Association of Treatment Strategies and Tumor Characteristics With Overall Survival Among Patients With Anaplastic Thyroid Cancer: A Single-Institution 21-Year Experience.

Importance: Survival outcomes for anaplastic thyroid cancer (ATC), the most aggressive subtype of thyroid cancers, have remained poor. However, targeted therapies and immunotherapies present new opportunities for treatment of this disease. Evaluations of survival outcomes over time with new multimodal therapies are needed for optimizing treatment plans. Objective: To evaluate the association of treatment strategies and tumor characteristics with overall survival (OS) among patients with ATC. Design, Setting, and Participants: This retrospective case series study evaluated the survival outcomes stratified by treatment strategies and tumor characteristics among patients with ATC treated at a tertiary level academic institution from January 1, 2000, to December 31, 2021. Demographic, tumor, treatment, and outcome characteristics were analyzed. Kaplan-Meier method and log rank test modeled OS by treatment type and tumor characteristics. Data were analyzed in May 2022. Main Outcomes and Measures: Overall survival (OS). Results: The study cohort comprised 97 patients with biopsy-proven ATC (median [range] age at diagnosis, 70 [38-93] years; 60 (62%) female and 85 [88%] White individuals; 59 [61%] never smokers). At ATC diagnosis, 18 (19%) patients had stage IVA, 19 (20%) had stage IVB, and 53 (55%) had stage IVC disease. BRAF status was assessed in 38 patients; 18 (47%) had BRAF-V600E variations and 20 (53%), BRAF wild type. Treatment during clinical course included surgery for 44 (45%) patients; chemotherapy, 41 (43%); definitive or adjuvant radiation therapy, 34 (RT; 35%); and targeted therapy, 28 (29%). Median OS for the total cohort was 6.5 (95% CI, 4.3-10.0) months. Inferior OS was found in patients who did not receive surgery (hazard ratio [HR], 2.12; 95% CI, 1.35-3.34; reference, received surgery), chemotherapy (HR, 3.28; 95% CI, 1.99-5.39; reference, received chemotherapy), and definitive or adjuvant RT (HR, 2.47; 95% CI, 1.52-4.02; reference, received definitive/adjuvant RT). On multivariable analysis, age at diagnosis (HR, 1.03; 95% CI, 1.01-1.06), tumor stage IVC (HR, 2.65; 95% CI, 1.35-5.18), and absence of definitive or adjuvant RT (HR, 1.90; 95% CI, 1.01-3.59) were associated with worse OS. Conclusions and Relevance: This retrospective single-institution study found that lower tumor stage, younger age, and the ability to receive definitive or adjuvant RT were associated with improved OS in patients with ATC.

Primary high-grade non-anaplastic thyroid carcinoma: a retrospective study of 364 cases.

AIMS: We aimed to study the clinicopathological and molecular features of high-grade non-anaplastic thyroid carcinomas (HGTCs), a carcinoma with a prognosis intermediate between those of well-differentiated carcinoma and anaplastic carcinoma. METHODS AND RESULTS: This study included 364 HGTC patients: 200 patients (54.9%) were diagnosed with poorly differentiated thyroid carcinoma (PDTC), based on the Turin consensus (HGTC-PDTC), and 164 were diagnosed with high-grade features that did not meet the Turin criteria (HGTC-nonPDTC). HGTCs are aggressive: the 3-year, 5-year, 10-year and 20-year disease-specific survival (DSS) rates were 89%, 76%, 60%, and 35%, respectively. Although DSS was similar between HGTC-PDTC and HGTC-nonPDTC patients, HGTC-PDTC was associated with higher rate of radioactive iodine avidity, a higher frequency of RAS mutations, a lower frequency of BRAF V600E mutations and a higher propensity for distant metastasis (DM) than HGTC-nonPDTC. Independent clinicopathological markers of worse outcome were: older age, male sex, extensive necrosis and lack of encapsulation for DSS; older age, male sex and vascular invasion for DM-free survival; and older age, necrosis, positive margins and lymph node metastasis for locoregional recurrence-free survival. The frequencies of BRAF, RAS, TERT, TP53 and PTEN alterations were 28%, 40%, 55%, 11%, and 10%, respectively. TP53, PTEN and TERT were independent molecular markers associated with an unfavourable outcome, independently of clinicopathological parameters. The coexistence of BRAF V600E and TERT promoter mutation increased the risk of DM. CONCLUSIONS: The above data support the classification of HGTC as a single group with two distinct subtypes based on tumour differentiation: HGTC-PDTC and HGTC-nonPDTC.

