Elham Khanafshar

A Large Multicenter Correlation Study of Thyroid Nodule Cytopathology and Histopathology

BACKGROUND Fine-needle aspiration (FNA) biopsies are the cornerstone of preoperative evaluation of thyroid nodules, but FNA diagnostic performance has varied across different studies. In the course of collecting thyroid FNA specimens for the development of a molecular diagnostic test, local cytology and both local and expert panel surgical pathology results were reviewed. METHODS Prospective FNAs were collected at 21 clinical sites. Banked FNAs were collected from two academic centers. Cytology and corresponding local and expert panel surgical pathology results were compared to each other and to a meta-review of 11 recently published U.S.-based thyroid FNA studies. RESULTS FNA diagnostic performance was comparable between the study specimens and the meta-review. Histopathology malignancy rates for prospective clinic FNAs were 34% for cytology indeterminate cases and 98% for cytology malignant cases, comparable to the figures found in the meta-review (34% and 97%, respectively). However, histopathology malignancy rates were higher for cytology benign cases in the prospective clinic FNA subcohort (11%) than in the meta-review (6%, with meta-review rates of 10% at community sites and 2% at academic centers, p < 0.0001). Resection rates for prospective clinic FNAs were also comparable to the meta-review for both cytology indeterminate cases (62% vs. 59%, respectively) and cytology malignant cases (82% vs. 81%, respectively). Surgical pathology categorical disagreement (benign vs. malignant diagnosis) was higher between local pathology and a consensus of the two expert panelists (11%) than between the two expert panelists both pre- (8%) and postconferral (3%). CONCLUSIONS Although recent guidelines for FNA biopsy and interpretation have been published, the rates of false-positive and false-negative results remain a challenge. Two-thirds of cytology indeterminate cases were benign postoperatively and may decrease with the development of an accurate molecular diagnostic test. High disagreement rates between local and expert panel histopathology diagnosis suggests that central review for surgical diagnoses should be used when developing diagnostic tests based on resected thyroid specimens.

Parathyroid carcinoma, atypical parathyroid adenoma, or parathyromatosis?

Parathyroid carcinoma, atypical parathyroid adenoma, and parathyromatosis can be differentiated relatively easily from typical parathyroid adenomas, but distinguishing them from each other is more difficult.

Identification of biomarkers of adrenocortical carcinoma using genomewide gene expression profiling.

HYPOTHESIS The gene expression profiles of benign and malignant adrenocortical tumors are different. DESIGN Genomewide gene expression profiling and validation. SETTING Tertiary medical center. PATIENTS Eighty-five patients with benign adrenocortical tumors (n = 74) and adrenocortical carcinoma (n = 11). INTERVENTION Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) in 89 adrenocortical tissue samples (11 malignant and 78 benign). The criteria for differentially expressed genes between benign and malignant adrenocortical tumors were a false discovery rate of less than 5% and an adjusted P < .01. Genes differentially expressed by 8-fold higher or lower were validated by RT-PCR. MAIN OUTCOME MEASURES The diagnostic accuracy of differentially expressed genes as determined by the area under the receiver operating characteristic curve (AUC). RESULTS We found 37 genes differentially expressed by 8-fold higher or lower. Fifteen genes were downregulated and 22 were upregulated in adrenocortical carcinoma. Of the 37 genes, 29 differentially expressed by microarray correlated with the gene expression levels by quantitative RT-PCR (P < or = .01). Of the 37 genes validated by RT-PCR, 22 were significantly differentially expressed between benign and malignant adrenocortical tumors (P < .05). Five of these 22 genes had an AUC of 0.80 or greater (the AUC for IL13RA2 was 0.90; HTR2B, 0.87; CCNB2, 0.86; RARRES2, 0.86; and SLC16A9, 0.80), indicating high diagnostic accuracy for distinguishing benign from malignant adrenocortical tumors. CONCLUSION We identified 37 genes that are dysregulated in adrenocortical carcinoma, and several of the differentially expressed genes have excellent diagnostic accuracy for distinguishing benign from malignant adrenocortical tumors.

