Well-differentiated Thyroid Carcinoma Research Articles

SUN-483 A Retrospective Diagnosis of Malignant Struma Ovarii After Discovery of Pulmonary Metastases

Background: Malignant struma ovarii is a rare ovarian tumor that is histologically identical to differentiated thyroid carcinoma.1 We present a case of a struma ovarii that was recognized as being malignant only after the discovery of pulmonary metastases. Clinical Case: A 29 year old female presented to the hospital with acute right lower abdominal pain, suspicious for ovarian torsion. She underwent urgent right salpingoopherectomy and pathology demonstrated a mature cystic teratoma with benign struma ovarii. Two years later, a CT of the abdomen incidentally revealed bilateral pulmonary nodules. Review of the imaging showed that these pulmonary nodules were also present two years prior, and had since become larger. Video-assisted thoracoscopic surgery was performed and lung biopsy was positive for well-differentiated thyroid carcinoma. The patient then underwent total thyroidectomy which revealed a 0.3 x 0.3 cm infiltrative papillary thyroid cancer, follicular variant, without lymphovascular invasion. Thyroglobulin level decreased from 169 ng/mL pre-operatively to 80 ng/mL post-operatively, but then continued to be variable ranging from 56 to 252 ng/mL (1.6-50 ng/mL). Thyroglobulin antibodies remained negative.Pathology from right ovary was re-reviewed at a second institution and found to be consistent with highly differentiated thyroid carcinoma with characteristic nuclear features of papillary thyroid carcinoma.A diagnostic whole body I-131 scan showed uptake within the thyroid bed, bilateral lung nodules, left distal thigh and right mid thigh. These thigh lesions were not visualized on lower extremity ultrasound. After dosimetry was performed, the patient received radioactive iodine-131 200 mCI. Post-therapy scan six days later demonstrated uptake in the thyroid bed, bilateral lungs and bilateral thighs. About five months later, thyroglobulin level had decreased to 0.4 ng/mL with a suppressed TSH. A repeat CT chest demonstrated that the lung nodules had all decreased in size, largest from 0.5 cm to 0.3 cm. Conclusion: Careful examination of struma ovarii pathology should be performed to evaluate for malignant features since benign appearing histology can present diagnostic difficulty.2 In this case, thyroglobulin level was lower than reported in previous cases; however, sites of metastases were responsive to radioactive iodine therapy indicating well differentiated disease and a favorable prognosis.

Incidence and Mortality Risk Spectrum Across Aggressive Variants of Papillary Thyroid Carcinoma

While well-differentiated papillary thyroid carcinoma (WDPTC) outcomes have been well characterized, the prognostic implications of more aggressive variants are far less defined. The rarity of these subtypes has led to their consolidation as intermediate risk for what are in fact likely heterogeneous diseases. To analyze incidence, clinicopathologic characteristics, and outcomes for aggressive variants of papillary thyroid carcinoma (PTC). This cohort study used data from 2000 to 2016 from hospital-based and population-based US cancer registries to analyze aggressive PTC variants, including diffuse sclerosing (DSV), tall-cell (TCV), insular, and poorly differentiated (PDTC) subtypes. These variants were compared against WDPTC and anaplastic cases. Data analysis was conducted from January 2019 to October 2019. Age-adjusted incidence was calculated via annual percentage change (APC) using the weighted least-squares method. Overall survival and disease-specific survival were analyzed via Cox regression. Propensity-score matching was used to adjust survival analyses for clinical and demographic covariates. Collectively, 5447 aggressive PTC variants were identified (including 415 DSV, 3339 TCV, 362 insular, and 1331 PDTC cases), as well as 35 812 WDPTC and 2249 anaplastic cases. Over the study period, a substantial increase in aggressive variant incidence was observed (APC, 9.1 [95% CI, 7.33-10.89]; P < .001), surpassing the relative increases observed in WDPTC (APC, 5.1 [95% CI, 3.98-6.12]; P < .001) and anaplastic cases (APC, 1.9 [95% CI, 0.75-3.05]; P = .003; parallelism P < .007). Survival varied markedly based on histologic subtype, with a wide spectrum of mortality risk noted; 10-year overall survival was 85.4% (95% CI, 84.6%-86.3%) in WDPTC, 79.2% (95% CI, 73.6%-85.3%) in DSV, 71.9% (95% CI, 68.4%-75.6%) in TCV, 45.1% (95% CI, 40.2%-50.6%) in PDTC, 27.9% (95% CI, 20.0%-38.9%) in the insular variant, and 8.9% (95% CI, 7.5%-10.6%) in anaplastic cases (P < .001). These differences largely persisted even after adjusting for inherent differences in baseline characteristics by multivariable Cox regression and propensity-score matching. An upsurge in aggressive PTC incidence was observed at a rate beyond that seen in WDPTC or anaplastic thyroid carcinoma. Moreover, long-term survival outcomes for aggressive PTC subgroups exhibit heterogeneous clinical behavior and a wide range of mortality risk, suggesting that treatment should be tailored to specific histologic subtypes. Given increasing prevalence and disparate outcomes, further investigation to identify optimal therapeutic strategies is needed in these diverse, understudied populations.

