Vascular endothelial growth factor receptor tyrosine kinase inhibitors are known to cause perforation as one of their severe side effects, and postoperative and postradiation therapy are known risk factors. However, there are few studies on perforation following tumor shrinkage. A 78-year-old woman with postoperative recurring left collecting duct carcinoma of the right hilar lymph nodes and mediastinum underwent eight courses of nivolumab plus cabozantinib, resulting in tumor shrinkage. Three days after the last administration, she developed fever and cough and was hospitalized for right lobar pneumonia. The patient received long-term antibiotics for bronchial fistula with the destruction of the bronchial wall and secondary lung abscess. When using nivolumab plus cabozantinib combination therapy for a tumor with bronchial invasion, physicians should be aware of bronchial perforation as the tumor shrinks.
Cabozantinib is a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) used in combination with nivolumab as the first-line treatment for metastatic recurrent clear cell renal cell carcinoma . Collecting duct carcinoma (CDC) is histologically classified as a non-clear cell renal cell carcinoma, and no standard treatment has been established. Therefore, VEGFR-TKI, or combination therapy with an immune checkpoint inhibitor (ICI), has been used in clinical trials [2, 3]. Because CDC is rare, only a few cases have been enrolled in these clinical trials. Therefore, little is known about the efficacy and toxicity of these therapies. We report a case with bronchial perforation secondary to tumor shrinkage following treatment with nivolumab plus cabozantinib (N + C) in a patient with CDC metastasized to the hilar and mediastinal lymph nodes.
A 78-year-old woman presented with gross hematuria, and imaging studies revealed a bladder tumor and left kidney mass. She underwent transurethral resection of the bladder tumor, and pathological examination of the tumor revealed urothelial carcinoma high-grade G2 pTa. Although ureteroscopy and urine cytology were negative, an invasive renal pelvis cancer was suspected, and laparoscopically assisted total left nephroureterectomy and retroperitoneal lymph node dissection were performed. However, the pathological examination of the renal mass revealed no existence of urothelial carcinoma in the renal pelvis and ureter, and immunohistochemistry staining of CK7 (+), CK20 (−), CK10 (+), AMACR (−), GATA3 (+/−, weakly and partly), uroplakin III (−), suggested the diagnosis of CDC (pT3aN0, Fuhrman grade 3, v1, ly1). No metastatic lesions were found, and the patient did not receive postoperative chemotherapy. Twenty-one months later, contrast-enhanced computed tomography (CT) revealed hilar and mediastinal lymph node metastases (37 × 30 mm) and intrabronchial invasion, which was diagnosed as a postoperative recurrence. N + C was started, and after eight courses, the best response was partial response (Fig. 1). Grade 2 proteinuria, grade 2 hand-foot syndrome, and grade 2 diarrhea were observed and were successfully managed.
Three days after completing the eight courses of N + C, the patient developed fever and cough, and CT showed infiltrative consolidation of the right lower lobe. She was diagnosed with right lobar pneumonia and started on piperacillin/tazobactam 4.5 g every 8 h. Subsequent contrast-enhanced CT revealed bronchial wall destruction and bronchial perforation (Fig. 2), resulting in enlargement of an abscess in the right pulmonary hilum. Antibiotic was changed to meropenem 0.5 g every 6 h. Bronchoscopy showed perforation secondary to the destruction of the lower lobe of the right bronchial wall and mucosal swelling caused by a lung abscess. Fungal infection was suspected, and empirical treatment with micafungin 100 mg every 24 h was added for pulmonary aspergillosis and fungal infections such as Mucor. After 2 weeks of administration, fungal infection was ruled out by negative serum galactomannan antigen and bronchial alveolar lavage cultures. Eight weeks after the diagnosis of bronchial perforation and lung abscess, contrast-enhanced CT showed shrinkage of the abscess in the right pulmonary hilar region, and antibiotics had an effect. However, CDC progression led to the enlargement of the right mediastinal and hilar lymph nodes. Subsequently, nivolumab monotherapy was started considering that resumption of cabozantinib would be risky due to her history of bronchial perforation.
This was a case of bronchial perforation associated with lung abscess after administration of N + C for CDC metastasis to the right hilar and mediastinal lymph nodes and bronchial invasion. Bronchial perforation was thought to be from tumor shrinkage due to response to combination immunotherapy with VEGFR-TKI.
Organ perforation is a well-known side effect of VEGFR-TKIs, with a reported incidence of gastrointestinal perforation of 1.3% . However, little information is known on the frequency of bronchial perforation. There are few case reports of aero-digestive fistula following cabozantinib use [5, 6] and a case report of bronchial fistula following sunitinib use . Moreover, there are few reports on ICI-induced perforation, with a case report on tracheoesophageal fistula following pembrolizumab use for squamous cell lung cancer  and bronchoesophageal fistula following nivolumab use for cancer of unknown primary origin .
The mechanism of VEGFR-TKI-induced organ perforation is not yet fully understood, but tissue necrosis may occur due to the vasoconstrictive effect of nitric oxide . Risk factors for organ perforation include a history of surgery, intestinal and abdominal trauma, presence of gastric ulcer or diverticulum, prolonged respiratory infection, and prior radiation therapy [6, 11].
Although the above risk factors were not present in this patient, the following three hypotheses for perforation were evoked. First, tumors invading or in contact with organs may be at risk for perforation. There is a case report of a tracheoesophageal fistula following lenvatinib treatment in a mediastinal lymph node lesion close to the esophagus . Second, a large tumor diameter could be a risk factor for perforation. An analysis of factors associated with the development of pneumothorax during treatment with pazopanib for metastatic or advanced soft tissue sarcoma showed that a large tumor diameter (>30 mm) of the lung lesion was significantly associated with the development of pneumothorax . In the present case, the tumor diameter exceeded 30 mm. Third, perforation may occur during tumor shrinkage. Previous case reports on sunitinib , lenvatinib , and pembrolizumab  treatments revealed the occurrence of perforation during tumor shrinkage. Although the present patient had no risk factors, such as a history of surgery or radiation therapy, the rapid shrinkage of the tumor of the hilar lymph node may have led to the formation of a bronchopleural fistula in the adjacent area.
In conclusion, this is the first report of bronchial perforation in a patient with CDC on combination therapy with an ICI and a VEGFR-TKI. Clinicians should be aware that this regimen may lead to organ perforation. Further studies on risk factors for perforation are needed.
We would like to thank Editage (www.editage.com) for English language editing.
Statement of Ethics
This case report was conducted ethically in accordance with the World Medical Association’s Declaration of Helsinki and was approved by the Local Ethics Committee of Toranomon Hospital, approval number 1879. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.
Conflict of Interest Statement
Y. Miura reports receiving honoraria from ONO Pharmaceutical, Bristol-Myers Squibb, MSD, Eisai, and Takeda separate from the submitted work.
No funding was used to acquire the information/data described in this case report.
H.O. and Y.M. planned the study and wrote the manuscript. H.O., K.M., S.O., R.K., T.Y., Y.T., K.S., K.S., S.U., and Y.M. contributed to the final version of the manuscript.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.