11C-metomidate PET CT versus Adrenal Vein Sampling for diagnosing surgically curable primary aldosteronism: prospective test validation, and impact of somatic genotype and ethnicity on outcomes

Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma (APA) is a common, curable cause of hypertension, but invasive methods of diagnosis and treatment contribute to <1% of patients being offered the chance of cure. The primary objective of our prospective within-patient study in 143 patients with PA was to compare accuracy of 11C-metomidate (MTO) PET-CT scanning with adrenal vein sampling (AVS) in predicting biochemical cure from PA and resolution of hypertension. Secondary outcomes addressed heterogeneity of underlying pathogenesis and prediction of patients most likely to achieve complete cure of hypertension. 128 patients reached 6-9 month follow-up. 77/78 surgical patients achieved one or more of the four hierarchically analysed Primary Aldosteronism Surgical Outcome (PASO) criteria for biochemical and clinical success. MTO was not superior to AVS but all four differences in accuracy favored MTO, with 95% CIs >-17%, the pre-specified margin of non-inferiority. The best univariate predictors of complete clinical cure were home systolic blood pressure (SBP) <135 mmHg after one month of spironolactone 100 mg daily (odds ratio 13.0 (3.72, 45.24) p<0.001) and KCNJ5 genotype of the APA (odds ratio 10.37 (2.50, 42.99) p=0.001). The latter remained significant in logistic regression on age, gender, ethnicity, and was itself predicted by elevated urine 18-hydroxycortisol:cortisol ratio. Our findings validate 11C-metomidate PET-CT for accurate, non-invasive detection of patients with unilateral PA, and identify patients most likely to benefit from adrenalectomy.

Preoperative calcitonin testing improves the diagnosis of medullary thyroid carcinoma in female and male patients

Calcitonin (Ctn) measurement in patients with thyroid disease could potentially increase the detection rates of medullary thyroid carcinoma (MTC) but remains a controversial issue. The aim of this study was to evaluate routine preoperative Ctn measurements. Methods: All patients with thyroid surgery documented in the prospective StuDoQ|Thyroid registry between 03/2017 and 09/2020 were included. Cutoff levels for Ctn were determined with ROC analyses to assess the preoperative diagnosis of MTC in subgroups for females and males. Findings: In 29.590 of 39.679 patients (75%) participating in the registry, routine preoperative Ctn testing was performed. In 357 patients (227 females, 130 males) histopathology confirmed MTC with a mean tumor size of 14.7 mm (± 12.43). Biochemical cure was achieved in 71.4% of the patients. Ctn levels between 11 and 20 pg/ml were seen in 2.6% of the patients, and only 0.7% of the patients had Ctn levels above 21 pg/ml. Cutoff levels for the diagnosis of MTC were 7.9 pg/ml for females and 15 pg/ml for males (p <0.001). The sensitivity and specificity for females were 95% and 98%, and 96% and 97% for males, respectively. Conclusion: Routine Ctn testing is a reliable predictor for MTC and provides the opportunity for earlier thyroidectomy before lymph node metastases occur, resulting in a better prognosis. Females with Ctn levels >7.9 pg/ml and males >15 pg/ml without any other extrathyroidal sources for an elevated Ctn should be monitored. Thyroid surgery should be considered if Ctn levels are increasing, or ultrasound detects suspicious thyroid lesions.

Surgical Outcomes in the Pheochromocytoma Surgery. Results From the PHEO-RISK STUDY.

Purpose: To identify presurgical and surgical risk factors for postsurgical complications in the pheochromocytoma surgery.Methods: A retrospective study of pheochromocytomas submitted to surgery in ten Spanish hospitals between 2011 and 2021. Postoperative complications were classified according to Clavien-Dindo scale.Results: One hundred and sixty-two surgeries (159 patients) were included. Preoperative antihypertensive blockade was performed in 95.1% of the patients, being doxazosin in monotherapy (43.8%) the most frequent regimen. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more frequently (49.4% vs 25.0%, P=0.003) than patients treated with phenoxybenzamine, but no differences in the rate of intraoperative and postsurgical complications were observed. However, patients treated with phenoxybenzamine had a longer hospital stay (12.2±11.16 vs 6.2±6.82, P<0.001) than those treated with doxazosin. Hypertension resolution was observed in 78.7% and biochemical cure in 96.6% of the patients. Thirty-one patients (19.1%) had postsurgical complications. Prolonged hypotension was the most common, in 9.9% (n=16), followed by hypoglycaemia in 6 patients and acute renal failure in 4 patients. 13.0% of complications had a score ≥3 in the Clavien-Dindo scale. Postsurgical complications were more common in in patients with diabetes, cerebrovascular disease, higher plasma glucose levels, higher urinary free metanephrine and norepinephrine, and with pheochromocytomas larger than 5 cm.Conclusion: Preoperative medical treatment and postsurgical monitoring of pheochromocytoma should be especially careful in patients with diabetes, cerebrovascular disease, higher levels of plasma glucose and urine free metanephrine and norepinephrine, and with pheochromocytomas >5 cm, due to the higher risk of postsurgical complications.

