Metastatic Differentiated Thyroid Cancer Survival Is Unaffected by Mode of Preparation for 131I Administration.

Context: Recombinant human thyrotropin (rhTSH) is currently not Food and Drug Administration approved for the treatment of high-risk patients with differentiated thyroid cancer (DTC). Objective: The goal of our study was to compare the outcomes in higher-risk patients with metastatic DTC prepared for radioiodine (RAI) therapy with rhTSH vs thyroid hormone withdrawal (THW). Methods: A retrospective chart review was performed of patients with metastatic DTC in follow-up at MedStar Washington Hospital Center and MedStar Georgetown University Hospital from 2009 to 2017. Patients were divided according to their preparation for RAI therapy, with assessment of progression-free survival (PFS) and overall survival (OS). Results: Fifty-five patients with distant metastases (16 men, 39 women) were prepared for RAI therapy exclusively either with rhTSH (n = 27) or with THW (n = 28). There were no statistically significant differences between the groups regarding clinicopathological features and history of RAI therapies. The median follow-up time for patients with rhTSH-aided therapies was 4.2 years (range, 3.3-5.5 years) and for patients with THW-aided therapies was 6.8 years (range, 4.2-11.6 years) (P = .002). Multivariate analysis showed that the method of thyrotropin stimulation was not associated with a difference in PFS or OS. Conclusion: As has been shown previously for low-risk DTC, this study indicates that the mode of preparation for RAI therapy does not appear to influence the outcomes of patients with metastatic DTC. PFS and OS were similar for patients with THW-aided or rhTSH-aided RAI therapies.

Biotin Interference in Assays for Thyroid Hormones, Thyrotropin and Thyroglobulin.

Background: Biotin has been reported to interfere with several commonly used laboratory assays resulting in misleading values and possible erroneous diagnosis and treatment. This report describes a prospective study of possible biotin interference in thyroid-related laboratory assays, with a comparison of different commonly used assay platforms. Materials and Methods: Thirteen adult subjects (mean age 45 ± 13 years old) were administered biotin 10 mg/day for eight days. Blood specimens were collected at three time points on day 1 and on day 8 (baseline, two, and five hours after biotin ingestion). Thyrotropin (TSH), free triiodothyronine (fT3), free thyroxine (fT4), total triiodothyronine (TT3), total thyroxine (TT4), thyroxine binding globulin (TBG), and thyroglobulin (Tg) levels were analyzed with four different platforms: Abbott Architect, Roche Cobas 6000, Siemens IMMULITE 2000, and liquid chromatography with tandem mass spectrometry (LC-MS/MS). TSH, fT3, fT4, TT3, and TT4 were measured with Abbott Architect and Roche Cobas 6000. fT3, fT4, TT3, and TT4 were also measured by LC-MS/MS. Tg was measured by Siemens IMMULITE 2000. TBG was assessed with Siemens IMMULITE 2000. Results: Significant changes in TSH, fT4, and TT3 measurements were observed after biotin exposure when the Roche Cobas 6000 platform was used. Biotin intake resulted in a falsely lower Tg level when measurements were performed with Siemens IMMULITE 2000. At the time points examined, maximal biotin interference was observed two hours after biotin exposure both on day 1 and day 8. Conclusions: A daily dose of 10 mg was shown to interfere with specific assays for TSH, fT4, TT3, and Tg. Physicians must be aware of the potential risk of erroneous test results in subjects taking biotin supplements. Altered test results for TSH and Tg can be particularly problematic in patients requiring careful titration of levothyroxine therapy such as those with thyroid cancer.

Do Molecular Profiles of Primary Versus Metastatic Radioiodine Refractory Differentiated Thyroid Cancer Differ?

