Does impotence improve after parathyroidectomy in men with primary hyperparathyroidism?

BACKGROUND: Erectile dysfunction (ED) is a common diagnosis associated with age, hypertension, cardiovascular disease, and diabetes. Primary hyperparathyroidism (PHP) is also seen with these comorbidities, but its association with ED has yet to be studied. We evaluated the rate and resolution of impotence after curative surgery for PHP. METHODS: Prospectively collected data, including a self-reported questionnaire of symptoms, were reviewed for men who had curative parathyroid exploration for sporadic PHP from July 2010 to January 2014. Data were compared with an age-matched cohort of men who had thyroidectomy during the same period. RESULTS: Among 160 men with PHP and mean age of 60 years (range, 19-88), preoperative ED was reported by 13%, and this group was older than patients without ED (mean age, 70 vs 58 years, P < .01). Self-reported resolution of ED after parathyroidectomy occurred in 67% compared with 43% of patients in a thyroidectomy cohort. Preoperative mean arterial blood pressure was less in men with postoperative resolution of ED (96.6 vs 105.4 mm Hg, P = .03). Among 3 of 21 men on specific ED medications, 2 no longer required them postoperatively. CONCLUSION: Impotence is reported often by men undergoing parathyroidectomy for PHP. After curative surgery, 67% of those affected may self-report ED resolution, which may be more pronounced in those patients with a lesser preoperative mean arterial blood pressure.

Tumor genotype determines phenotype and disease-related outcomes in thyroid cancer: a study of 1510 patients.

OBJECTIVES: To correlate thyroid cancer genotype with histology and outcomes. BACKGROUND: The prognostic significance of molecular signature in thyroid cancer (TC) is undefined but can potentially change surgical management. METHODS: We reviewed a consecutive series of 1510 patients who had initial thyroidectomy for TC with routine testing for BRAF, RAS, RET/PTC, and PAX8/PPARG alterations. Histologic metastatic or recurrent TC was tracked for 6 or more months after oncologic thyroidectomy. RESULTS: Papillary thyroid cancer (PTC) was diagnosed in 97% of patients and poorly differentiated/anaplastic TC in 1.1%. Genetic alterations were detected in 1039 (70%); the most common mutations were BRAFV600E (644/1039, 62%), and RAS isoforms (323/1039, 31%). BRAFV600E-positive PTC was often conventional or tall cell variant (58%), with frequent extrathyroidal extension (51%) and lymph node metastasis (46%). Conversely, RAS-positive PTC was commonly follicular variant (87%), with infrequent extrathyroidal extension (4.6%) and lymph node metastasis (5.6%). BRAFV600E and RET/PTC-positive PTCs were histologically similar. Analogously, RAS and PAX8/PPARG-positive PTCs were histologically similar. Compared with RAS or PAX8/PPARG-positive TCs, BRAFV600E or RET/PTC-positive TCs were more often associated with stage III/IV disease (40% vs 15%, P < 0.001) and recurrence (10% vs 0.7%, P < 0.001; mean follow-up 33 ± 21 mo). Distant metastasis was highest in patients with RET/PTC-positive TC (10.8%, P = 0.02). CONCLUSIONS: In this large study of prospective mutation testing in unselected patients with TC, molecular signature was associated with distinctive phenotypes including cancers, with higher risks of both distant metastasis and early recurrence. Preoperative genotype provides valuable prognostic data to appropriately inform surgery.

The clinical importance of parathyroid atypia: is long-term surveillance necessary?

BACKGROUND: The uncommon diagnosis of atypical parathyroid adenoma (APA) creates a clinical conundrum for surveillance. We evaluated a large series of APA to determine long-term outcomes. METHODS: Prospectively collected data were retrieved for patients with a diagnosis of histologic APA defined by presence of ≥2 criteria: clinical/intraoperative adherence, fibrotic bands, trabecular growth, or mitotic rate of >1/10 per high-power field without indisputable signs of malignancy. Follow-up was at 2 weeks, 6 months, and yearly thereafter. RESULTS: From 1970 to 2014, 51 patients (1.2%) with primary hyperparathyroidism had a diagnosed APA. Mean age was 56 years (range, 19-83), and 61% were women. Intraoperatively, 11 of 51 glands (22%) were adherent, requiring concurrent thyroid lobectomy. Common microscopic findings were fibrosis (78%), trabecular growth (37%), and increased mitotic count (24%); the mean APA weight was 3.14 g (range, 167 mg-38 g). Loss of heterozygosity occurred in 25 of 38 tested patients (66%) at the p21 locus in 9 cases, at CDC73 and PTEN in 6, and at RB1 in 4 cases, with mean fractional allelic loss of 24% (range, 6-79). With mean follow-up of 5 years (range, 0.5-18), no patient has developed recurrence. CONCLUSION: Over a mean follow-up of 5 years, we observed no recurrences after APA resection. Molecular features had no discernable impact, indicating that long-term follow-up may be unnecessary.

