples, tested by ThyroSeq v3 using Genomic Classifier and Cancer Risk Classifier at UPMC Molecular and Genomic Pathology laboratory, analyzed the prevalence of diagnostic, prognostic, and targetable genetic alterations in a total of 50 734 BCIII-VI nodules from 48 225 patients. RESULTS: Among 50 734 informative FNA samples, 65.3% were test-negative, 33.9% positive, 0.2% positive for medullary carcinoma, and 0.6% positive for parathyroid. The benign call rate in BCIII-IV nodules was 68%. Among test-positive samples, 73.3% had mutations, 11.3% gene fusions, and 10.8% isolated copy number alterations. Comparing BCIII-IV nodules with BCV-VI nodules revealed a shift from predominantly RAS-like alterations to BRAF V600E-like alterations and fusions involving receptor tyrosine kinases (RTK). Using ThyroSeq Cancer Risk Classifier, a high-risk profile, which typically included TERT or TP53 mutations, was found in 6% of samples, more frequently BCV-VI. RNA-Seq confirmed ThyroSeq detection of novel RTK fusions in 98.9% of cases. CONCLUSION: In this series, 68% of BCIII-IV nodules were classified as negative by ThyroSeq, potentially preventing diagnostic surgery in this subset of patients. Specific genetic alterations were detected in most BCV-VI nodules, with a higher prevalence of BRAF and TERT mutations and targetable gene fusions compared to BCIII-IV nodules, offering prognostic and therapeutic information for patient management.

Molecular Testing Predicts Incomplete Response to Initial Therapy in Differentiated Thyroid Carcinoma Without Lateral Neck or Distant Metastasis at Presentation: Retrospective Cohort Study.

Background: Molecular testing (MT) is emerging as a potential prognostic factor that can be available before treatment of differentiated thyroid carcinoma begins. Among patients eligible for either lobectomy or total thyroidectomy as their initial therapy, our study aims were to assess (1) if conventionally available preoperative factors are associated with incomplete response to initial therapy, and (2) if MT results can be a surrogate for the ATA Risk Stratification System (RSS) to estimate risk of recurrence. Methods: The data of consecutive thyroid cancer patients without preoperative lateral neck disease or distant metastasis who underwent index thyroidectomy between November 1, 2017 and October 31, 2021 were reviewed. Logistic regression models including preoperative variables such as MT and/or the postoperatively available RSS were constructed to predict disease recurrence, either structural or biochemical. Model discrimination using the c-statistic and goodness-of-fit test were compared. Results: Among 945 patients studied, 50 (5.2%) recurred with 18-month median follow-up. Recurrences were detected in 17 (2.9%), 20 (6.7%), and 13 (22.8%) patients with RSS-low, -intermediate, and -high cancers, respectively (p < 0.001). In multivariable analysis, only tumor size was associated with recurrence (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.1-1.5). In a different model analyzing 440 (46.6%) patients with available MT results, recurrence was associated with both larger tumor size (OR 1.4 [95% CI 1.1-1.8]) and MT results (p < 0.001). Including MT improved the c-statistic by 27%, which was statistically no different than the model incorporating only the RSS (p = 0.15). Conclusions: Disease recurrence was observed across all ATA RSS categories in short-term follow-up, and tumor size was the only conventional preoperative factor associated with recurrence. When MT results were incorporated, they not only improved predictive ability beyond tumor size alone, but also yielded similar ability as the gold standard ATA RSS. Thus, MT results might aid the development of novel preoperative risk stratification algorithms.

Association of comprehensive thyroid cancer molecular profiling with tumor phenotype and cancer-specific outcomes.

