Randall P. Owen

Validation of the histologic risk model in a new cohort of patients with head and neck squamous cell carcinoma

BackgroundHalf of the patients with head and neck squamous cell carcinoma (HNSCC) can be expected to fail therapy, indicating that more aggressive treatment is warranted for this group. We have developed a novel risk model that can become a basis for developing new treatment paradigms. Here we report on the performance of our model in a new multicenter cohort. DesignEligible patients from 3 institutions (Montefiore Medical Center, University of Manitoba, and New York University Medical Center) were identified and pathology slides from their resection specimens were reviewed by Margaret Brandwein-Gensler; risk category was assigned as previously published. Kaplan-Meier analysis was performed for disease progression and survival. Cox proportional hazards regression was performed, adjusted for potential confounders. A teaching module was also developed; attending pathologists were asked to score coded slides after a lecture and multiheaded microscope teaching session. Agreement was assessed by calculating Cohen unweighted κ coefficients. ResultThe validation cohort consisted of 305 patients, from the above institutions, with 311 primary HNSCC of the oral cavity, oropharynx, and larynx. The median follow-up period for all patients was 27 months. Risk category predicts time to disease progression (P=0.0005), locoregional recurrence (P=0.013), and overall survival (P=0.0000) by Kaplan-Meier analysis. High-risk status is significantly associated with decreased time to disease progression, adjusted for clinical confounders (P=0.015, hazard ratio 2.32, 95% confidence interval 1.18-4.58) compared with collapsed intermediate and low-risk groups. We also demonstrate substantial interrater agreement (κ=0.64), and very good rater agreement when compared with the standard (κ=0.87). ConclusionsWe demonstrate significant predictive performance of the risk model in a new cohort of patients with primary HNSCC, adjusted for confounders. Our training experience also supports the feasibility of adapting the risk model in clinical practice.

Aggressive variants of papillary thyroid carcinoma.

A number of histologic variants of well‐differentiated papillary carcinoma have been found to be associated with more aggressive tumor behavior. Tall cell, columnar cell, diffuse sclerosing, solid/trabecular, and insular variants of well‐differentiated papillary thyroid cancer are all potentially more aggressive than conventional papillary thyroid cancer. When subjected to multivariate analysis, however, evidence that the histologic subtype of tumor is an independent predictor of outcome is weak. Rather, the aggressive variants tend to present with features recognized by other staging systems as associated with a worse prognosis, including higher histologic grade, extracapsular spread, large tumor size, and the presence of distant metastases. Prognosis is directly related to the presence of these features. The state of our knowledge is limited by the relatively small number of cases that have been studied. The presence of an aggressive variant of papillary carcinoma should alert the surgeon that he is dealing with a potentially aggressive tumor. Clinical treatment decisions should be based on the stage of the disease, influenced by the knowledge that the aggressive variants tend to be associated with higher risk factors. The surgeon must be prepared to perform at the first, or second stage, a total thyroidectomy, central compartment neck dissection, additional lymphadenectomy, and/or resection of invaded surrounding structures, and search for distant metastasis. Postoperative radioactive iodine should generally be administered for these variants as they will generally be intermediate to advanced tumors. The tall cell variant is often refractory to such treatment but may be susceptible to treatment targeted against BRAF mutation. External beam irradiation may be used in cases of incomplete resection.

Contemporary management of cancer of the oral cavity

Oral cancer represents a common entity comprising a third of all head and neck malignant tumors. The options for curative treatment of oral cavity cancer have not changed significantly in the last three decades; however, the work up, the approach to surveillance, and the options for reconstruction have evolved significantly. Because of the profound functional and cosmetic importance of the oral cavity, management of oral cavity cancers requires a thorough understanding of disease progression, approaches to management and options for reconstruction. The purpose of this review is to discuss the most current management options for oral cavity cancers.

