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Antithyroid medications, radioactive iodine, or thyroidectomy are viable therapeutic options for the patient with thyrotoxicosis, with relative pros and cons for each modality varying with patient comorbidities and preferences, and the expertise of the treating physicians. Of the three modalities, surgery is the most invasive but also the most definitive, and is favoured for patients with symptomatic compression, concomitant documented/suspected malignancy, or coexisting hyperparathyroidism requiring surgical intervention. Thyroidectomy for treatment of thyrotoxicosis is also advantageous for women who are pregnant, lactating, or planning pregnancy, for patients with moderate to severe Graves’ orbitopathy, or when immediate control of symptoms is necessary. In experienced hands, thyroidectomy is performed with minimal morbidity and should be considered in the patient who places more relative emphasis on prompt and definitive control of symptoms with avoidance of radioactive therapy and/or medications, with less concerns regarding operative risks and/or need for lifelong thyroid hormone replacement.

BackgroundThe management of low-risk micropapillary thyroid cancer

Surgeons who treat patients with thyroid cancer and other endocrine diseases have varied clinical backgrounds. Their training or clinical practice may be based in general surgery, otolaryngology, head and neck surgery, surgical oncology, urology (for adrenal tumors), or endocrine surgery. Regardless of the title and background, a surgeon specializing in endocrine disease has a role and responsibility far beyond the operating room. This chapter examines the specialist endocrine surgeon in the context of thyroid and other endocrine surgery.

Approximately 100,000 new cases of primary hyperparathyroidism are diagnosed in the United States each year. Thus a disorder that was once considered to be rare is now known to be relatively common. Many patients with primary hyperparathyroidism are diagnosed today with only minimal hypercalcemia (serum calcium less than 1mg/dl above the upper limit of normal) and many have few or no classic symptoms or clinical manifestations of hyperparathyroidism, such as kidney stones or osteitis fibrosa cystica. Many patients with hyperparathyroidism today have fatigue or increased lethargy, muscular weakness, bone or joint pain and depression. It is difficult preoperatively to know whether these clinical manifestations are related to the primary hyperparathyroidism or not. Our own studies suggest that in about 80 per cent of patients with hyperparathyroidism the preoperative symptoms either improve or disappear after parathyroidectomy.

Thyroid cancer is the sixth most common cancer in women, and the majority of patients with thyroid cancer has sporadic disease. However, about 25% of patients with medullary thyroid cancer and 5% with papillary thyroid cancer have familial tumors. Currently, there are numerous controversies regarding the mode of inheritance, tumor behavior, extent of surgical resection for optimal results, coexisting thyroid pathology, risk of other cancers, and extent of postoperative treatment of patients with familial thyroid cancer. This review aimed to give insight to surgeons on this interesting topic.

Endocrine disorders are primarily caused by increased or decreased secretion of a hormone (from the Greek word first proposed in 1905 by Starling, meaning to excite, arouse, or set in motion) [1]. The first mentioned endocrine operation in antiquity was castration [2]. The last endocrine gland to be discovered was the parathyroid gland [3]. These tiny millet-sized structures are situated near the thyroid gland in the neck and were often inadvertently removed during thyroid operations that caused hypocalcemia and tetany. Parathyroid glands could also become neoplasms and secrete too much parathyroid hormone thus resulting in hypercalcemia with kidney and/or bone disorders. In this chapter I will clarify the progress leading to the discovery of primary hyperparathyroidism and how it should most effectively be treated.

BackgroundThe extent of thyroidectomy for low-risk well-differentiated thyroid cancer (WDTC) remains controversial. Historically, total thyroidectomy (TT) has been recommended for WDTC ≥1 cm in size. However, recent National Comprehensive Cancer Network and American Thyroid Association guidelines recognize unilateral thyroid lobectomy as a viable alternative for 1-4 cm cancers due to their otherwise favorable prognosis, with TT remaining the preferred option for tumors with unfavorable pathological characteristics. This study sought to determine how often a completion TT would be recommended based on these guidelines if lobectomy was initially performed in patients with 1-4 cm WDTC without preoperatively known risk factors.MethodsPatients who underwent thyroidectomy for 1-4 cm WDTC (January 2000 to January 2010) were retrospectively reviewed. Patients with preoperatively known high-risk characteristics, including gross extrathyroidal extension (ETE) on preoperative imaging, clinically apparent lymph node metastases, distant metastases, history of radiation, and positive family history, were excluded. The pathology specimens from the cancer-containing lobe were evaluated for features that would lead to a recommendation for TT based on current guidelines, including aggressive histology, vascular invasion, microscopic ETE, positive margins, and any positive lymph nodes within the specimen.ResultsOf 1000 consecutive patients operated for WDTC, 287 would have been eligible for lobectomy as the initial operation. The mean age in this cohort was 45 years, and 80% were women. Aggressive tall-cell variant histology was found in one patient (0.5%), angio-invasion in 34 (12%), ETE in 48 (17%), positive margins in 51 (18%), and positive lymph nodes in 49 (18%) patients. Completion TT would have been recommended in 122/287 (43%) patients. Even in those with 1-2 cm cancers, completion TT would have been recommended in 52/143 (36%) patients.ConclusionsNearly half of the patients with 1-4 cm WDTC who are eligible for lobectomy under current guidelines would require completion TT based on pathological characteristics of the initial lobe. Surgeons, endocrinologists, and patients need to balance the relative benefits, risks, and costs of initial TT versus the possible need for reoperative completion TT.

Background: Reoperation in the neck can be challenging and is associated with increased complication rates and operative times. Here we analyze our methylene blue dye injection method to localize reoperative neck pathology in patients with thyroid cancer and lymph node metastases. Study Design: We retrospectively reviewed the records of all patients at a single university tertiary care center who had reoperative neck surgery for recurrent thyroid cancer between 2004 and 2009, and who also underwent intraoperative methylene blue dye injection. Outcomes measured were efficacy and safety of the injection technique as well as complication rates. Results: Fifty-three operations were performed in 44 patients (average age, 51.2 years [range 16 to 83 years]). Ninety-one percent (48 of 53) of the operations resulted in successful resection of recurrent disease. Of these, 96% (46 of 48) were guided successfully by blue dye injection. Thyroglobulin became undetectable in 42% (11 of 26) of patients. Neck pathology included the following thyroid cancers: papillary (48 of 53), follicular (2 of 53), medullary (2 of 53), and tall cell variant (1 of 53). Among these patients, there were a total of 26 central and 38 lateral neck dissections. The average number of previous neck dissections was 2 (range 1 to 5). The mean intraoperative ultrasound/injection time was 21.3 min (n = 13). Median operative time was 90 minutes (range 40 to 300 minutes). Complications included 2 permanent vocal cord paralyses, 1 instance of permanent hypocalcemia, and 3 instances of temporary hypocalcemia. There were no complications related to the dye injection. Conclusions: Intraoperative, ultrasound-guided, methylene blue dye injection is a safe and effective technique. It facilitates tumor localization and removal especially in patients requiring reoperative neck surgery. © 2012 American College of Surgeons.

