ONCOLOGIC OUTCOMES BETWEEN ELECTIVE PARTIAL AND RADICAL NEPHRECTOMY IN PATIENTS WITH RENAL CELL CARCINOMA IN CT1B STADIUM

Background/Aim. In renal cell carcinoma (RCC) the choice of surgical technique, radical (RN) or partial nephrectomy (PN) is still centre dependant because there still are no absolute recommendations for this approach. This study aims to analyze the oncological aspects, time until recurrent disease appears and cancer-specific survival in patients with RCC in T1bN0М0 depending on the type of surgical procedure partial or radical nephrectomy. Methods. A clinical observational study of a series of cases was conducted that analyzed data of 154 patients operated in our institution with a mean follow up a period not less than five years. The inclusion criteria included: renal tumours 4-7 cm, histopathological confirmation of RCC, absence of metastasis and normal serum creatinine. Exclusion criteria included: the presence of other malignancies, solitary functional kidney or comorbidities that can compromise renal function, bilateral tumours or unilateral multiple tumours. Results. The study analyzed data of 154 patients, 97 radical nephrectomies and 57 patients that underwent partial nephrectomy. Analyzing cancer-specific survival in four patients with RN there was a disease advancement that led to a lethal outcome, one PN patient died as a result of local relapse and distant metastasis. Conclusion. Based on our results PN is a good and safe treatment option for patients with RCC in T1b stadium. Partial nephrectomy offers a similar tumour control and better cancer-specific survival.


Introduction
Renal cell carcinoma (RCC) presents the third most frequent urological malignancy, 2-3% of all adult malignancies and 80-85% of all primary renal carcinomas 1 . It is the most frequent solid renal tumour whose prevalence increases in Europe and North America 2 .
Worldwide over 350000 new cases of RCC have been diagnosed annually with over 140000 kidney cancer-related deaths (mortality rate around 40%). Therefore these patients represent a significant health issue 3,4 . In the European Union only just in 2012 84499 new cases of RCC have been diagnosed with 34700 cancer-related deaths 5 .
Surgical treatment is the usual management option for the patient with RCC.
Surgical resection is the standard treatment option in patients with localized RCC.
Historically, radical nephrectomy (RN) has been the benchmark surgical treatment of organ-confined RCC. Partial nephrectomy (PN) has taken over primacy in treatment of RCC up to 4 cm and in selected cases with tumours from 4 to 7 cm has proven to be as reliable as radical nephrectomy 6 , though now there are guidelines available that recommend that PN can be applied even in tumours that exceed 7 cm 7 . So far, a unified and definitive position on the role of PN in clinical-stage T1bN0M0 has not been proposed, when there is no absolute indication for this type of surgery. Most relevant studies specify from the oncological point of view, that PN is equally reliable as RN referring to"cancerfree survival" 8 . Also, the European Association of Urology (EAU) guideline from 2016 recommends that patients in T1a clinical stage should be treated with PN and applied whenever possible in patients in T1b clinical stage 9 .
This study aims to analyze the oncological aspects, as the time to tumour recurrence and CSS for patients with RCC in clinical-stage T1bN0M0 depending on the type of surgical treatment, partial or radical nephrectomy.

Materials and methods
The study was adopted as a case series clinical observational study and was conducted on patients that underwent surgical treatment in our institution for renal tumours with the histological confirmation of RCC as a result of partial or radical nephrectomy.
Patients were divided into two groups by the type of surgical resection: -Radical nephrectomy group and -Partial nephrectomy group.
Patients were recruited dependent on determining inclusion and exclusion criteria.
The two analyzed groups consisted of patients age from 18-80 years that underwent surgical treatment for renal tumours either by partial or radical nephrectomy in the period This imaging was performed not only in our institution but also in other medical institutions. In some instances, if the CT scan was inconclusive it was repeated in our institution. The contralateral kidney was defined as normal if the serum creatine level and CT scan were normal.
Following surgical treatment, the histopathological analysis was performed determining the tumour grade, vascular or lymphatic invasion, histopathological RCC subtype and histopathological TNM (Tumor-Nodes-Metastasis) stage.
