Leigh Delbridge

HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours

Background: Hyperparathyroidism is a common endocrinopathy characterised by the formation of parathyroid tumours. In this study, we determine the role of the recently identified gene, HRPT2, in parathyroid tumorigenesis. Methods: Mutation analysis of HRPT2 was undertaken in 60 parathyroid tumours: five HPT-JT, three FIHP, three MEN 1, one MEN 2A, 25 sporadic adenomas, 17 hyperplastic glands, two lithium associated tumours, and four sporadic carcinomas. Loss of heterozygosity at 1q24-32 was performed on a subset of these tumours. Results:HRPT2 somatic mutations were detected in four of four sporadic parathyroid carcinoma samples, and germline mutations were found in five of five HPT-JT parathyroid tumours (two families) and two parathyroid tumours from one FIHP family. One HPT-JT tumour with germline mutation also harboured a somatic mutation. In total, seven novel and one previously reported mutation were identified. “Two-hits” (double mutations or one mutation and loss of heterozygosity at 1q24-32) affecting HRPT2 were found in two sporadic carcinomas, two HPT-JT-related and two FIHP related tumours. Conclusions: The results in this study support the role of HRPT2 as a tumour suppressor gene in sporadic parathyroid carcinoma, and provide further evidence for HRPT2 as the causative gene in HPT-JT, and a subset of FIHP. In light of the strong association between mutations of HRPT2 and sporadic parathyroid carcinoma demonstrated in this study, it is hypothesised that HRPT2 mutation is an early event that may lead to parathyroid malignancy and suggest intragenic mutation of HRPT2 as a marker of malignant potential in both familial and sporadic parathyroid tumours.

Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma

OBJECTIVE We have determined the frequency of specific mutations in the RET proto‐oncogene in sporadic medullary thyroid carcinomas (MTCs) and correlated the presence or absence of a codon 918 mutation with the clinical characteristics of these tumours.

Scarless (in the neck) endoscopic thyroidectomy (SET): an evidence-based review of published techniques.

BackgroundExcision of the thyroid through a skin crease incision in the anterior neck provides good direct exposure to facilitate safe dissection and a quick operation with low morbidity and minimal mortality. However, these patients still have a scar in the neck. Technologic innovations have allowed surgeons to remove the thyroid gland from a remote site, providing a scarless outcome in the neck. This study was designed to assess the different techniques of scarless (in the neck) endoscopic thyroidectomy (SET) by reviewing the current literature.MethodsA computer-assisted search of the Medline database through September 2007 was undertaken. The combination of terms used included the following: endoscopic thyroidectomy; minimally invasive thyroidectomy; minimally invasive endocrine surgery; thyroidectomy via the axillary approach; thyroidectomy via the anterior approach; and thyroidectomy via the breast approach. Additional data were provided based on previously unpublished experience from our own unit with SET.ResultsThere were seven studies that involved 186 patients in whom the thyroid was excised via the axillary method and five published series that involved 169 patients who had thyroidectomies performed via the anterior approach. There were four published series of thyroidectomies performed via a hybrid approach, which is a combination of both the anterior and axillary approach, involving 180 patients. Four studies compared SET and another approach for a thyroidectomy. In our unpublished series of SET, we performed 20 cases during a 2-year period comprising 11 cases via the axillary approach and 9 cases via the anterior/breast approach. Nineteen cases were lobectomies and one case was an isthmusectomy. SET was associated with a longer operative time and increase postoperative pain. Patients who had SET were satisfied with the aesthetic outcome of the procedure.ConclusionScarless (in the neck) endoscopic thyroidectomy is not a minimally invasive technique but a maximally invasive one that involves a longer operative time and greater postoperative pain. What it does provide is a safe excision of the thyroid pathology with the absence of a scar in the neck. However, there is a steep learning curve. With experience and newer surgical instruments, the operative time and postoperative pain might decrease.

