Medullary thyroid cancer (MTC) is a rare tumour of neuroendocrine origin with a more aggressive profile than differentiated thyroid cancer. Familial cases of MTC are associated with RET mutations whilst RAS mutations appear to be a frequent finding in RET negative tumours. The aims of this study were to analyse survival outcomes in MTC and to evaluate the role of RAS immunohistochemistry in the identification of sporadic disease.

Journal Endocrine Surgery ES001 PRE-OPERATIVE SONOGRAPHIC VOLUMETRIC ASSESSMENT PREDICTS TUMOUR SIZE AND LYMPH NODE STATUS IN PAPILLARY THYROID CANCER THOMAS PENNINGTON, MAY THWIN, LEIGH DELBRIDGE, MARK SYWAK AND STAN SIDHU University of Sydney Endocrine Surgical Unit, NSW Purpose: Papillary thyroid cancers (PTC) are three dimensional tumours, yet staging systems employ one dimensional tumour measurements. PTCs are ellipsoid in shape such that measurement of maximum diameter alone is unlikely to predict tumour volume accurately. As a recent trend towards managing smaller PTCs with observation alone has gained traction, accurate sonographic assessment of tumour size takes on renewed importance. This study examines the relationship between sonographic maximum diameter and sonographic tumour volume with correlation to histopathology and nodal status. Methodology: The Sydney University Endocrine Surgery Unit database was queried for pre-operative sonographic nodule volumetric assessment in patients with subsequently confirmed PTC. Correlation between sonographic nodule volume and maximum diameter alone and histology was performed. Results: 121 patients met the inclusion criteria and were reviewed for histological size concordance and nodal status. Preoperative ultrasound overestimated the histological tumour size 59% of the time, with a mean difference of 4.5%. The maximum US diameter alone was only able to predict the actual US nodule volume within a 10% error, 28% of the time. Overall rate of lymph node metastasis was 47%. Nodal metastasis was observed in PTCs as small as 0.25mL. Nodules with a volume between 0.25–0.85mL had the highest rate of lymph node involvement at 68%. Conclusion: Maximum diameter alone is an inaccurate marker of PTC tumour size. Furthermore, small volume tumours have high rates of lymph node involvement, necessitating accurate pre-operative volume estimation to stratify risk and guide management decisions. ES002 PD-L1 EXPRESSION IS ASSOCIATED WITH EPITHELIALMESENCHYMAL TRANSITION IN PAPILLARY THYROID CANCER MARRA AGHAJANI, NAVIN NILES, TAO YANG, TARA ROBERTS AND PAUL DESOUZA Ingham Institute for Applied Medical Research, NSW Purpose: Thyroid cancer is the most common malignant endocrine tumour, accounting for ~2.1% of all cancer diagnoses worldwide. Accumulating evidence has shown that programmed cell death-ligand 1 (PD-L1) is associated with poor prognosis and resistance to conventional anti-cancer therapies. PD-1/PD-L1 pathway blockade has demonstrated encouraging results across multiple tumour types, including thyroid cancer; however, robust and sustained responses have not yet been realised. The identification of predictive molecular-based biomarker panels is needed in order to optimise patient benefit from these novel anti-tumour agents. The purpose of this study was to investigate the correlation between PDL1 expression and epithelial-mesenchymal transition (EMT) in papillary thyroid cancer (PTC) patients. Methodology: Immunohistochemistry for e-cadherin (epithelial marker), vimentin (mesenchymal marker) and PD-L1 was performed on 74 cases of PTC. Stained cells were manually counted and analysed for clinical and histopathological correlations. Results: Of the 74 patients included in this study, 49 (66.2%) were scored as PD-L1 positive. PD-L1 positivity was significantly higher in PTC patients with mesenchymal phenotypes (p=0.012), as determined by low e-cadherin and high vimentin expression. Moreover, an older age of diagnosis was significantly associated with an EMT positive phenotype (p=0.036). Whilst