Active Surveillance of Papillary Thyroid Cancer: Frequency and Time Course of the Six Most Common Tumor Volume Kinetic Patterns.

Background: The change in size of the papillary thyroid cancer (PTC) nodule during active surveillance has traditionally been characterized as either stable, increasing, or decreasing based on changes in maximal tumor diameter or tumor volume. More recently, it has been observed that the changes in tumor size observed during observation are more complex with tumor volume kinetic patterns that can be characterized either as stable (Pattern I), early increase in volume (Pattern II), later increase in volume (Pattern III), early increase in volume followed by stability (Pattern IV), stability followed by an increase in volume (Pattern V), or a decrease in tumor volume (Pattern VI). Methods: The frequency, time course, and clinical correlates of these six tumor volume kinetic patterns were analyzed in a cohort of 483 patients with low-risk PTC up to 1.5 cm in maximal diameter followed with active surveillance at our center for a median of 3.7 years. Results: The cumulative incidence of an increase in tumor volume for the entire cohort was 15.9% [confidence interval (CI) 11.8-20.0] at 5 years. At 5 years, most tumors demonstrated stability (78.8%, Pattern I) with 10.0% showing early growth (Pattern II), 4.1% late growth (Pattern III), 1.9% growth then stability (Pattern IV), 0.6% stability then growth (Pattern V), and 5.6% with a decrease in tumor volume (Pattern VI). Tumor volume doubling time during exponential growth significantly differed across the kinetic patterns, with median values of 2.4, 7.1, and 3.3 years for Patterns II, III, and IV, respectively (p < 0.01). Similarly, the time to a change in tumor volume was significantly different across the kinetic patterns, with median values of 1.5, 3, 1.6, 4.7, and 4.1 years for Patterns II, III, IV, V, and VI, respectively (analysis of variance, p < 0.01). Clinical correlates at baseline were not associated with tumor volume kinetic pattern. Conclusions: These six kinetic tumor volume patterns provide a comprehensive description of the changes in PTC tumor volume observed during the first 5 years of active surveillance.

Enhancing Radioiodine Incorporation in BRAF-Mutant, Radioiodine-Refractory Thyroid Cancers with Vemurafenib and the Anti-ErbB3 Monoclonal Antibody CDX-3379: Results of a Pilot Clinical Trial.

Background: Oncogenic activation of mitogen-activated protein kinase (MAPK) signaling is associated with radioiodine refractory (RAIR) thyroid cancer. Preclinical models suggest that activation of the receptor tyrosine kinase erbB-3 (HER3) mitigates the MAPK pathway inhibition achieved by BRAF inhibitors in BRAFV600E mutant thyroid cancers. We hypothesized that combined inhibition of BRAF and HER3 using vemurafenib and the human monoclonal antibody CDX-3379, respectively, would potently inhibit MAPK activation and restore radioactive iodine (RAI) avidity in patients with BRAF-mutant RAIR thyroid cancer. Methods: Patients with BRAFV600E RAIR thyroid cancer were evaluated by thyrogen-stimulated iodine-124 (124I) positron emission tomography-computed tomography (PET/CT) at baseline and after 5 weeks of treatment with oral vemurafenib 960 mg twice daily alone for 1 week, followed by vemurafenib in combination with 1000 mg of intravenous CDX-3379 every 2 weeks. Patients with adequate 124I uptake on the second PET/CT then received therapeutic radioactive iodine (131I) with vemurafenb+CDX-3379. All therapy was discontinued two days later. Treatment response was monitored by serum thyroglobulin measurements and imaging. The primary endpoints were safety and tolerability of vemurafenib+CDX-3379, as well as the proportion of patients after vemurafenb+CDX-3379 therapy with enhanced RAI incorporation warranting therapeutic 131I. Results: Seven patients were enrolled; six were evaluable for the primary endpoints. No grade 3 or 4 toxicities related to CDX-3379 were observed. Five patients had increased RAI uptake after treatment; in 4 patients this increased uptake warranted therapeutic 131I. At 6 months, 2 patients achieved partial response after 131I and 2 progression of disease. Next-generation sequencing of 5 patients showed that all had co-occurring telomerase reverse transcriptase promoter alterations. A deleterious mutation in the SWItch/Sucrose Non-Fermentable (SWI/SNF) gene ARID2 was discovered in the patient without enhanced RAI avidity after therapy and an RAI-resistant tumor from another patient that was sampled off-study. Conclusions: The endpoints for success were met, providing preliminary evidence of vemurafenib+CDX-3379 safety and efficacy for enhancing RAI uptake. Preclinical data and genomic profiling in this small cohort suggest SWI/SNF gene mutations should be investigated as potential markers of resistance to redifferentiation strategies. Further evaluation of vemurafenib+CDX-3379 as a redifferentiation therapy in a larger trial is warranted (ClinicalTrials.gov: NCT02456701).

