Development of a novel dynamic nomogram for predicting overall survival in anaplastic thyroid cancer patients with distant metastasis: a population-based study based on the SEER database.

Background: Anaplastic thyroid cancer (ATC) is highly invasive, prone to distant metastasis (DM), and has a very poor prognosis. This study aims to construct an accurate survival prediction model for ATC patients with DM, providing reference for comprehensive assessment and treatment planning. Methods: We extracted data of ATC patients with DM diagnosed between 2004 and 2019 from the SEER database, randomly dividing them into a training set and a validation set in a ratio of 7:3. Univariate and multivariate Cox regression analyses were sequentially performed on the training set to identify independent prognostic factors for overall survival (OS) and construct nomograms for 3-month, 6-month, and 8-month OS for ATC patients with DM based on all identified independent prognostic factors. Receiver operating characteristic (ROC) curve analysis, decision curve analysis (DCA) curve analysis, and calibration curves were separately plotted on the training and validation sets to demonstrate the model's performance. Furthermore, patients were stratified into high- and low-risk groups based on their risk scores, and the Kaplan-Meier (KM) survival curves were used to illustrate the survival differences between the two groups. Results: A total of 322 patients were included in this study. Univariate and multivariate Cox regression analyses identified five independent prognostic factors for OS in ATC patients with DM: surgery, tumor size, age, chemotherapy, and radiotherapy. Nomograms for 3-month, 6-month, and 8-month OS were established based on these factors. The training set AUC values (3-month AUC: 0.767, 6-month AUC: 0.789, 8-month AUC: 0.795) and validation set AUC values (3-month AUC: 0.753, 6-month AUC: 0.798, 8-month AUC: 0.806) as well as the calibration curves demonstrated excellent applicability and accuracy of the model. Additionally, the DCA curves indicated substantial clinical net benefit of the model. The KM curves also confirmed the model's excellent stratification ability for patient OS. Conclusion: The nomogram developed in this study accurately predicts OS for ATC patients with DM. It can assist clinicians in formulating appropriate treatment strategies for these patients.

Cervical lymph node metastasis as the first symptom of combined anaplastic thyroid carcinoma (squamous cell carcinoma) and follicular carcinoma: a case report.

BACKGROUND: Anaplastic thyroid carcinoma(ATC) is a rare pathological type of thyroid malignancy. Primary squamous cell carcinoma of thyroid(PSCCT) is now considered as a subtype of ATC, hereinafter referred to as ATC-SCC subtype. ATC-SCC subtype combined with follicular thyroid carcinoma is exceedingly rare, with fewer cases reported. The ATC-SCC subtype is a highly invasive tumor with a poor prognosis for patients after metastasis occurs, and current treatment of this type of tumor is tricky. CASE PRESENTATION: A 68-year-old female patient presented with a gradually growing swelling of right cervical region. Comprehensive auxiliary examinations and postoperative pathology confirmed the diagnosis of ATC-SCC subtype with follicular thyroid carcinoma, and the metastasis squamous cell carcinoma of the right cervical lymph nodes originates from ATC-SCC subtype. The patient received chemoradiotherapy postoperative. However, the residual cervical lymph nodes metastasis with squamous cell carcinoma still infiltrated surrounding structures in the neck extensively after palliative resection. The patient died 7 months after surgery. CONCLUSION: Our case highlights that cervical lymph node metastasis may be a significant factor in the poor prognosis of ATC-SCC subtype. This malignancy should be detected and treated early.

Promising Therapeutic Targets for Recurrent/Metastatic Anaplastic Thyroid Cancer.

OPINION STATEMENT: Anaplastic thyroid cancer presents formidable challenges, particularly in cases of recurrence or metastasis. Timely BRAF V600E testing is imperative at diagnosis, initially through immunohistochemistry, followed by comprehensive genomic profiling encompassing genes such as NTRK, RET, ALK, and assessment of tumor mutation burden (TMB). FDA-approved treatment options include dabrafenib and trametinib for patients with BRAF mutations, while those exhibiting high TMB may benefit from pembrolizumab. Further therapeutic decisions hinge upon mutational profile, urgency of response required, airway integrity, and access to targeted therapies There is growing use of immunotherapy for ATC based on published reports of activity, but currently there is no FDA approved agent for ATC. The off-label utilization of "precision medicine" combinations imposes a considerable financial strain, underscoring the necessity for further clinical trials to elucidate promising therapeutic avenues for this orphan disease. There is a pressing need for the development and support of clinical trials investigating genomically driven and immune-based therapies for anaplastic thyroid cancer.