Risk Factors and Outcomes of Postoperative Recurrent Well-Differentiated Thyroid Cancer: A Single Institution's 15-Year Experience.

Identify risk factors and outcomes of recurrent well-differentiated thyroid cancer. Retrospective case-control analysis. Tertiary care academic center in Nashville, Tennessee. This single-center analysis reviews 478 patients who underwent initial surgical management of well-differentiated thyroid carcinoma between 2002 and 2017. Patients were dichotomized with or without recurrent well-differentiated thyroid cancer. Demographic and clinicopathologic risk factors were carefully reviewed. Univariate, multiple regression, and survival analyses were used to evaluate predictors of recurrence. Thirty-eight patients (7.9%) who received initial surgical intervention for well-differentiated thyroid carcinoma at our institution recurred, with an average time to recurrence of 24 months. Male sex, tumor size, multifocality, extrathyroidal extension, lymphovascular invasion, number of positive lymph nodes, and low lymph node yield were all significantly associated with locoregional recurrence (P < .05). Multiple regression analysis showed that extrathyroidal extension, number of positive lymph nodes, and low lymph node yield were independent factors predictive of posttreatment recurrence (P < .05). Metastatic lymph node ratio, the ratio of positive lymph nodes extracted to lymph node yield, of ≥0.3 is associated with increased risk of recurrence (P < .001) and decreased 5-year recurrence free survival (P < .001). Extrathyroidal extension, number of positive lymph nodes, and low lymph node yield are independent clinicopathologic risk factors for postoperative recurrence of well-differentiated thyroid cancer. Metastatic lymph node ratio is uncommonly used but can be an important prognosticator of recurrence. Patients with metastatic lymph node ratio ≥0.3 should be counseled on their increased risk of recurrence and should undergo close surveillance following surgery.

Contribution of cytologic examination to diagnosis of poorly differentiated thyroid carcinoma.

BackgroundThe cytologic diagnosis of poorly differentiated thyroid carcinoma (PDTC) is difficult because it lacks salient cytologic findings and shares cytologic features with more commonly encountered neoplasms. Due to diverse cytologic findings and paucicellularity of PDTC, standardization of cytologic diagnostic criteria is limited. The purpose of this study is to investigate and recognize diverse thyroid findings of fine needle aspiration (FNA) cytology and frozen smear cytology in diagnosis of this rare but aggressive carcinoma.MethodsThe present study included six cases of FNA cytology and frozen smears of histologically diagnosed PDTCs.ResultsPDTC showed cytologic overlap with well-differentiated thyroid carcinomas (WDTCs). Five of six cases showed dedifferentiation arising from well differentiated thyroid carcinomas. Only one de novo PDTC showed highly cellular smears composed of discohesive small cells, high nuclear/cytoplasmic (N/C) ratio, prominent micronucleoli, and irregular nuclei. Retrospectively reviewed, these findings are highly suspicious for PDTC. Cytologic findings of nuclear atypia, pleomorphism, and irregularity were frequently found, whereas scattered small cells were seen only in the de novo case.ConclusionsHeterogeneous cytologic findings of PDTCs are shared with those of WDTCs and contribute to difficult preoperative cytologic diagnoses. Most PDTCs show dedifferentiation from WDTCs. Albeit rare, de novo PDTC should be considered with cytology showing discohesive small cells with high N/C ratio. This will enable precise diagnosis and prompt treatment of this aggressive malignancy

Association of Screening by Thyroid Ultrasonography with Mortality in Thyroid Cancer: A Case-Control Study Using Data from Two National Surveys.