Radiotherapy Plus Chemotherapy Leads to Prolonged Survival in Patients With Anaplastic Thyroid Cancer Compared With Radiotherapy Alone Regardless of Surgical Resection and Distant Metastasis: A Retrospective Population Study.

Background: Whether anaplastic thyroid cancer (ATC) patients benefit more from radiotherapy plus chemotherapy (RCT) than from radiotherapy alone (RT) was controversial. We aimed to investigate the effectiveness of RCT versus RT on ATC overall and within subgroups by surgical resection and distant metastasis in a large real-world cohort. Methods: Patients with ATC diagnosed between 2004 and 2015 were identified from the Surveillance, Epidemiology, and End Results Program database. Inverse probability weighting (IPW) was performed to balance variables between the two groups. Multivariate Cox proportional hazard model and Fine-Gray compete-risk model were carried out to investigate prognostic factors relating to overall survival (OS) and cancer-specific survival (CSS). Subgroup analysis was carried out, and a forest plot was graphed. Results: Of the 491 ATC patients, 321 (65.4%) were in the RCT group and 170 (34.6%) were in the RT group. The median OS was 4 months [interquartile range (IQR) 2-7] and 2 months (IQR 1-4) for patients in the RCT and RT groups, respectively. As indicated by the inverse probability weighting multivariate regression, RCT was associated with significantly improved OS (adjusted HR = 0.69, 95% CI = 0.56-0.85, p < 0.001) and CSS (adjusted subdistribution HR = 0.77, 95% CI = 0.61-0.96, p = 0.018). The prominent effect of RCT versus RT alone remains significant within each subgroup stratified by surgical resection and distant metastasis. Older age, single marital status, surgical resection, distant metastasis, and tumor extension were significant prognostic factors of survival. Conclusions: RCT contributes to prolonged OS and CSS compared with RT alone in ATC patients, regardless of surgical resection and distant metastasis. RCT should be preferentially applied to ATC patients.

Survival Benefit of Intervention Treatment in Advanced Anaplastic Thyroid Cancer.

BACKGROUND: The management of anaplastic thyroid cancer (ATC) is controversial; thus, proper treatment and prognostic factors should be investigated. OBJECTIVES: To compare the survival outcomes of the intervention and palliative treatment in ATC patients. METHODS: A hospital-based retrospective study was conducted at a single tertiary university hospital. The medical record charts were retrieved from November 20, 1987, to December 31, 2016. The final follow-up ended by December 31, 2017. The patients' demographic data, laboratory data, clinical presentation, and treatment modality results were analyzed. RESULTS: One hundred twenty-one records were analyzed with a one-year overall survival rate of 3.5% (median survival time: 77 days); however, 16 cases had insufficient data to classify staging and treatment modalities. Therefore, 105 ATC patients (37 with stage IVa, 39 with stage IVb, and 29 with stage IVc disease) were included with a one-year overall survival rate of 4.0% (median survival time of 82 days). Intervention treatment allowed longer median survival times (p < 0.05) and a better survival rate (p < 0.05). Among the interventional treatment groups, postoperative chemoradiation yielded the longest median survival time (187 days) and the highest survival rate (20%) (p < 0.05). The intervention modality allowed a better median survival time at all stages, particularly in stage IVa (p < 0.05). Unfavorable prognostic factors were adjusted for in a multiple Cox regression model showing that significant factors included age ≥65 years (hazard ratio HR: 2.57), palliative treatment (HR: 1.85), and leukocytosis ≥10,000 cells/mm3 (HR: 2.76). CONCLUSIONS: Intervention treatment provided a better survival outcome in all stages, particularly in stage IVa, with a significantly better median survival time. Among interventional treatments, postoperative chemoradiation led to the longest survival rate, suggesting that this treatment should be considered in ATC patients with resectable tumors and no poor prognostic factors, such as older age and leukocytosis.

