In this study, we investigated the outcomes and epidemiological changes of RCC diagnoses in a nationwide cohort spanning 50-years. We found that the incidence for the two morphological pRCC subtypes increased alongside an upward trend in survival, but unchanged mortality. Finally, although the survival rates of individual pRCC subtypes differed, the subtyping itself was not associated with worse CSS or OS after adjusting for nuclear grade, and TNM staging. Our results support prior findings on the impact of pRCC subtyping on survival and provide a more robust transferability due to our population detectability of cases [9,10,11,12,13,14,15].

PRCC had inferior survival to chRCC and more favorable survival than ccRCC, both of which has previously been reported in several studies, including from Iceland [5, 8, 25, 26]. Furthermore, type 2 pRCC patients had poorer 5-year OS and CSS than type 1 pRCC, which is also supported in previous studies [16, 27, 28]. A particularly positive finding is the positive association between CSS of pRCC and advanced calendar year. This development may have multiple explanations, including improved surgical techniques, such as minimal invasive approach replacing conventional open surgery [29]. However, the increase in the diagnosis of lower stage tumors, mainly due to an increase in incidental diagnoses, is probably a key contributor [30]. Finally, advances in the treatment for stage IV diseases with new targeted therapies may also have played a role, as reflected by the significantly improved survival of the stage IV disease [31, 32].

As in most RCC studies, the TNM stage of pRCC proved to be the strongest prognostic factor in multivariable analysis for both OS and CSS [33, 34]. This was also observed for Fuhrman grade 4, although that group only consisted of 5 patients. Several studies have reported nuclear grade as predictor for better outcome, including the more recent WHO/ISUP grading system [34,35,36,37]. However, in many of these studies, its significance in multivariable analysis diminishes after correcting for TNM stages [33].

Advanced age was an independent prognostic factor for both OS and CSS, which correlates to the findings of Ledezma et al. [11]. Importantly, when adjusting for age, gender, stage, grade, time period and type of diagnosis in the Cox multivariable analysis, the papillary subtype (type 1 or 2) did not predict either OS or CSS. Similar results have been reported previously [9,10,11,12, 15]. This was additionally supported by a meta-analysis of Yang et al., that did not find a difference in OS between pRCC subtypes, and the authors therefore concluded that grade and histology architecture should be used to predict OS rather than histological subtyping [12]. In contrast, Wong et al., with a cohort of 509 pRCC patients, found that pRCC subtyping was associated with better survival of type 1 pRCC tumors (HR: 8.2 p < 0.001) [16]. Importantly, this study did not include metastatic pRCC, which constituted 30.0% of type 2 pRCC and 8.7% of type 1 pRCC patients at diagnosis in the present study.

Papillary RCC constituted only 9.2% of RCCs in this study, which is a slightly higher ratio than in the SEER study (8.3%) (North American Surveillance, Epidemiology and End Results) by Saad et al. [38]. However, the proportion of pRCC in the SEER study, as well as the present study, is somewhat lower than reported in most epidemiologicalstudies, where it usually ranges from 10 to 15% [1, 2, 39]. The relatively low proportion of pRCC in Iceland may be explained by our nation-wide inclusion of cases. Although the SEER-study was not population based, it did include more than 100.000 patients with 8,730 pRCC cases [38]. Furthermore, pRCC has been shown to vary by race, with higher prevalence in black people, which represents a small percentage (< 1%) of the Icelandic population [40].

During the 50-year study period, the average ASI was 1.28 for the whole group; 1.97 and 0.60 per 100.000 males and females. This is in line with a study by Palumbo et al. that reported the ASI of 1.4/100.000 person years from 2001–2016 based on data from the SEER study [41]. Furthermore, they reported an average annual change in ASI of 4.9% for the whole group, 4.7% for males, and 5.4% for females during the periods 2001–2016, which is comparable to our results [41]. Another study from Saad et al. reported a steeper increase in incidence between 1992 and 2015 (9,1%), yet with a plateau from 2008 [38]. On the other hand, ASCSM in the present study did not change over the study period, which would imply that survival is improving, as ASI increased while mortality was unchanged.

The reasons for the increased ASI of pRCC is not fully understood, but similar trends have been observed for both ccRCC and chRCC. Known risk factors, such as obesity and rising age, may play a role, but a sharp rise in incidental detection due to more frequent use of abdominal imaging for unrelated disease has probably contributed to this change [42]. Another possibility is that the variable size criteria for the diagnosis of small, low grade, papillary tumors (5-15 mm), could also play a role [43, 44]. In addition, the prevalence of end stage kidney disease, which has shown a strong association to pRCC, has increased in the past decades [45, 46]. It should also be noted that the profile of risk factors has changed considerably in recent years, which limits inference. As an example, smoking has been eradicated in Iceland over the past decade, while obesity has increased to 25% of males and 27% of females, which must be regarded as high in European comparison [47, 48]. To the best of our knowledge, ASI and ASCSM have not been estimated for pRCC subtypes in a whole population, which also makes comparison with other studies more difficult.

Male sex was most common for all major histological RCC subtypes, which is in line with other studies, however, the proportion of males with type 1 pRCC was notably high [40, 49, 50]. Age, laterality, and tumor size were comparable between the pRCC subtypes. However, some studies have shown that type 1 pRCC is diagnosed at an earlier age than type 2, which influences tumor size at diagnosis [16]. Furthermore, bilateral pRCCs were only present in 2% of pRCC patients, although they have been described in up to 4% in the literature [51].

Patients with type 2 pRCC generally had more advanced TNM-stage and grade, and were significantly more likely than type 1 pRCC to have metastasis at diagnosis (30.0% for type 2 vs. 8.7% for type 1). This is a markedly higher proportion than reported by Pignot et al. (16.1% for type 2 vs. 4.4% for type 1) in a cohort of 130 pRCC patients [33]. However, their study only included patients that underwent surgery, while 11.2% of our cohort were notoperated on. Although, type 2 pRCC more often diagnosed on stage IV than type 1 pRCC tumors, when grades 1 and 2 were combined and compared to grades 3 and 4, there was a significant difference between the two pRCC subtypes, which is in line with the findings of other studies [33, 34].

The main strength of this study is the whole nation coverage of consecutive RCC cases. Similarly, we included both surgical and non-surgical patients. Another strength is that our access to centralized follow-up data allowed for robust OS and CSS estimations. Limitations include the retrospective nature of the study and small number of patients (n = 143) with pRCC subtypes. Finally, even though all 158 patients were included in our incidence and mortality analysis, 15 patients could not be subtyped and were therefore excluded from subtype comparisons.