Neutrophil-to-Lymphocyte Ratio Is Associated With the Proportion of Poorly Differentiated Components in Papillary Thyroid Carcinoma.

INTRODUCTION: Diagnosis of poorly differentiated thyroid cancer (PDTC) requires ≥ 50% of poorly differentiated components (PDC) in Japan. However, the optimal cutoff percentage of PDC for PDTC diagnosis remains controversial. Although high neutrophil-to-lymphocyte ratio (NLR) correlates with the aggressiveness of papillary thyroid cancer (PTC), whether NLR is associated with the proportion of PDC in PTC remains unstudied. MATERIALS AND METHODS: Patients with the pure PTC (n = 664), PTC with < 50% PDC (n = 19), or PTC with ≥ 50% PDC (n = 26) who underwent surgery were retrospectively analyzed. Twelve-year disease-specific survival and preoperative NLR were compared among these groups. RESULTS: Twenty seven patients died from thyroid cancer. The PTC with ≥ 50% PDC group (80.7%) showed significantly worse 12-year disease-specific survival than the pure PTC group (97.2%) (P < 0.001); however, the < 50% PDC group (94.7%) did not (P = 0.91). The PTC with ≥ 50% PDC group had a significantly higher NLR than the pure PTC (P < 0.001) and the PTC with < 50% PDC groups (P < 0.001), whereas there was no significant difference in the NLR between the pure PTC and the PTC with < 50% PDC groups (P = 0.48). CONCLUSIONS: PTC with ≥ 50% PDC is more aggressive than either pure PTC or PTC with < 50% PDC, and NLR potentially reflects the PDC proportion. These results support the validity of 50% PDC as a cut-off for PDTC diagnosis and indicate the utility of NLR as a biomarker for PDC proportion.

Newly proposed survival staging system for poorly differentiated thyroid cancer: a SEER-based study.

OBJECTIVE: Despite the recent release of the 8th edition TNM staging system, the risk stratification for poorly differentiated thyroid cancer (PDTC) remains controversial. STUDY DESIGN: Retrospective study. SETTING: SEER database and the First Hospital of China Medical University (FHCMU) database. METHODS: Between 2004 and 2015, 1201 PDTC patients from the SEER database were enrolled to propose a new staging system. 38 PDTC patients were included from the FHCMU. RESULTS: A retrospective analysis of 1201 PDTC cases was performed, and a new staging classification was developed as follows: stage I: age < 55 and T1/any N/M0 (n = 127, 10.57%); stage II: age < 55 and T2-4/any N/M0 or age ≥ 55 and T1-2/any N/M0 (n = 523, 43.55%); stage III: age < 55 and any T/N0/M1 or age ≥ 55 and any T3/any N/M0 (n = 239, 19.90%); stage IV: age < 55 and any T/N1/M1 or age ≥ 55 and T4/any N/M0, and T/any N/M1 (n = 312, 25.98%). The 10-year disease-specific survival rates of patients in the new stages I, II, III, and IV were 97.9%, 77.9%, 35.3%, and 12.1%, respectively. The proportion of variation explained (PVE) for disease-specific survival of the proposed system was higher than that of the 8th AJCC TNM staging (30.61% vs. 27.15%). The accuracy of the staging system was verified in 38 PDTC patients from the FHCMU. CONCLUSION: The proposed staging system provided a more accurate risk stratification for PDTC patients. The new staging model may facilitate the design of personalized treatment strategies for PDTC patients.

Prognostic significance of neutrophil-to-lymphocyte ratio for long-term outcomes in patients with poorly differentiated thyroid cancer.

