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.

Risk assessment for distant metastasis in differentiated thyroid cancer using molecular profiling: A matched case-control study.

BACKGROUND: Risk stratification for patients with differentiated thyroid cancer (DTC) is based primarily on pathologic tumor characteristics. Accurate preoperative prognostication could allow for more informed initial surgical recommendations, particularly among patients at a higher risk for distant metastasis (DM). The objective of this study was to characterize the genetic profile of DTC with DM and to validate a molecular-based risk stratification. METHODS: A case-control study design was used to analyze patients who had DTC with DM (n = 62) and a propensity matched cohort of patients who had DTC without DM after at least 5 years of follow-up using the ThyroSeq version 3 targeted next-generation sequencing assay. The results were classified into high-risk, intermediate-risk, and low-risk of aggressive disease. RESULTS: Most patients who had DTC with DM (66%) had a late-hit mutation in TERT, TP53, or PIK3CA. After propensity matching by age, tumor size, and sex, the high-risk molecular profile had strong association with DM (high-risk vs intermediate-risk: odds ratio, 25.1; 95% CI, 3.07-204.4; P < .001; high-risk vs low-risk: odds ratio, 122.5; 95% CI, 14.5-1038.4; P < .001). Overall, molecular risk categories were associated with DM risk, with a concordance index of 0.836 (95% CI, 0.759-0.913), which remained consistent after internal validation. Within the range of 5% to 10% of DM observed in DTC, the expected probability of DM would be 0.2% to 0.4% for the low-risk molecular profile, 4.7% to 9.4% for the intermediate-risk molecular profile, and 19.3% to 33.5% for the high-risk molecular profile. CONCLUSIONS: In this matched case-control study, genetic profiling using an available molecular assay provided accurate and robust risk stratification for DM in patients with DTC. The availability of preoperative prognostication may allow tailoring treatment for patients with DTC.

Molecular Testing for Thyroid Nodules Including Its Interpretation and Use in Clinical Practice.

Despite advances in imaging and biopsy techniques, the management of thyroid nodules often remains a diagnostic and clinical challenge. In particular, patients with cytologically indeterminate nodules often undergo diagnostic thyroidectomy although only a minority of patients are found to have thyroid malignancy on final pathology. More recently, several molecular testing platforms have been developed to improve the stratification of cancer risk for patients with cytologically indeterminate thyroid nodules. Based on numerous studies demonstrating its accuracy, molecular testing has been incorporated as an important diagnostic adjunct in the management of indeterminate thyroid nodules in the National Comprehensive Cancer Network Guidelines as well as in the American Thyroid Association (ATA) and American Association of Endocrine Surgeons (AAES) guidelines. This overview describes the currently available molecular testing platforms and highlights the published data to date on the clinical validity and utility of molecular testing in the contemporary management of thyroid nodules.

The Clinical Utility of Molecular Testing in the Management of Thyroid Follicular Neoplasms (Bethesda IV Nodules).

OBJECTIVE: FN present a management quandary as they are often benign but may also be aggressive TC. Consensus recommendations have historically advised thyroidectomy for definitive diagnosis. Although MT have robust benefit in hypothetical cost analyses, under current management guidelines a real-time study of their clinical utility in FN is awaited. We investigate if MT use for FN directs appropriate thyroidectomy for TC while triaging to surveillance nodules that are likely benign. METHODS: Data were analyzed for 389 consecutive patients managed from 11/14 to 9/19 for 405 FN, excluding oncocytic neoplasms. TC was defined as same-nodule histologic malignancy. When obtained, MT was performed using ThyroSeq (TS) v2 or 3. RESULTS: With a mean nodule size of 2.7 ±â€Š1.3 cm, MT was used in 89% and was positive in 39%. When MT was positive, thyroidectomy was more often utilized (91% v. MT- 27%; P < 0.001) and more likely for histologic TC (70% vs 16%, P < 0.001). With preoperative MT, all American Thyroid Association intermediate, high-risk, and medullary TC were positive whereas all MT- malignancies were low-risk. With TSv3, ultrasound surveillance was more likely for MT- FN (90% vs TSv2 65%, P < 0.001), and occurred for a total of 174 MT- FN. With mean follow-up of 24.6 months, 82% remained stable in size. CONCLUSIONS: MT use for FN increased the surgical yield of cancer by 4-fold, identified all potentially aggressive malignancies, and allowed apparently safe nonoperative surveillance for >80% of MT-negative patients. Thyroid nodule MT optimizes patient outcomes sufficiently to justify its incorporation into routine practice.