Prognostic Factors and Survival Score for Patients With Anaplastic Thyroid Carcinoma: A Retrospective Study from a Regional Registry.

BACKGROUND/AIM: Anaplastic thyroid carcinoma (ATC) is the least common but most lethal of thyroid cancer, despite various therapeutic options, with limited efficacy. In order to help therapeutic decision-making, the purpose of this study was to develop a new prognostic score providing survival estimates in patients with ATC. PATIENTS AND METHODS: Based on a multivariate analysis of 149 retrospectively analyzed patients diagnosed with ATC from 1968 to 2017 at a referral center, a propensity score was developed. A model was generated providing survival probability at 6 months and median overall survival estimates. RESULTS: The median survival was 96 days. The overall survival rate was 35% at 6 months, 20% at 1 year and 13% at 2 years. Stepwise Cox regression revealed that the most appropriate death prediction model included metastatic spread, tumor size and age class as explanatory variables. This model made it possible to define three categories of patients with different survival profiles. CONCLUSION: Distant metastasis, age and primary tumor size are strong independent factors that affect prognosis in patients with ATC. Using these significant pretreatment factors, we developed a score to predict survival in these patients with poor prognosis.

Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma.

Background: Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab. Patients and Methods: In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14-24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1-90%). Results: Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%. Conclusions: Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.

Survival and Surgical Complications in Anaplastic Thyroid Cancer Patients After Completed Multimodal Treatment.

BACKGROUND/AIM: This study aimed to examine survival and surgical complications in patients with anaplastic thyroid cancer (ATC) after multimodal treatment. PATIENTS AND METHODS: Since 2002, the recommended treatment strategy for ATC at our centre has been hyperfractionated accelerated radiotherapy (HART) with high doses to the neck (64 Gy), combined with weekly doxorubicin, and surgery after 4-8 weeks, if feasible. RESULTS: Between 2002 and 2014, 14 patients completed HART and thyroid surgery. Eight patients had preoperative HART, and six postoperative HART. Median survival was 20 months (range=4-110 months) in all patients, 51 months (range=4-110 months) and 18.5 months (range=9-56 months) in the preoperative and postoperative HART groups, respectively. Six patients survived for more than two years, and four patients survived for more than five years. Seven patients had postoperative complications. CONCLUSION: In this series of selected patients, an improved survival after aggressive, multimodal treatment was observed. Preoperative HART may promote survival although complications may be more frequent.

Dsg2-mediated c-Met activation in anaplastic thyroid cancer motility and invasion.

Anaplastic thyroid cancer (ATC) is a rapidly growing, highly metastatic cancer with limited therapeutic alternatives, thus targeted therapies need to be developed. This study aimed to examine desmoglein 2 (Dsg2) expression in ATC and its biological role and potential as a therapeutic target in ATC. Consequently, Dsg2 was downregulated or aberrantly expressed in ATC tissues. ATC patients with low Dsg2 expression levels also presented with distant metastasis. Dsg2 depletion significantly increased cell migration and invasion, with a relatively limited effect on ATC cell proliferation in vitro and increased distant metastasis in vivo. Dsg2 knockdown induced cell motility through the hepatocyte growth factor receptor (HGFR, c-Met)/Src/Rac1 signaling axis, with no alterations in the expression of EMT-related molecules. Further, specific targeting of c-Met significantly inhibited the motility of shDsg2-depleted ATC cells. Decreased membrane Dsg2 expression increased the metastatic potential of ATC cells. These results indicate that Dsg2 plays an important role in ATC cell migration and invasiveness. Therapies targeting c-Met might be effective among ATC patients with low membrane Dsg2 expression levels, indicating that the analysis of Dsg2 expression potentially provides novel insights into treatment strategies for ATC.

Survival With Lenvatinib for the Treatment of Progressive Anaplastic Thyroid Cancer: A Single-Center, Retrospective Analysis.