Management of Poorly Differentiated Thyroid Cancer and Differentiated High-Grade Thyroid Carcinoma.

Thyroid carcinoma of follicular cell origin exists on a histopathologic and clinical spectrum. The authors focus on the category of tumors that fall between the very favorable well-differentiated thyroid carcinomas and the very unfavorable anaplastic thyroid carcinomas. These intermediately aggressive tumors include poorly differentiated thyroid carcinoma and the newly defined differentiated high-grade thyroid carcinoma. Both diagnoses require certain histopathologic requirements be met in order to accurately identify these tumors post-operatively. Management remains primarily surgical though adjunctive treatments such as molecular targeted therapies (eg, tyrosine kinase inhibitors) and differentiation therapy (to restore tumor response to radioactive iodine) are also becoming available.

Targeting SIGLEC15 as an emerging immunotherapy for anaplastic thyroid cancer.

Anaplastic thyroid carcinoma (ATC) is the most aggressive subtype of thyroid cancer with few effective therapies. Though immunotherapies such as targeting PD-1/PD-L1 axis have benefited patients with solid tumor, the druggable immune checkpoints are quite limited in ATC. In our study, we focused on the anti-tumor potential of sialic acid-binding Ig-like lectins (Siglecs) in ATC. Through screening by integrating microarray datasets including 216 thyroid-cancer tissues and single-cell RNA-sequencing, SIGLEC family members CD33, SIGLEC1, SIGLEC10 and SIGLEC15 were significantly overexpressed in ATC, among which SIGLEC15 increased highest and mainly expressed on cancer cells. SIGLEC15high ATC cells are characterized by high expression of serine protease PRSS23 and cancer stem cell marker CD44. Compared with SIGLEC15low cancer cells, SIGLEC15high ATC cells exhibited higher interaction frequency with tumor microenvironment cells. Further study showed that SIGLEC15high cancer cells mainly interacted with T cells by immunosuppressive signals such as MIF-TNFRSF14 and CXCL12-CXCR4. Notably, treatment of anti-SIGLEC15 antibody profoundly increased the cytotoxic ability of CD8+ T cells in a co-culture model and zebrafish-derived ATC xenografts. Consistently, administration of anti-SIGLEC15 antibody significantly inhibited tumor growth and prolonged mouse survival in an immunocompetent model of murine ATC, which was associated with increase of M1/M2, natural killer (NK) cells and CD8+ T cells, and decrease of myeloid-derived suppressor cells (MDSCs). SIGLEC15 inhibited T cell activation by reducing NFAT1, NFAT2, and NF-κB signals. Blocking SIGLEC15 increased the secretion of IFN-γ and IL-2 in vitro and in vivo. In conclusion, our finding demonstrates that SIGLEC15 is an emerging and promising target for immunotherapy in ATC.

Development and validation of a nomogram to predict overall survival in patients with redefined anaplastic thyroid carcinoma based on the SEER database.