Parathyroid carcinoma is a rare but ominous cause of primary hyperparathyroidism. OBJECTIVES AND MAIN OUTCOME MEASURES: The objective of the study was to review the outcomes of parathyroid cancer patients and to evaluate the factors associated with mortality.This was a retrospective review performed on 37 patients with parathyroid cancer treated at a single university tertiary care center between 1966 and 2009.The average age at cancer diagnosis was 53 yr (range 23-75 yr), and 23 patients (62%) were men. Eighteen patients (49%) recurred after their initial cancer operation. The average number of neck dissections done for cancer was three (range 1-11). After initial diagnosis, 22 patients (60%) eventually developed complications, including unilateral (n = 11) or bilateral (n = 3) vocal cord paralysis (38%). Eight patients (22%) had, at some point, an associated benign parathyroid adenoma. Median overall survival was 14.3 yr (range 10.5-25.7 yr) from the date of diagnosis. Factors associated with increased mortality included lymph node or distant metastases, number of recurrences, higher calcium level at recurrence, and a high number of calcium-lowering medications. Factors not associated with mortality included age, race, tumor size, time to first recurrence, and extent of initial operation. Initial operations done at our center had improved survival (P = 0.037) and decreased complication rates (P0.001) vs. those done elsewhere.Parathyroid cancer patients typically have a long survival, which often includes multiple reoperations for recurrence and thus a high rate of surgical complications. Patients in whom there is a high index of suspicion for parathyroid cancer should be referred to a dedicated endocrine surgery center for their initial operation.

BACKGROUND: Approximately 30% of fine-needle aspiration (FNA) biopsies of thyroid nodules are indeterminate or nondiagnostic. Recent studies suggest microRNA (miRNA, miR) is differentially expressed in malignant tumors and may have a role in carcinogenesis, including thyroid cancer. The authors therefore tested the hypothesis that miRNA expression analysis would identify putative markers that could distinguish benign from malignant thyroid neoplasms that are often indeterminate on FNA biopsy. METHODS: A miRNA array was used to identify differentially expressed genes (5-fold higher or lower) in pooled normal, malignant, and benign thyroid tissue samples. Real-time quantitative polymerase chain reaction was used to confirm miRNA array expression data in 104 tissue samples (7 normal thyroid, 14 hyperplastic nodule, 12 follicular variant of papillary thyroid cancer, 8 papillary thyroid cancer, 15 follicular adenoma, 12 follicular carcinoma, 12 Hurthle cell adenoma, 20 Hurthle cell carcinoma, and 4 anaplastic carcinoma cases), and 125 indeterminate clinical FNA samples. The diagnostic accuracy of differentially expressed genes was determined by analyzing receiver operating characteristics. RESULTS: Ten miRNAs showed >5-fold expression difference between benign and malignant thyroid neoplasms on miRNA array analysis. Four of the 10 miRNAs were validated to be significantly differentially expressed between benign and malignant thyroid neoplasms by quantitative polymerase chain reaction (P < .002): miR-100, miR-125b, miR-138, and miR-768-3p were overexpressed in malignant samples of follicular origin (P < .001), and in Hurthle cell carcinoma samples alone (P < .01). Only miR-125b was significantly overexpressed in follicular carcinoma samples (P < .05). The accuracy for distinguishing benign from malignant thyroid neoplasms was 79% overall, 98% for Hurthle cell neoplasms, and 71% for follicular neoplasms. The miR-138 was overexpressed in the FNA samples (P = .04) that were malignant on final pathology with an accuracy of 75%. CONCLUSIONS: MicroRNA expression differs for normal, benign, and malignant thyroid tissue. Expression analysis of differentially expressed miRNA could help distinguish benign from malignant thyroid neoplasms that are indeterminate on thyroid FNA biopsy. Cancer 2011. © 2011 American Cancer Society.

The debate on the appropriate treatment of patients with papillary thyroid cancer (PTC) has persisted for several decades. The main controversies focus on the extent of surgery, the timing of central neck dissection, and the indications for radioactive iodine ablation. These controversies continue, for the most part, due to the good prognosis of PTC patients and the questionable effect these treatment modalities have on patient survival. This paper addresses these three controversies and the role of molecular tumor markers in the appropriate treatment selection.

There is considerable controversy about the prognostic implications of lymph node metastases in patients with papillary thyroid cancer and whether patients with papillary thyroid cancer should have a prophylactic or selective central (level VI) neck dissection. Some experts report that a prophylactic ipsilateral neck dissection results in fewer patients having elevated thyroglobulin levels but others do not agree. A comprehensive review of the literature suggests that the presence of macroscopic metastases of papillary thyroid cancer in cervical lymph nodes results in a higher recurrence rate and increased death rate, especially in patients 45 years of age or older, whereas microscopic nodal metastases do not appear to adversely influence survival. Until more information is available we recommend preoperative ultrasonography and a selective ipsilateral neck dissection for patients with papillary thyroid cancer.

This review on the unique patterns of metastases by common and rare types of cancer addresses regional lymphatic metastases but also demonstrates general principles by consideration of vital organ metastases. These general features of successfully treated metastases are relationships to basic biological behavior as illustrated by disease-free interval, organ-specific behavior, oligo-metastatic presentation, genetic control of the metastatic pattern, careful selection of patients for surgical resection, and the necessity of complete resection of the few patients eligible for long-term survival after resection of vital organ metastasis. Lymph node metastases, while illustrating these general features, are not related to overall survival because lymph node metastases themselves do not destroy a vital organ function, and therefore have no causal relationship to overall survival. When a cancer cell spreads to a regional lymph node, does it also simultaneously spread to the systemic site or sites? Alternatively, does the cancer spread to the regional lymph node first and then it subsequently spreads to the distant site(s) after an incubation period of growth in the lymph node? Of course, if the cancer is in its incubation stage in the lymph node, then removal of the lymph node in the majority of cases with cancer cells may be curative. The data from the sentinel lymph node era, particularly in melanoma and breast cancer, is consistent with the spectrum theory of cancer progression to the sentinel lymph node in the majority of cases prior to distant metastasis. Perhaps, different subsets of cancer may be better defined with relevant biomarkers so that mechanisms of metastasis can be more accurately defined on a molecular and genomic level.

Background The purpose of this study was to investigate the effects of treating human thyroid cancer cell lines with demethylating agents and histone deacetylase (HDAC) inhibitors to see if they would downregulate expression and activity of the matrix metalloproteinases (MMP)-2 and MMP-9, resulting in inhibition of growth and invasion. Methods A total of 1 papillary cancer cell line (TPC-1) and 3 follicular thyroid cancer cell lines (FTC-133, FTC-236, and FTC-238) were treated with the demethylating agent 5-azacytidine (5-AZC) and the HDAC inhibitors trichostatin A (TSA) and valproic acid (VA). The activity of MMP proteins was determined using gelatin zymography, and commercially available assays were used to quantify growth inhibition and thyroid cancer cell invasion. Results Treatment with TSA and VA resulted in decreased protein activity of MMP-2 and MMP-9 in all cell lines in a dose-dependent manner after 48 hours of treatment compared with untreated controls. In addition, 5-, TSA, and VA caused inhibition of growth in the range of 25–80% for all cell lines at 24, 48, and 72 hours. VA and TSA significantly decreased cell invasion in the FTC-133 and TPC-1 cell lines. Conclusion The HDAC inhibitors TSA and VA decreased the protein activity of MMP-2 and MMP-9 and, in combination with the demethylating agent 5-AZC, inhibited cellular growth in human papillary and follicular thyroid cancer cell lines. These results elucidate our understanding of the pathways affected by the demethylating agents and HDAC inhibitors, and provide further evidence that MMPs are a potentially useful target for molecular therapies in patients with aggressive or refractory thyroid cancers.

