Clinical and imaging presentations are associated with function in incidental adrenocortical adenomas: a retrospective cohort study.

OBJECTIVE: The aim of this study is to assess whether clinical and imaging characteristics are associated with the hormonal subtype, growth, and adrenalectomy for incidental adrenal cortical adenomas (ACAs). DESIGN: This is a single-center cohort study. METHODS: Consecutive adult patients with incidental ACA were diagnosed between 2000 and 2016. RESULTS: Of the 1516 patients with incidental ACA (median age 59 years, 62% women), 699 (46%) had nonfunctioning adenomas (NFAs), 482 (31%) had mild autonomous cortisol secretion (MACS), 62 (4%) had primary aldosteronism (PA), 39 (3%) had Cushing syndrome, 18 (1%) had PA and MACS, and 226 (15%) had incomplete work-up. Age, sex, tumor size, and tumor laterality, but not unenhanced computed tomography Hounsfield units (HU), were associated with hormonal subtypes. In a multivariable analysis, ≥1 cm growth was associated with younger age (odds ratio [OR] = 0.8 per 5-year increase, P = .0047) and longer imaging follow-up (OR = 1.2 per year, P < .0001). Adrenalectomy was performed in 355 (23%) patients, including 38% of MACS and 15% of NFA. Adrenalectomy for NFA and MACS was more common in younger patients (OR = 0.79 per 5-year increase, P = .002), larger initial tumor size (OR = 2.3 per 1 cm increase, P < .0001), ≥1 cm growth (OR = 15.3, P < .0001), and higher postdexamethasone cortisol (OR = 6.6 for >5 vs <1.8 µg/dL, P = .002). CONCLUSIONS: Age, sex, tumor size, and laterality were associated with ACA hormonal subtype and can guide diagnosis and management. Tumor growth was more common with younger age and longer follow-up. Unenhanced HU did not predict hormonal subtype or growth. Adrenalectomy for MACS and NFA was mainly performed in younger patients with larger tumor size, growth, and elevated postdexamethasone cortisol.

Adrenal Hemorrhage: A Comprehensive Analysis of a Heterogeneous Entity-Etiology, Presentation, Management, and Outcomes.

OBJECTIVE: To investigate the etiology, presentation, management, and outcomes of patients with adrenal hemorrhage (AH). PATIENTS AND METHODS: Longitudinal study of consecutive adult patients with radiologically confirmed AH (January 1, 2017, through December 31, 2021). RESULTS: Of the 363 patients with AH (median age, 62 years [interquartile range (IQR, 52-70 years]; 128 women [35%]), 338 (93%) had unilateral AH and 25 (7%) had bilateral AH. It was discovered incidentally in 152 patients (42%) and during the evaluation of trauma in 103 (28%), abdominal/back pain in 90 (25%), critical illness in 13 (4%), and symptoms of adrenal insufficiency in 5 (1%). Etiologies included postoperative complications in 150 patients (41%), trauma in 107 (30%), coagulopathy in 22 (6%), anticoagulant/antiplatelet therapy in 39 (11%), adrenal neoplasm in 22 (6%), and sepsis in 11, (3%). Overall, 165 patients (46%) were hospitalized, and no deaths occurred due to AH. Median (IQR) baseline AH size was 34 mm (24-40 mm) on the right and 29 mm (22-37 mm) on the left. Among 246 patients with follow-up imaging, AH resolution was complete in 155 (63%) and incomplete in 74 (30%) at a median of 15 months (IQR, 6-31 months). Patients with bilateral AH were more likely to have underlying coagulopathy (44% vs 3%) and to develop primary adrenal insufficiency (72% vs 0%) than those with unilateral AH (P<.001). CONCLUSION: Often, AH presents as an incidental unilateral lesion with normal adrenal function, commonly attributed to postoperative complications or trauma. In contrast, bilateral AH is rare and typically linked to underlying coagulopathy, with primary adrenal insufficiency developing in most patients.

Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study.

BACKGROUND: The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing). METHODS: We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants. FINDINGS: Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001). INTERPRETATION: Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma. FUNDING: Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino.

Severe thyrotoxicosis as initial presentation of gastric choriocarcinoma: a case report.

