Kepal N. Patel

Poorly differentiated and anaplastic thyroid cancer.

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.

Genome-wide profiling of papillary thyroid cancer identifies MUC1 as an independent prognostic marker.

Clinicopathological variables used at present for prognostication and treatment selection for papillary thyroid carcinomas (PTCs) do not uniformly predict tumor behavior, necessitating identification of novel prognostic markers. Complicating the assessment is the long natural history of PTC and our rudimentary knowledge of its genetic composition. In this study we took advantage of differences in clinical behavior of two distinct variants of PTC, the aggressive tall-cell variant (TCV) and indolent conventional PTC (cPTC), to identify molecular prognosticators of outcome using complementary genome wide analyses. Comparative genome hybridization (CGH) and cDNA microarray (17,840 genes) analyses were used to detect changes in DNA copy number and gene expression in pathological cPTC and TCV. The findings from CGH and cDNA microarray analyses were correlated and validated by real-time PCR and immunohistochemical analyses on a series of 100 cases of cPTC and TCV. Genes identified by this approach were evaluated as prognostic markers in cPTC by immunohistochemistry on tissue arrays. CGH identified significant differences in the presence (76 versus 27%; P = 0.001) and type of DNA copy number aberrations in TCV compared with cPTC. Recurrent gains of 1p34–36, 1q21, 6p21–22, 9q34, 11q13, 17q25, 19, and 22 and losses of 2q21–31, 4, 5p14-q21, 6q11–22, 8q11–22, 9q11–32, and 13q21–31 were unique to TCV. Hierarchical clustering of gene expression profiles revealed significant overlap between TCV and cPTC, but further analysis identified 82 dysregulated genes differentially expressed among the PTC variants. Of these, MUC1 was of particular interest because amplification of 1q by CGH correlated with MUC1 amplification by real-time PCR analysis and protein overexpression by immunohistochemistry in TCV (P = 0.005). Multivariate analysis revealed a significant association between MUC1 overexpression and treatment outcome, independent of histopathological categorization (P = 0.03). Analysis of a validation series containing a matched group of aggressive and indolent cPTCs confirmed the association between MUC1 overexpression and survival (relative risk, 2.3; 95% confidence interval, 1.1–5.5; P = 0.03). Our data suggest that MUC1 dysregulation is associated with aggressive behavior of PTC and may serve as a prognostic marker and potential therapeutic target in this disease.

Implications for Clinical Staging of Metastatic Cutaneous Squamous Carcinoma of the Head and Neck Based on a Multicenter Study of Treatment Outcomes

Cutaneous squamous cell carcinoma (SCC) of the head and neck is a common cancer that has the potential to metastasize to lymph nodes in the parotid gland and neck. Previous studies have highlighted limitations with the current TNM staging system for metastatic skin carcinoma. The aim of this study was to test a new staging system that may provide better discrimination between patient groups.

Squamous Cell Carcinoma Related Oncogene/DCUN1D1 Is Highly Conserved and Activated by Amplification in Squamous Cell Carcinomas

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.

Follicular Variant of Papillary Thyroid Cancer Encapsulated, Nonencapsulated, and Diffuse: Distinct Biologic and Clinical Entities

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.

Locally advanced thyroid cancer.

Purpose of reviewThe purpose of this review is to summarize existing literature with respect to locally advanced thyroid cancer and define the intricacies of preoperative evaluation, surgical management of involved sites and postoperative treatment. Recent findingsLocally invasive thyroid cancer is an uncommon disease process, which carries significant morbidity and mortality. Current treatment modalities include appropriate surgery, radioactive iodine treatment and external beam radiation therapy. Proper evaluation of the extent of disease, with complete gross tumor removal, is paramount in managing this difficult problem. Surgical treatment is still the mainstay for locally advanced thyroid cancer. SummaryLittle progress has been made in advancing the treatment of locally advanced thyroid cancer. Patient identification, evaluation and proper surgical management with adjuvant therapy, still remain the most effective course of treatment. Aggressive surgical treatment including removal of all gross tumor and still preserving vital structures along with adjuvant therapy is likely to offer the best results. There is a very high incidence of locoregional and distant failure in this group of patients. The understanding and recognition of histopathological variations, such as poorly differentiated thyroid cancer is also important. New molecular markers are needed to help identify and predict aggressive tumor behavior.

Clinical utility of immunohistochemistry for the detection of the BRAF v600e mutation in papillary thyroid carcinoma

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.

Genetic considerations in thyroid cancer

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.

Can noninvasive follicular thyroid neoplasm with papillary‐like nuclear features be distinguished from classic papillary thyroid carcinoma and follicular adenomas by fine‐needle aspiration?

Noninvasive encapsulated follicular variant of papillary thyroid carcinoma, a diagnosis implying malignancy as a variant of papillary thyroid carcinoma (PTC), has recently been reclassified to noninvasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP) on surgical pathology. Due to the effects of such a recategorization on rate of malignancy and clinical management algorithms, it is imperative that we explore whether presurgical fine‐needle aspiration can differentiate NIFTP from PTC and follicular adenoma (FA).

Poorly differentiated thyroid cancer.

Purpose of reviewPoorly 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 findingsThe 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. SummaryWe 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.