Proposal for A Rational Classification of Neck Dissections

Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FHKCORL, FRCPath, FASCP, IFCAP, K. Thomas Robbins, MD, FRCSC, Jatin P. Shah, MD, PhD (Hon), MS, FRCSEd (Hon), FRACS (Hon), FDSRCS, Jesus E. Medina, MD, Carl E. Silver, MD, Shawkat Al-Tamimi, MD, Johannes J. Fagan, MBChB, FCS (SA) MMed, Vinidh Paleri, MS, FRCS (ORL-HNS), Robert P. Takes, MD, PhD, Carol R. Bradford, MD, Kenneth O. Devaney, MD, JD, FCAP, Sandro J. Stoeckli, MD, Randal S. Weber, MD, Patrick J. Bradley, MB, BCh, BAO, DCH, MBA, FRCS (Ed, Eng, Ir), FHKCORL, FRCSLT (Hon), FRACS (Hon), Carlos Suarez, MD, PhD, C. Rene Leemans, MD, PhD, H. Hakan Coskun, MD, Karen T. Pitman, MD, Ashok R. Shaha, MD, Remco de Bree, MD, PhD, Dana M. Hartl, MD, PhD, Missak Haigentz, Jr, MD, Juan P. Rodrigo, MD, PhD, Marc Hamoir, MD, Avi Khafif, MD, Johannes A. Langendijk, MD, PhD, Randall P. Owen, MD, MS, Alvaro Sanabria, MD, MSc, PhD, Primož Strojan, MD, PhD, Vincent Vander Poorten, MD, PhD, Jochen A. Werner, MD, Stanislaw Bien, MD, PhD, Julia A. Woolgar, FRCPath, PhD, Peter Zbaren, MD, Jan Betka, MD, PhD, FCMA, Benedikt J. Folz, MD, Eric M. Genden, MD, Yoav P. Talmi, MD, Marshall Strome, MD, MS, Jesus Herranz Gonzalez Botas, MD, Jan Olofsson, MD, Luiz P. Kowalski, MD, PhD, Jon D. Holmes, DMD, MD, Yasuo Hisa, MD, PhD, Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSGlasg

Parathyroid carcinoma: A review†

Parathyroid carcinoma is a rare entity, comprising fewer than 1% of cases of hyperparathyroidism. The disease generally presents with severe hyperparathyroidism and occasionally with vocal cord paralysis or a firm palpable cervical mass.

Genetic–epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity

Significance Graves disease (GD) is an autoimmune disease caused by interactions between genetic, epigenetic, and environmental factors. The thyrotropin receptor (TSHR) is the major autoantigen in GD and is a key GD susceptibility gene. SNPs in intron 1 of the TSHR are associated with GD, but the causative variant and the mechanisms are unknown. By mapping epigenetic modifications induced by IFNα, a viral-induced cytokine triggering GD, we pinpointed the causative variant in intron 1 of the TSHR. We demonstrate that the disease-associated variant interacts epigenetically with a transcriptional repressor, promyelocytic leukemia zinc finger protein, and reduces thymic TSHR expression, leading to escape from tolerance and autoimmunity to the TSHR. These genetic–epigenetic interactions leading to decreased thymic self-antigen expression reveal a universal mechanism in autoimmunity. Graves disease (GD) is an autoimmune condition caused by interacting genetic and environmental factors. Genetic studies have mapped several single-nucleotide polymorphisms (SNPs) that are strongly associated with GD, but the mechanisms by which they trigger disease are unknown. We hypothesized that epigenetic modifications induced by microenvironmental influences of cytokines can reveal the functionality of GD-associated SNPs. We analyzed genome-wide histone H3 lysine 4 methylation and gene expression in thyroid cells induced by IFNα, a key cytokine secreted during viral infections, and overlapped them with known GD-associated SNPs. We mapped an open chromatin region overlapping two adjacent GD-associated SNPs (rs12101255 and rs12101261) in intron 1 of the thyroid stimulating hormone receptor (TSHR) gene. We then demonstrated that this region functions as a regulatory element through binding of the transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) at the rs12101261 site. Repression by PLZF depended on the rs12101261 disease susceptibility allele and was increased by IFNα. Intrathymic TSHR expression was decreased in individuals homozygous for the rs12101261 disease-associated genotype compared with carriers of the disease-protective allele. Our studies discovered a genetic–epigenetic interaction involving a noncoding SNP in the TSHR gene that regulates thymic TSHR gene expression and facilitates escape of TSHR-reactive T cells from central tolerance, triggering GD.

