Lenvatinib treatment strategy for thyroid carcinoma with malignant pleurisy: a case report

Introduction

Lenvatinib, which has a strong antitumor effect on thyroid carcinoma (1), is an effective treatment for unresectable advanced or recurrent thyroid carcinoma. Tyrosine kinase inhibitors (TKIs) are generally used as long-term therapies; therefore, the toxicities that may be experienced by patients should be effectively managed and minimized, enabling them to remain on treatment for as long as the therapies provide benefit (2). Clinicians should be prepared to manage various adverse events promptly and effectively (1,3).

Pneumothorax is a relatively rare complication during chemotherapy for malignant tumors. However, in cases of metastasis to the lung surface, this is not applicable. There have been several reports of pneumothorax during lenvatinib therapy, and pneumothorax during TKI administration is a refractory and fatal complication (4).

Herein, we report two cases of thyroid carcinoma with malignant pleurisy. The patient in Case 1 developed refractory pneumothorax after lenvatinib therapy. The patient in Case 2 underwent pleurodesis using talc before lenvatinib therapy. Based on this experience, we considered the treatment strategies for thyroid carcinomas with malignant pleurisy. We present this article in accordance with the CARE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-24-269/rc).

Case presentation

Case 1

A 78-year-old male was referred to our hospital (Tokushima University Hospital) because of hoarseness and dyspnea. Neck ultrasonography revealed a tumor (maximum diameter: 43 mm) in the left thyroid lobe with tracheal invasion. Fine needle aspiration and cytology (FNAC) of the tumor revealed papillary thyroid carcinoma. Chest radiography revealed bilateral pleural effusion (Figure 1A), and cytology revealed papillary thyroid carcinoma. Neck computed tomography (CT) revealed bulky lymph nodes extending from the left side of the neck to the left clavicle that had invaded the left carotid artery [cT4aN1bM1, Union for International Cancer Control (UICC)] (Figure 1B). Blood tests revealed a thyroglobulin level of 58.3 ng/mL (≤33.7 ng/mL) and an antithyroglobulin antibody level of <10 IU/mL (<19.3 IU/mL).

Figure 1 Imaging observations before and after starting lenvatinib. (A) Chest radiography revealed bilateral pleural effusion. (B) Neck computed tomography revealed a tumor in the left lobe. (C) Chest radiography revealed right pleural effusion. (D) Chest radiography revealed the right pneumothorax.

The patient had severe respiratory distress, and pleurodesis was performed using talc to treat a large amount of left pleural effusion. Total thyroidectomy was considered difficult for this patient, given the invasion of the surrounding organs and the low-performance status due to increased right pleural effusion (Figure 1C). Instead, first-line systemic lenvatinib therapy was initiated. The patient was treated with lenvatinib (14 mg/day), and the right pleural effusion decreased; however, he was unable to continue lenvatinib because of decreased appetite after 36 days of lenvatinib therapy.

Forty days after lenvatinib therapy, he was referred to our hospital with dyspnea, and right pneumothorax was revealed on chest radiography. Left pleural effusion and pneumothorax were prevented by pleurodesis (Figure 1D). He underwent thoracic drainage; however, a major air leak persisted, and thoracoscopic surgery was performed on the second day after drainage. During surgery, several disseminated nodules in the right thorax and air leakage points were observed in the lower lobe. We attempted wedge resection of the air-leak lesion using a stapler; however, the visceral pleura was fragile and ruptured easily (Figure 2). Therefore, we coated the lesion with a polyglycolic acid sheet and fibrin glue. Surgical pathology confirmed an anaplastic carcinoma of the thyroid. The elastic lamina of the pleura had ruptured, and there was an anaplastic carcinoma around it, which was thought to be the cause of the pneumothorax (Figure 3).

Figure 2 The visceral pleura was fragile and easily torn during surgery, making the damaged area enlarged and difficult to repair.

Figure 3 Histopathological analysis of the lung-tissue specimen. (A) Undifferentiated carcinoma components were detected in the pleural lesion (black arrowheads). (B) The elastic lamina of the pleura was torn due to carcinoma invasion, which was thought to be the cause of the pneumothorax (red arrowheads). HE, hematoxylin-eosin; EVG, Elastica van Gieson.