Executive Summary of the American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults.

OBJECTIVE: The aim of this study was to develop evidence-based recommendations for safe, effective and appropriate thyroidectomy. BACKGROUND: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the United States. METHODS: The medical literature from January 1, 1985 to November 9, 2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. RESULTS: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches Laryngology Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation. CONCLUSION: Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.

The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults.

OBJECTIVE: To develop evidence-based recommendations for safe, effective, and appropriate thyroidectomy. BACKGROUND: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the US. METHODS: The medical literature from 1/1/1985 to 11/9/2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. RESULTS: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches to Thyroidectomy, Laryngology, Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation. CONCLUSIONS: Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.

Novel Findings on SPECT-CT Tc-99 Sestamibi Imaging for Primary Hyperparathyroidism.

BACKGROUND: The addition of SPECT-CT to Tc-99 sestamibi has become a valuable tool for parathyroid localization in primary hyperparathyroidism (PHP). However, the enhanced sensitivity of this test can lead to unexpected and significant findings. We sought to identify the frequency and types of nonparathyroid detections by SPECT-CT. MATERIALS AND METHODS: With institutional approval, we reviewed all SPECT-CT studies performed for PHP between October 2012 and August 2018 for incidental nonparathyroid abnormalities. The electronic medical record was referenced to determine the type of lesion confirmed by additional evaluation. RESULTS: Among 2413 studies, 652 patients (27%) had 677 (28%) nonparathyroid findings. The most common were thyroid nodules (331/677, 49%), including 47 (6.9%) malignancies to date: 40 papillary thyroid cancers (11 microcarcinomas), five follicular thyroid cancers, one medullary carcinoma, and one noninvasive follicular thyroid neoplasm with papillary-like features. One hundred and seventy-seven patients had pulmonary nodules (26%), of whom nine were diagnosed with primary lung lesions (6 non-small-cell cancers, one small-cell cancer, one carcinoid, and one pulmonary sequestration). SPECT-CT revealed 14 patients (2.1%) with breast abnormalities, including three cancers. Nine patients (1.3%) demonstrated metastatic diseases within the lungs (4), bones (3), and mediastinum (2). One patient was diagnosed with follicular lymphoma. Two intracranial tumors were also identified, as well as dysplastic Barrett's esophagitis (1), hiatal hernia (20, 3%), and aortic aneurysm (13, 1.8%). In all, 72/677 (10.6%) PHP patients exhibited premalignant or malignant nonparathyroid SPECT-CT findings. CONCLUSIONS: In patients undergoing localization for PHP with Tc-99 sestamibi SPECT-CT, nonparathyroid findings are frequent (27%) and can lead to newly diagnosed malignant or premalignant lesions in at least 3% of patients to date.

Clinical and Biochemical Features of Pheochromocytoma Characteristic of Von Hippel-Lindau Syndrome.

