A nested case-control study of serum polychlorinated biphenyls and papillary thyroid cancer risk among U.S. military service members.

BACKGROUND AND OBJECTIVES: Although polychlorinated biphenyls (PCBs) were banned decades ago, populations are continuously exposed to PCBs due to their persistence and bioaccumulation/biomagnification in the environment. Results from limited epidemiologic studies linking PCBs to thyroid cancer have been inconclusive. This study aimed to investigate the association between individual PCBs and PCB mixture and papillary thyroid cancer (PTC), the most common thyroid cancer histologic subtype. METHODS: We carried out a nested case-control study including 742 histologically confirmed PTC cases diagnosed in 2000-2013 and 742 individually matched controls among U.S. military service members. Pre-diagnostic serum samples that were collected on average nine years before PTC diagnosis were used to measure PCB congeners by gas chromatography isotope dilution high resolution mass spectrometry (GC/ID-HRMS). Conditional logistic regression, Bayesian kernel machine regression (BKMR), and weighted quantile sum (WQS) regression were employed to estimate the association between single PCB congeners as well as their mixture and PTC. RESULTS: Four PCB congeners (PCB-74, PCB-99, PCB-105, PCB-118) had significant associations and dose-response relationships with increased risk of PTC in single congener models. When considering the effects from all measured PCBs and their potential interactions in the BKMR model, PCB-118 showed positive trends of association with PTC. Increased exposure to the PCB congeners as a mixturewas also associated with an increased risk of PTC in the WQS model, with the mixture dominated by PCB-118, followed by PCB-74 and PCB-99. One PCB congener, PCB-187, showed an inverse trend of association with PTC in the mixture analysis. DISCUSSION: This study suggests that exposure to certain PCBs as well as a mixture of PCBs were associated with an increased risk of PTC. The observed association was mainly driven by PCB-118, and to a lesser extent by PCB-74 and PCB-99. The findings warrant further investigation.

Polybrominated Diphenyl Ethers, Polybrominated Biphenyls, and Risk of Papillary Thyroid Cancer: A Nested Case-Control Study.

A nested case-control study was carried out using data from the US Department of Defense cohort between 2000 and 2013 to investigate the associations of papillary thyroid cancer (PTC) with serum concentrations of polybrominated diphenyl ethers and polybrominated biphenyls. This study included 742 histologically confirmed PTC cases (in 341 women and 401 men) and 742 matched controls with prediagnostic serum samples from the Department of Defense Serum Repository. Lipid-corrected serum concentrations of 8 congeners were measured. Multivariate conditional logistic regression analyses were performed for classical PTC and follicular variant of PTC, respectively. We also examined effect modification by sex. BDE-28, a polybrominated diphenyl ether congener, was associated with significantly increased risk of classical PTC (for the third tertile vs. below the limit of detection, odds ratio = 2.09, 95% confidence interval: 1.05, 4.15; P for trend = 0.02), adjusting for other congeners, body mass index, and branch of military service. This association was observed mainly for larger classical PTC (tumor size > 10 mm), with a significantly stronger association among women than men (P for interaction = 0.004). No consistent associations were observed for other congeners, including those at higher concentrations. This study found a significantly increased risk of classical PTC associated with increasing levels of BDE-28. The risk varied by sex and tumor size.

Genetic susceptibility may modify the association between cell phone use and thyroid cancer: A population-based case-control study in Connecticut.