BACKGROUND: Molecular testing improves the diagnostic accuracy of thyroid cancer. Whether specific molecular testing results are associated with tumor phenotype or provide prognostic information needs further delineation. METHODS: Consecutive thyroid cancer patients after index thyroidectomy with ThyroSeq version 3 (Rye Brook, NY) molecular testing obtained on preoperative fine-needle aspiration or thyroidectomy specimens from patients with thyroid cancer were categorized into 3 molecular risk groups based on detected mutations, fusions, copy number alterations, and/or gene expression alterations and correlated with histopathology and recurrence, defined as biochemical or structural. RESULTS: Of 578 patients, 49.9%, 37.5%, and 12.6% had molecular risk group-low, molecular risk group-intermediate, and molecular risk group-high cancers, respectively. With a median 19-month follow-up, 9.1% patients recurred. Compared with molecular risk group-low, molecular risk group-intermediate cancers were diagnosed in younger patients and more often had microscopic extrathyroidal extension, involved margins, and nodal disease. Compared with molecular risk group-intermediate, molecular risk group-high cancers were diagnosed in older patients and more often had gross extrathyroidal extension and vascular invasion. In multivariable analysis, recurrence was more likely in molecular risk group-high cancers than in molecular risk group-intermediate (hazard ratio = 4.0; 95% confidence interval, 1.9-8.6; P < .001) and more likely in molecular risk group-intermediate than in molecular risk group-low (hazard ratio = 5.0; 95% confidence interval, 2.0-12.5; P < .001). CONCLUSION: Using modern comprehensive genotyping, the genetic profile of thyroid cancers can be categorized into 3 novel molecular risk groups that were associated with histopathologic phenotype and recurrence in short-term follow-up.

Validity of the American College of Radiology Thyroid Imaging Reporting and Data System in Children.

OBJECTIVE: To assess the validity of the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) for evaluating thyroid nodules in children. METHODS: Patients aged <19 years with thyroid nodule(s) evaluated by ultrasound (US) from 2007-2018 at a tertiary children's hospital were included. Two radiologists scored de-identified thyroid US images using ACR TI-RADS (from 1, "benign" to 5, "highly suspicious"). The radiologists recorded size and rated vascularity for each nodule. Ultrasound findings were compared to pathology results (operative cases, n = 91) and clinical follow-up without disease progression (non-operative cases, n = 15). RESULTS: Thyroid images from 115 patients were reviewed. Nine patients were excluded due to the absence of an evaluable nodule. Forty-seven benign and 59 malignant nodules were included. Median age at ultrasound was 15 years (range 0.9-18 years). Twenty (18.9%) patients were male. There was moderate agreement between TI-RADS levels assigned by the two raters (kappa = 0.57, p < 0.001). When the raters' levels were averaged, >3 as the threshold for malignancy correctly categorized the greatest percentage of nodules (68.9%). Eleven (18.6%) malignant nodules received a TI-RADS level of 2 (n = 3) or 3 (n = 8). Sensitivity, specificity, and positive and negative predictive values were 81.4%, 53.2%, 68.6%, and 69.4%, respectively. Although not part of TI-RADS, vascularity was similar between benign and malignant nodules (p = 0.56). CONCLUSION: In a pediatric population, TI-RADS can help distinguish between benign and malignant nodules with comparable sensitivity and specificity to adults. However, the positive and negative predictive values suggest TI-RADS alone cannot eliminate the need for FNA. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2394-2401, 2023.

Changes in thyroid nodule cytology rates after institutional implementation of the Thyroid Imaging Reporting and Data System.

BACKGROUND: The American College of Radiology Thyroid Imaging Reporting and Data System for ultrasound classification of malignancy risk was developed to better triage thyroid nodules for fine-needle aspiration biopsy. To examine further, we compared thyroid cytologic classification rates in nodules before and after institutional Thyroid Imaging Reporting and Data System implementation. METHODS: Cytology diagnoses by Bethesda criteria (categories I-VI) from January 2014 to October 2021 were retrieved; observed changes in yearly category frequency were analyzed by linear regression; and pooled cohorts of pre- (2014-2018) and post-Thyroid Imaging Reporting and Data System (2019-2021) cytology call rates were compared. RESULTS: Overall, 7,413 cytologic specimens were included (range/year 715-1,444). From 2014 to 2021, the proportion of benign (Bethesda category II) diagnosis per year declined stepwise from 49.7% to 19.4%, and atypia of undetermined significance/follicular lesion of undetermined significance (Bethesda category III) increased sequentially from 21.3% to 51.5%. Between 2014 and 2021, Bethesda category III diagnosis increased on average by 4.8% per year (95% confidence internal, 3.29-5.54; P < .001) and Bethesda category II results decreased on average by 4.4% per year (95% confidence interval, 6.29-3.42; P < .001). When comparing pre- and post-Thyroid Imaging Reporting and Data System, the proportion of Bethesda category II cytology results decreased (43.1% vs 21%; P = .001) while Bethesda category III (28.3% vs 47.7%; P = .002) and Bethesda category V (1.1% vs 1.7%; P = .015) results increased. CONCLUSION: After implementation of American College of Radiology Thyroid Imaging Reporting and Data System ultrasound criteria, we observed a 2.5-fold decline in the rate of benign cytology and an increase in the proportion of atypia of undetermined significance/follicular lesion of undetermined significance results.