BACKGROUND: Extragonadal choriocarcinoma is rare and can be associated with hyperthyroidism when producing very high levels of human chorionic gonadotropin. CASE PRESENTATION: A 62-year-old Hispanic female presented with a 3-week history of shortness of breath, palpitations, extreme weakness, new-onset hot flashes, and right flank pain. Her physical examination was remarkable for tachycardia, hepatomegaly, hyperreflexia, and tremor; goiter was absent. Laboratory studies revealed increased lactate dehydrogenase, alkaline phosphatase, suppressed thyroid stimulating hormone, very elevated T4, and absent thyroid stimulating immunoglobulin. 18F-fluorodeoxyglucose positron emission tomography-computed tomography exhibited hepatomegaly with multiple large fluorodeoxyglucose-avid liver masses and a focus of fluorodeoxyglucose avidity in the stomach with no structural correlate. A thyroid scan (99mTcO 4 - ) showed diffusely increased tracer uptake. She was started on propranolol and methimazole. Upon stabilization of severe thyrotoxicosis, upper endoscopy was performed, showing a ~ 5 cm bleeding lesion in the greater stomach curvature body; biopsy was consistent with choriocarcinoma; beta-human chorionic gonadotropin hormone was 2,408,171 mIU/mL. The patient received methotrexate followed by etoposide and cisplatin. Methimazole was titrated down, and upon liver failure the medication was stopped. The thyrotoxicosis was effectively controlled with antithyroid drug and concurrent chemotherapy. At ~ 1.5 months after initial diagnosis, the patient died due to bleeding/acute liver failure with coagulation defects followed by multiple organ failure. CONCLUSIONS: Severe thyrotoxicosis can represent an unusual initial presentation of metastatic choriocarcinoma in the setting of extreme elevation of beta-human chorionic gonadotropin. Primary gastric choriocarcinoma is an aggressive malignancy with very poor outcomes. The co-occurrence of severe thyrotoxicosis with advanced primary gastric choriocarcinoma and imminent liver failure complicates management options.

Incidence and clinical characteristics of thyroid abnormalities in cancer patients treated with immune checkpoint inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICI) are a group of drugs that have been used in recent years for the treatment of advanced malignancies such as melanoma, non-small cell lung cancer and other tumors, significantly increasing survival. However, the use of ICI has been associated with an increased risk of autoimmune diseases, with endocrine organs, specifically the thyroid, being highly susceptible to this phenomenon. OBJECTIVE: To describe the incidence and clinical characteristics of patients treated with ICI who develop thyroid disease. METHODS: The medical records of all patients who received ICI treatment within the last three years were retrospectively reviewed, with those who developed thyroid abnormalities being identified. RESULTS: The prevalence of thyroiditis was 7 %, with an incidence of 21.4 % of patients-month. Median time for the development of thyroiditis was 63 days. Most patients had mild or moderate symptoms and did not require hospitalization, although all but one developed permanent hypothyroidism and required hormone replacement therapy with levothyroxine. CONCLUSIONS: Thyroid dysfunction secondary to immunotherapy is a common entity in our population. Clinical presentation is usually mild and does not require treatment discontinuation; however, due to the high incidence of these adverse events, non-oncology specialists must be familiar with the diagnosis and treatment of these alterations in order to provide multidisciplinary management.

INTRODUCCIÓN: Los inhibidores del punto de control inmunológico (IPCi) son utilizados en los últimos años en el tratamiento de neoplasias malignas avanzadas, con ellos se ha logrado un aumento significativo de la supervivencia; sin embargo, su uso se ha asociado a incremento del riesgo de enfermedades autoinmunes. OBJETIVO: Describir la incidencia y las características clínicas de los pacientes tratados con IPCi que desarrollaron tiroidopatía. MÉTODOS: Se revisaron retrospectivamente los expedientes de todos los pacientes que recibieron IPCi en los últimos tres años y se identificaron aquellos que desarrollaron anomalías tiroideas. RESULTADOS: La prevalencia de tiroiditis fue de 7 %, con una incidencia de 21.4 % pacientes/mes. La mediana del tiempo para el desarrollo de tiroiditis fue de 63 días. La mayoría de los pacientes presentó síntomas leves o moderados y no requirió hospitalización, si bien todos menos uno desarrollaron hipotiroidismo permanente y requirieron terapia de reemplazo hormonal con levotiroxina. CONCLUSIONES: La disfunción tiroidea secundaria a inmunoterapia es una entidad común en nuestra población. El cuadro clínico suele ser leve y no requiere suspender el tratamiento; sin embargo, debido a la alta incidencia de este evento adverso, los médicos no oncólogos deben estar familiarizados con su diagnóstico y tratamiento, para brindar un manejo multidisciplinario.

Inappropriate use of thyroid ultrasound: a systematic review and meta-analysis.