BACKGROUND: According to the latest classification of thyroid tumors released by the WHO in 2022, primary squamous cell carcinoma of the thyroid (PSCCTh) is classified as anaplastic thyroid carcinoma (ATC). The objective of this study was to determine the differences in characteristics between ATC and PSCCTh and develop a nomogram to predict overall survival patients with the redefined anaplastic thyroid carcinoma (rATC). METHODS: Patients diagnosed with ATC and PSCCTh between 2000 and 2018 from the Surveillance, Epidemiology, and End Results (SEER) database were enrolled and randomly divided into a training cohort and a validation cohort with a ratio of 7:3. Overall survival (OS) and cancer-specific survival (CSS) was estimated using the Kaplan-Meier method and compared using log-rank tests. The univariate and multivariate Cox proportional hazards regression analyses were used to determine independent prognostic factors of rATC patients. We then developed and validated nomograms to predict the 3-, 6- and 12-month OS of rATC and the results were evaluated by C-index and calibration curves. RESULTS: After application of the inclusion and exclusion criteria, a total of 1338 ATC and 127 PSCCTh patients were included in the study. Further, OS and CSS of patients with PSCCTh were better than that of patients with ATC. Prognostic factors were not identical for the two cancers. Multivariate Cox model analysis indicated that age, tumor size, metastasis, surgery, radiotherapy, chemotherapy are independent prognostic factors for CSS in patients with ATC; while for patients with PSCCTh, the corresponding factors are age, and surgery. We selected six survival predictors (age, tumor size, metastasis, surgery, radiation, and, chemotherapy) for nomogram construction. The C-indexes in the training and validation cohort were 0.740 and 0.778, respectively, reflecting the good discrimination ability of the model. The calibration curves also showed good consistency in the probability of 3-, 6-, and 12-month OS between the actual observation and the nomogram prediction. CONCLUSION: We constructed a nomogram to provide a convenient and reliable tool for predicting OS in rATC patients. Prognostic factors influencing CSS were not identical in patients with ATC and PSCCTh. These findings indicate that different clinical treatment and management plans are required for patients with these two types of thyroid cancer.

The value of multimodal treatment in anaplastic thyroid cancer patients with distant metastasis.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare and aggressive malignancy with a poor prognosis, particularly in patients presenting with distant metastasis (DM). This study aimed to assess the effect of combination treatment strategies on survival in ATC patients with DM. METHODS: A retrospective analysis was conducted using data from the Surveillance, Epidemiology, and End Results (SEER) database to identify primary ATC cases with DM at diagnosis. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent risk factors for survival. RESULTS: Of the 315 ATC patients with DM included in the study, surgery to the primary tumor, radiotherapy, chemotherapy, and lung metastasis were identified as independent risk factors for survival. Patients who received primary tumor surgery plus chemotherapy or surgery plus chemoradiation exhibited a superior outcome compared to those who received only one treatment modality. CONCLUSION: Our findings suggest that a combination treatment approach, particularly surgery combined with radiotherapy or surgery combined with chemoradiotherapy, may provide the most optimal treatment option for ATC patients with DM. These results may provide some evidence for clinical decision making, but larger sample cohorts are still needed for validation.

A distinct tumor microenvironment makes anaplastic thyroid cancer more lethal but immunotherapy sensitive than papillary thyroid cancer.

Both anaplastic thyroid cancer (ATC) and papillary thyroid cancer (PTC) originate from thyroid follicular epithelial cells, but ATC has a significantly worse prognosis and shows resistance to conventional therapies. However, clinical trials found that immunotherapy works better in ATC than late-stage PTC. Here, we used single-cell RNA sequencing (scRNA-Seq) to generate a single-cell atlas of thyroid cancer. Differences in ATC and PTC tumor microenvironment components (including malignant cells, stromal cells, and immune cells) leading to the polarized prognoses were identified. Intriguingly, we found that CXCL13+ T lymphocytes were enriched in ATC samples and might promote the development of early tertiary lymphoid structure (TLS). Last, murine experiments and scRNA-Seq analysis of a treated patient's tumor demonstrated that famitinib plus anti-PD-1 antibody could advance TLS in thyroid cancer. We displayed the cellular landscape of ATC and PTC, finding that CXCL13+ T cells and early TLS might make ATC more sensitive to immunotherapy.

