Paediatric differentiated thyroid carcinoma: a UK National Clinical Practice Consensus Guideline.

This guideline is written as a reference document for clinicians presented with the challenge of managing paediatric patients with differentiated thyroid carcinoma up to the age of 19 years. Care of paediatric patients with differentiated thyroid carcinoma differs in key aspects from that of adults, and there have been several recent developments in the care pathways for this condition; this guideline has sought to identify and attend to these areas. It addresses the presentation, clinical assessment, diagnosis, management (both surgical and medical), genetic counselling, follow-up and prognosis of affected patients. The guideline development group formed of a multi-disciplinary panel of sub-speciality experts carried out a systematic primary literature review and Delphi Consensus exercise. The guideline was developed in accordance with The Appraisal of Guidelines Research and Evaluation Instrument II criteria, with input from stakeholders including charities and patient groups. Based on scientific evidence and expert opinion, 58 recommendations have been collected to produce a clear, pragmatic set of management guidelines. It is intended as an evidence base for future optimal management and to improve the quality of clinical care of paediatric patients with differentiated thyroid carcinoma.

Rituximab: a novel treatment for refractory Riedel's thyroiditis.

This case report reviews the rare condition of Riedel's thyroiditis via a patient case. The report highlights the difficulties that one may encounter when managing such a case in regards to patient symptoms, side effects of medications and the relapsing nature of the condition. The case report also highlights novel treatment in the treatment of Riedel's thyroiditis, rituximab, how this works and the resolution of symptoms that we have achieved with our patient on this treatment. LEARNING POINTS: Riedel's thyroiditis is characterised by chronic inflammation, which causes dense fibrosis in the thyroid gland.Riedel's thyroiditis can present with neck pain, dysphagia and dyspnoea with a firm, non-tender mass found on examination.Riedel's thyroiditis is part of the IgG4-related systemic disorders.Rituximab is a monoclonal antibody that works against the protein CD20.

Optimal Management of a Synchronous Diagnosis of Phaeochromocytoma and Colorectal Neoplasia.

The incidence rates of phaeochromocytoma and colorectal cancer (CRC) are approximately 1 and 65 per 100,000 per year, respectively. Simultaneous presentation of these conditions is rare and poses unique management challenges. We report on treatment strategies and clinical outcomes in a series of patients with colorectal neoplasia and phaeochromocytoma. Demographic and clinical details of four patients over a 4-year period were reviewed. The median (range) age at first presentation was 66 (52-70) years. Phaeochromocytoma (2.5-12.5 cm) was confirmed on biochemistry after incidental detection of an adrenal mass on CT scan-three had CT for staging of CRC and one had CT scan for weight loss. Adrenalectomy (three retroperitoneoscopic and one open procedure) was first performed after maximally tolerated alpha blockade; no significant complications were observed. Normalisation of biochemistry was confirmed and the patients then underwent colorectal surgery-laparoscopic right hemicolectomy, open right hemicolectomy (with further extensive surgery) for locally advanced cancer, laparoscopic low anterior resection and open high anterior resection. One respiratory infection and a seroma were the post-operative complications seen. In patients with a simultaneous diagnosis of phaeochromocytoma and CRC, surgical interventions should be staged. Adrenalectomy should first be performed to avoid haemodynamic instability during colorectal resection. A retroperitoneoscopic approach to the adrenal in patients with ipsilateral colonic tumours avoids transgressing the planes for colorectal resection. The synchronous diagnosis of these two rare conditions and the reported stimulatory effect of catecholamines on colorectal epithelia raise the possibility of an increased incidence of colorectal neoplasia in patients with phaeochromocytoma.

Disease-modifying polymorphisms and C609Y mutation of RET associated with high penetrance of phaeochromocytoma and low rate of MTC in MEN2A.

