A Rare Case of Persistent Multifocal Cribriform-Morular Thyroid Carcinoma.

Background/Objective: Cribriform-morular thyroid carcinoma (CMTC) was considered a variant of papillary thyroid carcinoma (PTC) but is a separate entity in the 2022 World Health Organization classification. CMTC has an association with familial adenomatous polyposis (FAP). Our objective is to report a case of CMTC who was subsequently diagnosed with FAP, to highlight these associated entities and implications for management. Case Report: A 15-year-old female with a history of iron-deficiency anemia and alpha-gal syndrome presented with several years of goiter and dysphagia. She also noted unintentional weight loss, abdominal pain, melena and hematochezia, and symptomatic anemia. Physical examination was significant for multiple thyroid nodules. Laboratory results revealed normal thyroid function and iron deficiency. Multiple nodules were visualized on thyroid ultrasound, and fine needle aspiration biopsy was consistent with PTC. Total thyroidectomy was performed with a revised diagnosis of multifocal CMTC, with administration of adjuvant radioactive iodine due to persistent disease. Genetic testing confirmed FAP and she was referred for upper endoscopy, colonoscopy, and an evaluation for colectomy. Discussion: There are no best practice guidelines for management of CMTC. Management of CMTC is guided by FAP status; sporadic cases can be managed with hemithyroidectomy, while FAP-associated cases are better managed with total thyroidectomy. Recurrence is usually managed with surgical resection. The decision to treat with adjuvant radioactive iodine is often extrapolated from management of classic PTC. Conclusion: Thyroid carcinoma in the setting of extensive family history of colorectal carcinoma should arouse suspicion for CMTC. Patients with CMTC should receive a referral for colonoscopy and genetic testing for FAP.

Improved sexual function after parathyroidectomy in women with primary hyperparathyroidism.

BACKGROUND: The study aimed to evaluate whether women with primary hyperparathyroidism (PHPT) experience improvement in their sexual function after parathyroidectomy. METHODS: Women with PHPT or benign thyroid nodules (controls) undergoing surgery were administered the validated Parathyroidectomy Assessment Score (PAS), Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) and Female Sexual Function Index (FSFI) pre-operatively, at 3 months and 6 months postoperatively. RESULTS: Of the 26 PHPT and 18 control patients, PHPT patients were older (53.1 vs 45.3 years, p â€‹= â€‹0.008). Post-operatively, both PHPT (pre-op 2.4 vs 3-month 3.0 vs 6-month 2.4, p â€‹= â€‹0.022) and control patients (pre-operative 2.4 vs 3-month 3.3 vs 6-month 3.6, p â€‹= â€‹0.032) reported increased desire for sexual activities. In addition, PHPT patients experienced increased arousal (pre-operative 2.7 vs 3-month 3.9 vs 6-month 3.6, p â€‹= â€‹0.047) and satisfaction (pre-operative 3.0 vs 3-month 4.8 vs 6-month 4.0, p â€‹= â€‹0.006). CONCLUSIONS: The current study indicates that women with PHPT may experience improved sexual function after parathyroidectomy.

Characteristics, staging and outcomes of differentiated thyroid cancer in patients with and without Graves' disease.

Background: The incidence of thyroid cancer has increased over the last three decades with studies showing incidence of thyroid cancer is higher among patients with Graves' Disease (GD) when compared to Toxic multinodular goiter.1 We conducted a retrospective study to further investigate characteristics and outcomes in patients with thyroid cancer and GD. Methods: We retrospectively reviewed 62 patients with a diagnosis of Differentiated Thyroid Cancer (DTC). We compared age at diagnosis, type, size of tumor, radioactive iodine (RAI) use, and DTC recurrence amongst patients with GD, non-GD patients. We used Chi-square to test for independence among categorical variables at a nominal level of 0.05; comparison was based on t-test. Results: Out of 62 patients, 29 patients had GD and DTC (47%). 94% had papillary thyroid cancer. Patients with GD were diagnosed with DTC at a younger age (mean 46 years) in comparison to patients without GD (mean 53 years). There was no difference in the type of DTC. Patients with GD had significantly smaller tumor size (mean size 1.035 cm; p value = 0.002), more Stage 1 and 2 compared to patients without GD (p-value = 0.009). Both groups of patients had similar rates of recurrence on follow up and RAI use. Conclusion: We found patients with GD had smaller tumor size, early-stage DTC when compared to patients without GD and potentially favorable prognosis. More data is needed to understand whether this is due to pathogenesis like Graves antibodies promoting tumor formation or merely earlier detection of DTC in GD.

