Alireza Najafian

Malignancy risk and reproducibility associated with atypia of undetermined significance on thyroid cytology

BACKGROUND The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) describes several subcategories within atypia of undetermined significance (AUS), including (1) presence of focal nuclear atypia (AUS-N), (2) focal microfollicular proliferation (AUS-F), (3) focal Hürthle cell proliferation (AUS-HC), and (4) other (AUS-O). Several publications suggest that 5-15% is an underestimate of the malignancy risk for AUS, and that the underestimation is owing to the similarity between AUS-N and suspicious for malignancy (SFM). Thus, we investigated the AUS subcategories during morphologic re-review at a tertiary care center and their associated malignancy risk. METHODS Of 4,827 fine-needle aspiration specimens were sent between January 2009 and August 2013 for morphologic re-review, 806 were categorized as AUS. Comparison of AUS subcategory diagnoses were made between outside and re-review results. The malignancy risk was also determined for 255 nodules with available surgical pathology. RESULT The outside diagnoses of the 806 cases read as AUS on second review were as follows: 5 insufficient (0.1%), 149 benign (19%), 463 AUS (57%), 124 SFN or suspicious for follicular or Hürthle cell neoplasm (15%), 56 SFM (7%), and 9 malignant (1%). Of the 463 cases in which both the outside and re-review diagnosis was AUS, the distribution of the subcategories in order of increasing frequency was 53 AUS-HC (11%), 74 AUS-O (16%), 79 AUS-F (17%), and 257 AUS-N (56%). Of the 255 resected nodules, 99 (39%) were malignant. Subcategory malignancy rates were: AUS-HC, 19% (9/47); AUS-O, 26% (14/54); AUS-F, 39% (19/49); and AUS-N, 54% (57/105). Cases in which both the referring institution and re-review agreed about the AUS-N subcategory had an even greater risk of malignancy (68%; 17/25). CONCLUSION Disagreement about the diagnosis of AUS between institutions is frequent. The malignancy risk for AUS is higher than originally proposed by TBSRTC and attributable to the high risk of AUS-N. Furthermore, agreement on AUS-N after re-review portends a malignancy risk that borders on that of SFM. This suggests that AUS-N may have discrete features that can provide specific morphologic predictors and enable the consolidation of AUS-N into SFM.

Association of BRAFV600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers

BACKGROUND Studies have demonstrated an association of the BRAF(V600E) mutation and microRNA (miR) expression with aggressive clinicopathologic features in papillary thyroid cancer (PTC). Analysis of BRAF(V600E) mutations with miR expression data may improve perioperative decision making for patients with PTC, specifically in identifying patients harboring central lymph node metastases (CLNM). METHODS Between January 2012 and June 2013, 237 consecutive patients underwent total thyroidectomy and prophylactic central lymph node dissection (CLND) at four endocrine surgery centers. All tumors were tested for the presence of the BRAF(V600E) mutation and miR-21, miR-146b-3p, miR-146b-5p, miR-204, miR-221, miR-222, and miR-375 expression. Bivariate and multivariable analyses were performed to examine associations between molecular markers and aggressive clinicopathologic features of PTC. RESULTS Multivariable logistic regression analysis of all clinicopathologic features found miR-146b-3p and miR-146b-5p to be independent predictors of CLNM, while the presence of BRAF(V600E) almost reached significance. Multivariable logistic regression analysis limited to only predictors available preoperatively (molecular markers, age, sex, and tumor size) found miR-146b-3p, miR-146b-5p, miR-222, and BRAF(V600E) mutation to predict CLNM independently. While BRAF(V600E) was found to be associated with CLNM (48% mutated in node-positive cases vs. 28% mutated in node-negative cases), its positive and negative predictive values (48% and 72%, respectively) limit its clinical utility as a stand-alone marker. In the subgroup analysis focusing on only classical variant of PTC cases (CVPTC), undergoing prophylactic lymph node dissection, multivariable logistic regression analysis found only miR-146b-5p and miR-222 to be independent predictors of CLNM, while BRAF(V600E) was not significantly associated with CLNM. CONCLUSION In the patients undergoing prophylactic CLNDs, miR-146b-3p, miR-146b-5p, and miR-222 were found to be predictive of CLNM preoperatively. However, there was significant overlap in expression of these miRs in the two outcome groups. The BRAF(V600E) mutation, while being a marker of CLNM when considering only preoperative variables among all histological subtypes, is likely not a useful stand-alone marker clinically because the difference between node-positive and node-negative cases was small. Furthermore, it lost significance when examining only CVPTC. Overall, our results speak to the concept and interpretation of statistical significance versus actual applicability of molecular markers, raising questions about their clinical usefulness as individual prognostic markers.