Poorly differentiated thyroid cancer (PDTC) is a distinct but rare type of thyroid cancer with intermediate biological behavior between differentiated and anaplastic thyroid cancers. PDTC was first defined in 2005 in Japan, but the diagnostic criteria changed in 2015, requiring the tumor to have more than 50% of poorly differentiated components for diagnosis. Because only six years have passed since the PDTC definition change, prognostic factors for long-term survival who meet the latest criteria have not been determined. Neutrophil-to-lymphocyte ratio (NLR) is a prognostic marker in various solid malignancies. However, its impact on PDTC remains unclear. This study aimed to evaluate the significance of NLR as a prognostic factor for patients with PDTC diagnosed based on the latest criteria. In total, 28 PDTC cases (4.4%) of 637 thyroid cancer patients who underwent surgery between 2002 and 2012 were retrospectively analyzed. The median follow-up period was 120 months (range, 7-216 months). Of the 13 deaths (46.4%), 9 patients (32.1%) died from PDTC. The median preoperative NLR was 2.7 (0.67-8.62), and the NLR cut-off value determined by the receiver operating characteristic curve was 2.88. Patients with a high NLR (>2.88) showed significantly worse disease-specific survival (hazard ratio [HR] 4.67, p = 0.036) and overall survival (HR 4.94, p = 0.007) than those with a low NLR (≤2.88). Multivariate analysis revealed that a high NLR independently predicted a worse prognosis (HR 6.06, p = 0.0087). In conclusion, NLR is a useful prognostic marker for patients with PDTC.

Poorly differentiated thyroid carcinoma (PDTC) characteristics and the efficacy of radioactive iodine (RAI) therapy as an adjuvant treatment in a tertiary cancer care center.

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) is biologically more aggressive. Surgery remains the mainstay of treatment. The utility of radioactive iodine (RAI) after surgery is unclear. METHODS: In this retrospective study, patients treated between Jan 2012 and Dec 2017 were included. The demographic, clinical and treatment-related details, including RAI ablation, were recorded and their survival analyzed. RESULTS: Thirty-five patients fulfilled the eligibility criteria. Majority was treatment naïve at presentation. All patients underwent surgery followed by RAI ablation, with a cumulative median dose of 220 mCi (range 40-1140). Sixteen patients received more than one radioiodine treatment for distant metastases. Incomplete resection, age > 45 years and the presence of distant metastasis influenced survival the most. The 3-year PFS of patients with PDTC was 69%. CONCLUSION: All patients in our series showed uptake and responded to treatment. Further use of molecular markers and functional molecular imaging would better our understanding of this entity.

Poorly differentiated thyroid cancer in the context of the revised 2015 American Thyroid Association Guidelines and the Updated American Joint Committee on Cancer/Tumor-Node-Metastasis Staging System (eighth edition).

OBJECTIVE: Poorly differentiated thyroid cancer (PDTC) is a rare, but aggressive thyroid cancer (TC) and a main cause of death from non-anaplastic follicular cell-derived TC. Assessing the risk of PDTC-related death and the risk of recurrence is important for clinicians. The recent American Thyroid Association (ATA) 2015 guidelines and the updated 8th edition of the American Joint Committee on Cancer/Tumor-Node-Metastasis (AJCC/TNM) staging system should support clinicians in the management approach to PDTC patients. PATIENTS: Forty-six consecutive PDTC patients treated in a single oncologic centre, 2000-2017. MEASUREMENTS: Retrospective analysis of TNM stage, initial risk, response-to-therapy categories, follow-up and final disease status incorporating the ATA 2015 criteria and the 8th AJCC/TNM staging system. Disease-specific survival (DSS) using the Kaplan-Meier method. RESULTS: Of the 46 PDTC 21 (45.6%) were ATA high risk (HR), 22 (47.8%), 17 (37%) and seven (15.2%) were TNM stages I, II, and III-IV, respectively. During a median follow-up of 55.5 months, two (4.3%) patients were recurrent, 18 (39.1%) died of PDTC. The 5-/10-year DSS were 65/57%, respectively. According to the AJCC/TNM, the 5-/10-year DSS of I, II, and III-IV stage were 83/83%; 77/55%, and 0/0%, respectively. According to the 2015 ATA initial risk, the 5-/10-year DSS were 91/72% for ATA intermediate risk and 38/38% for ATA HR patients. CONCLUSIONS: In PDTC patients, the updated AJCC/TNM staging system accurately predicts a high risk of death in stage III-IV, whereas it seems to be inadequate for predicting a very low or low risk of death expected for differentiated TC in stage I-II. The ATA initial HR may be also used to predict a high risk of PDTC-related death.