Emerging studies have provided evidence on the carcinogenicity of radiofrequency radiation (RFR) from cell phones. This study aims to test the genetic susceptibility on the association between cell phone use and thyroid cancer. Population-based case-control study was conducted in Connecticut between 2010 and 2011 including 440 thyroid cancer cases and 465 population-based controls with genotyping information for 823 single nucleotide polymorphisms (SNPs) in 176 DNA genes. We used multivariate unconditional logistic regression models to estimate the genotype-environment interaction between each SNP and cell phone use and to estimate the association with cell phone use in populations according to SNP variants. Ten SNPs had P < 0.01 for interaction in all thyroid cancers. In the common homozygote groups, no association with cell phone use was observed. In the variant group (heterozygotes and rare homozygotes), cell phone use was associated with an increased risk for rs11070256 (odds ratio (OR): 2.36, 95% confidence interval (CI): 1.30-4.30), rs1695147 (OR: 2.52, 95% CI: 1.30-4.90), rs6732673 (OR: 1.59, 95% CI: 1.01-2.49), rs396746 (OR: 2.53, 95% CI: 1.13-5.65), rs12204529 (OR: 2.62, 95% CI: 1.33-5.17), and rs3800537 (OR: 2.64, 95% CI: 1.30-5.36) with thyroid cancers. In small tumors, increased risk was observed for 5 SNPs (rs1063639, rs1695147, rs11070256, rs12204529 and rs3800537), In large tumors, increased risk was observed for 3 SNPs (rs11070256, rs1695147, and rs396746). Our result suggests that genetic susceptibilities modify the associations between cell phone use and risk of thyroid cancer. The findings provide more evidence for RFR carcinogenic group classification.

Endocrine Surgery: A Hopkins Legacy.

: The field of Endocrine Surgery is linked to extraordinary contributions made by Hopkins leaders in surgery including William Stewart Halsted, Harvey Cushing, and John L Cameron. Halsted's contributions to the anatomic basis of thyroid and parathyroid surgery were based on his experimental and clinical work performed at Johns Hopkins Hospital. Halsted's disciple, Harvey Cushing, created the field of modern neurosurgery and recognized the disease and syndrome that are immortalized with his name. The Halstedian principles promulgated and transmitted by John L Cameron to subsequent generations of endocrine surgeons at Hopkins have transformed the field of Endocrine Surgery with the stamp of Johns Hopkins Hospital.

Alcohol Consumption and Risk of Thyroid Cancer: A Population Based Case-Control Study in Connecticut.

BACKGROUND: Studies examining the association between alcohol consumption and thyroid cancer risk have been inconsistent, in part due to varying types and amounts of alcohol consumption, incomplete information on confounders, and variations in genetic susceptibility in study populations. METHODS: The present study analyzed data from a population-based case-control study in Connecticut in 2010-2011 including 462 histologically confirmed incident thyroid cancer cases and 498 population-based controls. Unconditional logistic regression was used to estimate associations between alcohol consumption and risk of thyroid cancer. Potential confounding variables were age, gender, race, education, body mass index, family history of cancer among first-degree relatives, history of benign thyroid disease, smoking status, and physical activity. RESULTS: Ever consumption of alcohol was associated with a reduced risk of thyroid cancer (OR = 0.71, 95% CI: 0.54-0.95). The younger age at initiation and increasing duration of alcohol consumption were also associated with a reduced risk of thyroid cancer in a dose-dependent manner (P for trend = 0.041 and 0.0065, respectively). Compared to people who never drank alcohol, people who drank alcohol for >31 years were 50% less likely to develop thyroid cancer (OR = 0.50, 95% CI: 0.32-0.80). Alcohol consumption was associated with a reduced risk of papillary thyroid cancer (OR = 0.66, 95% CI: 0.49-0.88) and thyroid cancer with lager tumor size (>1 cm), but no significant association was found between alcohol consumption and non-papillary thyroid cancer or thyroid microcarcinoma. Analyses stratified by specific subtypes of alcohol demonstrated an inverse association for beer (OR = 0.69, 95% CI: 0.49-0.96) and wine consumption (OR = 0.71, 95% CI: 0.53-0.96) as compared to participants who never consumed alcohol, but no significant association was found for liquor consumption (OR = 0.75, 95% CI: 0.53-1.04). CONCLUSIONS: The study findings suggest an inverse association between alcohol consumption and risk of thyroid cancer. Future mechanistic study is warranted to elucidate the underlying mechanisms.

Occupational exposure to pesticides and other biocides and risk of thyroid cancer.