Higher rate of BRAF mutation in papillary thyroid cancer over time: A single institution study

The incidence of thyroid cancer has doubled over the past decade. The reason for this dramatic increase in incidence is controversial. Some investigators have suggested that the increased incidence is because of increased detection of small primary tumors as a result of diagnostic scrutiny. Conversely, some investigators have demonstrated an increased incidence across all tumor sizes, suggesting that other factors may play a role. This study was undertaken to investigate the clinical, pathologic, and molecular changes present in papillary thyroid cancer over a 15‐year period during which the incidence of papillary thyroid cancer doubled.

MicroRNA profiling of benign and malignant pheochromocytomas identifies novel diagnostic and therapeutic targets

MicroRNAs (miRNAs) are small RNAs ( approximately 22 bp) that post-transcriptionally regulate protein expression and are found to be differentially expressed in a number of human cancers. There is increasing evidence to suggest that miRNAs could be useful in cancer diagnosis, prognosis, and therapy. We performed miRNA microarray expression profiling on a cohort of 12 benign and 12 malignant pheochromocytomas and identified a number of differentially expressed miRNAs. These results were validated in a separate cohort of ten benign and ten malignant samples using real-time quantitative RT-PCR; benign samples had a minimum follow-up of at least 2 years. It was found that IGF2 as well as its intronic miR-483-5p was over-expressed, while miR-15a and miR-16 were under-expressed in malignant tumours compared with benign tumours. These miRNAs were found to be diagnostic and prognostic markers for malignant pheochromocytoma. The functional role of miR-15a and miR-16 was investigated in vitro in the rat PC12 pheochromocytoma cell line, and these miRNAs were found to regulate cell proliferation via their effect on cyclin D1 and apoptosis. These data indicate that miRNAs play a pivotal role in the biology of malignant pheochromocytoma, and represent an important class of diagnostic and prognostic biomarkers and therapeutic targets warranting further investigation.

Defining a molecular phenotype for benign and malignant parathyroid tumors

It is frequently difficult to establish histologically whether a parathyroid tumor is a parathyroid carcinoma, parathyromatosis, or an atypical adenoma. The authors asked whether these tumors have a distinctive molecular profile, whether benign tumors could be distinguished from malignant tumors, and whether parathyromatosis is a low‐grade parathyroid carcinoma or is benign tissue that can invade other organs.

A prospective study evaluating the accuracy of using combined clinical factors and candidate diagnostic markers to refine the accuracy of thyroid fine needle aspiration biopsy

BACKGROUND Approximately 30% of fine needle aspiration biopsies of the thyroid have inconclusive results. We conducted a prospective trial to determine whether clinical and molecular markers could be used in combination to improve the accuracy of thyroid fine needle aspiration biopsy. METHODS Clinical, tumor genotyping for common somatic mutations (BRAF V600E, NRAS, KRAS, RET/PTC1, RET/PTC3, and NTRK1), and the gene expression levels of 6 candidate diagnostic markers were analyzed by univariate and multivariate methods in 341 patients to determine whether they could distinguish reliably benign from malignant thyroid neoplasms, and a scoring model was derived. RESULTS By a multivariate analysis, fine needle aspiration biopsy cytology classification, the presence of a NRAS mutation, and the tissue inhibitor of metalloproteinase 1 expression level were associated jointly with malignancy. The overall accuracy of the scoring model, including these 3 variables, to distinguish benign from malignant thyroid tumors was 91%, including 67% for the indeterminate and 77% for the suspicious FNA subgroups. CONCLUSION Fine needle aspiration biopsy cytology classification, the presence of NRAS mutation, and tissue inhibitor of metalloproteinase 1 messenger RNA expression levels in combination provide a greater diagnostic accuracy than fine needle aspiration biopsy cytology alone to allow selection of more definitive initial operative treatment. The sensitivity of the scoring model, however, was too low to avoid the need for diagnostic thyroidectomies for indeterminate fine needle aspiration biopsy findings.