Frequent neck US in papillary thyroid cancer likely detects non-actionable findings.

BACKGROUND: American Thyroid Association (ATA) low-intermediate-risk papillary thyroid cancer (PTC) patients without structural and biochemical evidence of disease on initial post-treatment evaluation have a low risk of recurrence. Studies have shown that with current ultrasound scans (US) and thyroglobulin assays, recurrences mostly occurred 2-8 years after initial therapy. The ATA recommends that neck US be done 6-12 months after surgery to establish patient's response to therapy, then periodically depending on risk of recurrence. The lack of clarity in recommendations on timing of follow-up US and fear of recurrence leads to frequent tests. OBJECTIVES: To evaluate the utility of routine neck US in ATA low-intermediate-risk PTC patients with no structural disease on neck US and non-stimulated thyroglobulin <1.0 ng/mL after initial therapy. METHODS: A retrospective study of 93 patients from Singapore, Saudi Arabia and Argentina with ATA low (n = 49) to intermediate (n = 44) risk PTC was conducted between 1998 and 2017. The outcome was to measure the frequency of identifying structural disease recurrence and non-actionable US abnormalities. RESULTS: Over a median follow-up of 5 years, five of the 93 patients (5.4%) developed structural neck recurrence on US at a median of 2.5 years after initial treatment. Indeterminate US abnormalities were detected in 19 of the 93 patients (20.4%) leading to additional tests, which did not detect significant disease. CONCLUSION: In ATA low-intermediate-risk PTC with no suspicious findings on neck US and a non-stimulated thyroglobulin of <1.0 ng/mL after initial therapy, frequent US is more likely to identify non-actionable abnormalities than clinically significant disease.

Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers.

CONTEXT: BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI). OBJECTIVES: To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). DESIGN: This was a pilot trial that enrolled from June 2014 to January 2016. SETTING: Academic cancer center. PATIENTS: Patients with RAIR, BRAF mutant thyroid cancer. INTERVENTION: Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation. MAIN OUTCOME MEASURE: The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I. RESULTS: Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048). CONCLUSIONS: Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.

Pregnancy as a risk factor for thyroid cancer progression.

PURPOSE OF REVIEW: The current review evaluates the impact of pregnancy on women with thyroid cancer in three different clinical situations: those with newly diagnosed differentiated thyroid cancer (DTC), those under active surveillance for papillary thyroid microcarcinomas (PMCs), and those with previously treated DTC. RECENT FINDINGS: Recent pregnancy is not associated with high-risk pathological features of DTC. In women with known PMCs under active surveillance, pregnancy does not increase the risk of disease progression. Thus, deferring surgery for newly diagnosed DTC or known PMCs until after delivery is safe for both mother and the unborn child. If a woman with previously treated DTC is planning pregnancy, response-to-therapy status is an excellent guide for predicting pregnancy-associated disease progression or recurrence. SUMMARY: Clinical studies consistently show that pregnancy is not associated with significant disease progression in newly diagnosed thyroid cancer, PMCs under active surveillance, or previously treated DTC.