OBJECTIVES: To assess the associations between occupational exposure to biocides and pesticides and risk of thyroid cancer. METHODS: Using data from a population-based case-control study involving 462 incident thyroid cancer cases and 498 controls in Connecticut collected in 2010-2011, we examined the association with occupational exposure to biocides and pesticides through a job-exposure matrix. We used unconditional logistic regression models to estimate OR and 95% CI, adjusting for potential confounders. RESULTS: Individuals who were occupationally ever exposed to biocides had an increased risk of thyroid cancer (OR=1.65, 95% CI 1.16 to 2.35), and the highest risk was observed for the high cumulative probability of exposure (OR=2.18, 95% CI 1.28 to 3.73). The observed associations were similar when we restricted to papillary thyroid cancer and well-differentiated thyroid cancer. Stronger associations were observed for thyroid microcarcinomas (tumour size ≤1 cm). No significant association was observed for occupational exposure to pesticides. CONCLUSIONS: Our study provides the first evidence linking occupational exposure to biocides and risk of thyroid cancer. The results warrant further investigation.

NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States.

BACKGROUND: An increase in thyroid cancers, predominantly papillary thyroid carcinoma (PTC), has been recently reported in children. METHODS: The histopathology of 28 consecutive PTCs from the northeast United States was reviewed. None of the patients (ages 6-18 years; 20 females, 8 males) had significant exposure to radiation. Nucleic acid from tumors was tested for genetic abnormalities (n = 27). Negative results were reevaluated by targeted next-generation sequencing. RESULTS: Seven of 27 PTCs (26%) had neurotrophic tyrosine kinase receptor (NTRK) fusion oncogenes (NTRK type 3/ets variant 6 [NTRK3/ETV6], n =5; NTRK3/unknown, n = 1; and NTRK type 1/translocated promoter region, nuclear basket protein [NTRK1/TPR], n = 1), including 5 tumors that measured >2 cm and 3 that diffusely involved the entire thyroid or lobe. All 7 tumors had lymphatic invasion, and 5 had vascular invasion. Six of 27 PTCs (22%) had ret proto-oncogene (RET) fusions (RET/PTC1, n = 5; RET/PTC3, n = 1); 2 tumors measured >2 cm and diffusely involved the thyroid, and 5 had lymphatic invasion, with vascular invasion in 2. Thirteen PTCs had the B-Raf proto-oncogene, serine/threonine kinase (BRAF) valine-to-glutamic acid mutation at position 600 (BRAF(V) (600E)) (13 of 27 tumors; 48%), 11 measured <2 cm, and 6 had lymphatic invasion (46%), with vascular invasion in 3. Fusion oncogene tumors, compared with BRAF(V) (600E) PTCs, were associated with large size (mean, 2.2 cm vs 1.5 cm, respectively; P = .05), solid and diffuse variants (11 of 13 vs 0 of 13 tumors, respectively; P < .001), and lymphovascular invasion (12 of 13 vs 6 of 13 tumors, respectively; P = .02); BRAF(V) (600E) PTCs were predominantly the classic variant (12 of 13 vs 1 of 13 tumors). Two tumors metastasized to the lung, and both had fusion oncogenes (NTRK1/TPR, n = 1; RET/PTC1, n = 1). CONCLUSIONS: Fusion oncogene PTC presents with more extensive disease and aggressive pathology than BRAF(V) (600E) PTC in the pediatric population. The high prevalence of the NTRK1/NTRK3 fusion oncogene PTCs in the United States is unusual and needs further investigation.

Thyroid cancer.

Thyroid cancer is rapidly increasing in incidence, but the mortality rate remains flat. Debate has arisen over the need to detect or treat most thyroid cancers early, given their favorable natural history. The appropriate extent of surgery for thyroid cancer is also controversial: some researchers advocate partial and others total thyroidectomy; some advocate prophylactic central cervical lymph node dissection, whereas others only rarely recommend lymphadenectomy. Although radioactive iodine is effective, its appropriate use and dosage remain controversial. In addition, molecular analysis of thyroid cancer is frequently used for diagnostic purposes involving preoperative fine-needle biopsy specimens as well as to define targetable pathways altered in the disease to guide clinical trials of drug therapy for advanced thyroid cancers.

