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Implementation of highly sophisticated technologies, such as next-generation sequencing (NGS), into routine clinical practice requires compatibility with common tumor biopsy types, such as formalin-fixed, paraffin-embedded (FFPE) and fine-needle aspiration specimens, and validation metrics for platforms, controls, and data analysis pipelines. In this study, a two-step PCR enrichment workflow was used to assess 540 known cancer-relevant variants in 16 oncogenes for high-depth sequencing in tumor samples on either mature (Illumina GAIIx) or emerging (Ion Torrent PGM) NGS platforms. The results revealed that the background noise of variant detection was elevated approximately twofold in FFPE compared with cell line DNA. Bioinformatic algorithms were optimized to accommodate this background. Variant calls from 38 residual clinical colorectal cancer FFPE specimens and 10 thyroid fine-needle aspiration specimens were compared across multiple cancer genes, resulting in an accuracy of 96.1% (95% CI, 96.1% to 99.3%) compared with Sanger sequencing, and 99.6% (95% CI, 97.9% to 99.9%) compared with an alternative method with an analytical sensitivity of 1% mutation detection. A total of 45 of 48 samples were concordant between NGS platforms across all matched regions, with the three discordant calls each represented at10% of reads. Consequently, NGS of targeted oncogenes in real-life tumor specimens using distinct platforms addresses unmet needs for unbiased and highly sensitive mutation detection and can accelerate both basic and clinical cancer research.

Traditional block clerkship (BC) structures may not optimally support medical student participation in the workplace, whereas longitudinal integrated clerkship (LIC) structures seem more conducive to students' active engagement in patient care over time. Understanding the ways in which these two clerkship models influence students' roles and responsibilities can inform clinical learning programme design.This was a multicentre qualitative study. We conducted semi-structured interviews with LIC and BC medical students at three institutions early and late in the core clinical year to explore their experiences with patients and the roles they served. Using the framework of 'workplace affordances', qualitative coding focused on students' roles and qualities of the learning environment that invited or inhibited student participation. We compared transcripts of early- and late-year interviews to assess students' changing roles and conducted discrepant case analysis to ensure that coding fit the data.Fifty-four students participated in interviews. They described serving three major roles in clinical care that respectively involved: providing support to patients; sharing information about patients across health care settings, and functioning in a doctor-like role. Both LIC and BC students served in the providing support and transmitting information roles both early and late in the year. By contrast, LIC students commonly served in the doctor-like role in managing their patients' care, particularly late in the year, whereas BC students rarely served in this role. Continuity in settings and in supervisors, and preceptors' endorsement of students' legitimate role afforded opportunities for students to participate actively in patient care.Although both LIC and BC students reported serving in important roles in supporting their patients and sharing information about their care, only LIC students consistently described opportunities to grow into a doctor role with patients. The high level of integration of LIC students into care systems and their deeper relationships with preceptors and patients enhanced their motivation and feelings of competence to provide patient-centred care.

Longitudinal integrated clerkships (LICs) are established, rapidly growing models of education designed to improve the core clinical year of medical school using guiding principles about workplace learning and continuity. This study is the first to report data from direct observations of workplace learning experiences of students on LICs and traditional block clerkships (BCs), respectively.This multi-institution study used an observational, work-sampling methodology to compare LIC and BC students early and late in the core clinical year. Trained research assistants documented students' activities, participation (observing, with assistance, alone), and interactions every 10 minutes over 4-hour periods. Each student was observed one to three times early and/or late in the year. Data were aggregated at the student level and by in-patient or out-patient setting for BC students. One-way analysis of variance (anova) was used to compare two groups early in the year (LIC and BC students) and three groups late in the year (LIC, out-patient BC and in-patient BC students).Early-year observations included 26 students (16 LIC and 10 BC students); late-year observations included 44 students (28 LIC, eight out-patient BC and eight in-patient BC students). Out-patient activities and interactions of LIC and BC students were similar early in the year, but in the later period LIC students spent significantly more time performing direct patient care activities alone (25%) compared with out-patient (12%) and in-patient (7%) BC students. Students on LICs were significantly more likely to experience continuity with patients as 34% of their patients returned to them, whereas only 5% of patients did so for out-patient BC students late in the year.By late year, LIC students engage in patient care more independently and have more opportunities to see clinic patients on multiple occasions than BC students. Consistent with the principles of workplace learning, these findings suggest that yearlong longitudinal integrated education models, that rely mostly on ambulatory settings, afford students greater opportunities to participate more fully in the provision of patient care.

