Faculty Bibliography

BACKGROUND:Approximately 30% of fine-needle aspiration (FNA) biopsies of thyroid nodules are indeterminate or nondiagnostic. Recent studies suggest microRNA (miRNA, miR) is differentially expressed in malignant tumors and may have a role in carcinogenesis, including thyroid cancer. The authors therefore tested the hypothesis that miRNA expression analysis would identify putative markers that could distinguish benign from malignant thyroid neoplasms that are often indeterminate on FNA biopsy. METHODS:A miRNA array was used to identify differentially expressed genes (5-fold higher or lower) in pooled normal, malignant, and benign thyroid tissue samples. Real-time quantitative polymerase chain reaction was used to confirm miRNA array expression data in 104 tissue samples (7 normal thyroid, 14 hyperplastic nodule, 12 follicular variant of papillary thyroid cancer, 8 papillary thyroid cancer, 15 follicular adenoma, 12 follicular carcinoma, 12 Hurthle cell adenoma, 20 Hurthle cell carcinoma, and 4 anaplastic carcinoma cases), and 125 indeterminate clinical FNA samples. The diagnostic accuracy of differentially expressed genes was determined by analyzing receiver operating characteristics. RESULTS:Ten miRNAs showed >5-fold expression difference between benign and malignant thyroid neoplasms on miRNA array analysis. Four of the 10 miRNAs were validated to be significantly differentially expressed between benign and malignant thyroid neoplasms by quantitative polymerase chain reaction (P < .002): miR-100, miR-125b, miR-138, and miR-768-3p were overexpressed in malignant samples of follicular origin (P < .001), and in Hurthle cell carcinoma samples alone (P < .01). Only miR-125b was significantly overexpressed in follicular carcinoma samples (P < .05). The accuracy for distinguishing benign from malignant thyroid neoplasms was 79% overall, 98% for Hurthle cell neoplasms, and 71% for follicular neoplasms. The miR-138 was overexpressed in the FNA samples (P = .04) that were malignant on final pathology with an accuracy of 75%. CONCLUSIONS:MicroRNA expression differs for normal, benign, and malignant thyroid tissue. Expression analysis of differentially expressed miRNA could help distinguish benign from malignant thyroid neoplasms that are indeterminate on thyroid FNA biopsy.

CONTEXT/BACKGROUND:Parathyroid carcinoma is a rare but ominous cause of primary hyperparathyroidism. OBJECTIVES AND MAIN OUTCOME MEASURES: The objective of the study was to review the outcomes of parathyroid cancer patients and to evaluate the factors associated with mortality. DESIGN, SETTING, AND PATIENTS/METHODS:This was a retrospective review performed on 37 patients with parathyroid cancer treated at a single university tertiary care center between 1966 and 2009. RESULTS:The average age at cancer diagnosis was 53 yr (range 23-75 yr), and 23 patients (62%) were men. Eighteen patients (49%) recurred after their initial cancer operation. The average number of neck dissections done for cancer was three (range 1-11). After initial diagnosis, 22 patients (60%) eventually developed complications, including unilateral (n = 11) or bilateral (n = 3) vocal cord paralysis (38%). Eight patients (22%) had, at some point, an associated benign parathyroid adenoma. Median overall survival was 14.3 yr (range 10.5-25.7 yr) from the date of diagnosis. Factors associated with increased mortality included lymph node or distant metastases, number of recurrences, higher calcium level at recurrence, and a high number of calcium-lowering medications. Factors not associated with mortality included age, race, tumor size, time to first recurrence, and extent of initial operation. Initial operations done at our center had improved survival (P = 0.037) and decreased complication rates (P < 0.001) vs. those done elsewhere. CONCLUSION/CONCLUSIONS:Parathyroid cancer patients typically have a long survival, which often includes multiple reoperations for recurrence and thus a high rate of surgical complications. Patients in whom there is a high index of suspicion for parathyroid cancer should be referred to a dedicated endocrine surgery center for their initial operation.

BACKGROUND:Medullary thyroid cancer (MTC) commonly presents with lymph node (LN) metastases, and has a worse prognosis than papillary thyroid cancer (PTC). Tumor size and LN involvement have been shown to affect stage of disease; however, to our knowledge, ours is the first study that attempts to correlate anterior neck pain on presentation with the extent of disease. METHODS:We performed a retrospective review of patients with MTC who underwent an operation from February 1998 through December 2008. We compared the symptom of anterior neck pain with the pathologic extent of disease. Our control group comprised patients who underwent an operation for PTC. Analysis was performed using the Fisher's exact test and the Mann-Whitney test. RESULTS:Of the 109 patients with MTC, 50 (46%) met our inclusion criteria. Of the 50 patients with MTC, 11 presented with neck pain, compared to 3 of the 50 patients with PTC (p = 0.041). Of those 11 patients, 9 (82%) had LN involvement on final pathology, as compared with 14 (36%) of the 39 without neck pain (p = 0.014). Of patients with neck pain, 18% were diagnosed at stage I to II and 82% at stage III to IV, compared to 64% at stage I to II and 36% at stage III to IV (p = 0.014). CONCLUSIONS:Our study demonstrates that more patients with MTC present with anterior neck pain than do patients with PTC and that patients with MTC and neck pain have an increased risk of LN metastases. The results of this study suggest that MTC patients, who present with concomitant neck pain, should undergo a total thyroidectomy, prophylactic bilateral central neck dissection, and ipsilateral lateral neck dissection.