Shifting patterns of genomic variation in the somatic evolution of papillary thyroid carcinoma.

BACKGROUND: Cancer is increasingly understood to arise in the context of dynamically evolving genomes with continuously generated variants subject to selective pressures. Diverse mutations have been identified in papillary thyroid carcinoma (PTC), but unifying theories underlying genomic change are lacking. Applying a framework of somatic evolution, we sought to broaden understanding of the PTC genome through identification of global trends that help explain risk of tumorigenesis. METHODS: Exome sequencing was performed on 53 PTC and matched adjacent non-tumor thyroid tissues (ANT). Single nucleotide substitution (SNS) signatures from each sample pair were divided into three subsets based on their presence in tumor, non-tumor thyroid, or both. Nine matched blood samples were sequenced and SNS signatures intersected with these three subsets. The intersected genomic signatures were used to define branch-points in the evolution of the tumor genome, distinguishing variants present in the tissues' common ancestor cells from those unique to each tissue type and therefore acquired after genomic divergence of the tumor, non-tumor, and blood samples. RESULTS: Single nucleotide substitutions shared by the tumor and the non-tumor thyroid were dominated by C-to-T transitions, whereas those unique to either tissue type were enriched for C-to-A transversions encoding non-synonymous, predicted-deleterious variants. On average, SNSs of matched blood samples were 81 % identical to those shared by tumor and non-tumor thyroid, but only 12.5 % identical to those unique to either tissue. Older age and BRAF mutation were associated with increased SNS burden. CONCLUSIONS: The current study demonstrates novel patterns of genomic change in PTC, supporting a theory of somatic evolution in which the zygote's germline genome undergoes continuous remodeling to produce progressively differentiated, tissue-specific signatures. Late somatic events in thyroid tissue demonstrate shifted mutational spectra compared to earlier polymorphisms. These late events are enriched for predicted-deleterious variants, suggesting a mechanism of genomic instability in PTC tumorigenesis.

Use of Dietary Vitamin Supplements and Risk of Thyroid Cancer: A Population-Based Case-Control Study in Connecticut.

Certain dietary supplements have been reported to increase the risk of some cancers. Over half of the US population regularly uses dietary supplements. Thyroid cancer incidence has increased over the past several decades. However, few studies have investigated the association between dietary supplements and thyroid cancer. Thus, it is essential to clarify any association between dietary supplements and risk of thyroid cancer. MATERIALS AND METHODS: A population-based case-control study in Connecticut was conducted during 2010-2011 among 462 histologically confi rmed incident thyroid cancer cases and 498 population-based controls. Dietary supplement intake was ascertained through in-person interviews and a food frequency questionnaire. Multivariate unconditional logistic regression models were used to estimate the risk of thyroid cancer and dietary supplement use. RESULTS: Overall, no statistically signifi cant associations were observed between dietary supplementation and thyroid cancer risk. Stratifi ed analyses revealed a suggestive protective effect on risk of papillary microcarcinoma among longterm (> 10 years) use of multivitamins (OR = 0.59, 95 % CI: 0.33, 1.04) and calcium supplementation (OR = 0.45, 95 % CI: 0.22, 0.93). An increased risk of large papillary thyroid cancers (tumor size > 1 cm) was observed among short-term (< 5 years) users of calcium supplements (OR = 2.24, 95 % CI: 1.30, 3.88). DISCUSSION: No signifi cant associations were observed between supplementation and overall thyroid cancer risk. The different associations between calcium supplements and risk of papillary thyroid cancer by tumor size warrant further investigation.

Surgery for primary hyperparathyroidism.

In the Western world, primary hyperparathyroidism is now a relatively common disorder that is diagnosed in 0.7% of the general population and in 2% of postmenopausal women. Although patients today typically present with less severe manifestations of disease, the evaluation and management of patients with parathyroid disease remains challenging. Primary hyperparathyroidism is a complex disease process that requires careful diagnosis and thoughtful medical and surgical management. The surgical management of patients with persistent or recurrent disease, inherited primary hyperparathyroidism syndromes, and parathyroid carcinoma is particularly challenging. High-quality imaging and reliable intraoperative adjuncts are critical to success.