Background: Thyroid and lung cancers, two malignancies with similar immunohistological characteristics, have vastly different biologic behaviors and treatment approaches. As thyroid cancers commonly spread to the lungs, metastatic thyroid cancer should be included in the differential diagnosis of a pulmonary lesion or lesions. Summary: A 54-year-old woman with a remote history of stage IV non-small cell lung cancer was found to have FDG avidity in the thyroid and right cervical lymph nodes. Subsequent ultrasonographic findings and FNA cytology led to a total thyroidectomy, bilateral central lymphadenectomy, and right modified radical lymph node dissection for primary thyroid cancer. Reviews and comparisons of the pulmonary and cervical surgical specimens revealed that the patient had been misdiagnosed for the previous 6 years; she had metastatic papillary thyroid cancer to the lung. The patient's original diagnosis of stage IV lung cancer was based upon the original lung biopsy showing positive thyroid tr...

Background Approximately 30% of fine needle aspiration biopsies of the thyroid have inconclusive results. We conducted a prospective trial to determine whether clinical and molecular markers could be used in combination to improve the accuracy of thyroid fine needle aspiration biopsy. Methods Clinical, tumor genotyping for common somatic mutations (BRAF V600E, NRAS, KRAS, RET/PTC1, RET/PTC3, and NTRK1), and the gene expression levels of 6 candidate diagnostic markers were analyzed by univariate and multivariate methods in 341 patients to determine whether they could distinguish reliably benign from malignant thyroid neoplasms, and a scoring model was derived. Results By a multivariate analysis, fine needle aspiration biopsy cytology classification, the presence of a NRAS mutation, and the tissue inhibitor of metalloproteinase 1 expression level were associated jointly with malignancy. The overall accuracy of the scoring model, including these 3 variables, to distinguish benign from malignant thyroid tumors was 91%, including 67% for the indeterminate and 77% for the suspicious FNA subgroups. Conclusion Fine needle aspiration biopsy cytology classification, the presence of NRAS mutation, and tissue inhibitor of metalloproteinase 1 messenger RNA expression levels in combination provide a greater diagnostic accuracy than fine needle aspiration biopsy cytology alone to allow selection of more definitive initial operative treatment. The sensitivity of the scoring model, however, was too low to avoid the need for diagnostic thyroidectomies for indeterminate fine needle aspiration biopsy findings.

The molecular factors that control parathyroid tumorigenesis are poorly understood. In the absence of local invasion or metastasis, distinguishing benign from malignant parathyroid neoplasm is difficult on histologic examination. We studied the microRNA (miRNA) profile in normal, hyperplastic, and benign and malignant parathyroid tumors to better understand the molecular factors that may play a role in parathyroid tumorigenesis and that may serve as diagnostic markers for parathyroid carcinoma. miRNA arrays containing 825 human microRNAs with four duplicate probes per miRNA were used to profile parathyroid tumor (12 adenomas, 9 carcinomas, and 15 hyperplastic) samples normalized to four reference normal parathyroid glands. Differentially expressed miRNA were validated by real-time quantitative TaqMan polymerase chain reaction (PCR). One hundred fifty-six miRNAs in parathyroid hyperplasia, 277 microRNAs in parathyroid adenoma, and 167 microRNAs in parathyroid carcinomas were significantly dysregulated as compared with normal parathyroid glands [false discovery rate (FDR)

Background. The role of routine prophylactic central-neck lymph node dissection (CLND) for papillary thyroid cancer (PTC) remains controversial. We perform CLND for PTC only in patients with enlarged nodes as determined by preoperative ultrasound and intraoperative inspection and palpation. Methods. We identified all patients with PTC who underwent CLND during thyroidectomy (group 1) at our institution, and then we identified an equivalent number of demographically matched patients who underwent thyroidectomy without CLND (group 2) and compared the outcomes of the 2 groups. Results. In all, 191 patients were identified for each group; 49/191 (26%) patients in group 1 developed locoregional nodal recurrence (12% central neck and 21 % lateral neck), compared with 11/191 (6%) patients in group 2 (3% central neck and 3% lateral neck; P < .05). Overall, 161/191 (84 %) patients in group 1 were disease free at last survey, compared with 180/191 (94%) patients in group 2 (P < .05). Transient hypocalcemia was significantly greater in group 1. No difference was found in disease-specific mortality. Conclusion. Surgeon assessment of the central neck compartment is an accurate predictor of which patients with PTC will benefit from CLND. Patients with nonenlarged central neck nodes who undergo total thyroidectomy without CLND have a low risk of developing recurrence.

Background Adrenal incidentaloma remains a diagnostic challenge. Despite well-established management guidelines, the long-term results of following these guidelines are unknown. We sought to determine how accurately these guidelines identify functioning incidentalomas and how often these guidelines result in adrenalectomy for benign tumors. Methods We catalogued adrenal incidentalomas from a retrospective review of 500 consecutive adrenalectomies at a single institution. The outcome measures studied were patient demographics, preoperative biochemical analysis, imaging characteristics, tumor size, type of operation performed, and postoperative histologic diagnosis. Results Eighty-one of the 500 adrenalectomies performed were for incidentalomas. Size was the only significant characteristic that distinguished cortical cancers from benign adenomas. Only 1 out of 26 functioning tumors was incorrectly identified on preoperative workup. We also found that 25% of cortisol-secreting incidentalomas were cystic, and that benign adenomas accounted for 42% of all tumors resected. Conclusion Current guidelines accurately predict the functional status of adrenal incidentalomas. Some cystic lesions may be functioning and should therefore be screened for hormonal hypersecretion. However, even with the most up-to-date diagnostic tools available, most adrenal incidentalomas resected are benign tumors.

Most patients with primary hyperparathyroidism can have a minimally invasive parathyroidectomy based on localization studies showing single-gland disease. In patients with a history of head and neck irradiation, due to the increased risk of multigland disease and risk of concurrent thyroid cancer, minimally invasive parathyroidectomy is considered by some to be a contraindication. We postulated that previous history of head and neck irradiation should not be a contraindication for minimally invasive parathyroidectomy and tested this hypothesis in a prospective cohort of patients undergoing parathyroidectomy for primary hyperparathyroidism.We performed a retrospective analysis of a prospective database of 491 consecutive parathyroidectomies performed between May 2005 and May 2007 at a tertiary referral medical center.Fifty-two (12.6%) patients had a history of head and neck irradiation and 360 (87.4%) had no exposure to radiation. The 2 groups had no significant difference in terms of gender or ethnicity. The radiation group was older, with an average age of 65.1 years versus 58.1 years (p0.0009). There was no significant difference in concurrent benign thyroid neoplasm, thyroid cancer, and type of parathyroid disease (single vs multigland) in the 2 groups. There was no significant difference in the operative approach used between the 2 groups (focused vs unilateral or bilateral).Head and neck irradiation should not be a contraindication for minimally invasive parathyroidectomy in patients with primary hyperparathyroidism in the setting of preoperative localization studies showing single-gland disease and no concurrent thyroid neoplasm. Furthermore, history of head and neck irradiation is associated with a later age of presentation for parathyroidectomy.