Background: The incidence of thyroid cancer is increasing worldwide due to an increased detection of small well-differentiated papillary thyroid carcinomas. This study aimed to evaluate the effect of screening with ultrasonography on deaths from thyroid cancer. Materials and Methods: We conducted a matched case-control study using data from two sources representative of the adult Korean population. Cases were selected from the National Epidemiologic Survey of Thyroid Cancer database, and controls were selected from the Korean National Cancer Screening Survey database. Controls were individually matched to case patients with respect to age, sex, and area with a ratio of 10:1. The primary outcome was death from thyroid cancer. Controls were required to have been alive on the date of thyroid cancer diagnosis in the corresponding case. Results: The analysis included 120 patients who died from thyroid cancer and 1184 controls. Compared with those who had never been screened, the odds ratios for death from thyroid cancer among those who had been screened were 1.44 (95% confidence interval [CI] 0.68-3.05) if cases with missing information on screening were excluded and 1.13 [CI 0.49-2.63] if all cases were included, and missing information was imputed. Stratification by sex, year of diagnosis, and histological type did not show any statistically significant relationships between screening with ultrasonography and death from thyroid cancer, regardless of the statistical model used. Conclusions: Screening for thyroid cancer with ultrasonography does not prevent death from thyroid cancer; therefore, screening asymptomatic adults for thyroid cancer is unwarranted.

Recurrent DICER1 Hotspot Mutations in Malignant Thyroid Gland Teratomas: Molecular Characterization and Proposal for a Separate Classification.

Thyroid gland teratomas are rare tumors that span a wide clinicopathologic spectrum. Although benign and immature teratomas arise in infants and young children and generally have good outcomes, malignant teratomas affect adults and follow an aggressive course. This divergent behavior raises the possibility that benign/immature and malignant teratomas are separate entities rather than different grades of a single tumor. However, the histogenesis and molecular underpinnings of thyroid gland teratomas are poorly understood regardless of grade. In this study, we performed next-generation sequencing on 8 thyroid gland teratomas, including 4 malignant, 3 benign, and 1 immature. We identified DICER1 hotspot mutations in all 4 malignant cases (100%) but not in any benign/immature cases (0%). No clinically significant mutations in other genes were found in either group. We also performed immunohistochemistry to characterize the primitive components of malignant teratomas. Not only did all cases consistently contain immature neural elements (synaptophysin and INSM1 positive), but also spindled cells with rhabdomyoblastic differentiation (desmin and myogenin positive) and bland epithelial proliferations of thyroid follicular origin (TTF-1 and PAX8 positive). Although DICER1 mutations have previously been implicated in multinodular hyperplasia and well-differentiated thyroid carcinomas, these findings demonstrate the first recurrent role for DICER1 in primitive thyroid tumors. The combined neural, rhabdomyoblastic, and homologous epithelial elements highlighted in this series of malignant thyroid gland teratomas parallel the components of DICER1-mutated tumors in other organs. Overall, these molecular findings further expand the differences between benign/immature teratomas and malignant teratomas, supporting the classification of these tumors as separate entities.

Patient and tumor factors contributing to distant metastasis in well-differentiated thyroid cancer: a retrospective cohort study