Cure predictability during parathyroidectomy.

BACKGROUND: A mathematical model for primary hyperparathyroidism (1°HPTH) was developed and embedded in software to yield intraoperative predictability curves. METHODS: A total of 1,754 consecutive 1°HPTH operative cases were screened to select 617 [554 single adenoma (SA), 63 multigland] patients with complete preoperative, intraoperative (pre-exploration, time 0, every 5 min post-resection), and postoperative parathyroid hormone (PTH) and calcium data. Data transformations and models were hypothesized and tested, including inverse functions, differences, half-lives, differences from projected half-lives, second-order kinetics, second-order derivatives, and time-dependent ratios. Sub-models of ratios were developed for time-dependent and initial-value combinations. For each time segment the log odds were modeled using multiple logistic stepwise regression. An idealized model was selected, embedded in software, and installed in a laptop computer to enable intraoperative decision analyses, PTH curve plotting, and storage and transmission of data. A subsequent cohort of 100 consecutive unselected patients [81 SAs, 19 multigland (13 hyperplasia, 2 MEN1, 1 lithium, 3 double adenomas)] inclusive of seven remedial cervical explorations were tested. RESULTS: The model predicted an overall curative resection in 95 % of patients. In SA patients, cure was predicted in 78/81 patients with a mean probability of 99.3 % at 11.8 ± 10.4 min post-resection. In three cured patients, the software failed to suggest cure, because of a low baseline PTH or delayed clearance. The model also correctly predicted residual hyperfunctioning tissue in all tested multigland patients. All multigland patients underwent additional exploration with resection of residual disease resulting in a mean predicted cure rate of 97.9 % at 10.6 ± 7.3 min post-resection completion in 17 patients. In two patients, the software predicted a mean cure rate of 22 % due to either a low PTH baseline or delayed clearance. Overall, the software accurately predicted cure in 95 of 100 cured cases. CONCLUSIONS: This intraoperative prediction software expedites termination of surgery with a high level of curative confidence. Alternatively, the model accurately predicts residual disease prompting additional exploration. Because the model is based on a large set of multivariate regression curves, PTH values obtained at any post-resection sampling interval generate prediction data with far greater accuracy than existing algorithms. The software is designed for convenient operative use and can print, store, and electronically transmit probability analyses and PTH curves in real-time.

Modified Bethesda criteria for thyroid aspirates significantly decrease nondiagnostic rates without decreasing sensitivity.

INTRODUCTION: Previous studies suggest that the adequacy rate of thyroid aspirates can be improved by altering the adequacy criteria of the Bethesda System. We sought to measure the performance of these altered criteria in a prospective fashion. MATERIALS AND METHODS: Over a 6-year period, cases with 1 to 59 follicular cells were prospectively classified as "nondiagnostic, favor benign" or "scant but adequate". "Scant but adequate" cases were classified as either benign (Bethesda category 2) or atypia of undetermined significance (AUS) (Bethesda category 3). Bethesda category 3 cases were referred for Afirma testing (Veracyte, San Francisco, CA). RESULTS: Of 5147 cases, 131 (3%) were classified as "nondiagnostic, favor benign"; 45 (65%) of these had follow-up with a risk of malignancy of 2.6%. Additionally, 436 (8%) of all 5147 cases were classified as "scant but adequate" and "benign"; 49 (11%) of these had follow-up with a risk of malignancy of 0%. Lastly, 197 (4%) of all 5147 cases were classified as "scant but adequate" with AUS; 177 (90%) of these 197 cases had an adequate Afirma result. The "suspicious" rate was not significantly different than that of cases classified as "adequate" and AUS (Bethesda category 3 and 4) (35 of 197 [18%] versus 140 of 848 [17%] P = 0.67), and there was no significant difference in the risk of malignancy for these 2 categories ("scant but adequate" 9 of 18, "adequate" 50% versus 27 of 85, 32%, P = 0.10). Overall, the modified Bethesda criteria reduced the nondiagnostic rate from 22% to 10% (P <0.001) without lowering the sensitivity of the test. CONCLUSIONS: Modified Bethesda adequacy criteria can significantly lower nondiagnostic rates without lowering sensitivity.