A thyroid EIF1AX story: how clinical, cytologic, and molecular surveillance led to appropriate management.

INTRODUCTION: Indeterminate thyroid cytology diagnoses are associated with intermediate risks of malignancy. Application of molecular testing (MT) to indeterminate specimens provides additional diagnostic and prognostic information. While a positive or suspicious MT result may prompt surgery, a negative MT result is associated with a low probability of cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features and approximates that of a benign cytology diagnosis. Furthermore, ThyroSeq v3 MT has a "currently negative" result for findings with the probability of cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear feature that is slightly greater than that for the negative ThyroSeq v3 MT result but less than 10%, suggesting active surveillance. In this report, we discuss a case of a patient for whom clinical, cytologic, and molecular surveillance led to timely surgery and management. CLINICAL DETAILS: A 53-year-old man with a thyroid isthmus nodule had a fine-needle aspiration cytology diagnosis of atypia of undetermined significance and a subsequent ThyroSeq v3 MT, which revealed an EIF1AX mutation and a "currently negative" MT result. Surveillance with additional fine-needle aspiration samples demonstrated concerning genomic alterations (fluctuating EIF1AX allelic frequency and a non-V600E BRAF mutation), culminating in the conversion to a positive MT result 3 years later. Resection revealed an encapsulated noninvasive, oncocytic solid subtype of papillary thyroid carcinoma with increased mitotic activity. CONCLUSION: The case is notable for clinical, cytologic, and molecular surveillance demonstrating sequential pathologic alterations in an indeterminate thyroid nodule with EIF1AX mutation, leading to timely resection of the neoplasm before invasion manifested.

Identifying metastatic renal cell carcinoma in thyroid fine-needle aspirates by molecular testing.

Renal cell carcinoma (RCC) is the most common type of cancer found to metastasize to the thyroid gland. These tumors may represent a diagnostic challenge in cytology. However, most RCC tumors carry VHL alterations, which are rare in primary thyroid tumors. The aim of this study was to evaluate the utility of molecular testing in detecting metastatic RCC in thyroid fine-needle aspiration (FNA) samples. From November 2017 until March 2022, thyroid FNA samples with ThyroSeq v3 results showing both VHL alterations and low/absent expression of thyroid cell markers were analyzed. Eighteen samples from 15 patients met the inclusion criteria. On molecular analysis, deleterious VHL mutations were found in nine (50%) nodules, VHL copy number alteration (CNA) in two (11%), and both mutations and CNA in seven (39%). None of the cases showed mutations commonly found in thyroid tumors. The mean age of these patients was 68 (range, 49-89) years with a male to female ratio of 2:1. Eight (53%) patients had multiple thyroid nodules on ultrasound. On cytology, 14 (78%) nodules were diagnosed as Bethesda III, 2 (11%) as Bethesda IV, and 2 (11%) as Bethesda V. At the time of cytology review, the history of RCC, sometimes remote, was available for ten patients. Of the 14 patients with medical history or surgical follow-up available, all had history of RCC or renal mass or revealed metastatic RCC on thyroidectomy. This study demonstrates that molecular testing can reliably identify metastatic RCC in thyroid nodules with indeterminate cytology, which could improve patient management.

American Association of Endocrine Surgeons Guidelines for Adrenalectomy: Executive Summary.