BACKGROUND: Approximately 30% of patients with apparent sporadic pheochromocytoma (Pheo) may later prove to have an inherited predisposition syndrome, most commonly Von Hippel-Lindau (VHL) disease. Our aim was to compare the clinical and biochemical features of Pheo in VHL to those in sporadic disease to identify differences that may be used to guide management and surveillance of Pheo in VHL patients. METHODS: Data of all patients who had adrenalectomy for histologic Pheo from 2000 to 2018 (QIIRB1749) were retrospectively reviewed. VHL patients were diagnosed by standard clinical criteria and/or genetic testing. Patients were classified as having sporadic Pheo (sPheo) if they had no family/personal history consistent with an associated genetic disorder and/or had negative testing for VHL, MAX, MEN1, NF1, RET and SDHAF2/B/C/D/A mutations. RESULTS: Of 175 patients, 38 (22%) had VHL and 137 (78%) had sPheo including 27 (20%) with negative genetic testing. Compared to sPheo, VHL Pheo patients were younger (mean 25.9 vs. 51.2 years, p < 0.001), less symptomatic (55% vs. 72%, p = 0.074), less hypertensive (46% vs. 64%, p = 0.043) and were more likely to have normal plasma metanephrines (85% vs. 25%, p < 0.001). VHL-related Pheos were smaller (median 2.8 cm vs. 4.4 cm, p < 0.001) but more often multifocal (>1 adrenal Pheo) (16% vs. 0%, p < 0.001). Recurrence >6 months from initial resection was common in VHL (40% vs. 0%, p < 0.001), median time to recurrence 15 years, (range 1-38 years). CONCLUSIONS: Compared to those with sporadic Pheo, patients with VHL are more likely to be young, asymptomatic and normotensive and to have small, multifocal, normetanephrine-secreting tumors. Because recurrence is common in VHL and arises up to 38 years later, continued surveillance is advised.

THADA fusion is a mechanism of IGF2BP3 activation and IGF1R signaling in thyroid cancer.

Thyroid cancer development is driven by known point mutations or gene fusions found in ∼90% of cases, whereas driver mutations in the remaining tumors are unknown. The insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays an important role in cancer, yet the mechanisms of its activation in cancer cells remain poorly understood. Using whole-transcriptome and whole-genome analyses, we identified a recurrent fusion between the thyroid adenoma-associated (THADA) gene on chromosome 2 and the LOC389473 gene on chromosome 7 located 12 kb upstream of the IGF2BP3 gene. We show that THADA fusion to LOC389473 and other regions in the vicinity does not result in the formation of a chimeric protein but instead leads to strong overexpression of the full-length IGF2BP3 mRNA and protein, increased IGF2 translation and IGF1 receptor (IGF1R) signaling via PI3K and MAPK cascades, and promotion of cell proliferation, invasion, and transformation. THADA fusions and IGF2BP3 overexpression are found in ∼5% of thyroid cancers that lack any other driver mutations. We also find that strong IGF2BP3 overexpression via gene fusion, amplification, or other mechanisms occurs in 5 to 15% of several other cancer types. Finally, we provide in vitro and in vivo evidence that growth of IGF2BP3-driven cells and tumors may be blocked by IGF1R inhibition, raising the possibility that IGF2BP3 overexpression in cancer cells may predict an anti-IGF1R benefit.

Retropharyngeal Parathyroid Glands: Important Differences.

INTRODUCTION: In primary hyperparathyroidism (PHPT), parathyroid ectopia is seen in up to 22% leading to more difficult surgery. We aimed to determine the rate and characteristics of retropharyngeal (RP) parathyroid glands. METHODS: A prospective database was queried for patients with sporadic PHPT who had surgery from 1997 to 2016. The data of RP patients were compared to those who had surgery for sporadic PHPT over the same time period with hyperfunctioning parathyroids in anatomically normal positions (N). RESULTS: RP glands occurred in 47/3006 (1.6%) patients and were more common at reoperative than initial surgery (5.5 vs 1.4%, p < 0.01). RP patients had prior failed surgery more often than N patients (17 vs 3.1%, p < 0.01). Preoperative calcium levels (p = 0.06), PTH levels (p = 0.15), and mean gland weights (p = 0.07) were similar among groups. For RP glands, ultrasound imaging was negative in all but one patient, while 99mTc-sestamibi accurately indicated a posterior midline position in only 13/47 (28%) and was negative in 21%. All RP glands were anatomically superior. RP patients more often required > 1 post-resection intraoperative PTH level (36 vs 21%, p = 0.02). Failure due to persistent PHPT was more likely in RP patients (4.7 vs 2.1%, p = 0.2). CONCLUSION: In PHPT, hyperfunctioning RP glands are seen in 1.6% of cases and often associated with initial failure (17%). At reoperation, RP ectopia is 4X more common. RP glands are associated with a high rate of negative imaging, but imaging results suggestive of a midline abnormality can guide exploration. The RP space should be evaluated prior to ending an otherwise unfruitful surgery.