Background Although cervical endocrine operations are classified as clean cases, and prophylactic antibiotics (pABX) are generally not indicated, practice patterns vary. Study Design We distributed an Internet-based survey to all members of the American and International Associations for Endocrine Surgeons. As a second component of our study, University of California San Francisco hospital records were queried for all readmissions or reoperations within 30 days after thyroidectomy, parathyroidectomy, or neck dissections between January 1, 1999 and December 30, 2007. Results Of the 275 endocrine surgeons who responded, 62% "almost never" used pABX and 26.2% administered pABX "almost always." Surgeons' annual caseload (p = 0.21), their experience with past patients who had minor (p = 0.33) or severe (p = 0.83) surgical site infections (SSI) or adverse reactions to antibiotics (p = 0.78) were not associated with their likelihood to prescribe pABX. In the previous 3 years, most surgeons reported treating patients with minor SSIs, and 30% of surgeons treated more than 1 severe SSI. Surgeons who worked in community hospitals were more likely to give pABX than were surgeons in affiliated or university hospitals (49.6% vs 31.8% and 24.5%, respectively (p = 0.04). Unlike European (8.8%) or American surgeons (27.9%), surgeons in Asia were most likely to give pABX "almost always" (58.3%, p=0.0001). Two-thirds of surgeons would not want antibiotics if they, themselves, needed a cervical operation. Five of the 4,541 patients (0.11%) who underwent cervical operations were readmitted for infectious complications. Conclusions Infectious complications after endocrine cervical operations are rare and the use of preoperative antibiotics varies widely. Prescribing behavior appears dogmatic in that 90% of surgeons give preoperative antibiotics almost always or almost never.

Thyroid cancer is the most common malignancy of the endocrine system. The diagnosis of thyroid nodules, made by neck examination and ultrasonography, is a common event occurring in over 50% of the patient population over the age of 50. Yet, only 5% of these patients will be diagnosed with cancer. Fine needle aspiration biopsy is the gold standard for diagnosing thyroid nodules. However, 10-15% of these biopsies are inconclusive, ultimately requiring a diagnostic thyroid lobectomy. Consequently, research in thyroid biomarkers has become an area of active interest. In the 40 years since calcitonin was first described as the biomarker for medullary thyroid cancer, new biomarkers in thyroid cancer have been discovered. Advances in genomic and proteomic technologies have defined many of these novel thyroid biomarkers. The purpose of this article is to provide a comprehensive literature review of how these biomarkers have evolved from simple screening tests into a complex array of multiple markers to help predict the malignant potential and genetic signature of thyroid neoplasms.

Intraoperative parathyroid hormone monitoring (IOPTH) has changed the surgical approach to primary hyperparathyroidism (PHPT). The traditional approach for the treatment of PHPT is a bilateral neck exploration (BNE), which entails the identification of all parathyroid glands and resection of the abnormal glands. However, with the advent of improved surgical adjuncts, including preoperative ultrasound and sestamibi scintigraphy, and IOPTH monitoring, the pendulum has swung from bilateral exploration to minimally invasive parathyroidectomy. Minimally invasive parathyroidectomy (MIP) encompasses a myriad of “minimally invasive” procedures and includes focused, unilateral, videoscopic, endoscopic, and robotic parathyroidectomies. The standard that MIP is measured against is the traditional bilateral neck exploration which results in a >95% success rate in experienced hands.1-4 The most common and widely accepted adjuncts used with MIP are ultrasound (US) scanning, sestamibi (MIBI) scanning, and IOPTH. The reported accuracy for identifying a single adenoma is 71 to 80% for US and 74 to 88% for MIBI, and 64 to 95% when both are combined.5-8 On the other hand, the accuracy for identifying multigland disease is lower with either single (69% for US and 49% for MIBI) or combined (62%) imaging modalities.6 IOPTH is reported to have an overall accuracy of 80%.5 Similar to preoperative localizing studies, the best results of IOPTH occur in patients with single gland disease (87 to 99%),5,8 but IOPTH assay is less accurate in patients with multigland disease (58%).5 Others, contend that IOPTH is accurate and allows for the successful operative treatment of patients with both single gland and multiple gland parathyroid disease, and rely on parathyroid gland function rather than morphology or histology.9 Not many issues in surgery have been debated as extensively as the use of IOPTH during parathyroid surgery. Proponents supporting IOPTH (in conjunction with localizing studies) propose that the use of IOPTH allows for a less invasive approach, while providing the same operative success and risk of recurrence as a BNE.10,11 On the other hand, opponents of IOPTH argue that a minimally invasive approach underestimates the rate of multigland disease and can potentially lead to operative failure.6 A minimally invasive approach also allows for a shorter hospital stay, although most patients having a bilateral approach can be discharged within 24 hours, a more cosmetic appealing incision, and less postoperative pain are also reported. The risk of surgical complications can be argued to occur less frequently with MIP since only one side of the neck or two parathyroid glands and one recurrent laryngeal nerve are at risk. However, this argument is hard to defend because the complication risk during BNE is already nominal (1%) in the hands of experienced parathyroid surgeons. The contention surrounding the use of IOPTH is centered on the potential risk of operative failure. This comprehensive overview outlines the use of IOPTH during parathyroid surgery and outlines the arguments for and against the use of routine IOPTH.

To improve our understanding of the molecular mechanisms involved in malignant pheochromocytoma by examining differences in the gene expression profile between benign and malignant tumors.The molecular events involved in the malignant transformation of pheochromocytoma are poorly understood. There are also no reliable and uniformly accepted histopathologic criteria to distinguish benign from malignant pheochromocytoma.We performed genome-wide expression profiling of 58 pheochromocytomas (29 benign and sporadic, 16 benign and hereditary, 13 malignant) with technical and biologic replication.Unsupervised cluster analysis showed 3 main clusters of tumors that did not have complete concordance with the clinical and pathologic groupings of pheochromocytomas. Supervised cluster analysis showed almost completely separate clustering between benign and malignant tumors. The differentially expressed genes with known function belonged to 8 biologic process categories; signal transduction, transcription, protein transport, protein synthesis, smooth muscle contraction, ion transport, chemotaxis, and electron transport. Gene set enrichment analysis revealed significant correlation between the microarray profiles of malignant pheochromocytomas and several known molecular pathways associated with carcinogenesis and dedifferentiation. Ten differentially expressed genes had high diagnostic accuracy, and 5 of these genes (CFC1, FAM62B, HOMER1, LRRN3, TBX3, ADAMTS) in combination had an area under the receiver operating characteristic (ROC) curve of 0.96 for distinguishing benign versus malignant tumors.Differentially expressed genes between benign and malignant pheochromocytomas distinguish between these tumors with high diagnostic accuracy. Our findings provide new insight into the genes and molecular pathways that may be involved in malignant pheochromocytomas.