Redifferentiation of Differentiated Thyroid Cancer: Clinical Insights from a Narrative Review of Literature.

Background: Patients who have metastatic differentiated thyroid cancer (mDTC) frequently have negative diagnostic and/or post-therapy radioiodine scans. As a result, 131I therapy is frequently no longer considered a therapeutic option for these patients. However, with the knowledge of genomic alterations of patients with mDTC, the use of selected agents in specific patient groups may be used with the intention to re-establish 131I uptake (i.e., redifferentiation) and additional 131I therapy. The objectives of this narrative review are to present definitions of related terminology, a brief overview of the molecular mechanisms of redifferentiating agents, and a narrative review of the literature for redifferentiation in patients who have radioiodine refractory mDTC. Summary: We searched multiple electronic databases and reviewed the relevant English-language literature reported after 2010. Fourteen articles were included in this narrative review. Conclusions: Preliminary data suggest that select agents may offer potential for re-establishing 131I uptake in selected patients with radioiodine refractory mDTC (e.g., negative diagnostic and/or post-therapy radioiodine scans). These agents may also enhance uptake (e.g., uptake enhancement) in patients who have 131I uptake in mDTC on a diagnostic and/or post-therapy radioiodine scan. As a result, this may facilitate higher absorbed dose delivered (Gy (rad]) per 131I activity administered [GBq (mCi)]. This in turn may increase the likelihood of a better therapeutic effect for the planned administered 131I activity or a reduction in the originally planned administered 131I activity, while achieving the same intended therapeutic effect with potentially less untoward effects. Further studies are warranted to confirm these preliminary observations and to confirm acceptable subsequent 131I therapy responses after redifferentiation and/or uptake enhancement.

Efficacy of machine learning to identify clinical factors influencing levothyroxine dosage after total thyroidectomy.

BACKGROUND: We employed Machine Learning (ML) to evaluate potential additional clinical factors influencing replacement dosage requirements of levothyroxine. METHOD: This was a retrospective study of patients who underwent total or completion thyroidectomy with benign pathology. Patients who achieved an euthyroid state were included in three different ML models. RESULTS: Of the 487 patients included, mean age was 54.1 ± 14.1 years, 86.0% were females, 39.0% were White, 53.0% Black, 2.7% Hispanic, 1.4% Asian, and 3.9% Other. The Extreme Gradient Boosting (XGBoost) model achieved the highest accuracy at 61.0% in predicting adequate dosage compared to 47.0% based on 1.6 mcg/kg/day (p < 0.05). The Poisson regression indicated non-Caucasian race (p < 0.05), routine alcohol use (estimate = 0.03, p = 0.02), and osteoarthritis (estimate = -0.10, p < 0.001) in addition to known factors such as age (estimate = -0.003, p < 0.001), sex (female, estimate = -0.06, p < 0.001), and weight (estimate = 0.01, p < 0.001) were associated with the dosing of levothyroxine. CONCLUSIONS: Along with weight, sex, age, and BMI, ML algorithms indicated that race, ethnicity, lifestyle and comorbidity factors also may impact levothyroxine dosing in post-thyroidectomy patients with benign conditions.

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.

Clinical Factors Predictive of Lymph Node Metastasis in Thyroid Cancer Patients: A Multivariate Analysis.