Incidental Diagnosis of Parathyroid Lesions by Preoperative Use of Next-Generation Molecular Testing.

BACKGROUND: Parathyroid glands can mimic thyroid follicular lesions on fine-needle aspiration (FNA) cytology and can lead to unnecessary or incorrect surgery. Newer molecular panel tests using next-generation sequencing (NGS) include analysis of cell type-specific gene expression profiles such as parathyroid. The study aim is to determine the frequency and clinical implications of parathyroid tissue identification by molecular testing in cytologically indeterminate "thyroid" lesions. METHODS: Molecular analysis of indeterminate thyroid FNA specimens is obtained routinely and relies on amplification-based NGS inclusive of PTH-specific expression profiles. For this study, we retrospectively examined the clinical data and management of patients with molecular results positive for PTH expression from May 2014 until May 2016. RESULTS: Among 4765 consecutive patients with indeterminate cytology for a presumed thyroid nodule, NGS instead indicated a parathyroid lesion in 20 patients (0.42%). The clinical data of 15 patients were available, and the subsequent clinical management was altered in 93% (14/15 patients), including five (33%) eucalcemic patients who could avoid unnecessary surgery. Primary hyperparathyroidism was not suspected in seven patients until the molecular analysis results, and primary hyperparathyroidism was diagnosed in one (14%). During parathyroid exploration, most patients (6/8, 75%) required concurrent thyroidectomy or lobectomy, but thyroid preservation was still possible in two patients. A parathyroid gland was histologically confirmed in 89%. CONCLUSIONS: In 0.42% of patients with indeterminate cytology results, next-generation molecular results will indicate the presence of a parathyroid lesion. When this occurs, it is accurate and can robustly impact clinical management (93%).

Clinical Predictors of Malignancy in Patients with Pheochromocytoma and Paraganglioma.

BACKGROUND AND PURPOSE: Factors associated with malignancy in patients with pheochromocytoma (adrenal tumors, Pheo) and paraganglioma (extra-adrenal, PGL) are not well-defined and all patients require lifelong surveillance. The primary aim of our study was to determine genetic and clinical variables associated with malignancy in patients with Pheo/PGL. METHODS: Single institution retrospective review was performed of all patients who underwent surgery (1/95-1/15) for Pheo/PGL. Malignancy was defined as histology-confirmed distant metastasis, lymph nodal involvement, or tumor bed recurrence. RESULTS: A total of 157 Pheo/PGL patients (44 malignant, 113 benign) with mean follow-up of 87 months were included. Compared with patients with benign Pheo/PGL, patients with malignant Pheo/PGL were younger (median 42 vs 50 years, p = 0.014), had larger tumors (median 6.5 vs 4 cm, p < 0.001) and had PGL (63.6 vs 4.4%, p < 0.001). Genetic testing was performed in 60 patients and was positive in 38 (63%). Although positive genetic results were equally likely in malignant vs benign Pheo/PGL (76 vs 54%, p = 0.1), all 11 patients with germline SDHB mutations had malignant disease. In multivariable analysis, younger age, larger tumor size, and PGL were associated with malignancy (p < 0.05). Pheo patients with negative genetic testing and negative family history who developed metachronous metastases all had primary tumors ≥4 cm in size. CONCLUSIONS: Patients who are young, have larger tumors, positive genetic testing (especially SDHB) or have PGL require long-term follow-up. Patients with negative genetic testing or family history and Pheo <4 cm have a lower risk of malignancy, and de-escalated long-term surveillance may be appropriate follow-up.

Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer.

Thyroid cancer is a common endocrine malignancy that encompasses well-differentiated as well as dedifferentiated cancer types. The latter tumors have high mortality and lack effective therapies. Using a paired-end RNA-sequencing approach, we report the discovery of rearrangements involving the anaplastic lymphoma kinase (ALK) gene in thyroid cancer. The most common of these involves a fusion between ALK and the striatin (STRN) gene, which is the result of a complex rearrangement involving the short arm of chromosome 2. STRN-ALK leads to constitutive activation of ALK kinase via dimerization mediated by the coiled-coil domain of STRN and to a kinase-dependent, thyroid-stimulating hormone-independent proliferation of thyroid cells. Moreover, expression of STRN-ALK transforms cells in vitro and induces tumor formation in nude mice. The kinase activity of STRN-ALK and the ALK-induced cell growth can be blocked by the ALK inhibitors crizotinib and TAE684. In addition to well-differentiated papillary cancer, STRN-ALK was found with a higher prevalence in poorly differentiated and anaplastic thyroid cancers, and it did not overlap with other known driver mutations in these tumors. Our data demonstrate that STRN-ALK fusion occurs in a subset of patients with highly aggressive types of thyroid cancer and provide initial evidence suggesting that it may represent a therapeutic target for these patients.

Tumor genotype determines phenotype and disease-related outcomes in thyroid cancer: a study of 1510 patients.

OBJECTIVES: To correlate thyroid cancer genotype with histology and outcomes. BACKGROUND: The prognostic significance of molecular signature in thyroid cancer (TC) is undefined but can potentially change surgical management. METHODS: We reviewed a consecutive series of 1510 patients who had initial thyroidectomy for TC with routine testing for BRAF, RAS, RET/PTC, and PAX8/PPARG alterations. Histologic metastatic or recurrent TC was tracked for 6 or more months after oncologic thyroidectomy. RESULTS: Papillary thyroid cancer (PTC) was diagnosed in 97% of patients and poorly differentiated/anaplastic TC in 1.1%. Genetic alterations were detected in 1039 (70%); the most common mutations were BRAFV600E (644/1039, 62%), and RAS isoforms (323/1039, 31%). BRAFV600E-positive PTC was often conventional or tall cell variant (58%), with frequent extrathyroidal extension (51%) and lymph node metastasis (46%). Conversely, RAS-positive PTC was commonly follicular variant (87%), with infrequent extrathyroidal extension (4.6%) and lymph node metastasis (5.6%). BRAFV600E and RET/PTC-positive PTCs were histologically similar. Analogously, RAS and PAX8/PPARG-positive PTCs were histologically similar. Compared with RAS or PAX8/PPARG-positive TCs, BRAFV600E or RET/PTC-positive TCs were more often associated with stage III/IV disease (40% vs 15%, P < 0.001) and recurrence (10% vs 0.7%, P < 0.001; mean follow-up 33 ± 21 mo). Distant metastasis was highest in patients with RET/PTC-positive TC (10.8%, P = 0.02). CONCLUSIONS: In this large study of prospective mutation testing in unselected patients with TC, molecular signature was associated with distinctive phenotypes including cancers, with higher risks of both distant metastasis and early recurrence. Preoperative genotype provides valuable prognostic data to appropriately inform surgery.

Adrenal Imaging Features Predict Malignancy Better than Tumor Size.