Importance: Adrenalectomy is the definitive treatment for multiple adrenal abnormalities. Advances in technology and genomics and an improved understanding of adrenal pathophysiology have altered operative techniques and indications. Objective: To develop evidence-based recommendations to enhance the appropriate, safe, and effective approaches to adrenalectomy. Evidence Review: A multidisciplinary panel identified and investigated 7 categories of relevant clinical concern to practicing surgeons. Questions were structured in the framework Population, Intervention/Exposure, Comparison, and Outcome, and a guided review of medical literature from PubMed and/or Embase from 1980 to 2021 was performed. Recommendations were developed using Grading of Recommendations, Assessment, Development and Evaluation methodology and were discussed until consensus, and patient advocacy representation was included. Findings: Patients with an adrenal incidentaloma 1 cm or larger should undergo biochemical testing and further imaging characterization. Adrenal protocol computed tomography (CT) should be used to stratify malignancy risk and concern for pheochromocytoma. Routine scheduled follow-up of a nonfunctional adrenal nodule with benign imaging characteristics and unenhanced CT with Hounsfield units less than 10 is not suggested. When unilateral disease is present, laparoscopic adrenalectomy is recommended for patients with primary aldosteronism or autonomous cortisol secretion. Patients with clinical and radiographic findings consistent with adrenocortical carcinoma should be treated at high-volume multidisciplinary centers to optimize outcomes, including, when possible, a complete R0 resection without tumor disruption, which may require en bloc radical resection. Selective or nonselective α blockade can be used to safely prepare patients for surgical resection of paraganglioma/pheochromocytoma. Empirical perioperative glucocorticoid replacement therapy is indicated for patients with overt Cushing syndrome, but for patients with mild autonomous cortisol secretion, postoperative day 1 morning cortisol or cosyntropin stimulation testing can be used to determine the need for glucocorticoid replacement therapy. When patient and tumor variables are appropriate, we recommend minimally invasive adrenalectomy over open adrenalectomy because of improved perioperative morbidity. Minimally invasive adrenalectomy can be achieved either via a retroperitoneal or transperitoneal approach depending on surgeon expertise, as well as tumor and patient characteristics. Conclusions and Relevance: Twenty-six clinically relevant and evidence-based recommendations are provided to assist surgeons with perioperative adrenal care.

Long-Term Outcomes for Patients with Multiple Endocrine Neoplasia Type 1 and Duodenopancreatic Neuroendocrine Neoplasms.

BACKGROUND: Liver metastasis from duodenopancreatic neuroendocrine neoplasms (DP-NENs) is a major cause of mortality in multiple endocrine neoplasia type 1 (MEN1) patients, yet much of their natural history is unknown. METHODS: This longitudinal, retrospective cohort study analyzed all MEN1 patients with imageable functional (F) and nonfunctional (NF) DP-NENs (1990-2021) for liver metastasis-free survival (LMFS) and overall survival (OS). RESULTS: Of 138 patients, 85 (61.6%) had imageable DP-NENs (28 F, 57 NF), and the mean largest tumor size was 1.8 ± 1.4 cm. Multifocality was present in 32 patients (37.7%). Surgery was performed for 49 patients (57.7%). During an 11-year median follow-up period (IQR, 6-17 years), 23 (27.1%) of the patients had liver metastasis, and 19 (22.4%) patients died. Death was attributed to liver metastasis in 60% of cases. The patients with F-DP-NENs versus NF-DP-NENs more often had liver metastasis (46.4% vs. 15.8%; p = 0.002) but had similar 10-year LMFS (80.9 vs. 87.0%; p = 0.44) and OS (82.7 vs. 94.3%; p = 0.69). The patients with NF-DP-NENs had surgery when their tumors were larger (p < 0.001). Tumor size was not associated with liver metastasis (p = 0.89). The average growth rate was 0.04 cm/year (SE, 0.02 cm/year; p = 0.01) during active surveillance for NF-DP-NENs (n = 38). Liver metastasis developed in four patients with tumors smaller than 2 cm. The risk of liver metastasis was independent of surgery (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.21-2.93; p = 0.72) and death (HR, 0.51; 95% CI, 0.08-3.06; p = 0.46). CONCLUSIONS: Although the observed outcomes in this study were better than historical data, small NF-DP-NENs still developed liver metastasis and liver metastasis remains a major cause of death. These results suggest that size as a sole criterion for surgery may be insufficient to predict tumor behavior.

Clinicopathologic Characteristics and Postsurgical Follow-Up of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features in the Postnomenclature Revision Era.