Laryngeal physiology and voice acoustics are maintained after minimally invasive parathyroidectomy.

OBJECTIVES: This prospective single-arm study investigated both laryngeal physiology and voice acoustic measures in patients undergoing minimally invasive parathyroidectomy (MIP) due to primary hyperparathyroidism (primary HPTH). BACKGROUND: Avoidance of recurrent or superior laryngeal nerve injury and maintenance of normal laryngeal physiology and vocal function are key goals in the treatment of primary HPTH. No data are available comparing pre- and postoperative MIP laryngeal physiology and voice acoustics. METHODS: Patients served as their own controls and underwent identical pre- and postoperative assessment. True vocal fold mobility was assessed and recorded using transnasal fiber-optic laryngoscopy. Vocal capacity was recorded with maximum phonation time and vocal stability by frequency-based voice measures, that is, mean fundamental frequency (F0), standard deviation of the fundamental frequency (F0SD), and jitter and shimmer as measured by relative average perturbation and mean shimmer in decibels, respectively. RESULTS: A total of 104 patients were enrolled [26 men, mean age = 53 years, range 29-79 years; 78 women, mean age = 56 years, range 16-83 years). All completed the protocol and were analyzed according to intent to treat. MIP was accomplished in 95 patients, and 9 were converted to general anesthesia. The cure rate was 100%, as evidenced by normalization of serum calcium levels. Both real-time agreement and blinded inter- and intrarater reliability testing for laryngeal physiology ratings were 100%. One patient (<1%) exhibited a recurrent laryngeal nerve injury. No significant differences (P > 0.05) were found for any voice acoustic parameter between pre- and postoperative MIP (ie, maximum phonation time, F0, F0SD, relative average perturbation, or shimmer in decibels). CONCLUSIONS: MIP can be performed with exquisite disease control and without significant effects on laryngeal physiology or voice acoustic measures. For the first time, both physiologic and acoustic data support the use of MIP.

BRAFV600E mutation in papillary thyroid microcarcinoma: a genotype-phenotype correlation.

BRAF(V600E) mutation has emerged as a marker of aggressive behavior in papillary thyroid carcinoma but its significance in microcarcinoma is not entirely clear. One-hundred and twenty-nine papillary thyroid microcarcinomas were tested for BRAF(V600E) mutation by single-strand conformation polymorphism, and their clinicopathologic features (age, sex, tumor size, multifocality, nodal metastases, histologic subtype, tumor cell morphology, architecture, tumor-associated stromal reaction, tumor interface to non-neoplastic thyroid (well circumscribed vs infiltrative), extrathyroidal extension, lymphovascular invasion, intratumoral multinucleated giant cells, and adjacent non-neoplastic thyroid pathology) were examined. Compared with tumors without the mutation (39/129, 30%), the mutated microcarcinomas (90/129, 70%) showed significantly higher prevalence of infiltrative tumor borders (78/90 vs 23/39, P=0.001), tumor-associated stromal desmoplasia/fibrosis and/or sclerosis (80/90 vs 25/39, P=0.002), classic nuclear features of papillary thyroid carcinoma (90/90 vs 35/39, P=0.008) and cystic change (43/90 vs 11/39, P=0.05). BRAF(V600E) mutation was more frequent in classic (75%), tall cell (91%), and other variants (>70%) than in follicular variant (21%) of papillary thyroid microcarcinoma. Tumors without the mutation were significantly more likely to be solid, well circumscribed, and lacked desmoplasia/fibrosis or sclerosis. However, on multivariate analysis, only the follicular variant of papillary microcarcinoma was significantly associated with the absence of mutation (odds ratio (95% confidence interval): 0.09 (0.01-0.54)). Lymph node metastases (n=24) were more frequent in microcarcinomas with mutation than without (21/24 vs 3/24, P=0.02). All patients with lateral cervical node metastasis (n=9), and all but one tumor with extrathyroidal extension (n=17/18) showed BRAF(V600E) mutation. No significant differences were noted in age, sex, tumor size, multifocality, lymphovascular invasion, psammoma bodies, stromal calcification, intratumoral multinucleated osteoclastic-type giant cells, and lymphocytic infiltration between the two groups of tumors. BRAF(V600E) mutation is an early event in thyroid carcinogenesis, and is associated with distinctive morphology and aggressive features even in papillary thyroid microcarcinomas.