Nonfunctioning parathyroid carcinoma: case report and review of literature.

OBJECTIVE To report a case of nonfunctioning parathyroid carcinoma that was incidentally found during a thyroidectomy for multinodular goiter. METHODS We present a case report, detailing the clinical course and histologic findings in a patient with a nonfunctional parathyroid carcinoma. The related literature is also reviewed. RESULTS A 67-year-old woman presented with a 30-year history of a multinodular goiter that was symptomatic. A total thyroidectomy was performed. Histologic examination revealed not only a multinodular thyroid but also a mass in the left lobe, which was diagnostic of a parathyroid carcinoma. Serum calcium and parathyroid hormone levels were normal postoperatively. Eleven months after the initial operation, a suprasternal mass developed, and she underwent neck reexploration and subtotal resection of an invasive recurrent nonfunctioning parathyroid carcinoma. The serum parathyroid hormone and calcium levels were normal before and after the operation. Postoperatively, the patient underwent radiation therapy. Twenty-three months after the initial operation, a computed tomographic scan of the chest revealed an interval increase in size of a nodule in the left lower lobe of the lung, and 30 months after her initial operation, she underwent resection of an isolated, 1-cm (greatest diameter), metastatic parathyroid carcinoma in the left lower lobe of the lung. The patient is currently doing well without evidence of recurrent disease. CONCLUSION Nonfunctioning parathyroid carcinomas are difficult to diagnose and to treat. Recurrent disease after operation is common, and radiation therapy may help stabilize tumor growth. Patients with nonfunctioning parathyroid carcinomas appear to have a poorer prognosis than do those with functioning parathyroid cancers.

Does the 3‐gene diagnostic assay accurately distinguish benign from malignant thyroid neoplasms?

A 3‐gene (PCSK2, PLAB, CCND2) assay has been reported to have high accuracy for distinguishing benign from malignant thyroid tumors that are often indeterminate on fine–needle aspiration (FNA) biopsy. The aim of the current study was to determine the diagnostic accuracy of the 3‐gene assay in thyroid tissue and in FNA biopsy for distinguishing benign from malignant thyroid neoplasms.

Mitogen-inducible gene-6 expression correlates with survival and is an independent predictor of recurrence in BRAFV600E positive papillary thyroid cancers

BACKGROUND Mitogen-inducible gene-6 (Mig-6) is an immediate early response gene that negatively regulates signaling. EGFR overexpression and activating mutations in MAPK signaling effectors are common events in papillary thyroid cancer (PTC). The purpose of this study was to determine if Mig-6 expression is associated with EGFR expression or surgical outcomes in PTC. METHODS We determined Mig-6 transcript levels from a microarray in 19 patients with PTC who underwent thyroidectomy. We established a maximally selected cutoff to discriminate Kaplan-Meier survival estimates. For cross-validation, we performed quantitative RT-PCR on resected well-differentiated PTC from an additional 106 patients. RESULTS Mig-6 and EGFR mRNA levels correlated directly (P < .0001). Mig-6 expression above the cutoff of 1.10 (2;-dCt[Mig6-GUS]) was associated with greater survival (P = .008). When this cutoff was applied in the cross-validation, high Mig-6 expression was associated with longer survival (P = .03) and disease-free survival (P = .07). Furthermore, high Mig-6 expression was independently predictive of greater disease-free survival in BRAF(V600E)-positive PTC. CONCLUSION High Mig-6 expression in PTC is associated with favorable outcomes. Mig-6 is a novel tumor suppressor that may be a candidate for targeted cancer therapeutics in patients with PTC refractory to conventional therapy.