Background: Noninvasive encapsulated follicular variant papillary thyroid carcinoma (EFVPTC) was reclassified as "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) in 2016. Most existing studies that examined outcomes included patients managed as EFVPTC and only retrospectively reclassified as NIFTP. This is the first study to evaluate the clinicopathologic, molecular, and surveillance characteristics of patients diagnosed with NIFTP at the time of surgery and managed based on this diagnosis. Methods: We performed a retrospective cohort study of consecutive cases diagnosed as NIFTP from June 2016 to October 2021 identified from electronic medical records at a large tertiary care institution. Patients with coexisting low-risk thyroid cancers ≥1.0 cm in size or any size aggressive histology were excluded, and review of demographic, clinical, imaging, cytologic, and molecular genetic data was performed. Initial care was delivered according to existing clinical guidelines, with a consensus institutional plan for five-year follow-up after surgery. Results: Among 79 patients with 84 nodules diagnosed as NIFTP after surgery, 83.5% (66/79) were women and the mean age was 51 years (range, 21-84). Mean NIFTP size was 2.4 cm (range 0.15-8.0). On ultrasound, the majority of nodules were categorized as thyroid imaging, reporting and data system TI-RADS 3 (55.3%, 42/76), and TI-RADS 4 (36.8%, 28/76). On cytology, they were typically diagnosed as Bethesda III (69.1%, 47/68) or Bethesda IV (23.5%, 16/68). Molecular testing was performed on 62 nodules, and molecular alterations were found in 93.5% (58/62). The most common alterations identified in NIFTP were RAS mutation (75.4%, 43/57), THADA fusion (12.3%, 7/57), and BRAFK601E mutation (7.0%, 4/57). Fifty-two (65.8%) patients underwent lobectomy and 27 (34.2%) total thyroidectomy, and no patient received completion thyroidectomy. Twenty-one patients (26.5%) had coexisting papillary or follicular microcarcinoma. None of the patients received radioiodine ablation. On a mean follow-up of 28.5 months (range, 6-69 months), no structural or biochemical recurrences were observed. Conclusions: In this large cohort of patients with NIFTP diagnosed at the time of surgery and managed typically by lobectomy with no radioiodine ablation, no evidence of tumor recurrence was identified on a limited follow-up. This finding supports indolent clinical course of NIFTP.

Performance of a Multigene Genomic Classifier in Thyroid Nodules with Suspicious for Malignancy Cytology.

Background: Molecular testing is increasingly used to refine the probability of cancer and assess recurrence risk in thyroid nodules with Bethesda III/IV fine needle aspiration (FNA) cytology. However, limited data exist for Bethesda V (suspicious for malignancy [SFM]) samples. This study evaluated the performance of ThyroSeq v3 (TSv3) in thyroid nodules with SFM cytology. Methods: In this single-institution retrospective cohort study, consecutive thyroid FNA samples diagnosed as SFM with TSv3 testing and known surgical outcome were identified. Clinical, pathology, and molecular findings were reviewed. The TSv3 Cancer Risk Classifier was used to determine molecular risk groups (MRGs). For test-negative cases diagnosed as cancer/noninvasive follicular thyroid neoplasm with papillary-like nuclear features, TSv3 was performed on the resected tumors. Results: Among 128 SFM samples studied, 100 (78.1%) were TSv3 positive, and 28 (21.9%) were negative. The cancer prevalence on surgery was 82.8%. Among test-positive samples, 95% were malignant and 5% benign. Among test-negative samples, 17 (60.7%) were benign and 11 (39.3%) malignant. Overall, TSv3 had a sensitivity of 89.6% (confidence interval; CI 82.4-94.1) and a specificity of 77.3% (CI 56.6-89.9). For a cancer prevalence of 50-75% expected in SFM cytology by the Bethesda system, the negative predictive value was expected to range from 71.2% to 88.1% and the positive predictive value from 79.8% to 92.2%. Among test-positive nodules, 20% were MRG-Low (mostly RAS-like alterations), 66% MRG-Intermediate (mostly BRAF-like alterations), and 14% MRG-High. Among patients with cancer, 65 (61.3%) were American Thyroid Association low risk, 25 (23.6%) intermediate risk, and 6 (5.7%) high risk. During the mean follow-up of 51.2 months (range: <1 to 470 months), 12 (13.0%) patients had disease recurrence, which was more common in MRG-High (54.6%) compared with MRG-Intermediate (9.5%) and MRG-Low (0%) cancers (p < 0.001). Upon reexamining tumors with false-negative results, half of evaluable cases had alterations likely missed due to limiting FNA sampling, and the remainder represented low-risk tumors. Potentially targetable alterations were identified in 10 samples. Conclusions: In this large series of SFM thyroid nodules, TSv3 further improved cancer prediction and detected RAS-like, BRAF-like, high-risk, and potentially targetable alterations, all of which may inform more optimal patient management. MRGs were associated with recurrence-free survival, offering potential preoperative cancer risk stratification.