Mutations of the rearranged during transfection (RET) proto-oncogene, located on chromosome 10q11.2, cause multiple endocrine neoplasia type 2A (MEN2A). Patients with mutations at the codon 609 usually exhibit a high penetrance of medullary thyroid cancer (MTC), but a sufficiently low penetrance of phaeochromocytoma that screening for this latter complication has been called to question. Patients with other RET mutations are at higher risk of younger age onset phaeochromocytoma if they also possess other RET polymorphisms (L769L, S836S, G691S and S904S), but there are no similar data for patients with 609 mutations. We investigated the unusual phenotypic presentation in a family with MEN2A due to a C609Y mutation in RET. Sanger sequencing of the entire RET-coding region and exon-intron boundaries was performed. Five family members were C609Y mutation positive: 3/5 initially presented with phaeochromocytoma, but only 1/5 had MTC. The index case aged 73 years had no evidence of MTC, but presented with phaeochromocytoma. Family members also possessed the G691S and S904S RET polymorphisms. We illustrate a high penetrance of phaeochromocytoma and low penetrance of MTC in patients with a RET C609Y mutation and polymorphisms G691S and S904S. These data highlight the need for life-long screening for the complications of MEN2A in these patients and support the role for the screening of RET polymorphisms for the purposes of risk stratification. LEARNING POINTS: C609Y RET mutations may be associated with a life-long risk of phaeochromocytoma indicating the importance of life-long screening for this condition in patients with MEN2A.C609Y RET mutations may be associated with a lower risk of MTC than often quoted, questioning the need for early prophylactic thyroid surgery discussion at the age of 5 years.There may be a role for the routine screening of RET polymorphisms, and this is greatly facilitated by the increasing ease of access to next-generation sequencing.

First surgery for pancreatic neuroendocrine tumours in a patient with MEN1: enucleation versus disease-modifying surgery.

Pancreatic neuroendocrine tumours (PNETs) are the second most common manifestation of MEN1, affecting up to 80% of patients. The secretion of peptide hormones by PNETs causes clinical syndromes requiring therapeutic intervention. Malignant progression of PNETs is a leading cause of mortality in patients with MEN1. The goal of surgery, when required, is to alleviate a biochemical syndrome or to treat established tumour(s) to reduce the risk of local progression or metastases against the background of preservation of pancreatic function. Determining the need and optimum timing for an operative intervention is complex and requires an approach individualized for each patient. When a clinically significant biochemical syndrome is confirmed, the time course to surgery is clear. In patients with a potentially malignant PNET, the decision as to when to intervene is more challenging. In all cases surgical treatment carries the potential for harm, of more than usual concern because many of the patients are young. In this study, we explain an approach to the surgical treatment of MEN1 patients with biochemical or radiological evidence of PNETs where other manifestations of the syndrome are either treated or controlled and the patient lacks comorbidity that would preclude pancreatic surgery. In each scenario we present, a normal serum gastrin will be assumed as the surgical approach to this usually duodenal manifestation of MEN1 is significantly different to the management of other PNETs.

Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas.

CONTEXT: Incidental benign adrenocortical adenomas, adrenal incidentalomas are found in 4.5% of abdominal computed tomography scans, with the incidence increasing to 10% in patients older than 70 years of age. These incidentalomas frequently show evidence of excess cortisol secretion but without overt Cushing's syndrome. The mortality rate is increased in Cushing's syndrome. OBJECTIVE: This study sought to investigate whether patients with adrenal incidentalomas have an increased mortality. DESIGN: This was a retrospective, longitudinal cohort study. SETTING: The study was carried out in an Endocrine Investigation Unit in a University Teaching Hospital. PATIENTS: Two hundred seventy-two consecutive patients with an incidental adrenal mass underwent a dedicated diagnostic protocol, which included dexamethasone testing for hypercortisolism between 2005 and 2013. Overall survival was assessed in 206 patients with a benign, adrenocortical adenoma. MAIN OUTCOME MEASURES: Survival analysis was carried out by using Kaplan-Meier curves and the effect of dexamethasone cortisol estimated by Cox-regression analysis. Cause-specific mortality was ascertained from death certificates and compared with local and national data. RESULTS: Eighteen of 206 patients died and the mean time (SD) from diagnosis to death was 3.2 (1.7) years. Seventeen of 18 patients who died had a post dexamethasone cortisol >1.8 µg/dL and there was a significant decrease in survival rate with increasing dexamethasone cortisol levels (P = .001). Compared with the <1.8 µg/dL group, the hazard ratio (95% confidence interval) for the 1.8-5 µg/dL group was 12.0 (1.6-92.6) whereas that of the >5 µg/dL group was 22.0 (2.6-188.3). Fifty percent and 33% of deaths were secondary to circulatory or respiratory/infective causes, respectively. CONCLUSIONS: PATIENTS with adrenal incidentalomas and a post-dexamethasone serum cortisol >1.8 µg/dL have increased mortality, mainly related to cardiovascular disease and infection.

Near infrared fluorescence imaging of rabbit thyroid and parathyroid glands.

