Associations Between Presenting Symptoms, Clinicopathological Parameters, and Prognosis in a Contemporary Series of Patients With Renal Cell Carcinoma

Historically, more than 90% of patients with renal cell carcinoma (RCC) present with symptoms and advanced stage disease [1, 2, 3]. With the widespread use of routine cross-sectional abdominal imaging, however, the landscape of patients presenting with RCC has changed dramatically. Although the incidence of RCC increased initially [4], a migration toward asymptomatic and early stages was observed [4, 5], which ultimately led to better overall prognosis [6].

About 50% of patients present with symptoms related to a renal tumor [3, 5], which in turn leads to the initiation of imaging or consultation with a urologist. The presence of symptoms is associated with more advanced tumor stages, metastatic disease, and an inverse prognosis [3, 7, 8, 9]. Because this factor is available for all patients, it can be included in preoperative and postoperative prognostic assessment. It may therefore be relevant for urologists when planning therapy and surveillance. There are, however, few data on the proportion of asymptomatic or incidental and symptomatic cases among patients treated in the contemporary era of incidental renal tumors. Furthermore, the "incidentalness" of incidental tumors, i.e., the true indications and symptoms of these patients that led to imaging, are not well characterized. This may be significant for both urologists and nonurologic specialties.

The goals of this study were to assess the prevalence of presenting symptoms in a contemporary series and to evaluate associations with clinicopathological parameters and survival. Furthermore, with the identification of an increasing number of incidental renal tumors, we evaluated the true indications for imaging.

We analyzed associations between presenting symptoms, pathology, and survival in a contemporary series of 633 consecutive RCC patients. We confirmed that presenting symptoms are associated with pathology and RCC-specific survival. At our institution, about 70% of RCCs were diagnosed incidentally. In our cohort, a nonsignificant trend toward a better prognosis for patients without any symptoms than for those presenting with symptoms not related to RCC was noted.

It has been shown that presenting symptoms are prognostically relevant in patients with RCC. This relationship is mainly based on the association of RCC with T stage and M stage, which are considered the most powerful prognostic factors [8, 9]. Because the evidence suggests that the symptom classification adds prognostic information independent of these variables [3, 7], stage does not entirely explain the relationship between presenting symptoms and prognosis.

In past decades, the proportion of incidental renal tumors has increased continuously as a result of the widespread use of routine cross-sectional abdominal imaging. The majority of these patients present either without any symptoms or with symptoms not related to RCC. Whereas only 7% to 13% of all RCCs were found incidentally in the 1960s [11, 12], this proportion may now be as high as 80% [13]. However, there is considerable variability in recent research. For example, in the studies of Tsui et al. [14] and Sunela et al. [5], only 15% to 19% of renal tumors were diagnosed incidentally, whereas this proportion was 58% to 80% in other series [13, 15]. Several explanations for these differences may exist. First, definitions and classifications of symptoms are somewhat general and are not standardized. This is specifically true for pain, which is multifactorial and can be related to many pathologic states. Differing judgment of symptoms and signs may lead to different symptom classification and thus in part account for the differing proportions of patients presenting with incidental tumors. For the current study, definitions from Kim et al. [10] and Patard et al. [8] were used. These definitions were a proposal for standardization and were adapted by the majority of recent studies.

Classification of symptoms remains subjective, however, and studies on symptom prevalence are difficult to compare. In addition, different referral patterns from primary to tertiary care centers may contribute to differing proportions of incidental renal tumors. Finally, health care systems differ considerably between countries. Because ultrasound studies are frequently performed in Austria and many patients are screened by ultrasound during general health checkups or while being treated for other medical conditions, more tumors are discovered incidentally, although ultrasound screening is not recommended in an unselected cohort [16, 17].

The indications for imaging that have led to the detection of incidental renal tumors in contemporary series are not well documented. To our knowledge, only one such study has been published in the literature. Sand et al. [18] reported that 33% of incidental renal tumors were found during staging or follow-up of other malignant diseases. Another 20% of tumors were discovered on imaging conducted because of signs or symptoms unrelated to RCC. The authors subdivided incidental renal tumors into categories of true and unrelated. In their study, the definitions differed considerably from the standard classification by Patard et al. [8]. Sand et al. [18] defined true incidental renal tumors as those discovered in patients with a known preexisting medical condition under surveillance and unrelated as those associated with symptoms that could not be classified as classic symptoms from RCC. The definition of unrelated incidental renal tumors is almost identical to the S1b group in the present study. In contrast with the true incidental renal tumors [18], the S1a group in the present study also included patients who were totally asymptomatic. Thus, our cohort covered patients with incidental renal tumors that were found during a general health checkup. In contrast with the case in Austria, in Norway, routine imaging in healthy subjects or patients with other medical conditions is rarely performed [18], which may explain this difference.

Our study confirms that presenting symptoms are associated with clinicopathological variables and are prognostically relevant. The symptom classification was significantly associated with ECOG PS, T stage, N stage, M stage, and Fuhrman grade. Interestingly, in the subgroup analysis, we showed that Fuhrman grade was significantly lower in asymptomatic patients than in patients presenting with symptoms not related to disease (S1b). This relationship could bring new insights to our understanding of the role of tumor grade in presenting symptoms. In the Kaplan-Meier analysis, we found that patients with S1b tumors had worse survival than did those with S1a tumors, although this difference was not statistically significant. This may indicate that symptoms judged as not being related to RCC, such as abdominal pain and back pain, may have been in part due to RCC. Symptom classification was a significant prognostic factor in the univariate but not in the multivariate analysis, which is possibly due to the strong association between symptoms and the presence of metastatic disease. In all, the role of incidental detection as an independent prognostic factor is not clear and considerable disagreement exists in the literature [3, 8, 19, 20, 21].

We analyzed both symptom classification and ECOG PS. Although there was a very high intercorrelation between both variables (Table 3) that may have impacted the multivariate statistical analysis, the variables measure different aspects in particular patients. Whereas the ECOG scale is a general measure of PS, the symptom classification is directly related to the disease. One may have an impaired PS due to concomitant comorbidity such as coronary heart disease or other malignancies and may be diagnosed with an incidental tumor (S1) [8]. Furthermore, it is possible that symptoms leading to the diagnosis of RCC do not impact PS. Because the ECOG PS is a dynamic variable and we analyzed only the preoperative ECOG PS, further research in this field is necessary.

Our study had several limitations. First, the study had a retrospective design although the data were collected prospectively. There was no standard for postoperative surveillance, which may have impacted the outcome measure and subsequent statistical evaluation. Furthermore, several additional prognostic factors, such as tumor necrosis, were not assessed. It was a single-center series, which introduces selection bias. Moreover, it is likely that this study was underpowered to detect a significant difference in the univariate analysis between the S1a and S1b groups, because the numbers of included patients and events were low. Correspondingly, we found no significant difference between all symptom groups in the multivariate analysis, although recent data have confirmed symptoms to be an independent prognostic factor [7, 8, 9]. Further prospective studies are necessary.

This study confirms that presenting symptoms are associated with tumor characteristics and survival. Most RCCs are diagnosed incidentally without any symptoms or with symptoms not related to RCC. Patients in the latter group tend to have a worse prognosis than do patients who are completely asymptomatic. With an increasing number of incidentally diagnosed RCCs, substratification of patients with incidental tumors may be prognostically relevant.