Faculty Bibliography

BACKGROUND: Recent advances in research on thyroid carcinogenesis have yielded applications of diagnostic molecular biomarkers and profiling panels in the management of thyroid nodules. The specific utility of these novel, clinically available molecular tests is becoming widely appreciated, especially in perioperative decision making by the surgeon regarding the need for surgery and the extent of initial resection. METHODS: A task force was convened by the Surgical Affairs Committee of the American Thyroid Association and was charged with writing this article. RESULTS/CONCLUSIONS: This review covers the clinical scenarios by cytologic category for which the thyroid surgeon may find molecular profiling results useful, particularly for cases with indeterminate fine-needle aspiration cytology. Distinct strengths of each ancillary test are highlighted to convey the current status of this evolving field, which has already demonstrated the potential to streamline decision making and reduce unnecessary surgery, with the accompanying benefits. However, the performance of any diagnostic test, that is, its positive predictive value and negative predictive value, are exquisitely influenced by the prevalence of cancer in that cytologic category, which is known to vary widely at different medical centers. Thus, it is crucial for the clinician to know the prevalence of malignancy within each indeterminate cytologic category, at one's own institution. Without this information, the performance of the diagnostic tests discussed below may vary substantially.

PURPOSE OF REVIEW: Poorly differentiated thyroid carcinomas (PDTCs) comprise a small subset of heterogeneous thyroid tumors, occupying an intermediate area between well differentiated follicular or papillary carcinoma and anaplastic carcinomas, from both a histopathogenetic and a clinical point of view. PDTCs are more aggressive than the well differentiated, but less aggressive than the anaplastic thyroid cancers. They have a distinct biological behavior, and the classification of these tumors into a separate group appears justified. RECENT FINDINGS: The criteria used to diagnose PDTC have been an area of controversy. The multiple definitions of PDTC make the literature difficult to interpret. No clinical features can accurately diagnose PDTCs. Thus, the results of histocytology, immunohistochemistry, and molecular genetics tests aid in diagnosis. Given the aggressiveness of PDTCs, with increased recurrence and decreased survival rates, a multimodality treatment approach is required. SUMMARY: We conducted a comprehensive review of the current diagnostic and therapeutic tools in the management of patients with PDTCs. The present article aims to review the various aspects of this tumor type, from morphology to immunohistochemistry, and molecular abnormalities from a practical and daily practice-oriented point of view.

Background: The incidence of well-differentiated thyroid cancer (WDTC) in the United States is increasing rapidly. Much of this increase is due to the detection by imaging of small, nonpalpable tumors. The incidence of advanced WDTC is also increasing, suggesting a true increase in the incidence of WDTC. This study was performed to determine how WDTCs of all sizes and stages are initially detected. Methods: A retrospective chart review of 519 patients who underwent surgery for WDTC from January 1, 2007, through August 31, 2010, was performed. A total of 473 patients suitable for inclusion in this study were divided into three groups based upon the method by which the tumor was initially detected: tumors detected by an imaging study (184 patients-39%), those detected because a mass was felt in the neck (218 patients-46%), and those detected incidentally on pathological study of the surgical specimen (71 patients-15%). Method of detection was correlated with age and sex of the patient, and size, stage, and nodal status of the tumor. Results: Patients in the Palpation group were more likely to be female (79% vs. 67% vs. 74%), younger (46 vs. 51 vs. 52), and to have larger tumors than those in the Imaging or Incidental groups. In the Imaging group, the tumor was detected on thyroid sonogram in 98 (53%), computed tomography in 38 (21%), magnetic resonance imaging in 19 (10%), carotid duplex scan in 14 (8%), and positron-emission tomography or other imaging studies in 15 (8%). Thirty-three percent of tumors <1 cm, 51% 1-2 cm, 29% 2-4 cm, and 38% >4 cm were first detected on an imaging study. Forty-seven percent of Stage III and IV cancers in patients aged >/=45 years and 39% of patients with positive central nodes were in the Imaging group. Conclusion: This study demonstrates that while most tumors discovered by imaging were small and early stage, almost half of advanced (Stage III and IV) WDTCs were initially discovered by imaging studies. These findings are consistent with the hypothesis that the frequent use of imaging studies may explain not only the increasing incidence of early WDTC, but more advanced thyroid cancers as well.