The role of EIF1AX in thyroid cancer tumourigenesis and progression.

PURPOSE: The EIF1AX gene was recently described as a new thyroid cancer-related gene. Its mutations were mainly reported in poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC), but also in well-differentiated thyroid cancer (WDTC) and in benign thyroid lesions, although less frequently. Our aim was to address whether EIF1AX mutations are present in the different stages of thyroid tumourigenesis (from hyperplasia to well-differentiated and to poorly differentiated/undifferentiated lesions), and to clarify its role in this process. METHODS: We analysed the EIF1AX gene in a series of 16 PDTC and ATC cases with coexistent well-differentiated regions and/or benign lesions. In EIF1AX mutant cases we also assessed the presence of RAS genes mutations. RESULTS: We identified the mutation p.Ala113_splice in the EIF1AX gene in two PDTCs (neither present in the well-differentiated counterparts nor in the benign areas). One of these tumours also evidenced the mutation p.Glu61Arg in NRAS in both poorly and well-differentiated regions, further suggesting that the EIF1AX p.Ala113_splice mutation could be associated with tumoural progression. In another patient we did not find any EIF1AX alteration in the PDTC component, but we detected the EIF1AX p.Gly6_splice mutation in the PTC area (both regions were RAS wild-type). This mutation did not seem to be related with dedifferentiation. CONCLUSIONS: According to our results, distinct mutations on EIF1AX may be related to different phenotypes/behaviours. Despite being a small series, which reflects the difficulty in retrieving PDTC and ATC surgical samples with well-differentiated and/or benign areas, our study may provide new insights into thyroid cancer tumourigenesis and dedifferentiation.

Immune and Inflammatory Cells in Thyroid Cancer Microenvironment.

A hallmark of cancer is the ability of tumor cells to avoid immune destruction. Activated immune cells in tumor microenvironment (TME) secrete proinflammatory cytokines and chemokines which foster the proliferation of tumor cells. Specific antigens expressed by cancer cells are recognized by the main actors of immune response that are involved in their elimination (immunosurveillance). By the recruitment of immunosuppressive cells, decreasing the tumor immunogenicity, or through other immunosuppressive mechanisms, tumors can impair the host immune cells within the TME and escape their surveillance. Within the TME, cells of the innate (e.g., macrophages, mast cells, neutrophils) and the adaptive (e.g., lymphocytes) immune responses are interconnected with epithelial cancer cells, fibroblasts, and endothelial cells via cytokines, chemokines, and adipocytokines. The molecular pattern of cytokines and chemokines has a key role and could explain the involvement of the immune system in tumor initiation and progression. Thyroid cancer-related inflammation is an important target for diagnostic procedures and novel therapeutic strategies. Anticancer immunotherapy, especially immune checkpoint inhibitors, unleashes the immune system and activates cytotoxic lymphocytes to kill cancer cells. A better knowledge of the molecular and immunological characteristics of TME will allow novel and more effective immunotherapeutic strategies in advanced thyroid cancer.

Single-Institution Experience of Larotrectinib Therapy for Patients With NTRK Fusion-Positive Thyroid Carcinoma.