The air leak disappeared 20 days after surgery, and the patient died 22 days after surgery because of the progression of the underlying disease.

Case 2

A 54-year-old female was referred to our hospital (Tokushima University Hospital) with neck discomfort and dyspnea. She underwent a left thyroid lobectomy for papillary thyroid carcinoma when she was 33 years old. Neck ultrasonography revealed a tumor (maximum diameter: 29 mm) in the right thyroid lobe (Figure 4A) and an enlargement of the right cervical lymph node with suspected metastasis. Chest CT revealed diffuse tumors in both lungs and enlarged lymph nodes from the left side of the neck to the left clavicle and mediastinal lymph nodes. FNAC of the tumor revealed a primary poorly differentiated thyroid carcinoma [cT2N1bM1 (UICC)]. Blood tests revealed a thyroglobulin level of 77.4 ng/mL (≤33.7 ng/mL) and an antithyroglobulin antibody level of 15.4 IU/mL (<19.3 IU/mL). The thyroid hormone levels were within normal limits. We performed a right thyroid lobectomy and lateral segmental lymph node dissection. Surgical pathology revealed a poorly differentiated carcinoma of the thyroid. The supply of sodium iodide capsules (100 mCi) from abroad had been discontinued. However, as a supply of iodine for outpatient treatment (30 mCi) was still available, the patient underwent ablation with 30 mCi ¹³¹I. There was only accumulation in the thyroid bed and no clear accumulation in the lung metastatic site or mediastinal lymph nodes. Chest CT revealed pleural effusion on the right side, and cytological examination of the pleural effusion revealed carcinoma 2 months after surgery (Figure 4B). She underwent a cancer genomic profiling (CGP) test; however, lenvatinib was started before the results were available due to the progression of the carcinoma. Thoracic drainage and pleurodesis were performed using talc to prevent a lenvatinib-associated pneumothorax. Three days after pleurodesis, the patient was treated with lenvatinib (10 mg/day). Two months after starting lenvatinib, chest CT revealed shrinking of the lung metastasis and partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST). She had a good clinical status, except for mild hypertension, which was well controlled with olmesartan [Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade2] (5).

Figure 4 Imaging observations before and after surgery. (A) Neck ultrasonography revealed a tumor (maximum diameter: 29 mm) in the right thyroid lobe. (B) Chest computed tomography revealed multiple lung metastases and pleural effusion in the right thorax.

The results of the CGP test revealed BRAFV600E-mutated tumors. Therefore, we are considering using dabrafenib/trametinib as the disease progresses.

Ethical considerations

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Publication of this case report and accompanying images was waived from patient consent according to the Tokushima University Hospital Institutional Review Board.

Discussion

Herein, we report two cases of thyroid carcinoma complicated by malignant pleurisy that were treated with lenvatinib with different clinical outcomes. In Case 1, pneumothorax was prevented in the left lung, where pleurodesis was performed. Whereas in the right lung, where pleurodesis was not performed, pneumothorax developed during lenvatinib therapy, and lenvatinib was discontinued. In Case 2, pneumothorax was prevented by pleurodesis before lenvatinib therapy, enabling control of the disease. Performing pleurodesis for malignant pleurisy was useful in preventing pneumothorax associated with the adverse events of lenvatinib.

Pleural effusion is very common, and differential diagnoses vary widely. The most common causes are heart failure, carcinoma, pneumonia, and pulmonary embolism (6). The most common primary malignancies causing pleural effusion due to malignant pleurisy are lung carcinoma (37.5%), breast carcinoma (16.8%), and malignant lymphoma (11.5%), whereas thyroid carcinoma is extremely rare at 0.4–0.6% (6,7). Malignant pleurisy is a poor prognostic factor for thyroid carcinoma (8). Tomoda et al. reported that the median survival rate of patients with thyroid carcinoma with malignant pleurisy was 10 months (range, 1–28 months), and there was no effective systemic therapy because most patients had iodine-resistant diseases (9). Lenvatinib and sorafenib are effective in controlling malignant pleurisy in patients with thyroid carcinoma (10,11); therefore, it is necessary to take TKIs for as long as possible to prolong survival while managing adverse events appropriately.