BACKGROUND: The BRAF V600E (BRAF+) mutation activates the mitogen-activated protein kinase (MAPK/ERK) pathway and may confer an aggressive phenotype in papillary thyroid cancer (PTC). Clinically, the behavior of BRAF+ PTC, however, varies from an indolent to an aggressive course. SPRY2 is a negative feedback regulator of the MAPK/ERK pathway. We hypothesize that the level of SPRY2 expression contributes to MAPK/ERK pathway output and accounts for BRAF+ and clinical heterogeneity. METHODS: A tissue microarray with BRAF-positive PTCs (BRAF+ PTCs) was constructed and analyzed for SPRY2 expression and MAPK/ERK output. Data were studied in the context of clinicopathologic factors to develop a risk stratification system predictive of tumor biology. SPRY2 function was studied by silencing SPRY2 in BRAF+ PTC cells. These cells were treated with MAPK/ERK pathway inhibitors and assessed for growth effects. RESULTS: BRAF+ PTCs with an intact MAPK/ERK feedback pathway do not exhibit lymph node metastases. BRAF+ PTCs with dysregulated feedback pathways have nodal metastasis. When SPRY2 is silenced, the BRAF+ PTC cells are significantly more sensitive to MAPK/ERK inhibition. CONCLUSION: PTC behavior likely is dependent on both the driver of the MAPK/ERK pathway and its regulatory feedback. When the feedback pathway is intact, the tumor phenotype seems to be less aggressive. This observation has direct and important clinical implications and may alter our treatment strategies.

BACKGROUND: BRAF V600E mutation is the most common genetic alteration in papillary thyroid cancer (PTC). We used a mutation-specific antibody for immunohistochemical (IHC) detection of the BRAF V600E mutation and correlated expression with clinicopathologic features. The study was designed to validate the accuracy and determine the clinical importance of IHC detection of the BRAF V600E mutation in PTC. METHODS: Direct sequencing and IHC for BRAF V600E mutation was performed in 37 consecutive patients with PTCs. IHC was scored on an intensity proportion scale. IHC positive tumors were stratified into intensity categories. The categories were assessed for clinicopathologic variables, including age, extrathyroidal extension, lymphovascular invasion, and lymph node metastases. RESULTS: A total of 25 PTCs were BRAF V600E-positive and 12 were BRAF mutation-negative on IHC. The BRAF V600E mutation-specific antibody had a sensitivity of 89% and specificity of 100% for detecting the mutation. Tumors with high-intensity staining were more likely to have extrathyroidal extension. CONCLUSION: IHC is an accurate method for the detection of the BRAF V600E mutation in PTC, and its ability to quantify the mutation expression may serve as a better predictor of tumor behavior than molecular sequencing. It provides a potentially rapid, easily applicable, and economic alternative to current techniques.

Patients in a US public hospital were recently found to present with more advanced differentiated thyroid carcinoma (DTC) than those in an adjacent university hospital. 37% of public hospital patients with DTC were primarily Spanish-speaking. We used focus groups and key informant interviews to examine access to care and knowledge of diagnosis/treatment among Spanish-speaking patients with DTC. All adult patients treated for DTC between 2000-2011 and who indicated Spanish as their preferred language met inclusion criteria. Focus groups and key informant interviews were conducted in Spanish by trained facilitators, utilizing a phenomenology approach. Discussions focused on diagnosis and treatment of DTC. 16/50 eligible patients participated. While all expressed a preference for Spanish when discussing medical care, no patient found language to be a barrier due to ready availability of interpreting services. All reported unimpeded access to primary care, with community networks serving as an important information source of public health services. The majority of patients presented with a selfreported nodule or symptoms associated with hypo/hyperthyroidism, which prompted furtherwork-up. DTCwas discovered incidentally on imaging in a small minority of patients. The majority of patients reported limited to no knowledge of thyroid cancer prior to diagnosis. Although only one patient used alternativemedicine as a treatment for thyroid cancer,many expressed a belief in its value as a complementary modality. Access to care proved unhindered among this patient population, though was contingent on strong community networks and availability of interpreter services. Despite limited patient knowledge, DTC was most commonly diagnosed following presentation with a self-discovered nodule or symptoms of hypo/hyperthyroidism. Beliefs in alternative medicine did not affect timely treatment. These data emphasize the importance of patient education and a culturally sensitive approach to optimize care in this demogr!

Recent molecular studies have described a number of abnormalities associated with the pathogenesis of thyroid carcinoma. These distinct molecular events are often associated with specific stages of tumor development and may serve as prognostic factors and therapeutic targets. A better understanding of the mechanisms involved in thyroid cancer pathogenesis, will hopefully help translate these discoveries to improved patient care.