BACKGROUND: Early-stage thyroid cancers have excellent survival. However, lymph node metastases (LNM) confer a worse prognosis and are not always known preoperatively. Therefore, investigation on the clinical and histological factors predictive of LNM in thyroid cancers was conducted to tailor the extent of surgery and radioactive iodine therapy. STUDY DESIGN: Multivariate logistic regressions were performed based on retrospective data from thyroid cancer patients seen between 2013 and 2020 at a single institution. RESULTS: Among 913 patients, mean age was 49.4 years, 76.5% were female, 58.3% were White, 21.2% were Black, and 27.9% had LNM. In the multivariate analyses in which the outcome was LNM, White (odds ratio [OR] 1.74, 95% CI 0.98 to 3.15, p = 0.064) and Hispanic patients (OR 2.36, 95% CI 0.97 to 5.77, p = 0.059) trended toward higher risk of LNM compared to Black patients, whereas age (OR 0.98, 95% CI 0.97 to 1.00, p = 0.008) showed protective effect. Tumor size (OR 1.04, 95% CI 1.01 to 1.07, p = 0.007), extrathyroidal extension (OR 2.46, 95% CI 1.53 to 3.97, p < 0.001), lymphovascular invasion (OR 6.30, 95% CI 3.68 to 11.14, p < 0.001), and multifocality (OR 1.47, 95% CI 1.01 to 2.12, p = 0.042) were associated with higher risk of LNM. In another model with outcome as >5 LNM, tumor size (OR 1.07, 95% CI 1.03 to 1.11, p = 0.001), age (OR 0.95, 95% CI 0.93 to 0.97, p < 0.001), extrathyroidal extension (OR 3.20, 95% CI 1.83 to 5.61, p < 0.001), and lymphovascular invasion (OR 6.82, 95% CI 3.87 to 12.17, p < 0.001) remained significant predictors. CONCLUSION: Our analyses demonstrated and confirmed that age, tumor size, extrathyroidal extension, and lymphovascular invasion are independent predictors of significant LNM, thereby conferring higher risk of recurrence. Risk of LNM based on these patient characteristics should be considered when planning an operative approach.

Sex Differences in Differentiated Thyroid Cancer.

Background: Sex dimorphism strongly impacts tumor biology, with most cancers having a male predominance. Uniquely, thyroid cancer (TC) is the only nonreproductive cancer with striking female predominance with three- to four-fold higher incidence among females, although males generally have more aggressive disease. The molecular basis for this observation is not known, and current approaches in treatment and surveillance are not sex specific. Summary: Although TC has overall good prognosis, 6-20% of patients develop regional or distant metastasis, one third of whom are not responsive to conventional treatment approaches and suffer a 10-year survival rate of only 10%. More efficacious treatment strategies are needed for these aggressive TCs, as tyrosine kinase inhibitors and immunotherapy have major toxicities without demonstrable overall survival benefit. Emerging evidence indicates a role of sex hormones, genetics, and the immune system in modulation of both risk for TC and its progression in a sex-specific manner. Conclusion: Greater understanding of the molecular mechanisms underlying sex differences in TC pathogenesis could provide insights into the development of sex-specific, targeted, and effective strategies for prevention, diagnosis, and management. This review summarizes emerging evidence for the importance of sex in the pathogenesis, progression, and response to treatment in differentiated TC with emphasis on the role of sex hormones, genetics, and the immune system.

Comparing the rate and extent of malignancy in surgically excised thyroid nodules across race and ethnicity.