Context: The real world efficacy and tolerabiltiy of NTRK inhibitor larotrectinib has not yet been reported in the literature although trial data has shown promising results. Objective: We report a retrospective analysis of patients with thyroid cancer harboring NTRK fusions who underwent treatment with larotrectinib. Methods: A single-institution, retrospective case series of patients with NTRK fusion-positive thyroid cancers treated with neurotrophic tyrosine receptor kinase (NTRK) inhibitors from January 1, 2007, to January 1, 2023, was performed. This study was conducted at a single academic tertiary referral center. Patients with confirmed NTRK-fusion thyroid cancer who received larotrectinib were included. Larotrectinib was administered in accordance with clinical judgment from oncology providers. The primary end point was progression-free survival (PFS). Results: Eight patients with NTRK fusion-positive thyroid cancer treated with larotrectinib were identified: 4 with papillary thyroid cancer (PTC) (50%), 3 with poorly differentiated thyroid cancer (PDTC) (38%), and 1 with anaplastic thyroid cancer (ATC) (12%). The median PFS (mPFS) for all patients was 24.7 months (95% CI, 11.3-38.1). mPFS in PTC was higher than PDTC (34.6 months [24.7-48.7 months] vs 17.5 [7.1-21.1 months]; P = .017). The median overall survival (OS) was 43.8 months (29.8-56.8 months) overall. The single patient with ATC had a PFS and OS of 23 months. Two patients remained on treatment/alive at data cutoff, with a duration of response of 33.5 months and a median follow-up of 52 months. Patients achieved 1 complete response (12%), 6 partial responses (75%), and 1 stable disease (12%). Conclusion: In this single-institution cohort of patients with NTRK fusion-positive thyroid cancer, NTRK inhibition led to an mPFS of 25 months, with survival surpassing historic benchmarks for ATC and PDTC.

Selenomethionine Suppress the Progression of Poorly Differentiated Thyroid Cancer via LncRNA NONMMUT014201/miR-6963-5p/Srprb Pathway.

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) is a special type of thyroid cancer that threatens the life of the patients. Unfortunately, there are no effective treatments for PDTC right now, so it is urgent to search for new efficacious drugs. This experiment was designed to elucidate the effects of selenomethionine (SeMet) on PDTC in vitro and vivo. METHODS: A xenograft animal model was used to assay the volume and weight of PDTC. LncRNA NOMMMUT014201 expression was detected by fluorescence in situ hybridization and Real-time quantitative PCR (qRT-PCR). In vitro experiments were carried on in WRO cells. The Cell Counting Kit-8 assay was performed to test the effect of SeMet on the proliferation of cells. And the migration and invasion of WRO cells by the wound-healing assay, Transwell migration and invasion assays. The cell apoptosis was measured by flow cytometry. In addition, genes related to proliferation, migration, invasion and apoptosis were detected through qRT-PCR and Western Blot. RESULTS: SeMet inhibited the proliferation, migration and invasion and promoted the apoptosis of WRO cells in a dose-dependent manner. Then vivo, SeMet significantly suppressed the volume and weight of PDTC. And SeMet downregulated the expressions of Ki67, PCNA, MMP2, MMP9 and BCL2, but upregulated that of BAX and Cleaved-Caspase 3. Moreover, SeMet upregulated the level of LncRNA NOMMMUT014201 both vivo and in vitro. In addition, repression of LncRNA NOMMMUT014201 removed the inhibition effect of SeMet on WRO cell growth significantly (p<0.05). Further investigation showed that LncRNA NOMMMUT014201 downregulated the expression of miR-6963-5p in PDTC cells, but miR-6963-5p inhibited the level of Srprb. In addition, sh-LncRNA NOMMMUT014201 enhanced the proliferation, migration and invasion but inhibited the apoptosis of WRO cells. However, inhibited miR-6963-5p or overexpressed Srprb relieved the effects of sh-LncRNA NOMMMUT014201on WRO cells. CONCLUSION: Collectively, SeMet inhibits the growth of PDTC in a dose-dependent manner through LncRNA NONMMUT014201/miR-6963-5p/Srprb signal pathway, thus suggesting that SeMet might be a potential drug for PDTC treatment.

Poorly differentiated thyroid carcinomas: conceptual controversy and clinical impact.

Poorly differentiated thyroid carcinomas (PDTC) are rare diseases; nevertheless, they account for the majority of deaths from non-anaplastic follicular cell-derived thyroid carcinomas. Establishing the diagnosis and treatment of PDTC is challenging given the low incidence and the lack of standardization of diagnostic criteria. These limitations hamper the ability to compare therapeutic modalities and outcomes between recent and older studies. Recently, the 5th edition of the classification of endocrine tumors has been published, which includes changes in nomenclature and the addition of the disease entity of "differentiated high-grade follicular cell-derived carcinomas". On the other hand, the recently witnessed advances in molecular diagnostics have enriched therapeutic options and improved prognosis for patients. We herein review the various historical variations and evolution in the diagnostic criteria for PDTC. This systematic review attempts to clarify the evolution of the histological and molecular characteristics of this disease, its prognosis, as well as its treatment options.