BackgroundDistant metastasis in thyroid cancer significantly reduces survival in patients with well-differentiated thyroid carcinoma (WDTC). There is limited information available to clinicians regarding pathological features that confer a higher risk of distant metastasis (DM). This study aimed to identify patient and tumor factors that were associated with the development of DM over time in patients with WDTC.MethodsA retrospective cohort analysis of patients with WDTC (n = 584) at our institution was performed between 2007 and 2017. A total of 39 patients with DM and 529 patients with no DM (NDM) were included. Patient demographics, tumor characteristics and patient survival were compared between the DM and NDM groups using a univariate analysis. Multivariate Cox-proportional hazards model was used to evaluate the risk of developing distant metastasis over time. Kaplan-Meier analysis was used to compare survival between the DM and NDM groups.ResultsDistant metastasis had a substantial impact on disease-specific survival (DSS) at 5 and 10-years in the DM group; 71.0% (SE 8.4%) and 46.9% (SE 11.6%) respectively, compared to 100% survival in the NDM group (p < 0.001). The DM group had significantly higher proportions of males, lymphovascular invasion (LVI), nodal metastasis (NM), large tumor size (TS), extrathyroidal extension (ETE), positive resection margins, multifocality, follicular thyroid cancer (FTC), tall cell variant of papillary thyroid cancer (PTC), and Hurthle cell carcinoma (HCC), when compared to the NDM group (p < 0.05). A TS ≥ 2 cm (Hazard Ratio (HR) 1.370), NM (HR 3.806) and FTC (HR 7.068) were associated with a significantly increased hazard of developing distant metastasis in patients with WDTC.ConclusionsTS ≥ 2 cm, NM and FTC are associated with a significantly increased propensity for developing DM in our cohort of WDTC patients.Graphical abstract

Evaluation of CYFRA 21.1 as a dedifferentiation marker of advanced thyroid cancer

Purpose of the Study:Well-differentiated thyroid carcinomas have good prognosis, but as it de-differentiates, the survival rates go down. Early identification of such patients needs a marker which indicates the dedifferentiation process. CYFRA 21.1 has also shown to be increased in patients with 131I refractory thyroid cancer. We tested whether CYFRA 21.1 can differentiate between 131I avid and refractory tumors.Methodology:Well-differentiated thyroid cancer patients with known distant metastases were accrued and tested for stimulated and unstimulated thyroglobulin and CYFRA 21.1. All patients underwent 131I whole-body scan, 131I post therapy scan, and 18F-Fluorodeoxyglucose positron emission tomography-computed tomography. Those with even a single 131I nonavid lesion were considered 131I refractory disease. CYFRA 21.1 of both 131I avid and nonavid was compared, and CYFRA 21.1 levels against disease extent were analyzed.Results:CYFRA 21.1 levels were significantly elevated in 131I refractory group. A cutoff value of 2.07 ng/ml distinguished between 131I avid and refractory disease with high sensitivity and specificity (88% and 89. 7%, respectively). However, CYFRA 21.1 levels were similar in patients when analyzed based on disease sites.Conclusion:CYFRA 21.1 can be utilized to differentiate between 131I avid and refractory diseases. Further long-term studies are required to use it as a predictive and prognostic marker.

Aberrant DNA repair as a potential contributor for the clonal evolution in subsets of anaplastic thyroid carcinomas arising through dedifferentiation: implications for future therapeutic algorithms?

Well-differentiated thyroid carcinoma (WDTC, including papillary thyroid carcinoma and follicular thyroid carcinoma) are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine therapy. Subsets of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), of which especially the latter has an exceptionally poor patient outcome. The underlying genetics responsible for this tumor progression is only partly understood, and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable, pre-existing WDTC. Even so, recent advances using next generation sequencing (NGS) techniques have identified a genetic link between WDTCs and ATCs, suggesting a step-wise accumulation of mutations driving the loss of differentiation for most cases. In this Commentary, recent findings from an NGS study on synchronous FTC, PDTC, and ATC tumor components from the same patient are highlighted. By using whole-genome data, clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair, with sub-clones in each tumor component that were identified also in the less differentiated, neighboring tumor. Moreover, mutational signatures suggested a general mismatch repair (MMR) deficiency along with microsatellite instability. These findings support the chained progression model of dedifferentiation in thyroid cancer, and pinpoint a central role for defective DNA repair. Since effective treatment modalities for ATCs are urgently needed, studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.

Prophylactic Central Neck Dissection in Well-differentiated Thyroid Cancer.