Postoperative assessment of the patients was performed in an outpatient setting a month and then six months subsequently following the surgical treatment. All of them included physical examination, laboratory analysis, ultrasound of the abdomen and pelvis minor, chest x-ray and annually a multi-slice CT scan. Determining the presence of postoperative metastasis and local relapse involved ultrasound scan, chest x-ray and multislice CT scan. All of these examinations were performed by a radiologist.
Statistical data analysis vas performed by PASW Statistics version 18 statistical software. Chi-square test was used for statistical analysis between some categories and also Mann Whitney U test for assessing differences in the continual variables. p < 0.05 was considered statistically significant.
The principles of ICH Good Clinical Practice were strictly followed, and approval from the Ethics Committee of our institution was obtained.

Results
This study analysed data from 154 patients, 97 with radical nephrectomy and 57 with partial nephrectomy ( Table 1). The male/female ratio was nearly 3/1 (115 vs. 39, respectively). Also, males were more represented in both groups of patients, but the frequency was statistically more significant in the PN group compared to the RN group (87.7% vs. 67.0%, respectively). When comparing the age of the patients at the time of diagnosing RCC in the analyzed groups there is a statistically significant difference in the median age in the RN group (61.00 years) compared to the PN group where the median age was 55.00 (Mann-Whitney test; p = 0.027).
Regarding the histopathological characteristic of the tumours, initially, at the time of surgical treatment all patients were in clinical T1bN0M0 stage (Stage I). Table 2 presents the largest diameter of the tumour mass in the PN and RN group. Between the groups, there is a statistically significant difference (p < 0.001). In the RN group, the mean tumour diameter was 53.00 mm while in the PN group it was 43,00 mm. Considering the tumour localization in the RN group it was noted that in 37.1% of patients it was the upper pole and in 35.1% interpolar localisation (Table 2). In the PN group, the tumour was localized mostly in the lower pole of the kidney (43.8%). Evaluating the tumour localization no statistically significant difference in the RN and PN group was registered.
In over 80% of patients in both groups, the confirmed histopathological diagnosis was the clear -cell subtype of RCC.
More than 74% of patients in both groups were asymptomatic (Table 3). If present the most frequent symptom in both groups was pain, following by hematuria. Evaluating symptoms, no significant statistical difference was determined between the groups (p = 0.323).
Following surgical tumour resection, the pathohistological analysis was performed with defining the tumour grade. No statistically significant difference concerning the tumour grade between the RN and PN group was established (p = 0.670). The most frequent tumour grade in both of the groups was grade 2 and 3 (in over 95%) (Таble 4).
The lymphatic invasion was statistically significantly more frequent in the RN group in over 70% of the cases compared to the PN group where it was present in 50% of the cases.
The same was with vascular invasion with 75% of cases in the RN group, while in the PN group it wast present in 41.2% of cases.
However, considering the pathohistological stage or tumour size a statistically significant difference was established between the RN and PN group (p < 0.001). In the RN group, it was mostly the T1b and T3a stage while in the PN group it was T1a and T1b stage ( Table 5).
The overall surveillance period in the RN group was 2343 days (365-4297) while in the PN group it was 2175 days (868-4045). Evaluating the Clinical progression-free survival in patients with RCC had shown a low rate of tumour relapse (Table 6). From the overall number of patients in the RN group only in 6 patients, a relapse of the tumour was registered while in the PN group it was registered in two patients. The average time for relapse to occur in the RN group was 1470 days and 1142 days in the PN group. This has proven not to be statistically significant (Log Rank (Mantel-Cox) test; p = 0.436) ( Figure   1).
When analysing the cause of death in five patients the occurrence of tumour relapse was connected to the lethal outcome or the appearance of metastasis was related to causing death (Table 7). In all of the other patients, the leading cause of death was not related to the operated RCC but due to other comorbidities (cerebrovascular or cardiovascular).
When analysing the cancer-specific survival, or the mortality from RCC as the single cause of death we registered that in four patients lethal outcome was the result of metastasis, while one patient died because of local relapse and distant metastasis (Table 7 and Figure 2).

Discussion
Based on a global assessment of data from 167 countries in 2017, RCC was the seventh most frequent malignancy and represented 3.3% of all newly detected carcinomas 10 . Annually 338000 new cases of RCC were detected worldwide with an estimated increase of 22% till 2020 3 . Obesity, smoking and hypertension are known risk factors for RCC. With the global population ageing, there is also an increase in the prevalence of this malignancy 11 . RCC represents around 90-95% of all kidney tumours and at the time of diagnosis, 25-30% of patients have already metastatic disease 10 .