BACKGROUND: Near infrared fluorescence imaging using intravenous methylene blue (MB) is a novel technique that has potential to aid the parathyroid gland (PG) localization during thyroid and parathyroid surgery. The aim of this study was to examine MB fluorescence in the rabbit neck and determine the influence of MB dose and time following administration on fluorescence from thyroid and PGs. METHODS: Thyroid and external PGs were exposed in six New Zealand white rabbits under anesthesia. Varying doses of MB (0.025-3 mg/kg) were injected through the marginal ear vein. Near infrared fluorescence from exposed tissues was recorded at different time intervals (10-74 min) using Fluobeam 700. Specimens of identified glands were then resected for histologic assessment. RESULTS: Histology confirmed accurate identification of all excised thyroid and PGs; these were the only neck structures to demonstrate significant fluorescence. The parathyroid demonstrated lower fluorescence intensities and reduced washout times at all MB doses compared with the thyroid gland. A dose of 0.1 mg/kg MB was adequate to identify fluorescence; this also delineated the blood supply of the external PGs. CONCLUSIONS: The study demonstrates that near infrared fluorescence with intravenous MB helps differentiate between thyroid and PGs in the rabbit. This has potential to improve outcomes in thyroid and parathyroid surgery by increasing the accuracy of parathyroid identification; however, the findings require replication in human surgery. The use of low doses of MB may also avoid the side effects associated with currently used doses in humans (3-7 mg/kg).

Treatment related morbidity in differentiated thyroid cancer-a survey of clinicians.

BACKGROUND: Differentiated thyroid cancer (DTC) has excellent long term survival in most patients. Long-term treatment related morbidity is therefore important, but may not be well characterised. The aim of this study was to conduct an electronic survey of clinicians involved in the care of patients with DTC to determine their views on treatment related morbidity. METHODS: A nine item questionnaire was developed, piloted locally and sent by email to members of three United Kingdom (UK) medical organisations (Thyroid Cancer Forum, British Association of Endocrine and Thyroid Surgeons, British Thyroid Association). RESULTS: 125 responses were received. Less than 5% of respondents had a formal protocol to detect morbidity associated with TSH suppression. Over 50% agreed that morbidity from TSH suppression is not well defined. The majority of responders also agreed that the long-term morbidity of hypocalcaemia, significant voice change and TSH suppression in DTC are not well characterised. Physicians perceived treatment related morbidity to be a bigger problem than surgeons (P = 0.019). CONCLUSION: Clinicians treating thyroid cancer agree that long-term treatment related morbidity from DTC is not well characterised. A study of the prevalence and severity of treatment related morbidity and its impact on health of patients with DTC is warranted.

Outcome of operation in patients with adrenocortical cancer invading the inferior vena cava--a European Society of Endocrine Surgeons (ESES) survey.

BACKGROUND: Most patients with adrenocortical cancer (ACC) continue to present with advanced disease. Invasion into the inferior vena cava (IVC) defines stage III disease and the management of such patients raises additional difficulties. METHOD: A multicentre survey was organized by emailing a standardized proforma to members of the European Society of Endocrine Surgery (ESES). Anonymised retrospective clinical data were collected. RESULTS: Replies were received from 18 centres in nine countries. ACC with IVC invasion was encountered in 38 patients (18F:20M, age 15-84 years, median 54 years). There were 16 nonfunctioning tumours and 22 functioning tumours predominantly right-sided (26R:12L) and measuring 18-255 mm (median 115 mm). Fourteen patients had metastatic disease at presentation. Tumour thrombus extended in the prehepatic IVC (n = 21), subdiaphragmatic IVC (n = 6) or into the SVC/right atrium (n = 3). Open adrenalectomy was associated with resection of surrounding viscera in 24 patients (nephrectomy n = 16, liver resection n = 14, splenectomy n = 3, Whipple procedure n = 2). IVC was controlled locally (n = 27), at suprahepatic levels (n = 6) or necessitated cardiac bypass (n = 5). Complete resection (R0, n = 20) was achieved in the majority of patients, with a minority having microscopic persistent disease (R1, n = 7) or macroscopic residual disease (R2, n = 4). Perioperative 30-day mortality was 13% (n = 5). Postoperative Mitotane was used in 23 patients and chemotherapy in eight patients. Twenty-five patients died 2-61 months after their operation (median 5 months). Currently, 13 patients are alive at 2-58 months (median 16 months) with known metastatic disease (n = 7) or with no signs of distant disease (n = 6). CONCLUSION: This dataset is limited by the lack of a denominator as it remains unknown how many other patients with ACC presenting with IVC invasion did not undergo surgery. The relatively low perioperative mortality and the long disease-free survival achieved by some patients should encourage surgeons with adequate experience to offer surgical treatment to patients presenting with advanced adrenocortical cancers.