INTRODUCTION/BACKGROUND:Intraoperative aspiration of a nodule and parathyroid hormone (PTH) assay has been shown to accurately confirm parathyroid tissue. However, the reported aspiration technique varies in the literature. We sought to determine if the number of passes affected the accuracy of PTH analysis. METHODS:A prospective analysis was performed on 25 consecutive patients who underwent a parathyroidectomy for primary hyperparathyroidism. The excised parathyroid gland was aspirated using 1, 3, and 5 passes. The data were analyzed using the Wilcoxon rank, chi-square, and Fisher exact tests to calculate the 2-tailed P value. RESULTS:Of the 26 glands aspirated, the mean PTH value varied with the number of passes, 2,073 pg/mL for 1 pass, 2,347 for 3 passes, and 2,695 for 5 passes (P = .02). Accuracy was dependent on the number of passes, with 5 passes (P = .018) having less PTH variation than 1 or 3 passes. CONCLUSIONS:Aspiration of nodules to determine the PTH level helps confirm the presence of parathyroid tissue. The number of needle passes affects the accuracy of the PTH level, with 5 passes being the optimal number of passes to attain no false-negative results.

BACKGROUND:The role of routine prophylactic central-neck lymph node dissection (CLND) for papillary thyroid cancer (PTC) remains controversial. We perform CLND for PTC only in patients with enlarged nodes as determined by preoperative ultrasound and intraoperative inspection and palpation. METHODS:We identified all patients with PTC who underwent CLND during thyroidectomy (group 1) at our institution, and then we identified an equivalent number of demographically matched patients who underwent thyroidectomy without CLND (group 2) and compared the outcomes of the 2 groups. RESULTS:In all, 191 patients were identified for each group; 49/191 (26%) patients in group 1 developed locoregional nodal recurrence (12% central neck and 21% lateral neck), compared with 11/191 (6%) patients in group 2 (3% central neck and 3% lateral neck; P < .05). Overall, 161/191 (84%) patients in group 1 were disease free at last survey, compared with 180/191 (94%) patients in group 2 (P < .05). Transient hypocalcemia was significantly greater in group 1. No difference was found in disease-specific mortality. CONCLUSION/CONCLUSIONS:Surgeon assessment of the central neck compartment is an accurate predictor of which patients with PTC will benefit from CLND. Patients with nonenlarged central neck nodes who undergo total thyroidectomy without CLND have a low risk of developing recurrence.

BACKGROUND:Serum thyroglobulin (Tg) is the most accurate biomarker for thyroid cancer recurrence. However, some clinicians measure preoperative Tg as a diagnostic cancer marker despite lack of supporting evidence. We examined whether Tg accurately predicts malignancy in follicular or Hürthle-cell neoplasms. METHODS:We reviewed 366 patients who underwent thyroidectomies for follicular/Hürthle-cell neoplasms. We compared Tg in malignant versus benign tumors by univariate and receiver-operator characteristic analyses. We also examined several Tg-derived indices that normalized Tg to known confounding factors including nodule size, thyroid function, and type of Tg assay. RESULTS:Thirty-nine patients met inclusion criteria for analysis. There were no differences between malignant (n = 16) and benign (n = 23) lesions in Tg or any of the normalized indexes. Receiver-operator characteristic analysis revealed an area under the curve of .59. Lesions with Tg levels greater than 500 mug/L had a positive predictive value of .75. CONCLUSIONS:Tg has poor accuracy for predicting malignancy in follicular or Hürthle-cell thyroid neoplasms.