Surgical treatment of RCC is still the gold standard in the treatment of this malignancy 12,13 . In the early stages of RCC when the lesions are small and surgical resection is possible, several surgical modalities are available. In the previous decade, an offset occurred from radical nephrectomy towards the necessity of nephron-sparing techniques (partial nephrectomy). Preservation surgical techniques have as a goal to preserve renal function and at the same time to have identical oncological results as in radical nephrectomies 14,15 . Also when considering quality of life, renal function and overall survival the majority of studies agree that partial nephrectomy has a significant advantage over radical nephrectomy [16][17][18][19] . Also, an offset from open to laparoscopic and robot-assisted surgery occurred 20 . Now in the leading countries in the world partial nephrectomy is performed mostly laparoscopically or by robot-assisted techniques.
The classical triad of symptoms (flank pain, macroscopic haematuria and palpable mass) is present in around 6-10% of cases, but when present it rises a doubt on RCC 21 . In both of our groups, more than 74% of patients were asymptomatic. That is similar to the majority of studies that show that RCC has a devious development so in most cases it is incidentally detected 22,23 . The most frequent symptom in our study in both groups was abdominal pain in around 15% of patients. Haematuria was present in only 9 patients. This is explained by the fact that tumour was low grade and developed pain but not haematuria, anaemia and other symptoms.
Available literature has shown that tumour size has major significance and influences the patient's survival following tumour resection 24  They also showed that in 1712 patients the tumour recurrence more than 5 years was related to the mean size of the tumour of 60 mm, while the mean tumour diameter of 70 mm was related with the tumour recurrence period less than 5 years following the operation 25 . In tumours 40-70 mm in diameter, there is a probability that 6% of patients have already regional or distant metastasis at the time of diagnosis 26 . Results of these studies can have a role in the selecting of patients into subgroups, as a candidate for more aggressive treatment because of the probability of distant metastasis appearance or tumour recurrence following tumour resection.
Radical nephrectomy was performed in our patients with tumours mostly localized in the upper pole of the kidney and somewhat lesser in the interpolar region. Partial nephrectomy was performed in our patients with the tumour mostly localized in the lower pole of the kidney. An easier anatomical approach to the tumour localized at the lower pole can be the explanation why partial nephrectomy is mostly the treatment option in these cases and also why radical nephrectomy is more frequent in tumours that are localized in the upper pole or interpolar.
After tumour resection, by the protocol is followed by a pathohistological examination that determines the tumour tissue differentiation or tumour grade, vascular and lymphatic invasion, tumour histological subtype and TNM stage. Published studies have shown a direct connection between tumour size and its differentiation, so that increase of tumour diameter increases the volume of patients who have higher tumour grade 26 . The most frequent tumour grade in both of our groups was grade 2 and 3 in over 95% of cases.
In the RN group, the lymphatic invasion was significantly more frequent than in the PN group (70.1% vs. 50.0%). It is the same case with vascular invasion which is more frequent in the RN group (75.0%); than in the PN group 41.2%. The microvascular invasion is defined as the presence of malignant cells that invade the wall of the blood vessel or neoplastic emboluses in the intra-tumour blood vessels is present in 13.6-44.6% of RCC 27 . It s more frequent in higher grades of RCC and larger tumours. This is a significant prognostic factor, but the results in many studies are still controversial 28,29 .
In both of the analyzed groups, clear-cell RCC (ccRCC) was the most frequent histological subtype of RCC in over 82% of patients. Similar results have been presented in other published studies 18,26 because it is a known fact that ccRCC is the most commonly encountered histological subtype of RCC and is present in over 75% of patients, while the others are significantly less common 30 .
