Autofluorescence in Parathyroidectomy: Signal Intensity Correlates with Serum Calcium and Parathyroid Hormone but Routine Clinical Use is Not Justified.

BACKGROUND: The inability to identify the pathological gland at surgery results in failure to cure hyperparathyroidism in 2-5%. The poorly understood characteristic of parathyroid tissue to manifest autofluorescence (AF) under near-infrared (NIR) light has been promoted as an intraoperative adjunct in parathyroid surgery. This study sought to explore potential clinical correlates for AF and assess the clinical utility of AF in parathyroid surgery. METHODS: Consecutive patients undergoing parathyroid surgery for primary and renal disease were included. NIR imaging was used intraoperatively and the degree of AF of parathyroid glands graded by the operating surgeon. Variables assessed for correlation with AF were: pre-operative serum calcium and PTH, SestaMIBI positivity, gland weight and histological composition. RESULTS: Ninety-six patients underwent parathyroidectomy over an 8-month period: 49 bilateral explorations, 41 unilateral and 6 focussed lateral approaches: 284 potentially 'visualisable' glands in total. Two hundred and fifty-seven glands (90.5%) were visualised with NIR. Correlation was found between the degree of fluorescence and pre-operative serum calcium and PTH, but not between gland weight and SestaMIBI positivity. In those with renal hyperparathyroidism, a predominance of oxyphil cells correlated with increased AF. CONCLUSION: Autofluorescence intensity correlates with serum calcium, PTH and gland composition. Further refinements would be required for this information to be of value in a clinical setting. Improvements allowing NIR to visualise the additional 9.5% of parathyroids and overcome the variation in signal intensity due to depth of access are required for the routine adoption of this technology. At present, its routine use in a clinical setting cannot be justified.

Undiagnosed Primary Hyperparathyroidism and Recurrent Miscarriage: The First Prospective Pilot Study.

BACKGROUND: Primary hyperparathyroidism (pHPT) in pregnancy is reported to be associated with significant maternal and foetal complications and an up to threefold increase in the risk of miscarriage. However, the true incidence of pHPT in pregnancy, complete and miscarried, is unknown and there are no data on the prevalence of undiagnosed pHPT in recurrent miscarriage (RM) (≥3 consecutive miscarriages under 24-week gestation). This is the first prospective study aiming to establish the prevalence of undiagnosed pHPT in RM. METHODS: Following UK National ethics committee approval, women who had experienced 3 or more consecutive miscarriages were recruited from a nationwide RM clinic. Serum corrected calcium, phosphate, PTH and vitamin D were evaluated. Patients with raised serum calcium and/or PTH were recalled for confirmatory tests. Power calculations suggested that a minimum of 272 patients were required to demonstrate a clinically significant incidence of pHPT. RESULTS: Three hundred women were recruited, median age 35 years (range 19-42). Eleven patients had incomplete data, leaving 289 patients suitable for analysis; 50/289 patients (17%) with abnormal tests were recalled. The prevalence of vitamin D deficiency (<25 nmol/l) and insufficiency (25-75 nmol/l) was 8.7 and 67.8%, respectively. One patient was diagnosed with pHPT (0.34%) and underwent successful parathyroidectomy. CONCLUSIONS: The prevalence of undiagnosed pHPT (0.34%) in RM in this study appears to be many times greater than the 0.05% expected in this age group. The findings of this pilot study merit follow-up with a larger-scale study. Routine serum calcium estimation is not currently undertaken in RM and should be considered.

Correlation of Preoperative Imaging Findings and Parathyroidectomy Outcomes Support NICE 2019 Guidance.