Adrenal Imaging Features Predict Malignancy Better than Tumor Size.

INTRODUCTION: In adrenal tumors, size ≥ 4 cm has been an indication for adrenalectomy due to concern for malignancy. We compared mass size to imaging features (ImF) for accuracy in diagnosing adrenal malignancy. METHODS: Data were retrieved for 112 consecutive patients who had adrenalectomy from January 2011 to August 2014. ImF was classified as nonbenign if HU > 10 on unenhanced CT scan or if loss of signal on out-of-phase imaging was absent on chemical-shift MRI. Indications for resection included hormonal hypersecretion, nonbenign ImF, and/or size ≥ 4 cm. RESULTS: Of 113 resected adrenals, 37 % were functional. Histologic malignancy occurred in 18 % (20/113) and included 3 adrenocortical carcinomas (ACC), 1 epithelioid liposarcoma, 1 lymphoma, 1 malignant nerve sheath tumor, and 14 adrenal metastases. Patients with malignancies were older (mean age, 60 ± 13 vs. 51 ± 14 years, p = 0.01). Malignant tumors were larger on preoperative imaging (mean 5.3 ± 3.2 vs. 3.9 ± 2.4 cm, p = 0.03). All 20 malignant masses had nonbenign ImF. In predicting malignancy, the sensitivity, specificity, NPV, and PPV of nonbenign ImF was 100, 57, 100, and 33 %, respectively. Size ≥ 4 cm was less predictive with sensitivity, specificity, NPV, and PPV of 55, 61, 86, and 23 %, respectively. If size ≥ 4 cm had been used as the sole criterion for surgery, 45 % of malignancies (9/20) would have been missed including 8 metastases and an ACC. CONCLUSIONS: In resected adrenal tumors, the presence of nonbenign ImF is more sensitive for malignancy than mass size (100 vs. 55 %) with equivalent specificity. Regardless of mass size, adrenalectomy should be strongly considered when non-benign ImF are present.

IRF-1 inhibits NF-κB activity, suppresses TRAF2 and cIAP1 and induces breast cancer cell specific growth inhibition.

Interferon Regulatory Factor (IRF)-1, originally identified as a transcription factor of the human interferon (IFN)-ß gene, mediates tumor suppression and may inhibit oncogenesis. We have shown that IRF-1 in human breast cancer cells results in the down-regulation of survivin, tumor cell death, and the inhibition of tumor growth in vivo in xenogeneic mouse models. In this current report, we initiate studies comparing the effect of IRF-1 in human nonmalignant breast cell and breast cancer cell lines. While IRF-1 in breast cancer cells results in growth inhibition and cell death, profound growth inhibition and cell death are not observed in nonmalignant human breast cells. We show that TNF-α or IFN-γ induces IRF-1 in breast cancer cells and results in enhanced cell death. Abrogation of IRF-1 diminishes TNF-α and IFN-γ-induced apoptosis. We test the hypothesis that IRF-1 augments TNF-α-induced apoptosis in breast cancer cells. Potential signaling networks elicited by IRF-1 are investigated by evaluating the NF-κB pathway. TNF-α and/or IFN-γ results in decreased presence of NF-κB p65 in the nucleus of breast cancer cells. While TNF-α and/or IFN-γ can induce IRF-1 in nonmalignant breast cells, a marked change in NF-κB p65 is not observed. Moreover, the ectopic expression of IRF-1 in breast cancer cells results in caspase-3, -7, -8 cleavage, inhibits NF-κB activity, and suppresses the expression of molecules involved in the NF-κB pathway. These data show that IRF-1 in human breast cancer cells elicits multiple signaling networks including intrinsic and extrinsic cell death and down-regulates molecules involved in the NF-κB pathway.