Clinicopathological features and outcomes of thyroid nodules with EIF1AX mutations.

EIF1AX gene mutations are reported in both benign and malignant thyroid tumors, with unclear outcomes when detected preoperatively. The aim of this study was to determine the features and outcomes of thyroid nodules with various types of mutation identified in cytologic (fine-needle aspiration) samples on preoperative ThyroSeq testing and with surgical outcomes. In this single-institution retrospective study of 31 consecutive patients, 77% were female and nodule size ranged from 1.5 to 9.4 cm with widely varying cytologic and TI-RADS ultrasound categorizations. Among two main mutational hotspots, 55% were located in exon 2 and 45% at the intron 5/exon 6 splice site. On histology, 45% of -positive nodules were cancer/noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) including 19% encapsulated follicular variant papillary thyroid carcinoma, 10% follicular carcinoma, 10% anaplastic carcinoma (ATC), and 7% NIFTP. Almost half (48%) of patients had one or more coexisting mutations, most frequently RAS. The prevalence of cancer/NIFTP was 80% for mutation with coexisting molecular alteration vs 13% with an isolated mutation (P = 0.0002). Cancer probability was associated with mutation type and was 64% for splice-site mutation and 29% for non-splice mutation (P = 0.075). All 3 nodules with EIF1AX+RAS+TERT+TP53 mutations were ATC. In summary, in this study, all nodules with an isolated non-splice mutation were benign, one-third of those with an isolated splice mutation were cancer, and most nodules with coexisting with RAS or other alterations were malignant. These findings suggest that clinical management decisions for patients with EIF1AX-mutant nodules should consider both the type of mutation and its co-occurrence with other genetic alterations.

Granular cell tumor of thyroid: a case series with molecular characterization highlighting unique pitfalls.

Primary granular cell tumors (GCTs) of the thyroid are exceptionally rare. We report the clinicopathologic and molecular features of three cases and review the literature. Two patients (20-year-old, Case 1, and 26-year-old, Case 2, black American females) presented with painless masses with a preoperative fine-needle aspiration biopsy (FNAB) diagnosis of "Hürthle cell neoplasm," while one additional patient, 51-year-old white American female (Case 3), presented as an incidental finding within a background of chronic lymphocytic thyroiditis. On resection, morphologic, histochemical and immunohistochemical features were typical of GCT in all cases. Cases 1 and 2 had adequate material for molecular testing and demonstrated a clonal ATP6AP1 p.G381Vfs*15 frameshift mutation (Case 1) and a clonal ATP6AP2 p.L182Pfs*22 frameshift mutation along with a PIK3CA H1047R hotspot mutation (Case 2). All patients showed no evidence of GCT following resection (Cases 1, 3: 96-month follow-up; Case 2: 48-month follow-up). A literature review demonstrates similar clinicopathologic features and indolent course with only rare histologically or clinically aggressive outcomes. On FNAB, lesional cells are frequently miscategorized as Hürthle cells or oncocytes. In summary, GCT of the thyroid is rare but shows similar clinical, morphologic, immunophenotypic and genetic characteristics of GCT of other sites. This unusual site poses unique differential diagnostic pitfalls by mimicking other oncocytic head and neck lesions, particularly thyroid Hürthle cell neoplasms. We confirm that thyroid GCT also harbor V-ATPase component inactivating mutations that characterize these tumors, and that additional PI3K pathway alterations may not necessarily predict aggressive behavior.