Neoadjuvant therapy and surgical resection successfully treating primary thyroid squamous cell carcinoma: a case report
Case Report

Neoadjuvant therapy and surgical resection successfully treating primary thyroid squamous cell carcinoma: a case report

Yuhao Huang1, Qihuan Shen1, Jiong Lin1, Hechao Zhou1, Wenhua Hu2, Zhi Zhang3, Zumin Xu1 ORCID logo

1Cancer Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China; 2Department of Pathology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China; 3Department of Thyroid Disease, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China

Contributions: (I) Conception and design: Y Huang; (II) Administrative support: Z Xu, Z Zhang; (III) Provision of study materials or patients: J Lin, H Zhou, Z Xu; (IV) Collection and assembly of data: Q Shen, W Hu; (V) Data analysis and interpretation: Y Huang, Q Shen; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Zumin Xu, MD. Cancer Center, Affiliated Hospital of Guangdong Medical University, No. 57 Renmin Avenue South, Xiashan District, Zhanjiang 524000, China. Email: zuminxu@163.com.

Background: Primary squamous cell carcinoma of the thyroid is a rare, highly lethal malignancy, comprising less than 1% of all thyroid cancers. It is associated with poor prognosis due to its rapid progression, resistance to conventional therapies, and frequent presentation at an advanced stage. The preferred treatment approach combines surgical resection with adjuvant radiotherapy or chemotherapy, yet outcomes remain unsatisfactory.

Case Description: We report a case involving a 69-year-old female who presented with a progressively enlarging mass in the anterior neck. Computed tomography (CT) scans identified a right thyroid nodule measuring 4.0 cm × 4.7 cm × 5.3 cm. Subsequent fine needle aspiration biopsy confirmed thyroid squamous cell carcinoma, with molecular analysis revealing a positive BRAF (exon15:c.1801A>G:p.K601E) mutation. Given the substantial size of the neck mass and the unsuitability for surgical resection, neoadjuvant therapy was initiated. This included a combination of tislelizumab immunotherapy, chemotherapy, and anlotinib targeted therapy, which significantly reduced the size of tumor. The patient subsequently underwent a total thyroidectomy and remained disease-free for 2 years.

Conclusions: The present case demonstrates the potential of a multimodal treatment regimen encompassing chemotherapy, immunotherapy and targeted therapy, followed by surgical excision, for primary thyroid squamous cell carcinoma. Further studies are needed to validate the efficacy and safety of this combined treatment modality in larger patient populations.

Keywords: Thyroid squamous cell carcinoma; anlotinib; tislelizumab; case report; neoadjuvant therapy

Submitted Feb 27, 2025. Accepted for publication May 26, 2025. Published online Jul 28, 2025.

doi: 10.21037/gs-2025-88

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Key findings

• A novel neoadjuvant regimen (chemotherapy, tislelizumab, anlotinib) enabled surgical resection and 22-month disease-free survival in BRAF K601E-mutated primary thyroid squamous cell carcinoma, a typically lethal malignancy.

What is known and what is new?

• Primary squamous cell carcinoma of the thyroid is a rare and aggressive malignancy, with treatment outcomes traditionally being poor.

• A BRAF mutation (K601E) was identified in thyroid squamous cell carcinoma. Neoadjuvant chemoimmunotherapy and targeted therapy significantly reduced tumor size, enabling curative resection and sustained remission.

What is the implication, and what should change now?

• Multimodal neoadjuvant strategies (chemotherapy, immunotherapy, targeted therapy) may improve resectability and outcomes in advanced thyroid squamous cell carcinoma, warranting further clinical investigation.

• A shift toward preoperative systemic therapy should be considered for unresectable or bulky primary thyroid squamous cell carcinoma cases.

Introduction

Primary squamous cell carcinoma of the thyroid (PSCCT) is an extremely aggressive and lethal cancer with a poor prognosis. This tumor is very rare, accounting for under 1% of all primary thyroid cancers (1). PSCCT is characterized by a rapidly growing, invasive neck mass (2). Due to its rarity, a standardized treatment approach for this cancer is currently lacking. Treatment options encompass radiation therapy, surgery, and chemotherapy (3). We present a case of primary thyroid squamous cell carcinoma. The patient achieved sustained tumor remission following a comprehensive treatment regimen: initially receiving tislelizumab immunotherapy, combined with nab-paclitaxel chemotherapy and anlotinib targeted therapy, and subsequently undergoing total thyroidectomy (Figure 1A). We present this case in accordance with the CARE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-88/rc).

Figure 1 Case summary. (A) Disease course and treatment summary. (B) HE and IHC staining of the tumor. HE (×400), P63 (×100), PAX8 (×100), CK19 (×100), PD-L1 (×100), and postoperative HE (×400). (C) Representative images showing the patient response to the treatment of Anl, Pac, and Tis. Anl, anlotinib; FNAB, fine needle aspiration biopsy; HE, hematoxylin-eosin; IHC, immunohistochemistry; mos, months; Pac, paclitaxel; PR, partial response; Tis, tislelizumab.

