RCC has been frequently described as a second cancer event following the diagnosis of other primary cancers.10 Although there have been reports relating to the increased risk of 2nd RCC in cancer survivors, there have been few studies that investigated how 2nd RCC were different from 1st RCC. Thus, our study compared the clinical features, diagnosis, treatment, and prognosis of 2nd and 1st RCC. To our knowledge, this study is the largest and most comprehensive profile of this clinical scenario.
In our study, the age at diagnosis of 2nd RCC was higher than that of 1st RCC (58.2 vs. 55.0 years, p = 0.008). Sato et al. reported that RCC patients with other primary malignancies were approximately five years older than those without.8 Other SPM have also shown similar results. Jo et al. reported that the age at diagnosis of 2nd pancreatic cancers was older than that of 1st pancreatic cancers.11 It is well known that the incidence of epithelial cancers generally increased with age.12 The age at diagnosis may differ because patients with first primary cancers have lived long enough to develop another primary cancer.
Previous studies have confirmed that smoking is a high-risk factor for RCC and multiple malignancies.7,13 In our study, it was found that the smoking rate of patients with 2nd RCC was higher than that of patients with 1st RCC. Previous studies have also found that continued smoking is considered the strongest adverse predictor among cancer survivors. Conversely, smoking cessation after the first cancer diagnosis prolongs the time before a new malignancy develops, as well as the total survival time.14,15 Therefore, smoking patients diagnosed with malignancies must quit smoking to reduce the risk of developing 2nd RCC and improve survival.
Obesity is also a risk factor for many malignancies. 16,17 Unlike smoking, this study found that there was no significant difference in the BMI of patients with 2nd RCC versus 1st RCC. This finding suggests that smoking is a higher risk of cancer than obesity. Whether weight loss can reduce the risk of SPM needs to be further explored.
Previous studies have reported that genetic factors are another important cause of multiple primary malignancies, which may be related to a variety of multi-system neoplasm syndromes or genetic susceptibility.3 In this study, we found that the proportion of patients with 2nd RCC who had a family history of cancer was higher than that of patients with 1st RCC. However, the difference was not significant (p = 0.068). This may be linked to the limited sample size of 2nd RCC in this study. Nevertheless, it still suggests that in cancer survivors with a family history of cancer, more attention should be paid to the development of 2nd RCC during follow-up.
Abdel-Rahman et al. found that the diagnosis of 2nd RCC usually occurs within 5 years after the first primary malignancy.10 In our study, 81.4% of 2nd RCC cases occurred within 5 years of the primary tumor diagnosis, which is consistent with previous studies. It is worth noting that synchronous 2nd RCC accounted for 61.9% in our study. The rate is higher than the 34.6% reported by Beisland but similar to the 59.4% reported by Sato.8,9 This result suggests that we need to carry out a systematic examination before the treatment of patients with RCC to prevent the risk of missing malignant tumors in other parts of the body. However, our study also found that 18.6% of 2nd RCC cases occurred 5 years after the first primary malignancies. Therefore, we speculated that there may be two peaks in the incidence of 2nd RCC, namely, within 6 months and 5 years after the initial diagnosis. This is similar to the timeframe reported by Czene and Hemminki.18 This suggests that long-term follow-up is needed after the treatment of malignancies to detect not only the recurrence and metastasis of primary malignancies but also the 2nd RCC.
Beisland et al. reported that the most common extrarenal malignancies in SPRCC included prostate, bladder, lung, breast, and colorectal cancers, malignant melanoma (MM), and non-Hodgkin's lymphoma (NHL).9 Liu et al. reported that the common types of extrarenal malignancies were lung, breast, prostate, bladder, thyroid, adrenal, and nervous system cancers, as well as melanoma and non-Hodgkin's lymphoma.19 A Japanese study showed that the most common extrarenal malignancies in 2nd RCC originated from the gastrointestinal tract, which may be related to the high incidence of gastrointestinal cancers in Japan.8 Our study found that the common types of extrarenal primary malignancies included lung, colorectal, breast, gynecological, thyroid, gastric, nasopharyngeal, and esophageal cancers. The different distributions in these reports may be closely related to the tumor spectrum in different regions.