Background Pheochromocytomas vary in presentation, tumor size, and in catecholamine production. Whether pheochromocytoma size correlates with hormone levels, clinical presentation, and perioperative complications is not known. The goal of this study was to determine if tumor size and hormone level correlate according to the clinical presentation at diagnosis. Study Design We retrospectively analyzed all patients who underwent an adrenalectomy with a diagnosis of a pheochromocytoma from February 1996 to October 2008. We grouped patients according to their clinical presentation at diagnosis (routine biochemical screening, incidentaloma, classic symptoms, pheochromocytoma crisis) and obtained preoperative radiographic tumor size and catecholamine hormone levels. ANOVA was used for the group effects and the Kruskal–Wallis rank test was used for pairwise comparison between groups with the Sidak/Bonferroni method for multiplicity adjustment according to age, tumor size, and hormone level. The Pearson correlation coefficient was then calculated to determine if hormone level correlated with tumor size. Results Eighty-one of 107 patients had data available for complete analysis. The average age at diagnosis for all patients was 47.1 years, and the average tumor size was 4.9 cm. The average highest hormone ratio among all patients was 27.4. Tumor size and hormone ratio levels differed among all groups (p ≤ 0.03). A direct correlation (p = 0.014) was apparent between tumor size and hormone level. Complication rates also differed among the four groups of patients (p ≤ 0.02). Conclusions Our study showed that tumor size directly correlates with hormone level. Smaller tumors tend to secrete lower levels of catecholamines, but larger tumors have a wider variation in secretory potential. Larger tumors, however, produced the highest hormone ratios.

There has been considerable progress identifying biomarkers in thyroid tumors that improve the accuracy of fine-needle aspiration biopsy and also help predict tumor aggressiveness or behavior. In this review we address both the clinical potential of molecular biomarkers and their usefulness, based on the most recent literature. We describe the current best clinical staging systems and the common somatic mutations in thyroid cancer. The BRAF mutation is the most common mutation in papillary thyroid cancer and has recently been reported to be associated with disease aggressiveness; it is also an independent predictor of tumor behavior. Combined testing of RET/PTC, NTRK, RAS and PAX8–PPARγ, which are mutually exclusive mutations, helps improve the accuracy of fine-needle aspiration biopsy. Gene-expression profiling studies have identified a variety of potential molecular markers to help distinguish benign from malignant thyroid neoplasms. Expression analysis of differentially expressed microRNAs also appears to be a promising diagnostic approach for distinguishing benign from malignant thyroid neoplasm. It is especially useful for indeterminate nodules by fine-needle aspiration biopsy.

Rosiglitazone is a peroxisome proliferator-activated receptor (PPAR) gamma agonist that has shown promise as both an antiproliferative and redifferentiating agent for the treatment of thyroid cancer in preclinical studies. We investigated the efficacy and side effects of rosiglitazone therapy in patients with differentiated thyroid cancer of follicular cell origin that fails to take up radioiodine or is unresectable.Twenty patients with differentiated thyroid cancer were enrolled in an open-label, phase II trial of oral rosiglitazone treatment (4 mg daily for 1 week, then 8 mg daily for 7 weeks).Five of 20 patients had a positive radioiodine scan after rosiglitazone treatment. Four patients had radioiodine uptake in the neck and one patient had uptake in the pelvis. Unstimulated thyroglobulin levels after rosiglitazone treatment increased in five patients, remained stable in 12 patients, and decreased in three patients. Seven patients had progressive disease on follow-up cross-sectional imaging; six patients in the size and number of lung metastasis and two patients in the size of the neck tumors. Overall, five patients had a partial response (decreased thyroglobulin or positive radioiodine uptake), three patients had stable disease (no change in thyroglobulin and radioiodine uptake status), and 12 patients had disease progression (increased thyroglobulin). By RECIST criteria, no patient had a complete or partial response to rosiglitazone treatment at 3 months follow-up. The mean follow-up time after protocol treatment was 12 months (median 12 months).Our findings suggest that rosiglitazone therapy may induce radioiodine uptake and reduce serum thyroglobulin levels in some patients with differentiated thyroid cancer but this did not result in clinically significant response on long-term follow-up. Moreover, no patients had response to rosiglitazone therapy by anatomic imaging studies.

Background Because of improvements in the medical management of end-stage renal disease, some surgeons perceive that they now perform fewer operations for secondary hyperparathyroidism, and that current patients have more advanced disease. Methods One hundred and seventy-two patients undergoing 202 operations for secondary hyperparathyroidism between 1988 and 2007 were reviewed. Patients operated on in the past decade (1998–2007) were compared with those from the previous decade (1988–1997). The main outcome measures were pre- and post-operative biochemical and symptom profiles, operation performed, and recurrence. Results One hundred and thirty first-time operations and 72 reoperations were performed. From 1988 to 1997, 106 operations were performed, compared with 96 from 1998 to 2007. There were no demographic differences between decades. There were no differences in preoperative serum calcium (10.0 mg/dL vs 10.2 mg/dL), PTH (1622 ng/L vs 1424 ng/L), phosphate (6.9 mg/dL vs 7.0 dL), and alkaline phosphatase (339 U/L vs 347 U/L). Symptom profiles were similar. Patients in the past decade were less likely to require reoperation (6% vs 22%) ( P Conclusion Despite improvements in medical management, the population of patients requiring parathyroidectomy for secondary hyperparathyroidism has remained constant in number and preoperative biochemical and symptom profiles over the past 2 decades. However, fewer patients have required reoperation in the past decade.

To compare the preoperative clinical symptoms and associated conditions and findings in operations in age- and sex-matched patients with primary hyperparathyroidism (PHPT) living in the two different regions of the world to determine whether PHPT differs in various countries.Fifty-two patients from Bursa, Turkey were matched with 52 age and sex matched patients from San Francisco, USA. Patients' preoperative symptoms, biochemical and radiologic findings and surgical procedures were documented.More patients in the American Group (15%) had preoperatively persistant or recurrent hyperparathyroidism, P = 0.016. Serum parathyroid hormone levels were higher in Turkish group (546 +/- 75.33 pg/mL) than in American group (146 +/- 75.33 pg/mL). More Turkish patients had osteoporosis (P0.05). The size of parathyroid adenomas was significantly greater in Turkish patients (25.2 +/- 1.18 mm) than in American patients (17.5 +/- 1.18 mm), P0.001.Patients with PHPT from Bursa, Turkey have higher plasma parathyroid hormone levels, larger parathyroid adenomas and more severe bone disease than in age and sex matched patients with PHPT in San Francisco.

Thyroid stimulating hormone (TSH) causes differentiation and epidermal growth factor (EGF) causes dedifferentiation of thyroid cells in vitro. In undifferentiated thyroid cancer cell lines, TSH stimulates tumor cell migration and invasion, a dedifferentiated function, presumably due to an escape of tumor cells from the control of differentiating growth factors. In a highly differentiated thyroid carcinoma cell line of Hurthle cell origin (XTC), we tested the hypothesis that TSH would stimulate thyroglobulin secretion (a differentiated function) more than EGF, and EGF would stimulate invasion (a de-differentiated function) more than TSH. Proliferation, adhesion, cell migration and invasion were measured by the MTT assay, human thyroglobulin by RIA and protease activity by substrate-gel zymography. TSH induced differentiated morphologic changes in XTC cells and stimulated secretion of human thyroglobulin in a dose dependent manner, whereas EGF did not. The effects of TSH on growth, adhesion, migration and invasion were dose dependent and biphasic, with an increase at low and a decrease at high concentrations of TSH. These effects were always more pronounced than those observed with EGE Gelatinolytic activity, consistent with metalloproteinase activity was revealed by zymography, but the pattern of secretion was not altered by neither TSH nor EGF. These results suggest, that TSH has pleiotropic effects on differentiated thyroid cancer cells in vitro that involve differentiated morphology and function but also affect features commonly associated with the malignant in vitro phenotype.

