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.

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Germline mutations in PTEN (MMAC1/TEP1) are found in patients with Cowden syndrome, a familial cancer syndrome which is characterized by a high risk of breast and thyroid neoplasia. Although somatic intragenic PTEN mutations have rarely been found in benign and malignant sporadic thyroid tumors, loss of heterozygosity (LOH) has been reported in up to one fourth of follicular thyroid adenomas (FAs) and carcinomas. In this study, we examined PTEN expression in 139 sporadic nonmedullary thyroid tumors (55 FA, 27 follicular thyroid carcinomas, 35 papillary thyroid carcinomas, and 22 undifferentiated thyroid carcinomas) using immunohistochemistry and correlated this to the results of LOH studies. Normal follicular thyroid cells showed a strong to moderate nuclear or nuclear membrane signal although the cytoplasmic staining was less strong. In FAs the neoplastic nuclei had less intense PTEN staining, although the cytoplasmic PTEN-staining intensity did not differ significantly from that observed in normal follicular cells. In thyroid carcinomas as a group, nuclear PTEN immunostaining was mostly weak in comparison with normal thyroid follicular cells and FAs. The cytoplasmic staining was more intense than the nuclear staining in 35 to 49% of carcinomas, depending on the histological type. Among 81 informative tumors assessed for LOH, there seemed to be an associative trend between decreased nuclear and cytoplasmic staining and 10q23 LOH (P ‫؍‬ 0.003, P ‫؍‬ 0.008, respectively). These data support a role for PTEN in the pathogenesis of follicular thyroid tumors.

Abstract. The cornerstone of safe and effective thyroid surgery is thorough training in and understanding of thyroid anatomy and pathology. With appropriate techniques, total thyroid lobectomy and total thyroidectomy (which should be considered simply as a bilateral total thyroid lobectomy performed during the same operation) can be undertaken with minimal risk of damage to the recurrent laryngeal nerves, the external branches of the superior laryngeal nerves, and the parathyroid glands. Safe surgery requires a specific operative plan, progressing in a series of logical, orderly, anatomically based steps. Exposure of the thyroid gland is followed by careful dissection of the superior pole, utilizing the avascular plane between the superior pole and the cricothyroid muscle to identify and preserve the external branch of the superior laryngeal nerve. Medial retraction of the gland then allows dissection of the lateral aspect of the thyroid lobe. Protection of the recurrent laryngeal nerves and preservation of the blood supply to the parathyroid glands is best achieved by "capsular dissection," ligating the tertiary branches of the inferior thyroid artery on the gland surface. If a parathyroid gland cannot be preserved or becomes ischemic after dissection of its vascular pedicle, it should be immediately minced and autotransplanted into the ipsilateral sternocleidomastoid muscle. The current evolution of outpatient or shortstay thyroidectomy emphasizes the need to avoid complications by utilizing meticulous surgical technique. Minimally invasive thyroidectomy utilizing endoscopic techniques may also affect the practice of thyroid surgery. Even so, understanding the surgical anatomy of the thyroid gland and its possible variations is paramount to safe and effective surgery.During the latter half of the nineteenth century a revolution in surgery and surgical technique occurred. Before that time, thyroid surgery was limited to treating only life-threatening conditions. With a reported mortality rate of more than 20%, the reputation of thyroid surgery was so poor that the French Academy of Medicine banned its practice in 1850. Indeed, when Greene reported his successful thyroidectomies in America, he warned that the operations should be used "never, for the relief of deformity or discomfort merely; only, to save life" [1]. However, by the time the Nobel Prize was awarded to Kocher in 1909, the mortality rate in his hands had been reduced to 0.18% [2].The key to increasing safety of thyroid surgery was then, as now, a thorough understanding of thyroid anatomy and pathology. The general developments in surgical techniques and instrumentation, and the improvements in antisepsis and anesthetic techniques, were also crucial. When thyroidectomy became safe to perform, the specific complications of the procedure could be addressed, including prevention of injury to the recurrent laryngeal nerves and avoidance of accidental injury to, or removal of, the parathyroid glands. The surgical techniques developed at that time were, i...