Bryan McIver

Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer

BACKGROUND Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Associations guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. METHODS Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. RESULTS The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, and suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound and serum thyroglobulin as well as those related to management of recurrent and metastatic disease. CONCLUSIONS We created evidence-based recommendations in response to our appointment as an independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940-1999): Temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients

It is uncertain whether more extensive primary surgery and increasing use of radioiodine remnant ablation (RRA) for papillary thyroid carcinoma (PTC) have resulted in improved rates of cause-specific mortality (CSM) and tumor recurrence (TR). Details of the initial presentation, therapy, and outcome of 2444 PTC patients consecutively treated during 1940–1999 were recorded in a computerized database. Patients were followed for more than 43,000 patient-years. The 25-year rates for CSM and TR were 5% and 14%, respectively. Temporal trends were analyzed for six decades. During the six decades, the proportion with initial MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) scores <6 were 77%, 82%, 84%, 86%, 85%, and 82%, respectively (p = 0.06). Lobectomy accounted for 70% of initial procedures during 1940–1949 and 22% during 1950–1959; during 1960–1999 bilateral lobar resection (BLR) accounted for 91% of surgeries (p <0.001). RRA after BLR was performed during 1950–1969 in 3% but increased to 18%, 57%, and 46% in successive decades (p <0.001). The 40-year rates for CSM and TR during 1940–1949 were significantly higher (p = 0.002) than during 1950–1999. During the last 50 years the 10-year CSM and TR rates for the 2286 cases did not significantly change with successive decades. Moreover, the 10-year rates for CSM and TR were not significantly improved during the last five decades of the study, either for the 1917 MACIS <6 patients or the 369 MACIS ? 6 patients. Increasing use of RRA has not apparently improved the already excellent outcome, achieved before 1970, in low risk (MACIS <6) PTC patients managed by near-total thyroidectomy and conservative nodal excision.

Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study

BACKGROUND Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. METHODS This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. FINDINGS 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35-68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=-0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. INTERPRETATION Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patients response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. FUNDING National Cancer Institute, supported in part by NCI CA15083 and CM62205.

The PAX8/PPARγ fusion oncoprotein transforms immortalized human thyrocytes through a mechanism probably involving wild-type PPARγ inhibition

Follicular thyroid carcinoma (FTC) frequently harbors the PAX8/PPARγ fusion gene (PPFP); however, its oncogenic role and mechanism(s) of action remain undefined. We investigated PPFPs effects on cell growth, apoptosis, cell–cell, and cell–matrix interactions in immortalized human thyroid cells (Nthy-ori 3-1) and NIH 3T3 cells. PPFP expression increased the growth of transient and stable Nthy-ori transfectants (∼threefold by 72 h). There was an 8.4% increase of cells in the S+G2/M phase, a 7.8% decrease in cells in the G0+G1 phase and a 66% decline in apoptosis at 72 h. Stable Nthy-ori PPFP transfectants grew in soft agar, and PPFP-transfected NIH 3T3 cells exhibited efficient focus formation, suggesting loss of anchorage-dependent growth and contact inhibition, respectively. Overexpression of PPARγ in Nthy-ori cells did not recapitulate PPFPs growth effects. Treatment of Nthy-ori cells with an irreversible PPARγ inhibitor mimicked the growth-promoting effects of PPFP and co-expression of PPFP and PPARγ blocked PPARγ transactivation activity. Our data provide functional evidence that PPFP acts as an oncoprotein, whose transforming properties depend in part on inhibition of PPARγ. Our data suggest that PPFP contributes to malignant transformation during FTC oncogenesis by acting on several cellular pathways, at least some of which are normally regulated by PPARγ.

Enhanced Survival in Locoregionally Confined Anaplastic Thyroid Carcinoma: A Single-Institution Experience Using Aggressive Multimodal Therapy