Management of metastatic radioiodine refractory differentiated thyroid cancer (DTC) can be a therapeutic challenge. Generally, little is known about the paired molecular profile of the primary tumor and the metastases and whether they harbor the same genetic abnormalities. The present study compared the molecular profile of paired tumor specimens (primary tumor/metastatic sites) from patients with radioiodine refractory DTC in order to gain insight into a possible basis for resistance to radioiodine. Twelve patients with radioiodine refractory metastases were studied; median age at diagnosis of 61 years (range, 25-82). Nine patients had papillary TC (PTC), one had follicular TC (FTC), and two had Hürthle cell TC (HTC). Distant metastases were present in the lungs (n = 10), bones (n = 4), and liver (n = 1). The molecular profiling of paired tumors was performed with a panel of 592 genes for Next Generation Sequencing, RNA-sequencing, and immunohistochemistry. Digital microfluidic PCR was used to investigate TERT promoter mutations. The genetic landscape of all paired sites comprised BRAF, NRAS, HRAS, TP53, ATM, MUTYH, POLE, and NTRK genes, including BRAF and NTRK fusions. BRAF V600E was the most common point mutation in the paired specimens (5/12). TERT promoter mutation C228T was detected in one case. PD-L1 expression at metastatic sites was highly positive (95%) for one patient with HTC. All specimens were stable for microsatellite instability testing, and the tumor mutation burden was low to intermediate. Therefore, the molecular profile of DTC primary and metastatic lesions can show heterogeneity, which may help explain some altered responses to therapeutic intervention.

A Novel Risk Stratification System for Thyroid Nodules With Indeterminate Cytology-A Pilot Cohort Study.

Background: Thyroid ultrasound (US), fine needle aspiration biopsy (FNAB), and molecular testing have been widely used to stratify the risk of malignancy in thyroid nodules. The goal of this study was to investigate a novel diagnostic approach for cytologically indeterminate thyroid nodules (ITN) based upon a combination of US features and genetic alterations. Methods: We performed a pilot cohort study of patients with ITN (Bethesda III/IV), who underwent surgical treatment. Based on standardized sonographic patterns established by the American Thyroid Association (ATA), each ITN received an US score (XUS), ranging between 0 and 0.9 according to its risk of thyroid cancer (TC). DNA and RNA were extracted from pathologic material, available for all patients, and subjected to Oncomine™ Comprehensive Assay v2 (OCAv2) next-generation sequencing. Each genetic alteration was annotated based on its strength of association with TC and its sum served as the genomic classifier score (XGC). The total risk score (TRS) was the sum of XUS and XGC. ROC curves were generated to assess the diagnostic accuracy of XUS, XGC, and TRS. Results: The study cohort consisted of 50 patients (39 females and 11 males), aged 47.5 ± 14.8 years. Three patients were excluded due to molecular testing failure. Among the remaining 47 patients, 28 (59.6%) were diagnosed with TC. BRAFV600E was the most common mutation in papillary TC, PAX8-PPARG fusion was present in NIFTP, pathogenic variants of SLX4, ATM, and NRAS were found in Hürthle cell TC and RET mutations in medullary TC. The diagnostic accuracy of XGC and TRS was significantly higher compared with XUS (88 vs. 62.5%, p < 0.001; 85.2 vs. 62.5%, p < 0.001, respectively). However, this increased accuracy was due to significantly better sensitivity (80.7 vs. 34.6%, p < 0.001; 84.6 vs. 34.6%, p < 0.001, respectively) without improved specificity (94.7 vs. 90%, p = 0.55; 85.7 vs. 90%, p = 0.63, respectively). Conclusion: Molecular testing might not be necessary in ITN with high-risk US pattern (XUS = 0.9), as specificity of TC diagnosis based on Xus alone is sufficient and not improved with molecular testing. OCAv2 is useful in guiding the management of ITN with low-to-intermediate risk US features (XUS < 0.9), as it increases the accuracy of TC diagnosis.

Nationwide Survey on Implementation of 2011 Nuclear Regulatory Commission Policy on Release of Patients After 131I Therapy for Thyroid Cancer.