Surgery in primary hyperparathyroidism: extensive personal experience.

Parathyroidectomy is the optimal treatment for primary hyperparathyroidism (PHPT) and provides a cure in the vast majority of cases. Over the last 2 decades, improvements in preoperative localization and the development of intraoperative parathyroid hormone monitoring have opened the door for new surgical approaches to parathyroidectomy. Minimally invasive parathyroidectomy is performed under regional or local anesthesia. It requires less surgical dissection resulting in decreased trauma to tissues and is more effective and less costly than traditional bilateral cervical exploration. This article reviews our approach reflecting advances in preoperative localization, anesthetic techniques, and intraoperative management of patients undergoing parathyroidectomy for the treatment of PHPT.

Surgical approach and outcomes in patients with lithium-associated hyperparathyroidism.

BACKGROUND: Patients receiving lithium therapy are at elevated risk of developing hyperparathyroidism. In lithium-associated hyperparathyroidism (LAH), the incidence of multiglandular disease (MGD) is unclear, and the need for routine bilateral cervical exploration remains controversial. Therefore, in LAH patients, surgical approaches, pathologic findings, cure rates, and factors associated with persistent or recurrent disease were investigated. METHODS: Retrospective analysis of 27 patients with LAH undergoing parathyroidectomy with the intraoperative parathyroid hormone (PTH) assay. RESULTS: The median postoperative follow-up was 7 months; 17 patients had >6 months follow-up. Cervical exploration was unilateral in 9, bilateral in 18 (3 were converted from unilateral). Sixteen patients (62%) had MGD, 12 with four-gland hyperplasia and 4 with double adenomas. Ten patients (38%) had a single adenoma. Twenty-five (93%) of 27 patients had initially successful surgery. Of the 17 patients with >6 months follow-up, two had persistent disease and two experienced recurrent disease. All patients with a single adenoma remain free of disease. Three (75%) of four patients with persistent/recurrent disease had MGD and were receiving lithium at the time of surgery. Patients with persistent/recurrent disease were older (p = 0.01) and had experienced a longer duration of hypercalcemia (p = 0.04). CONCLUSIONS: LAH patients have a high incidence of MGD, and bilateral exploration is frequently necessary. With access to the intraoperative PTH assay, it is reasonable to initiate a unilateral approach because many patients will harbor single adenomas and can be reliably rendered normocalcemic. Patients with MGD remain at higher risk of persistent/recurrent disease.

Papillary thyroid carcinomas with and without BRAF V600E mutations are morphologically distinct.

AIMS: The BRAF V600E mutation resulting in the production of an abnormal BRAF protein has emerged as the most frequent genetic alteration in papillary thyroid carcinomas (PTCs). This study was aimed at identifying distinctive features in tumours with and without the mutation. METHODS AND RESULTS: Thirty-four mutation-positive and 22 mutation-negative tumours were identified by single-strand conformation polymorphism of the amplified BRAF V600E region in the tumour DNA. Mutation-positive tumours were more common in patients older than 45 years (24/33, P = 0.05), in classic (23/30, P = 0.01), tall cell (4/5) and oncocytic/Warthin-like (2/2) variants of PTC, and in subcapsular sclerosing microcarcinomas (4/4). In contrast, all 12 follicular variants (P < 0.0001) and two diffuse sclerosing variants were negative for the mutation. Mutation-positive tumours displayed infiltrative growth (32/34, P = 0.02), stromal fibrosis (33/34, P < 0.001), psammoma bodies (17/34, P = 0.05), plump eosinophilic tumour cells (22/34, P = 0.01), and classic fully developed nuclear features of PTC (33/34, P = 0.0001). Encapsulation was significantly associated with mutation-negative tumours (15/22, P = 0.02). CONCLUSIONS: BRAF V600E mutation-positive and negative PTCs are morphologically different. Recognition of their morphology may help in the selection of appropriate tumours for genetic testing.

