The prognosis of ccRCC has significantly improved with the development of targeted therapy and immunotherapy [9]. However, CDC, as a rare type of renal non-ccRCC, still poses great challenges to oncologists because of its aggressiveness and poor therapeutic response. Here, we analyzed 74 patients with CDC from two high-volume centers in a span of 20 years. By comprehensively describing the clinical features, imaging findings, diagnosis and treatment courses, and pathological features of patients with CDC, we hereby provide a reference with a large sample study.
CDC is likely to present with clinical symptoms. In fact, about 65.2% of the patients had symptoms according to previous studies [10, 11]. The percentage of patients with symptoms in our study was 74.3%, which was significantly higher than that of patients with ccRCC [12]. This might be associated with the high aggressiveness and rapid progression of CDC. Patients with CDC likely presented with hematuria. Tokuda et al. reported that the incidence of hematuria in patients with CDC was 37.0% [11]. In our study, 29.7% of the patients had hematuria. The high incidence of hematuria may be related to the nature of CDC, which can easily invade the collecting system.
The incidence of venous tumor thrombus in RCC is 4% [13]. The occurrence of venous tumor thrombus is associated with the tumor size, stage, and grade. In addition, tumor thrombus is a predictor of poor outcomes [13]. However, the incidence of tumor thrombus in patients with CDC has not been previously reported. Here, we reported that 17.6% of CDC patients had a tumor thrombus. The higher incidence of tumor thrombus in CDC may be related to CDC’s aggressiveness, high nuclear grade, and advanced stage. In addition, the presence of a tumor thrombus greatly increases the difficulty of CDC surgery.
The clinical diagnosis of CDC mainly depends on imaging examinations, and CT is the most common method. On CT scan, CDC tumors are solitary, solid, and poorly defined. They have cystic components, calcifications, and lymph node metastases. In addition, they are centered in the medulla, which results in the compression of the renal pelvis [14]. The degree of enhancement of the lesion was lower than that in the normal renal cortex and medulla. This suggests that the tumor is atypical with a lack of blood supply [15]. The differential diagnoses for CDC included invasive transitional cell or squamous cell carcinoma of the renal collecting system, renal lymphoma, renal metastases, mesoblastic nephroma, renal medullary carcinoma, and bacterial pyelonephritis [15]. Around 61.1% of CDCs were reported to oppress or infiltrate the collecting systems, which was quite difficult to distinguish from UC involving the renal parenchyma [16]. In our study, as many as 10.8% of CDCs were misdiagnosed as UC radiologically. In addition, CDC might not necessarily show a renal mass on imaging. When the tumor infiltrated the entire renal parenchyma, it needed to be distinguished from benign diseases such as renal tuberculosis, pyelonephritis, or xanthogranuloma. Our study showed that three patients with CDC were misdiagnosed with tuberculosis on CT scan. Mathisekaran et al. presented a CDC patient with complaints of low-grade fever, loss of appetite, left loin pain, and dyspnea, which was masquerading as genitourinary tuberculosis. Finally, the patient was diagnosed with CDC after radical nephrectomy [17]. Because some patients with CDC also had symptoms such as fever and weight loss, the possibility of CDC should be considered in patients who were suspected of having renal tuberculosis, but in whom tuberculosis-related tests were negative or anti-tuberculosis treatment was ineffective.
