Variation of inflammatory indexes in patients with chronic abacterial prostatitis treated with an herbal compound/extract

Summary

Introduction: Inflammation is a highly prevalent finding in the prostate Men with inflammation have higher IPSS score and increased prostate size For men with prostatic inflammation, there is a significantly increased risk of developing acute urinary retention and the need of a surgical approach to the disease Some laboratory tests (i e fibrinogen, C-reactive protein), can play a role in identifying patients at greatest risk of complications and adverse outcomes after surgery There have been several experiences exploring the role of nutraceutical approach to the prostate inflammation Aim of our study were to describe the variation in symptoms and inflammatory indexes in men affected by chronic abacterial prostatitis, treated with an herbal extract containing Curcuma Longa 500 mg, Boswellia 300 mg, Urtica dioica 240 mg, Pinus pinaster 200 mg and glycine max 70 mg

Materials and methods: A prospective multicenter study was conducted from February 2021 and March 2022 One hundred patients, with a diagnosis of Chronic Prostatitis were enrolled in a multicentric phase III observational study They were treated with the herbal extract, one capsule per day, for 60 days. No placebo arm was included In each patient, inflammatory indexes, PSA, prostate volume, IIEF-5, PUF, uroflowmetry (Qmax), IPSS-QoL, NIH-CPPS were registered and statistically compared at baseline and at the follow up visit.

Results: The variation obtained on the inflammation indexes showed a global improvement after treatment, including the PSA reduction We also recorded a significant improvement on IPSS-QoL, NIH-CPPS, PUF and Qmax scores

Conclusions: The herbal extract considered in our study may represent a promising and safe therapeutic agent leading to a reduction of inflammation markers, and could be used in the treatment of prostatitis and benign prostatic hyperplasia

KEY WORDS: Nutraceuticals; Inflammation; Inflammatory indexes; PSA

Submitted 1 May 2023; Accepted 11 May 2023

Introduction

In recent years many authors highlighted the central role of inflammation in the pathogenesis of urological diseases In particular, in patients with some neoplastic diseases, it has been shown that the presence of locoregional chronic inflammation is involved in carcinogenesis (1, 2) In the field of prostate diseases, recent studies have shown that patients with chronic inflammation of the prostate are at greater risk of more severe voiding symptoms, acute urinary retention and prostate surgery (3, 4) The gold standard for the diagnosis of tissue inflammation is represented by histological examination of tissue specimen A biopsy cannot always be performed for both ethical and procedural issues (5) For this reason, in recent years, several studies attempted to identify a serological marker of inflammation for the various neoplastic and benign urological pathologies (6) However, most of the markers used at preclinical and in vitro levels have poor diagnostic specificity, significant variability over time or high costs

In recent years, several authors have shown how some laboratory tests (Complete Blood Count/CBC, albumin, fibrinogen, C-protein reactive/PCR and procalcitonin/PCT), that are routinely performed in preparation for various urological surgeries, can play a role in identifying patients at greatest risk of complications and adverse outcomes after surgery (7) In particular, these markers can be considered as proxies of inflammation of the organism and are related to an increased risk of mortality in numerous diseases

The role of these inflammation markers in urology is still unclear today and the scientific evidence comes mainly from retrospective studies (8) There is currently no consensus on the pharmacological management of inflammatory prostatic diseases in a unique way

Nonsteroidal anti-inflammatory drugs (NSAIDs) are typically prescribed together with antibiotics without clear evidence The use of herbal remedies is very common, but the clinical evidence remains scarce (9) Above all, it remains unclear whether the use of such preparations can affect the reduction of the inflammatory state inferred on blood chemistry tests The primary purpose of this multicenter study is to describe the variation in subjective, objective and biochemical inflammatory indexes in men affected by chronic abacterial prostatitis, treated with herbal extracts, containing Curcuma Longa 500 mg, Boswellia 300 mg, Urtica dioica 240 mg, Pinus pinaster 200 mg and glycine max 70 mg, for each administration, as described in the manufacturer’s instructions (Naturneed, Macerata, Italy)