BACKGROUND Historical outcomes in anaplastic thyroid carcinoma (ATC) are poor, with a median survival of only 5 months and <20% of patients surviving 1 year from diagnosis. We hypothesized that survival in newly diagnosed patients with stages IVA and IVB locoregionally confined ATC might be improved by utilizing an aggressive therapeutic approach, prioritizing both the eradication of disease in the neck and preemptive treatment of occult metastatic disease. METHODS Between January 1, 2003, and December 31, 2007, 25 new ATC patients were evaluated at our institution. Of these 25 patients, 10 (40%) had metastatic disease at diagnosis and therefore underwent palliative treatment, whereas 5 (20%) had regionally confined disease and desired treatment at their local medical facilities. The remaining 10 consecutive patients (40%) had regionally confined ATC and elected aggressive therapy combining individualized surgery (where feasible), intensity-modulated radiation therapy (IMRT), and radiosensitizing + adjuvant chemotherapy intending four cycles of docetaxel + doxorubicin. Outcomes were assessed on an intention to treat basis. RESULTS There were no deaths from therapy, but hospitalization was required in two patients (20%) because of treatment-related adverse events. Five patients (50%) are alive and cancer-free, all having been followed >32 months (range: 32-89 months; median: 44 months) with a median overall Kaplan-Meier survival of 60 months. Overall survival at 1 and 2 years was 70% and 60%, respectively, compared to <20% historical survival at 1 year in analogous patients previously treated with surgery and conventional postoperative radiation at our and other institutions. CONCLUSIONS Although based upon a small series of consecutively treated patients, an aggressive approach combining IMRT and radiosensitizing plus adjuvant chemotherapy appears to improve outcomes, including survival in stages IVA and IVB regionally confined ATC, but remains of uncertain benefit in patients with stage IVC (metastatic) disease. Also uncertain is the optimal chemotherapy regimen to use in conjunction with IMRT. Further multicenter randomized trials are required to define optimal therapy in this rare but deadly cancer.

The Impact of Benign Gene Expression Classifier Test Results on the Endocrinologist–Patient Decision to Operate on Patients with Thyroid Nodules with Indeterminate Fine-Needle Aspiration Cytopathology

BACKGROUND Seventy-five percent of thyroid nodules with indeterminate fine-needle aspiration (FNA) cytology are found to be benign postoperatively. A novel genomic test, the Afirma gene expression classifier (AGEC), has been available for clinical use in the United States, since late 2010. In 2010, two modest-sized validation studies showed that the AGEC could identify a benign gene expression signature in indeterminate cytology thyroid FNA samples with a negative predictive value >95%. The objective of this study was to evaluate how the AGEC impacted the joint decision of the endocrinologist and patient to operate when FNA cytology was indeterminate, but the AGEC reading of the nodule was benign. METHODS In this cross-sectional cohort study, data were contributed retrospectively by 51 endocrinologists at 21 practice sites that had previously obtained ≥3 benign AGEC readings in ≥1 cm nodules with indeterminate FNA cytology readings. Information regarding demographic data, nodule size and location, decision to operate, surgery type (hemithyroidectomy [HT] or total thyroidectomy [TT]), and reason for recommending surgery was retrospectively collected. RESULTS Compared to a 74% previous historical rate of surgery for cytologically indeterminate nodules, the operative rate fell to 7.6% during the period that AGEC were obtained in the clinical practices, a highly significant reduction in the decision to operate (p<0.001). The rate of surgery on cytologically indeterminate nodules that were benign by the AGEC reading did not differ from the historically reported rate of operation on cytologically benign nodules (p=0.41). The four primary reasons reported by the physicians for operating on nodules with a benign AGEC reading, in descending order: large nodule size (46.4%), symptomatic nodules (25.0%), rapidly growing nodules (10.7%), or a second suspicious or malignant nodule in the same patient (10.7%). These reasons are concordant with those typically given for operation on cytologically benign nodules. CONCLUSIONS In a substantial group of medical practices, obtaining an AGEC test in patients with cytologically indeterminate nodules was associated with a striking reduction in the rate of diagnostic thyroidectomy. Approximately, one surgery was avoided for every two AGEC tests run on thyroid FNAs with indeterminate cytology.

Intragenic PTEN/MMAC1 Loss of Heterozygosity in Conventional (Clear-Cell) Renal Cell Carcinoma is Associated with Poor Patient Prognosis

Inactivation of the PTEN/MMAC1 tumor suppressor gene has been linked to tumor progression in several human malignancies. However, the role of PTEN/MMAC1 in the development and progression of the major renal cell carcinoma morphotypes remains controversial. We examined microdissected specimens from 80 conventional (clear cell) renal cell carcinomas (cRCC), 27 papillary renal cell carcinomas (pRCC), and 16 chromophobe renal cell carcinomas (chRCC) for loss of heterozygosity (LOH) at and around the PTEN/MMAC1 locus and for mutations in the PTEN/MMAC1 gene. The results of the molecular studies were correlated with tumor stage, grade, and patient survival. LOH at one or more of the examined loci occurred in 37.5% of cRCC, 29.6% of pRCC and 87.5% of chRCC specimens. The chRCC specimens showed increasing rates of LOH the further that a marker was located toward the q telomer of chromosome 10, consistent with nonspecific genetic disarray in genomically highly unstable tumors. No such pattern was discernible in the cRCC and pRCC. In the cRCC, LOH at intragenic PTEN/MMAC1 microsatellite markers (indicating deletional events involving the actual PTEN/MMAC1 gene) was significantly associated with tumor death, with 85.7% of such patients dying, whereas only 45.3% of patients without intragenic LOH died (P = .018). There were no PTEN/MMAC1 mutations in our specimens. We conclude that PTEN/MMAC1 inactivation may play a role in the progression of cRCC. Biallelic inactivation may preferentially occur by nonmutational mechanisms, or, alternatively, haploinsufficiency of PTEN/MMAC1 may be sufficient to affect tumor progression in cRCC.