Surgeon volume and adequacy of thyroidectomy for differentiated thyroid cancer.

INTRODUCTION: We aimed to determine influence of surgeon volume on (1) frequency of appropriate initial surgery for differentiated thyroid cancer (DTC) and (2) completeness of resection. METHODS: We reviewed all initial thyroidectomies (Tx; lobectomy and total) performed in a health system during 2011; surgeons were grouped by number of Tx cases per year. For patients with histologic DTC ≥ 1 cm, surgeon volume was correlated with initial extent of the operation, and markers of complete resection including uptake on I(123) prescan, thyrotropin-stimulated thyroglobulin levels, and I(131) dose administered. RESULTS: Of 1,249 patients who underwent Tx by 42 surgeons, 29% had DTC ≥ 1 cm without distant metastasis. At a threshold of ≥ 30 Tx per year, surgeons were more likely to perform initial total Tx for DTC ≥ 1 cm (P = .01), and initial resection was more complete as measured by all 3 quantitative markers. For patients with advanced stage disease, a threshold of ≥ 50 Tx per year was needed before observing improvements in I(123) uptake (P = .004). CONCLUSION: Surgeons who perform ≥ 30 Tx a year are more likely to undertake the appropriate initial operation and have more complete initial resection for DTC patients. Surgeon volume is an essential consideration in optimizing outcomes for DTC patients, and even higher thresholds (≥ 50 Tx/year) may be necessary for patients with advanced disease.

Fibromyalgia symptoms and medication requirements respond to parathyroidectomy.

BACKGROUND: Fibromyalgia (FM), an ill-defined symptom complex, is characterized by musculoskeletal pain, headache, depression, fatigue, and cognitive decline, symptoms also seen commonly in primary hyperparathyroidism (PHP). Prevalence of concurrent PHP and FM and response to parathyroidectomy (PTX) of those with both conditions are unknown. METHODS: We reviewed prospective data of 4,000 patients with sporadic PHP who had PTX from 1995 to 2013 examining perioperative symptoms and medication usage for those with diagnosed FM. Cure was defined by normocalcemia at ≥ 6 months. RESULTS: Of 2,184 patients, 80 (4%) had a prior diagnosis of FM. Of evaluable FM patients, 97.3% had definitive cure of PHP. After PTX, 89% had improvement in ≥ 1 symptom attributed to FM, with improved cognition/memory most common (80%). Improvement in ≥ 2, ≥ 3, and ≥ 4 FM symptoms was appreciated by 71%, 43%, and 25%, respectively. Quality of life and wellness improved in >50%. Postoperative use of drugs prescribed for FM often improved or resolved (narcotics, 77%; anti-inflammatories, 74%; "FM-specific medications," 33%; antidepressants, 30%); 21% discontinued all FM medications postoperatively. CONCLUSION: FM is common in patients operated on for sporadic PHP. Of those with both conditions, after PTX 89% appreciate symptom response and 77% and 21% had a decrease in or discontinuation or medications, respectively. Before diagnosing FM, providers should exclude PHP, which is surgically correctable.

A clinical algorithm for fine-needle aspiration molecular testing effectively guides the appropriate extent of initial thyroidectomy.

OBJECTIVE: To test whether a clinical algorithm using routine cytological molecular testing (MT) promotes initial total thyroidectomy (TT) for clinically significant thyroid cancer (sTC) and/or correctly limits surgery to lobectomy when appropriate. BACKGROUND: Either TT or lobectomy is often needed to diagnose differentiated thyroid cancer. Determining the correct extent of initial thyroidectomy is challenging. METHODS: After implementing an algorithm for prospective MT of in-house fine-needle aspiration biopsy specimens, we conducted a single-institution cohort study of all patients (N = 671) with nonmalignant cytology who had thyroidectomy between October 2010 and March 2012, cytological diagnosis using 2008 Bethesda criteria, and 1 or more indications for thyroidectomy by 2009 American Thyroid Association guidelines. sTC was defined by histological differentiated thyroid cancer of 1 cm or more and/or lymph node metastasis. Cohort 2 patients did not have MT or had unevaluable results. In cohort 1, MT for a multigene mutation panel was performed for nonbenign cytology, and positive MT results indicated initial TT. RESULTS: MT guidance was associated with a higher incidence of sTC after TT (P = 0.006) and a lower rate of sTC after lobectomy (P = 0.03). Without MT results, patients with indeterminate (follicular lesion of undetermined significance/follicular or oncocytic neoplasm) cytology who received initial lobectomy were 2.5 times more likely to require 2-stage surgery for histological sTC (P < 0.001). In the 501 patients with non-sTC for whom lobectomy was the appropriate extent of surgery, lobectomy was correctly performed more often with routine preoperative MT (P = 0.001). CONCLUSIONS: Fine-needle aspiration biopsy MT for BRAF, RAS, PAX8-PPARγ, and RET-PTC expedites optimal initial surgery for differentiated thyroid cancer, facilitating succinct definitive management for patients with thyroid nodules.