Natural History and Tumor Volume Kinetics of Papillary Thyroid Cancers During Active Surveillance.

Importance: Active surveillance of low-risk papillary thyroid cancer (PTC) is now an accepted alternative to immediate surgery, but experience with this approach outside of Japan is limited. The kinetics (probability, rate, and magnitude) of PTC tumor growth under active surveillance have not been well defined. Objective: To describe the kinetics of PTC tumor growth during active surveillance. Design, Setting, and Participants: Cohort study of 291 patients undergoing active surveillance for low-risk PTC (intrathyroidal tumors ≤1.5 cm) with serial tumor measurements via ultrasonography at a tertiary referral center in the United States. Intervention: Active surveillance. Main Outcomes and Measures: The cumulative incidence, rate, and magnitude of the change in tumor diameter or volume, as well as associations with patient and tumor characteristics. Results: Of the 291 patients, 219 (75.3%) were women; mean (SD) age was 52 (15) years. During a median (range) active surveillance of 25 (6-166) months, growth in tumor diameter of 3 mm or more was observed in 11 of 291 (3.8%) patients, with a cumulative incidence of 2.5% (2 years) and 12.1% (5 years). No regional or distant metastases developed during active surveillance. In all cases, 3-dimensional measurements of tumor volume allowed for earlier identification of growth (median, 8.2 months; range, 3-46 months before increase in tumor diameter). In multivariable analysis, both younger age at diagnosis (hazard ratio per year, 0.92; 95% CI, 0.87-0.98; P = .006) and risk category at presentation (hazard ratio for inappropriate, 55.17; 95% CI, 9.4-323.19; P < .001) were independently associated with the likelihood of tumor growth. Of the tumors experiencing volume growth, kinetics demonstrated a classic exponential growth pattern, with a median doubling time of 2.2 years (range, 0.5-4.8 years; median r2 = 0.75; range, 0.42-0.99). Conclusions and Relevance: The rates of tumor growth during active surveillance in a US cohort with PTCs measuring 1.5 cm or less were low. Serial measurement of tumor volumes may facilitate early identification of tumors that will continue to grow and thereby inform the timing of surveillance imaging and therapeutic interventions.

Pilot Study of a Web-based Decision Tool on Post-operative Use of Radioactive Iodine.

Background: The Thyroid Cancer Care Collaborative developed a web-based clinical decision-making module (CDMM) to inform risk-adjusted decisions on post-thyroidectomy radioactive iodine (RAI) use in papillary thyroid cancer (PTC). Methods: In a pilot study, we evaluated the CDMM in 19 PTC cases representing low- (five), intermediate- (seven) and high-risk (seven) disease. Two PTC experts and 10 PTC physicians reviewed cases and assigned risk level and RAI recommendation. The experts used a standard approach while the others used the CDMM. We assessed agreement between responses using a weighted Kappa. Results: Between experts, risk-assignment was concordant in 100%, 57% and 86% of low-, intermediate- and high-risk cases, respectively. Between CDMM users, risk-assignment was concordant in 100%, 29% and 14% in low-, intermediate- and high-risk cases, respectively (p=0.01). CDMM-assigned risk agreed with the expert-assigned risk in 100%, 25% and 0% of low-, intermediate- and high-risk cases, respectively (Kappa=0.69). For RAI use, the experts agreed in 15 cases while CDMM users agreed in eight. On further analysis, interpretation of extrathyroidal extension and lymph node staging led to discrepancies with the CDMM. Conclusions: For a web-based CDMM to accurately inform appropriate use of RAI in PTC, standard pathological and surgical reports are necessary.

Response to Therapy Status Is an Excellent Predictor of Pregnancy-Associated Structural Disease Progression in Patients Previously Treated for Differentiated Thyroid Cancer.

