Diana L. Learoyd

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.

Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs approximately US

Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications

2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age <or=40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care.

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

Familial hyperparathyroidism is not uncommon in clinical endocrine practice. It encompasses a spectrum of disorders including multiple endocrine neoplasia types 1 (MEN1) and 2A, hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH), and familial isolated hyperparathyroidism (FIHP). Distinguishing among the five syndromes is often difficult but has profound implications for the management of patient and family. The availability of specific genetic testing for four of the syndromes has improved diagnostic accuracy and simplified family monitoring in many cases but its current cost and limited accessibility require rationalisation of its use. No gene has yet been associated exclusively with FIHP. FIHP phenotypes have been associated with mutant MEN1 and calcium-sensing receptor (CASR) genotypes and, very recently, with mutation in the newly identified HRPT2 gene. The relative proportions of these are not yet clear. We report results of MEN1, CASR, and HRPT2 genotyping of 22 unrelated subjects with FIHP phenotypes. We found 5 (23%) with MEN1 mutations, four (18%) with CASR mutations, and none with an HRPT2 mutation. All those with mutations had multiglandular hyperparathyroidism. Of the subjects with CASR mutations, none were of the typical FHH phenotype. These findings strongly favour a recommendation for MEN1 and CASR genotyping of patients with multiglandular FIHP, irrespective of urinary calcium excretion. However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred. Also apparent is the need for further investigation to identify additional genes associated with FIHP.

Increasing incidence of thyroid cancer is due to increased pathologic detection

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 There has been a marked increase in the incidence of thyroid cancer worldwide over recent decades. Patients with retrosternal goiter (RSG) are not picked up generally by common surveillance techniques such as ultrasound. The aim of this project was to study the incidence of thyroid cancer in patients with RSG. METHODS This is a retrospective cohort study. Documented were patient demographics as well as the size, type, and numbers of thyroid cancers. The number of routine histologic blocks examined for multinodular goiter in the different time periods was also examined. RESULTS Within a cohort of 13,793 thyroidectomies performed over 40 years, there were 2,260 patients (14%) who underwent surgery for RSG. The percentage of patients with RSG containing thyroid cancer increased from 3.6 to 7.5% (P < .05); however, once papillary microcarcinomas (PMC) (</=10 mm) were excluded there was no increase in cancer incidence (3.4-3.5%, P = .9). The increase in the number of PMCs diagnosed is associated with the increase in the routine number of blocks sampled over the 40-year time period (P < .01). CONCLUSION This study has confirmed an increase in the incidence of thyroid cancer over 4 decades. However, that increase appears to be due to an increase in the diagnosis of PMC associated with increased sampling of resected specimens by pathologists, raising the possibility that the current epidemic of thyroid cancer may be largely manmade.

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

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.

Molecular genetics of thyroid tumors and surgical decision-making.

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.

Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations

The study of thyroid tumor genetics has great relevance to surgeons and facilitates understanding tumor pathogenesis, prediction of tumor behavior, and management decisions. The genes implicated can be broadly categorized as oncogenes or tumor-suppressor genes. The RET oncogene has well established roles in the development of both papillary (PTC) and medullary (MTC) thyroid carcinoma. Genetic screening for germline RET mutations in members of multiple endocrine neoplasia type II (MEN-II) families is now widely performed, and prophylactic thyroidectomy in gene carriers is advisable at an early age. Patients with apparently sporadic MTC can also be screened to rule out familial disease. The demonstration of a RET rearrangement in a patients PTC may have prognostic significance, but as yet there are no management implications. The thyrotropin receptor (TSH-R) and Gsα become oncogenic through point mutation and are associated with the development of toxic thyroid adenomas. The ras oncogene is implicated in the early stages of development of several thyroid tumor types. Tumor-suppressor genes also have a role in thyroid tumor formation. The p53 gene appears to be involved in the process of transformation to the anaplastic phenotype and the PTEN gene in the development of follicular adenomas but not carcinomas. There is still limited evidence for the so called adenoma–carcinoma sequence of the thyroid follicular cell. Loss of heterozygosity studies have enabled identification of tumor-suppressor genes, and their findings suggests differences in the pathogenesis of PTCs compared with follicular cancers. Surgical decision-making will benefit from these basic molecular advances, which rapidly translates into improved patient management.

Association of FOXE1 Polyalanine Repeat Region with Papillary Thyroid Cancer

Objective and design  Genetic screening in multiple endocrine neoplasia type 2 (MEN 2) has led to specific management guidelines based on genotype–phenotype analysis. However, there is controversy regarding the appropriate age for prophylactic thyroidectomy in families with mutations in codon 804 in exon 14 of the RET proto‐oncogene, where medullary thyroid cancer (MTC) may not develop until adulthood. We prospectively studied two MEN 2A families, one with the V804L and the other with the V804M RET mutation, to report our experience of genetic and biochemical screening and prophylactic thyroidectomy. Family 1 is one of the largest MEN 2A families in the literature, where 22 prophylactic thyroidectomies have been performed.