A multicenter cohort study of total thyroidectomy and routine central lymph node dissection for cN0 papillary thyroid cancer

BACKGROUND The role of routine central lymph node dissection (CLND) for papillary thyroid cancer (PTC) remains controversial. The aim of this study was to evaluate the impact of routine CLND after total thyroidectomy (TTx) in the management of patients with PTC who were clinically node negative at presentation with emphasis on stimulated thyroglobulin (Tg) levels and reoperation rates. METHODS This retrospective, multicenter, cohort study used pooled data from 3 international Endocrine Surgery units in Australia, the United States, and England. All study participants had PTC >1 cm without preoperative evidence of lymph node disease (cN0). Group A patients had TTx alone and group B had TTx with the addition of CLND. RESULTS There were 606 patients included in the study. Group A had 347 patients and group B 259 patients. Stimulated Tg values were lower in group B before initial radioiodine ablation (15.0 vs 6.6 ng/mL; P = .025). There was a trend toward a lower Tg at final follow-up in group B (1.9 vs 7.2 ng/mL; P = .11). The rate of reoperation in the central compartment was lower in group B (1.5 vs 6.1%; P = .004). The number of CLND procedures required to prevent 1 central compartment reoperation was calculated at 20. CONCLUSION The addition of routine CLND in cN0 papillary thyroid carcinoma is associated with lower postoperative Tg levels and reduces the need for reoperation in the central compartment.

BRAFV600E mutation is associated with an increased risk of nodal recurrence requiring reoperative surgery in patients with papillary thyroid cancer

BACKGROUND The role of the B-isoform of the Raf kinase (BRAF) mutation BRAF(V600E) as an independent prognostic factor in papillary thyroid cancer (PTC) remains controversial. Some studies suggest that tumors containing BRAF(V600E) have decreased radioiodine avidity and present a greater risk of nodal recurrence and distant metastases. METHODS Paraffin-embedded specimens from consecutive patients who underwent surgery for PTC before 2003 were independently reviewed by an endocrine pathologist. DNA was extracted, amplified by polymerase chain reaction, and the presence of the BRAF(V600E) mutation was determined by restriction digest. Tumor characteristics and long-term disease outcomes were analyzed according to BRAF(V600E) status. RESULTS BRAF(V600E) was identified in 60 (59%) of 101 patients. At a median follow-up of 106 months, the overall disease-free survival was 78%. Clinically evident nodal recurrence occurred in 11% of BRAF(V600E)-positive patients, and all patients required lateral neck dissection (P = .02). In contrast, subclinical nodal recurrence occurred in 7% of BRAF(V600E)-negative patients, and all recurrences were successfully ablated with radioactive iodine. There was a trend toward poorer disease-free survival among patients with stage III/IV PTC and BRAF(V600E) mutation (P = .08). All 5 disease-related deaths occurred in patients with BRAF(V600E)-positive primary tumors (P = .06). CONCLUSION The BRAF(V600E) mutation in PTC is associated with an increased risk of palpable nodal recurrence and the need for reoperative surgery.

Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP)

Familial forms of primary hyperparathyroidism (PHPT) constitute a broad group of disorders in which PHPT is either a main or an associated feature. With the advances in disease gene identification, some of the genetic abnormalities underlying familial PHPT have been clarified.1,2 In hyperparathyroidism–jaw tumour syndrome (HPT-JT; OMIM #145001) the affected family members frequently develop PHPT, ossifying jaw fibromas, and cystic and neoplastic renal lesions.3–6 A typical feature of HPT-JT is adenomas and carcinomas of the parathyroid glands, which often have cystic features.1 This is in contrast to the other forms of familial PHPT in which the parathyroid tumours are generally benign. The disease locus was first mapped to chromosomal region 1q25–q32 by linkage in affected families3,5–7 and recently the causal HRPT2 gene was isolated through a positional cloning approach.3 The HRPT2 gene consists of 17 exons encoding an evolutionarily well conserved, 531 amino acid protein named parafibromin. The inactivating mutations demonstrated in the germline of HPT-JT kindreds and as somatic events in some sporadic parathyroid adenomas3 are in agreement with the observations of somatic loss of the wild type alleles,6 suggesting that parafibromin has a tumour suppressor function.3,6 The importance of the multiple endocrine neoplasia type 1 gene ( MEN1 ) in familial PHPT has been well established. MEN1 is a tumour suppressor gene located in 11q13,8–10 and its encoded protein menin has been shown to interact with several proteins involved in transcriptional regulation.11,12 The MEN1 syndrome (OMIM #131100) is clinically characterised by the frequent development of tumours in the parathyroids, the endocrine pancreas and duodenum, and the anterior pituitary gland. MEN1, which is the most common form of hereditary PHPT, is caused by germline mutations of MEN1 , both in the form of inherited …

Total thyroidectomy is now the preferred option for the surgical management of Graves’ disease

Purpose:  Subtotal thyroidectomy has been advocated as the standard treatment for Graves’ disease because of the possibility of avoiding thyroxine therapy as well as the assumed lower risk of complications compared to total thyroidectomy. However, the long‐term results of subtotal thyroidectomy are not as good as they were previously believed to be, as evidenced by the increasing incidence of hypothyroidism. If the risk of complications from total thyroidectomy is no higher, then that procedure offers significant advantages in the surgical management of Graves’ disease. The aim of this study therefore was to compare the complication rate of the two procedures in patients with Graves’ disease.