tumoral PD-L1 expression was not significantly associated with DFS (p=0.053), poorer DFS was evident in PD-L1+ patients with EMT features compared to PD-L1+/EMTand PD-L1subgroups (p=0.014). Conclusion: This study demonstrates that PD-L1 overexpression in PTC is associated with EMT. Patients with EMT positive phenotype PTC may benefit from PD-1/PD-L1 blocking immunotherapy. ES003 DEVELOPMENT OF A BI-NATIONAL THYROID CANCER CLINICAL QUALITY REGISTRY LIANE IOANNOU, JONATHAN SERPELL, SUSANNAH AHERN, CINO BENDINELLI, JOANNE DEAN, JENNY GOUGH, DEAN LISEWSKI, WIN MEYER-ROCHOW, JULIE MILLER, STAN SIDHU, DUNCAN TOPLISS, DAVID WALTERS AND JOHN ZALCBERG Monash University, VIC Background: The occurrence of thyroid cancer is increasing throughout the developed world, including Australia, and since the 1990s has become the fastest increasing malignancy. In 2014, 2,693 Australians were diagnosed with thyroid cancer, with this number projected to rise to 3,300 in 2018. Objectives: To establish a bi-national clinical quality registry with the aim of monitoring and improving the quality of care provided to patients diagnosed with thyroid cancer in Australia and New Zealand. Patients & Methods: The Australian and New Zealand Thyroid Cancer Registry (ANZTCR) captures clinical data for all patients, over the age of 18 years, diagnosed with thyroid cancer, confirmed by histopathology report that have been diagnosed or treated at a contributing hospital. Data is collected by endocrine surgeons via direct data entry using a web-based interface, REDCap. Results: The ANZTCR is currently operating across sites in Victoria, New South Wales and South Australia, with over 30 sites expected to come on board in 2018 across Australia, as well as additional sites in New Zealand. A modified-Delphi process was undertaken to determine the key quality indicators to be reported by the registry and a minimum dataset was developed comprising information regarding diagnosis, pathology, surgery and 30-day follow up. Conclusion: There are very few established thyroid cancer registries internationally, yet clinical quality registries have shown valuable outcomes and patient benefits in other cancers. The ANZTCR provides the opportunity for Australia to be an international leader in this area, as well as to further understand current practice in the treatment of thyroid cancer and reasons for variation in outcomes. ES004 APPARENT LOW-RISK DIFFERENTIATED THYROID CANCERS ARE UNDER-TREATED WITH INITIAL THYROID LOBECTOMIES ONLY MAN-SHUN WONG, DANE COLE-CLARK, JAYANI JAYASEKARA, LEIGH DELBRIDGE, MARK SYWAK AND STAN SIDHU Royal North Shore Hospital, NSW Purpose: The 2015 American Thyroid Association (ATA) guidelines make recommendations for thyroid lobectomy as a viable treatment for "low-risk" differentiated thyroid cancers. There has been concern regarding these recommendations as it may initially under-treat apparent "low-risk" thyroid cancers, requiring a significant proportion to undergo a second completion procedure after final histopathological analysis. This study examines the application of these ATA guidelines to the patients of a large-volume Australian endocrine surgical unit. Methodology: A retrospective cohort analysis was performed on patients with Papillary Thyroid Cancer PTC (1-4cm) between 2013-2016. Variables such as rates of thyroid lobectomy, and subsequent completion lobectomy based on final histology were accrued. These were compared to our historical lobectomy rates. Results: Of all the PTC, 297/600 (49.5%) patients with 1-4cm nodules biopsied as Bethesda V/VI were included in the study. Based on preoperative investigations, 221/297 (74.4%) lobectomies would be recommended by the ATA guidelines as the initial treatment. Thyroid lobectomy would have been adequate treatment for 129/221 (58.4%) patients, but Editorial material and organization © 2018 Royal Australasian College of Surgeons. Copyright of individual abstracts remains with the authors. ANZ J. Surg. 2018; 88 (S1) 48–53