SUMMARYWell-differentiated cancers, both papillary and follicular, account for 90% of all diagnosed thyroid cancers. They have an indolent disease course with a 20-year disease-specific survival over 90%. According to current guidelines, the therapy of choice for well-differentiated thyroid carcinoma is total thyroidectomy or lobectomy. The indication for prophylactic central neck dissection is still a controversial issue and the subject of unfinished and ongoing debate. There is no indication for prophylactic central neck dissection in follicular thyroid carcinomas, which primarily metastasize hematogenously. In small solitary papillary thyroid carcinomas (T1 and T2), prophylactic central neck dissection is not indicated as it does not bring benefits in terms of improved patient survival and at the same time significantly increases the risk of temporary and permanent postoperative complications. Prophylactic central neck dissection is indicated in advanced papillary thyroid cancers (T3 and T4) and all other high-risk well-differentiated thyroid cancer, as well as in the presence of metastatic lymph nodes in the lateral neck.

Papillary Carcinoma of Thyroid Developing in a Dyshormonogenetic Goitre: a Report of Two Cases in One Family

Dyshormonogenetic goitre is a rare condition frequently managed conservatively. Its association with malignancy has rarely been documented. We report three siblings with dyshormonogenetic goitre born to parents of consanguineous marriage. The eldest sibling had symptoms of hypothyroidism at 3 months of age; the second had a goitre at birth, while the youngest was screen detected to have hypothyroidism at birth. All three siblings were euthyroid on supplementation with levothyroxine. All of them developed an asymptomatic goitre which gradually increased in size over a decade. Though ultrasound and FNAC of the thyroid did not reveal a malignant lesion, all three underwent total thyroidectomy in view of the large size of the goitre. Histopathology revealed a well-differentiated thyroid carcinoma in two of the siblings – one with a macro follicular variant of papillary carcinoma while the other a micropapillary carcinoma. The sibling with the macro carcinoma underwent a 131I whole-body scan following thyroidectomy which was negative for metastatic disease. All three siblings are doing well on follow-up. Although a benign condition, the possibility of development of an associated well-differentiated thyroid carcinoma should be kept in mind while evaluating these patients.

A 15 year institutional experience of well-differentiated follicular cell-derived thyroid carcinomas; impact of the new 2017 TNM and WHO Classifications of Tumors of Endocrine Organs on the epidemiological trends and pathological characteristics.

Our study aimed to describe the evolution of the rate of pathological subtypes of well-differentiated follicular-cell derived thyroid carcinomas (DTCs) in the Department of Pathology, Emergency County Hospital Targu-Mures, Romania over a 15 year period and to assess the impact the new 2017 WHO and TNM classifications of thyroid tumors had on our cases. The pathological data were retrieved from the original pathological reports. After applying the exclusion criteria the remaining cases were reviewed on a double-headed microscope and reclassified according to the 2017 WHO and TNM staging system. The follow-up data were collected from the Institute of Oncology Cluj-Napoca, Romania. Our study included 396 cases of DTCs (375 papillary, 11 follicular, and 10 Hürthle cell carcinomas). PTCs revealed a significant increasing trend over the study period, whereas follicular and Hurthle cell carcinomas remain rare; 125/131 of noninvasive encapsulated follicular variant PTC (EFVPTC) were reclassified as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), resulting in a 33.3% reduction in the number of PTCs. According to 2017 TNM stage-grouping 31% of 271 patients with DTC were downstaged. Follow-up data were available for most of the patients (65.7%, mean period 58.1 months). All patients with noninvasive EFVPTC were disease free at the last clinical assessment. The increasing rate of PTC was maintained even after exclusion of NIFTP. By applying 2017 TNM criteria, a significant number of DTC cases were downstaged into a more favorable group. Follow-up data highlight the indolent behavior of noninvasive EFVPTCs reclassified as NIFTPs.

Isthmusectomy in selected patients with well-differentiated thyroid carcinoma.

Isthmusectomy in the treatment of well-differentiated thyroid carcinoma (WDTC) is controversial. In this study, we analyze the outcomes of WDTC managed by isthmusectomy alone. Forty-three patients treated with isthmusectomy alone were identified from an institutional database of 6259 surgically treated patients with WDTC. Patient and tumor characteristics were analyzed. Disease-specific survival (DSS) and recurrence-free survival (RFS) were calculated using the Kaplan-Meier method. The pT classification was T1 for 41 and T2 for two patients. All were clinical N0, but 10 pts were pN1a. Using the American Thyroid Association risk stratification system, 9 patients were low-risk and 22 were intermediate-risk. One patient developed local recurrence, and two developed regional lymph node metastases; the 5- and 10-year DSS was 100.0%. The 5- and 10-year RFS was 93.1%. Isthmusectomy alone is an acceptable procedure in selected patients with low- and intermediate-risk WDTC limited to the isthmus.