BACKGROUND: Few studies have compared the features of thyroid cancer among races and ethnicities. We hypothesized that race and ethnicity may influence the frequency and features of thyroid malignancy in thyroid nodules. METHOD: This was a retrospective chart review of patients between 2013 and 2020 who underwent thyroidectomy. RESULTS: In the analysis of 2737 patients, thyroid cancer was less prevalent among Blacks (24.0% vs Whites 52.1%, Hispanics 58.7%, Asians 71.7%, and Others 57.9%, p < 0.001). Thyroid cancer in Blacks was less likely to have extrathyroidal extension (9.7% vs Whites 18.6%, Hispanics 25.8%, Asians 18.2%, and Others 17.8%, p = 0.01), overall nodal involvement (12.4% vs Whites 31.1%, Hispanics 37.5%, Asians 36.3%, and Others 30.1%, p < 0.01), and lateral neck metastasis (4.4% vs Whites 10.8%, Hispanics 6.3%, Asians 13.2%, and Others 9.6%, p = 0.02). CONCLUSIONS: Race and ethnicity may play important roles in the risk of malignancy as well as in the extent of thyroid cancer.

Do Ultrasound Patterns and Clinical Parameters Inform the Probability of Thyroid Cancer Predicted by Molecular Testing in Nodules with Indeterminate Cytology?

Background: Molecular testing (MT) is commonly used to refine cancer probability in thyroid nodules with indeterminate cytology. Whether or not ultrasound (US) patterns and clinical parameters can further inform the risk of thyroid cancer in nodules predicted to be positive or negative by MT remains unknown. The aim of this study was to test if clinical parameters, including patient age, sex, nodule size (by US), Bethesda category (III, IV, V), US pattern (American Thyroid Association [ATA] vs. American College of Radiology Thyroid Image Reporting and Data System [TI-RADS] systems), radiation exposure, or family history of thyroid cancer can modify the probability of thyroid cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) predicted by MT. Methods: We studied 257 thyroid nodules in 232 patients from 10 study centers with indeterminate fine needle aspiration cytology and informative MT results using the ThyroSeq v3 genomic classifier (TSv3). Univariate and multivariate logistic regression was used for data analysis. Results: The presence of cancer/NIFTP was associated with positive TSv3 results (odds ratio 61.39, p < 0.0001). On univariate regression, patient sex, age, and Bethesda category were associated with cancer/NIFTP probability (p < 0.05 for each). Although ATA (p = 0.1211) and TI-RADS (p = 0.1359) US categories demonstrated positive trends, neither was significantly associated with cancer/NIFTP probability. A multivariate regression model incorporating the four most informative non-MT covariates (sex, age, Bethesda category, and ATA US pattern; Model No. 1) yielded a C index of 0.653; R2 = 0.108. When TSv3 was added to Model number 1, the C index increased to 0.888; R2 = 0.572. However, age (p = 0.341), Bethesda category (p = 0.272), and ATA US pattern (p = 0.264) were nonsignificant, and other than TSv3 (p < 0.0001), male sex was the only non-MT parameter that potentially contributed to cancer/NIFTP risk (p = 0.095). The simplest and most efficient clinical model (No. 3) incorporated TSv3 and sex (C index = 0.889; R2 = 0.588). Conclusions: In this multicenter study of thyroid nodules with indeterminate cytology and MT, neither the ATA nor TI-RADS US scoring systems further informed the risk of cancer/NIFTP beyond that predicted by TSv3. Although age and Bethesda category were associated with cancer/NIFTP probability on univariate analysis, in sequential nomograms they provided limited incremental value above the high predictive ability of TSv3. Patient sex may contribute to cancer/NIFTP risk in thyroid nodules with indeterminate cytology.

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.

Optimal Time for 124I PET/CT Imaging in Metastatic Differentiated Thyroid Cancer.