In this issue of the Journal, Schlumberger et al.1 and Mallick et al.2 describe the administration of radioiodine (iodine-131) after total thyroidectomy in patients with low-risk thyroid cancer. Postsurgical treatment has long played an important role in the management of this increasingly common cancer.2 In the United States, the incidence nearly tripled (from 2.7 to 7.7 cases per 100,000) from 1973 through 2002.3 Similar increases have been reported in Europe.4 Such increases appear to result largely from more frequent radiologic detection and subsequent fine-needle aspiration of small thyroid nodules, leading to the diagnosis of low-risk thyroid cancer. Guidelines of the . . .

PURPOSE OF REVIEW Thyroid disease is common during pregnancy. There are multiple alterations in maternal thyroid physiology, leading to an increased demand for thyroid hormone during gestation, that have significant implications for both maternal and fetal health. Importantly, pregnant reference ranges must be used for appropriate diagnosis and treatment of maternal hypothyroidism. There is currently broad interest in the maternal and fetal complications of hypothyroidism during pregnancy, with significant debate regarding the nuances of screening, despite universal agreement regarding the need for treatment. RECENT FINDINGS Current literature has provided new evidence demonstrating maternal and fetal complications of hypothyroidism during pregnancy. There is evidence for improved outcomes with appropriate treatment of maternal hypothyroidism. SUMMARY Although universal screening for hypothyroidism in pregnancy is currently controversial, it is increasingly apparent that maternal hypothyroidism can significantly affect both maternal and fetal health outcomes. Because of the ease and low risk of treatment, current recommendations emphasize appropriate case recognition and treatment to minimize the risk of unnecessary complications.

Hypothyroidism occurs in 3% to 7% of women of child-bearing age. Maternal hypothyroidism may be harmful to the developing fetus during the first half of pregnancy. Previous studies have shown that there is increasing T4 demand during pregnancy and a 20% to 40% increase in maternal LT4 production is required to maintain a euthyroid state and prevent maternal hypothyroidism. It is unclear how LT4 should be adjusted in newly pregnant woman at risk and how frequently thyroid function should be evaluated during gestation. The primary aim of this prospective randomized trial was to investigate whether administration of LT4 would prevent early gestational hypothyroidism and replicate the normal physiologic patterns found in pregnant euthyroid women. The safety of LT4 was also investigated. A total of 60 newly pregnant women with treated hypothyroidism were randomized to increase LT4 by either 2 additional tablets per week (29% increase; group A) or 3 additional tablets per week (43% increase; group B). After increased LT4 supplementation was initiated, follow-up serum testing was performed to assess thyroid function every 2 weeks until mid-pregnancy and at 30 weeks. The LT4 dosage was adjusted every 4 weeks (through week 30) per the protocol to maintain goal thyroid-stimulating hormone (TSH) concentrations. A total of 48 women successfully completed the protocol. The data showed that increasing the LT4 dose in newly pregnant women normalized serum TSH below 5.0 mIU/L in all women for the remainder of the first trimester and replicated the physiological changes of a normal pregnancy. The early LT4 augmentation in pregnancy resulted in TSH suppression less than 0.5 mIU/L in 32% (8/25) of the women in group A, compared with 65% (15/23) of women in group B (P < 0.01). This risk of TSH suppression was significantly increased in women receiving prepregnancy LT4 doses ≥100 mg/d (odds ratio [OR], 7.2; 95% confidence interval [CI], 1.7-30.6), those with prepregnancy TSH < 1.5 mIU/L (OR, 4.6; 95% CI, 1.3-16.2), and in athyreotic women (OR, 3.3; 95% CI, 1.1-11.1). With use of a trimester-specific TSH lower reference range of 0.1 mIU/L, dosage reduction was required in only 8% (2/25) of patients in group A. An every 4 weeks testing protocol would have detected 92% (24/26) of abnormal TSH values. These findings demonstrate that the risk of maternal hypothyroidism during the first trimester is reduced by a 2-tablet increase in LT4 initiated once pregnancy is confirmed. This protocol appears to be safe and mimics normal thyroid gestational physiology. Following LT4 adjustment, monitoring thyroid function every 4 weeks through midgestation and at 30 weeks will detect more than 90% of abnormal values.