INTRODUCTION/BACKGROUND:Hürthle cell carcinoma (HCC) is a rare tumor that tends to metastasize to the lymph nodes. Some studies have correlated size of Hürthle cell tumors with the risk of malignancy. Whether the size of HCC correlates with the risk of lymph node (LN) metastases, to our knowledge has not been addressed. METHODS:A retrospective analysis was performed on all patients diagnosed with HCC on final pathology between 1997 and 2008. The tumor size and lymph node status was obtained for each patient. The data were analyzed utilizing Student's t-test and the Fisher's exact test to calculate the two-tailed p-value. RESULTS:Out of 39 patients diagnosed with HCC 3(8%) had LN metastases; 1 had ipsilateral central LN metastasis and 2 had ipsilateral central and lateral LN metastasis. LN dissection was performed in patients with known metastasis (2 were evident on preoperative ultrasound and 1 intraoperatively). Patients with LN metastasis were older than those without (mean age: 86.7 and 56.4 years, respectively), had larger tumors (mean size: 6 and 4 cm) and were commonly male (2 of 3). No tumor < 5cm presented with lymph node involvement (3/15 with >5cm cancer had node metastasis, 0/24 with <5cm cancer had node metastasis). CONCLUSIONS:Similar to what has been found in patients with papillary thyroid cancer, older male patients with Hürthle cell carcinomas greater than 5cm are more likely to have lymph node metastasis. Our data suggest that these patients may benefit from a prophylactic ipsilateral central neck dissection at the time of their initial operation.

BACKGROUND:The American Thyroid Association recently changed its management guidelines for papillary thyroid cancer (PTC) to include routine central neck lymph node dissection (CLND) during thyroidectomy. We currently perform CLND during thyroidectomy only if enlarged central nodes are detected by palpation or ultrasonography; we perform CLND in the reoperative setting for recurrence in previously normal-appearing or incompletely resected nodes. Critics of this approach argue that reoperative CLND has higher complication and recurrence rates than initial CLND. We sought to test this argument, using it as our hypothesis. DESIGN/METHODS:Retrospective review. SETTING/METHODS:University hospital. PATIENTS/METHODS:All patients undergoing CLND for PTC between January 1, 1998, and December 31, 2007. INTERVENTIONS/METHODS:Thyroidectomy and CLND. MAIN OUTCOME MEASURES/METHODS:Complications (neck hematoma, recurrent laryngeal nerve injury, and hypoparathyroidism) and recurrence of PTC. RESULTS:Altogether, 295 CLNDs were performed: 189 were initial operations and 106 were reoperations. The rate of transient hypocalcemia (41.8% vs 23.6%) was significantly higher in patients undergoing initial CLND compared with those undergoing reoperative CLND. Rates of neck hematoma (1.1% vs 0.9%), transient hoarseness (4.8% vs 4.7%), permanent hoarseness (2.6% vs 1.9%), and permanent hypoparathyroidism (0.5% vs 0.9%) were not different between initial and reoperative CLND. In addition, recurrence rates in the central (11.6% vs 14.1%) and lateral (21.7% vs 17.0%) compartments were not different between the 2 groups. CONCLUSIONS:Reoperative CLND for PTC has a lower rate of temporary hypocalcemia, the same rate of other complications, and the same rate of recurrence compared with initial CLND. Choosing to observe nonenlarged central neck lymph nodes for PTC does not result in increased complications or recurrence if reoperation is required.

HYPOTHESES/OBJECTIVE:Decitabine recovers expression of silenced genes on chromosome 11q13 and has antineoplastic effects in adrenocortical carcinoma (ACC) cells. DESIGN/METHODS:NCI-H295R cells were treated with decitabine (0.1-1.0 microM) over 5 days. Cells were evaluated at 24-hour intervals for the effects of decitabine on ACC cell proliferation, cortisol secretion, and cell invasion. Expression was quantified for 6 genes on 11q13 (DDB1, MRPL48, NDUFS8, PRDX5, SERPING1, and TM7SF2) that were previously shown to be underexpressed in ACC. SETTING/METHODS:Academic research. Study Specimen Human ACC cell line. MAIN OUTCOME MEASURES/METHODS:Adrenocortical carcinoma cell proliferation, cortisol secretion, and cell invasion were measured using immunometric assays. Quantitative reverse transcription-polymerase chain reaction was used to measure gene expression relative to GAPDH. RESULTS:Decitabine inhibited ACC cell proliferation by 39% to 47% at 5 days after treatment compared with control specimens (P < .001). The inhibitory effect was cytostatic, time dependent, and dose dependent. Decitabine decreased cortisol secretion by 56% to 58% at 5 days after treatment (P = .02) and inhibited cell invasion by 64% at 24 hours after treatment (P = .03). Of 6 downregulated genes on 11q13, decitabine recovered expression of NDUFS8 (OMIM 602141) (P < .001) and PRDX5 (OMIM 606583) (P = .006). CONCLUSIONS:Decitabine exhibits antitumoral properties in ACC cells at clinically achievable doses and may be an effective adjuvant therapy in patients with advanced disease. Decitabine recovers expression of silenced genes on 11q13, which suggests a possible role of epigenetic gene silencing in adrenocortical carcinogenesis.