Primary tumour iodine avidity in relation to uptake in persistent metastatic disease in papillary and poorly differentiated thyroid cancer.

PURPOSE: Patients with persistent or recurrent papillary and poorly differentiated thyroid cancer can be effectively treated with radioiodine, if the tumour tissue is iodine-avid. However, iodine-avidity status is often unknown at the time of initial radioiodine treatment, limiting any adaptive approach. This study aimed to clarify the relationship between pre-therapeutic iodine avidity in primary tumour tissue, initial lymph node metastases and iodine uptake in subsequent metastases. METHODS: Iodine avidity was prospectively assessed pre-therapeutically in 35 patients by injection of tracer amounts of iodine-131 two days prior to surgery. Iodine concentrations in resected tissue samples were measured, enabling accurate and histologically verifiable iodine avidity data for both primary tumour and initial lymph node metastases. Iodine uptake in persistent metastatic disease was assessed by review of radiology, and treatment response was examined through journal studies. RESULTS: Out of data from 35 patients, 10 had persistent disease at presentation or during follow-up (range 19-46 months). Four patients had non-avid persistent metastatic disease, all with low iodine avidity in their primary tumours and initial lymph node metastases. Patients with low pre-therapeutic iodine avidity did not appear to have greater risk of persistent disease. CONCLUSION: The results indicate a close link between pre-therapeutically measured iodine concentrations in primary tumours with iodine avidity of any subsequent metastases.

I-131 Avid Tumor Thrombus in a Case of Poorly Differentiated Thyroid Cancer.

Intravenous tumor extension is a well-recognized phenomenon occurring in various malignancies but is a relatively rare entity in thyroid carcinoma. In patients with poorly differentiated thyroid cancer (pDTC), I-131 avid superior vena cava tumor (SVC) thrombus at initial presentation is infrequent and potential life threatening. Tumor thrombus can form either due to direct vascular extension of the primary mass or by hematogenous spread. Hybrid nuclear imaging can differentiate the two entities, which can impact the treatment plan of the patient. We present images of an interesting case of evolution of SVC thrombus in a 46-year-old woman with diagnosed pDTC over the span of two years.

Prognostic Impact of Focal Poorly Differentiated Areas in Follicular Differentiated Thyroid Cancer: Is It a Distinct Entity from Poorly Differentiated Thyroid Cancer?

Poorly differentiated thyroid cancer (PDC) and especially poorly differentiated areas (PDA) within follicular cell-derived differentiated thyroid cancer are ill-defined clinicopathological entities. We report our experience on their comparative prognostic outcomes This is a retrospective study of 61 patients (PDC = 29; PDA = 32) from Endocrine and Metabolic Surgery Department (2009 to 2017). Clinical and follow-up details are collected and digitally tabulated from departmental database. Gender ratio was M:F = 1:1.3 and 1:1.6. Mean age was 51 ± 12 years (16-76) and 54 ± 10.5 years (36-81) in PDA and PDC, respectively. Mean tumour size (4.6 ± 0.9 cm; 4.9 ± 1.2 cm), extrathyroidal invasion (59%; 73%) and regional lymphadenopathy were 50% and 55% in PDA and PDC, respectively. Total thyroidectomy was possible in 94% of PDA and in only 77% of PDC. Radioiodine ablation was utilised in 65% (PDA); 29% (PDC). With mean follow-up of 64 ± 23.5 months (12-103) in PDA and 37 ± 22 months (6-94) in PDC, nodal recurrence (PDC = 29%; PDA = 22%) and systemic metastasis was 41% in PDC (synchronous = 24%; metachronous = 17%); 19% in PDA (synchronous = 16%; metachronous = 3%). Five-year event-free survival (EFS) and overall survival (OS) was 90% and 93% in PDA, and 42% and 44% in PDC, respectively. Our study shows that PDA is a separate clinicopathological entity with significantly positive prognosis compared to PDC.