The third year of medical school, in which students traditionally receive their first immersion into hospital-based clinical medicine, often results in a degradation of attitudes toward medicine and patient care. The authors present data collected in the 2005-2006 academic year from a pilot program aimed at enhancing this experience, thereby enabling students to resist these negative influences.Thirty-two Harvard Medical School students, who spent their entire principal clinical experience (PCE) at one of three clinical sites (PCE group), completed the Patient-Practitioner Orientation Scale (PPOS), a measure of patient-centered attitudes, at the beginning of the year. They completed the PPOS again at year's end as well as the Community, Curriculum, and Culture (C3) hidden curriculum measure of patient-centered clinical experiences. Their responses on these measures were compared with those of a traditional-rotation control group that moved from site to site.At the beginning of the year, no PPOS differences were found within PCE groups or between PCE and control students. Traditional students' attitudes became significantly less patient-centered at year's end, whereas PCE students' attitudes did not change. PCE students reported more support for their patient-centered behaviors, and, across all students, C3 scores and changes in PPOS scores were significantly correlated.Innovations in clinical education may help inoculate medical students against the degradation of attitudes. Although this research was a test of a small pilot program, the consistent pattern of findings across those clinical sites and educational models studied provides suggestive evidence that the oft-cited negative impacts of the principal clinical year are not inevitable.

Background: Fine-needle aspiration remains the primary diagnostic intervention for the evaluation of most thyroid nodules larger than 1–1.5 cm. Although most aspirates provide diagnostic cytology, approximately 15–25% will be classified indeterminate (often referred to as follicular neoplasm, suspicious for carcinoma, or atypical). In such cases, abnormal cellular findings preclude interpretation of benignity, although only a minority will prove cancerous upon final histopathology. Nonetheless, patients with indeterminate aspirates are commonly referred for consideration of hemi- or near-total thyroidectomy. Recently, improved understanding and novel investigation of clinical, radiological, cytological, and molecular factors has allowed improved stratification of cancer risk. Conclusion: Although surgery continues to be commonly recommended, strategies for such patients should increasingly seek to define treatment based on the estimation of an individual’s thyroid cancer risk in comparison with associated operative risk and morbidity. In doing so, the rate of unnecessary surgical procedures and associated complications can be reduced.

The National Cancer Institute (NCI) sponsored the NCI Thyroid Fine-Needle Aspiration (FNA) State of the Science Conference on October 22-23, 2007 in Bethesda, MD. The 2-day meeting was accompanied by a permanent informational website and several on-line discussions between May 1 and December 15, 2007 (http://thyroidfna.cancer.gov). This document summarizes the indications for performing an FNA of a nodule discovered by physical examination or an imaging study; the indications for using ultrasound versus palpation for guidance when performing a thyroid FNA; the issues surrounding informed consent for thyroid FNA; and the information required on a requisition form that accompanies a thyroid FNA specimen. (http://thyroidfna.cancer.gov/pages/info/agenda/)

BACKGROUND. The diagnostic evaluation of patients with thyroid nodules is imprecise. Despite the benefits of fine-needle aspiration (FNA), most patients who are referred for surgery because of abnormal cytology prove to have benign disease. Recent technologic and procedural advances suggest that this shortcoming can be mitigated, although few data confirm this benefit in unselected patients. METHODS. A total of 2587 sequential patients were evaluated by thyroid ultrasound and were offered ultrasound-guided FNA (UG-FNA) of all thyroid nodules that measured � 1 cm during a 10-year period. Results of aspiration cytology were correlated with histologic findings. The prevalence of thyroid cancer in all patients and in those who underwent surgery was determined. Surgical risk was calculated. RESULTS. Tumors that measured � 1 cm were present in 14% of patients: Fortythree percent of patients had tumors that measured \2 cm in greatest dimension, and 93% had American Joint Committee on Cancer stage I or II disease. The cytologic diagnoses ‘positive for malignancy’ and ‘no malignant cells’ were 97% predictive and 99.7% predictive, respectively. Repeat FNA of initial insufficient aspirates, as well as more detailed classification of inconclusive aspirates, improved preoperative assessment of cancer risk and reduced surgical intervention. Fifty-six percent of patients who were referred for surgery because of abnormal cytology had cancer compared with from 10% to 45% of patients historically. An analysis of operative complications from a subset of 296 patients demonstrated a 1% risk of permanent surgical complications. CONCLUSIONS. The current findings demonstrated the benefits of UG-FNA and of a more detailed classification of inconclusive aspirates in the preoperative risk assessment of thyroid nodules, supporting adherence to recently published guidelines. Cancer (Cancer Cytopathol) 2007;111:508–16. a 2007 American Cancer Society.