BACKGROUND: The objective of this study was to determine the optimal time for 124I PET/CT imaging to maximize the detection of locoregional and/or distant metastases of differentiated thyroid cancer. METHODS: Differentiated thyroid cancer patients suspected of having metastatic disease were prepared with low-iodine diet and appropriate thyroid-stimulating hormone stimulation. 124I PET and low-dose localization CT were performed over 4 days after oral administration of 31.5 or 62.9 MBq (0.85 or 1.7 mCi) of 124I. Each scan was independently reviewed by 2 nuclear medicine physicians. All foci of activity were categorized, and the visual intensity of uptake was scored by a semiquantitative 3-point grading system (1: mild uptake, 2: moderate uptake, 3: intense uptake). Lesion volumes were determined on the CT image or on the PET images. Background (bkg) was also measured for each lesion and on each individual PET image. For each lesion, the mean activity concentration rate per unit administered activity (ACRmean/AA) and lesion-to-bkg ratios were compared across the 5 different time points. The semiquantitative grade and the quantitative measurements were compared. RESULTS: A total of 45 124I PET/CT scans were reviewed for 9 patients. In the visual assessment, a total of 31 foci suggestive for or highly suggestive of metastasis were identified on 124I PET/CT. Of these, 6 were seen on the 2-h, 18 on the 24-h, 27 on the 48-h, 24 on the 72-h, and 20 on the 96-h scan. There was a significant difference between the 24- and 48-h scans in the total number of foci (ie, locoregional and distant metastasis) (P < 0.05) and in the number of distant metastases (P < 0.05). The 24-, 48-, and 72-h scans identified the same number of locoregional foci. The 48-h scan visualized more of the distant metastases than any other time point. 124I PET/CT with dual-time-point imaging was superior to single-time-point imaging (97% vs 87%). In the quantitative analysis, the median ACRmean/AA was highest at 24 and 48 h, and the median lesion-to-bkg ratio was variable for different lesion locations. For lung metastases, the highest median lesion-to-bkg ratio was at 72 and 96 h. CONCLUSIONS: 124I PET/CT with dual-time-point imaging was superior to any single-time-point imaging (P < 0.10). Based on the visual assessment, dual time points at 48 + 72 h or 48 + 96 h yielded the highest lesion detection rate, whereas for single-time-point imaging, the 48-h images had the highest lesion detection rate. If the 48-h scan is completely negative or has negative 124I uptake in the region of interest, then a 72- or 96-h scan may be valuable. If lung metastases are suspected, then one should consider additional imaging at 72 or 96 h.

30 mCi exploratory scan for two-step dosimetric 131I therapy in differentiated thyroid cancer patients: A novel approach and case report.

Differentiated thyroid cancer patients with significantly elevated or rapidly rising serum thyroglobulin (Tg) levels and negative diagnostic radioiodine scans (DxScan) often present a therapeutic dilemma in deciding whether or not to administer an 131I treatment. In this report, we describe a novel two-step approach of a 30 mCi 131I exploratory scan before a dosimetric 131I therapy to help "un-blind" the treating physician of the benefit/risk ratio of a further "blind" 131I treatment. A 51-year-old man presented with rising Tg levels, a negative DxScan, and a history of widely metastatic follicular thyroid cancer. He had undergone total thyroidectomy, remnant ablation with 3.8 GBq (103.5 mCi) of 131I, Gammaknife®, and treatment with 12.1 GBq (326 mCi) of 131I for multiple metastases. However, at 19 months after the treatments, his Tg levels continued to rise, and scans demonstrated no evidence of radioiodine-avid metastatic disease. In anticipation of a "blind" 131I treatment, the medical team and the patient opted for a 30 mCi exploratory scan. The total dosimetrically guided prescribed activity (DGPA) was decided based on the whole-body dosimetry. The patient was first given 30 mCi of 131I, and the exploratory scan was performed 22 h later, which demonstrated 131I uptake in the left lung, left humeral head, T10, and right proximal thigh muscle. Based on the positive exploratory scan, the remainder of the DGPA was administered within several hours after the scan. On the post-DGPA treatment scan performed at 5-7 days, the lesions seen on the ~ 22 h exploratory scan were confirmed, and an additional lesion was observed in the left kidney. The 30 mCi exploratory scan suggested the potential for a response in the radioiodine-avid lesions despite a negative diagnostic scan. This method allows 131I treatment to be administered to patients who may have a greater potential for a therapeutic response while avoiding unwarranted side effects in those patients with nonavid disease.

Comprehensive guidance on the diagnosis and management of primary mesenchymal tumours of the thyroid gland.