PURPOSE: Nearly half the cases of thyroid cancer, a malignancy rapidly rising in incidence within the United States, are attributable to small and asymptomatic papillary thyroid cancers that will not increase mortality. A primary driver of thyroid cancer overdiagnosis is ultrasound use. It is therefore valuable to understand how inappropriate use of thyroid ultrasound is defined, analyze the current evidence for its frequency, and identify interventions to lessen misuse. METHODS: Ovid MEDLINE(R), Ovid EMBASE, and Scopus databases were searched from inception to June 2020 for studies assessing inappropriate use of thyroid ultrasound. Reviewers, working independently and in duplicate, evaluated studies for inclusion, extracted data, and graded risk of bias. We used a random-effects model with a generalized linear mixed approach to calculate the mean overall proportion estimates of inappropriate use. RESULTS: Seven studies (total n = 1573) met the inclusion criteria with moderate to high risk of bias. Inappropriate thyroid ultrasound use was described variably, using published practice guidelines, third-party expert reviewers, or author interpretations of the literature. The overall frequency of inappropriate thyroid ultrasound use was 46% (95% CI 15-82%; n = 388) and 34% (95% CI 16-57%; n = 190) among studies using guideline based definitions. The pooled frequency of iUS due to thyroid dysfunction (either hypothyroidism or thyrotoxicosis) was 17% (95% CI 7-37%; n = 191) and the frequency of iUS due to nonspecific symptoms without a palpable mass was 11% (95% CI 5-22%; n = 124). No study examined interventions to address inappropriate use. CONCLUSIONS: Low quality evidence suggests that inappropriate use of thyroid ultrasound is common. Interventional studies aiming to decrease the inappropriate use of thyroid ultrasound are urgently needed.

Endocrine hypertension secondary to adrenal tumors: clinical course and predictive factors of clinical remission.

PURPOSE: Endocrinopathies constitute ~ 10% of secondary hypertension (SH) etiologies. Primary aldosteronism, pheochromocytoma (PHEO), and Cushing's syndrome are common causes. Early identification and treatment result in resolution/improvement of SH. The aim of this study was to characterize the clinical course, outcomes, and remission-associated prognostic factors of SH related to adrenal tumors. METHODS: Retrospective cohort study including patients with SH who underwent adrenalectomy from 2000 to 2019. Postoperative outcomes were analyzed. Remission was defined as normalization of blood pressure without drug use. RESULTS: Eighty-three patients with SH were included. Mean ± SD age was 38.8 ± 14.2 years and 75.9% were women. Diagnosis was PHEO in 35 patients (42.2%), aldosteronoma (APA) in 28 (33.7%), cortisol producing adenoma (CPA) in 16 (19.3%), and ACTH-dependent Cushing's in 4 (4.8%). Laparoscopic adrenalectomy was performed in 81 (97.6%) patients. Mean ± SD follow-up was 57.4 ± 49.6 months (range 1-232). Surgical morbidity occurred in 7.2% of patients and there was no mortality. Remission of SH occurred in 61(73.5%): 100% of ACTH-dependent Cushing's, 85.7% of PHEO, 68.8% of CPA, and 57.1% of APA. Biochemical phenotype and the combination of larger tumor size, number of antihypertensive drugs, male gender, older age, obesity, and preoperative SH for more than 5 years were associated with less likely clinical remission in patients with APA (p = 0.004), CPA (p < 0.0001), and PHEO (p < 0.0001). CONCLUSION: SH remission rates are 57-100% after adrenalectomy. Several prognostic factors could be used to predict SH control. Adrenalectomy provides good clinical outcome and must be considered a treatment option in all surgical candidates.

Incidencia y características clínicas de la enfermedad tiroidea en pacientes con neoplasias malignas tratados con inhibidores de punto de control inmunológico / Incidence and clinical characteristics of thyroid abnormalities in cancer patients treated with immune checkpoint inhibitors

Resumen Introducción: Los inhibidores del punto de control inmunológico (IPCi) son utilizados en los últimos años en el tratamiento de neoplasias malignas avanzadas, con ellos se ha logrado un aumento significativo de la supervivencia; sin embargo, su uso se ha asociado a incremento del riesgo de enfermedades autoinmunes. Objetivo: Describir la incidencia y las características clínicas de los pacientes tratados con IPCi que desarrollaron tiroidopatía. Métodos: Se revisaron retrospectivamente los expedientes de todos los pacientes que recibieron IPCi en los últimos tres años y se identificaron aquellos que desarrollaron anomalías tiroideas. Resultados: La prevalencia de tiroiditis fue de 7 %, con una incidencia de 21.4 % pacientes/mes. La mediana del tiempo para el desarrollo de tiroiditis fue de 63 días. La mayoría de los pacientes presentó síntomas leves o moderados y no requirió hospitalización, si bien todos menos uno desarrollaron hipotiroidismo permanente y requirieron terapia de reemplazo hormonal con levotiroxina. Conclusiones: La disfunción tiroidea secundaria a inmunoterapia es una entidad común en nuestra población. El cuadro clínico suele ser leve y no requiere suspender el tratamiento; sin embargo, debido a la alta incidencia de este evento adverso, los médicos no oncólogos deben estar familiarizados con su diagnóstico y tratamiento, para brindar un manejo multidisciplinario.