This interactive feature presents the case of a 24-year-old man with abnormal and agitated behavior. Test your diagnostic and therapeutic skills at NEJM.org.

Background Hyperthyroidism caused by Graves’ disease is common in women, yet little is known about risk factors for the disease. We sought to determine whether lifestyle factors, including smoking, alcohol consumption, physical activity level, and body mass index, are risk factors for Graves’ hyperthyroidism. Methods This analysis was conducted using data from the Nurses’ Health Study II, among 115109 women aged 25 to 42 at entry. Incident reports of women with Graves’ hyperthyroidism, confirmed to have the disorder, were included. Results During 1 328 270 person-years of follow-up, incident diagnoses of Graves’ hyperthyroidism were confirmed in 543 women; the 12-year incidence was 4.6 per 1000 women. Cigarette smoking was a predictor of Graves’ hyperthyroidism. The hazard ratio among current smokers was 1.93 (95% confidence interval [CI], 1.54-2.43), and among past smokers it was 1.27 (95% CI, 1.03-1.56), after adjusting for recent pregnancy, parity, and other variables. Among current smokers, the hazard ratio increased with the intensity of smoking and was 2.63 (95% CI, 1.71-4.04) among women who smoked 25 or more cigarettes daily. Obesity was associated with a decreased risk of Graves’ hyperthyroidism. The hazard ratio for the disorder among women with a body mass index of 30 kg/m 2 or higher was 0.68 (95% CI, 0.49-0.92). Alcohol intake and physical activity level were not associated with risk of Graves’ hyperthyroidism. Conclusions Smoking is a risk factor for Graves’ hyperthyroidism in women. Obesity may be associated with a reduced risk, although weight loss as the first manifestation of hyperthyroidism cannot be excluded.

Thyroid nodules are common; the vast majority benign. Preoperative determination of malignancy remains imprecise, despite fine-needle aspiration (FNA). Numerous risk factors have been proposed for predicting malignancy, though few have been found useful. Oxygen delivery is a crucial component for tumor cell growth. It has been hypothesized that malignant tumors may configure their shape to maximize access to local nutrient delivery. Mathematically, surface area to volume is maximized by a spherical shape. We sought to determine if spherical shape is a predictor of malignancy.Seven hundred forty-seven consecutive patients underwent ultrasound evaluation and FNA of 993 solid thyroid nodules (25% cystic) between 1995 and 2000 and were retrospectively analyzed. Nodules were classified as benign or malignant based on FNA and/or surgical pathology. Spherical shape was estimated by calculating a ratio of the longest to shortest dimensions, and rate of malignancy correlated.Spherical shape was independently correlated with risk of malignancy (p0.001). Thyroid cancer was detected in 11% of all nodules, but ranged from 18% in spherical nodules to 5% in those least spherical. Nodules found to have suspicious or intermediate cytology showed similar variation in malignant risk. A long to short axis ratio greater than 2.5 was 100% predictive of a benign process, although present in only 4% of our cohort. A prospective validation was performed and confirmed consistent results (p0.01).Spherical shape is associated with an increased rate of malignancy in solid thyroid nodules. Determination of shape may assist in clinical risk assessment of thyroid cancer.