The BRAF V600E mutation is a recognised molecular marker in papillary thyroid cancer (PTC), reported incidence from 30 to 80 %. BRAFV600E aberrantly activates the MAPK pathway, a central regulator of cell growth and proliferation. Previous studies have reported conflicting data regarding the impact of BRAFV600E on clinicopathological features of PTC. The study aims to determine whether BRAFV600E is useful as a prognostic biomarker in PTC.

Follicular thyroid carcinomas are associated with a chromosomal translocation that fuses the thyroid-specific transcription factor paired box gene 8 (PAX8) with the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). This study investigated the transcriptional mechanisms by which PAX8-PPARgamma regulates follicular thyroid cells. In HeLa cells, rat follicular thyroid (FRTL-5) cells, or immortalized human thyroid cells, PAX8-PPARgamma stimulated transcription from PAX8-responsive thyroperoxidase and sodium-iodide symporter promoters in a manner at least comparable with wild-type PAX8. In contrast, PAX8-PPARgamma failed to stimulate transcription from the thyroglobulin promoter and blocked the synergistic stimulation of this promoter by wild-type PAX8 and thyroid transcription factor-1. Unexpectedly, PAX8-PPARgamma transcriptional function on a PPARgamma-responsive promoter was cell-type dependent; in HeLa cells, PAX8-PPARgamma dominantly inhibited expression of the PPARgamma-responsive promoter, whereas in FRTL-5 and immortalized human thyroid cells PAX8-PPARgamma stimulated this promoter. In gel shift analyses, PAX8-PPARgamma bound a PPARgamma-response element suggesting that its transcriptional function is mediated via direct DNA contact. A biological model of PAX8-PPARgamma function in follicular thyroid cells was generated via constitutive expression of the fusion protein in FRTL-5 cells. In this model, PAX8-PPARgamma expression was associated with enhanced growth as assessed by soft agar assays and thymidine uptake. Therefore, PAX8-PPARgamma disrupts normal transcriptional regulation by stimulating some genes and inhibiting others, the net effect of which may mediate follicular thyroid cell growth and loss of differentiation that ultimately leads to carcinogenesis.

Introduction: Mutation testing for the MEN1 gene is a useful method to diagnose and predict individuals who either have or will develop multiple endocrine neoplasia type 1 (MEN 1). Clinical selection criteria to identify patients who should be tested are needed, as mutation analysis is costly and time consuming. This study is a report of an Australian national mutation testing service for the MEN1 gene from referred patients with classical MEN 1 and various MEN 1-like conditions. Results: All 55 MEN1 mutation positive patients had a family history of hyperparathyroidism, had hyperparathyroidism with one other MEN1 related tumour, or had hyperparathyroidism with multiglandular hyperplasia at a young age. We found 42 separate mutations and six recurring mutations from unrelated families, and evidence for a founder effect in five families with the same mutation. Discussion: Our results indicate that mutations in genes other than MEN1 may cause familial isolated hyperparathyroidism and familial isolated pituitary tumours. Conclusions: We therefore suggest that routine germline MEN1 mutation testing of all cases of “classical” MEN1, familial hyperparathyroidism, and sporadic hyperparathyroidism with one other MEN1 related condition is justified by national testing services. We do not recommend routine sequencing of the promoter region between nucleotides 1234 and 1758 (Genbank accession no. U93237) as we could not detect any sequence variations within this region in any familial or sporadic cases of MEN1 related conditions lacking a MEN1 mutation. We also suggest that testing be considered for patients <30 years old with sporadic hyperparathyroidism and multigland hyperplasia.

Bachground: Familial isolated hyperparathyroidism (FIHP) is an autosomal dominantly inherited form of primary hyperparathyroidism. Although comprising only about 1% of cases of primary hyperparathyroidism, identification and functional analysis of a causative gene for FIHP is likely to advance our understanding of parathyroid physiology and pathophysiology.Methods: A genome-wide screen of DNA from seven pedigrees with FIHP was undertaken in order to identify a region of genetic linkage with the disorder.Results: Multipoint linkage analysis identified a region of suggestive linkage (LOD score 2.68) on chromosome 2. Fine mapping with the addition of three other families revealed significant linkage adjacent to D2S2368 (maximum multi-point LOD score 3.43). Recombination events defined a 1.7 Mb region of linkage between D2S2368 and D2S358 in nine pedigrees. Sequencing of the two most likely candidate genes in this region, however, did not identify a gene for FIHP.Conclusions: We conclude that a causative gene for FIHP lies within this interval on chromosome 2. This is a major step towards eventual precise identification of a gene for FIHP, likely to be a key component in the genetic regulation of calcium homeostasis.

J W Cardinal, L Bergman, N Hayward, A Sweet, J Warner, L Marks, D Learoyd, T Dwight, B Robinson, M Epstein, M Smith, B T Teh, D P Cameron, J B Prins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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.