BACKGROUND: Pregnancy may be associated with an increased risk of recurrence/progression of differentiated thyroid cancer (DTC). However, it is unclear if the impact of pregnancy would differ based on pre-pregnancy response to therapy status. The objective of this study was to investigate the risk of recurrence/progression of DTC, applying the response to therapy assessments to pre-pregnancy status as recommended by the 2015 American Thyroid Association thyroid cancer guidelines. METHODS: This was a retrospective review of 235 women followed at Memorial Sloan Kettering Cancer Center for DTC who had a term pregnancy after initial treatment for DTC between 1997 and 2015. RESULTS: Structural disease recurrence/progression after pregnancy was documented in 5% (11/235) of the patients. When evaluated 3-12 months after delivery, patients who had an excellent, indeterminate, or biochemical incomplete response before pregnancy continued to show no evidence of structurally identifiable disease. Conversely, in women with a structural incomplete response to therapy prior to pregnancy, structural progression (defined as ≥3 mm increase in the size of known disease or identification of new metastatic foci) was identified after delivery in 29% (11/38). However, additional therapy was recommended during the first postpartum years in only 8% (3/38) of those patients who had a structural incomplete response to therapy prior to pregnancy, while the remainder (92%) continued to be followed with observation. CONCLUSION: None of the patients with an excellent, indeterminate, or biochemical incomplete response to therapy prior to pregnancy developed structurally identifiable disease after a full-term delivery. Even though structural disease progression was seen in almost a third of the patients with known structural disease prior to pregnancy, only a minority of these patients had changes sufficient to warrant additional therapy. These data confirm that pre-pregnancy response to therapy status is an excellent predictor of pregnancy-associated disease progression in women previously treated for DTC.

SERIAL NECK ULTRASOUND IS MORE LIKELY TO IDENTIFY FALSE-POSITIVE ABNORMALITIES THAN CLINICALLY SIGNIFICANT DISEASE IN LOW-RISK PAPILLARY THYROID CANCER PATIENTS.

OBJECTIVE: American Thyroid Association (ATA) low-risk papillary thyroid cancer (PTC) patients without structural evidence of disease on initial posttreatment evaluation have a low risk of recurrence. Despite this, most patients undergo frequent surveillance neck ultrasound (US). The objective of the study was to evaluate the clinical utility of routine neck US in ATA low-risk PTC patients with no structural evidence of disease after their initial thyroid surgery. METHODS: We performed a retrospective review of 171 ATA low-risk PTC patients after total thyroidectomy, with or without radioactive iodine (RAI) ablation, who had a neck US without suspicious findings after therapy. The main outcome measure was a comparison of the frequency of finding false-positive US abnormalities and the frequency of identifying structural disease recurrence. RESULTS: Over a median follow-up of 8 years, 171 patients underwent a median of 5 neck US (range 2-17). Structural recurrence with low-volume disease (≤1 cm) was identified in 1.2% (2/171) of patients at a median of 2.8 years (range 1.6-4.1 years) after their initial diagnosis. Recurrence was associated with rising serum thyroglobulin (Tg) level in 1 of the 2 patients and was detected without signs of biochemical recurrence in the other patient. Conversely, false-positive US abnormalities were identified in 67% (114/171) of patients after therapy, leading to additional testing without identifying clinically significant disease. CONCLUSION: In ATA low-risk patients without structural evidence of disease on initial surveillance evaluation, routine screening US is substantially more likely to identify false-positive results than clinically significant structural disease recurrence.

Frequent screening with serial neck ultrasound is more likely to identify false-positive abnormalities than clinically significant disease in the surveillance of intermediate risk papillary thyroid cancer patients without suspicious findings on follow-up ultrasound evaluation.