Case presentation

In October 2022, a 69-year-old female was presented to Affiliated Hospital of Guangdong Medical University for a neck mass identified 2 months prior. Contrast-enhanced computed tomography (CT) imaging disclosed a 40 mm × 47 mm × 53 mm nodule in the right thyroid lobe, accompanied by bilateral neck level IV lymph node metastases. A fine-needle aspiration biopsy (FNAB) of the right neck mass identified squamous cell carcinoma of the thyroid. FNAB immunohistochemistry results were negative for TTF-1, TPO and BRAF V600E, while positive for PAX-8, CK19, MC (focal), Ki67 (30%), Vimentin, CK5/6, P63, P53 (70%). Genetic testing revealed a positive BRAF mutation (exon15:c.1801A>G:p.K601E). The immune marker programmed death-ligand 1 (PD-L1) was positive, with a combined positive score (CPS) of 50 as determined by the 22C3 pharmDx assay, indicating high PD-L1 expression (Figure 1B). Subsequently, the patient underwent positron emission tomography (PET)/CT imaging to rule out metastatic tumors. The patient had no significant past medical history. After a thorough assessment by the multidisciplinary team in Affiliated Hospital of Guangdong Medical University, an integrated treatment plan was formulated. The surgical team determined that surgery was not feasible due to the tumor’s encasement by blood vessels, which posed a significant risk. Consequently, a regimen of targeted therapy, immunotherapy, and chemotherapy was advised. Treatment began on October 28, 2022, involving anlotinib (12 mg daily, days 1–14 of each 3-week cycle), paclitaxel (albumin-bound) at 190 mg/m2, and tislelizumab at 200 mg, both administered tri-weekly. During this period, the patient experienced leukopenia, bilateral foot numbness, and a rash. Following two treatment cycles, the neck mass decreased in size (21 mm × 20 mm × 15 mm), achieving a partial response (Figure 1C). Subsequent consultation with thyroid surgeons identified surgery as the optimal treatment. The patient successfully underwent total thyroidectomy with lymph node dissection of the right neck levels II, III, IV, V, and VI, as well as left neck level VI on December 21, 2022, achieving R0 resection. The procedure was performed without complications such as hemorrhage, recurrent laryngeal nerve injury, hypoparathyroidism, or surgical site infection. The patient was monitored over a 30-day postoperative period and demonstrated favorable recovery. Postoperative pathology revealed predominantly coagulative necrotic tissue within the tumor, featuring focal calcification in approximately 97% of the mass, and a minor portion of remaining tumor tissue indicative of squamous cell carcinoma (Figure 1B). Immunohistochemical markers were positive for CK5/6, P63, CK19, and Ki67 (60%), but negative for TPO and TTF-1. Serial CT images are depicted in Figure 2. Despite the recommendation for adjuvant radiotherapy, the patient opted against this approach. Following further discussions, she agreed to proceed with immunotherapy and received a single dose of tislelizumab (200 mg tri-weekly) on March 1, 2023. However, the patient declined further treatment thereafter. Using the date of surgery as the index point, the patient’s disease-free survival reached 2 years as of the latest follow-up in December 2024, with an outstanding quality of life (Figure 1A).

Figure 2 Computed tomography images showing the patient response to the treatment of Anl, Pac, Tis, and the radical surgery. Red circles indicate tumor regions, which disappeared after radical surgery. Anl, anlotinib; Pac, paclitaxel; Tis, tislelizumab.

All procedures performed in this study were in accordance with the ethical standards of the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

PSCCT is an uncommon thyroid cancer, typically diagnosed at an advanced stage and linked to poor outcomes (4). The median survival following diagnosis is just 9 months (4). Currently, surgery and adjuvant radiochemotherapy are common treatment for PSCCT. A review of the recent literature on PSCCT (Table 1) indicates that surgery is an effective strategy for improving survival. Relevant studies indicate that surgical resection may improve the prognosis of patients with PSCCT (4,12). One study utilized the Kaplan-Meier method to analyze 242 patients from the Surveillance, Epidemiology, and End Results (SEER) database, the median survival time for patients who had surgery alone was predicted to be 10 months, while it was only 2 months for untreated patients (12). In this case, the patient was diagnosed with a large tumor, making it difficult to achieve a complete radical resection. Neoadjuvant therapy can render previously unresectable tumors operable, thereby improving patient prognosis by enabling more complete tumor resection.

Table 1

Treatment and survival of PSCCT

Reference Year No. of cases Tumor Survival Treatment
Iwak et al. (5) 2022 1 PSCCT >2 years Weekly paclitaxel
Yan et al. (6) 2022 11 PSCCT 6 months Surgery (n=9) + RT (n=1) + CT (n=2)/refuse (n=2)
Brandenburg et al. (7) 2021 1 PSCCT >12 months Dabrafenib and trametinib
Torrez et al. (8) 2020 1 PSCCT >4 months Surgery + RT + dabrafenib and trametinib
Zhao et al. (9) 2022 1 PSCCT >7 months Surgery
Wang et al. (10) 2019 12 PSCCT 10.5 months Surgery (n=6) + RT (n=11) + CT (n=6)
Raggio et al. (11) 2019 1 PSCCT <1 months CT

CT, chemotherapy; PSCCT, primary squamous cell carcinoma of the thyroid; RT, radiotherapy.