The indeterminate adrenal mass.

PURPOSE: This paper is a review of the evidence base carried out to provide recommendations to aid the clinical management of patients with a CT/MRI-detected lipid-poor/indeterminate adrenal mass in whom phaeochromocytoma and metastatic adrenal disease are excluded. METHODS: A Medline keyword search of English-language articles led to the production of a draft document and consensus statement containing levels of evidence and grading of recommendations as proposed by the Agency for Healthcare Research and Quality. RESULTS: Literature review clearly defines the extent and definition of what constitutes a lipid-poor adrenal mass. The ability of MRI to better distinguish adrenocortical adenoma from adrenocortical cancer is increasing, although there is little high-level evidence to confirm this. FDG PET appears promising in its ability to predict that an adrenal lesion is benign. CONCLUSIONS: The management of a patient with an indeterminate adrenal mass in the absence of clear clinical, biochemical, and radiological indications for adrenalectomy may be aided by further assessment using chemical-shift/contrast-enhanced MRI and (18)F-FDG PET/CT.

Osteoprotegerin (OPG) and related proteins (RANK, RANKL and TRAIL) in thyroid disease.

BACKGROUND: Osteoprotegerin (OPG), receptor activator of nuclear factor kappaB (RANK), RANK ligand (RANKL), and TNF related apoptosis inducing ligand (TRAIL) are the key proteins in the development of bone metastases. Osteoprotegerin improves tumor cell survival and inhibits TRAIL induced apoptosis of cancer cell lines. It also binds to RANKL and inhibits its interaction with RANK (cell surface receptor), which influences osteoclast formation and function. The aim of the present study was to characterize the expression of OPG, RANK, RANKL, and TRAIL in benign and malignant thyroid tissue and thyroid cell lines. METHODS: Archived thyroid tissue from 79 patients (60 differentiated thyroid cancers and 19 benign thyroids) was stained for OPG, RANK, RANKL, and TRAIL by immunohistochemistry. Staining was assessed semiquantitatively and correlated with pathology. Western blots were performed on three human thyroid cell lines: Nthy-ori 3-1 (thyroid follicular epithelium), FTC-133 (follicular thyroid carcinoma), and K1E7 (subclone of papillary thyroid carcinoma). RESULTS: Osteoprotegerin and RANKL staining was cytoplasmic; RANK staining was nuclear; and TRAIL staining was predominantly cytoplasmic. All four proteins were expressed in benign and malignant tissue. There was significant difference in RANK expression between malignant and benign tissue (8 vs. 84%, respectively; Fisher's exact test; P < 0.001). RANKL expression was significantly increased in malignant tissue (Fisher's exact test; P = 0.04). Western blotting showed OPG expression in all cell lines and TRAIL in none. RANK and RANKL were not detected in papillary and follicular cell lines, respectively. CONCLUSIONS: Nuclear expression of RANK protein in thyroid tissue is paradoxical; it could be due to nuclear migration after ligand binding. Suppression of RANK and increased expression of RANKL in malignant tissue warrant further investigation.

Post-parathyroidectomy parathyroid hormone levels: the impact on patient survival - a single-centre study in a stage 5 chronic kidney disease population.

BACKGROUND/AIMS: Both severe, uncontrolled and low parathyroid hormone (iPTH) levels are associated with adverse outcomes in stage 5 chronic kidney disease (CKD) patients; however, the impact of iPTH levels following parathyroidectomy (PTX) is unexplored. METHODS: A total of 235 stage 5 CKD patients who underwent PTX between 1990 and 2007 were identified, and iPTH levels following surgery were used to divide patients according to the quartile of maximum iPTH recovery during the 5 years following PTX. Survival, biochemistry and pharmacotherapy were analysed. RESULTS: The maximum iPTH level in each quartile during the follow-up period was <46, 47-139, 140-420 and >420 pg/ml. The overall 5-year survival for the group was 81%. Adjusting for age, time on renal replacement therapy and the presence of diabetes identified an increased hazard for mortality of 2.459 in the quartile of lowest iPTH recovery (p = 0.035). The median 1-alfacalcidol dose during the follow-up period was higher (0.5 µg/day) in the lower iPTH group compared to the 3 quartiles of higher iPTH recovery (0.25 µg/day). CONCLUSION: An association between the lowest quartile of iPTH recovery in the 5 years following PTX and poorer patient survival was found. This finding should be tested in larger datasets.

Intraoperative adjuncts in surgery for primary hyperparathyroidism.