The role of the PAX8/PPARγ fusion oncogene in the pathogenesis of follicular thyroid cancer

When identified at early stages, most well-differentiated thyroid cancers are readily treated and yield excellent outcomes. Follicular thyroid cancer (FTC) however, when diagnosed at a late stage, may be very resistant to treatment, and exhibits 10-year survival rates less than 40%. Despite substantial progress in recent years, we still have limited understanding of the molecular and biological interrelationships between the various subtypes of benign and malignant follicular thyroid neoplasms. In contrast to the wealth of information available regarding papillary thyroid carcinoma (PTC), the triggering mechanisms of FTC development and the major underlying genetic alterations leading to follicular thyroid carcinogenesis remain obscure. Recent studies have focused on a chromosomal translocation, t(2;3) (q13;p25), fusing PAX8, a transcription factor that is essential for normal thyroid gland development, with the peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the steroid/thyroid nuclear receptor family. This chromatin rearrangement results in the expression of a PAX8/PPARgamma fusion protein, designated PPFP, whose incidence is relatively common in FTC and may represent an initiating event in the genesis of FTC. Here we review progress on the studies of PPFP that assess its involvement in FTC tumorigenesis.

Prevalence of Thyroid Cancer in Multinodular Goiter Versus Single Nodule: A Systematic Review and Meta-Analysis

BACKGROUND Whether the prevalence of thyroid cancer is different in thyroid glands with a single nodule (SN) versus multinodular goiter (MNG) remains uncertain. Therefore, a meta-analysis was performed to evaluate the extant literature on the comparative prevalence of thyroid cancer in SN compared with MNG. METHODS We searched MEDLINE, EMBASE, Scopus, Cochrane Central, and reference list for selected observational, cross-sectional, and longitudinal studies evaluating thyroid cancer in SN and MNG. Toxic nodules were not included in the analysis. Two reviewers working independently extracted descriptive, methodological and outcome data from each study with consensus resolution of discrepancies. Meta-analytic estimates of treatment effects were generated using a random-effect model. RESULTS Fourteen studies encompassing 23565 patients with MNG and 20723 patients with SN were eligible for inclusion. Most eligible studies were at a moderate risk of bias. MNGs were associated with a lower risk of thyroid cancer than SN (pooled odds ratio 0.8 [95% confidence interval 0.67-0.96]; I(2)=35%). Subgroup analysis suggested that this difference depends on the inclusion of studies conducted outside the United States (odds ratio 0.71 [95% confidence interval 0.60-0.83]; I(2)=11%). CONCLUSIONS Thyroid cancer may be less frequent in MNG compared to SN, particularly outside the United States and perhaps in iodine-deficient areas.

A Multicenter Phase 2 Trial of Pazopanib in Metastatic and Progressive Medullary Thyroid Carcinoma: MC057H

CONTEXT Pazopanib is a small molecule inhibitor of kinases principally including vascular endothelial growth factor receptors-1, -2, and -3; platelet-derived growth factor receptors-α and -β; and c-Kit. We previously reported a tumor response rate of 49% in patients with advanced differentiated thyroid cancer and 0% in patients with advanced anaplastic thyroid cancer. The present report details results of pazopanib therapy in advanced medullary thyroid cancer (MTC). OBJECTIVE, DESIGN, SETTING, PATIENTS, INTERVENTION, AND OUTCOME MEASURES: Having noted preclinical activity of pazopanib in MTC, patients with advanced MTC who had disease progression within the preceding 6 months were accrued to this multiinstitutional phase II clinical trial to assess tumor response rate (by Response Evaluation Criteria In Solid Tumors criteria) and safety of pazopanib given orally once daily at 800 mg until disease progression or intolerability. RESULTS From September 22, 2008, to December 11, 2011, 35 individuals (80% males, median age 60 y) were enrolled. All patients have been followed up until treatment discontinuation or for a minimum of four cycles. Eight patients (23%) are still on the study treatment. The median number of therapy cycles was eight. Five patients attained partial Response Evaluation Criteria In Solid Tumors responses (14.3%; 90% confidence interval 5.8%-27.7%), with a median progression-free survival and overall survival of 9.4 and 19.9 months, respectively. Side effects included treatment-requiring (new) hypertension (33%), fatigue (14%), diarrhea (9%), and abnormal liver tests (6%); 3 of 35 patients (8.6%) discontinued therapy due to adverse events. There was one death of a study patient after withdrawal from the trial deemed potentially treatment related. CONCLUSIONS Pazopanib has promising clinical activity in metastatic MTC with overall manageable toxicities.