Abstract Introduction: Immune checkpoint inhibitors (ICI) are a group of drugs that have been used in recent years for the treatment of advanced malignancies such as melanoma, non-small cell lung cancer and other tumors, significantly increasing survival. However, the use of ICI has been associated with an increased risk of autoimmune diseases, with endocrine organs, specifically the thyroid, being highly susceptible to this phenomenon. Objective: To describe the incidence and clinical characteristics of patients treated with ICI who develop thyroid disease. Methods: The medical records of all patients who received ICI treatment within the last three years were retrospectively reviewed, with those who developed thyroid abnormalities being identified. Results: The prevalence of thyroiditis was 7 %, with an incidence of 21.4 % of patients-month. Median time for the development of thyroiditis was 63 days. Most patients had mild or moderate symptoms and did not require hospitalization, although all but one developed permanent hypothyroidism and required hormone replacement therapy with levothyroxine. Conclusions: Thyroid dysfunction secondary to immunotherapy is a common entity in our population. Clinical presentation is usually mild and does not require treatment discontinuation; however, due to the high incidence of these adverse events, non-oncology specialists must be familiar with the diagnosis and treatment of these alterations in order to provide multidisciplinary management.

The "Quiet TED"-A Special Subgroup of Thyroid Eye Disease.

PURPOSE: Thyroid eye disease (TED) or Graves' orbitopathy starts with an active inflammatory stage (active disease) followed by resolution of inflammation and progression to a fibrotic, inactive stage. In our practice, we have encountered cases that have not had active disease despite presence of fibrotic sequelae and disease progression. We aim to delineate the clinical characteristic of this unique group of patients. METHODS: We conducted a single-center (Mayo Clinic Rochester) retrospective chart review of TED patients who throughout the course of their disease had only evidence for inactive TED, defined as clinical activity score <3. RESULTS: Median age in the cohort (n = 19) was 54 years (IQR 47-61). 58% had a prior diagnosis of Graves' disease (GD) before referral. 80% (n = 15) were euthyroid at the time of TED onset (median thyroid-stimulating hormone 1.7 mIU/L). The most common finding was diplopia (100%, n = 19) followed by proptosis (63%, n = 12). Interestingly the disease was asymmetric in 42% of cases. Overall median clinical activity score on presentation was 1 (IQR 0-1). Severity wise, 85% (n = 16) of patients were classified as moderate-to-severe during follow up. Orbital decompression was performed in only 1 case, while extraocular muscle surgery was performed in 13 cases. CONCLUSIONS: Quiet TED is a subgroup of TED patients that defies the classic disease paradigm. It presents primarily with diplopia and proptosis. Further evaluation of this group might identify useful insights in TED pathophysiology and help optimize therapeutic choices.

Inability of Radioiodine Remnant Ablation to Improve Postoperative Outcome in Adult Patients with Low-Risk Papillary Thyroid Carcinoma.

OBJECTIVE: To determine whether radioiodine remnant ablation (RRA) reduces cause-specific mortality (CSM) or tumor recurrence (TR) rate after bilateral lobar resection (BLR). PATIENTS AND METHODS: There were 2952 low-risk adult papillary thyroid cancer (LRAPTC) patients (with MACIS scores <6) who underwent potentially curative BLR during 1955-2014. During 1955-1974, 1975-1994, and 1995-2014, RRA was administered in 3%, 49%, and 28%. Statistical analyses were performed using SAS software. RESULTS: During 1955-1974, the 20-year CSM and TR rates after BLR alone were 1.0% and 6.8%; rates after BLR+RRA were 0% (P=.63) and 5.9% (P=.82). During 1975-1994, post-BLR 20-year rates for CSM and TR were 0.3% and 7.5%; after BLR+RRA, rates were higher at 0.9% (P=.31) and 12.8% (P=.01). When TR rates were examined separately for 448 node-negative and 317 node-positive patients, differences were nonsignificant. In 1995-2014, post-BLR 20-year CSM and TR rates were 0% and 9.2%; rates after BLR+RRA were higher at 1.4% (P=.19) and 21.0% (P<.001). In 890 pN0 cases, 15-year locoregional recurrence rates were 3.4% after BLR and 3.7% after BLR+RRA (P=.99). In 740 pN1 patients, 15-year locoregional recurrence rates were 10% higher after BLR+RRA compared with BLR alone (P=.01). However, this difference became nonsignificant when stratified by numbers of metastatic nodes. CONCLUSION: RRA administered to LRAPTC patients during 1955-2014 did not reduce either the CSM or TR rate. We would therefore not recommend RRA in LRAPTC patients undergoing BLR with curative intent.