50 Treatment and Outcomes in PT4 Well-Differentiated Thyroid Carcinoma

50 Treatment and Outcomes in PT4 Well-Differentiated Thyroid Carcinoma

Treatment and Outcomes in pT4 Well-Differentiated Thyroid Carcinoma

Locally advanced, pT4 well differentiated thyroid carcinoma is a relatively rare entity and the benefit of external beam radiotherapy (EBRT) is unclear. The purpose of this study is to evaluate locoregional control (LRC) and cancer specific survival (CSS) of patients with pT4 well differentiated thyroid carcinoma in the largest retrospective cohort to date. Electronic records of patients with pT4 well-differentiated thyroid carcinoma treated at our institution from 2001 to 2013 were reviewed. Log-rank test and multivariable Cox regression were used to establish factors impacting locoregional control and cancer specific survival. A total of 232 patients were treated during this time period. The most common histologies were papillary carcinoma (n=192) and follicular carcinoma (n=11). The median age was 58 and 61% were female. Median follow up time was 11 years. The median tumor size was 3.1cm (interquartile range: 2.0-5.0cm), 60% had multifocal disease, 33% lymphovascular invasion, 9% perineural invasion and 64% had node positive disease. Local invasion into the strap muscles was seen in 51%, trachea 33%, larynx 4%, pharynx 3%, and recurrent laryngeal nerve 1%. 22% patients had an R0 resection, 55% R1 and 23% R2. 92% patients received adjuvant radioactive iodine therapy. A total of 88 patients received external beam radiotherapy with a median dose of 60Gy. There were 7 acute grade 3 toxicities (3 dysphagia, 2 nausea, and 2 pain) and 7 late grade 3 toxicities in the cohort (2 dysphagia, 3 esophageal stricture, 1 pain, 1 laryngeal stenosis). There were no grade 4 toxicities observed. Ten year LRC was 65%, CSS was 85%, and OS was 75%. On multivariate analysis, older age (p=0.02, HR 1.02, 95% CI 1.0-1.04), larynx invasion (p=0.05, HR 3.32, 95% CI 1.0-11.0) and larger tumor size (p=0.01, HR 1.17, 95% CI 1.04-1.32) were associated with worse LRC. Older age (p<0.001, HR 1.10, 95% 1.06-1.15), lymphovascular invasion (p=0.002, HR 3.3, 95% 1.5-7.2), perineural invasion (p=0.02, HR 2.9, 95% 1.19-7.48), and tracheal invasion (p=0.009, HR 2.7, 95% CI 1.3-5.5) were associated with worse CSS. Adjuvant RT was not associated with improved LRC and CSS when the entire cohort was assessed. However, for patients with microscopic or macroscopic residual disease (R1 and R2 resection), adjuvant radiotherapy was associated with improved LRC on multivariable analysis (p=0.02, HR 0.45, 95% CI 0.23-0.90). Despite locally advanced disease; 10 year CSS was 85% in this cohort of patients with pT4 DTC. Adjuvant radiotherapy improved LRC for patients with R1 and R2 resections. There was a low rate of toxicity from EBRT for the cohort.

Clinicopathological features and outcomes after radioactive iodine treatment of oncocytic well-differentiated thyroid carcinomas.