Materials And Methods

From February 2021 and March 2022, all 100 consecutive patients, with prostatitis-like symptoms (10) attending each one of participating urologic centers, were enrolled in a multicentric phase III observational study The patients were treated with an herbal extract, containing Curcuma Longa 500 mg, Boswellia 300 mg, Urtica dioica 240 mg, Pinus pinaster 200 mg and glycine max 70 mg (PROSTAFLOG®), taking one capsule at bedtime every 24h for 60 days No placebo arm was included The demographic characteristics were studied using descriptive analysis tables and the calculation on the sample size has not been determined because the sample will be a "convenience sample" Inclusion criteria were: age more than 18 years, diagnosis of diagnosis of chronic abacterial prostatitis, any prostatic volume, Qmax between 11 and 25, post voiding volume < 50 ml Exclusion criteria were patient under 18 years old, history of neurological or psychiatric disorders which may impair evaluation of urinary symptoms, patients with urethral stricture or history of bladder or prostatic cancer or concomitant bladder stones, previous pelvic radiation therapy, inability to assess urinary symptoms, chronic opioid or opioid derivatives (for any reason) or cortisone therapy, alpha blockers or 5-alpha-reductase therapies, phosphodiesterase-5 inhibitors (PDE5i) or NSAIDs assumption during the study period, intolerance/allergies to the ingredients of the herbal extracts After the diagnosis of chronic prostatitis, all patients who met the inclusion criteria signed a written informed consent and underwent baseline questionnaires: Inter national Prostatic Symptoms Score-Quality of Life (IPSS-QoL), National Institutes of Health

Chronic Prostatitis Symptom Index (NIH-CPSI), P e l v i c P a i n a n d U rg e n c y / F re q u e n c y ( P U F )

Patient Symptom Scale, International Index of Erectile Function-5 (IIEF-5) (11, 14) A urological examination using the expressed prostatic secrete (EPS) culture or seminal fluid culture and a prostatic transrectal ultrasound (TRUS) were performed Uroflowmetry, CBC, inflamm a t i o n i n d i c e s ( e r y t h ro c y t e s e d i m e n t a t i o n rate/ESR; PCR; prothrombin time/PT; partial thromboplastin time/PTT; fibrinogen; PSA) were tested The first follow-up visit was scheduled at 2 months from starting therapy, with a urol o g i c a l a n d m i c ro b i o l o g i c a l e x a m i n a t i o n , questionnaire collection, transrectal ultrasound (TRUS), Treatment Benefit Scale (TBS) questionnaire compilation (15)

The softwares used for statistical analyses were Excel 2019, StatPlus Pro 7 6 5 (Med Calc to confirm) Mean, standard deviation, median, differences were calculated for the quantitative variables interquartile

The scores obtained in the responses to the IPSS, NIH CPSI, PUF and IIEF 5 questionnaires were assimilated to variables quantitative, but IPSS and IIEF 5 were also evaluated b a s e d o n t h e f re q u e n c y d i s t r i b u t i o n f o r expected score ranges, which is perhaps a more correct way of considering them, since there is a division into interpretation classes

For the QOL questionnaire, the frequency distributions recorded in the baseline versus follow up visit were evaluated, for the 5 scheduled answers For TBS, the distribution of frequencies recorded in each of the 4 responses was equally evaluated as provided in the questionnaire For each quantitative variable examined, the normality of the distribution of data was preliminarily evaluated, using Shapiro Wilk's test In case of confirmed H0 and of normal distribution, parametric tests were used in the evaluation of the statistical significance of the differences between the different variables at baseline and after follow up (ANOVA within subjects) In case of data non-normally distributed, the evaluation of the differences between the variables (baseline vs follow-up) was performed using nonparametric tests (Wilcoxon Signed Rank Test) The differences between the frequency distributions were evaluated by Pearson's Chi-square test

Results

One hundred patients were included in the study The main characteristics were: mean age 52 1 ± 12 0 yeras, mean Body Mass Index 25 5 ± 2 8 Essential systemic arterial hypertension, dyslipidemia and diabetes mellitus occurred in 37%, 37% and 13%, respectively

The changes in baseline vs follow up clinical and biochemical variables were reported in Table 1 and 2 These changes between visit 1 and visit 2 were significant for prostate volume, Qmax and for all the questionnaires but the IIEF score variation which showed was not significant (Table 1) The TBS score revealed an interesting improve- ment of perceived clinical status At follow up visit, the patients declared an improvement (great also) in 76% of cases No changes were declared in 22% and a worsened situation only in 2% (Figure 1) For the IIEF-5 questionnaire the differences are not significant both if we evaluate the scores or if we consider it a quantitative variable dividing the patients into categories based on the score intervals (Figure 2a, b) The variation obtained on the biochemical inflammation indexes was reported in Table 2, showing a global improvement of all parameters at follow-up visit, including a significant reduction in PSA as proxy of inflammatory status