Background: Survival rates for anaplastic thyroid cancer (ATC) have not improved in the past four decades; however, preliminary clinical data indicate that lenvatinib may provide efficacy benefits for patients with ATC. This real-world study aimed to define the potential role of lenvatinib in ATC by examining the impact of treatment administered alongside existing therapies. Methods: This was a retrospective, single-center analysis of Korean patients with confirmed ATC who received lenvatinib between October 2015 and February 2018. Eighteen patients were included (mean ± standard deviation age, 64.9 ± 11.1 years; 61.1% female). Six [33.3%] had resectable disease that progressed after a combination of surgery, radiotherapy, and chemotherapy, and 12 [66.7%] had unresectable disease that progressed after radiation treatment and chemotherapy. Study endpoints were overall survival (OS) and change in volume of the largest tumor assessed via imaging. Results: Median OS for the 18 lenvatinib-treated patients was 230 days (range 64-839 days). Survival rates at 6 months and 1 year were 61.1 and 22.2%, respectively. Three patients (16.7%) survived beyond 1 year; 15 patients died, of whom four (26.7%) had local disease and 11 (73.3%) had distant metastasis. Two patients (11.1%) had tumor volume increases of 9-10%. The other 16 patients (88.9%) had tumor volume reductions of 2-69%. Six patients (33.3%) had tumor volume reductions ≥50%. Conclusions: In patients with ATC who had progressed on prior therapy, addition of lenvatinib could improve survival duration and reduce tumor volume. Further studies of lenvatinib in ATC are warranted.

Clinical Development of BRAF plus MEK Inhibitor Combinations.

Genomic profiling shows that many solid tumors are characterized by specific driver aberrations, and this has expanded the therapeutic options for many patients. The mitogen-activated protein kinase (MAPK) pathway is a key cell signaling pathway involved in regulating cellular growth, proliferation, and survival. Driver mutations in the BRAF gene, a key player in the MAPK pathway, are described in multiple tumor types, including subsets of melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC), making BRAF a desirable target for inhibition. BRAF inhibitors have shown efficacy in several cancers; however, most patients eventually develop resistance. To delay or prevent resistance, combination therapy targeting BRAF and MEK, a downstream signaling target of BRAF in the MAPK pathway, was evaluated and demonstrated synergistic benefit. BRAF and MEK inhibitor combinations have been approved for use in various cancers by the US FDA. We review the clinical data for various BRAF plus MEK combination regimens in three cancer types with underlying BRAF driver mutations: melanoma, NSCLC, and ATC. We also discuss practical treatment considerations and management of selected combination therapy toxicities.

Histopathologic Features and Clinical Outcome of Anaplastic Thyroid Carcinoma with a Minor Anaplastic Component.

Although prior studies have reported that patients with anaplastic thyroid carcinoma (ATC) with a focal anaplastic component may have a prolonged survival compared to other ATC patients, the outcome data are limited. We evaluated a cohort of ATC resected between 2003 and 2018. Tumor slides were reviewed to confirm the diagnosis and to identify cases with a minor ATC component (defined as comprising < 10% of the tumor). We evaluated the clinical outcome of these patients compared to that of all other cohort patients (characterized as having conventional ATC). Our cohort was composed of 24 cases of ATC that underwent resection, including 8 (33%) with a minor ATC component. Tumors with a minor ATC component were predominantly associated with papillary thyroid carcinoma. For patients with tumors with a minor ATC component, the 1-year and 2-year survival rates and median survival for patients who died of disease were 88%, 43%, and 17 months (range 6-73 months), respectively. In comparison, for patients with conventional ATC, the 1-year and 2-year survival rates and median survival for patients who died of disease were 56%, 44%, and 7 months (range 2-26 months), respectively. There was no difference in 1- and 2-year survival or overall survival by Kaplan-Meier analysis for patients with tumors with a minor ATC component and those with conventional ATC. In conclusion, the difference in overall survival between ATC groups in our cohort was not significant; however, this could be due to the small cohort size or due to characteristics of our group with a minor ATC component; that is, no tumors in this group were limited to the thyroid (stage IVA), resectability with negative margins was infrequent, and 38% of this group had distant metastases at diagnosis (stage IVC).

