Administration of multikinase inhibitor followed by radioiodine therapy for poorly differentiated thyroid cancer: a case description and systematic review

Introduction

Poorly differentiated thyroid cancer (PDTC) accounts for fewer than 5% of all thyroid cancer cases. Its pathological characteristics and biological behavior result in a significantly worse prognosis than does differentiated thyroid cancer (DTC), but it is not as severe as anaplastic thyroid cancer. PDTC is the most common disease-specific cause of mortality among patients with thyroid cancer, while distant metastasis is the primary cause of death among patients with PDTC, accounting for up to 85% of disease-related deaths (1). The overall 10-year survival rate of those with PDTC is approximately 50%. Unlike the treatment of DTCs, the treatment of PDTC has not been standardized due to the rarity of the disease and the heterogeneity of inclusion criteria. Therapeutic decisions on PDTC have thus been mainly extrapolated from the treatment experience in DTC. However, in contrast to low-risk thyroid cancers, these tumors require a more aggressive treatment strategy (2).

Complete surgical resection, when feasible, is considered the optimal initial approach for PDTC and may involve the excision of invaded adjacent structures (e.g., the trachea and recurrent laryngeal nerve) and regional lymph nodes. However, the aggressive behavior of PDTC often leads to extensive local invasion, complicating complete resection and elevating recurrence risk. Although various adjuvant therapies have been proposed, none consistently demonstrate high efficacy (2,3). Radioiodine (RAI) uptake in PDTC is variable and generally reduced compared to that in well-differentiated thyroid cancer, due to dedifferentiation and loss of sodium-iodide symporter (NIS) expression. Consequently, RAI therapy is often ineffective, with supporting evidence largely limited to case reports (4). A portion of patients may initially respond but develop RAI refractoriness over time. Poorly differentiated histology, advanced age, invasive growth, and mutations such as BRAF and TERT further diminish iodine avidity (5,6). External beam radiotherapy can provide local control in unresectable disease but does not significantly improve survival. Similarly, chemotherapy has not shown substantial survival benefits (7). Targeted therapy has emerged as a promising research direction; however, the molecular landscape of PDTC is heterogeneous, involving diverse alterations (e.g., in BRAF, RAS, TERT, and TP53), and no dominant targetable driver has been established. Most evidence has been derived from preclinical models or small case series with limited follow-up (2,7). High intertumor heterogeneity at the genomic and proteomic levels contributes to variable treatment responses, and predictive biomarkers are currently lacking. Furthermore, the rarity of PDTC has impeded the completion of large randomized trials, and most recommendations are based on retrospective or small-sample studies (8). In light of these challenges, treatment personalization remains a critical but lacking need for PDTC.

The case described in this report highlights the importance of disease assessment and combination therapy in PDTC. Although RAI treatment has demonstrated limited value in PDTC, the appropriate timing of RAI intervention may carry significant clinical implications.

Case presentation

A 48-year-old woman was admitted to the Department of Head and Neck Surgery at Shanxi Cancer Hospital with worsening dyspnea and hoarseness, symptoms that emerged more than 16 years after initial right hemithyroidectomy for nodular goiter. Enhanced computed tomography (CT) demonstrated a large (6.1 cm × 2.9 cm × 6.9 cm), irregular mass completely replacing the right thyroid lobe, exhibiting infiltrative growth with poorly defined margins. The lesion showed markedly heterogeneous enhancement with areas of necrosis and scattered calcifications. It was encasing and significantly compressing the trachea, resulting in notable luminal narrowing. The mass extended across the midline to invade the left thyroid lobe. On May 20, 2022, tracheotomy was initially performed in the patient to secure the airway. This was followed by an extended total thyroidectomy, resection of the first through ninth tracheal rings with laryngotracheal anastomosis, central compartment (level VI) lymph node dissection, and excision of the right level III jugular lymph nodes. The procedure was completed with the establishment of a permanent tracheostomy. Intraoperative exploration revealed a highly complex surgical field. The right lobe of the thyroid gland was replaced by diffuse malignant sclerosis that had invaded and penetrated the lumen of the trachea. The tumor in the right thyroid lobe extended through the tracheal membrane to the contralateral side, with adhesions to the strap muscles, omohyoid muscle, and esophagus. The right recurrent laryngeal nerve was observed traversing through the tumor mass. Ultimately, the esophagus and the recurrent laryngeal nerve were separated, but the invaded muscles were removed. Surgical pathology confirmed a poorly differentiated carcinoma of the right lobe, with hemorrhage and necrosis (Figure 1). The tumor involved the entire right thyroid lobe and isthmus with intravascular cancer thrombus, but no nerve invasion. Immunohistochemical results showed the following: TTF-1 (partial +), Pax8 (+), Ki-67 (approximately 40%), wild-type P53, Syn (−), CK19 (+), and calcitonin (−). The final diagnosis was metastatic poorly differentiated thyroid carcinoma. Hybridization capture-based next-generation sequencing performed at AmoyDx (Xiamen, China) identified the presence of three mutations: TP53 (p.E1113Yfs*2), ATRX (p.F270V), and DICER1 (p.E1813D).