The aim of this study was to compare the clinicopathological features of Hürthle cell carcinomas (HCC) and oncocytic papillary thyroid carcinomas (OPTC) and to evaluate their response to radioactive iodine (RAI) treatment. We retrospectively reviewed the charts of patients with histopathologically verified OPTC (group 1) and HCC (group 2), during a 17-year period. All patients underwent total thyroidectomy and received RAI adjuvant therapy. Clinicopathological characteristics of the two groups were compared. Response to initial therapy was assessed 6 to 24 months after RAI ablation according to the American Thyroid Association dynamic risk reclassification. Clinical outcomes were evaluated. A total of 28 patients (8 OPTC and 20 HCC) were included. There was no significant difference in clinicopathological features including sex, age, tumour size and vascular invasion. Distant metastases were absent in both groups. OPTC, however, presented more features of local invasion (50% vs. 10%, P = 0.03), extrathyroidal extension (25% vs. 0%, P = 0.07) and lymph node involvement (37.5% vs. 0%, P = 0.01). Median cumulative RAI activity administered to both groups was 200 mCi (range: 100-300 mCi). Response to RAI therapy was excellent in all HCC and 87.5% of OPTC (P = 0.28). One patient with OPTC (12.5%) presented an indeterminate response. Clinical outcomes were favourable after a median follow-up of 87.5 and 49 months, respectively. Although OPTC presented more locoregional invasion, clinicopathological characteristics of OPTC and HCC were comparable. Both OPTC and HCC were iodine responsive. We suggest that adjuvant RAI therapy after total thyroidectomy is beneficial for OPTC and HCC and may improve disease-free survival.

Mouse Model of Thyroid Cancer Progression and Dedifferentiation Driven by STRN-ALK Expression and Loss of p53: Evidence for the Existence of Two Types of Poorly Differentiated Carcinoma.

Background: Thyroid tumor progression from well-differentiated cancer to poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) involves step-wise dedifferentiation associated with loss of iodine avidity and poor outcomes. ALK fusions, typically STRN-ALK, are found with higher incidence in human PDTC compared with well-differentiated cancer and, as previously shown, can drive the development of murine PDTC. The aim of this study was to evaluate thyroid cancer initiation and progression in mice with concomitant expression of STRN-ALK and inactivation of the tumor suppressor p53 (Trp53) in thyroid follicular cells. Methods: Transgenic mice with thyroid-specific expression of STRN-ALK and biallelic p53 loss were generated and aged on a regular diet or with methimazole and sodium perchlorate goitrogen treatment. Development and progression of thyroid tumors were monitored by using ultrasound imaging, followed by detailed histological and immunohistochemical evaluation. Gene expression analysis was performed on selected tumor samples by using RNA-Seq and quantitative RT-PCR. Results: In mice treated with goitrogen, the first thyroid cancers appeared at 6 months of age, reaching 86% penetrance by the age of 12 months, while a similar rate (71%) of tumor occurrence in mice on regular diet was observed by 18 months of age. Histological examination revealed well-differentiated papillary thyroid carcinomas (PTC) (n = 26), PDTC (n = 21), and ATC (n = 8) that frequently coexisted in the same thyroid gland. The tumors were frequently lethal and associated with the development of lung metastasis in 24% of cases. Histological and immunohistochemical characteristics of these cancers recapitulated tumors seen in humans. Detailed analysis of PDTC revealed two tumor types with distinct cell morphology and immunohistochemical characteristics, designated as PDTC type 1 (PDTC1) and type 2 (PDTC2). Gene expression analysis showed that PDTC1 tumors retained higher expression of thyroid differentiation genes including Tg and Slc5a5 (Nis) as compared with PDTC2 tumors. Conclusions: In this study, we generated a new mouse model of multistep thyroid cancer dedifferentiation with evidence of progression from PTC to PDTC and ATC. Further, PDTC in these mice showed two distinct histologic appearances correlated with levels of expression of thyroid differentiation and iodine metabolism genes, suggesting a possibility of existence of two PDTC types with different functional characteristics and potential implication for therapeutic approaches to these tumors.

Prognostic Value of Lymph Node Uptake on Pretreatment F-18 FDG PET/CT in Patients with N1B Papillary Thyroid Carcinoma