Dietary iodine intake, therapy with radioiodine, and anaplastic thyroid carcinoma.

Background Anaplastic thyroid cancer (ATC) is one of the most aggressive tumors. The aim of the study was to determine the correlation between a higher dietary intake of iodine, frequency of ATC and the characteristics of ATC, and to find out how often patients with ATC had a history of radioiodine (RAI) therapy. Patients and methods This retrospective study included 220 patients (152 females, 68 males; mean age 68 years) with ATC who were treated in our country from 1972 to 2017. The salt was iodinated with 10 mg of potassium iodide/ kg before 1999, and with 25 mg of potassium iodide/kg thereafter. The patients were assorted into 15-year periods: 1972-1986, 1987-2001, and 2002-2017. Results The incidence of ATC decreased after a higher iodination of salt (p = 0.04). Patients are nowadays older (p = 0.013) and have less frequent lymph node metastases (p = 0.012). The frequency of distant metastases did not change over time. The median survival of patients in the first, second, and third periods was 3, 4, and 3 months, respectively (p < 0.05). The history of RAI therapy was present in 7.7% of patients. Conclusions The number of patients with a history of RAI therapy did not change statistically over time. The incidence of ATC in Slovenia decreased probably because of higher salt iodination.

Anaplastic thyroid carcinoma: a nationwide cohort study on incidence, treatment and survival in the Netherlands over 3 decades.

OBJECTIVE: To perform a nationwide population based study in ATC on incidence, treatment and survival. DESIGN: Retrospective cohort study. METHODS: All patients with primary ATC between 1989 and 2016 were identified in the Netherlands Cancer Registry (NCR). Of all these patients excerpts from the pathology reports from PALGA: Dutch Pathology registry were linked to the data of the NCR. Standardized incidences were calculated, survival was estimated using Kaplan-Meier method and univariable statistically significant factors were included in a multivariable regression model. RESULTS: In total, 812 patients were included. Mean standardized incidence rates were 0.18/100 000 (range 0.11-0.27/100 000) with a significant trend over the years with an estimated annual percentage change of 1.3% per year (95% CI 0.4-2.1%). Median overall survival was 2.2 months, and estimated 1-year survival was 12%. Patients without distant metastases at diagnosis had an estimated 1-year survival of 21.6%. Prognostic factors for prolonged survival were double or triple therapy, age below 65 years, M0-status and absence of bilateral lymph node metastases. CONCLUSIONS: ATC is rare, but often lethal, form of thyroid cancer, with a median survival of 2 months and 1-year survival of approximately 10%. The incidence is slightly rising in the Netherlands over the past 3 decades. There appears to be a subgroup of patients that survive longer, mainly those with relatively limited disease who underwent double or triple therapy. Further research is needed to define these patients more distinctively.

Outcomes of multimodal therapy in a large series of patients with anaplastic thyroid cancer.

BACKGROUND: The role of radiotherapy (RT) in the treatment of patients with anaplastic thyroid cancer (ATC) for local tumor control is critical because mortality often is secondary to complications of tumor volume rather than metastatic disease. Herein, the authors report the long-term outcomes of RT for patients with ATC. METHODS: A total of 104 patients with histologically confirmed ATC were identified who presented to the study institution between 1984 and 2017 and who received curative-intent or postoperative RT. Locoregional progression-free survival (LPFS), overall survival (OS), and distant metastasis-free survival were assessed. RESULTS: The median age of the patients was 63.5 years. The median follow-up was 5.9 months (interquartile range, 2.7-17.0 months) for the entire cohort and 10.6 months (interquartile range, 5.3-40.0 months) for surviving patients. Thirty-one patients (29.8%) had metastatic disease prior to the initiation of RT. Concurrent chemoradiation was administered in 99 patients (95.2%) and 53 patients (51.0%) received trimodal therapy. Systemic therapy included doxorubicin (73.7%), paclitaxel with or without pazopanib (24.3%), and other systemic agents (2.0%). The 1-year OS and LPFS rates were 34.4% and 74.4%, respectively. On multivariate analysis, RT ≥60 Gy was associated with improved LPFS (hazard ratio [HR], 0.135; P = .001) and improved OS (HR, 0.487; P = .004), and trimodal therapy was associated with improved LPFS (HR, 0.060; P = .017). The most commonly observed acute grade 3 adverse events included dermatitis (20%) and mucositis (13%), with no grade 4 subacute or late adverse events noted (adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). CONCLUSIONS: RT appears to demonstrate a dose-dependent, persistent LPFS and OS benefit in patients with locally advanced ATC with an acceptable toxicity profile. Aggressive RT should be strongly considered for the treatment of patients with ATC as part of a trimodal treatment approach.