Figure 1 Tumor cells were arranged in solid sheets, nests, and islands, exhibiting frequent mitotic figures along with foci of necrosis and intratumoral hemorrhage, features consistent with the diagnosis of PDTC. Hematoxylin and eosin staining; magnification, ×40. PDTC, poorly differentiated thyroid cancer.

On June 10, 2022, the patient was referred to the Department of Nuclear Medicine at Shanxi Bethune Hospital in Taiyuan, China, for RAI. She had an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Serological assays were performed showing a thyroid-stimulating hormone (TSH) level of 0.38 ng/mL (0.27–4.2 ng/mL), a thyroglobulin (Tg) level of 2,938 ng/mL (3.5–77 ng/mL), and a Tg antibody (TgAb) level of 22.92 IU/mL (0–115 IU/mL). Examination with fluorine-18-fluorodeoxyglucose positron emission tomography-computed tomography (¹⁸F-FDG PET/CT) on a Discovery Elite scanner (GE HealthCare, Chicago, IL, USA) was performed. PET/CT imaging revealed a nodular area of intense hypermetabolism at the surgical bed, suggestive of residual tumor (Figure 2). Additionally, enlarged and FDG-avid lymph nodes were identified in the bilateral level II and right level III cervical regions, raising suspicion for metastatic involvement. Furthermore, multiple pulmonary nodules with partial FDG avidity were noted that were consistent with metastatic disease (Figure 3). Treatment with lenvatinib (14 mg/day), a multikinase inhibitor (MKI), was initiated on June 20, 2022. During the 2 weeks of administration, multiple grade 1–2 adverse reactions were encountered, including hypertension, proteinuria, abnormal liver function, gingival bleeding, diarrhea, fatigue, and joint pain. These improved and were well controlled when the dose of lenvatinib was reduced to 10 mg/day. One month after the beginning of treatment, the serum Tg level decreased significantly to 402 ng/mL. A PET/CT scan performed 3 months later showed that the diameter of the largest pulmonary metastatic nodule had decreased from 1.4 to 0.7 cm, and FDG metabolism was also significantly reduced. The patient continued to improve and was able to return to work. Sixteen months after initiating MKI therapy (July 2023), following self-discontinuation of treatment, the serum Tg level increased from 224.7 to 470.6 ng/mL despite radiologically stable pulmonary metastases on CT. In November 2023, the patient was administered 7,400 MBq of iodine-131 orally and underwent a posttherapy whole-body scan (RxWBS) within 3 days after RAI. RxWBS revealed iodine-131-avid pulmonary metastases (Figure 4). Three months after RAI, the Tg level decreased from 470.6 to 204.7 ng/mL, and the diameter of the lung metastases decreased from 0.8 to 0.5 cm. In May 2024, the patient received a second course of iodine-131 at 7,400 MBq. RxWBS was performed at the same time interval and with the same equipment as that used in the initial therapy. The pulmonary metastases still exhibited RAI-avidity metastases on RxWBS (Figure 5). The RAI dose and RxWBS for the patient were administered based on the American Thyroid Association (ATA) and Chinese guidelines. On June 24, 2025, the Tg level was 254.4 ng/mL, and CT showed stable pulmonary metastases. The patient was followed up for 37 months and is currently in good condition, with follow-up still ongoing. All procedures performed in this study were in accordance with the ethical standards of Shanxi Bethune Hospital Ethics Committee and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 2 The ¹⁸F-FDG PET/CT cross-sectional fusion image demonstrated intensely hypermetabolic nodular foci adjacent to the right thyroid cartilage (red arrow), with an SUVmax of 5.42, highly suggestive of residual malignant tumor. CT, computed tomography; FDG, fluorodeoxyglucose; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