MMP1 acts as a potential regulator of tumor progression and dedifferentiation in papillary thyroid cancer.

Papillary thyroid cancer (PTC) is one of the malignancies with an excellent prognosis. However, in PTC, progression or dedifferentiation into poorly differentiated thyroid cancer (PDTC) or anaplastic thyroid cancer (ATC) extremely jeopardizes patients' prognosis. MMP1 is a zinc-dependent endopeptidase, and its role in PTC progression and dedifferentiation is unclear. In this study, transcriptome data of PDTC/ATC and PTC from the Gene Expression Omnibus and The Cancer Genome Atlas databases were utilized to perform an integrated analysis of MMP1 as a potential regulator of tumor progression and dedifferentiation in PTC. Both bulk and single-cell RNA-sequencing data confirmed the high expression of MMP1 in ATC tissues and cells, and further study verified that MMP1 possessed good diagnostic and prognostic value in PTC and PDTC/ATC. Up-regulated MMP1 was found to be positively related to more aggressive clinical characteristics, worse survival, extracellular matrix-related pathways, oncogenic immune microenvironment, more mutations, higher stemness, and more dedifferentiation of PTC. Meanwhile, in vitro experiments verified the high level of MMP1 in PDTC/ATC cell lines, and MMP1 knockdown and its inhibitor triolein could both inhibit the cell viability of PTC and PDTC/ATC. In conclusion, our findings suggest that MMP1 is a potential regulator of tumor progression and dedifferentiation in PTC, and might become a novel therapeutic target for PTC, especially for more aggressive PDTC and ATC.

Resistance to RET targeted therapy in Thyroid Cancer: Molecular basis and overcoming strategies.

Thyroid cancer is the most frequently diagnosed endocrine malignancy, with an increasing incidence over the last decades. The recent advances in understanding the molecular mechanisms underlying the carcinogenesis of thyroid cancer have led to a better therapeutic approach of these tumors. This has allowed the development and approval of several drugs during the past decade. The rearranged during transfection [RET] protooncogene encodes a transmembrane receptor tyrosine kinase, which is activated by chromosomal rearrangements or point mutations in multiple malignancies, including thyroid cancer. Selective RET inhibitors have proved their value in the treatment algorithm in molecularly selected patients with significantly high response rates and duration of response. Notwithstanding, there are patients who experiment rapid progression or tumor recurrence after an early response to those targeted therapies, which suggest the existence of primary and acquired mechanisms of resistance that have been largely unknown to date. In the present review, we attempt to provide a comprehensive analysis of the most relevant mechanisms of resistance to RET inhibitors which could help in the development of next generation MKI and RET inhibitors, along with combination strategies with different targeted therapies that could potentially overcome these resistances.

Poorly Differentiated Thyroid Carcinoma: Single Centre Experience and Review of the Literature.

There is controversy in the literature regarding a distinct subset of thyroid carcinoma whose histologically classification falls between well-differentiated and anaplastic carcinomas, previously identified as 'poorly differentiated thyroid carcinoma' (PDTC), or 'insular carcinoma', in view of the peculiar morphological characteristics of the cell groupings. The correct diagnosis and treatment of this entity have important prognostic and therapeutic significance. In this review, we describe the epidemiology, diagnosis, and management of PDTC and report our single centre experience to add to the limited evidence existing in the literature.

The role of lymph node status in cancer-specific survival and decision-making of postoperative radiotherapy in poorly differentiated thyroid cancer: a population-based study.

