Kathryn G. Schuff

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer

BACKGROUND Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Associations (ATAs) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. METHODS The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members. RESULTS The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research. CONCLUSIONS We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopamine-dependent and -independent mechanisms

Hypothalamic dopamine inhibits pituitary prolactin secretion and proliferation of prolactin-producing lactotroph cells by activating lactotroph dopamine D2 receptors (D2Rs). Conversely, prolactin (PRL) stimulates hypothalamic dopamine neurons via PRL receptors (PRLRs) in a short-loop feedback circuit. We used Drd2(-/-) and Prlr(-/-) mutant mice to bypass this feedback and investigate possible dopamine-independent effects of PRL on lactotroph function. The absence of either receptor induced hyperprolactinemia and large prolactinomas in females. Small macroadenomas developed in aged Prlr(-/-) males, but only microscopic adenomas were found in Drd2(-/-) male mice. Pharmacologic studies in Prlr(-/-) mice with D2R agonists and antagonists demonstrated a significant loss of endogenous dopamine tone, i.e., constitutive inhibitory signaling by the D2R, in the pituitary. However, Prlr(-/-) mice exhibited more profound hyperprolactinemia and larger tumors than did age-matched Drd2(-/-) mice, and there were additive effects in compound homozygous mutant male mice. In vitro, PRL treatment markedly inhibited the proliferation of wild-type female and male Drd2(-/-) lactotrophs, but had no effect on female Drd2(-/-) lactotrophs, suggesting a downregulation or desensitization of PRLR in response to chronic hyperprolactinemia. We conclude that PRL inhibits lactotrophs by two distinct mechanisms: (a) indirectly by activation of hypothalamic dopamine neurons and (b) directly within the pituitary in a dopamine-independent fashion.

Multiplex Mutation Screening by Mass Spectrometry: Evaluation of 820 Cases from a Personalized Cancer Medicine Registry

There is an immediate and critical need for a rapid, broad-based genotyping method that can evaluate multiple mutations simultaneously in clinical cancer specimens and identify patients most likely to benefit from targeted agents now in use or in late-stage clinical development. We have implemented a prospective genotyping approach to characterize the frequency and spectrum of mutations amenable to drug targeting present in urothelial, colorectal, endometrioid, and thyroid carcinomas and in melanoma. Cancer patients were enrolled in a Personalized Cancer Medicine Registry that houses both clinical information and genotyping data, and mutation screening was performed using a multiplexed assay panel with mass spectrometry-based analysis to detect 390 mutations across 30 cancer genes. Formalin fixed, paraffin-embedded specimens were evaluated from 820 Registry patients. The genes most frequently mutated across multiple cancer types were BRAF, PIK3CA, KRAS, and NRAS. Less common mutations were also observed in AKT1, CTNNB1, FGFR2, FGFR3, GNAQ, HRAS, and MAP2K1. Notably, 48 of 77 PIK3CA-mutant cases (62%) harbored at least one additional mutation in another gene, most often KRAS. Among melanomas, only 54 of 73 BRAF mutations (74%) were the V600E substitution. These findings demonstrate the diversity and complexity of mutations in druggable targets among the different cancer types and underscore the need for a broad-spectrum, prospective genotyping approach to personalized cancer medicine.

Efficacy of Nodal Dissection for Treatment of Persistent/Recurrent Papillary Thyroid Cancer†

Context: Although commonly performed, data are lacking regarding efficacy and safety of lymph node dissection (LND) for recurrent/persistent papillary thyroid cancer (PTC).

Perioperative parathyroid hormone levels in thyroid surgery

Objective: Perioperative hypocalcemia from temporary parathyroid gland dysfunction is common after thyroid surgery. No reliable cutoff values for parathyroid hormone (PTH) and the subsequent possibility of developing hypocalcemia exist. The purpose of this study is to determine a criterion for predicting hypocalcemia based on different PTH levels as cutoff values.

Phase II study of transdermal estradiol in androgen-independent prostate carcinoma.

Oral estrogen therapy has activity in patients with hormone‐naive and androgen‐independent prostate carcinoma (AIPC), but its utility is limited by the associated risk of thromboembolic toxicity. Parenteral administration may be safer as it avoids “first pass” liver exposure to estrogen. The authors tested the safety and efficacy of transdermal estradiol (TDE), as well as the effect of therapy on hot flashes, sex hormones, the procoagulant cascade, and bone turnover in patients with AIPC.

Health Status, Mood, and Cognition in Experimentally Induced Subclinical Thyrotoxicosis

OBJECTIVE Our objective was to determine whether subclinical thyrotoxicosis alters health status, mood, and/or cognitive function. DESIGN This was a double-blinded, randomized, cross-over study of usual dose l-T(4) (euthyroid arm) vs. higher dose l-T(4) (subclinical thyrotoxicosis arm) in hypothyroid subjects. PATIENTS A total of 33 hypothyroid subjects receiving l-T(4) were included in the study. MEASUREMENTS Subjects underwent measurements of health status, mood, and cognition: Short Form 36 (SF-36); Profile of Mood States (POMS); and tests of declarative memory (Paragraph Recall, Complex Figure), working memory (N-Back, Subject Ordered Pointing, and Digit Span Backwards), and motor learning (Pursuit Rotor). These were repeated after 12 wk on each of the study arms. RESULTS Mean TSH levels decreased from 2.15 to 0.17 mU/liter on the subclinical thyrotoxicosis arm (P < 0.0001), with normal mean free T(4) and free T(3) levels. The SF-36 physical component summary and general health subscale were slightly worse during the subclinical thyrotoxicosis arm, whereas the mental health subscale was marginally improved. The POMS confusion, depression, and tension subscales were improved during the subclinical thyrotoxicosis arm. Motor learning was better during the subclinical thyrotoxicosis arm, whereas declarative and working memory measures did not change. This improvement was related to changes in the SF-36 physical component summary and POMS tension subscales and free T(3) levels. CONCLUSIONS We found slightly impaired physical health status but improvements in measures of mental health and mood in l-T(4) treated hypothyroid subjects when subclinical thyrotoxicosis was induced in a blinded, randomized fashion. Motor learning was also improved. These findings suggest that thyroid hormone directly affects brain areas responsible for affect and motor function.

