Faculty Bibliography

In recent years, our understanding of the genetic alterations underlying thyroid oncogenesis has greatly expanded. The use of molecular markers, including RAS, in the management of thyroid carcinoma is also increasing. This review summarizes the current literature surrounding RAS and discusses its potential as a diagnostic and prognostic indicator in the management of thyroid cancer.

BACKGROUND: BRAF mutations are highly specific for papillary thyroid carcinoma (PTC) and many cytology specimens with BRAF mutations are expected to demonstrate cytologic features typical of PTC. However, indeterminate thyroid cytology cases are inevitable and understanding the significance of the BRAF mutation within the context of the Bethesda System for Reporting Thyroid Cytopathology would be valuable. METHODS: Thyroid cytology cases submitted for conventional cytomorphologic evaluation and BRAF mutational analyses were selected from the authors' cytopathology files from April 2007 to October 2011. From this group, the diagnostic usefulness of BRAF mutations in indeterminate and malignant cases was assessed and analyses of cytologic and histopathologic features associated with the mutations in this gene were performed. RESULTS: A total of 131 cases with a BRAF mutation were identified. Of these, 119 underwent surgical pathology resection follow-up and demonstrated PTC. Approximately 75% of the cases were cytologically diagnosed as being positive for malignancy and these cases were associated with both the classic and tall cell variants of PTC at the time of resection, a greater likelihood of extrathyroidal extension, and the V600E type of BRAF mutation. In contrast, BRAF-mutated cases with diagnoses of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) and follicular neoplasm/suspicious for follicular neoplasm were found to be more strongly associated with the follicular variant of PTC, a K601E BRAF mutation, and a lower likelihood of extrathyroidal extension. However, a subset of AUS/FLUS cases with the V600E BRAF mutation appeared to represent sampling variability of the classic or tall cell variants of PTC. CONCLUSIONS: Bethesda thyroid diagnoses in the setting of a BRAF mutation reflect differences in PTC subtypes, the nature of cytology specimens, and molecular characteristics.

INTRODUCTION: RAS mutations are common in thyroid tumors and confer a high risk of cancer when detected in fine-needle aspiration (FNA) specimens. Specific characteristics of RAS-positive thyroid cancers are not well described. METHODS: From April 2007 to April 2009, 921 consecutive patients undergoing FNA were evaluated prospectively with a panel of molecular markers. Ultrasonographic, cytological, histological, and surgical outcomes were retrospectively assessed. RESULTS: Sixty-eight aspirates from 66 patients were positive for RAS mutations including 63 cytologically indeterminate (93%), 3 malignant (4%), and 2 benign (3%) specimens. Cancer was histologically confirmed in 52 of 63 aspirates (83%) including the following: 46 papillary thyroid cancers, 4 follicular thyroid cancers, 1 medullary cancer, and 1 anaplastic cancer. All 46 RAS-positive papillary thyroid cancers, including 1 metastatic cancer, had follicular variant histology papillary thyroid cancer; only 11 tumors demonstrated vascular/capsular invasion and 4 had infiltrative growth. Of 48 patients with differentiated thyroid cancer, lymph node metastasis was uncommon and bilateral cancer was present in 48%. Only 33% of malignant nodules were suspicious by preoperative ultrasonography. At a mean follow-up of 22 months, 31 of 35 differentiated thyroid cancer patients (89%) have no evidence of recurrence, 4 patients (9%) have detectable thyroglobulin, 1 patient has bone metastases, and both patients with medullary and anaplastic cancer have died. CONCLUSION: Most RAS-positive thyroid cancers have indeterminate cytology, lack suspicious ultrasound features, and are histologically low-grade follicular variant histology papillary thyroid cancer. Lymph node and distant metastases are uncommon but bilateral disease is frequent. Total thyroidectomy should be considered for initial surgical management of most patients with RAS-positive FNA results. The role of prophylactic lymphadenectomy remains unclear.

Findley first proposed the presence of age-related dysfunction of the hypothalamic-neurohypophyseal-renal axis more than 60 years ago. More sophisticated studies have since corroborated his findings. As a result, it is now clear that multiple abnormalities in water homeostasis occur commonly with aging, and that the elderly are uniquely susceptible to disorders of body volume and osmolality. This article summarizes the distinct points along the hypothalamic-neurohypophyseal-renal axis where these changes have been characterized, as well as the clinical significance of these changes, with special attention to effects on cognition, gait instability, osteoporosis, fractures, and morbidity and mortality.

BACKGROUND: In thyroid nodule fine-needle aspiration (FNA) cytology, the atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) category has a 5-15% malignancy risk that increases to 85-99% when mutation testing for BRAF, RAS, RET/PTC, or PAX8/PPARgamma is positive. However, negative testing does not exclude malignancy. The study objective was to identify clinical and imaging features that predict cancer in mutation-negative AUS/FLUS thyroid nodules. METHODS: All patients were reviewed (April 2007 to April 2009) who had AUS/FLUS cytology, negative prospective molecular testing of FNA, and histopathology. RESULTS: Of the 230 nodules, 12 (5.2%) were malignant in 11 of 190 patients, and known clinical risk factors for thyroid cancer did not predict malignancy. On preoperative imaging, >/=1 suspicious ultrasound feature was identified in 33% of nodules and occurred regardless of histology (P = .23). Malignant mutation-negative AUS/FLUS nodules were larger than benign nodules (mean maximum diameter, 33.6 vs 24.0 mm; P = .007). On multivariate analysis, nodule size remained an independent predictor of malignancy (odds ratio, 1.043; P = .018). We observed no malignancies in 88 mutation-negative AUS/FLUS nodules <18.5 mm. CONCLUSION: Size is an independent predictor of malignancy in mutation-negative AUS/FLUS nodules and the risk increased 4.3% with every millimeter increase in nodule size. Selected patients with small, mutation-negative AUS/FLUS thyroid nodules may be managed with ultrasound surveillance in lieu of thyroidectomy.

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.

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 papillary microcarcinoma (TPMC) is an incidentally discovered papillary carcinoma that measures