Elimination of Locoregional Recurrences and Skin Metastases in Papillary Thyroid Cancer by Ethanol Ablation and Mohs Surgery.

Ultrasound-guided percutaneous ethanol ablation procedures for locoregional recurrences in papillary thyroid carcinoma (PTC) can be repeatedly performed over years. Skin metastases (SM) from PTC generally portend a lethal prognosis. Our patient case report demonstrates the innovative use in low-risk PTC (LRPTC) of treatment modalities designed to prevent neck re-explorations and capable of eliminating both locoregional recurrences and SM. In 2004, a 48-year-old man presented with neck nodal metastases due to PTC. He underwent a near-total thyroidectomy and nodal dissection, confirming an 8-mm PTC involving 2 ipsilateral node metastases. Postoperatively, he received 2 doses of radioactive iodine (RAI) for remnant uptake (cumulative dose 338 mCi); posttherapy scanning was unrevealing. In 2007, he underwent right neck dissection for further node metastases. In 2008, a guided biopsy confirmed a level IV node metastasis. He was referred to our institution for ethanol ablation. Two node metastases were ablated and subsequently disappeared. During 2010-2016, he developed an additional 6 node metastases, which were treated with ethanol ablation; all disappeared on high-resolution sonography. FDG-PET-CT scans in 2009 and 2016 were negative for distant spread. In 2016, a SM in his right neck was removed by dermatologic surgery. In 2017-2018, 2 further SM were excised with negative margins, one after Mohs surgery. He has now been disease-free for 20 months. In conclusion, despite 3 neck surgeries and 2 RAI therapies, our patient repeatedly developed both locoregional recurrences and SM. All 11 disease foci were eliminated with minimally invasive procedures which should more often be considered as effective treatment options in LRPTC.

Foundation One Genomic Interrogation of Thyroid Cancers in Patients With Metastatic Disease Requiring Systemic Therapy.

CONTEXT: Clinical applications of genomic assessment of thyroid cancers are rapidly evolving. OBJECTIVES, DESIGN, AND SETTING: We studied tumor samples from patients with imminently threatening and rare thyroid cancers to identify genomic alterations that might correlate with outcomes and/or be productively therapeutically targetable. PATIENT CONTEXT: Progressive and metastatic, and/or rare, thyroid cancers were studied, 2012 to 2016, at Mayo Clinic sites. INTERVENTION: The intervention was Foundation One tumor interrogation. MAIN OUTCOME MEASURES: Main outcome measures included genomic alterations, patient characteristics, and overall survival. RESULTS: Samples from 55 patients were evaluated: 20 anaplastic thyroid cancers (ATCs) (36%), 25 radioactive iodine-refractory differentiated thyroid cancers (DTCs)/poorly differentiated thyroid cancers (PDTCs) (45%; 14 papillary thyroid cancer [PTCs], 6 PDTCs, 5 Hürthle cell cancers), 8 medullary thyroid cancers (MTCs) (15%), and 2 others (a spindle epithelial tumor with thymus-like differentiation, and a primary thyroid sarcoma). Overall, 72% of DTCs, 79% of ATCs, and 75% of MTCs were deemed to have potentially productively targetable alterations. The most commonly encountered mutation was of TERT promoter (56% of DTCs, 68% of ATCs)-but this is not presently targetable. Targetable BRAFV600E mutations were found in 40% of DTCs/PDTCs (83% of PTCs) and 32% of ATCs; of MTCs, 75% had targetable RET mutations, and 25% HRAS mutations. Of patient tumors with nonmutated BRAFV600E, 53% of DTC/PDTCs and 69% of ATCs had other potentially productively targetable mutations. Genomic alterations in our series of poor prognosis metastatic DTC/PDTCs also closely resembled those seen in ATC. CONCLUSIONS: Whereas genomic interrogation of favorable prognosis thyroid cancer seems ill advised, potentially productively targetable mutations were demonstrated in the majority of tumors from patients with metastatic thyroid cancers requiring systemic therapy, suggesting a rationale for the selective application of this technology.