The Role of Molecular Markers and Tumor Histological Type in Central Lymph Node Metastasis of Papillary Thyroid Carcinoma

OBJECTIVE To look for genetic mutations that might predict central compartment lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) using strict criteria for N0 and N1 disease. DESIGN We identified patients with PTC from our institutions pathology archives. Strict criteria were used for assessing the presence or the absence of central neck LNM. Disease was classified as N0 only if a comprehensive ipsilateral and pretracheal central neck dissection was performed and if pathological analysis revealed no evidence of LNM. Primary tumor samples were analyzed for a panel of known or suspected PTC-associated molecular markers, including BRAF, RET -PTC, KRAS, NRAS, HRAS, PIK3CA, and their variants. SETTING Academic medical center. PATIENTS Three hundred eighty-nine patients with PTC. MAIN OUTCOME MEASURE Molecular mutations in tumors with and without LNM. RESULTS Of 389 identified cases, 209 fit the inclusion criteria, with 158 classified as node positive (N1) and 51 as node negative (N0). The follicular variant histological type was present in 7 of 158 N1 tumors (4.4%) and 24 of 51 N0 tumors (47.1%) and thus was strongly associated with lack of central neck metastasis in this study (odds ratio, 0.05; 95% CI, 0.02-0.14). Predictive factors for central LNM included extracapsular extension, angiolymphatic invasion, and higher T stage (T3 and T4). The BRAF mutation was more prevalent in the classic PTC histological type than the follicular variant. None of the molecular marker mutations that were analyzed in this study, including the BRAF mutation, predicted LNM in classic PTC. CONCLUSIONS Positive risk factors for central LNM include male sex, extracapsular extension, angiolymphatic invasion, and advanced T stage. The follicular variant histological type has a significantly lower incidence of central neck metastasis. In contrast to recent studies, the BRAF mutation was not significantly associated with central neck LNM from PTC when using a strict definition of a central neck dissection.

Utility of Computed Tomography in the Detection of Subclinical Nodal Disease in Papillary Thyroid Carcinoma

OBJECTIVE To characterize the ability of computed tomography (CT) to identify subclinical cervical metastatic disease in papillary thyroid carcinoma (PTC). DESIGN Retrospective review. SETTING Tertiary academic center. PATIENTS Consecutive patients undergoing neck dissection for PTC between July 1, 2004, and July 1, 2006. INTERVENTION Preoperative CT scans were reevaluated in a blinded fashion by a single head and neck radiologist. Positive criteria included node with size larger than 10 mm, round shape, calcification, cystic character, or abnormal enhancement. MAIN OUTCOME MEASURE Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated separately for central compartment (level VI) and lateral compartment (levels III and IV) dissections. RESULTS One hundred four patients underwent selective neck dissection for PTC during the study period. Forty-three patients had disease that involved primary lymphadenectomy at the time of thyroidectomy, and 61 had persistent or recurrent disease. There were 111 lateral compartment dissections and 145 central compartment dissections. The overall sensitivity was 59% for both the central and lateral compartments, and the specificity was 76% and 71%, respectively. The PPV and NPV were 84% and 47% for the central compartment and 73% and 57% for the lateral compartment, respectively. CONCLUSIONS Computed tomography has a limited capability to identify subclinical metastatic cervical disease in PTC, with a sensitivity near 60% and an NPV near 50%. Sole reliance on CT findings will miss a significant portion of disease likely because of the high incidence of microscopic foci. However, using strict criteria, a positive finding on a CT scan provides useful information because it predicts with a fairly high assurance that disease will in fact be found in a specific compartment during surgical dissection.

Issues in the diagnosis of Cushing's syndrome for the primary care physician

The diagnosis of Cushings syndrome is one of the most difficult and yet one of the most important ones a primary care physician can make. The clinical presentation overlaps that of many other common diseases, but more specific signs such as unexplained osteoporosis, muscle weakness, ecchymoses, hypokalemia, and central obesity, the presence of multiple symptoms affecting different body systems, and a demonstrated change over time should prompt the screening evaluation. We recommend a step-wise approach to the diagnostic evaluation. Step 1 involves demonstrating pathologic hypercortisolemia and thus making the diagnosis of Cushings syndrome. In step 2, distinguishing ACTH-independent disease from ACTH-dependent disease and then adrenal imaging is done. Finally, for patients with ACTH-dependent disease, step 3 entails anatomic localization of the ACTH source by MRI, if unequivocal, or by IPSS or CSS. Only when the evaluation is done in a step-wise fashion can the clinician be assured that appropriate treatment recommendations can be made. Although a fair amount of the testing is complex, requiring special facilities and usually the assistance of an endocrinologist, the most critical step is that done by the primary care physician--considering the diagnosis and initiating the screening algorithm.