ROUTINE LEVEL VI LYMPH NODE DISSECTION FOR PAPILLARY THYROID CANCER: SURGICAL TECHNIQUE

Total thyroidectomy is the treatment of choice for clinically significant papillary thyroid cancer (PTC); however, 10–15% develop palpable local recurrence in the cervical lymph nodes. Metastases in the cervical lymph nodes account for 75% of loco‐regional recurrence and up to 50% of these patients eventually die of their disease. It is generally accepted that surgical excision of grossly involved lymph node disease should be carried out. The role of routine lymph node dissection, however, is greeted with far more controversy. Regional lymph node metastases have been shown to be associated with more frequent tumour recurrence. Not only is recurrence associated with increased disease‐related mortality, but recent data have shown that the presence of involved lymph nodes is associated with adverse survival. Additionally, there have been significant changes to the way patients are managed after treatment for PTC in recent years. Surveillance previously relied on clinical assessment and radioiodine scans whereas now the use of serum thyroglobulin and high‐resolution ultrasound are the standard as evidenced by recommendations by the American Thyroid Association. These techniques have greater sensitivity and subsequently lymph node metastases are being detected earlier and more frequently. This has led to a paradigm shift in the aims of treatment of PTC, from a focus on survival data to a focus on disease‐free status. Routine central neck lymph node dissection can be carried out with no increased morbidity and can achieve lower 6‐month stimulated thyroglobulin levels when compared with total thyroidectomy alone. Routine ipsilateral level VI lymph node dissection in addition to total thyroidectomy should be carried out for the management of clinically significant PTC.

Nerve stimulation in thyroid surgery : is it really useful?

Background:  Monitoring of the recurrent laryngeal nerve (RLN) has been claimed in some studies to reduce rates of nerve injury during thyroid surgery compared with anatomical dissection and visual identification of the RLN alone, whereas other studies have found no benefit. Continuous monitoring with endotracheal electrodes is expensive whereas discontinuous monitoring by laryngeal palpation with nerve stimulation is a simple and inexpensive technique. This study aimed to assess the value of nerve stimulation with laryngeal palpation as a means of identifying and assessing the function of the RLN and external branch of the superior laryngeal nerve (EBSLN) during thyroid surgery.

Management of follicular thyroid carcinoma should be individualised based on degree of capsular and vascular invasion

INTRODUCTION Follicular thyroid carcinoma (FTC) includes a spectrum of neoplasms with varying propensity for metastasis. The aim of this study is to describe outcomes for FTC following multimodality treatment, with particular reference to the degree of capsular and vascular invasion and to recommend a rational management approach based on these characteristics. METHODS Patients with histologically confirmed FTC were identified from a prospectively maintained database. Details of intervention and long-term outcomes were obtained. Outcomes were compared between patients with minimally invasive follicular carcinoma (MI FTC) without vascular invasion (Group 1); angioinvasive MI FTC (Group 2); and those with widely invasive FTC (Group 3). RESULTS Between May 1983 and December 2008, 124 patients with FTC were identified. The overall disease-free survival rate was 85% at a median of 40 months follow-up. Disease-free survival was 97%, 81% and 46%, respectively, in Groups 1, 2 and 3, and significantly different between groups (p<0.001). Thirteen patients in this series developed distant metastases including 2 in Group 1 and 6 in Group 2. Only patients <45 years of age with MI FTC and no vascular invasion had 100% disease-free survival. After multivariate linear regression, age (p=0.03) and the presence of vascular invasion (p=0.03) were the most powerful predictors of distant metastasis. CONCLUSIONS Survival is improved in those with minimally invasive compared with widely invasive FTC. In patients <45 years with MI FTC without vascular invasion, hemithyroidectomy may be adequate treatment. All other patients with FTC should undergo total thyroidectomy and radioactive iodine ablation.