Somatic mutations in adrenals from patients with primary aldosteronism not cured after adrenalectomy suggest common pathogenic mechanisms between unilateral and bilateral disease

Objective: Primary aldosteronism (PA) is the most common form of secondary and curable hypertension. Different germline and somatic mutations are found in aldosterone producing adenoma (APA) and familial forms of the disease, while the causes of bilateral adrenal hyperplasia (BAH) remain largely unknown. Adrenalectomy is the recommended treatment for patients with APA; however, 6% of patients are not cured and show persistent PA after surgery suggesting BAH. The objective of this study was to analyze clinical data of patients with APA without biochemical success after adrenalectomy as well as the histological and genetic characteristics of their adrenal glands. Design and Methods: Clinical data of 12 patients without biochemical cure were compared to those from 39 PA patients with hormonal cure after surgery. Histological, morphological and genetic characterization of the adrenals was carried out by CYP11B2 and CYP11B1 immunostaining and by CYP11B2-guided NGS. Results: Patients with absent hormonal cure displayed longer duration of arterial hypertension and lower lateralization index of aldosterone production. In 10 patients, APA expressing CYP11B2 were identified. No difference in histological and morphological characteristics was observed between patients with our without hormonal cure. Somatic mutations in APA driver genes were identified in all CYP11B2 positive APA; CACNA1D mutations were the most frequent genetic abnormality. Conclusions: Patients with absent biochemical cure were diagnosed later and exhibited lower lateralization index of aldosterone production, suggesting asymmetric aldosterone production in the context of BAH. Somatic mutations in adrenal glands from those patients indicate common mechanisms underlying BAH and APA.

Parathyroid Adenoma - From Surgical to Biochemical Cure

Parathyroid glands, minute endocrine glands, located in posterior aspect of thyroid glands secrete parathormone which plays an important role in maintaining calcium homeostasis in the body. The superior and inferior parathyroid glands originate from the 4th and 3rd branchial pouches respectively and migrate to occupy their normal positions in relation to the thyroid gland.1 Hyperparathyroidism is defined as hyper functioning of parathyroid gland and can be primary, secondary or tertiary. Primary hyperparathyroidism is due to parathyroid gland proliferative disorders which include parathyroid adenoma, parathyroid hyperplasia, parathyroid carcinoma or in association with other conditions in MEN syndrome. In more than 90 % patients, primary hyperparathyroidism is caused by a single parathyroid adenoma. Very rarely double parathyroid adenomas are seen. Secondary Hyperparathyroidism is caused in response to any chronic hypocalcaemic conditions like renal failure, gastrointestinal malabsorption, dietary rickets & drugs, like phenytoin, phenobarbital & laxative. Prolonged secondary hyperparathyroidism leads to tertiary hyperparathyroidism due to autonomous secretion. The clinical presentation of hyperparathyroidism is classically described as kidney stones, abdominal groans, painful bones, psychic moans, and fatigue overtones. In the initial course of the disease, the patients present with vague symptoms of fatigue, muscle and joint pain, frequent urination, nausea, constipation, and decreased appetite. If high index of suspicion is maintained, they can be conveniently diagnosed by routine blood tests which show increased calcium levels. However, in India still majority of people are diagnosed when they present with palpable neck mass, skeletal manifestations or deranged renal function. We hereby present 5 cases of parathyroid adenoma managed at our centre over a period of 2 years. P

Evaluation of diagnostic efficacy for localization of parathyroid adenoma in patients with primary hyperparathyroidism undergoing repeat surgery