PURPOSE: This paper is a review of the evidence base to produce recommendations for the use of intraoperative parathyroid hormone (PTH), radioguided parathyroidectomy (RGP), methylene blue (MB), frozen section, and intraoperative neuromonitoring during surgery for primary hyperparathyroidism (PHPT). MATERIALS AND METHODS: A Medline keyword search of English-language articles led to the production of a draft document, subsequently revised by committee, containing levels of evidence and the grading of recommendations as proposed by the Agency for Healthcare Research and Quality. RESULTS: Literature review provides the basis for clear recommendations on the use of intraoperative PTH at surgery for PHPT. There is little evidence to support the use of RGP, MB, routine frozen section, and intraoperative neuromonitoring.

What steps should be considered in the patient who has had a negative cervical exploration for primary hyperparathyroidism?

The key to cure of the patient with persistent primary hyperparathyroidism is a clear understanding of the investigations, operative procedure and pathology related to the initial procedure. Reinvestigation and subsequent surgery should be performed in a specialist unit. A logical pathway of increasingly sophisticated localization studies (MIBI, ultrasound, CT/MRI, selective venous catheterization for PTH) will usually guide the surgeon to the missing parathyroid gland/s. Improved preoperative localization can facilitate the use of a minimally invasive small incision approach. The surgeon must have a detailed knowledge of the nuances of parathyroid embryology and a meticulous surgical technique, not only to identify and safely remove the retained gland/s but also do so without causing unnecessary morbidity. Results of re-operation (84-98% cure) from centres of excellence are highly commendable, yet the use of 'new' technology (that includes intra-operative PTH) has not translated into improved outcomes in all cases. Some parathyroid glands are extremely difficult to find! Re-operative parathyroid surgery is a challenge, sometimes easy, and on other occasions extremely difficult.

Continuous glucose monitoring in patients with insulinoma.

BACKGROUND: Insulinomas are rare neuroendocrine tumours that are usually small and may take time to localize. They cause recurrent life-threatening spontaneous hypoglycaemia. Recurrent hypoglycaemia causes loss of hypoglycaemia awareness, putting the patient at further risk, but this has rarely been described in insulinoma. We describe the utility of continuous glucose monitoring (CGM) in patients with insulinoma. PATIENTS AND METHODS: Three patients, aged 72 years (patient 1), 37 years (patient 2) and 24 years (patient 3), with suspected insulinoma attended our investigation unit, in a university teaching hospital. Biochemical diagnosis was confirmed by elevated plasma insulin and C-peptide during biochemical hypoglycaemia [plasma glucose < 2.2 mM (40 mg/dl)]. Surgery confirmed histology in all. CGM was used to monitor frequency and time of hypoglycaemia during diagnosis and medical treatment, and after definitive surgical treatment. RESULTS: All patients had evidence of hypoglycaemia unawareness. At diagnosis in patients 1-3, CGM revealed 6.1%, 21.9% and 71.0% of time spent in moderate hypoglycaemia (plasma glucose 2.2-3.0 mM), and 1.4%, 11.4% and 48.1% of time in severe hypoglycaemia (plasma glucose < 2.2 mM), respectively. On diazoxide this reduced to 0.6%, 5.4% and 5.7% time in moderate hypoglycaemia, and no severe hypoglycaemia in patients 1 and 3, and 0.5% in patient 2. Octreotide therapy in patients 2 and 3 resulted in 5.8% and 0% of time in moderate hypoglycaemia, respectively, and no severe hypoglycaemia. After surgical excision CGM confirmed cure in all. CONCLUSIONS: CGM in insulinoma is useful in detecting hypoglycaemia, and hypoglycaemia unawareness, monitoring response to medical therapy and for confirming cure postoperatively, and is useful in the management of this uncommon but dangerous condition.

Endocrine surgical aspects of multiple endocrine neoplasia syndromes in children.

BACKGROUND: All patients diagnosed with medullary thyroid carcinoma (MTC) should undergo RET mutation analysis to exclude familial disease - multiple endocrine neoplasia (MEN)-2A and -2B and familial medullary thyroid carcinoma (FMTC). In young patients at risk of genetically determined MTC, the key to a good outcome is an appropriate first operation, and this will depend upon the codon mutation, patient age, calcitonin level and disease extent at presentation. When MTC has already developed, a therapeutic intervention is required. CONCLUSIONS: The thyroid, pituitary, adrenal, parathyroid and pancreatic components of MEN-1 and -2 require close collaboration of a specialist and experienced multidisciplinary team.