The MAPK and PI3K-AKT pathways are essential in the progression of thyroid cancer (13). Frequently observed genetic modifications in the MAPK pathway consist of mutations in RAS and BRAF (14). In the case of the PI3K pathway, prevalent genetic changes include mutations in PIK3CA, AKT1, and PTEN (15). Receptor tyrosine kinases (RTKs) serve as critical upstream hubs in both signaling pathways. RTKs mediate critical signaling pathways involved in cell proliferation, differentiation, survival, and migration (16). RTK is associated with tumor proliferation and metastasis (17). RTK inhibitors (TKIs) exhibit significant antitumor activity in thyroid cancer (18). Lenvatinib and sorafenib have been established as first-line therapies for advanced malignant thyroid tumors (19). Unfortunately, a BRAF K601E mutation rather than the more common BRAF V600E mutation was detected in the MAPK pathway in our patient. Current therapeutics target BRAF V600E, leaving no specific targeted therapy for this mutation. We elected to use anlotinib due to its broader range of targets and comparable tolerability (20). Anlotinib is a novel multi-targeted kinase inhibitor that demonstrates significant antitumor activity and favorable safety across various types of thyroid cancer (21). A single-arm phase II clinical trial showed that anlotinib antitumor activity in neoadjuvant therapy facilitates R0/R1 resection in most patients with locally advanced thyroid cancer (22). These studies demonstrate the therapeutic potential of anlotinib in thyroid cancer.

The programmed death-1 (PD-1)/PD-L1 pathway is crucial in regulating the interaction between immune cells and cancer cells (23). Tumor cells that express PD-L1 can evade detection by the immune system (24,25). Immunotherapies, including PD-1/PD-L1 inhibitors, have been shown to inhibit cancer progression (24). Immune checkpoint inhibitors (ICIs), including PD-1/PD-L1 inhibitors, have been widely used in the treatment of various cancer types (26). Tumor types with high PD-L1 expression exhibit increased sensitivity to PD-L1 inhibitor therapy (27,28). In a study of PD-1 blockade therapy for anaplastic thyroid carcinoma, PD-L1-positive patients exhibited a one-year survival rate of 52.1% and an overall response rate of 29% (29). These suggest that PD-1/PD-L1 inhibitors may serve as a therapeutic option for advanced thyroid cancer.

Tislelizumab, a human immunoglobulin G4 (IgG4) monoclonal antibody, blocks the PD-1 receptor on activated immune cells, enhancing the anti-cancer response. Its low affinity for the Fc gamma receptor I (FcγRI) receptor may enhance its anti-cancer effects (30). Tislelizumab has demonstrated preliminary antitumor activity across multiple tumor types (31) but has not been studied in PSCCT. Relevant case report has demonstrated the successful treatment of anaplastic thyroid cancer with the combination of tislelizumab and radiotherapy (32). The patient showing high PD-L1 expression (CPS 50) may benefit from tislelizumab treatment.

The combined use of chemotherapy, immunotherapy, and targeted therapy may enhance antitumor efficacy (33). Given the poor prognosis of PSCCT and the absence of standardized treatment, we considered combination chemotherapy to achieve significant tumor reduction. Research has shown that paclitaxel not only directly eliminates tumor cells but also modulates diverse immune cells (34). A case demonstrated the efficacy of paclitaxel treatment for inoperable PSCCT (5). In a clinical trial, paclitaxel-induced therapy led to tumor reduction in 2 out of 3 patients (35). These suggest that combination paclitaxel chemotherapy may benefit the patient.

Our patient received combination therapy with anlotinib, tislelizumab, and paclitaxel, which yielded remarkable outcomes. After two treatment cycles, the tumor significantly reduced in size and became nearly undetectable, permitting surgical resection. These results underscore the potential efficacy of the three-drug combination therapy.

Conclusions

PSCCT is an uncommon condition marked by locally advanced signs and an unfavorable prognosis. Treatment options for PSCCT are limited, with surgical resection currently being the primary approach. The combination of TKIs, chemotherapy and ICIs may represent an effective neoadjuvant therapy for PSCCT. Further clinical studies are warranted to determine the efficacy of this treatment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-88/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-88/prf

Funding: This work was supported by the Research on Circulating Tumor DNA Based on NGS Technology for the Diagnosis and Personalized Treatment of Nasopharyngeal Carcinoma (No. 2021A05061, to Z.X.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-88/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 the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report 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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Cite this article as: Huang Y, Shen Q, Lin J, Zhou H, Hu W, Zhang Z, Xu Z. Neoadjuvant therapy and surgical resection successfully treating primary thyroid squamous cell carcinoma: a case report. Gland Surg 2025;14(7):1399-1405. doi: 10.21037/gs-2025-88

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