Objective: The aim of this study was to investigate the prognostic value of metabolic characteristics of metastatic lymph node (LN) using pretreatment F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for patients with papillary thyroid carcinoma (PTC) and metastatic lateral LN (N1b). Methods: Ninety-six PTC patients (female:male = 72:24; median age, 44.5 years) with pathologic N1b who underwent pretreatment FDG PET/CT, total thyroidectomy, and radioactive iodine ablation were retrospectively reviewed. To predict responses to initial therapy and recurrence, clinicopathologic factors and metabolic parameters were reviewed, such as sex, age, tumor size, extranodal extension, number and ratio of metastatic LNs, serum thyroglobulin, and maximum standardized uptake value (SUVmax). Results: Among the 96 PTC patients, 81 (84.4%) were classified into the acceptable response (58 excellent; 23 indeterminate) and 15 (15.6%) into the incomplete response (8 biochemical incomplete; 7 structural incomplete) by the 2015 American Thyroid Association management guideline for differentiated thyroid carcinoma. The multivariate analysis showed that SUVmax of N1b (P = .018), pre-ablation stimulated thyroglobulin level (P = .006), and the ratio of metastatic LNs (P = .018) were related to incomplete response. The cutoff value of each variable was determined by receiver operating characteristic analysis. Nine (9.4%) patients experienced recurrences (median follow-up: 50 months). The Kaplan-Meier analysis revealed that SUVmax of N1b (cutoff value: 2.3; P = .025) and ratio of metastatic LNs (cutoff value: 0.218; P = .037) were significant prognostic factors for recurrence. Conclusion: High SUVmax of N1b cervical LN on pretreatment FDG PET/CT could predict incomplete responses to initial therapy and recurrence in patients with N1b PTC. Abbreviations: ATA = American Thyroid Association; DTC = well-differentiated thyroid carcinoma; FDG = F-18 fluorodeoxyglucose; IQR = interquartile range; LN = lymph node; N1b = metastatic lateral cervical lymph node; PET/CT = positron emission tomography/computed tomography; PTC = papillary thyroid carcinoma; RAI = radioactive iodine; ROC = receiver operating characteristic; SUVmax = maximum standardized uptake value; Tg = thyroglobulin; USG = ultrasonography.

Targeting PLKs as a therapeutic approach to well-differentiated thyroid cancer.

Polo-like kinases (PLKs) are pivotal regulators of cell proliferation and cell survival; therefore, PLKs may be potential targets in the treatment of malignancy. The therapeutic effects of volasertib, a PLKs inhibitor for papillary and follicular thyroid cancer (known as well-differentiated thyroid cancer (WDTC)), were evaluated in this study. Volasertib inhibited cell proliferation in two papillary and two follicular thyroid cancer cell lines in a dose-dependent manner. Volasertib treatment reduced cells in the S phase and increased cells in the G2/M phase. Volasertib activated caspase-3 activity and induced apoptosis. Drug combinations of volasertib and sorafenib showed mostly synergism in four well-differentiated thyroid carcinoma cell lines in vitro. Volasertib treatment in vivo retarded the growth of a papillary thyroid tumor model. Furthermore, the combination of volasertib with sorafenib was more effective than a single treatment of either in a follicular thyroid cancer xenograft model. Promising safety profiles appeared in animals treated with either volasertib alone or volasertib and sorafenib combination therapy. These findings support volasertib as a potential drug for the treatment of patients with WDTC.

Cholesterol and 27-hydroxycholesterol promote thyroid carcinoma aggressiveness

Cholesterol mediates its proliferative and metastatic effects via the metabolite 27-hydroxycholesterol (27-HC), at least in breast and endometrial cancer. We determined the serum lipoprotein profile, intratumoral cholesterol and 27-HC levels in a cohort of patients with well-differentiated papillary thyroid carcinoma (PTC; low/intermediate and high risk), advanced thyroid cancers (poorly differentiated, PDTC and anaplastic thyroid carcinoma, ATC) and benign thyroid tumors, as well as the expression of genes involved in cholesterol metabolism. We investigated the gene expression profile, cellular proliferation, and migration in Nthy-ori 3.1 and CAL-62 cell lines loaded with human low-density lipoprotein (LDL). Patients with more aggressive tumors (high-risk PTC and PDTC/ATC) showed a decrease in blood LDL cholesterol and apolipoprotein B. These changes were associated with an increase in the expression of the thyroid’s LDL receptor, whereas 3-hydroxy-3-methylglutaryl-CoA reductase and 25-hydroxycholesterol 7-alpha-hydroxylase were downregulated, with an intratumoral increase of the 27-HC metabolite. Furthermore, LDL promoted proliferation in both the Nthy-ori 3.1 and CAL-62 thyroid cellular models, but only in ATC cells was its cellular migration increased significantly. We conclude that cholesterol and intratumoral accumulation of 27-HC promote the aggressive behavior process of PTC. Targeting cholesterol metabolism could be a new therapeutic strategy in thyroid tumors with poor prognosis.