INTRODUCTION: In adrenal tumors, size ≥ 4 cm has been an indication for adrenalectomy due to concern for malignancy. We compared mass size to imaging features (ImF) for accuracy in diagnosing adrenal malignancy. METHODS: Data were retrieved for 112 consecutive patients who had adrenalectomy from January 2011 to August 2014. ImF was classified as nonbenign if HU > 10 on unenhanced CT scan or if loss of signal on out-of-phase imaging was absent on chemical-shift MRI. Indications for resection included hormonal hypersecretion, nonbenign ImF, and/or size ≥ 4 cm. RESULTS: Of 113 resected adrenals, 37 % were functional. Histologic malignancy occurred in 18 % (20/113) and included 3 adrenocortical carcinomas (ACC), 1 epithelioid liposarcoma, 1 lymphoma, 1 malignant nerve sheath tumor, and 14 adrenal metastases. Patients with malignancies were older (mean age, 60 ± 13 vs. 51 ± 14 years, p = 0.01). Malignant tumors were larger on preoperative imaging (mean 5.3 ± 3.2 vs. 3.9 ± 2.4 cm, p = 0.03). All 20 malignant masses had nonbenign ImF. In predicting malignancy, the sensitivity, specificity, NPV, and PPV of nonbenign ImF was 100, 57, 100, and 33 %, respectively. Size ≥ 4 cm was less predictive with sensitivity, specificity, NPV, and PPV of 55, 61, 86, and 23 %, respectively. If size ≥ 4 cm had been used as the sole criterion for surgery, 45 % of malignancies (9/20) would have been missed including 8 metastases and an ACC. CONCLUSIONS: In resected adrenal tumors, the presence of nonbenign ImF is more sensitive for malignancy than mass size (100 vs. 55 %) with equivalent specificity. Regardless of mass size, adrenalectomy should be strongly considered when non-benign ImF are present.

Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay.

BACKGROUND: Fine-needle aspiration (FNA) cytology is a common approach to evaluating thyroid nodules, although 20% to 30% of FNAs have indeterminate cytology, which hampers the appropriate management of these patients. Follicular (or oncocytic) neoplasm/suspicious for a follicular (or oncocytic) neoplasm (FN/SFN) is a common indeterminate diagnosis with a cancer risk of approximately 15% to 30%. In this study, the authors tested whether the most complete next-generation sequencing (NGS) panel of genetic markers could significantly improve cancer diagnosis in these nodules. METHODS: The evaluation of 143 consecutive FNA samples with a cytologic diagnosis of FN/SFN from patients with known surgical outcomes included 91 retrospective samples and 52 prospective samples. Analyses were performed on a proprietary sequencer using the targeted ThyroSeq v2 NGS panel, which simultaneously tests for point mutations in 13 genes and for 42 types of gene fusions that occur in thyroid cancer. The expression of 8 genes was used to assess the cellular composition of FNA samples. RESULTS: In the entire cohort, histologic analysis revealed 104 benign nodules and 39 malignant nodules. The most common point mutations involved the neuroblastoma RAS viral oncogene homolog (NRAS), followed by the Kirsten rat sarcoma viral oncogene homolog (KRAS), the telomerase reverse transcriptase (TERT) gene, and the thyroid-stimulating hormone receptor (TSHR) gene. The identified fusions involved the thyroid adenoma associated (THADA) gene; the peroxisome proliferator-activated receptor γ (PPARG) gene; and the neurotrophic tyrosine kinase, receptor, type 3 (NTRK3) gene. Performance characteristics were similar in the retrospective and prospective groups. Among all FN/SFN nodules, preoperative ThyroSeq v2 performed with 90% sensitivity (95% confidence interval [CI], 80%-99%), 93% specificity (95% CI, 88%-98%), a positive predictive value of 83% (95% CI, 72%-95%), a negative predictive value of 96% (95% CI, 92%-100%), and 92% accuracy (95% CI, 88%-97%). CONCLUSIONS: The current results indicate that comprehensive genotyping of thyroid nodules using a broad NGS panel provides a highly accurate diagnosis for nodules with FN/SFN cytology and should facilitate the optimal management of these patients.