However, when analysing the pathohistological T stage a significant difference in patients in the RN and PN group was established. In the RN group, T1b and T3a stage was most common, while in the PN group it was T1a and T1b stage. Since one of the inclusion criteria to enter the study was that all of the patients should be in clinical T1b stage, in the RN group only in 44.8% of cases this stage had been confirmed, while in the PN group it was more present (57.9%). In the RN group, the rest of the patients had a lower or more commonly a higher stage. In the PN group mostly it was a lower stage present and only 5 patients had a higher stage. Data from published studies are similar concerning the difference in pre and post-operative stages 31 , with а established difference in T and N stage around 35%. Most commonly an error was made in measuring the size of the tumour in 92% of the cases and the assessment of local tumour invasion of perirenal fat. The N stage was assessed adequately in 94% of patients. However, Multislice CT scan still represents the best method for identifying and preoperative stage assessment of RCC. The major limitation is in assessing the tumour size and local expansion in suspected borderline cases 31 .
The ipsilateral adrenal gland in the PN group during tumour resection was left intact while in the RN group was removed in nearly 60% of the patients. When removed, in nearly all of the cases, had no tumour involvement except in two patients in the RN group.
Antonelli et al. analyzing data in 1179 patients with RCC showed that preservation of the ipsilateral adrenal gland is recommended only in patients with tumours smaller than 4 cm 32 . Or that local expansion and the size of RCC, are the best risk predictors of the presence of metastasis in the adrenal gland. Similar results presented Siemer et al. and also emphasized that the tumour diameter of 4 cm is crucial for the decision to perform ipsilateral adrenalectomy or not 33 . The incidence of diagnosing metastasis in the adrenal gland is significantly higher in autopsy studies (6-29%) compared to clinical diagnosis, 2-10% [33][34][35][36] . Involvement of the ipsilateral adrenal gland is present 19% in autopsies and 5.5% in urology studies, while even up to 11% involvement of the contralateral adrenal gland is reported 37 . Also, it is relevant to take into consideration the possibility of metastasis in other organs, for the example thyroid gland, lungs, bone metastasis or other locations because they are common especially in higher stages 23  When analysing the cancer-specific survival, our study has shown that RCC was the cause of death in 4 patients in the RN group where metastasis led directly to a lethal outcome while in the PN group this was the cause of death in one patient. Our study showed significantly better results than other studies. Jang et al. in their study didn't establish a significant difference in the 10-year cancer-specific survival in RCC patients with partial and radical nephrectomies (85.7% vs. 84.4%) 18 . Similar conclusions were made by other authors who didn't prove the advantage of partial nephrectomy to radical nephrectomy based on cancer-specific survival 8,39,40 . However, a recent study showed a major difference in the cancer-specific survival rate between partial and radical laparoscopic nephrectomies where the overall survival, cancer-specific survival and metastasis-free survival were significantly better in the partial nephrectomy patients 41 . In comparison with the RN group, patients of the PN group had a 1.9-fold overall survival, 2.9-fold cancer-specific survival and 2.3-fold metastasis-free survival 41 .
In the PN group, both relapses were local. In the first patient, the reoperation was performed 5 years after the partial nephrectomy where the initial tumour was 47x45 mm in diameter localized at the lower pole. The recurrent tumour was 36mm localized at the site of the previous resection. This was the only partial nephrectomy patient in whom the resection margin was positive. This patient is alive, without tumour recurrence. In the other patient, the tumour at the time of resection was 50x45 mm in diameter localized in the interpolar region of the left kidney in pT3a stage, with vascular and lymphatic invasion. In less than a year he developed local tumour relapse and after nephrectomy, also less than a year developed metastatic disease and shortly died. In the RN group, no local relapse was detected but the patients developed distant pulmonary and cerebral metastasis. In a systematic review and meta-analysis of comparative studies that involved 21 studies with over 11000 patients included, concluded that partial nephrectomy is a sustainable treatment option for large renal tumours because it provides acceptable surgical morbidity, equivalent cancer control and better preservation of renal function compared to radical nephrectomy with a potential for better overall survival of patients 42 .

Conclusion
Radical and partial nephrectomies are benchmark methods in the treatment of localized RCC. However, partial nephrectomy is a preservation method that preserves the renal parenchyma, so partial nephrectomy vs. radical nephrectomy provides better postoperative renal function. The results of our study strongly suggest that in patients in clinical stage T1b, partial nephrectomy provides the same cancer control as radical nephrectomy. Taking this into consideration, when planning surgical treatment in this clinical-stage, elective partial nephrectomy presents the standard treatment option and must be offered to the patient as an option.