Chromosomal translocations encoding fusion oncoproteins are common in hematological malignancies, sarcomas, and papillary thyroid carcinomas. A recent study of follicular thyroid carcinomas reported a novel chromosomal translocation, t(2;3)(q13;p25), that fused the thyroid-specific transcription factor PAX8 with a nuclear receptor, peroxisome proliferatoractivated receptor gamma (PPARgamma). Herein we report the detection of this putative oncoprotein in 6 of 17 (35%) follicular thyroid carcinomas as well as in 6 of 11 (55%) follicular thyroid adenomas. Concordant expression of protein was found in 91% of those tumors in which PAX8-PPARgamma mRNA was detected by RT-PCR, whereas a further 20% of follicular tumors were positive for PPARgamma immunohistochemistry alone. Our findings suggest that the PAX8-PPARgamma fusion protein promotes differentiated follicular thyroid neoplasia, although it is not sufficient per se for carcinogenesis.

BACKGROUND: Familial isolated hyperparathyroidism (FIHP) is a hereditary disorder characterised by uni- or multiglandular parathyroid disease. A subset of families are likely to be genetic variants of other familial tumour syndromes in which PHPT is the main feature, for example multiple endocrine neoplasia type 1 (MEN 1) and the hyperparathyroidism-jaw tumour syndrome (HPT-JT). OBJECTIVE: To investigate seven families diagnosed with FIHP, each with two to eight affected family members, to clarify the underlying genetic mechanism. METHODS: The entire MEN1 gene was sequenced for germline mutations and, in addition, tumour specimens were analysed in comparative genomic hybridisation and loss of heterozygosity studies. RESULTS: Two families exhibited MEN1 mutations, L112V and 1658delG, which were associated with loss of the wild-type 11q13 alleles in all tumours analysed. In the remaining five families, no MEN1 mutation was identified. CONCLUSION: These results support the involvement of the MEN1 tumour suppressor gene in the pathogenesis of some of the FIHP kindreds. However, loss on chromosome 11 was seen in all tumours exhibiting somatic deletions, although in two families the tumour deletions involved 11q distal to MEN1. We conclude that the altered MEN1 gene function is of importance in the development of FIHP.

Radiation is inherently harmful to human beings. Perhaps the first description of the harmful effects of radiation was made unwittingly by Paracelsus when, in 1530, he attributed the high incidence of death among miners to a gas recognized much later as radon. The earliest observations of erythema were made a few months after Roentgen'discovery of X-ray in 1895 followed by reports of skin cancer in heavily irradiated areas. 1 Since those early times, members of the medical profession have become increasingly concerned about the induction of cancers by irradiation exposure. With the increasing use of devices such as image intensification, a constant reminder is needed if surgeons are to avoid excessive exposure.

Causative germline missense mutations in the RET proto-oncogene have been associated with over 92% of families with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). MEN 2A is characterized primarily by medullary thyroid carcinoma (MTC) and pheochromocytoma, both tumors of neural crest origin. Parathyroid hyperplasia or adenoma is also seen in MEN 2A, but rarely in MEN 2B, which has additional stigmata, including a marfanoid habitus, mucosal neuromas, and ganglioneuromatosis of the gastrointestinal tract. In familial MTC, MTC is the only lesion present. Somatic RET mutations have also been identified in a subset of sporadic MTCs, pheochromocytomas, and rarely, small cell lung cancer, but not in sporadic parathyroid hyperplasias/adenomas or other neuroendocrine tumors. Glial cell line-derived neurotrophic factor (GDNF) and its receptor molecule GDNFR-alpha, have recently been identified as members of the RET ligand binding complex. Therefore, the genes encoding both GDNF and GDNFR-alpha are excellent candidates for a role in the pathogenesis of those MEN 2 families and sporadic neuroendocrine tumors without RET mutations. No mutations were found in the coding region of GDNF in DNA samples from 9 RET mutation negative MEN 2 individuals (comprising 6 distinct families), 12 sporadic MTCs, 17 sporadic cases of parathyroid adenoma, and 10 small cell lung cancer cell lines. Therefore, we find no evidence that mutation within the coding regions of GDNF plays a role in the genesis of MEN 2 and sporadic neuroendocrine tumors.

A 74-year old female taking medroxyprogesterone acetate (MPA) presented with Cushing's syndrome together with low serum cortisol and plasma ACTH and an impaired response to synthetic ACTH (Synacthen, CIBA). When the medroxyprogesterone therapy was ceased the cushingoid features resolved and serum cortisol, ACTH and ACTH responsiveness all returned to normal. The MPA was acting as an exogenous glucocorticoid causing Cushing's syndrome.