CONTEXT: American Thyroid Association (ATA) intermediate-risk thyroid cancer patients who achieve an excellent treatment response demonstrate a low risk of structural disease recurrence. Despite this fact, most patients undergo frequent surveillance neck ultrasound (US) during follow-up. OBJECTIVE: The objective of the study was to evaluate the clinical utility of routine screening neck US in ATA intermediate-risk patients documented to have a nonstimulated thyroglobulin less than 1.0 ng/mL and a neck US without suspicious findings after therapy. PATIENTS AND DESIGN: Retrospective review of 90 ATA intermediate-risk papillary thyroid carcinoma patients treated with total thyroidectomy and radioactive iodine ablation in a tertiary referral center. MAIN OUTCOME MEASURES: A comparison between the frequency of finding false-positive US abnormalities and the frequency of identifying structural disease recurrence in the study cohort was measured. RESULTS: Over a median of 10 years, 90 patients had a median of six US (range 2-16). Structural disease recurrence was identified in 10% (9 of 90) at a median of 6.3 years. Recurrence was associated with other clinical indicators of disease in 5 of the 90 patients (5.6%, 5 of 90) and was detected without other signs of recurrence in four patients (4.8%, 4 of 84). False-positive US abnormalities were identified in 57% (51 of 90), leading to additional testing, which failed to identify clinically significant disease. CONCLUSIONS: In ATA intermediate-risk patients who have a nonstimulated thyroglobulin less than 1.0 ng/mL and a neck US without suspicious findings after therapy, frequent US screening during follow-up is more likely to identify false-positive abnormalities than clinically significant structural disease recurrence.

Results of a prospective thyroid ultrasound screening program in adenomatous polyposis patients.

BACKGROUND: Patients with adenomatous polyposis may be at increased risk for developing thyroid cancer (TC). However, screening guidelines for TC in these patients are not well established. METHODS: Patients with a diagnosis of familial adenomatous polyposis, attenuated familial adenomatous polyposis, and gene mutation-negative adenomatous polyposis enrolled in our Hereditary Colorectal Cancer Family Registry were eligible for a screening thyroid ultrasound (US). Findings were reviewed by the study endocrinologist and intervention and/or follow-up determined. RESULTS: Fifty patients underwent screening thyroid US. Thirty-four (68%) patients had abnormal findings on US, including 27 (79%) with thyroid nodules. In 7 patients, US-detected thyroid nodules met established criteria for fine-needle aspiration. Of the 6 patients who underwent fine-needle aspiration, 2 (4%) were diagnosed with papillary TC. Both of these patients were female. CONCLUSIONS: A large proportion of adenomatous polyposis patients will have abnormal results on thyroid US, including suspicious-appearing thyroid nodules that when biopsied are malignant. Female patients have an apparently greater risk of developing TC. Polyposis patients, especially women, should be offered participation in a thyroid US screening program.

Cribriform-morular variant of papillary thyroid carcinoma: an indication to screen for occult FAP.

Cribriform-morular variant (CMV) is a rare subtype of papillary thyroid carcinoma (PTC) that is associated with familial adenomatous polyposis (FAP). Given the high likelihood for multi-organ malignancies in FAP patients, this study explores the yield of diagnosing occult FAP among CMV-PTC patients. Institutional database was searched in order to identify patients with pathologically-confirmed CMV-PTC from 2000 to 2012. Medical records were reviewed, and clinical and pathological features were analyzed. Eleven cases of CMV were identified from 6,901 patients with PTC, for a prevalence of 0.16 %. All 11 patients were female. The median age at CMV-PTC diagnosis was 36 years (range 18-46). Two patients had pre-existing FAP at the time of PTC diagnosis. The other nine patients were referred for colonoscopy and/or genetic testing. Six patients underwent colonoscopy and one (17 %) was diagnosed with FAP based on polyposis phenotype and genetic testing. The mean age of patients at the time of CMV-PTC diagnosis was younger in the FAP group (23 years, range 18-34) than in the sporadic group (37 years, range 25-46). All three patients with FAP-associated CMV-PTC had multicentric tumors, while all five sporadic patients did not. Our study found that approximately one-sixth of patients with CMV-PTC may have occult FAP. Patients with FAP-associated CMV-PTC appear to be younger and more likely to have multicentric tumors than those with sporadic CMV-PTC. Due to the increased risk of malignancy in patients with FAP, patients with CMV-PTC should be referred for colonoscopy and/or genetic evaluation for FAP.