Nomograms Predict Survival in Patients with Anaplastic Thyroid Carcinoma.

BACKGROUND Anaplastic thyroid carcinoma (ATC) is a very rare, highly lethal malignant cancer. Our aim in this study was to develop nomograms that predict survival in ATC patients. MATERIAL AND METHODS ATC incidence and mortality were assessed via joinpoint regression analysis of 567 ATC patients selected from the Surveillance, Epidemiology, and End Results 18 Registries Research database. Predictive models were established via univariate and multivariate Cox regression analysis of potential risk factors and used to produce nomograms. Performance of the nomograms in terms of discrimination ability and calibration was evaluated by determining the concordance index (C-index) and by generating calibration plots, respectively. RESULTS The incidence and mortality rates for ATC increased from 2000 to 2015 according to the collected data (p<0.05). Two nomograms were constructed based on 2 predictive models: nomogram 1 considered age, tumor size, and metastasis (all before surgery), and nomogram 2 considered age, tumor size, metastasis, surgery, and extrathyroidal extension (all after surgery). Both nomogram 1 (C-index, 0.6803; 95% confidence interval, 0.6517-0.7089) and nomogram 2 (C-index, 0.7064; 95% confidence interval, 0.6783-0.7345) had good discrimination ability. The validated C-index values were 0.6783 and 0.7029 for nomogram 1 and 2, respectively. The observed values were in agreement with the calibration curves. CONCLUSIONS Nomogram 1 can assist in preoperative prediction of survival time in ATC patients, whereas nomogram 2 can provide additional outcome-related information.

Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer.

Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAFV600E and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.

Cytologic features of aggressive variants of follicular-derived thyroid carcinoma.

Certain carcinomas of the thyroid gland behave aggressively resulting in increased patient morbidity and poor patient prognosis. The diagnosis of these aggressive thyroid cancer subtypes is sometimes challenging and subject to increased interobserver variability. This review deals with the cytological features of such tumors including aggressive variants of papillary thyroid carcinoma, poorly differentiated thyroid carcinoma, and anaplastic thyroid carcinoma. These malignancies fall into 2 groups based on their cytomorphology: those that exhibit distinct microscopic features (eg, nuclear findings typical of classical papillary thyroid carcinoma or marked anaplasia) and those that present with more subtle cytologic features (eg, nuclear pseudostratification, "soap bubble" nuclei, supranuclear or subnuclear cytoplasmic vacuoles, rosette-like structures, hobnail cells). We review the literature regarding these aggressive thyroid cancers and highlight important phenotypic characteristics that can be useful for their diagnosis based on fine needle aspiration.

Clinicopathologic Features of Mismatch Repair-Deficient Anaplastic Thyroid Carcinomas.