Purpose Repeat surgery in patients with primary hyperparathyroidism (pHPT) is associated with an increased risk of complications and failure. This stresses the need for optimized strategies to accurately localize a parathyroid adenoma before repeat surgery is performed. However, evidence on the extent of required diagnostics for a structured approach is sparse. Methods A retrospective single-center evaluation of 28 patients with an indication for surgery due to pHPT and previous thyroid or parathyroid surgery was performed. Diagnostic workup, surgical approach, and outcome in terms of complications and successful removement of parathyroid adenoma with biochemical cure were evaluated. Results Neck ultrasound, sestamibi scintigraphy, C11-methionine PET-CT, and selective parathyroid hormone venous sampling, but not MRI imaging, effectively detected the presence of a parathyroid adenoma with high positive predictive values. Biochemical cure was revealed by normalization of calcium and parathormone levels 24–48h after surgery and was achieved in 26/28 patients (92.9%) with an overall low rate of complications. Concordant localization by at least two diagnostic modalities enabled focused surgery with success rates of 100%, whereas inconclusive localization significantly increased the rate of bilateral explorations and significantly reduced the rate of biochemical cure to 80%. Conclusion These findings suggest that two concordant diagnostic modalities are sufficient to accurately localize parathyroid adenoma before repeat surgery for pHPT. In cases of poor localization, extended diagnostic procedures are warranted to enhance surgical success rates. We suggest an algorithm for better orientation when repeat surgery is intended in patients with pHPT.

Clinical Behaviors of Atypical Parathyroid Adenomas

Background: Atypical parathyroid adenoma is a rare entity that share some pathology features of parathyroid carcinoma such as fibrosis. Little is known about the clinical behavior of atypical parathyroid adenomas. Pathologically, it is defined as a hypercellular parathyroid lesion with intratumoral banding fibrosis, mitotic figures, trabecular growth and presence of tumor in the surrounding capsule but lacks unequivocal evidence of invasion, such as invasion to peritumoral vessels, perineural invasion and surrounding structures. Methods: A retrospective study of 15 consecutive patients with atypical parathyroid adenoma treated at a single center between 2010 and 2020 was performed. Patient demographics, clinical characteristics, biochemical profile, indications for surgery, preoperative localization studies, intraoperative findings, histopathological characteristics, disease recurrence or persistence and survival were collected. Results: 7 of 15 were female with a median age of 62 (IQR: 52–67). Five of the 15 patients (33%) were re-operative. No patients presented with palpable neck mass. Presentations were consistent with usual primary hyperparathyroidism. Average calcium on presentation was 11.2, and average PTH was 199. One patient had known MEN1 syndrome and one patient had family history of hyperparathyroidism but had negative genetic testing. Most patients 12/15 had correctly localizing imaging pre-operatively with the other 3 having equivocal or non-localizing studies. Two patients did not have biochemical resolution of hyperparathyroidism, both were re-operative. Of the patients with biochemical cure, 6 did not have follow up beyond 6 months, and 7 patients had long term follow up with persistent biochemical resolution and no recurrence of disease for a median of 4 years (IQR: 3.75–9.25). On review of pathology, no patients had invasive features and all patients had presence of thick fibrous bands or capsule. Conclusion: Patients with atypical adenoma have good response to surgery and low recurrence rates. Reoperation with associated scarring and fibrous bands can confound pathological findings. Our experience shows that patients found to have atypical parathyroid adenoma at their primary operation with resulting biochemical cure can be followed long-term with seemingly indolent and nonaggressive behavior.

Re-Evaluating Absent Clinical Success After Adrenalectomy in Unilateral Primary Aldosteronism

Introduction: Adrenalectomy cures unilateral primary aldosteronism (PA), and improves or cures hypertension. However, a significant proportion of patients are classified with absent clinical success post-surgery, suggesting that surgery was ineffective. Methods: We assessed all patients 6–12 months after unilateral adrenalectomy for clinical outcomes using Primary Aldosteronism Surgical Outcomes (PASO), AVIS-2 and CONNsortium criteria. We estimated blood pressure (BP) changes after adjustment for changes in defined daily dosages (DDD) of antihypertensive medications. Finally, patients were reassessed using PASO at their most recent clinical visit. Results: 104 patients with unilateral PA underwent adrenalectomy at two tertiary centres from 2000–2019. 24 (23%), 31(30%) and 54 (52%) patients were classified with absent clinical success using PASO, AVIS-2 and CONNsortium criteria respectively. Amongst 24 patients with absent clinical success using PASO criteria, 10 had complete biochemical cure, 3 partial, 2 absent, and 9 had resolution of hypokalemia. On multivariate analysis, absent clinical success was associated with presence of hyperlipidemia, diabetes mellitus and lower DDD at baseline. After adjustment for changes in DDD, 7 of 24 patients showed BP improvement ≥20/10mmHg. After follow-up of mean 5.6 years, 12 of 24 patients showed partial or complete clinical success when reassessed using PASO criteria. Only 6 of 104 (5.8%) patients failed to show any clinical improvement after surgery. Conclusions: Although some patients may be classified with absent clinical success post-surgery, majority demonstrate evidence of clinical benefit. Unilateral adrenalectomy remains the recommended treatment option for patients with unilateral PA.