Figure 3 An ¹⁸F-FDG PET/CT cross-sectional fusion image demonstrated multiple hypermetabolic pulmonary nodules. The largest lesion was located in the left lower lobe (red arrow), measured approximately 1.6 cm × 1.3 cm, and had intense FDG avidity, with an SUVmax of 6.75, which was highly suggestive of metastatic disease. CT, computed tomography; FDG, fluorodeoxyglucose; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

Figure 4 The first RxWBS demonstrated intense radioiodine avidity in both the cervical lymph node metastases and pulmonary metastases, confirming the presence of functional metastatic disease. RxWBS, posttherapy whole-body scan.

Figure 5 Following the second administration of radioiodine therapy, RxWBS revealed complete resolution of previously noted radioiodine-avid cervical lymph node metastases. Residual but diminished radioiodine uptake was observed in the pulmonary metastatic lesions, along with moderate focal uptake in the thyroid bed, indicating a partial therapeutic response. RxWBS, posttherapy whole-body scan.

Discussion

The sequential strategy of MKIs followed by RAI is reshaping the treatment paradigm of radioactive iodine-refractory PDTC. In contrast to the conventional emphasis on early RAI administration, the key insight from this case is that administering RAI during the window of achieved disease stability after MKI treatment may represent a more rational and effective timing strategy. This successful example suggests that for patients with initially RAI-non-avid PDTC, the treatment approach should not be administering treatment as soon as possible but rather creating the conditions for optimal treatment and then seizing the opportunity when it is available. MKIs inhibit tumor proliferation and modulate the tumor microenvironment, thereby laying the groundwork for subsequent RAI redifferentiation. This prompts several key concerns, including the means to scientifically defining the optimal treatment window, the underlying molecular mechanisms involved, and the determination of which patients are the most likely to benefit from this approach. To address these issues systematically, we examined our case with reference to a systematic review of the related literature, with the aim to identify the predictive factors, optimal timing, and clinical implications of RAI therapy following MKI administration.

PDTC is frequently characterized by mutations in genes such as ALK, PTEN, RAS, and TP53, which are associated with aggressive clinical behavior and poor prognosis and thus may serve as targets for therapy. Within this context, ALK inhibitors such as crizotinib have demonstrated significant clinical efficacy by specifically inhibiting kinase activity. The mutation or loss of PTEN may confer sensitivity to mTOR or PI3K/AKT pathway inhibitors, providing a rational strategy for refractory cases. RAS mutations occur in approximately 35% of PDTC cases and stimulate both MAPK and PI3K/AKT signaling, representing a critical event in tumor dedifferentiation (9). TP53 mutations are detected in about 8% of cases, and loss of this tumor suppressor enhances the invasive potential and malignant phenotype (9,10). Aside from these common alterations, our case also harbored the ATRX and DICER1 variants. ATRX mutations are present in approximately 10% of thyroid cancers and may promote tumor immortalization via dysregulated DNA methylation and mutagenesis (11). DICER1-mutant thyroid carcinomas often exhibit invasive growth confined to the thyroid gland and high aggressiveness without vascular invasion. Molecular profiling in this case indicated highly aggressive intra- and extrathyroidal disease, suggesting a poor prognosis. Surgical findings revealed local invasion, and ¹⁸F-FDG PET/CT confirmed bilateral lung metastases, consistent with an aggressive phenotype. The patient was treated with the MKI lenvatinib. The clinical outcomes of patients with PDTC treated by MKIs remain poorly documented. In the study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT) trial, lenvatinib achieved a median progression-free survival (PFS) of 14.8 months in patients with PDTC, which was greater than the PFS of 2.1 months yielded by placebo (12). The reported PFS from real-world studies including both differentiated and a subset of PDTC cases range from 10.0 to 35.3 months (13,14). Roque et al. enrolled patients with PDTC who had experienced disease progression within 6 months before enrollment, half of whom had an ECOG performance status of 2. They found that lenvatinib was effective and well tolerated in this population, although adverse events were observed in all participants (15).