PAX8/PPARγ rearrangement in thyroid nodules predicts follicular-pattern carcinomas, in particular the encapsulated follicular variant of papillary carcinoma.

BACKGROUND: PAX8/PPARγ rearrangement is a common genetic alteration in follicular thyroid carcinoma (FTC) and has been reported with variable frequency in papillary thyroid carcinoma (PTC). The diagnostic and phenotypic features of thyroid nodules positive for PAX8/PPARγ on preoperative examination are not well understood. METHODS: The prevalence of PAX8/PPARγ rearrangement was analyzed in a series of 2015 consecutive thyroid nodules that underwent molecular analysis on cytology specimens and in 446 surgically removed PTCs. For all PAX8/PPARγ positive cases, cytology and surgical pathology slides were examined and the available clinical records were reviewed. RESULTS: Twenty-two PAX8/PPARγ rearrangements were identified, including 16 detected preoperatively and 6 postoperatively. The incidence of PAX8/PPARγ in PTC was 1.1%. Cytologically, most of these nodules were diagnosed as a follicular neoplasm (73%), followed by the diagnosis of atypia of undetermined significance (19%), and none of the cases was diagnosed as cytologically malignant. All nodules with PAX8/PPARγ detected preoperatively and surgical follow-up available were found to be malignant, among which the most common diagnosis was the encapsulated follicular variant of PTC. Overall, among 20 PAX8/PPARγ-positive tumors that were surgically excised, 17 (85%) were PTC and 3 (15%) were FTC. On follow-up available for 17 patients (mean, 22.4 months), 16 PAX8/PPARγ-positive cancers showed no evidence of biochemical or structural recurrence, whereas 1 patient with FTC developed bone metastasis. CONCLUSIONS: In this series, PAX8/PPARγ rearrangement found in thyroid nodules had a 100% predictive value for differentiated thyroid cancer, and was more predictive of PTC than FTC. However, almost all PTC carrying PAX8/PPARγ were encapsulated follicular-pattern tumors, distinguished from FTC only by nuclear features. Although most tumors carrying this mutation appear to be clinically indolent, at least on short-term follow-up, distant metastasis can develop from FTC positive for PAX8/PPARγ.

The small abnormal parathyroid gland is increasingly common and heralds operative complexity.

BACKGROUND: Over decades, improvements in presymptomatic screening and awareness of surgical benefits have changed the presentation and management of primary hyperparathyroidism (PHPT). Unrecognized multiglandular disease (MGD) remains a major cause of operative failure. We hypothesized that during parathyroid surgery the initial finding of a mildly enlarged gland is now frequent and predicts both MGD and failure. METHODS: A prospective database was queried to examine the outcomes of initial exploration for sporadic PHPT using intraoperative PTH monitoring (IOPTH) over 15 years. All patients had follow-up ≥6 months (mean = 1.8 years). Cure was defined by normocalcemia at 6 months and microadenoma by resected weight of <200 mg. RESULTS: Of the 1,150 patients, 98.9 % were cured and 15 % had MGD. The highest preoperative calcium level decreased over time (p < 0.001) and varied directly with adenoma weight (p < 0.001). Over time, single adenoma weight dropped by half (p = 0.002) and microadenoma was increasingly common (p < 0.01). MGD risk varied inversely with weight of first resected abnormal gland. Microadenoma required bilateral exploration more often than macroadenoma (48 vs. 18 %, p < 0.01). When at exploration the first resected gland was <200 mg, the rates of MGD (40 vs. 11 %, p = 0.001), inadequate initial IOPTH drop (67 vs. 79 %, p = 0.002), operative failure (6.6 vs. 0.7 %, p < 0.001), and long-term recurrence (1.6 vs. 0.3 %, p = 0.007) were higher. CONCLUSIONS: Single parathyroid adenomas are smaller than in the past and require more complex pre- and intraoperative management. During exploration for sporadic PHPT, a first abnormal gland <200 mg should heighten suspicion of MGD and presages a tenfold higher failure rate.