The objective of this nationwide survey was to evaluate whether there has been a change in the practice regarding hospital release of differentiated thyroid cancer patients treated with 131I since the publication of Nuclear Regulatory Commission Regulatory Issue Summary 2011-01 addressing patient release. Methods: A survey was emailed to approximately 25,000 members of ThyCa: Thyroid Cancer Survivors' Association, Inc., and was available online from March to August 2018. Responses were included from adult patients regarding their most recent 131I therapy received between 2011 and 2018 ("after 2011"). Responses to this survey were compared with those of a similar previous survey for 131I therapies received between 1997 and 2009 ("before 2009"). Results: Of the 2,136 responses, 1,111 met the inclusion criteria. A similar percentage (∼98%) of patients were given oral or written radiation safety instructions (RSIs) after 2011 and before 2009, with a shift away from nuclear medicine physicians providing instructions after 2011 (43%) in comparison with before 2009 (54%; P < 0.001). More patients were able to discuss and individualize the RSIs after 2011 (67%) than before 2009 (29%; P < 0.001). However, 2% of patients do not recall ever receiving RSIs after 2011. After 2011, more patients were treated as outpatients (87%) than before 2009 (66%; P < 0.001). For outpatients, more patients were discharged within 30 min after receiving 131I therapy after 2011 (78%) than before 2009 (72%; P = 0.002). The same percentage (0.6%) of patients traveled more than 2 h with at least 2 occupants in the vehicle within approximately 1 m of the patient after 2011 and before 2009. Immediately after therapy, a similar percentage of patients stayed in a nonprivate residence after 2011 (4%) and before 2009 (5%; P = 0.28). Of the 27 outpatients released within 30 min to nonprivate residences, 2 patients received 5.55-11.1 GBq (150-299 mCi) of 131I. Conclusion: This survey suggests that since publication of the Nuclear Regulatory Commission Regulatory Issue Summary 2011-01 on patient release after radioiodine therapy, there have been improvements in some radiation safety practices on release of outpatients, as well as improvements in patient compliance on travel and lodging.

Improved Survival After Multimodal Approach with 131I Treatment in Patients with Bone Metastases Secondary to Differentiated Thyroid Cancer.

Background: The objective of this study was to evaluate the overall survival (OS) of radioiodine (131I) treatments alone or combined with non-131I treatments in patients with bone metastases (BM) of differentiated thyroid cancer (DTC). Methods: This was a retrospective study of patients who were evaluated between 2001 and 2018 at MedStar Washington Hospital Center and who had DTC, BM, and at least one 131I treatment after the diagnosis of BM. The OS was analyzed by Kaplan-Meier survival curves and was compared by log-rank test between two groups: patients who received 131I treatments alone and those who received treatments combining 131I with non-131I treatments (CombTx). Non-131I treatments include surgery, radiofrequency ablation, cryotherapy, arterial embolization, external beam radiation, Cyberknife, systemic targeted therapy, and anti-resorptive medication. Results: A total of 77 patients met the above criteria and were followed up to 41 years. Thirty percent (23/77) of patients received 131I treatment alone, and 70% (54/77) received CombTx. For 131I treatment alone, the median survival was 3.9 years, and the 1-, 2-, 3-, 5-, and 10-year OS rates were 86%, 81%, 61%, 35%, and 23%, respectively. For CombTx, the median survival was 7.7 years, and the 1-, 2-, 3-, 5-, and 10-year OS rates were 96%, 92%, 86%, 69%, and 30%, respectively. Patients who had undergone initial 131I therapy within six months post thyroidectomy demonstrated a better median survival after BM diagnosis than those whose initial 131I therapy was six months or more after thyroidectomy (6.5 vs. 0.5 years; p < 0.001). Patients who received external beam radiation therapy demonstrated a better median survival than those who did not (7.8 vs. 4.4 years; p = 0.016). Patients who received denosumab demonstrated a better median survival than those who did not (7.7 vs. 5.2 years; p = 0.03). Patients who were <55 years of age at the initial diagnosis of DTC or at the initial diagnosis of BM had a better median OS than those diagnosed at ≥55 years of age (both p = 0.01). In the multivariate analysis, only age at initial diagnosis of DTC and initial 131I therapy within six months post thyroidectomy, and multiple 131I treatments were independent prognostic factors. Conclusions: In patients with DTC with BM, 131I treatment in combination with one or more non-131I direct and systemic treatments was associated with a significant increase in OS compared with those patients who were treated by 131I treatment alone.