The common symptoms of RCC are flank pain, visible hematuria, and palpable abdominal mass. With greater access to imaging examinations, more than 60% of patients are diagnosed incidentally.20 In our study, it was found that patients with 2nd RCC presented fewer symptoms, and the tumor size and postoperative pathological stage in patients with 2nd RCC were also significantly lower than those in patients with 1st RCC. Previous studies reported that 76.3% of patients with 2nd RCC had no obvious symptoms. In contrast, only 39.0% of patients with 1st RCC had no obvious symptoms. Moreover, the tumor size was smaller than 4 cm in 60.5% of patients with 2nd RCC, compared to 28.1% of patients with 1st RCC. These results are consistent with the findings in our study.8 Patients with other non-renal malignancies tend to receive more frequent imaging examinations, which contributes to the early detection of RCC. The fact that the proportion of partial nephrectomy in the patients with 2nd RCC was significantly higher than that in the patients with 1st RCC was also related to the smaller tumor size of the 2nd RCC.
Current guidelines recommend that renal surgery be performed in patients with localized RCC.20 However, when choosing the treatment method for renal tumors in patients with 2nd RCC, the condition of the extrarenal malignancies needs to be considered, including tumor stage, life expectancy, and treatment complications. The European Association of Urology Guidelines on RCC indicates that elderly and comorbid patients with incidentally detected small renal masses can be managed by active surveillance (AS).20 However, considering that the sporadic RCC has a high risk of metastasis, AS of sporadic RCC should only be adopted in patients who cannot tolerate surgery.21 A population-based study using the Surveillance, Epidemiology, and End Results (SEER)-9 database showed that local treatment modalities utilized with 2nd RCC were partial nephrectomy in 16% of patients, radical nephrectomy in 33% of patients, and ablation in 5.5% of patients, while 18% of patients received no local treatment.10 In our results, the proportion of patients with 2nd RCC who received surgical treatment was 95.6%, which was higher than that reported in previous studies. This may be due to most patients with extrarenal malignancies in our study being stage I/II, which led to more patients with 2nd RCC choosing curable surgical treatment for the renal tumors.
Patients with localized RCC generally have a long OS. However, due to the existence of non-renal malignancies, the survival time of 2nd RCC is quite different from that of 1st RCC. Beisland et al. found that the OS of patients with 2nd RCC was worse than that of patients with 1st RCC.9 Sato et al. showed that for patients with T1-2N0M0, the OS of patients with 2nd RCC was significantly worse than that of patients with 1st RCC.8 These results are consistent with those of the present study. However, if extrarenal malignancies are excluded, Sato et al. showed that the CSS of patients with 2nd RCC was significantly longer than that of patients with 1st RCC. In contrast, our study indicated that there was no significant difference in PFS and CSS between 2nd RCC and 1st RCC. A possible reason may be that 40.1% of patients with 1st RCC reported by Sato et al. were staged as T3/4, N1, or M1, while only 9.1% of patients with 1st RCC were staged as T3/4 or N1 in our study. These differences may have influenced the results of the two studies.
The prognostic factors of simple RCC include tumor stage, histopathological factors (such as nuclear grade, pathological type, sarcomatoid differentiation), and molecular markers.20 In our study, univariate and multivariate analyses showed that for patients with 1st RCC, the influencing factors of OS included symptoms and stage, which was consistent with previous studies. However, the prognostic factors for 2nd RCC are more complex. Previous studies of multiple primary malignancies showed relationships between OS and the type of first primary malignancies or the interval between the two primary cancers.4,22 In our study, univariate analysis showed that for 2nd RCC patients, OS was significantly correlated with the type of extrarenal malignancies and renal surgery, but there was no significant difference between OS and tumor interval, symptom, and stage. The prognosis of patients receiving renal surgery is better than that of patients without, and this may be related to the late-stage and poor prognosis of extrarenal malignancies, which leads to non-surgical treatment, resulting in a selection bias.
The present study has several limitations. First, this study is retrospective. Hence, recall errors are possible and may affect the results. Second, this study excluded metastatic RCC patients both in 2nd RCC group and 1st RCC group, thus, there may be a certain selection bias. Third, the follow-up time was relatively short, which may have affected the survival-related data analyses.