The age standardized renal cancer incidence rate in Estonia is 11,7 and in Finland 7,9 \cite{Capitanio_2019}.
An increasing incidence of RC is paralleled by high mortality in Eastern Europe. According to one study that compared 39 different countries around the world, the highest mortality rates were reported in the Lithuania (4.9), Czech Republic (4.8), Latvia (4.7) and Estonia (4.6) (The age standardized mortality rate per 100 000 persons.)(\cite{countries}).
The drivers of the high and increasing incidence of RCin Eastern Europe are not clear. It is also unclear, why the incidence between Estonia and Finland differs.
Renal cancer is often asymptomatic for prolonged periods and literature has shown, that symptomatic presentation correlates with a histology of more aggressive subtype(s) and advanced disease \cite{Lee2002}(Lee 2002).
There are many RC types: renal cell cancer (the most common RC), Wilms tumor, urothelial cancer and renal sarcoma. Renal cell carcinomas (RCC) are divided into three major subtypes: clear-cell renal carcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma. There are also different less common histologically differentiated RCC forms (such as multilocular cystic RCC, collecting duct carcinoma, medullary carcinoma, mucinous tubular and spindle cell carcinoma, neuroblastoma-associated RCC), but these are rather uncommon\cite{Prasad_2006} Clear-cell renal carcinoma makes up to 90% of the RCC cases \cite{Ljungberg_2011}{Ljungberg2011}.
Clear-cell renal carcinomas and papillary renal cell carcinomas are seen as more aggressive types and chromophobe has so far been repoerted to be less aggressive
\cite{Leibovich2010} (Histological subtype is an independent predictor of outcome for patients with renal cell carcinoma.
Leibovich BC1,
Lohse CM,
Crispen PL,
Boorjian SA,
Thompson RH,
Cheville JC.
J Urol. 2010 Apr;183(4):1309-15.).
The 5-year overall survival for all types of RCC is 49% and it has improved since 2006 probably due to an early detection - increase in incidental findings of RC and improvements in systematic treatment options (\cite{pubmeda}).
Different subtypes of renal cancer have a different prognosis in their 5-year survival rate: the most common clear-cell renal carcinoma 5-year cancer specific survival rate is 71%, papillary 91% and chromophobe 88% \cite{Leibovich2010}(histological subtype is an independent predictor of outcome for patients with renal cell carcinoma. Leibovich BC1, Lohse CM, Crispen PL, Boorjian SA, Thompson RH, Blute ML, Cheville JC. J Urol. 2010 Apr;183(4):1309-15. ).
Data on the effect of RCC subtype and course of the disease is conflicting. Some studies have indicated worse survival outcomes for clear-cell RCC, there are not many large population based studies to prove it. So far there is one large population based study based on data of 10 000 patients documented the histologic type of RCC as an independent risk factor for RCC mortality (\cite{study}).
The Treatment
Renal cancer treatment is dependent upon the cancer stage at diagnosis. In the past three decades the world has seen a big shift in renal cancer stage at diagnosis. There has been a shift towards a lower stage at diagnosis (\cite{pubmedb}). The TNM stage in renal cancer takes in consideration the tumor size, lymph node involvement and possible growth into neighbouring organs or metastases. All of which play a major role in cancer specific survival (\cite{improvement}).
If the disease is localized, or only minimally advanced locally, the treatment of choice will be partial or total nephrectomy. Both methods have shown excellent improvement in survival \cite{pubmedc}). In most European countries the surgery is performed in a minimally invasive way- either laparoscopically or using robotic surgery (i.e the Da Vinci system.) The usage of laparoscopy has improved postoperative outcomes: the advantages of less blood loss, shorter hospital stay, decreased analgesic requirement and rapid recovery compared with open radical nephrectomy. Radiation therapy is not primarily used in RC treatment and is still very much under investigation in cases of non-operable RC \cite{pubmedd}). There is also the possibility to use ablation therapy, but the usage of this method is rather low and saved for patients who are in poor condition and therefore not candidates for surgical management. So far ablation therapy is not often used and data on the oncological outcomes longterm is poor (\cite{pubmede}).