Bilateral pheochromocytoma: Clinical characteristics, treatment and longitudinal follow-up.

OBJECTIVE: Comprehensive data about patients with bilateral pheochromocytoma are limited. We aimed to describe the clinical presentation, genetic analysis, treatment and outcomes of patients with bilateral pheochromocytoma. DESIGN: A retrospective study at a tertiary care centre. PATIENTS: All patients with bilateral pheochromocytoma evaluated at Mayo Clinic in Rochester, Minnesota between January 1951 and December 2015. MEASUREMENTS: Tumour size, genetic testing, plasma/urine metanephrines and catecholamines. RESULTS: A total of 94 patients (51% women) were diagnosed with bilateral pheochromocytoma at a median age at first presentation of 31 years (range, 4-70). Bilateral disease was noted in 8.0% of pheochromocytoma patient overall and 37.5% of patients 18 years of younger. Most patients presented with synchronous tumours (80%). Median time to metachronous tumours was 4.5 years (range, 1-38). Genetic disease was identified in 75 (80%) patients, including MEN 2A (42.6%), VHL (19.1%), MEN 2B (9.6%) and NF1 (8.5%). Excess catecholamines were present in 97% of patients. Patients with synchronous pheochromocytoma commonly underwent simultaneous bilateral adrenalectomy (99%), and 18 (24%) had cortical-sparing surgery. Multicentric tumours were reported in 23 of 77 (30%) patients with available data. Recurrent disease was found in 9.6% of patients, and 8.5% developed metastatic disease. Median follow-up was 8.5 years. At the study conclusion, 4 patients had died due to pheochromocytoma or adrenalectomy. CONCLUSIONS: Bilateral pheochromocytoma occurred in 7.0% of adults with pheochromocytoma and 37.5% of paediatric patients. Genetic disease was identified in 80% of patients, predominantly MEN2A. Multicentric tumours were common, but most were still cured following adrenalectomy.

Clinical course of adrenal myelolipoma: A long-term longitudinal follow-up study.

OBJECTIVE: We aimed to describe clinical course of myelolipoma and to identify predictors of tumour growth and need for surgery. DESIGN: A retrospective study. PATIENTS: Consecutive patients with myelolipoma. RESULTS: A total of 321 myelolipomas (median size, 2.3 cm) were diagnosed in 305 patients at median age of 63 years (range, 25-87). Median follow-up was 54 months. Most myelolipomas were incidentally detected (86%), whereas 9% were discovered during cancer staging and 5% during workup of mass effect symptoms. Thirty-seven (12%) patients underwent adrenalectomy. Compared to myelolipomas <6 cm, tumours ≥6 cm were more likely to be bilateral (21% vs 3%, P < .0001), cause mass effect symptoms (32% vs 0%, P < .0001), have haemorrhagic changes (14% vs 1%, P < .0001) and undergo adrenalectomy (52% vs 5%, P < .0001). Among patients with ≥6 months of imaging follow-up, median size change was 0 mm (-10, 115) and median growth rate was 0 mm/y (-6, 14). Compared to <1 cm growth, ≥1 cm growth correlated with larger initial size (3.6 vs 2.3 cm, P = .02), haemorrhagic changes (12% vs 2%, P = .007) and adrenalectomy (35% vs 8%, P < .0001). CONCLUSIONS: Most myelolipomas are incidentally discovered on cross-sectional imaging. Myelolipomas ≥6 are more likely to cause mass effect symptoms, have haemorrhagic changes and undergo resection. Tumour growth ≥1 cm is associated with larger myelolipoma and haemorrhagic changes. Adrenalectomy should be considered in symptomatic patients with large tumours and when there is evidence of haemorrhage or tumour growth.

Bone metastases in thyroid cancer.