The final intraoperative parathyroid hormone level: how low should it go?

BACKGROUND: In minimally invasive surgery for primary hyperparathyroidism (HPT), intraoperative parathyroid hormone (IOPTH) monitoring assists in obtaining demonstrably better outcomes, but optimal criteria are controversial. METHODS: The outcomes of 1,108 initial parathyroid operations for sporadic HPT using IOPTH monitoring from 1997 to 2011 were stratified by final post-resection IOPTH level. All patients had adequate follow-up to verify cure. RESULTS: With mean follow-up of 1.8 years (range 0.5-14.3 years), parathyroidectomy using IOPTH monitoring failed in 1.2 % of cases, with an additional 0.5 % incidence of long-term recurrence at a mean of 3.2 years (range 0.8-6.8 years) postoperatively. Operative success was equally likely with a final IOPTH drop to 41-65 pg/mL vs ≤40 pg/mL (p = 1). In the 76 patients with an elevated baseline IOPTH level that did not drop to ≤65 pg/mL, surgical failure was 43 times more likely than with a drop into normal range (13 vs. 0.3 %; p < 0.001). When the final IOPTH level dropped by >50 % but not into the normal range, surgical failure was 19 times more likely (3.8 vs. 0.2 %; p = 0.015). Long-term recurrence was more likely in patients with a final IOPTH level of 41-65 pg/mL than with a level ≤40 pg/mL (1.2 vs. 0; p = 0.016). CONCLUSIONS: Adjunctive intraoperative PTH monitoring facilitates a high cure rate for initial surgery of sporadic primary hyperparathyroidism. A final IOPTH level that is within the normal range and drops by >50 % from baseline is a strong predictor of operative success. Patients with a final IOPTH level between 41-65 pg/mL should be followed beyond 6 months for long-term recurrence.

Thyroid nodules (≥4 cm): can ultrasound and cytology reliably exclude cancer?

BACKGROUND: Whether a threshold nodule size should prompt diagnostic thyroidectomy remains controversial. We examined a consecutive series of patients who all had thyroidectomy for a ≥4 cm nodule to determine (1) the incidence of thyroid cancer (TC) and (2) if malignant nodules could accurately be diagnosed preoperatively by ultrasound (US), fine needle aspiration biopsy (FNAB) cytology and molecular testing. METHODS: As a prospective management strategy, 361 patients with 382 nodules ≥4 cm by preoperative US had thyroidectomy from 1/07 to 3/12. RESULTS: The incidence of a clinically significant TC within the ≥4 cm nodule was 22 % (83/382 nodules). The presence of suspicious US features did not discriminate malignant from benign nodules. Moreover, in 86 nodules ≥4 cm with no suspicious US features, the risk of TC within the nodule was 20 %. US-guided FNAB was performed for 290 nodules, and the risk of malignancy increased stepwise from 10.4 % for cytologically benign nodules, 29.6 % for cytologically indeterminate nodules and 100 % for malignant FNAB results. Molecular testing was positive in 9.3 % (10/107) of tested FNAB specimens, and all ten were histologic TC. CONCLUSIONS: In a large consecutive series in which all ≥4 cm nodules had histology and were systematically evaluated by preoperative US and US-guided FNAB, the incidence of TC within the nodule was 22 %. The false negative rate of benign cytology was 10.4 %, and the absence of suspicious US features did not reliably exclude malignancy. At minimum, thyroid lobectomy should be strongly considered for all nodules ≥4 cm.

Outcome and prognostic factors after adrenalectomy for patients with distant adrenal metastasis.