Evaluation of the Effect of Diagnostic Molecular Testing on the Surgical Decision-Making Process for Patients With Thyroid Nodules

IMPORTANCE Diagnostic molecular testing is used in the workup of thyroid nodules. While these tests appear to be promising in more definitively assigning a risk of malignancy, their effect on surgical decision making has yet to be demonstrated. OBJECTIVE To investigate the effect of diagnostic molecular profiling of thyroid nodules on the surgical decision-making process. DESIGN, SETTING, AND PARTICIPANTS A surgical management algorithm was developed and published after peer review that incorporated individual Bethesda System for Reporting Thyroid Cytopathology classifications with clinical, laboratory, and radiological results. This algorithm was created to formalize the decision-making process selected herein in managing patients with thyroid nodules. Between April 1, 2014, and March 31, 2015, a prospective study of patients who had undergone diagnostic molecular testing of a thyroid nodule before being seen for surgical consultation was performed. The recommended management undertaken by the surgeon was then prospectively compared with the corresponding one in the algorithm. Patients with thyroid nodules who did not undergo molecular testing and were seen for surgical consultation during the same period served as a control group. MAIN OUTCOMES AND MEASURES All pertinent treatment options were presented to each patient, and any deviation from the algorithm was recorded prospectively. To evaluate the appropriateness of any change (deviation) in management, the surgical histopathology diagnosis was correlated with the surgery performed. RESULTS The study cohort comprised 140 patients who underwent molecular testing. Their mean (SD) age was 50.3 (14.6) years, and 75.0% (105 of 140) were female. Over a 1-year period, 20.3% (140 of 688) had undergone diagnostic molecular testing before surgical consultation, and 79.7% (548 of 688) had not undergone molecular testing. The surgical management deviated from the treatment algorithm in 12.9% (18 of 140) with molecular testing and in 10.2% (56 of 548) without molecular testing (P = .37). In the group with molecular testing, the surgical management plan of only 7.9% (11 of 140) was altered as a result of the molecular test. All but 1 of those patients were found to be overtreated relative to the surgical histopathology analysis. CONCLUSIONS AND RELEVANCE Molecular testing did not significantly affect the surgical decision-making process in this study. Among patients whose treatment was altered based on these markers, there was evidence of overtreatment.

Below-knee endovascular interventions have better outcomes compared to open bypass for patients with critical limb ischemia:

Both open surgery and endovascular peripheral interventions have been shown to effectively improve outcomes in patients with peripheral artery disease, but minimal data exist comparing outcomes performed at and below the knee. The purpose of this study was to compare outcomes following infrageniculate lower extremity open bypass (LEB) versus peripheral vascular intervention (PVI) in patients with critical limb ischemia. Using data from the 2008–2014 Vascular Quality Initiative, 1-year primary patency, major amputation, and mortality were compared among all patients undergoing LEB versus PVI at or below the knee for rest pain or tissue loss. Overall, 2566 patients were included (LEB=500, PVI=2066). One-year primary patency was significantly worse following LEB (73% vs 81%; p<0.001). One-year major amputation (14% vs 12%; p=0.18) and mortality (4% vs 6%; p=0.15) were similar regardless of revascularization approach. Multivariable analysis adjusting for baseline differences between groups confirmed inferior primary patency following LEB versus PVI (HR 0.74; 95% CI, 0.60–0.90; p=0.004), but no significant differences in 1-year major amputation (HR 1.06; 95% CI, 0.80–1.40; p=0.67) or mortality (HR 0.71; 95% CI, 0.44–1.14; p=0.16). Based on these data, we conclude that endovascular revascularization is a viable treatment approach for critical limb ischemia resulting from infrageniculate arterial occlusive disease.

Gastric and small intestine gastrointestinal stromal tumors: Do outcomes differ?

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Previous literature has suggested that small intestine GISTs are more aggressive than gastric GISTs. Our primary objective was to compare the outcomes of gastric and small intestine GISTs in the decade after approval of imatinib for treatment.