Background: Prior studies have reported mutations in mismatch repair (MMR) genes in a small subset of anaplastic thyroid carcinomas (ATC). The aim of this study was to identify MMR-protein-deficient (MMR-D) ATC and investigate their histopathologic features and clinical outcome. Methods: A cohort of 28 ATC diagnosed between 2003 and 2017 with tissue blocks available were evaluated. Immunohistochemistry for MMR proteins was performed to identify MMR-D tumors. Clinicopathologic features, molecular findings (determined by a targeted next-generation sequencing assay), and clinical outcome data for MMR-D tumors were recorded and compared to that of MMR-protein-intact (MMR-I) tumors. Results: There were four (14%) MMR-D ATC, all of which showed complete loss of MSH2 and MSH6 with intact expression of MLH1 and PMS2. Three of these tumors had MSH2 mutations and a hypermutated phenotype by next-generation sequencing. All four patients (two male; Mage at diagnosis = 64 years) presented with stage IVB disease (i.e., gross extrathyroidal extension or a lymph node metastasis at presentation). There were no differences in tumor size or rates of gross extrathyroidal extension, lymph node metastases, or positive resection margins between MMR-D and MMR-I ATC. Patients with MMR-D tumors were less likely to have distant metastatic disease at presentation (p = 0.035), although half did eventually develop distant metastases. MMR-D tumors were not histologically distinct. All four patients with MMR-D tumors lived for more than one year. One patient died of disease at 15 months, while the remaining three were alive at last follow-up, with survival of 19, 38, and 48 months. Patients with MMR-D ATC had significantly better survival compared to those with MMR-I tumors (p = 0.033), which was maintained when considering only patients with stage IVB disease at presentation (p = 0.030). Conclusion: MMR-D tumors comprised 14% of this ATC cohort. Although the findings must be interpreted with caution given the small number of MMR-D ATC in the cohort, the results suggest that MMR status may be prognostically significant in ATC.

Low Lymphocyte-to-Monocyte Ratios Are Associated with Poor Overall Survival in Anaplastic Thyroid Carcinoma Patients.

Background: The lymphocyte-to-monocyte ratio (LMR), which reflects the tumor-infiltrating immune cell status and host immunity, has been reported as a prognostic marker in various cancers. The aim of the present study was to evaluate the role of the LMR as a prognostic marker in predicting the survival of patients with anaplastic thyroid carcinoma (ATC). Methods: This study retrospectively included 35 ATC patients with available complete blood cell count data. The primary outcome was the overall survival (OS) of patients with ATC. Results: There were no significant differences between the LMR of the baseline and that of the follow-up complete blood cell count data (p = 0.53). The patients were divided into two groups based on their baseline LMR: a low LMR group (<4; n = 23, 66%) and a high LMR group (≥4; n = 12, 34%). The proportion of cervical lymph node metastasis in the low LMR group was significantly higher than that in the high LMR group (p = 0.021). The OS curves were significantly different based on the LMR values, and the median OS of the low and high LMR groups were 3.0 and 9.5 months, respectively (p = 0.004). In multivariate analysis, a low LMR was also an independent risk factor for all-cause mortality in patients with ATC (hazard ratio = 2.55 [confidence interval 1.08-6.00], p = 0.032) after adjusting for sex, tumor size, and distant metastasis. Conclusions: A low LMR is associated with poor survival in patients with ATC. The LMR could be a simple and stable prognostic biomarker reflecting host immunity in patients with ATC. Further studies are needed to confirm the prognostic role of the LMR in ATC.

KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC.

Anaplastic thyroid cancer (ATC) is an aggressive cancer with poor clinical prognosis. However, mechanisms driving ATC aggressiveness is not well known. Components of the DNA damage response (DDR) are frequently found mutated or aberrantly expressed in ATC. The goal of this study is to establish the functional link between histone acetyltransferase lysine (K) acetyltransferase 5 (KAT5, a critical DDR protein) and ATC invasiveness using clinical, in vitro and in vivo models. We analyzed the expression of KAT5 by immunohistochemistry and assessed its relationship with metastasis and overall survival in 82 ATC patients. Using cellular models, we established functional connection of KAT5 expression and C-MYC stabilization. We then studied the impact of genetically modified KAT5 expression on ATC metastasis in nude mice. In clinical samples, there is a strong correlation of KAT5 expression with ATC metastasis (P = 0.0009) and overall survival (P = 0.0017). At the cellular level, upregulation of KAT5 significantly promotes thyroid cancer cell proliferation and invasion. We also find that KAT5 enhances the C-MYC protein level by inhibiting ubiquitin-mediated degradation. Further evidence reveals that KAT5 acetylates and stabilizes C-MYC. Finally, we prove that altered KAT5 expression influences ATC lung metastases in vivo. KAT5 promotes ATC invasion and metastases through stabilization of C-MYC, demonstrating it as a new biomarker and therapeutic target for ATC.