As a third alternative care approach has been proposed - active surveillance – that, so far in RC it is usually reserved for patients with higher surgical risks such as patients who are older or have many comorbidities (\cite{pubmedf}). There is no recognized evidence based clinical guideline for of the active surveillance in RC , and it is clinically implemented for some cancer types, for example prostate cancer (\cite{pubmedg}). So far the data on active surveillance in renal cancer is limited, but promising. One of the largest prospective studies done by McIntosh enrolled 457 patients into an active surveillance program with a 5 year follow up and found it to be a safe choice for patients. the tumour growth rate and shape (cystic or solid in CT or MRT imaging) were used as outcome measures. Most interventions were done in the first 2-3 years of surveillance (\cite{McIntosh_2018}).
For advanced and metastasized renal cancer in some cases a cytoreductive nephrectomy is done, but in most cases a systematic therapy is indicated. As mentioned before the therapy chosen depends of the histology of RCC type. It can either be chemotherapy, immunotherapy or molecular-targeted therapy. Different RCC subtypes have react differently to immuno- and chemotherapy on a molecular level. For example monoclonal antibodies against VEGFR (vascular endothelial growth factor receptor) for example bevacizumab or tyrosine kinase inhibitors (sorafenib, sunitinib and pazopanib) can be used in clear cell renal carcinoma, where these specific proteins are highly unregulated (\cite{guideline}). (for the advanced… lõigu viide(.So far it is known that the second most common RCC subtype- papillary RCC is refractory to chemotherapy, immunotherapy and hormonal therapy. \cite{directions})
The main debate remains - on what is the best treatment option for only locally advanced RCC the same way? Some argue that we should be less aggressive in treating RCC’s depending upon their subtype and how this will influence the cancer specific survival for the patients. For example, patients with papillary and chromophobe pathology are less likely to present with T3 or greater disease then clear cell renal cancer (\cite{stage}).
Risk factors for RC
The development of renal cell cancer is multifactorial. Some risk factors such as obesity, hypertension and diabetes are well documented and linked to higher risk of RC by multiple systematic reviews (Systematic review of ...;\cite{pubmedh}) ).
Some risk factors on the other hand are still debatable such as renal calculi \cite{van2019}(Kidney stones and the...). A 2015 metanalysis demonstrated that renal calculi are associated with and increased risk of developing RCC, and upper urinary tract transitional cell carcinoma (the pooled risk ratio for RCC in patients with renal calculi 1,76 (95% CI, 1.24-2.49).Also, the history of kidney stones was associated with increased RCC risk only in males (RR, 1.41 [95% CI, 1.11-1.80]), but not in females (RR, 1.13 [95% CI, 0.86-1.49]).\cite{Cheungpasitporn2015}(Cheungpasitporn 2015). A case-cohort study from Netherlands documented an increased RCC risk among individuals with kidney stones (HR: 1.39, 95% CI 1.05–1.84, vs. no kidney stones) in patients withpapillary RCC but not clear-cell RCC (the latter is the most common histological subtype). \cite{van2019}\cite{van2019} It has been suggested, that the increased cancer risk associated with renal stones is due to the chronic inflammation and infections, which may lead to an altered proliferation in urothelial cells\cite{Chow_1997}. However, the role of renal calculi in developing renal cancer is still questioned. Renal cancer is often diagnosed incidentally as the patient recieves imaging due to other medical complaints. There is very little literature questioning if the link between RC and renal stones may just be a coincidental finding. Renal calculi can cause severe pain in the flank, nausea and vomiting and fevers. Leading the patient to seek medical help and therefore the incidental findings of RC that would otherwise not been detected. A study from Czech Republic, looking at the trends in RC incidence from 1980-2005 underlined the potential role of improved imaging factoring into the increasing incidence rates \cite{Ondrusova2011}((Trends in the kidney ...). This argument is supported by the fact that almost half the renal cancer cases are to be diagnosed as an incidental finding\cite{Jayson1998} (Jayson 1998), and the classical triad of renal cancer symptoms (flank pain, visible haematuria, palpable abdominal mass) is very rare finding nowadays (<10% of RC cases) \cite{Patard2003}(Patard 2003). Incidental tumors are more frequently detected in female and elderly patients, as these groups tend to seek medical care more regularly due to other medical issues \cite{Lee2002}(Lee 2002).