OBJECTIVE: This study aimed to investigate the prognostic value of lymph node (LN) status for patients with poorly differentiated thyroid cancer (PDTC), and to develop a reliable nomogram to predict the 3-, 5- and 10-year cancer-specific survival (CSS) and assist the decision-making of postoperative radiotherapy (PORT). METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was utilized to screen eligible patients who were diagnosed between 2004 and 2016. The optimal values of age, metastatic lymph node ratio (LNR), and the number of metastatic lymph nodes (MLN) were determined and incorporated into the construction of a nomogram. The performance of the model was evaluated by generating a calibration curve and calculating the consistency index (C-index). Based on the nomogram, patients were classified into three risk cohorts. The prognostic efficacy of PORT was evaluated in each cohort. RESULTS: A total of 522 PDTC patients were included in this study. The LN status-associated parameters (MLN and LNR) were independent risk factors for CSS of PDTC patients. Based on MLN, LNR, and other clinical characteristics (age and T stage), an individualized nomogram was constructed that showed an acceptable predictive performance. Furthermore, we proposed a novel risk-classification system to stratify PDTC patients and to assess the prognostic efficacy of PORT. Only patients in high-risk cohort were found eligible to benefit from PORT. CONCLUSION: LN status is statistically associated with the prognosis of PDTC patients. In addition, the individualized nomogram may be a significant tool to assist the evaluation of patients' long-term prognosis and to guide the decision-making for PORT.

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.

Course of Disease and Clinical Management of Patients with Poorly Differentiated Thyroid Carcinoma.

BACKGROUND: In patients with poorly differentiated thyroid carcinoma, the clinical course and prognostic value of response to initial radioiodine therapy is evaluated. METHODS: In 47 patients, clinical and imaging features were analyzed. Patients were stratified in no (NED), biochemical (B-ED) and structural evidence of disease (S-ED) assessed at the first diagnostic control and its impact on survival was evaluated. Further, possible risk factors for a shorter disease-specific survival rate (DSS) were analyzed. RESULTS: In total, 17/47 patients consisted of NED, 10/47 were B-ED and 20/47 S-ED patients. At the last follow-up, 18/47 patients were NED, 2/47 patients B-ED and 27/47 patients S-ED. The median survival time was only reached for the S-ED group (median 3.9 years, 95%CI 2.8-5.1 years) and was not reached in the B-ED and NED groups. Metastases were diagnosed by a 18F-FDG-PET/CT scan in all cases and a multivariate analysis showed that the PET-positivity of metastases was the only significant predictor of DSS (p = 0.036). CONCLUSION: The response to initial surgery and radioiodine therapy in PDTC patients can achieve an excellent outcome and a further follow-up should be refined based on findings at the first diagnostic control. However, patients with an incomplete response and metastatic patients who become mostly radioiodine refractory show a significantly shorter survival, which makes accurate staging by 18F-FDG-PET/CT imaging crucial.

Pre-Therapeutic Measurements of Iodine Avidity in Papillary and Poorly Differentiated Thyroid Cancer Reveal Associations with Thyroglobulin Expression, Histological Variants and Ki-67 Index.

Papillary thyroid cancer (PTC) and poorly differentiated thyroid cancer (PDTC) are treated with radioiodine to reduce recurrence and to treat the spread of disease. Adequate iodine accumulation in cancer tissue, iodine avidity, is important for treatment effect. This study investigated which clinical and histological tumour characteristics correlate with avidity. To quantify avidity in cancer tissue, tracer amounts of iodine-131 were given to 45 patients with cytologically confirmed thyroid cancer. At pathology grossing, representative samples of tumour and lymph nodes were taken and subjected to radioactivity quantification ex vivo to determine avidity. Afterwards, samples underwent extended pathology work-up and analysis. We found that tumoural Tg expression and Ki-67 index were correlated with avidity, whereas tumour size and pT stage were not. The histological variant of thyroid cancer was also correlated with iodine avidity. Variants associated with worse clinical prognoses displayed lower avidity than variants with better prognoses. This work provides new information on which tumours have low iodine avidity. Lower avidity in aggressive histological PTC variants may explain their overall poorer prognoses. Our findings also suggest that radioiodine dosage could be adapted to Tg expression, Ki-67 index or histological variant instead of pT stage, potentially improving the efficacy of radioiodine therapy.