Spontaneous adrenal hemorrhage with associated masses: etiology and management in 6 cases and a review of 133 reported cases.

BACKGROUND: Spontaneous adrenal hemorrhage associated with a mass is uncommon and treatment strategies are not standardized. Current treatment modalities range from supportive management and blood transfusion to embolization or immediate operative extirpation. Our objectives were to describe six cases from a single institution and to perform a literature review of the etiology of the condition and recommended management of patients with hemorrhagic adrenal masses. METHODS: Records from six patients diagnosed with adrenal hemorrhage and an associated mass at a single institution were reviewed. Clinical records and outcomes were analyzed. A comprehensive review of 133 reported cases in the literature was performed. RESULTS: Six patients presented with spontaneous adrenal hemorrhage that appeared to be associated with a mass, with tumor sizes ranging from 3.7 to 15 cm. Three patients underwent adrenalectomy for pheochromocytoma or adrenocortical cancer. Three patients did not undergo adrenalectomy: one had a metastasis from lung cancer, one underwent embolization, and one had resolution of the mass on interval imaging. A comprehensive review of the literature identified 133 cases, with pheochromocytoma the most commonly reported lesion (48%). CONCLUSIONS: Spontaneous adrenal hemorrhage is rare. When it does occur, a high level of suspicion for malignant disease or pheochromocytoma should be maintained. The possibility of a hematoma masquerading as a neoplasm should also be considered. In cases of ongoing hemorrhage, embolization may be a lifesaving temporizing measure. Acute surgical intervention should be considered in selected patients, and surgery may not be required in all patients. A cautious approach with a comprehensive biochemical and imaging work-up is advised prior to operation.

Parathyroid four-dimensional computed tomography: evaluation of radiation dose exposure during preoperative localization of parathyroid tumors in primary hyperparathyroidism.

BACKGROUND: Parathyroid four-dimensional computed tomography (4DCT) provides greater sensitivity than sestamibi with single photon emission CT (SPECT, or SeS) for preoperative localization of parathyroid tumors in patients with primary hyperparathyroidism (PHPT). The radiation dose imparted to the patient during preoperative parathyroid imaging, however, has not been analyzed. METHODS: Patients with biochemically unequivocal PHPT referred for minimally invasive parathyroidectomy underwent 4DCT or SeS. 4DCT was performed using a 64 detector row CT scanner, and SeS used a standardized protocol of 20 mCi of technetium-99m followed by planar and SPECT imaging. The CT radiation dose was estimated using the Imaging Performance Assessment of CT Scanners (ImPACT) calculator, and the SeS dose was estimated using the US Nuclear Regulatory Commission Regulation (NUREG) method. RESULTS: The calculated effective doses of 4DCT and SeS were 10.4 and 7.8 mSv, respectively, in contrast to an estimated annual background radiation exposure of approximately 3 mSv. The dose to the thyroid with 4DCT, however, was about 57 times higher (92.0 vs. 1.6 mGy) than that with SeS. Based on age- and sex-dependent risk factors, the calculated risk of 4DCT-related thyroid cancer developing in a 20 year old woman was 1,040/million (i.e., about 0.1%). CONCLUSIONS: 4DCT, a superior preoperative imaging modality for locating parathyroid tumors, imparts a significantly higher thyroid radiation dose than SeS. Given the enhanced risk of thyroid cancer in individuals with radiation exposure at a young age, 4DCT should be used judiciously in young PHPT patients.