Estonia
Ultrasound became routinely used in Estonia in clinical practice in the early 1990s and computed tomography followed. In Estonian regional hospitals , the proportion of RC cases diagnosed by abdominal ultrasonography increased from 21% to 82% and abdominal computed tomography (CT) from zero to 11% from late 1980s to late 1990s\cite{Padrik_2006} (Padrik 2006).
Aims:
1) To study trends in kidney cancer incidence, mortality and survival in Estonia 1995-2014 with special focus on age, birth cohorts, morphology and TNM stage and offered treatment.
2)To assess the role of renal stones on RC incidence.
3) To study the effect of renal cancer histological type on RCC- cancer specific survival and mortality in Finland from 1995 to 2012.
Methods
Data sources:
Aim 1
1) Estonian Cancer Registry (ECR)
Data on all incident cases of kidney cancer (ICD-10 code C64), diagnosed in adults (age ≥15 years) in Estonia during 1995 − 2014, were obtained from the ECR, which is population-based, and covers the whole country.
2) Estonian Population Registry (EPR)
Follow-up for vital status from the date of diagnosis through 2014 was conducted by the ECR at the EPR using unique personal identification numbers. In case of death or emigration, the respective dates were obtained.
3) Causes of Death Registry (CDR)
Data on kidney cancer deaths were obtained from the CDR, and population denominator data from Statistics Estonia.
Methods: Relative survival ratios (RSR) were calculated as the ratio of the observed survival of cancer patients to the expected survival of the underlying population.
Age-specific and age-standardized (world) incidence (1970–2014) and mortality (1995–2016) rates were modeled, and the estimated annual percentage change (APC) and average annual percentage change (AAPC) with 95% confidence intervals (CI) calculated with Joinpoint Regression Program.
Data sources (aims 2 and 3):-
Finnish cancer registry, where we have collected the records of renal cancer cases from 1995 to 2012 based on the ICD code C64. The data of 13933 cases were included for this study. The Finnish cancer registry data registry includes date of cancer diagnosis, tumor extent (localized, contained diagnoses and procedures recorded at hospital contacts at Finnish health care units.
2) HILMO (Hoitoilmoitusjärjestelmä) (\cite{hilmo}).
HILMO is a nationwide social and health care data collection and reporting system in Finland. The HILMO data will be used to obtain data on (i) comorbidities (such as diabetes, heart disease, liver disease etc) to calculate the Charlston comorbidity rate; (ii) timing and the method of treatment such as partial or total nephrectomy. Surgical procedures were identified by procedure Nomesco codes; (iii) imaging used.
Finnish Cancer Registry data were linked to the HILMO information based on personal unique identification numbers.
Methods:
We will use a retrospective population based 10-year study in two cohorts: those with the gallbladder stones and those with the renal stones to assess the effect of renal calculi on RC incidence.
Gallstones cause similar symptoms (pain, nausea … prompting patients/doctors for imaging investigations), but so far no study ever has shown any linkage between gallstones and renal cancer.
Main outcome measure will be renal cancer incident case that will be compared in the two cohorts in the study.
For aim 3 We will use a retrospective study based on data from 1995 to 2012 and following two cohorts: those with the clear cell RC and those with other subtypes of RCC to assess the effect of RC survival. Data on potential confounders (age, gender, stage at diagnosis, comorbidities) will be collected for analysis.
The emphasis of this study is to find possible differences, if our treatment should be aimed differently for different histological renal cancer types.