PDTC is an aggressive and RAI-refractory thyroid malignancy with limited therapeutic options. The management of our case involved several critical considerations. Postoperatively, the patient presented with vocal impairment and significant physical weakness, corresponding to an ECOG performance status of 2. As targeted therapy has been associated with improved PFS and overall survival, particularly in patients with an ECOG status of 0–1, lenvatinib was initiated early in the treatment course (16). Although genetic profiling identified TP53 and ATRX mutations, targeted agents for these alterations remain under clinical investigation; thus, an MKI-based approach was deemed appropriate. Second, despite the standard recommended dose of lenvatinib being 24 mg, a reduced initial dose of 14 mg was selected due to the patient’s poor clinical condition. The dose was further reduced to 10 mg during treatment due to the emergence of adverse events, and the patient eventually self-discontinued therapy at 14 months, leading to biochemical progression. Active symptom management and psychological support were provided, leading to a prompt improvement in the patient’s physical condition. Regarding RAI, its limited efficacy in PDTC, along with the risk of disease progression and delayed recovery associated with thyroid hormone withdrawal, precluded its use in the early postoperative phase.

As indicated by Liu et al., intensive treatment strategies and close monitoring are critical during the initial diagnostic phases (17). Accordingly, upon detecting a rebound elevation in serum Tg levels in this patient, we promptly recommended combined therapy with RAI. Although the efficacy of RAI therapy for PDTC remains controversial, previous studies have established distant metastasis as the primary cause of mortality in patients with PDTC and recommend RAI for high-risk patients (18). In this case, the first RAI administration demonstrated excellent avidity in pulmonary metastases and achieved a satisfactory therapeutic response. However, the second RAI treatment had markedly reduced iodine uptake and limited efficacy on follow-up. Current evidence supports a single course of RAI therapy as necessary in patients with PDTC, whereas the benefit of repeated RAI administration remains uncertain (19,20). Based on our experience, early RAI initiation may not be optimal for patients with PDTC with a high tumor burden. A more rational approach may involve initial disease stabilization achieved through other modalities, after which RAI can be considered. Although the pulmonary metastases in this case exhibited strong FDG avidity, they simultaneously demonstrated good iodine-131 avidity, indicating that FDG positivity cannot reliably predict RAI response in PDTC. It is worth noting that the observed iodine uptake occurred following treatment with MKIs. It should be noted, however, that such agents are not known to induce iodine reuptake in metastatic thyroid cancer (21). In experimental models of BRAF p.V600E-mutated tumors, mitogen-activated protein kinase (MAPK) pathway inhibition was found to reverse dedifferentiation and restore RAI avidity (22). A landmark study in RAI-refractory DTC reported that the inhibition of the MAPK pathway with the MAPK ERK kinase (MEK) inhibitor selumetinib restored significant RAI uptake in 44% of patients with BRAF p.V600E-mutant DTC (23). Other studies suggest that oral estrogen receptor γ inverse agonists may also resensitize DTC to RAI therapy (24). Therefore, MEK inhibitors targeting the MAPK pathway or estrogen receptor γ inverse agonists may represent promising strategies for restoring RAI responsiveness in PDTC.

The widely accepted clinical practice in TSH suppression therapy is the reduction of TSH serum level to <0.1 IU/mL for all DTC cases, including patients with PDTC, who have persistent structural disease in the absence of specific contraindications (25). We also recommend TSH suppression therapy in patients with PDTC, especially those with high Tg levels, regardless of whether the lesions have iodine uptake, as was the case with patient described in this report.

Conclusions

This encountered a case of PDTC that could not be completely resected surgically, for which individualized treatment was implemented based on the tumor’s biological characteristics and adjusted according to various patient-specific considerations. It was crucial to select therapeutic agents through a comprehensive assessment of both the tumor and the patient. The combining RAI with targeted drugs, especially MAPK or MEK pathway inhibitors, may enhance the iodine uptake capacity of lesions, thereby broadening the potential application of RAI in PDTC. In addition, the initiation of RAI can be adjusted appropriately according to the patient’s disease control status.

Acknowledgments

None.

Footnote

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-381/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of Shanxi Bethune Hospital Ethics Committee and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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