Hypothyroidism during pregnancy has been associated with impaired cognitive development and increased fetal mortality. During pregnancy, maternal thyroid hormone requirements increase. Although it is known that women with hypothyroidism should increase their levothyroxine dose during pregnancy, biochemical hypothyroidism occurs in many. In this prospective study we attempted to identify precisely the timing and amount of levothyroxine adjustment required during pregnancy.Women with hypothyroidism who were planning pregnancy were observed prospectively before and throughout their pregnancies. Thyroid function, human chorionic gonadotropin, and estradiol were measured before conception, approximately every two weeks during the first trimester, and monthly thereafter. The dose of levothyroxine was increased to maintain the thyrotropin concentration at preconception values throughout pregnancy.Twenty pregnancies occurred in 19 women and resulted in 17 full-term births. An increase in the levothyroxine dose was necessary during 17 pregnancies. The mean levothyroxine requirement increased 47 percent during the first half of pregnancy (median onset of increase, eight weeks of gestation) and plateaued by week 16. This increased dose was required until delivery.Levothyroxine requirements increase as early as the fifth week of gestation. Given the importance of maternal euthyroidism for normal fetal cognitive development, we propose that women with hypothyroidism increase their levothyroxine dose by approximately 30 percent as soon as pregnancy is confirmed. Thereafter, serum thyrotropin levels should be monitored and the levothyroxine dose adjusted accordingly.

A series of 88 conventional follicular and Hurthle cell thyroid tumors were analyzed for RAS mutations and PAX8-PPAR gamma rearrangements using molecular methods and for galectin-3 and HBME-1 expression by immunohistochemistry. A novel LightCycler technology-based method was developed to detect point mutations in codons 12/13 and 61 of the H-RAS, K-RAS, and N-RAS genes. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPAR gamma rearrangement, and only one (3%) had both. In follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPAR gamma rearrangement, and 48% had neither. Follicular carcinomas with PAX8-PPAR gamma typically showed immunoreactivity for galectin-3 but not for HBME-1, tended to present at a younger patient age and be smaller size, and were almost always overtly invasive. In contrast, follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hurthle cell tumors infrequently had PAX8-PPAR gamma rearrangement or RAS mutations. These results suggest that conventional follicular thyroid carcinomas develop through at least two distinct and virtually nonoverlapping molecular pathways initiated by either RAS point mutation or PAX8-PPAR gamma rearrangement.

Investigations of cancer-specific gene rearrangements have increased our understanding of human neoplasia and led to the use of the rearrangements in pathological diagnosis of blood cell and connective tissue malignancies. Here, we have investigated 3p25 rearrangements of the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene in follicular epithelial tumors of the human thyroid gland. Eleven of 42 (26%) low-stage follicular carcinomas, 0 of 40 follicular adenomas, 1 of 30 Hurthle cell carcinomas, 1 of 90 papillary carcinomas, and 0 of 10 nodular goiters had 3p25 rearrangements by interphase fluorescence in situ hybridization. All 11 follicular carcinomas with 3p25 rearrangement exhibited strong, diffuse nuclear immunoreactivity for PPAR gamma, consistent with expression of PPAR gamma fusion protein. Twelve of 42 (29%) low-stage follicular carcinomas had 3p25 aneusomy without PPAR gamma rearrangement (P = 0.01), suggesting that PPAR gamma rearrangement and aneuploidy are independent early events in follicular cancer. Eleven of 12 follicular carcinomas with 3p25 aneusomy exhibited no PPAR gamma immunoreactivity, supporting the existence of two independent pathways. Follicular carcinoma patients with PPAR gamma rearrangement more frequently had vascular invasion (P = 0.01), areas of solid/nested tumor histology (P0.001), and previous non-thyroid cancers (P0.01) compared with follicular carcinoma patients without PPAR gamma rearrangement. Our experiments identify genetic subgroups of low-stage follicular thyroid cancer and provide evidence that follicular carcinomas with PPAR gamma rearrangement are a distinct biological entity. The findings support a model in which separate genetic alterations initiate distinct pathways of oncogenesis in thyroid carcinoma subtypes.