CONTEXT: Preoperative localization studies are standard practice in patients undergoing parathyroidectomy for primary hyperparathyroidism (pHPT). The most common modalities are neck ultrasound (US) and sestamibi scanning. However, the nature of pHPT is changing, with imaging increasingly yielding negative results. Numerous studies suggest unlocalized disease is associated with poor outcomes, calling into question whether such patients are best treated conservatively. OBJECTIVE: This study aims to correlate parathyroidectomy outcomes with preoperative imaging in a single, high-volume institution. METHODS: Data from a prospectively maintained departmental database of operations performed from 2017 to 2019 were analyzed. All patients undergoing first-time surgery for sporadic pHPT were included. Data collected included patient demographics, preoperative imaging, surgical strategy, and postoperative outcomes. RESULTS: A total of 609 consecutive parathyroidectomies were included, with a median age of 59 years (range 20-87 years). The all-comer cure rate was 97.5%; this was 97.9% in dual localized patients (those with positive US and sestamibi), compared to 95.8% in the dual unlocalized group (those with negative US and sestamibi) (P = 0.33). Unilateral neck exploration was the chosen approach in 59.9% of patients with double-positive imaging and 5.7% of patients with double-negative imaging (otherwise, bilateral parathyroid visualization was performed). There was no significant difference in postoperative complications between patients undergoing unilateral or bilateral neck exploration. CONCLUSIONS: Patients with negative preoperative imaging who undergo parathyroidectomy are cured in almost 96% of cases, compared to 98% when the disease is localized. This difference does not reach statistical or clinical significance. These findings therefore support current recommendations that all patients with pHPT who are likely to benefit from operative intervention should be considered for parathyroidectomy, irrespective of preoperative imaging findings.

Synacthen Stimulation Test Following Unilateral Adrenalectomy Needs to Be Interpreted With Caution.

Background: Cortisol levels in response to stress are highly variable. Baseline and stimulated cortisol levels are commonly used to determine adrenal function following unilateral adrenalectomy. We report the results of synacthen stimulation testing following unilateral adrenalectomy in a tertiary referral center. Methods: Data were collected retrospectively for 36 patients who underwent synacthen stimulation testing one day post unilateral adrenalectomy. None of the patients had clinical signs of hypercortisolism preoperatively. No patient received pre- or intraoperative steroids. Patients with overt Cushing's syndrome were excluded. Results: The median age was 58 (31-79) years. Preoperatively, 16 (44%) patients had a diagnosis of pheochromocytoma, 12 (33%) patients had primary aldosteronism and 8 (22%) patients had non-functioning adenomas with indeterminate/atypical imaging characteristics necessitating surgery. Preoperative overnight dexamethasone suppression test results revealed that 6 of 29 patients failed to suppress cortisol to <50 nmol/L. Twenty (56%) patients achieved a stimulated cortisol ≥450 nmol/L at 30 minutes and 28 (78%) at 60 minutes. None of the patients developed clinical adrenal insufficiency necessitating steroid replacement. Conclusions: Synacthen stimulation testing following unilateral adrenalectomy using standard stimulated cortisol cut-off values would wrongly label many patients adrenally insufficient and may lead to inappropriate prescriptions of steroids to patients who do not need them.

Seventeen Cases of Primary Hyperparathyroidism in Pregnancy: A Call for Management Guidelines.

CONTEXT: The risks of primary hyperparathyroidism (pHPT) to pregnant women and their fetuses appear to increase commensurate with serum calcium levels. The management strategy for pHPT must be adapted in pregnancy and should reflect the severity of hypercalcemia. However, no guidelines exist to assist clinicians. METHODS: The experience of a high-volume multidisciplinary endocrine surgical service in treating a consecutive series of pregnant women with pHPT referred for parathyroidectomy is presented and data are compared with a nonpregnant cohort with pHPT. A review of pHPT and pregnancy outcomes in the literature is provided. RESULTS: Seventeen pregnant women and 247 age range-matched nonpregnant women with pHPT were referred for surgery over 11 years. Mean serum calcium level was higher in the pregnant cohort (2.89 vs 2.78 mmol/L; P = 0.03). Preoperative localization with ultrasound succeeded in eight pregnant women (47%) and sestamibi scanning did in two of six (33% imaged preconception), compared with 84 (34%) and 102 (42%) control subjects, respectively (not significant). Parathyroidectomy was performed under general anesthesia between 12 and 28 weeks' gestation with no adverse pregnancy outcomes resulting. Cure rate was 100% vs 96% in controls. CONCLUSION: pHPT in pregnancy is a threat to mother and child. Medical management may be appropriate in mild disease, but in moderate to severe disease, parathyroidectomy under general anesthesia in the second trimester is safe. Localization using ionizing radiation/MRI is unnecessary, because surgical intervention in a high-volume multidisciplinary setting has excellent outcomes. Guidelines on the topic would assist clinicians.