BACKGROUND: The purpose of this study was to describe a single-institution experience with adrenal metastasectomy and to elucidate factors that may bear prognostic significance. METHODS: This is a single-center, retrospective review of patients with adrenal metastasis who underwent adrenalectomy performed with curative intent between 2000 and 2012. The Kaplan-Meier method was used to evaluate overall survival from time of adrenalectomy to death or last follow-up. Primary endpoint was death from any cause. Clinical variables were examined for association with survival. RESULTS: The study included 62 patients with mean age of 60 (±12) years; 55 % (34 of 62) were male, 85 % (53 of 62) presented with isolated adrenal metastasis, and 82 % (51 of 62) had metachronous disease with median disease-free interval (DFI) of 22 months (range, 6-217 months). Non-small cell lung cancer (NSCLC) was the most common primary comprising 50 % of cases. Median survival for the study population was 30 months (range, 1-145 months) and 5-year survival was 31 %. Patients with NSCLC had significantly shortened survival compared with non-NSCLC with median and 5-year survival of 17 versus 47 months and 27 % versus 38 %, respectively (p = .033). Synchronous metastasis (p = .028) and DFI < 12 months (p = .038) were also associated with worse survival outcome, though male gender (p = .69) and oligometastatic disease (p = .62) were not. CONCLUSIONS: Adrenal metastasectomy resulted in median survival of 30 months and 5-year survival of 31 %. Shorter survival was associated with lung primary, short disease-free interval, and synchronous metastasis, but not with the presence of oligometastatic disease provided that the primary cancer and additional metastatic lesions were adequately controlled and amenable to resection.

BRAF V600E mutation independently predicts central compartment lymph node metastasis in patients with papillary thyroid cancer.

PURPOSE: This study was designed to examine whether available preoperative clinical parameters, including B-type Raf kinase (BRAF) V600E mutation status, can identify patients at risk for central compartment lymph node metastasis (CLNM). METHODS: Under an institutional review board-approved protocol, we conducted a single-center, retrospective review of all patients who had initial thyroidectomy for histologic papillary thyroid carcinoma (PTC) during 2010. The presence of CLNM was examined for correlation with available preoperative clinical parameters, including tumor size, gender, age, and BRAF mutation status. RESULTS: Cervical lymph node resection and molecular testing on FNAB or histopathologic specimen was performed on a consecutive series of 156 study patients with histologic PTC. Overall, CLNM was diagnosed in 37% and 46% were BRAF-mutation-positive. BRAF positivity was the only clinical parameter associated with CLNM (BRAF, p=0.002; tumor size≥2 cm, p=0.16; male gender, p=0.1; age≥45 years, p=0.3) and remained an independent predictor of CLNM on multiple logistic regression analysis (odds ratio (OR) 3.2, p=0.001). The PPV and NPV of BRAF positivity for CLNM was 50 and 74%, respectively. When restricting the analysis to the subset of 38 patients who had molecular testing performed preoperatively on FNAB, the PPV and NPV of BRAF positivity for CLNM was 47 and 91%, respectively, and BRAF positivity was still a significant predictor of CLNM on both univariate (OR 8.4, p=0.01) and multivariate (OR 9.7, p=0.02) analyses. CONCLUSIONS: Of the commonly used clinical parameters available preoperatively, the BRAF V600E mutation is the only independent predictor of CLNM in PTC and can be utilized to guide the extent of initial surgery.

Intraoperative pathologic examination in the era of molecular testing for differentiated thyroid cancer.