Surgery combined with adjuvant radiation and chemotherapy prolonged overall survival in stage IVC anaplastic thyroid cancer: a SEER-based analysis.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare but aggressive malignancy, which accounts for only 1-2% of all thyroid cancers. The median overall survival (OS) time for all stages patients is at about 5 months. The benefit of surgery combined with adjuvant radiation and chemotherapy in stage IVC anaplastic thyroid cancer is still controversial. The aim of this study is to investigating surgery combined with adjuvant radiation and chemotherapy and survival outcomes in stage IVC ATC patients. METHOD: Anaplastic thyroid carcinoma patients from the Surveillance, Epidemiology, and End Results database from 2004 to 2016 were used to conduct a cross-sectional study in the analysis. The endpoint of this study was overall survival. RESULTS: The median OS of the overall population was 2.0 months. Multivariate analysis showed that age (<67 vs. ≥67 years old, P = 0.017, HR = 1.355, 95% CI: 1.057-1.738), tumor size (<7 cm vs. ≥7 cm, P = 0.001, HR = 1.579, 95% CI: 1.202-2.073), Surgery (thyroidectomy vs. non-surgery, P < 0.001, HR = 0.554, 95% CI: 0.401-0.766), radiation therapy (P < 0.001, HR = 0.571, 95% CI: 0.445-0.733) and chemotherapy (P = 0.003, HR = 0.684, 95% CI: 0.531-0.881) were independent prognostic factor for worse OS in stage IVC ATC patients. Surgery combined with adjuvant radiation and chemotherapy exhibited the better overall survival time for 4 months. CONCLUSIONS: Surgery combined with adjuvant radiation and chemotherapy can improve overall survival in stage IVC ATC patients. We recommend surgical approach with fully evaluation combined with radiation therapy and chemotherapy for selected stage IVC ATC patients.

[Personalized approach to anaplastic thyroid carcinoma]. / Personalisiertes Vorgehen beim anaplastischen Schilddrüsenkarzinom.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) represents the rarest but most aggressive tumor entity of the thyroid gland. In this respect, the treatment of advanced ATC has rapidly evolved in recent years. Recently, new personalized forms of treatment that address the somatic mutational status of the tumor have been increasingly used. The aim of this article is to provide an overview of current molecular-based and personalized treatment options for ATC. METHODS: A current literature search was performed with a focus on personalized molecular-based treatment options for ATC. RESULTS: The majority of patients suffering from ATC have an advanced tumor disease at the time of initial diagnosis. Despite multimodal treatment approaches consisting of surgery, external beam radiation therapy (EBRT) and chemotherapy (CTX), the prognosis of ATC is still poor. Accordingly, the focus of innovative treatment approaches is on molecular-based, individualized tumor therapy, including in particular BRAFV600E and multikinase inhibitors. The potential of the latter seems to lie particularly in combination therapy with immune checkpoint inhibitors. These treatment options can be used in both adjuvant and neoadjuvant settings. Neoadjuvant treatment of advanced ATC can achieve a potentially resectable treatment setting and improve the poor prognosis of affected patients; however, larger prospective and randomized studies on these combination therapies are currently pending. CONCLUSION: The focus of future treatment approaches for ATC will be on individualized, molecular-based tumor therapy. In particular, the neoadjuvant use of these therapies may change the paradigm of ATC surgery as locally advanced as well as metastatic carcinomas can be converted to a potentially resectable status and made amenable to surgery.

Anaplastic thyroid cancer:Improved understanding of what remains a deadly disease.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare, undifferentiated form of thyroid cancer accounting for less that 2 % of thyroid cancers. Here we provide an overview of the contemporary understanding of ATC as well as discussing in detail any pertinent updates in the molecular understanding and treatment of this disease with reference to the 2021 American Thyroid Association (ATA) guidelines. METHODS: A review of the literature regarding the understanding, management and prognosis of ATC was undertaken using both Pubmed and Cochrane databases along with local institutional experience. Studies published in the last 5 years were prioritised for inclusion. RESULTS: Between 80 and 90 % of patients will have disease that has spread beyond the thyroid gland at presentation. Despite the use of aggressive, multimodal, conventional treatment strategies encompassing surgery and chemoradiotherapy, the median overall survival has remained between 3 and 6 months. Our understanding has evolved regarding the key oncogenic mutations involved in the development of ATC. These include BRAF, RAS, PI3K, PTEN, TP53 and TERT mutations. There is growing evidence that novel targeted therapies against these mutations may improve outcomes in this disease which has led to FDA approval of dabrafenib/trametinib combined BRAF/Mek inhibition. CONCLUSIONS: The prognosis of ATC remains dismal. Recent development and approval of targeted therapies offers hope of improved oncologic outcomes with further data eagerly awaited surrounding the impact of these targeted therapies.