Malignancy rate in thyroid nodules classified as Bethesda category III (AUS/FLUS).

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology is the standard for interpreting fine needle aspiration (FNA) specimens. The "atypia of undetermined significance/follicular lesion of undetermined significance" (AUS/FLUS) category, known as Bethesda Category III, has been ascribed a malignancy risk of 5-15%, but the probability of malignancy in AUS/FLUS specimens remains unclear. Our objective was to determine the risk of malignancy in thyroid FNAs categorized as AUS/FLUS at a comprehensive cancer center. METHODS: The management of 541 AUS/FLUS thyroid nodule patients treated at Memorial Sloan-Kettering Cancer Center between 2008 and 2011 was analyzed. Clinical and radiologic features were examined as predictors for surgery. Target AUS/FLUS nodules were correlated with surgical pathology. RESULTS: Of patients with an FNA initially categorized as AUS/FLUS, 64.7% (350/541) underwent immediate surgery, 17.7% (96/541) had repeat FNA, and 17.6% (95/541) were observed. Repeat FNA cytology was unsatisfactory in 5.2% (5/96), benign in 42.7% (41/96), AUS/FLUS in 38.5% (37/96), suspicious for follicular neoplasm in 5.2% (5/96), suspicious for malignancy in 4.2% (4/96), and malignant in 4.2% (4/96). Of nodules with two consecutive AUS/FLUS diagnoses that were resected, 26.3% (5/19) were malignant. Among all index AUS/FLUS nodules (triaged to surgery, repeat FNA, or observation), malignancy was confirmed on surgical pathology in 26.6% [CI 22.4-31.3]. Among AUS/FLUS nodules triaged to surgery, the malignancy rate was 37.8% [CI 33.1-42.8]. Incidental cancers were found in 22.3% of patients. On univariate logistic regression analysis, factors associated with triage to surgery were younger patient age (p<0.0001), increasing nodule size (p<0.0001), and nodule hypervascularity (p=0.032). CONCLUSIONS: In patients presenting to a comprehensive cancer center, malignancy rates in nodules with AUS/FLUS cytology are higher than previously estimated, with 26.6-37.8% of AUS/FLUS nodules harboring cancer. These data imply that Bethesda Category III nodules in some practice settings may have a higher risk of malignancy than traditionally believed, and that guidelines recommending repeat FNA or observation merit reconsideration.

Use of the afirma® gene expression classifier for preoperative identification of benign thyroid nodules with indeterminate fine needle aspiration cytopathology.

Ruling out malignancy in thyroid nodules historically depended on thyroid resection and histopathological evaluation until fine needle aspiration (FNA) biopsy was introduced into the United States in the 1970's. Thyroid FNA biopsy identified a majority of thyroid nodules as benign, obviating the need for surgery in over half of the patients. However, 15%-30% of thyroid FNAs have indeterminate cytology that still requires operation, even though most of these operated nodules prove to be benign post-operatively. In order to predict which cytologically indeterminate thyroid nodules are benign and to potentially avoid surgery on these nodules, a recently described commercially available Gene Expression Classifier (GEC) test (Afirma®, Veracyte, Inc., South San Francisco, CA) has been developed that can be run on the FNA sample. This paper reviews the published literature and technology assessments/guidelines by independent parties and professional groups regarding the clinical utility as well as the analytic and clinical validity of the Afirma GEC.

A low postoperative nonstimulated serum thyroglobulin level does not exclude the presence of radioactive iodine avid metastatic foci in intermediate-risk differentiated thyroid cancer patients.