Whereas preemptive screening for the presence of lymph node and lung metastases is standard-of-care in thyroid cancer patients, bone metastases are less well studied and are often neglected in thyroid cancer patient surveillance. Bone metastases in thyroid cancer are, however, independently associated with poor/worse prognosis with a median overall survival from detection of only 4 years despite an otherwise excellent prognosis for the vast majority of thyroid cancer patients. In this review we summarize the state of current knowledge as pertinent to bony metastatic disease in thyroid cancer, including clinical implications, impacts on patient function and quality of life, pathogenesis, and therapeutic opportunities, proposing approaches to patient care accordingly. In particular, bone metastasis pathogenesis appears to reflect cooperatively between cancer and the bone microenvironment creating a "vicious cycle" of bone destruction rather than due exclusively to tumor invasion into bone. Additionally, bone metastases are more frequent in follicular and medullary thyroid cancers, requiring closer bone surveillance in patients with these histologies. Emerging data also suggest that treatments such as multikinase inhibitors (MKIs) can be less effective in controlling bone, as opposed to other (e.g. lung), metastases in thyroid cancers, making special attention to bone critical even in the setting of active MKI therapy. Although locoregional therapies including surgery, radiotherapy and ablation play important roles in palliation, antiresorptive agents including bisphosphonates and denosumab appear individually to delay and/or lessen skeletal morbidity and complications, with dosing frequency of every 3 months appearing optimal; their early application should therefore be strongly considered.

Preoperative and Postoperative Risk Stratification of Thyroid Papillary Microcarcinoma: A Comparative Study Between Kuma Criteria and 2015 American Thyroid Association Guidelines Risk Stratification.

Background: The incidence of micropapillary thyroid carcinoma (mPTC) has increased in the last decade. Active surveillance (AS) has been proposed as an alternative management for low-risk mPTC based on preoperative Kuma criteria. Controversy still exists on how to appropriately manage this group of patients, as some low-risk mPTC may harbor some postoperative features associated with disease recurrence as described in the 2015 American Thyroid Association (ATA) guidelines. Methods: We retrospectively reviewed 108 patients with histopathologic diagnosis of mPTC after surgery at a third level hospital in Mexico City from 2000 to 2018. Demographic and clinicopathologic data were analyzed as predictors for disease recurrence and/or metastatic disease (lymph node or distant). Comparison between group stratification based on preoperative Kuma criteria and postoperative 2015 ATA guidelines risk criteria for disease recurrence was performed. Measures of diagnostic accuracy were obtained for preoperative risk features according to the Kuma criteria. Results: Of 108 patients, 79 (73%) were classified as preoperative high-risk mPTC and 29 (27%) as low risk based on the Kuma criteria. Of these 79 high-risk patients, 38 (48%) were reclassified as low risk for disease recurrence, 12 (15%) as intermediate risk, and 29 (37%) remained as high risk based on the 2015 ATA risk criteria. Of the 29 preoperative low-risk patients, 19 (65.5%) remained as postoperative low risk for disease recurrence, 2 (7%) as intermediate risk, and 8 (27.5%) as high risk. Higher accuracy of preoperative risk features was obtained for lymph node and distant metastases, 84.2% and 97.2%, respectively. After multivariate analysis, age <40 years and microscopic extrathyroidal extension (ETE) were associated with higher risk for metastatic disease (lymph node or distant) in our cohort. Conclusions: Patients with mPTC under 40 years old and microscopic ETE are more prone to develop metastatic disease (lymph node or distant). One-third of our patients stratified as low-risk mPTC according to the Kuma criteria for AS had histopathologic features associated with a more aggressive clinical behavior or structural recurrence. In addition, lymph node and distant metastases are the preoperative risk features with the highest diagnostic accuracy for preoperative risk stratification.

Patterns of Use, Efficacy, and Safety of Treatment Options for Patients with Graves' Disease: A Nationwide Population-Based Study.

Background: Considerable uncertainty remains about the pattern of use of treatment options for Graves' disease (GD) and their comparative effectiveness and safety. Methods: Between 2005 and 2013, we identified patients with GD who received antithyroid drugs (ATDs), radioactive iodine (RAI) or surgery, and were represented in a large administrative data set in the United States (OptumLabs® Data Warehouse). Results: We identified 4661 patients with GD: mean age 48 (SD ±14) years, white (63%), and female (80%). Patients received ATD, n = 2817 (60%), RAI, n = 1549 (33%), or surgery, n = 295 (6%). Success rates were 50% for ATD, 93% for RAI, and 99% for surgery. Median time to treatment failure was 6.8 months for ATD and 3 months for RAI and surgery. When patients were required to be on ATD for at least one year before assessing failure, the failure rate decreased to 25%. Adverse effects occurred in 12% of patients receiving ATD, 6% with RAI, and 24% with surgery. Factors associated with treatment success were age >55 years (for ATD) and female sex (for RAI). About 12% of patients receiving ATD continued this treatment for >24 months as initial therapy. When patients failed ATD therapy, the most common second-line therapy was reinitiation of ATD (65%), RAI (26%), and surgery (9%). Overall, 26% of patients remain on ATD therapy (combined first or second line). Conclusions: ATD therapy was the most common GD therapy and demonstrated the lowest efficacy and infrequent significant adverse effect profile. With one fourth of patients remaining on ATD treatment (initial or second modality treatment), it becomes imperative to determine the long-term efficacy, safety, costs, and burdens of this modality of treatment.