Thyroid nodules are common and most often benign. The natural history of benign thyroid nodules, however, is unclear.To determine the natural history of cytologically benign thyroid nodules using ultrasonography.Retrospective case series.Single tertiary care clinic.All patients referred to the Brigham and Women's Hospital Thyroid Nodule Clinic, Boston, Massachusetts, who had benign cytologic results on ultrasonography-guided fine-needle aspiration of a thyroid nodule between 1995 and 2000 and returned for a requested follow-up examination 1 month to 5 years later.Nodule dimensions were measured at both visits, and growth was defined as an increase in calculated volume of 15% or greater. These results were correlated with the time between examinations, age, sex, baseline serum thyroid-stimulating hormone concentration, and cystic content of each nodule.Nodule volume increased over time (P0.001). The estimated proportion of nodules with an increase in volume of 15% or greater after 5 years was 89%. Nodules with greater cystic content were less likely to grow than solid nodules (P = 0.01). Seventy-four of the 330 nodules were reaspirated on the second visit. Despite an average increase in volume of 69%, only 1 of 74 reaspirated nodules was malignant.Most solid, benign thyroid nodules grow. Therefore, an increase in nodule volume alone is not a reliable predictor of malignancy.

Necrolytic migratory erythema (NME), the characteristic rash associated with the glucagonoma syndrome, is a cause of substantial morbidity among patients with this rare malignancy. Treatment options are suboptimal, and often useful for only short or moderate durations. We report the effective, long-term (1 year) use of intermittent infusions of amino acids (AA) and fatty acids (FA) administered via peripheral intravenous access for the treatment of NME in the glucagonoma syndrome. Despite resolution of the NME, serum amino acid (initially subnormal) and fatty acid (initially normal) levels remained unchanged. Tumour growth and other symptoms related to the glucagonoma syndrome appear unaffected by such infusions.

Thyroid nodules are common. Evaluation of patients with thyroid nodules typically includes fine needle aspiration biopsy (FNA), an approach that has proven to be accurate for the detection of thyroid cancer. Although the majority of biopsies are adequate for a cytological diagnosis, up to 20% will be insufficient or nondiagnostic. Current opinion suggests that such aspirates should be repeated, although no systematic study has investigated the usefulness of this approach, especially when ultrasound guidance is used to direct the initial FNA. We sought to define the predictors and optimal follow-up strategy for initial nondiagnostic ultrasound-guided FNAs of thyroid nodules. Data were collected for all patients at the Brigham and Women’s Hospital Thyroid Nodule Clinic between 1995–2000 who underwent ultrasound-guided FNA of a thyroid nodule. All patients with nondiagnostic cytology were advised to return for a repeat ultrasound-guided FNA. Patient age, gender, nodule size, cystic content, solitary vs. multinodular thyroid, and nodule location were documented and evaluated as possible predictors of a nondiagnostic biopsy in a multivariable model. The rate of diagnostic cytology obtained on repeat ultrasound-guided FNA was calculated. A total of 1128 patients with 1458 nodules were biopsied over a 6-yr period. A total of 1269 aspirations (950 patients) were diagnostic, and 189 (178 patients) were nondiagnostic. The cystic content of each nodule was the only significant independent predictor of nondiagnostic cytology (P < 0.001). The fraction of specimens with initial nondiagnostic cytology increased with greater cystic content (P < 0.001 for trend). A diagnostic ultrasound-guided FNA was obtained on the first repeat biopsy in 63% of nodules and was inversely related to increasing cystic content of each nodule (P = 0.03). One hundred and nineteen patients with 127 nodules returned for follow-up as advised, and malignancy was documented in 5%. Despite ultrasound-guided FNA, there remains a significant risk of initial nondiagnostic cytology, largely predicted by the cystic content of each nodule. Repeat aspiration is often successful and should be the standard approach to such nodules, given their risk of malignancy.

Uncertainty exists about the best approach to manage levothyroxine dosage in women with hypothyroidism, once they become pregnant. The etiology of an individual's hypothyroidism might be a key determinant of the optimal time and duration of dose adjustments, say the authors of a retrospective review published in the journal Thyroid.