Pneumothorax can occur as a complication of chemotherapy for malignant lung metastases. Several reports of pneumothorax during TKI therapy have been published (4,12-15), with a reported incidence of 2.4% among patients with pulmonary metastases (16), and this pneumothorax is usually a refractory and fatal complication (4). The following factors have been considered as mechanisms for the occurrence of pneumothorax during chemotherapy: rupture of bullae or blebs directly under the pleura, formation of bronchopleural fistulas secondary to tumor necrosis, development of pleural lesions secondary to damage to the lung parenchyma induced by chemotherapy or radiation therapy, formation of cavities or emphysematous lesions in the peripheral tissues with subsequent rupture by the check-valve mechanism due to obstruction or stenosis of bronchi due to tumors, and elevation of the intrathoracic pressure caused by vomiting as a side effect of chemotherapy, resulting in rupture of the pleura (14). In addition, it is necessary to be cautious about the flare-up phenomenon that causes rapid disease progression after discontinuation or decrease in the dose of TKIs (17). Uchida et al. reported patients with rapid accumulation of pleural effusion after the discontinuation of lenvatinib (11). In Case 1, there were several possible causes of pneumothorax. First, the presence of anaplastic carcinoma in the lung lesions suggests that anaplastic transformation had occurred and that discontinuation of lenvatinib may have led to disease progression and rupture of the pleural elastic lamina. Second, there was a lesion in the pleura, and pneumothorax may have developed as the lesion shrank due to lenvatinib therapy. Consequently, due to the refractory pneumothorax, it was not possible to restart lenvatinib, which had a significant impact on survival.

The mechanism of action of lenvatinib is troubling when planning the treatment for pneumothorax. Thus, lenvatinib inhibits the maintenance of vascular integrity, epithelialization, and wound strength, delaying or impairing wound healing (18). Therefore, it is extremely unlikely that pneumothorax can be cured with conservative treatment; when pneumothorax occurs, lenvatinib should be suspended, and surgery should be considered. However, surgery is indicated in few cases because of the progression of the primary carcinoma due to drug discontinuation or poor general conditions. Moreover, even if surgery is possible, repair of the air leak is not easy, as in Case 1.

Based on Case 1 and considering the clinical course in which pneumothorax was prevented in the left thoracic cavity after pleurodesis, we judged that the patient in Case 2 had a risk of pneumothorax in the right lung during lenvatinib therapy because of the presence of a metastatic lesion in the right pleura. Therefore, pleurodesis using talc was performed prior to lenvatinib therapy. Pleurodesis using talc is an effective and safe process, even for older patients and those with a low-performance status (19). In Case 2, there were no adverse events, and the patient was able to continue lenvatinib therapy and obtain sufficient antitumor effects. Considering the risks of pneumothorax and delayed healing of the drainage wound, lenvatinib was started at a low dose, which was gradually increased if there were no problems at the wound site. In Case 1, there was a risk of pneumothorax; the patient’s general condition was poor, and lenvatinib was initiated at a low dose.

Currently, in addition to multi-kinase inhibitors, such as sorafenib and lenvatinib, new molecularly targeted drugs are available for the treatment of unresectable thyroid carcinoma in patients with BRAFV600E-mutated or RET-fusion-positive tumors. In Case 2, the patient had BRAFV600E-mutated tumors, and dabrafenib/trametinib was available. Dabrafenib/trametinib has a low incidence of grade 3 or higher adverse events, and no adverse events related to delayed wound healing have been reported (20). Therefore, it may be an effective option for patients at risk of developing pneumothorax.

Conclusions

Malignant pleurisy is associated with the risk of developing pneumothorax associated with lenvatinib therapy. Once pneumothorax occurs, therapeutic intervention becomes difficult, and patients follow a course with poor prognosis. Therefore, pleurodesis should be performed prior to lenvatinib therapy.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-269/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-269/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-269/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 institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Publication of this case report and accompanying images was waived from patient consent according to the Tokushima University Hospital Institutional Review Board.

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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