The role of targeted therapy and/or immunotherapy therapy in anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a highly invasive malignant tumor with a poor prognosis. Traditional treatment methods have not been effective. However, advancements in targeted therapy and immunotherapy in recent years have shed new light on the management of ATC. The aim of this study was to examine the treatment plan and prognostic factors of ATC. METHODS: This study conducted a retrospective analysis of ATC patients who received treatment at our institution between 2000 and 2023 to evaluate the clinical characteristics, treatment methods, and factors influencing survival. Survival analysis was performed by the Kaplan‒Meier method and log-rank test, and multivariate analysis was performed using the Cox proportional hazard model. RESULTS: The 6-month and 1-year disease-specific OS rates were 49% and 29%, respectively. The presence of clinical symptoms and the timing of treatment significantly impacted patient prognosis (P < 0.05). Compared with surgery + radiotherapy/chemotherapy and only surgery, targeted therapy and targeted + immunotherapy represented an improved overall survival, The 6-month/1-year survival rates of which were 81%/61% and 91%/73% (P < 0.05), respectively. Multivariate analysis indicated that the symptoms at initial diagnosis, year of presentation, performance status and treatment plan were independent factors affecting the prognosis. The year of presentation (P = 0.048) and the treatment plan (P = 0.038) were significantly meaningful in predicting prognosis. CONCLUSION: Targeted therapy and targeted+immune therapy can effectively prolong the survival period of ATC patients. Symptoms at initial diagnosis and treatment plan have a significant impact on the prognosis.

New Insights into Immune Cells and Immunotherapy for Thyroid Cancer.

Thyroid cancer (TC) is the most common endocrine malignancy worldwide, and the incidence of TC has gradually increased in recent decades. Differentiated thyroid cancer (DTC) is the most common subtype and has a good prognosis. However, advanced DTC patients with recurrence, metastasis and iodine refractoriness, as well as more aggressive subtypes such as poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC), still pose a great challenge for clinical management. Therefore, it is necessary to continue to explore the inherent molecular heterogeneity of different TC subtypes and the global landscape of the tumor immune microenvironment (TIME) to find new potential therapeutic targets. Immunotherapy is a promising therapeutic strategy that can be used alone or in combination with drugs targeting tumor-driven genes. This article focuses on the genomic characteristics, tumor-associated immune cell infiltration and immune checkpoint expression of different subtypes of TC patients to provide guidance for immunotherapy.

Disparities in Presentation, Treatment, and Survival in Anaplastic Thyroid Cancer.

BACKGROUND: Disparities have been previously described in the presentation, management, and outcomes of other thyroid cancer subtypes; however, it is unclear whether such disparities exist in anaplastic thyroid cancer (ATC). METHODS: We identified patients with ATC from the National Cancer Database (2004-2020). The primary outcomes were receipt of surgery, chemotherapy, and radiation. The secondary outcome was 1-year survival. Multivariable logistic and Cox proportional hazards regressions were used to assess the associations between sex, race/ethnicity, and the outcomes. RESULTS: Among 5359 patients included, 58% were female, and 80% were non-Hispanic white. Median tumor size was larger in males than females (6.5 vs. 6.0 cm; p < 0.001) and in patients with minority race/ethnicity than in white patients (6.5 vs. 6.0 cm; p < 0.001). After controlling for tumor size and metastatic disease, female patients were more likely to undergo surgical resection (odds ratio [OR]: 1.20; p = 0.016) but less likely to undergo chemotherapy (OR: 0.72; p < 0.001) and radiation (OR: 0.76; p < 0.001) compared with males. Additionally, patients from minority racial/ethnic backgrounds were less likely to undergo chemotherapy (OR: 0.69; p < 0.001) and radiation (OR: 0.71; p < 0.001) than white patients. Overall, unadjusted, 1-year survival was 23%, with differences in treatment receipt accounting for small but significant differences in survival between groups. CONCLUSIONS: There are disparities in the presentation and treatment of ATC by sex and race/ethnicity that likely reflect differences in access to care as well as patient and provider preferences. While survival is similarly poor across groups, the changing landscape of treatments for ATC warrants efforts to address the potential for exacerbation of disparities.