BACKGROUND: Postsurgical thyrotropin (TSH)-stimulated serum thyroglobulin (Tg) level can be used to predict the likelihood of finding radioactive iodine (RAI) avid metastatic foci on postablation scanning. However, there is little data regarding the predictive value of a nonstimulated postoperative Tg obtained on levothyroxine therapy in patients being considered for recombinant human TSH (rhTSH)-assisted remnant ablation. METHODS: The study included 290 intermediate-risk differentiated thyroid cancer (DTC) patients with a postsurgical nonstimulated Tg<10 ng/mL prior to rhTSH-assisted remnant ablation. Patients were stratified into four groups based on the postsurgical nonstimulated Tg value: Tg<0.6 ng/mL (n=146), Tg 0.6-0.9 ng/mL (n=76), Tg 1-5 ng/mL (n=51), and Tg>5-10 ng/mL (n=17). RAI avid metastatic foci were identified using post-therapy scanning with SPECT/CT (single photon emission computed tomography). RESULTS: RAI avid metastases were identified in 16% (46/290) of patients, including 12% (17/146) with Tg<0.6 ng/mL, 14% (11/76) with Tg 0.6-0.9 ng/mL, 25% (13/51) with Tg 1-5 ng/mL, and 29% (5/17) with Tg>5-10 ng/mL (p=0.02). While 99% of the RAI avid foci were located in the neck, lung uptake was seen in one patient with Tg<0.6 ng/mL (0.7%, 1/146), one patient with Tg 0.6-0.9 ng/mL (1.3%, 1/76), and 2 patients with Tg>5-10 ng/mL (11%, 2/17 patients). CONCLUSIONS: A postoperative nonstimulated Tg<0.6 ng/mL does not exclude identification of RAI avid metastatic foci on postablation SPECT/CT scanning in intermediate-risk DTC patients. Therefore, patient selection for RAI ablation in the intermediate-risk group must be based on an integration of multiple risk factors rather than any single clinicopathologic risk factor.

The prevalence of thyroid cancer and benign thyroid disease in patients with familial adenomatous polyposis may be higher than previously recognized.

PURPOSE: Patients with familial adenomatous polyposis (FAP) are at increased risk for colorectal cancer and extracolonic neoplasms. The prevalence of thyroid cancer (TC) and benign thyroid disease in this patient population is unclear, and guidelines for screening for TC in these patients are not well established. The purpose of this study was to report the prevalence of TC and benign thyroid disease in patients with FAP. METHODS: The prospectively maintained Hereditary Colorectal Cancer Family Registry at Memorial Sloan-Kettering Cancer Center was queried to identify patients with FAP and with TC and/or benign thyroid disease. RESULTS: Sixty-six patients with FAP were identified. There were 30 men and 36 women, with a median age of 38.6 years. Four (6.1%) patients had a history of TC. All were women, with a mean age at TC diagnosis of 36.5 years. Three of the 4 TCs were papillary thyroid cancer. Two patients with TC presented with palpable nodules. An additional 6 (9.1%) patients with FAP had a history of benign thyroid disease, including nodules (3), hypothyroidism (2), cysts (2), goiter (1), and thyroiditis (1). Three of 4 patients with TC and all 6 patients with benign thyroid disease had other extracolonic manifestations associated with FAP. CONCLUSIONS: The prevalences of TC (6.1%) and benign thyroid disease (9.1%) are increased in our patients with FAP and are higher than noted in some previous reports. Periodic thyroid ultrasound screening should be considered in patients with FAP to further elucidate the prevalence and for possible early detection of TC and benign thyroid disease in this population.

Ultrasonographically detected small thyroid bed nodules identified after total thyroidectomy for differentiated thyroid cancer seldom show clinically significant structural progression.

