Faculty Bibliography

Hyperthyroidism describes the sustained increase in thyroid hormone biosynthesis and secretion by a thyroid gland with increased metabolism. Although the use of radioiodine scanning serves as a useful surrogate that may help characterize the cause of thyrotoxicosis, it only indirectly addresses the underlying physiologic mechanism driving the increase in serum thyroid hormones. In this article, thyrotoxic states are divided into increased or decreased thyroid metabolic function. In addition to the diagnosis, clinical presentation, and treatment of the various causes of hyperthyroidism, a section on functional imaging and appropriate laboratory testing is included.

BACKGROUND: Thyroid paraganglioma (TP) is a very rare neoplasm that can be misdiagnosed. We evaluated the clinical and pathologic characteristics of three patients with TP. PATIENT FINDINGS: The records of all patients from 1981 to 2008 who had thyroidectomy with a final histologic diagnosis of TP were retrieved, and histology was reviewed by a single pathologist. Head and neck paragangliomas arising outside of the thyroid were excluded. TP accounted for 3 of all 6782 (0.04%) patients undergoing thyroidectomy during three decades. One patient has been previously reported and will not be discussed. In the remaining two patients and a surgical pathology consult case that we also describe herein, the mean age at diagnosis was 56 years (40-67) and two patients were men. Presenting features were indicative of advanced local invasion, including stridor, tracheal invasion, compression of the great vessels, and hemoptysis. The diagnosis of TP was not suspected preoperatively; in two patients, fine-needle aspiration (FNA) cytology was inadequate for diagnosis because of excessive blood. Intraoperative frozen section analysis suggested medullary thyroid cancer in two patients and oncocytic (Hurthle) cell carcinoma in one patient. Local invasion was common, requiring concurrent tracheal resection in two of three patients, and present histologically in all three patients. In all three cases, immunohistochemical analysis was negative for cytokeratin AE1/3, calcitonin, and thyroglobulin but positive for S100, highlighting sustentacular cells. After resection of a large TP with tracheal and vascular invasion, a 67-year-old woman experienced a 7-year disease-free interval. CONCLUSIONS: Primary TP is indeed rare. It does occur in men, frequently presents with compressive symptoms, and is typically locally aggressive, but does not appear to cause symptoms suggestive of catecholamine excess. Despite invasion of adjacent structures, aggressive resection can achieve a long disease-free interval.

PURPOSE: This study was designed to examine the aggressive features of BRAF-positive papillary thyroid cancer (PTC) and association with age. METHODS: We compared the clinicopathologic parameters and BRAF V600E mutation status of 121 elderly (age >/=65 years) PTC patients who underwent thyroidectomy from January 2007 to December 2009 to a consecutive cohort of 98 younger (age <65 years) PTC patients. RESULTS: Younger and elderly PTC patients had similar incidences of BRAF-positive tumors (41% vs. 38%; p = 0.67). The elderly cohort was more likely to have smaller tumors (mean 1.6 vs. 2.1 cm; p = 0.001), present with advanced TNM stage (36% vs. 19%; p = 0.008), and have persistent/recurrent disease (10% vs. 1%; p = 0.006). BRAF-positive status was associated with PTC that were tall cell variant (p < 0.001), had extrathyroidal extension (p < 0.001), lymph node involvement (p = 0.008), advanced (III/IV) TNM stage (p < 0.001), and disease recurrence (p < 0.001). Except for lymph node involvement, the association between aggressive histology characteristics at presentation and BRAF-positive PTC also was observed within the age-defined cohorts. In short-term follow-up (mean, 18 months), persistent/recurrent PTC was much more likely to occur in patients who were both BRAF-positive and elderly (22%). CONCLUSIONS: BRAF mutations are equally present in younger and older patients. Aggressive histology characteristics at presentation are associated with BRAF-positive PTC, irrespective of age. However, the well-established association of BRAF with recurrence is limited to older (age >/=65 years) patients.

CONTEXT: Thyroid nodules are common in adults, but only a small fraction of them is malignant. Fine-needle aspiration (FNA) cytology provides a definitive diagnosis of benign or malignant disease in many cases, whereas about 25% of nodules are indeterminate, hindering most appropriate management. OBJECTIVE: The objective of the investigation was to study the clinical utility of molecular testing of thyroid FNA samples with indeterminate cytology. DESIGN: Residual material from 1056 consecutive thyroid FNA samples with indeterminate cytology was used for prospective molecular analysis that included the assessment of cell adequacy by a newly developed PCR assay and testing for a panel of mutations consisted of BRAF V600E, NRAS codon 61, HRAS codon 61, and KRAS codons 12/13 point mutations and RET/PTC1, RET/PTC3, and PAX8/PPARgamma rearrangements. RESULTS: The collected material was adequate for molecular analysis in 967 samples (92%), which yielded 87 mutations including 19 BRAF, 62 RAS, 1 RET/PTC, and five PAX8/PPARgamma. Four hundred seventy-nine patients who contributed 513 samples underwent surgery. In specific categories of indeterminate cytology, i.e. atypia of undetermined significance/follicular lesion of undetermined significance, follicular neoplasm/suspicious for a follicular neoplasm, and suspicious for malignant cells, the detection of any mutation conferred the risk of histologic malignancy of 88, 87, and 95%, respectively. The risk of cancer in mutation-negative nodules was 6, 14, and 28%, respectively. Of 6% of cancers in mutation-negative nodules with atypia of undetermined significance/follicular lesion of undetermined significance cytology, only 2.3% were invasive and 0.5% had extrathyroidal extension. CONCLUSION: Molecular analysis for a panel of mutations has significant diagnostic value for all categories of indeterminate cytology and can be helpful for more effective clinical management of these patients.