Recent advances in anaplastic thyroid cancer management.

PURPOSE OF REVIEW: To summarize recent developments in the diagnosis and management of patients with anaplastic thyroid cancer (ATC). RECENT FINDINGS: An updated edition of the Classification of Endocrine and Neuroendocrine Tumors was released by the World Health Organization (WHO), in which squamous cell carcinoma of the thyroid are now a subtype of ATC. Broader access to next generation sequencing has allowed better understanding of the molecular mechanisms driving ATC and improved prognostication. BRAF-targeted therapies revolutionized the treatment of advanced/metastatic BRAFV600E -mutated ATC, offering significant clinical benefit and allowing better locoregional control of disease through the neoadjuvant approach. However, inevitable development of resistance mechanisms represents a major challenge. Addition of immunotherapy to BRAF/MEK inhibition has shown very promising results and significant improvement in survival outcomes. SUMMARY: Major advancements took place in the characterization and management of ATC in recent years, especially in patients with a BRAF V600E mutation. Still, no curative treatment is available, and options are limited once resistance to currently available BRAF-targeted therapies develops. Additionally, there is still a need for more effective treatments for patients without a BRAF mutation.

Combination of Novel Therapies and New Attempts in Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies, and it is rapidly falling without any effective therapeutic options. Although radical surgery, radiotherapy, and chemotherapy are performed on patients, the curative effect is suboptimal, and the survival rate is still poor. The discovery of altered gene pathways involved in this aggressive disease has advanced, but molecular targeted drugs targeting these pathways are still in clinical trials. To date, there is no effective way to treat this disease, so it is particularly urgent to find new treatments. At present, multimodal therapy is gradually being applied in clinical practice, which provides a new possibility for prolonging the survival time and improving the prognosis of anaplastic thyroid carcinoma. In this study, we retrospectively analyzed the current clinical multimodal therapy for patients with anaplastic thyroid cancer to evaluate its effect on improving the survival of patients with anaplastic thyroid cancer at different stages.

PD-L1 expression in rare and aggressive thyroid cancers: A preliminary investigation for a role of immunotherapy.

Background and Aim: Programmed cell death ligand-1 (PD-L1) immunoexpression status determines the response to immunotherapy in many cancers. Limited data exist on PD-L1 status in aggressive thyroid tumors. We investigated PD-L1 expression across thyroid cancers and correlated it with their molecular profile. Materials and Methods: Sixty-five cases of differentiated thyroid carcinoma, poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC) were assessed for PD-L1 expression (clone SP263, VENTANA). The differentiated cases encompassed the aggressive hobnail and tall cell subtypes of papillary thyroid carcinoma (PTC) besides classical PTC and follicular thyroid carcinoma (FTC). Ten nodular goiters (NG) were also evaluated. Tumor proportion score (TPS) and H-score were calculated. BRAFV600E and H-/K-/N-RAS were assessed using allele-specific real-time polymerase chain reaction (PCR). Fisher's exact and Kruskal-Wallis tests were used to investigate the associations between the categorical variables and compare PD-L1 scores with the mutation status. Results: Most PTC (87%) and ATC (73%) cases were PD-L1 positive (TPS ≥1%), with significantly higher positivity rates than NG (20%). TPS >50% was seen in 60% ATC and 7% PTC cases. The median TPS and H-score of ATC were 56 (0-96.6) and 168 (0-275), respectively, and of PTC were 9.6 (4-16.8) and 17.8 (6.6-38.6), respectively. The scores were similar across the PTC subtypes. Only one case each of FTC and PDTC was PD-L1 positive. PD-L1 expression correlated significantly with BRAFV600E, but not with RAS mutation. Conclusions: ATC showed intense and diffuse PD-L1 staining. Although most PTCs were PD-L1 positive, the expression was weaker and patchy, irrespective of the histological subtype. Results of this pilot study indicate that ATC is most likely to respond to immunotherapy. PTC, FTC, and PDTC may be less amenable to immunotherapy. PD-L1 expression correlated significantly with BRAFV600E, allowing for combined targeted therapy.