Brain Metastases From Differentiated Thyroid Carcinoma: Prevalence, Current Therapies, and Outcomes.

BACKGROUND AND OBJECTIVE: The brain is an unusual site for distant metastases of differentiated thyroid carcinoma (DTC). The aim of this study was to document the prevalence of brain metastases from DTC at our institutions and to analyze the current therapies and the outcomes of these patients. METHODS: We performed a retrospective chart review of patients with DTC and secondary neoplasia of the brain. RESULTS: From 2002 to 2016, 9514 cases of thyroid cancer were evaluated across our institutions and 24 patients met our inclusion criteria, corresponding to a prevalence of 0.3% of patients with DTC. Fourteen (58.3%) were female and 10 (41.7%) were male. Fifteen patients had papillary thyroid cancer (PTC) (62.5%). Brain metastases were diagnosed 0 to 37 years (mean ± SD, 10.6 ± 10.4 years) after the initial diagnosis of thyroid cancer. Patients undergoing surgery had a median survival time longer than those that did not undergo surgery (27.3 months vs 6.8 months; P = 0.15). Patients who underwent stereotactic radiosurgery (SRS) had a median survival time longer than those that did not receive SRS (52.5 months vs 6.7 months; P = 0.11). Twelve patients (50%) were treated with tyrosine kinase inhibitors (TKIs), and they had a better survival than those who have not used a TKI (median survival time, 27.2 months vs 4.7 months; P < 0.05). CONCLUSION: The prevalence of brain metastases of DTC in our institutions was 0.3% over 15 years. The median survival time after diagnosis of brain metastases was 19 months. In our study population, the use of TKI improved the survival rates.

Synchronous Independent Papillary Thyroid Carcinomas in Struma Ovarii and the Thyroid Gland With Different RAS Mutations.

Struma ovarii is a rare ovarian teratoma predominantly composed of thyroid tissue. The simultaneous presence of thyroid carcinoma in the struma ovarii and the thyroid gland is extremely rare. It remains unclear if these carcinomas represent independent primary tumors and whether the molecular mechanisms of the tumors developing in the thyroid and ovarian tissues are similar. We present the case of a patient with two independent papillary thyroid carcinomas (PTCs) in struma ovarii and the thyroid gland that are driven by different RAS mutations. A 62-year-old woman with a history of chronic lymphocytic leukemia/small lymphocytic lymphoma was diagnosed with a pelvic mass during a CT scan. She had surgery that included removal of her ovaries. A 7.2-cm classical variant of PTC arising in a struma ovarii was identified in the right ovary. Two months after the pelvic surgery, total thyroidectomy was performed, and a small nodule (0.8 cm) in the left lobe was diagnosed as a classical variant of PTC. Molecular analysis of tissues obtained from both the malignant struma ovarii and thyroid gland was performed. RAS mutations both in the PTC located in the thyroid and ovarian tissues were identified. However, whereas the thyroid gland tumor showed an HRAS Q61R mutation, the PTC in struma ovarii harbored an NRAS Q61R mutation. In this case, the finding of distinct types of RAS point mutation in thyroid cancers at two different locations provides definitive evidence that these cancers are synchronously developed independent primary tumors.

Use of 99mTc-sestamibi SPECT/CT when conventional imaging studies are negative for localizing suspected recurrence in differentiated thyroid cancer: a method and a lesson for clinical management.