This Practice Point commentary discusses the findings and limitations of a retrospective analysis by Mihailescu and Schneider, in which the authors investigated the prevalence of thyroid nodular disease and thyroid cancer in a cohort of patients exposed to ionizing radiation during childhood. Thyroid nodular disease and thyroid cancer were both prevalent in this population. Contrary to previous hypotheses, however, multinodularity was not associated with a decreased risk of malignancy, as thyroid cancer was diagnosed in 30.7% of patients with two or more thyroid nodules, each larger than 1cm. In this commentary, I highlight strategies that are critical to effective patient care. When present, multiple thyroid nodules larger than 1cm must be evaluated by fine-needle aspiration cytology in order to reliably exclude thyroid cancer. Although retrospective in design, this investigation provides insight into the natural history of thyroid disease in a unique patient cohort.

The care of a patient with a thyroid nodule has become increasingly complex. Although early detection and interventionare sought formosthumanmalignant tumors, thesemandateshaveproved less certain for thyroidcancerbecausemany affectedpatients (evenwhen untreated) do not die of their disease. Thus, physicians increasingly seek noninvasive means by which to identify patients who can avoid unnecessary diagnostic or therapeutic intervention. During the last 2 decades, sonographic imaging of the thyroid has become the most valued tool. The investigation published in this week’s JAMA Internal Medicine by Smith-Bindman and colleagues1 lends further support. The authors performed a large-scale analysis of all thyroid ultrasongraphic examinations performed at a single institution during a 5-year period. Radiologic findings were linkedwith the California Cancer Registry, allowingmaskedassessmentof sonographic features that conveybenignormalignantdisease.This investigationconfirmsthe importance of analyzing parenchymal tissue (solid or cystic), measuring nodule size, and identifying sonographic features, suchasmicrocalcifications, irregularmargins,andincreasedvascular flow. These results are important because the large-scale andmasked analysis by Smith-Bindman et al validates results from less stringently performed, retrospective analyses. However, thedataabout suspiciousnodule characteristicswerederived from a total of only 96malignant tumors. Accurate interpretation and effective translation of these findings intoclinicalpractice is critical.Currently, expertguidelines generally recommend diagnostic fine-needle aspiration (FNA)only for thyroidnodules larger than1.0 to 1.5 cminmaximaldiameter.2 This is becausedata confirm the indolent, nonharmfulnatureofmost thyroidmicrocarcinomas smaller than 1 cm in diameter.3 Furthermore, FNA cytologic diagnoses are nonspecific, often conveying indeterminate results in which cytologic abnormalities raise concern for malignancy, althoughmost areultimately found tobebenign.4 In suchcases, the risk of cancermust also be balanced against the risk of unnecessary surgical intervention. In the current study, the retrospective, case-control design mandates readers carefully compare cohort characteristics anddiagnosticprocesses toexpected standards. In doing so, some features of this investigation are notable. For example, it has been well established that the prevalence of thyroid cancer in a population of consecutively evaluated nodules approximates 8% to 15%.5 The current study, however, analyzed a cohort in which cancer prevalencewasonly1.6%,whereas29%to48%ofnoduleswere smaller than 1 cm. In addition, the number of nodules in the thyroid increased with age in patients with cancer but not amongcontrols.These facts suggest anonrepresentative study population and an increased potential for sampling bias. It alsoappearsunlikely thatall euthyroidpatientswith thyroidnoduleswereevaluatedwithultrasonography-guidedFNA. Because this would be necessary to fully understand the tissuecharacteristics (benignormalignant)ofeachnodule, theauthor’s assumption that all patients not listed in the cancer registryhavebenigndisease isunfounded.Thus,notwithstanding thehigh-qualitynatureof theauthor’s sonographic reviewand dataanalysis, the study’s epidemiologic interpretationsarenot readily transferrable to clinical practice. Specifically, testmetrics, such as positive or negative predictive value and calculations of number needed to diagnose, are influenced by population characteristics and the prevalence of disease. Does this imply that the author’s conceptual framework should not be applied to thyroid nodule evaluation? The answer ismost certainlyno.Sonographic featuresare, andshould remain, the principal tool to guide thyroid cancer risk assessment.2,6 Solid nodules larger than 1 cm, especiallywith microcalcifications, should be the primary focus of diagnostic evaluation. Conversely, purely cystic nodules canbe safely monitored.Unfortunately, the authors alsodonot address the spongiform nodule, which also has a high benignity rate.7 Although they combine cystic honeycomb nodules with purely cystic nodules, it is unclear that such nodules are the same as spongiformnodules. All sonographic findings should be considered so that nodules can be prioritized for possible tissue evaluation. Similarly, to allow clinicians to use such sonographic characteristics in clinical decision making, reporting by radiologists must also include asmany descriptors as possible. All too often, ultrasonographic reports provide nodule Related article page 1788 Research Original Investigation Thyroid Cancer Risk

