Faculty Bibliography

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.

BACKGROUND: BRAF mutations activate the mitogen-activated protein kinase pathway and often confer an aggressive thyroid cancer (TC) phenotype. Spry2 is an inducible negative feedback regulator of the mitogen-activated protein kinase (MAPK) pathway. The aim of this study was to investigate the role of Spry2 in TC. METHODS: TC cell lines were analyzed for Spry2 expression and MAPK pathway activation. Cells were treated with MEK inhibitor and Spry2 small hairpin RNA. Cells were analyzed for Spry2 expression and MEK/ERK phosphorylation (pMEK, pERK). Thirty human papillary TCs were analyzed for mitogen-activated protein kinase pathway activating mutations and Spry2 expression. RESULTS: Increased baseline pMEK levels and Spry2 expression was found in BRAF V600E mutant (BRAF+) cells. MEK inhibition in BRAF+ cells showed decreased Spry2 expression and decreased pMEK/pERK levels. From our tissue samples, 10 papillary TCs had BRAF mutation, and increased Spry2 expression was found only in BRAF+ tumors. CONCLUSION: Spry2 expression correlates with BRAF status in vitro and in human tissue. Spry2 may serve as a negative feedback regulator of the mitogen-activated protein kinase pathway in BRAF+ TC. Increased Spry2 expression may serve as a surrogate marker of mitogen-activated protein kinase pathway activation with prognostic and therapeutic implications

BACKGROUND: The 2009 ATA Guidelines state 'lobectomy alone may be sufficient treatment for small (<1 cm), low risk, unifocal, intrathyroidal papillary carcinomas in the absence of . . . nodal metastases.' We determined how often these criteria are satisfied, and whether tumor size alone can dictate operative management. METHODS: Medical records of 346 patients with well-differentiated thyroid cancer (WDTC) who underwent thyroidectomy from January 1, 2007 to November 10, 2009, were reviewed. There were 130 patients with tumors </=1 cm and negative lateral nodes. Pathology reports were reviewed to identify adverse features including multifocality, extrathyroidal extension, vascular invasion, and central node metastases. RESULTS: Eighty-four percent underwent total thyroidectomy and 16% central node dissection. All but 2 patients had papillary cancer. Sixty-one percent with cancers 6-10 mm (group 1) had adverse pathologic features compared with 32% with cancers <6 mm (group 2). Multifocality was most common: 55% in group 1 versus 32% in group 2 (P = .004). Positive central nodes were identified in 23% of group 1 versus 4% of group 2 (P = .004). Of patients in group 1, 88% had positive or suspicious fine-needle aspiration biopsy (FNAB) preoperatively. CONCLUSION: We recommend that total thyroidectomy be considered as the initial operation for thyroid tumors 6-10 mm in size in which the preoperative FNAB is diagnostic or suspicious for WDTC

BACKGROUND: The tall cell variant (TCV) is a histologic subtype of papillary thyroid carcinoma (PTC) that is more aggressive than 'classical' PTC. Most authors believe that TCV's worse prognosis is related to older age at presentation, larger tumor size, and high frequency of extrathyroid tumor extension (ETE). To assess the biologic and clinical behavior of TCV without ETE, we performed a detailed comparative clinicopathologic analysis of classical PTC and TCV without ETE. METHODS: TCV was defined as a PTC harboring >50% tall cells, while classical PTC was restricted to those tumors containing >1% papillae and <30% tall cells. Microscopic analysis and chart review identified 62 cases of TCV and 83 classical PTC without ETE. These patients were analyzed for various pathologic, imaging, and clinical parameters including outcome. RESULTS: There was no statistical difference between TCV and classical PTC in relation to age, gender, tumor size, risk stratification, type of therapy, and length of follow-up. TCV displayed more invasion of the tumor capsule and more often infiltrated into the thyroid capsule (p = 0.047 and 0.0004, respectively). Among patients with microscopically assessable regional lymph node (LN), 33 of 49 (67.3%) patients with TCV had LN metastasis at presentation, while only 24 of 60 (40%) classical PTC had positive nodes (p = 0.004). In multivariate analysis, histologic subtype (TCV vs. classical PTC) was the only independent factor associated with LN metastases (p = 0.007). In patients with adequate follow-up, 4 of 62 (6.5%) classical PTC and 7 of the 47 (14.9%) TCV had thyroid cancer recurrence (p = 0.202). TCV recurred at a distant site (3 of 47, 6.4%) while none of the 62 classical PTC developed distant metastases (p = 0.077). CONCLUSION: TCV without ETE is biologically a more aggressive tumor than classical PTC without ETE independent of age, gender, and tumor size

Chromosomal amplification at 3q is common to multiple human cancers, but has a specific predilection for squamous cell carcinomas (SCC) of mucosal origin. We identified and characterized a novel oncogene, SCC-related oncogene (SCCRO), which is amplified along the 3q26.3 region in human SCC. Amplification and overexpression of SCCRO in these tumors correlate with poor clinical outcome. The importance of SCCRO amplification in malignant transformation is established by the apoptotic response to short hairpin RNA against SCCRO, exclusively in cancer cell lines carrying SCCRO amplification. The oncogenic potential of SCCRO is underscored by its ability to transform fibroblasts (NIH-3T3 cells) in vitro and in vivo. We show that SCCRO regulates Gli1--a key regulator of the hedgehog (HH) pathway. Collectively, these data suggest that SCCRO is a novel component of the HH signaling pathway involved in the malignant transformation of squamous cell lineage

BACKGROUND: Poorly differentiated thyroid carcinoma (PDTC) and anaplastic (undifferentiated) thyroid carcinoma (ATC) comprise a small subset of thyroid tumors that are associated with a poor prognosis and account for a significant portion of the morbidity and mortality related to thyroid cancer. Since management strategies vary between these two entities, it is important for clinicians to be able to differentiate PDTC from ATC. METHODS: We reviewed the literature on PDTC and ATC and compared clinical and histopathologic features important in defining the disease process. RESULTS: Both PDTC and ATC display aggressive behavior with increased locoregional and distant disease. In most cases, patients are older and have large, locally advanced tumors. PDTC may represent an intermediate entity in the progression of well-differentiated thyroid carcinoma to ATC. The use of surgical management may be curative or palliative and differs between PDTC and ATC. The roles of radiotherapy and chemotherapy have not been well described. CONCLUSIONS: PDTC and ATC are rare diseases that carry a poor prognosis. Recognition of their different clinicopathologic features is important to the optimal management of these tumors

BACKGROUND: Recent molecular studies have described a number of abnormalities associated with the progression and dedifferentiation of thyroid carcinoma. These distinct molecular events are often associated with specific stages of tumor development. A better understanding of the mechanisms involved in thyroid cancer pathogenesis may help to translate these discoveries toward improvements in patient care. METHODS: We reviewed the literature on the molecular pathogenesis of thyroid cancer and compared clinical, histopathologic, and genetic features important in defining the disease process. RESULTS: The progression of thyroid cancer from well-differentiated to poorly differentiated and undifferentiated carcinoma represents a biological continuum. Specific genetic events serve as early initiating and late triggering events. Poorly differentiated thyroid carcinomas occupy an intermediate position in this progression model. CONCLUSIONS: With sophisticated genetic tools generating a wealth of information, we have gained better insight into the mechanisms driving thyroid tumor progression. Recognition of these features is crucial to the management of patients with thyroid cancer. Novel treatments are being designed based on our enhanced understanding of this disease process