Intraoperative PTH May Not Be Necessary in the Management of Primary Hyperparathyroidism Even with Only One Positive or Only Indeterminate Preoperative Localization Studies

BackgroundIntraoperative PTH (IOPTH) monitoring has been widely used to confirm the removal of the culprit lesion during operation. However, the true benefit of IOPTH in patients with preoperatively well-localized single adenoma has been questioned. The aim of this study was to examine how or if IOPTH changes the surgical management and outcomes in patients with only one positive or only indeterminate localization studies.MethodsThis is a retrospective review of data from a parathyroid surgery database and patient records from July 2004 to June 2014, including patients with primary hyperparathyroidism with a planned MIP by two experienced endocrine surgeons after ≥1 positive/indeterminate preoperative localization study by ultrasound and/or sestamibi.ResultsA total of 482 patients with positive (342: 259 only 1, 83 with ≥2) or indeterminate (140: 105 only 1, 35 with ≥2) preoperative imaging studies were included. IOPTH changed the management in only 16 (3%) patients, with an additional lesion found in 12 of them. Surgical cure was achieved in 471 (98%) of patients (98% in the positive vs. 97% in the indeterminate group, p 0.58). With or without IOPTH, the cure rate would not have been significantly different in patients with only 1 positive preoperative imaging (96 vs. 98%, p 0.12). Similar results were seen in those with ≥2 indeterminate (100% cure rate with or without IOPTH).ConclusionOur study suggests that MIP may be safely and successfully performed without IOPTH for patients with ≥1 positive or ≥2 indeterminate preoperative imaging studies. This study is retrospective within inherent biases, and future prospective study is warranted.

Molecular Profiles and the “Indeterminate” Thyroid Nodule

Although fine-needle aspiration (FNA) biopsy is the most accurate and reliable diagnostic test available for the evaluation of a thyroid nodule, 20–30 % of FNA results are indeterminate or suspicious. In order to improve upon the diagnostic accuracy of FNA, several ancillary molecular tests have emerged to further refine the diagnostic role of FNA biopsy and improve the accuracy of preoperative diagnosis of indeterminate thyroid lesions. Over the past decade, significant progress has been made in the investigation of these molecular markers, and promising findings have been reported. However, because of the complexity of surgical decision-making processes, the clinical usefulness and impact of these markers remain unclear. This chapter will review the efficacy and potential clinical utility of these molecular markers in preoperative diagnosis of an indeterminate thyroid nodule.

Unusual findings in thyroid cytology and histology

Although cytology and histopathology of thyroid lesions generally fall into common, well‐defined categories, there are uncommon cases with unusual fine needle aspiration (FNA) findings or histology. Herein, we review the prevalence and characteristics of rare thyroid cytology and histopathology findings at a tertiary hospital.

Abstract 4268: DNA copy number variation and driver mutation patterns of follicular thyroid tumors

Background Our previous study using single nucleotide polymorphism (SNP) array identified significant differences in copy number variation (CNV) between tumor subtypes. This study was conducted to extend our previous findings, using both Fluorescent In-Situ Hybridization (FISH) and quantitative PCR (qPCR), and to investigate the possible relationship with major thyroid cancer driver mutations, and their association with aggressive features in follicular thyroid tumors. Methods For the validation, we obtained paraffin blocks of all cases with CNVs identified in our prior study (7 samples with Ch12 amplification, and 6 samples with Ch22 deletion), as well as 6 control samples with no CNV, for FISH analysis and qPCR. We used centromeric and distal probes to differentiate partial vs whole chromosome alterations. We then extended the study to characterize the relation between CNV and driver mutations and possible associations with aggressive features in a larger cohort of tumors, consisting of: 35 follicular adenoma (FA), 19 non-aggressive follicular variant papillary thyroid carcinoma (FVPTC), 22 aggressive FVPTC, 16 non-aggressive follicular carcinoma (FC), and 15 aggressive FC. Results Our FISH and qPCR results confirmed our earlier CNV results in this expanded sample cohort. Furthermore, FISH indicated that in each case, CNV involved the entire chromosome rather than sub-chromosomal alterations. Ch12 amplification was significantly more prevalent in FA and non-aggressive tumor than aggressive tumor subtypes (p-value Conclusion Our study suggests that Ch12 amplification is associated with indolent tumors. Since FAs are a common source of inconclusive pre-operative cytopathology, a molecular signature such as Ch12 amplification that identifies follicular tumors with little aggressive potential could be useful. Further independent external testing is warranted. Citation Format: Hyun-seok Kim, Kathleen Wilsbach, Aurelien Marti, Alireza Najafian, Alan K. Meeker, James R. Eshleman, Justin A. Bishop, Martha Zeiger, Christopher B. Umbricht. DNA copy number variation and driver mutation patterns of follicular thyroid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4268. doi:10.1158/1538-7445.AM2015-4268