Clinical management of thyroid neoplasms is based on light microscopic diagnosis, but its accuracy and precision are poorly defined.To assess inter- and intraobserver variability of preoperative cytopathologic and postoperative histopathologic thyroid diagnoses.Samples were collected in a prospective, multicenter trial validating a gene expression classifier between June 2009 and December 2010.14 academic and 35 community clinical sites.653 patients with 776 surgically resected thyroid nodules of 1 cm or greater.Intraobserver concordance among 2 or more central histopathologists who independently read histopathology slides was calculated. Interobserver concordance between the diagnoses made by the central histopathologists and those made by local pathologists were calculated. Intra- and interobserver concordance for cytopathology was similarly calculated by comparing diagnoses made by local pathologists with those made by a central panel of 3 cytopathologists.Concordance on the histopathologic distinction between benign and malignant diagnoses was 91% comparing local with central histopathologists and 90% comparing 2 central histopathologists. Using the 6-category Bethesda System, 64.0% of diagnoses made by local and central cytopathologists and 74.7% of intraobserver diagnoses were concordant. Central cytopathologists made fewer indeterminate diagnoses than local pathologists (41.2% vs. 55.0%).Many local pathologists did not use the Bethesda System, so their reports were translated to allow comparison. The study required histopathology, and the study population and specimens did not encompass all newly evaluated patients with a thyroid nodule.Substantial inter- and intraobserver variability exists in the cytopathologic and histopathologic evaluation of thyroid nodules, confirming an inherent limitation of visual microscopic diagnosis.Veracyte.

Background Thyroid hormones may be involved in tumorigenesis and metastasis in hormone sensitive cancers. Thyroid hormones strongly influence the menstrual cycle, implantation and fertility, suggesting that thyroid hormones also could play a role in the development of endometrial cancer (EC), which is hormone-sensitive. No prospective studies have examined this association. Methods We prospectively evaluated the association between self-reported physician-diagnosed hypothyroidism and hyperthyroidism in the Nurses’ Health Study (NHS) from 1976 - 2010. Reports of thyroid dysfunction were based on self-report on biennial follow-up questionnaires, and have shown high validity when compared to medical records. Incident EC cases were confirmed with medical, pathology and death records. Multivariate rate ratios (RRs) for endometrial cancer were calculated, adjusting for major EC risk factors (i.e., body mass index, smoking, parity, age at last birth, oral contraceptive use, family history, age at menarche, age at menopause, postmenopausal hormone use, type 2 diabetes, and height). Results During 34 years of follow-up in NHS, we documented 917 cases of incident EC. Compared to those without any reported thyroid dysfunction, the multivariable RR for hypothyroidism was 0.99 (95% CI, 0.75-1.30) and the null associations were consistent across categories of time since hypothyroidism diagnosis. The multivariable RR for hyperthyroidism was 1.38 (95% CI 0.79 - 2.41). An association was observed with longer time since hyperthyroidism diagnosis (median time since hyperthyroidism diagnosis was 6 years in NHS); the RR for EC associated with 6+ years since hyperthyroidism diagnosis was 2.08 (95% CI, 1.02, 4.23). Conclusions Overall self-reported hypothyroidism and hyperthyroidism were not associated with risk of EC; however, longer time since hyperthyroidism diagnosis may be associated with an increased risk of EC. Due to the overall small number of cases with hyperthyroidism, on-going analyses will incorporate results from the Nurses’ Health Study II to increase power for these analyses. Citation Format: Angela Kueck, Jae Hee Kang, Richard Stevens, Gary Curhan, Erik Alexander, Bernard Rosner, Immaculata DeVivo, Shelley Tworoger. Hypothyroidism and hyperthyroidism in relation to endometrial cancer: A prospective study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 153. doi:10.1158/1538-7445.AM2013-153