BACKGROUND: Diagnostic thyroidectomy is typically indicated for indeterminate thyroid cytology results. Traditionally, intraoperative pathologic examination (IOPE) helped to guide the extent of initial surgery. Preoperative molecular testing (MT) of fine needle aspiration cytology has emerged as another diagnostic adjunct, is highly specific for thyroid cancer, and can lead to appropriate initial total thyroidectomy. We hypothesized that preoperative MT obviates the need for routine IOPE during lobectomy. STUDY DESIGN: In a retrospective, consecutive cohort study, we compared outcomes of 670 patients undergoing thyroidectomy. Cohort A (January 2005 to December 2006) received surgery without MT, and cohort B (January 2008 to September 2010) had preoperative MT for BRAF, RAS, RET/PTC, and PAX8/PPARγ mutations, and cytology assessment by the 2007 modified Bethesda criteria. In both cohorts, IOPE was performed during lobectomy and a positive result prompted total thyroidectomy. RESULTS: In cohort B, total thyroidectomy was more often the initial surgery (62% vs A 45%; p < 0.001) and a positive MT result was the only factor prompting initial total thyroidectomy in 18 (9%) patients. Among 315 patients who had initial lobectomy, thyroid cancer was infrequently diagnosed by IOPE in both cohorts (A 3.6% vs B 1.7%; p = 0.5). The sensitivity of IOPE in detecting differentiated thyroid cancer ≥1 cm decreased >60% with routine use of MT and the Bethesda criteria (A 18.4% vs B 5.9%). After lobectomy, differentiated thyroid cancer ≥1 cm was equally likely to be diagnosed in both cohorts (p = 0.1), but follicular variant papillary thyroid cancer was more common in cohort B (74% vs 45%; p = 0.02). CONCLUSIONS: Together with the Bethesda cytologic criteria, preoperative MT allows for an increased rate of initial definitive total thyroidectomy and eliminates the need for routine intraoperative pathologic examination during diagnostic lobectomy.

Immediate laparoscopic adrenalectomy versus observation: cost evaluation for incidental adrenal lesions with atypical imaging characteristics.

BACKGROUND: Because of controversy in the management of nonfunctional adrenal masses <6 cm with lipid-poor imaging characteristics, the study was conducted to compare the costs of observation versus immediate laparoscopic adrenalectomy. METHODS: A total of 370 patients who were evaluated for incidental adrenal masses between January 1999 and December 2007 were identified, and 32 (8.7%) patients had lesions with imaging characteristics that were inconsistent with a benign adenoma (ie, atypical appearing). Sixteen patients underwent immediate surgery and 16 had observation with serial imaging and biochemical studies. The associated total costs were subjected to intention-to-treat analysis. RESULTS: In the observation cohort, 7 patients converted and underwent adrenalectomy after a mean of 13.1 months. Initially, costs of immediate surgery exceeded those of observation ($12,015.72 vs $11,601.18, P = .10). After projecting costs of annual surveillance, a cost advantage for immediate surgery was demonstrated after 9 years (P = .02). CONCLUSIONS: In patients with <6 cm atypical-appearing adrenal lesions, the costs of surgery and of observation are initially equal. After 9 years, the costs of surveillance exceed that of initial laparoscopic adrenalectomy.

Suspicious ultrasound characteristics predict BRAF V600E-positive papillary thyroid carcinoma.

BACKGROUND: Current American Thyroid Association (ATA) guidelines recommend routine cervical ultrasound (US) in thyroid nodule evaluation. Specific US characteristics can help diagnose papillary thyroid carcinoma (PTC). The aim of this blinded cohort study was to determine whether these specific US characteristics can also reliably detect the more aggressive variants of PTC that are often associated with the BRAF(V600E) mutation. METHODS: After Institutional Review Board approval, we identified a cohort of patients from January 2007 to December 2009 with histologic PTC≥1 cm who had cervical US, initial thyroid surgery, and molecular testing for BRAF(V600E) on fine-needle aspiration biopsy or histology. Preoperative US images were evaluated by a single radiologist, who was blinded to BRAF status, for nodule size and the presence or absence of the following suspicious US features: taller-than-wide shape, ill-defined margins, hypoechogenicity, calcifications, noncystic composition, and absent halo. RESULTS: BRAF-positivity was associated with most known suspicious US findings, including taller-than-wide shape (47% vs. 7%, p<0.001), ill-defined margins (42% vs. 9%, p<0.001), hypoechogenicity (83% vs. 36%, p<0.001), micro/macrocalcifications (87% vs. 24%, p<0.001), and absent halo (85% vs. 27%, p<0.001) but was not associated with noncystic composition. When ≥3 suspicious US features were present, BRAF-positivity was predicted with a positive predictive value of 82%. The absence of suspicious US features together with negative BRAF testing predicted PTC without extrathyroidal extension or lymph node metastasis (negative predictive value 88%). CONCLUSIONS: With routine preoperative cervical US and molecular testing, a trained radiologist or surgeon can improve the preoperative characterization of PTC, potentially impacting risk stratification and initial surgical management.

Positional dyspnea and tracheal compression as indications for goiter resection.

