Localized pleural metastasis without other organ metastases after nephrectomy for renal cell carcinoma

We present a case of a 69-year-old man who had localized pleural metastasis without other organ metastases after nephrectomy for right renal cell carcinoma (RCC). He complained of respiratory symptoms for more than two years after the operation and was confirmed to have right pleural effusion and multiple pleural masses on computed tomography (CT). There were no abnormal findings in the other organs, but the pleural mass gradually increased in size on CT. We suspected malignant tumors such as malignant pleural mesothelioma and synovial sarcoma in addition to RCC metastasis. Finally, we performed surgical resection of the pleural mass under general anesthesia, and we diagnosed pathologically as metastasis from RCC. Distant metastases of RCC are common in the lungs, bones, brain, and liver. To our knowledge, localized pleural metastases from RCC is rare.


Introduction
Renal cell carcinoma (RCC) most often metastasizes hematogenously to the lungs, and pleural metastases generally accompany lung metastases. Saito reported that 154 of 1451 (12%) autopsy cases of RCC had pleural metastases, but none of them had localized pleural metastasis [1]. In addition, Chernow et al. reported that only 1 of 96 patients with pleural metastasis had RCC as the primary cancer [2]. Here, we reported a rare case of RCC with localized metastatic masses in the pleura. The existence of the Batson venous plexus, which does not pass through the lung, has been revealed as the mechanism of metastasis to the pleura [3]. This plexus is a venous network that has no valve surrounding the spine; it extends from the skull to the pelvis, creating anastomoses with the odd veins, semi-odd veins, bronchial veins, and intercostal veins. It forms retrograde blood flow by changes in intrathoracic and intraabdominal pressures, causing tumor metastasis to the pleura. Since 2008, the therapeutic effects of molecular targeted drugs and immune checkpoint inhibitors have been observed for renal cancer. Particularly in cases of metastatic pleural tumors, in which only few can undergo highly invasive operation, longer prognosis can be expected with these drugs.
Throughout this case report, we reviewed the diagnostic method and effective treatment, with reference to past similar cases.

Case presentation
We encountered a 69-year-old man who had localized right pleural metastases after undergoing nephrectomy in September 2017 for right RCC (8.0 × 7.0 × 7.0 cm), clinical stage 3, clear cell type histology, grade 2 ( Fig. 1A and B and 2A-2C). The tumor was histologically solid, with hemorrhage, necrosis, scarring, and pseudocapsule formation, and infiltrated into the renal parenchyma. The tumor spread to the right renal vein, but no infiltration into the inferior vena cava was observed. He didn't receive adjuvant chemotherapy following the nephrectomy. Postoperatively, he did not present with any symptoms and received regular follow-up with chest and abdominal computed tomography (CT) every three months. There were no confirmed recurrence and metastasis until March 2020, when he visited our hospital complaining of right chest pain and dyspnea. At this time, CT scan revealed right pleural effusion and multiple pleural masses ( Fig. 1C and D). There were no abnormal radiologic findings in the other organs. He had no smoking  history, no past medical history, and no asbestos exposure. We suspected the following possibilities: metastasis from RCC, malignant pleural mesothelioma, and synovial sarcoma. For investigation and diagnosis, we performed two pleural effusion tests before surgery, but both cytological results were class I. After one month, there were no new abnormal radiologic findings, but we confirmed that the tumors obviously grew on CT ( Fig. 1E and F). Finally, we performed intrathoracic tumor resection under general anesthesia and diagnosed histologically as pleural metastasis from clear cell type RCC (Fig. 2D-F). Thoracoscopy showed multiple reddish, soft, bleeding encapsulated tumors (Fig. 3). The pleural fluid cytology had no malignant cells. A total of eight bleeding tumors were completely resected, with the largest measuring 5.0 × 3.8 × 2.2 cm. This case is currently being treated for pembrolizumab plus axitinib, which has been reported to be superior to sunitinib in overall survival and progression-free survival [4]. This was a very rare case of localized metastatic pleural tumors from RCC diagnosed by thoracoscopic surgical resection.

Discussion
According to a previous systematic review, complete surgical resection is expected to improve the survival rate of patients with distant metastases [5]. However, surgical operation seems to be possible on only few cases of RCC with pleural metastasis, because it is highly invasive and includes lung resection. Table 1 shows a summary of 15 cases including this case of RCC with localized pleural metastasis. Most patients were diagnosed by thoracoscopic, ultrasound-guided, or CT-guided biopsy and were treated by interferon (IFN) or chemotherapy not surgical operation. Total pleural pneumonectomy was performed on only one case (case 3). As a diagnostic procedure, pleural fluid cytology was performed on some cases, but it was not enough for a definitive diagnosis. In fact, the positive rate of pleural fluid cytology for cancerous pleurisy has been said to be about 60% [6]. We suggest performing pleural biopsies, if possible, for definitive diagnosis.
In general, RCC has a mean diameter growth rate of 0.59 cm/year and volume growth rate of 19.1 cm 3 /year, and tumors <4 cm show even lower growth rates [7]. However, compared with primary tumors, which have very slow growth, metastatic pleural mass may progress rapidly, as in this case. In fact, in this case, the metastatic pleural mass obviously grew on CT after one month (Fig. 1B-E). As shown in Table 1, some cases developed recurrence after more than five years of nephrectomy, consistent with the feature of slow growth. Moreover, case 8 had metastatic pleural tumors 16 years after nephrectomy and died 15 months later, despite treatment. Therefore, we need to pay attention to the appearance of respiratory symptoms and pleural effusion, and longer follow-up may be required even after nephrectomy.
With regard to treatment, IFN and interleukin (IL) have been used for advanced RCC, but their reported response rates have been low at 5%-27% [8,9]. At present, the number of treatment drugs has increased with the advent of molecular targeted and immunotherapy. The effects of these drugs are highly expected, especially in patients with pleural metastases, among whom only few can undergo surgery. In fact, reduction in the size of the pleural mass was confirmed in some cases (cases 4, 12, and 13). In the future, more similar case reports are required to determine the better treatment in patients with pleural metastases from RCC.

Conclusions
Localized metastatic pleural mass secondary to RCC is extremely rare, and most cases have been treated by IFN, IL, and chemotherapy not surgery. More information about the therapeutic effects and prognosis of cases of pleural metastases from RCC needs to be collected.

Funding
This research received no specific grant from any funding agency in the public commercial, or not-for-profit sectors.

Ethical approval
Informed consent was obtained from the patient and it is available upon request.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.