Objective To report the limitations of frozen section examination and the value of intraoperative tissue aspiration for parathyroid hormone assay to distinguish parathyroid adenomas from metastatic thyroid carcinoma. Methods We describe 2 patients with a biochemical diagnosis of primary hyperparathyroidism who underwent intraoperative frozen section analysis of suspected parathyroid tumors. Parathyroid gland aspiration for parathyroid hormone was also performed for confirmation. Results The intraoperative frozen section examination of the suspected parathyroid tumors inaccurately identified the tumors as follicular carcinomas. The parathyroid gland aspirate, however, accurately substantiated the presence of parathyroid adenomas, rather than follicular cancers. Conclusion Aspiration of a suspected parathyroid tumor for parathyroid hormone assay accurately determines whether a nodule is a parathyroid gland and facilitates intraoperative decision making, especially when frozen section diagnosis is misleading. (Endocr Pract. 2009; 15:454-457)

Background Intraoperative parathyroid hormone (IOPTH) measurement is used to confirm biochemical cure during parathyroidectomy. Falsely decreased IOPTH measurements could result in false-negative or false-positive results and lead to failed parathyroidectomy or unnecessary additional exploration. Study design The records of all patients who underwent parathyroidectomy with IOPTH between May and August 2007 were retrospectively reviewed, and the frequency of hemolysis of IOPTH samples was determined. Separately, 10 split-samples were hemolyzed using the freeze-thaw technique. Results Forty-seven patients underwent parathyroidectomy, and 226 IOPTH samples were sent. Seventeen (7.5%) specimens from 9 (18.8%) patients were hemolyzed. In 8 split-samples, the range of decrease caused by hemolysis was 24.5% to 53.8% compared with nonhemolyzed controls. Conclusions Hemolysis of IOPTH samples occurs commonly and falsely decreases IOPTH levels. Unrecognized hemolysis in pre-excision specimens could result in false-negative IOPTH results and lead to unnecessary continued exploration. Unrecognized hemolysis in postexcision specimens could lead to false-positive IOPTH results and lead to failed parathyroidectomy and the need for reoperation. Thus, hemolysis may be an easily preventable cause of erroneous IOPTH measurements.

Small, nonpalpable lymph node recurrences are frequently identified in the follow-up of patients with thyroid cancer, and finding and removing these lesions in a reoperative field can be very challenging. The goal of this study was to evaluate the utility of preincision ultrasound-guided injection of blue dye into the abnormal lymph nodes to facilitate their safe and efficient removal. We performed a prospective study between January and June 2007 at a single academic institution. Ten patients with isolated, nonpalpable nodal recurrences of papillary thyroid cancer underwent an operation for a neck recurrence (8 central, 2 lateral). A preincision ultrasound was performed in the operating room to localize the lesions, and 0.1 ml of blue dye was injected under ultrasound guidance into each abnormal lymph node. We examined the feasibility of the injection procedure, the accuracy of identifying pathologic lymph nodes, and the complications of injection. The pathologic lymph nodes averaged 11 mm in size (range = 6–16 mm) and were detectable by ultrasound in all cases. Ultrasound-guided blue dye injection was successful in all cases. There were no complications related to dye injection. The blue node was easily identified and removed in all cases. The mean operative time was 80.4 min (range = 37–157 min). Blue dye injection was feasible and was very useful for the identification of lymph node recurrences, especially in the reoperative neck. There were no complications related to the injection in this series. Further study is needed to determine the widespread safety and efficacy of this technique.

BACKGROUND. A 3-gene (PCSK2, PLAB, CCND2) assay has been reported to have high accuracy for distinguishing benign from malignant thyroid tumors that are often indeterminate on fine–needle aspiration (FNA) biopsy. The aim of the current study was to determine the diagnostic accuracy of the 3-gene assay in thyroid tissue and in FNA biopsy for distinguishing benign from malignant thyroid neoplasms. METHODS. The messenger ribonucleic acid (mRNA) expression level of 3 genes (PCSK2, PLAB, CCND2) was analyzed by real-time quantitative reverse transcriptase–polymerase chain reaction in 261 frozen thyroid tissue samples (138 benign and 123 malignant), and prospectively, in 144 clinical thyroid FNA samples. To determine the diagnostic accuracy of the 3-gene assay, the area under the curve (AUC) of the receiver operating characteristic curve for each gene individually and in combination was determined. RESULTS. PCSK2 and CCND2 mRNA expression levels were found to be significantly different between benign and malignant thyroid tissue samples (P < .0001 and P = .0007, respectively), but PLAB mRNA expression level was not (P = .099). In the thyroid tissue samples, the AUC was 0.67 for PCSK2 and 0.62 for CCND2. In the thyroid FNA samples, PCSK2 and CCND2 were significantly differentially expressed between benign and malignant samples (P = .039 and P = .023, respectively). The AUC was 0.59 for PCSK2 and 0.61 for CCND2. CONCLUSIONS. Although PCSK2 and CCND2 were significantly differentially expressed between benign and malignant thyroid tumors both in tissue and in FNA samples, the diagnostic accuracy of the 3-gene assay was low. These findings demonstrate that it is essential for studies to validate the diagnostic accuracy and clinical utility of emerging candidate diagnostic thyroid cancer markers if they are to be translated into clinically useful markers for making patient care decisions. Cancer 2008. © 2008 American Cancer Society.

OBJECTIVE: To provide a review on current knowledge about the pathogenesis, epidemiology, and clinical complications of persistent hyperparathyroidism after kidney transplantation (3HPT) and to discuss the surgical approaches. BACKGROUND: 3HPT usually regresses within the first months after transplantation. Parathyroidectomy for 3HPT is therefore not usually needed. Consequently, few studies have been published regarding the best medical management for 3HPT and indications for parathyroidectomy. METHODS: Medical literature databases were searched for studies on the surgical treatment of 3HPT published in English. RESULTS: Forty-one studies were identified and included in this review. CONCLUSIONS: 3HPT most commonly occurs in patients who have severe secondary hyperparathyroidism at the time of transplantation. Indications for parathyroidectomy in patients with 3HPT include persistent severe hypercalcemia, defined as a serum calcium level greater than 11.5 mg/dl, unexplained renal function deterioration, or progressive bone mineral density loss. Published studies suggest that the best surgical approach for patients with 3HPT is subtotal parathyroidectomy or total parathyroidectomy with autotransplantation. 3HPT poses important health risks, particularly concerning bone density and the cardiovascular system. Because spontaneous improvement of parathyroid function is uncommon after 3 months of transplantation, waiting for more than 6 months before parathyroidectomy should be discouraged.