Most primary thyroid tumours are of epithelial origin. Primary thyroid mesenchymal tumours are rare but are being increasingly detected. A vast majority of thyroid mesenchymal tumours occur between the fourth and seventh decades of life, presenting as progressively enlarging thyroid nodules that often yield non-diagnostic results or spindle cells on fine needle aspiration biopsy. Surgery is the preferred mode of treatment, with adjuvant chemoradiotherapy used for malignant thyroid mesenchymal tumours. Benign thyroid mesenchymal tumours have excellent prognosis, whereas the outcome of malignant thyroid mesenchymal tumours is variable. Each thyroid mesenchymal tumour is characterised by its unique histopathology and immunohistochemistry. Because of the rarity and aggressive nature of malignant thyroid mesenchymal tumours, a multidisciplinary team-based approach should ideally be used in the management of these tumours. Comprehensive guidelines on the management of thyroid mesenchymal tumours are currently lacking. In this Review, we provide a detailed description of thyroid mesenchymal tumours, their clinical characteristics and tumour behaviour, and provide recommendations for the optimal management of these tumours.

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.

Assessment of Thyroid Function in Patients With Alkaptonuria.

Importance: Alkaptonuria is an autosomal recessive disorder caused by pathogenic variants in the HGD gene. Deficiency of the HGD enzyme leads to tissue deposition of homogentisic acid (HGA), causing severe osteoarthropathies and cardiac valve degeneration. Although HGD is vital for the catabolism of tyrosine, which provides the basis for thyroid hormone synthesis, the prevalence of thyroid dysfunction in alkaptonuria is unknown. Objective: To assess thyroid structure and function in patients with alkaptonuria. Design, Setting, and Participants: A single-center cohort study was conducted in a tertiary referral center including patients with alkaptonuria followed up for a median of 93 (interquartile range, 48-150) months between February 1, 2000, and December 31, 2018. The alkaptonuria diagnosis was based on clinical presentation and elevated urine HGA levels. A total of 130 patients were considered for participation. Main Outcomes and Measures: Prevalence of thyroid dysfunction in adults with alkaptonuria compared with the general population. Thyrotropin and free thyroxine levels were measured by immunoassay and repeated in each patient a median of 3 (interquartile range, 2-22) times. Neck ultrasonographic scans were analyzed in a subset of participants. Logistic regression was used to test the association of thyroid dysfunction with age, sex, thyroid peroxidase (TPO) antibodies, serum tyrosine levels, and urine HGA levels. Results: Of the 130 patients, 5 were excluded owing to thyroidectomy as the cause of hypothyroidism. The study cohort consisted of 125 patients; the median age was 45 (interquartile range, 35-51) years. Most of the patients were men (72 [57.6%]). The prevalence of primary hyperthyroidism was 0.8% (1 of 125 patients), similar to 0.5% observed in the general population (difference, 0.003; 95% CI, -0.001 to 0.04; P = .88). The prevalence of primary hypothyroidism was 16.0% (20 of 125 patients), which is significantly higher than 3.7% reported in the general population (difference, 0.12; 95% CI, 0.10-0.24; P < .001). Women were more likely to have primary hypothyroidism than men (odds ratio, 10.99; 95% CI, 3.13-38.66; P < .001). Patients with TPO antibodies had a higher likelihood of primary hypothyroidism than those without TPO antibodies (odds ratio, 7.36; 95% CI, 1.89-28.62; P = .004). There was no significant difference in the prevalence of thyroid nodules between patients in this study (29 of 49 [59.2%]) vs the general population (68%) (difference, 0.088; 95% CI, -0.44 to 0.73; P = .20) or of cancer (7% vs 5%; difference, 0.01; 95% CI, -0.01 to 0.17; P = .86). Conclusions and Relevance: The high prevalence of primary hypothyroidism noted in patients with alkaptonuria in this study suggests that serial screening in this population should be considered and prioritized.

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.