Surgery is the main treatment for localized CDC. Tokuda et al. reported that 98.8% of the 81 CDC patients received surgical treatment, including radical nephrectomy (88.9%), partial nephrectomy (2.5%), and full-length nephroureterectomy (7.4%) [11]. In our study, 82.4% of patients underwent renal surgical procedures, including radical nephrectomy (66.2%), partial nephrectomy (2.7%), and full-length nephroureterectomy (12.2%). Despite its aggressiveness and poor therapeutic response, some patients with an earlier disease stage may have a better prognosis. Chao et al. reported that one patient with pT1N0M0 cancer remained disease-free at five years of follow-up after nephrectomy [18]. Peyromaure et al. reported that two patients without metastatic disease remained alive at 13 and 17 months after nephrectomy [19]. In our study, 10 patients achieved long-term disease-free survival, and the longest survival time was 147 months after surgery. However, most patients with CDC have lymph nodes and/or distant metastasis at presentation; therefore, radical surgeries in most patients are actuary cytoreductive nephrectomy (CNx). Whether CNx is beneficial for metastatic CDCs is currently controversial. In a SEER database study involving 62 mCDC patients, the cancer-specific survival of patients who received CNx was significantly better than that of patients who did not [20]. Another report from the National Cancer Database showed that the OS of CNx + chemotherapy was significantly longer than that of surgery or chemotherapy alone. However, there was no significant difference in survival between patients with CNx and those who received chemotherapy alone [8]. In addition, considering the advanced stage and venous tumor thrombus of the CDC, the perioperative risk of CNx is quite high. Méjean et al. reported 10 cases of CDC patients undergoing renal surgery, of which three patients died after surgery, and the median OS after surgery was 6 ± 8 months. Therefore, the authors did not recommend surgery alone for patients with mCDC [21]. Our study revealed that for metastatic CDC, whether to undergo CNx had no significant effect on survival time. However, due to the small sample size and selection bias in this study, future studies with larger sample sizes are needed to confirm the significance of CNx in patients with mCDC.
The biological behavior of CDC is similar to that of UC; therefore, the NCCN guidelines recommend chemotherapy as a treatment option for patients with mCDC [22]. In a multicenter prospective study, 23 patients with mCDC with no prior systemic chemotherapy were treated with gemcitabine plus cisplatin or carboplatin. They demonstrated an ORR of 26%, a median OS of 10.5 months, and a median progress free survival (PFS) of 7.1 months [3]. In another prospective, phase 2 trial, 26 mCDC patients with no prior systemic chemotherapy were treated with sorafenib combined with chemotherapy (gemcitabine plus cisplatin). The results showed that PFS and OS were 8.8 months and 12.5 months, respectively, with the ORR being 30.8% [4]. Moreover, Pécuchet et al. reported five previously untreated patients with mCDC who received bevacizumab in combination with gemcitabine and platinum salt with three cases of PR, one case of SD, and one case of complete remission after surgery of the only metastatic site [23]. In our study, 12 patients received chemotherapy (gemcitabine combined with cisplatin), with three patients achieving PR. This finding suggests that chemotherapy is a relatively effective treatment for mCDCs.
ICIs have become one of the main treatments for advanced RCC. However, their application in patients with CDC is mainly based on case reports [6, 7, 24, 25]. Mizutani et al. reported a case of mCDC treated with nivolumab after chemotherapy and targeted therapy, and the lung metastasis was completely relieved, while the lymph node metastasis remained stable [7]. Watanabe et al. reported that an mCDC patient was treated with nivolumab and ipilimumab after cytoreductive nephrectomy. This resulted in complete relief from lymph node metastasis [24]. In our study, 8 patients with mCDC were treated with ICIs alone or ICIs combined with chemotherapy/targeted therapy as first or second line of therapy. These treatment regimens resulted in good responses and the ORR achieved as high as 50%. Therefore, ICIs can be another treatment option for patients with mCDC.
For CDC patients, previous studies have shown that an American Society of Anesthesiologists (ASA) score of 3–4, tumor size greater than 7 cm, M1 stage, a Fuhrman grade of 3–4, and the presence of lymphovascular invasion independently predicted disease-specific mortality [26]. Wilson et al. reported that T stage ≥ T3, high nuclear grade, distant metastasis, surgical treatment, and surgery combined with chemotherapy/radiotherapy are prognostic factors for CDC [8]. Taguchi et al. described another independent negative prognostic marker, neutrophil/lymphocyte ratio, and stated that a ratio ≥ 4 was associated with poor CSS [27]. Our study showed that no lymph node metastasis, distant metastasis, earlier stage, sarcomatoid differentiation, and surgery predicted longer OS in patients.
The present study has several limitations. First, our series has all the limitations inherent to retrospective evaluations, such as susceptibility to recall bias and selection bias. Second, due to the long duration of the study, there was incomplete clinical data for several patients, and there was a high rate of patients lost to follow-up. Third, the decision-making of the treatment plan was often based on the patient's condition and general conditions, which might have caused selection bias in the treatment decision, resulting in differences in the condition of the group in the univariate analysis, thereby affecting the accuracy of the results.