Hashimoto's thyroiditis is usually treated medically; however, thyroidectomy is sometimes indicated. Thyroiditis can make thyroid dissection more difficult and possibly increase the risk of surgical complications. The aim of this study was to determine the rate of complications and associated cancer in patients with Hashimoto's thyroiditis.Retrospective series of 474 patients treated surgically at the University of California, San Francisco, between January 1985 and June 2005 with final pathology demonstrating Hashimoto's thyroiditis, chronic lymphocytic thyroiditis, or chronic thyroiditis. Parameters evaluated included demographics, surgical indications, and postoperative complications.Among the 474 patients, 133 had thyroidectomy because of preoperative diagnosis of thyroid cancers (median age 39 years; 116 females and 17 males), 316 had thyroidectomy because of benign thyroid nodules or goiter (median age 47.5 years; 292 females and 24 males), and 25 had thyroidectomy to relieve local symptoms caused by thyroiditis but did not have thyroid nodules (median age 42 years; 25 females). No death or permanent surgical complications occurred. One hundred and fifty-two patients (32.1%) had transient postoperative hypocalcemia, 2 (0.4%) had transient recurrent nerve palsy, and 4 (0.8%) had a postoperative neck hematoma. Fifty-three percent had thyroid cancer at final histological examination.Thyroidectomy can be performed in patients with Hashimoto's thyroiditis with a low risk of permanent surgical complications. Cancer is common in patients who have a thyroidectomy for Hashimoto's thyroiditis even when not suspected preoperatively.

The most common genetic change observed in adrenocortical carcinoma is loss of heterozygozity on chromosome 11q13. As genes on this chromosome may be important in the pathogenesis of adrenocortical carcinoma, we compared their expression profile between benign and malignant adrenocortical tissue.We used the Affymetrix GeneChip (U133 plus 2.0) array in 54 adrenocortical tumors (11 carcinoma and 43 benign). Differential gene expression was defined as a twofold higher or lower gene expression level (p0.05). Differentially expressed genes on microarray analysis were validated by real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR). The area under the receiver operating characteristic (ROC) curve (AUC) was used to determined the diagnostic accuracy of the differently expressed genes for distinguishing benign from malignant tumors.We found 25 of the 314 genes on chromosome 11q13 to be differentially expressed between adrenocortical carcinoma and benign adrenocortical tumor. All 25 were downregulated in adrenocortical carcinoma by 2-fold to 4.8-fold; 21 were validated to be differentially expressed by RT-PCR (Pearson's coefficient0.5). Six genes (SERPING1, MRPL48, TM7SF2, DDB1, NDUSF8, PRDX5) validated by RT-PCR were significantly differentially expressed between benign and malignant adrenocortical tumors (p0.05) with an overall accuracy of 89% for SERPING1, 91% for MRPL48, 87% for TM7SF2, 88% for DDB1, 91% for NDUFS8, and 89% for PRDX5. The AUC was 0.89 for the combination of SERPING1, MRPL48, TM7SF2, DDB1, and NDUFS8.We have identified 25 genes located on chromosome 11q13 that are downregulated in adrenocortical carcinoma and may be candidate tumor suppressor genes. Six of these genes were good diagnostic markers for distinguishing adrenocortical carcinoma from adenoma.

Primary hyperparathyroidism (HPT) is diagnosed in approximately 100,000 patients in the US each year, with a 2–3:1 female-to-male distribution. In most cases, occurrence is sporadic rather than familial, and 80% to 85% of cases of sporadic primary HPT are caused by a solitary parathyroid adenoma. The diagnosis is made by hypercalcemia with an inappropriately elevated parathyroid hormone (PTH) level and a 24-hour urine calcium excretion level that is normal or high. Truly asymptomatic primary HPT is rare, as most patients have symptoms or metabolic complications when carefully evaluated by standardized health questionnaires. The National Institutes of Health (NIH) published guidelines in 2002, recommending parathyroidectomy for all symptomatic patients and for asymptomatic patients less than age 50 years or those who cannot participate in medical surveillance. These criteria have been called into question as being too limited, because multiple studies have demonstrated symptomatic and metabolic benefits of parathyroidectomy in “asymptomatic” patients. Given the studies showing an improvement in quality-of-life measures, future risk for developing renal calculi, bone density, cardiovascular health, and risk of death, we believe that virtually all patients with primary HPT should undergo surgical resection. An improvement in preoperative localization studies as well as the development of a rapid intraoperative PTH assay has changed the approach to parathyroid surgery since the 1980s. Because most sporadic primary HPT is caused by a single gland adenoma, our preferred procedure has now changed from a bilateral neck exploration to a focused or unilateral approach, with similar rates of success in patients with a solitary tumor identified preoperatively.

To evaluate whether selective rather than universal use of adrenal vein sampling (AVS) may be warranted in patients with hyperaldosteronism to characterize and lateralize disease before adrenalectomy.Fifty-nine consecutive patients with biochemically diagnosed hyperaldosteronism underwent unilateral adrenalectomy at a single center during a 10-year period. In one group (n = 30), adrenalectomy was based on computed tomography (CT) only; in another (n = 29), it was based on CT and AVS. The indication for AVS was equivocal CT finding (n = 26) or patient request (n = 3). Outcome variables were postoperative serum potassium and aldosterone levels, number of hypertensive medications, and mean arterial blood pressure at 6 months.Preoperatively, both groups were matched for age, years of hypertension, mean arterial blood pressure, and number of hypertensive medications. Average tumor sizes were 2 cm (range, 1-3 cm) in the CT-only group and 1 cm (range, 0-2.5 cm) in the CT/AVS group. Unilateral tumor was identified on CT in 30 patients (100%) in the CT-only group and in 17 patients (59%) in the CT/AVS group (P.05). Postoperatively, aldosterone levels were lower in the CT-only group (6.3 ng/dL +/- 5.9 vs 13.5 ng/dL +/- 16; P.05). Both groups had similar improvements in mean arterial blood pressure at 6 months (92 mm Hg +/- 12 vs 96 mm Hg +/- 9; P = .14), reductions in number of hypertensive medications (to 1.1 +/- 1.3 vs 1.2 +/- 1.1; P = .4), and improvements in hypokalemia (3.8 mEq/L +/- 0.5 vs 3.8 mEq/L +/- 0.5; P = .5).The clinical impact of adrenalectomy was similar in both groups. CT can be used to reliably diagnose adenomas larger than 1.0 cm. AVS should be used when CT findings are equivocal or both adrenal glands are abnormal.

Spironolactone is frequently used before adrenalectomy for hyperaldosteronism to control blood pressure. Response to spironolactone has been suggested to predict a better outcome. However, whether using other antihypertensive medications to control blood pressure predicts outcome remains unknown. We sought to determine the relationship between preoperative normalization of blood pressure with antihypertensive medications and response to adrenalectomy for hyperaldosteronism.A retrospective cohort study of 102 patients who underwent adrenalectomy for hyperaldosteronism at a tertiary medical center were included. Blood pressures were measured at first clinical presentation, preoperatively, postoperatively, and at 1 and 6 months postoperatively. The primary outcome measure was complete resolution of hypertension (blood pressure140/90) without antihypertensive medications, versus incomplete resolution requiring antihypertensive medications.Hypertension resolved and medications were discontinued in 39% of patients. Hypertension resolved without medications in 53% of patients who were normotensive preoperatively versus 24% of patients who were hypertensive (P = .006). In contrast, hypertension resolved without medications in only 45% of patients who were normotensive on spironolactone preoperatively versus 34% of patients who were hypertensive (P = .38).Patients with good preoperative control of hypertension on antihypertensive medications, irrespective of response to spironolactone, are more likely to have complete resolution.