DLK1/PREF1 marks a novel cell population in the human adrenal cortex.

The adrenal cortex governs fundamental metabolic processes though synthesis of glucocorticoid, mineralocorticoids and androgens. Studies in rodents have demonstrated that the cortex undergoes a self-renewal process and that capsular/subcapsular stem/progenitor cell pools differentiate towards functional steroidogenic cells supporting the dynamic centripetal streaming of adrenocortical cells throughout life. We previously demonstrated that the Notch atypical ligand Delta-like homologue 1 (DLK1)/preadipocyte factor 1 (PREF1) is expressed in subcapsular Sf1 and Shh-positive, CYP11B1-negative and CYP11B2-partially positive cortical progenitor cells in rat adrenals, and that secreted DLK1 can modulate GLI1 expression in H295R cells. Here we show that the human adrenal cortex remodels with age to generate clusters of relatively undifferentiated cells expressing DLK1. These clusters (named DLK1-expressing cell clusters or DCCs) increased with age in size and were found to be different entities to aldosterone-producing cell clusters, another well-characterized and age-dependent cluster structure. DLK1 was markedly overexpressed in adrenocortical carcinomas but not in aldosterone-producing adenomas. Thus, this data identifies a novel cell population in the human adrenal cortex and might suggest a yet-to be identified role of DLK1 in the pathogenesis of adrenocortical carcinoma in humans.

Breast cancer metastases to the thyroid gland - an uncommon sentinel for diffuse metastatic disease: a case report and review of the literature.

BACKGROUND: Metastases to the thyroid are rare. The most common primary cancer to metastasize to the thyroid is renal cell carcinoma, followed by malignancies of the gastrointestinal tract, lungs, and skin, with breast cancer metastases to the thyroid being rare. Overall, the outcomes in malignancies that have metastasized to the thyroid are poor. There are no prospective studies addressing the role of surgery in metastatic disease of the thyroid. Isolated thyroidectomy has been proposed as a local disease control option to palliate and prevent the potential morbidity of tumor extension related to the airway. Here, we present a case of a patient with breast cancer metastases to the thyroid gland and discuss the role of thyroidectomy in the context of the current literature. CASE PRESENTATION: A 62-year-old Afro-Caribbean woman was diagnosed as having bilateral breast carcinoma in 2004, for which she underwent bilateral mastectomy. The pathology revealed multifocal disease on the right, T2N0(0/20)M0 grade 1 and 2 invasive ductal carcinoma, and on the left side, T3N1(2/18)M0 grade 1 invasive ductal carcinoma. Surgery was followed by adjuvant chemotherapy and regional radiotherapy. The disease was under control on hormonal therapy until 2016, when she developed cervical lymphadenopathy. The fine-needle aspiration cytology of the thyroid was reported as papillary thyroid cancer; and the fine-needle biopsy of the left lateral nodal disease was more suggestive of breast malignancy. She underwent a total thyroidectomy and a clearance of the central compartment lymph nodes and a biopsy of the lateral nodal disease. The histopathological analysis was consistent with metastatic breast cancer in the thyroid and lymph nodes with no evidence of a primary thyroid malignancy. CONCLUSIONS: A past history of a malignancy elsewhere should raise the index of suspicion of metastatic disease in patients presenting with thyroid lumps with or without cervical lymphadenopathy. Detection of metastases to the thyroid generally indicates poor prognosis, obviating the need of surgery in an already compromised patient. An empirical thyroidectomy should be considered in select patients for local disease control.