BACKGROUND: High-resolution ultrasound (US) is the primary tool used to identify locoregional recurrences in differentiated thyroid cancer. Although small thyroid bed (TB) nodules are a commonly reported sonographic finding, their natural history, regardless of whether they are benign or malignant, has not been well characterized. This study was designed to determine the likelihood, magnitude, and rate of growth of small TB nodules identified on routine surveillance neck US after thyroidectomy for differentiated thyroid cancer as well as to identify ultrasonographic and clinical predictors of growth. METHODS: This retrospective review identified 191 patients with at least one TB nodule (≤ 11 mm) on the first postoperative US performed at a comprehensive cancer center. Change in size of each TB nodule was determined using serial US studies over time. Clinicopathologic and sonographic characteristics were analyzed as possible predictors for growth of the TB nodules. RESULTS: Over a median clinical follow-up of 5 years, 9% (17/191) of patients had increase in size of at least one TB nodule. Median size of the TB nodules was 5 mm (range: 2-11 mm). Suspicious US features were seen in 63% (121/191) of patients with TB nodules identified on initial US and in 31% (21/67) of those with TB nodules detected on subsequent follow-up US. The rate of growth was 1.3 mm/year in those nodules showing an increase in size and thus demonstrated a significant increase in size only after several years of follow-up. The negative predictive values associated with the absence of any suspicious US features (0.97), the absence of abnormal cervical lymph nodes (0.94), and the lack of a rising serum thyroglobulin (0.93) provided clinically useful information regarding the likelihood that nodules would not increase in size. CONCLUSION: Most TB nodules do not show clinically significant growth over several years of follow-up. Thus, TB nodules can be followed up with cautious observation and serial ultrasonography using an approach similar to that recommended by the American Thyroid Association thyroid cancer guidelines for the management of small abnormal cervical lymph nodes.

Sonographic imaging of thyroid nodules and cervical lymph nodes.

The initial application of sonography for the evaluation of the neck, more than 30 years ago, was to differentiate cystic and solid thyroid nodules. With improvements in technology, ultrasound has been applied to characterize distinct features in the appearance of thyroid nodules. More recently, its function has been expanded to assess cervical lymph nodes for metastatic thyroid cancer. This article discusses the sonographic features of thyroid nodules associated with malignancy and the role of ultrasound in the management of patients with thyroid cancer.

Morbidity following central compartment reoperation for recurrent or persistent thyroid cancer.

OBJECTIVE: To determine the incidence of recurrent laryngeal nerve injury and hypoparathyroidism, we reviewed our experience with central compartment reoperation. DESIGN: Patients underwent preoperative ultrasonography and magnetic resonance imaging of the neck. Ultrasound-guided fine-needle aspiration biopsy was performed and demonstrated evidence of tumor in 15 patients. At the time of surgery, hook wire electrodes were placed endoscopically into 1 or both vocal cords to monitor the integrity of the recurrent laryngeal nerve. PATIENTS: The study population comprised 20 patients who had undergone reoperative central compartment dissections between the years 1997 and 2001. There were 15 women and 5 men whose mean age was 49.4 years. All of the patients had prior total or subtotal thyroidectomy, and 4 patients had prior neck dissections. A primary thyroid cancer recurrence in the thyroid bed was present in 7 patients, and the remainder of the patients had cytological evidence of paratracheal or mediastinal metastases. A single patient had evidence of distant metastases involving the lung. MAIN OUTCOME MEASURE: Short- and long-term postoperative morbidity. RESULTS: Of the 20 patients, 18 had histologic evidence of metastases to the paratracheal lymph nodes, whereas 8 patients had metastases involving the anterior mediastinal lymph nodes. The mean number of lymph nodes removed was 6.5, and the mean number of positive lymph nodes was 4.7. None of the patients with normal preoperative laryngeal function had postoperative recurrent laryngeal nerve paresis or paralysis. There were 18 patients with normal preoperative parathyroid function. Four patients developed transient postoperative hypocalcemia. All 4 patients with transient postoperative hypocalcemia are currently eucalcemic. A single patient continues to receive calcium and calcitriol supplementation 1 month following her third central compartment dissection for recurrent thyroid cancer. CONCLUSIONS: Reoperation for recurrent or persistent thyroid cancer presents a significant challenge. However, intraoperative recurrent laryngeal nerve monitoring and preservation of the vascular pedicle of the parathyroid glands has reduced the morbidity of reoperative central compartment dissections to acceptable levels. Revision surgery in the central compartment of the neck is compatible with successful eradication of recurrent thyroid cancers and acceptable morbidity.