Objective: To examine the prevalence of BRAF mutation among thyroid cancer histologic subtypes and determine the association of BRAF mutation with indicators of poor prognosis for papillary thyroid cancer and patient outcome. Background Data: The appropriate extent of surgical treatment, adjuvant therapy and follow-up monitoring for thyroid cancer remains controversial. Advances in the molecular biology of thyroid cancer have helped to identify candidate markers of disease aggressiveness. A commonly found genetic alternation is a point mutation in the BRAF oncogene (BRAF V600E), which is primarily found in papillary thyroid cancer and is associated with more aggressive disease. Methods: BRAF V600E mutation status was determined in 347 tumor samples from 314 patients with thyroid cancer (245 with conventional papillary thyroid cancer, 73 with follicular thyroid cancer, and 29 with the follicular variant of papillary thyroid cancer). Univariate and multivariate analyses were performed to determine the association of BRAF V600E with clinicopathologic factors and patient outcome. Results: The prevalence of BRAF V600E mutation was higher in conventional papillary thyroid cancer (51.0%) than in follicular variant of papillary thyroid cancer (24.1%) and follicular thyroid cancer (1.4%) (P < 0.0001). In patients with conventional papillary thyroid cancer, BRAF V600E mutation was associated with older age (P = 0.0381), lymph node metastasis (P = 0.0323), distant metastasis (P = 0.045), higher TNM stage (I and II vs. III and IV, P = 0.0389), and recurrent and persistent disease (P = 0.009) with a median follow-up time of 6.0 years. Multivariate analysis showed that BRAF V600E mutation [OR (95% CI) = 4.2 (1.2-14.6)] and lymph node metastasis [OR (95% CI) = 7.75 (2.1-28.5)] were independently associated with recurrent and persistent disease in patients with conventional papillary thyroid cancer. Conclusions: BRAF V600E mutation is primarily present in conventional papillary thyroid cancer. It is associated with an aggressive tumor phenotype and higher risk of recurrent and persistent disease in patients with conventional papillary thyroid cancer. Testing for this mutation may be useful for selecting initial therapy and for follow-up monitoring.

The incidence of thyroid cancer has been increasing over the past 30 years, and it is now the seventh most common cancer in women. Papillary thyroid cancer is the most common subtype of thyroid cancer, occurring in 80% of cases. Its main pattern of spread is to cervical lymph nodes, with distant metastases occurring uncommonly. Initial treatment of papillary thyroid cancer involves resection of the primary tumor, with resection of regional lymph nodes if involved with metastatic disease. Postoperative adjuvant therapy consists of radioactive iodine ablation for most patients, followed by thyroid-stimulating hormone (TSH) suppression with thyroxine. An ongoing controversy in the surgical treatment of papillary thyroid cancer is that of extent of thyroid gland and nodal resection. Consensus guidelines recommend total or near-total thyroidectomy, rather than thyroid lobectomy, as the initial procedure of choice, given its advantages of treating potential multicentric disease, facilitating maximal uptake of adjuvant radioactive iodine, and facilitating the post-treatment follow-up by monitoring serum thyroglobulin (Tg) levels. In the hands of an experienced endocrine surgeon, complication rates are comparable to those for lobectomy. Major changes in the management of patients with papillary thyroid cancer over the last 10 years include the use of preoperative neck ultrasound, which can detect nonpalpable cervical lymph node metastases and potentially change the initial operation. In addition, neck ultrasound and measurement of serum Tg levels have taken the place of routine whole body radioactive iodine scans in the postoperative follow-up of patients with papillary thyroid cancer. Recurrent locoregional cervical lymph node disease should be treated by compartmental lymph node dissection, followed by another treatment dose of radioactive iodine. Chemotherapy is generally ineffective for the treatment of metastatic disease. For those patients whose tumor has become radioactive iodine resistant, emerging therapies include redifferentiation agents, antiangiogenic agents, and multi-tyrosine kinase inhibitors.

Primary hyperparathyroidism (PHPT) is caused by a parathyroid adenoma in 85%, parathyroid hyperplasia in 15%, and parathyroid carcinoma in less than 1% of patients. This disease is classically described by the pentad of painful bones, renal stones, abdominal groans, psychic moans, and fatigue overtones. Today about 20% of patients referred for parathyroidectomy have renal stones, 30% have osteopenia or osteoporosis, and about 2% have osteitis fibrosa cystica. There are now three different presentations for PHPT: symptomatic, minimally symptomatic, and asymptomatic. PHPT is currently diagnosed by biochemical testing with an elevated serum calcium, an elevated or non-suppressed parathyroid hormone level, and the absence of hypocalciuria. Given the wide spectrum of disease that is diagnosed based on biochemical markers, the NIH made specific recommendations for the treatment of the non-classical PHPT. Many experts in this field have challenged these recommendations because numerous long-term follow-up investigations have shown the detrimental effects of hyperparathyroidism on bone density and fracture rate, renal function, cardiovascular mortality, and neuropsychiatric function. Parathyroidectomy is the only curative treatment for PHPT with a success rate of about 95%.

Approximately 5% of nonmedullary thyroid cancers are of familial origin. When two or more family members are diagnosed with nonmedullary thyroid cancer in the absence of other known associated syndromes it is termed familial nonmedullary thyroid cancer (FNMTC). The genetic inheritance of FNMTC remains unknown, but it is believed to be an autosomal dominant mode of inheritance with incomplete penetrance and variable expressivity. FNMTC has been shown to be more aggressive and to have a worse prognosis than sporadic nonmedullary thyroid cancer. For example, studies have demonstrated that individuals with FNMTC have an increased risk of multifocal disease, local invasion, and lymph node metastases. These aggressive features appear to contribute to the higher recurrence rate and decreased disease-free survival seen in FNMTC patients compared to those with sporadic differentiated thyroid cancer. This article is an overview of the literature available in the English language discussing FNMTC. Critical questions regarding the screening, management, and follow-up of these patients are addressed with answers proposed based on the available literature. The quality of the evidence is ranked according to Sackett’s criteria. Overall, the literature quality is somewhat limited, based on the low prevalence of FNMTC, the difficulty in identifying familial cases, the variable study designs, and limited long-term follow-up. Conclusions: To date, the optimal clinical approach is yet to be established, but improved awareness and screening will permit earlier detection, more timely intervention, and hopefully improved outcomes for patients and their families.

Thyroid nodules are rare in children compared to adults. Although most thyroid nodules are benign, the risk of malignancy is greater in pediatric patients. Papillary and follicular cell tumors account for the majority of thyroid neoplasms; Hürthle cell tumors account for less than 5%. Despite being uncommon, malignant Hürthle cell tumors are potentially more aggressive than papillary and follicular cell tumors. Therefore, distinguishing between types of thyroid neoplasms in a timely fashion has implications for prognosis and therapy. We describe a 12-year-old peripubertal girl who presented with a large right-sided thyroid nodule that was subsequently diagnosed as a Hürthle cell adenoma. To our knowledge, she represents the youngest patient with a Hürthle cell neoplasm.