PURPOSE: The detection of recurrent disease in differentiated thyroid cancer (DTC) patients with elevated or rising serum thyroglobulin (Tg) levels and multiple negative conventional imaging studies can be challenging, especially when 18F-FDG PET/CT scan is also negative. We report a patient and review the literature on the diagnostic use of 99mTc-sestamibi scans to identify the source of elevated or rising Tg in patients with negative conventional imaging including negative 18F-FDG PET/CT scans. PATIENT AND METHODS: A 73-year-old woman was referred for widely-invasive metastatic follicular thyroid cancer with bone metastasis to her left mandible. She had a total thyroidectomy, left mandibular resection, and 131I therapy of 145 mCi (5.4 GBq) and her subsequent unstimulated serum Tg level was 29 ng/ml (TgAb negative). At six months' follow-up, her stimulated Tg was 527 ng/ml (TSH 188 mIU/L, TgAb negative). All imaging studies performed within the prior 12 months were reported as negative for recurrence or metastasis; this included neck ultrasound, diagnostic radioiodine scan, chest CT and, 18F-FDG PET/CT. The patient was injected with 24.6 mCi (910 MBq) of 99mTc-sestamibi intravenously, and whole-body and SPECT/CT images were acquired. RESULTS: The 99mTc-sestamibi whole-body posterior image demonstrated abnormal focal uptake in the right posterior calvarium and corresponded to an occipital lytic bone lesion on the SPECT/CT. The patient underwent surgical resection of the skull metastasis, and pathology confirmed metastatic follicular thyroid cancer. Five months post-surgery, the suppressed Tg was markedly reduced and remained stable at ~3.2 ng/ml. With the knowledge of the DTC recurrence location, the two sets of 18F-FDG images were re-evaluated. The more thorough and targeted interpretation underscored the importance of structured image reporting. The current literature on the utility of 99mTc-sestamibi scans when radioiodine, 18F-FDG PET/CT, and other imaging studies are negative is sparse and inconsistent. CONCLUSIONS: 99mTc-sestamibi may have a role in thyroid cancer localization when physical exam, neck ultrasound, radioiodine scan, chest/abdomen CT, and 18F-FDG PET/CT does not identify the source of elevated Tg levels in DTC.

Selected Radiation Safety Aspects Including Transportation and Lodging After Outpatient 131I Therapy for Differentiated Thyroid Cancer.

BACKGROUND: Whether radioactive iodine (131I) treatments for differentiated thyroid cancer should be performed as an outpatient or inpatient remains controversial. The objective of this study was to survey selected aspects of radiation safety of patients treated with 131I for differentiated thyroid cancer as an outpatient. METHODS: An e-mail invitation was sent to over 15,000 members of ThyCa: Thyroid Cancer Survivors' Association, Inc. to complete a web-based survey on selected aspects of radiation safety regarding their last outpatient 131I treatment. RESULTS: A total of 1549 patients completed the survey. Forty-five percent (699/1541) of the respondents reported no discussion on the choice of an inpatient or outpatient treatment. Moreover, 5% (79/1541) of the respondents reported that their insurance company made the decision. Survey respondents recalled receiving oral and written radiation safety instructions 97% (1459/1504) and 93% (1351/1447) of the time, respectively. Nuclear medicine physicians delivered oral and written instructions to 54% (807/1504) and 41% (602/1462) of the respondents, respectively. Eighty-eight percent (1208/1370) of the respondents were discharged within 1 hour after receiving their 131I treatment, and 97% (1334/1373) traveled in their own car after being released from the treating facility. Immediately post-therapy, 94% (1398/1488) of the respondents stayed at their own home or a relative's home, while 5% (76/1488) resided in a public lodging. The specific recommendations received by patients about radiation precautions varied widely among the respondents. Ninety-nine percent (1451/1467) of the respondents believed they were compliant with the instructions. CONCLUSION: This is the largest, patient-based survey published regarding selected radiation safety aspects of outpatient 131I treatment. This survey suggests several concerns about radiation safety, such as the decision process regarding inpatient versus outpatient treatment, instructions about radiation safety, transportation, and lodging after radioiodine therapy. These concerns warrant further discussion, guidelines, and/or policies.