Thyroid nodules: diagnostic evaluation based on thyroid cancer risk assessment.

Thyroid nodules are extremely common and can be detected by sensitive imaging in more than 60% of the general population. They are often identified in patients without symptoms who are undergoing evaluation for other medical complaints. Indiscriminate evaluation of thyroid nodules with thyroid biopsy could cause a harmful epidemic of diagnoses of thyroid cancer, but inadequate selection of thyroid nodules for biopsy can lead to missed diagnoses of clinically relevant thyroid cancer. Recent clinical guidelines advocate a more conservative approach in the evaluation of thyroid nodules based on risk assessment for thyroid cancer, as determined by clinical and ultrasound features to guide the need for biopsy. Moreover, newer evidence suggests that for patients with indeterminate thyroid biopsy results, a combined assessment including the initial ultrasound risk stratification or other ancillary testing (molecular markers, second opinion on thyroid cytology) can further clarify the risk of thyroid cancer and the management strategies. This review summarizes the clinical importance of adequate evaluation of thyroid nodules, focuses on the clinical evidence for diagnostic tests that can clarify the risk of thyroid cancer, and highlights the importance of considering the patient's values and preferences when deciding on management strategies in the setting of uncertainty about the risk of thyroid cancer.

Documentation of hypoglycemia assessment among adults with diabetes during clinical encounters in primary care and endocrinology practices.

PURPOSE: To examine the proportion of diabetes-focused clinical encounters in primary care and endocrinology practices where the evaluation for hypoglycemia is documented; and when it is, identify clinicians' stated actions in response to patient-reported events. METHODS: A total of 470 diabetes-focused encounters among 283 patients nonpregnant adults (≥18 years) with type 1 or type 2 diabetes mellitus in this retrospective cohort study. Participants were randomly identified in blocks of treatment strategy and care location (95 and 52 primary care encounters among hypoglycemia-prone medications (i.e. insulin, sulfonylurea) and others patients, respectively; 94 and 42 endocrinology encounters among hypo-treated and others, respectively). Documentation of hypoglycemia and subsequent management plan in the electronic health record were evaluated. RESULTS: Overall, 132 (46.6%) patients had documentation of hypoglycemia assessment, significantly more prevalent among hypo-treated patients seen in endocrinology than in primary care (72.3% vs. 47.4%; P = 0.001). Hypoglycemia was identified by patient in 38.2% of encounters. Odds of hypoglycemia assessment documentation was highest among the hypo-treated (OR 13.6; 95% CI 5.5-33.74, vs. others) and patients seen in endocrine clinic (OR 4.48; 95% CI 2.3-8.6, vs. primary care). After documentation of hypoglycemia, treatment was modified in 30% primary care and 46% endocrine clinic encounters; P = 0.31. Few patients were referred to diabetes self-management education and support (DSMES). CONCLUSIONS: Continued efforts to improve hypoglycemia evaluation, documentation, and management are needed, particularly in primary care. This includes not only screening at-risk patients for hypoglycemia, but also modifying their treatment regimens and/or leveraging DSMES.

Assessment of The Bethesda System for Reporting Thyroid Cytopathology.

OBJECTIVES: Long-term follow-up is important for determining performance characteristics of thyroid fine-needle aspiration (FNA). METHODS: Histologic or 3 or more years of clinical follow-up was used to calculate performance characteristics of thyroid FNA before and after implementation of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) classification was also investigated. RESULTS: Follow-up was obtained for 1,277/1,134 and 1,616/1,393 aspirates/patients (median clinical follow-up, 9.9 and 4.4 years, pre- and post-TBSRTC, respectively). Nondiagnostic, suspicious for follicular neoplasm, and suspicious for malignancy (SFM) diagnoses decreased and benign diagnoses increased post-TBSRTC, while atypical rate remained less than 1%. Negative predictive value for benign nodules and positive predictive value (PPV) for SFM increased significantly. Eleven nodules were reclassified as NIFTP, slightly decreasing PPV/risk of malignancy (ROM). CONCLUSIONS: Appropriate ROM for thyroid FNA can be achieved through application of TBSRTC terminology with minimal use of atypical category.