HYPOTHESES: Goiter is a surgically reversible cause of positional dyspnea (PD). Substernal tracheal compression (TC) predicts PD relief after thyroidectomy (Tx). DESIGN: Retrospective analysis of a prospective structured management algorithm. SETTING: Endocrine surgery academic center. METHODS: Before Tx, 1081 patients were queried about PD. Those patients with substernal goiter underwent computed tomography, and their degree of TC was estimated as greatest percent reduction of transverse tracheal diameter. For 197 patients with PD, TC, or both, surgical outcomes were examined with a mean follow- up of 12.6 months. After Tx, patients who carried the diagnosis of obstructive sleep apnea were referred for repeat sleep study evaluation. RESULTS: Positional dyspnea was reported by 188 of 1081 patients, and after Tx the PD improved or resolved in 82.4%. In the 151 patients with substernal goiter, TC was present on imaging in 97.2%; the mean (range) TC was 34% (5%-90%). Patients with TC had a high likelihood of PD (93.5%). After substernal goiter resection, PD improved in stepwise association with total resected thyroid gland weight. Improvement in PD was strongly predicted by both gland weight of 100 g or more (P.001) and by TC of 35% or more (P.01). After Tx, 59 of 77 snorers (76.6%) reported improvement in snoring, 77.1% of patients with obstructive sleep apnea reported improved PD, and 2 of 3 retested patients with obstructive sleep apnea demonstrated objective improvement in sleep study apnea-hypopnea index. CONCLUSIONS: Resection of bulky goiter frequently improves PD, which in substernal goiter is highly associated with TC. Either PD or TC of 35% or more prompt Tx. Goiter should be considered when obstructive sleep apnea is diagnosed.

Thyroid paragangliomas are locally aggressive.

BACKGROUND: Thyroid paraganglioma (TP) is a very rare neoplasm that can be misdiagnosed. We evaluated the clinical and pathologic characteristics of three patients with TP. PATIENT FINDINGS: The records of all patients from 1981 to 2008 who had thyroidectomy with a final histologic diagnosis of TP were retrieved, and histology was reviewed by a single pathologist. Head and neck paragangliomas arising outside of the thyroid were excluded. TP accounted for 3 of all 6782 (0.04%) patients undergoing thyroidectomy during three decades. One patient has been previously reported and will not be discussed. In the remaining two patients and a surgical pathology consult case that we also describe herein, the mean age at diagnosis was 56 years (40-67) and two patients were men. Presenting features were indicative of advanced local invasion, including stridor, tracheal invasion, compression of the great vessels, and hemoptysis. The diagnosis of TP was not suspected preoperatively; in two patients, fine-needle aspiration (FNA) cytology was inadequate for diagnosis because of excessive blood. Intraoperative frozen section analysis suggested medullary thyroid cancer in two patients and oncocytic (Hurthle) cell carcinoma in one patient. Local invasion was common, requiring concurrent tracheal resection in two of three patients, and present histologically in all three patients. In all three cases, immunohistochemical analysis was negative for cytokeratin AE1/3, calcitonin, and thyroglobulin but positive for S100, highlighting sustentacular cells. After resection of a large TP with tracheal and vascular invasion, a 67-year-old woman experienced a 7-year disease-free interval. CONCLUSIONS: Primary TP is indeed rare. It does occur in men, frequently presents with compressive symptoms, and is typically locally aggressive, but does not appear to cause symptoms suggestive of catecholamine excess. Despite invasion of adjacent structures, aggressive resection can achieve a long disease-free interval.

Interferon Regulatory Factor 1 (IRF-1) induces p21(WAF1/CIP1) dependent cell cycle arrest and p21(WAF1/CIP1) independent modulation of survivin in cancer cells.

We have shown that the ectopic expression of Interferon Regulatory Factor 1 (IRF-1) results in human cancer cell death accompanied by the down-regulation of the Inhibitor of Apoptosis Protein (IAP) survivin and the induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1). In this report, we investigated the direct role of p21 in the suppression of survivin. We show that IRF-1 down-regulates cyclin B1, cdc-2, cyclin E, E2F1, Cdk2, Cdk4, and results in p21-mediated G1 cell cycle arrest. Interestingly, while p21 directly mediates G1 cell cycle arrest, IRF-1 or other IRF-1 signaling pathways may directly regulate survivin in human cancer cells.