Background MEN-2B syndrome is comprised of the association of MTC, PHEOs and multiple mucosal neuromas. The latter is a phenotype pathognomonic of this syndrome, but expressivity of the mucosal neuroma phenotype is less than 100%. The RET genotype-phenotype correlations are well recognized. MEN-2B is transmitted as an autosomal dominant trait. The germline point mutations are gain-of-function, causing RET activation. Most cases of MEN-2B have a codon 918 mutation (exon 16) of the intracellular tyrosine kinase domain of RET proto-oncogene. Recently, classification based on the pathogenesis and molecular correlation of the mutations involved in MEN-2A and MEN-2B places these mutations into a cluster 2 (kinase receptor signaling) and its downstream pathway: the mutated protein RET interacts with and alters the activity of several effector proteins of the receptor kinase intracellular signaling pathway. Case presentation 9 year old female presenting with 2 weeks of neck pain and left anterior neck mass. No history of radiation exposure to the head or neck; no family history of thyroid cancer or pheochromocytoma. VS: BP 90/60 mm Hg, HR 85 bpm, height 130 cm (-1.1 SD). Phenotype: long faces, lingual mucosal neuromas with involvement of the lips, pectus excavatum, and arachnodactyly. Thyroid exam: left, firm ~ 2cm x 2cm-sized thyroid nodule, not fixed. Laboratory studies: Calcitonin: 226 pg/mL (0-5)- high; Chromogranin A: 8 nmol/L (0 - 5) elevated; CEA: 4.4 ng/ml (0 - 4.7) borderline high. Thyroid US: left thyroid lobe hypoechoic complex nodule 1.5 x 1.8 x 2.8 cm with coarse calcifications. US-guided FNAB, cytology: atypical cells, salt/pepper chromatin, amyloid (+). Immunohistochemical staining (+) for calcitonin. Diagnosis: MTC (Medullary Thyroid Carcinoma). Pheochromocytoma screen: plasma free metanephrine: 33 pg/mL (0-62), pelvic MRI with/without contrast and I-123 MIBG were normal. Genetic study: germline mutation, RET M918T (highest aggressiveness). Total thyroidectomy with central compartment lymph node dissection was performed. Pathology: pT1b (> 1 cm, < 2 cm), no nodal extension. Postoperative Calcitonin: < 2.0 pg/mL. Conclusions Identification of the mucosal neuroma phenotype in a child should alert the clinician to the diagnosis of MTC, a rare aggressive cancer syndrome. The diagnosis of MTC is made from calcitonin measurements and FNAB. Confirmation by positive immunostaining of tumor tissue for calcitonin is necessary with exclusion of pheochromocytoma. The finding of a germline mutation (sporadic/hereditary) in the RET gene in proband necessitates genetic testing in all first-degree relatives. After surgical intervention (in accordance to genotype-phenotype stratification), surveillance with calcitonin levels (as a marker of persistent/recurrent disease), CEA, Chromogranin A, and thyroid US along with plasma free metanephrines is recommended

Metastatic renal cell carcinoma to the head and neck is rare. Most reported cases of metastases to the head and neck involve the thyroid and parotid glands. Metastasis to other salivary glands is exceedingly rare. This report describes a case of a solitary metastasis of renal cell carcinoma to the submandibular gland 9 years after nephrectomy. To the authors' knowledge, this is the first case successfully diagnosed preoperatively using a combination of fine-needle aspiration and clinical history. The patient subsequently underwent a submandibular gland resection with preservation of the facial nerve branches. For the 3 years since resection of the submandibular gland, the patient has been free of disease.

OBJECTIVE: To examine genotypic and clinical differences between encapsulated, nonencapsulated, and diffuse follicular variant of papillary thyroid carcinoma (EFVPTC, NFVPTC, and diffuse FVPTC, respectively), to characterize the entities and identify predictors of their behavior. DESIGN: Retrospective medical chart review and molecular analysis. SETTING: Referral center of a university hospital. PATIENTS: The pathologic characteristics of 484 consecutive patients with differentiated thyroid cancer who underwent surgery by the 3 members of the New York University Endocrine Surgery Associates from January 1, 2007, to August 1, 2010, were reviewed. Forty-five patients with FVPTC and in whom at least 1 central compartment lymph node was removed were included. MAIN OUTCOME MEASURES: Patients with FVPTC were compared in terms of age, sex, tumor size, encapsulation, extrathyroid extension, vascular invasion, central nodal metastases, and the presence or absence of mutations in BRAF, H-RAS 12/13, K-RAS 12/13, N-RAS 12/13, H-RAS 61, K-RAS 61, N-RAS 61, and RET/PTC1. RESULTS: No patient with EFVPTC had central lymph node metastasis, and in this group, 1 patient (4.5%) had a BRAF V600E mutation and 2 patients (9%) had RAS mutations. Of the patients with NFVPTC, none had central lymph node metastasis (P > .99) and 2 (11%) had a BRAF V600E mutation (P = .59). Of the patients with diffuse FVPTC, all had central lymph node metastasis (P < .001), and 2 (50%) had a BRAF V600E mutation (P = .06). CONCLUSIONS: FVPTC consists of several distinct subtypes. Diffuse FVPTC seems to present and behave in a more aggressive fashion. It has a higher rate of central nodal metastasis and BRAF V600E mutation in comparison with EFVPTC and NFVPTC. Both EFVPTC and NFVPTC behave in a similar fashion. The diffuse infiltrative pattern and not just presence or absence of encapsulation seems to determine the tumor phenotype. Understanding the different subtypes of FVPTC will help guide appropriate treatment strategies.