Comparison of Radiation Exposure and Cost Between Dynamic Computed Tomography and Sestamibi Scintigraphy for Preoperative Localization of Parathyroid Lesions

IMPORTANCE Dynamic computed tomography (CT) is emerging as a first-line alternative to sestamibi scintigraphy for preoperative localization of parathyroid lesions. In recent years, there has been increased concern over the impact of radiation exposure from medical imaging, as well as on the cost of diagnostic medical procedures. An ideal diagnostic procedure would be cost effective while minimizing hazardous exposures and complication rates. OBJECTIVE To compare the radiation dose and financial cost of dynamic CT with sestamibi scintigraphy. DESIGN, SETTING, AND PATIENTS A retrospective review of 263 patients at a large, urban, tertiary referral center who underwent either dynamic parathyroid CT or sestamibi scintigraphy for any etiology of hyperparathyroidism from 2006 through 2010. MAIN OUTCOMES AND MEASURES The 2 primary study outcomes were radiation exposure measured in millisieverts (mSv) and medical charges for the respective diagnostic procedures. The study was conducted with the hypothesis that dynamic parathyroid CT would have slightly greater radiation exposure with similar cost to sestamibi scintigraphy. RESULTS Dynamic parathyroid CT and sestamibi scintigraphy delivered mean radiation doses of 5.56 and 3.33 mSv, respectively (P < .05). Charges totaled

Mammary analog secretory carcinoma, low-grade salivary duct carcinoma, and mimickers: a comparative study.

1296 for thin-cut dynamic parathyroid CT and a mean of

Neuromonitoring of the laryngeal nerves in thyroid surgery: a critical appraisal of the literature.

1112 for sestamibi scintigraphy, depending on the type and amount of radiotracer injected. Although multiphase CT scanning took less than 5 minutes, sestamibi scintigraphy lasted a mean time of 306 minutes. A total of 62 of 119 patients (52%) in the CT group have undergone operative treatment to date, whereas all patients in the sestamibi arm underwent operative treatment of their hyperparathyroidism. Of the patients who underwent a surgical procedure, CT correctly identified the side of the parathyroid adenoma in 54 of 62 patients (87%), while sestamibi scintigraphy only correctly lateralized 90 of 122 adenomas (74%) as confirmed by exploratory surgery, intraoperative parathyroid hormone levels, and pathologic features. A dynamic parathyroid CT correctly predicted multiglandular disease in 1 of 7 patients (14%), while sestamibi scintigraphy correctly predicted multiglandular disease in 8 of 23 patients (35%). CONCLUSIONS AND RELEVANCE In patients who underwent directed parathyroid surgery, dynamic CT is comparable to sestamibi scintigraphy in patients with hyperparathyroidism. Although CT delivers a higher dose of radiation, the average background radiation exposure in the United States is 3 mSv/y, and added exposures of less than 15 mSv are considered low risk for carcinogenesis. Overall, dynamic parathyroid CT is a safe, cost-effective alternative to sestamibi scintigraphy.

Endoplasmic Reticulum Stress as a Novel Mechanism in Amiodarone-Induced Destructive Thyroiditis

Mammary analog secretory carcinoma (MASC) is a recently recognized low-grade salivary carcinoma characterized by a specific ETV6 rearrangement. We describe 14 new MASCs and examine their immunophenotypic and genetic profiles in the context of look-alikes, namely, low-and high-grade salivary duct carcinoma and acinic cell carcinoma. ETV6 rearrangement, and robust expression of mammaglobin and S100, were demonstrated in 11/11, 14/14, and 12/14 MASCs, respectively. All low-grade salivary duct carcinomas coexpressed S100/mammaglobin (6/6); none harbored ETV6 rearrangements (0/5). Given that S100/mammaglobin coexpression and absence of zymogen granules are features of both MASC and low-grade salivary duct carcinoma, these two are best distinguished histologically. The former is predominantly an extraductal neoplasm with bubbly pink cytoplasm, whereas the latter is a distinct intraductal micropapillary and cribriform process. Querying ETV6 gene status may be necessary for difficult cases. No acinic cell carcinoma expressed mammaglobin (0/13) or harbored an ETV6 rearrangement (0/7); only 1/13 acinic cell carcinomas weakly expressed S100. DOG1 expression was limited or absent among all tumor types, except acinic cell carcinoma which expressed DOG1 diffusely in a canalicular pattern. Therefore, histology and immunohistochemistry (mammaglobin, S100, DOG1) suffices in distinguishing acinic cell carcinoma from both MASC and low-grade salivary duct carcinoma. HER2 (ERBB2) amplification was detected in only 1/10 acinic cell carcinomas, but none of the MASCs or low-grade salivary duct carcinomas tested. High-grade salivary duct carcinomas frequently expressed mammaglobin (11/18) and harbored HER2 amplifications (13/15); none harbored ETV6 rearrangements (0/12). High-grade salivary duct carcinomas can easily be distinguished from these other entities by histology and HER2 amplification.