Discussion

Inflammation is a highly prevalent finding in the prostate, both at histological and biochemical level Men with inflammation have higher IPSS scores and increased prostate size, even if these differences appear to be imperceptibly small For men with prostatic inflammation, there is a significantly increased risk of developing acute urinary retention and the need of a surgical approach to the disease (4) In recent years, several authors have shown how some laboratory tests (CBC, albumin, ESR, fibrinogen, PCR) that are routinely performed in preparation for various urological surgeries can play a role in identifying patients at greatest risk of complications and adverse outcomes after surgery (6) The effects of systemic inflammatory conditions, most notably metabolic syndrome, and their role in lower urinary tract symptoms (LUTS) have also been examined When the data are examined at a clinically relevant level, we must take into high consideration that inflammation is a common process in the prostate and that the clinically significant impact of ingland inflammation is variable and difficult to define For a long time, we know that the location of inflammation is important and that there are subsets of inflammation that are more frequently associated with the development of urinary symptoms or the prostate growth (16) In recent years, there was several experiences exploring the role of nutraceutical approach to the prostate inflammation In particular, Cai and co-workers (17) evaluated the efficacy of a combination of soyabean extracts associated with Curcuma Longa, Boswellia, Pinus pinaster and Urtica dioica ( P R O S TA F L O G ® ) i n p a t i e n t s a ff e c t e d b y C P / C P P S , through the evaluation of interleukin-8 (IL-8) plasma seminal levels All patients diagnosed with CP/CPPS, attending the same urologic center, were enrolled in this randomized, controlled phase III study Participants were randomized to receive oral capsules of PROSTAFLOG® (two capsules at bedtime every 24 h) or Ibuprofen 600 mg (1 tablet daily), lasting for a period of four weeks NIHCPSI and SF-36 questionnaires in association with urological evaluations with TRUS, Meares-Stamey test, and IL-8 dosage in seminal plasma were performed at baseline and at 3 months follow-up A total of 77 patients were enrolled [PROSTAFLOG® (n = 39); ibuprofen (n = 38)] in t h e s t u d y a n d f o l l o w e d f o r 3 m o n t h s I n t h e PROSTAFLOG® series, 69 2% of patients showed a significant reduction in the NIH-CPSI score, compared with 34 2% in the ibuprofen group (p < 0 0001) The mean IL8 levels were significantly lower in the PROSTAFLOG® cohort compared with the ibuprofen series (p < 0 0001), while a significant reduction in the IL-8 level between the e n ro l l m e n t a n d l a s t f o l l o w - u p e v a l u a t i o n w a s a l s o observed in this group (p < 0 0001) Additionally, a significant reduction in the volume of the seminal vesicles assessed by TRUS was also found in the PROSTAFLOG® series during the observational timeframe The Authors concluded that PROSTAFLOG® significantly improves the QoL in patients affected by CP/CPPS and provides a significant reduction in IL-8 seminal levels as the overall seminal vesicles volume In our present study, the same observation in terms of QoL improvement was made (Figure 3) Especially in case of moderate QoL alteration, patients declared a positive impact from therapy on symptoms These data are confirmed at the follow up evaluation with TBS questionnaire The 20% of population studied reported a great improvement after treatment The rate moves to 76%

Considering Improvement To Any Extent

The statistically significant amelioration recorded at the follow-up visit after two months of therapy in IPSS, NIH CPPS and PUF scores (Figures 4a-b, 5, 6) confirms how the control of prostatic inflammation is correlated closely with a better perception of urinary symptoms characteristic of chronic prostatitis The IIEF-5 scores registered before treatment did not improve This finding could be related to the markedly multifactorial nature of the etiology of erectile dysfunction (ED) Given the age of the patients enrolled and the presence of known risk factors for ED, such as systemic hypertension and diabetes mellitus, the lack of improvement after treatment is not surprising as the therapy is aimed at the management of the prostatic inflammatory process which is only one of the possible causative factors of ED Considering inflammation indicators, we preferred to investigate laboratory tests more accessible in daily clinical practice than seminal IL-8 levels The routinely determined markers of inflammation showed a statistically significative improvement between the first visit and the visit performed at the follow-up This clearly depends on prostatic inflammation etiology and confirm the anti-inflammatory role of the nutraceutical product The first experience with PROSTAFLOG® was by Fabiani et al. (18) They described their real-life experience with this anti-inflammatory mixture on PSA levels and, in a prospective mono-institutional study of 50 patients, admitted for a first PSA raising, reported a lowered PSA value in 80% of cases, with a mean of reduction of 2 94 ng/ml (0 26-16 2 ng/ml) in one month therapy (two pill per day) No differences were reported in term of prostate volume variation They concluded that PROSTAFLOG® use was able to lower the value of PSA, inviting to evaluate in appropriate studies the nutraceuticals products use in the treatment of prostatic pathology In our present experience, we can confirm the lowering effect on PSA value by the PROSTAFLOG® administration After 60 days of treatment, with one pill per day, we observed, at followup visit, a mean PSA levels of 2 74 ng/ml, starting from a 4 63 ng/ml mean value (Figure 7) Moreover, in our results, we reported a statistically significant reduction on prostate volume (38 01 ml vs 35 86 ml), presumably linked to the anti-inflammatory effect of prolonged administration (Figure 8) From a functional point of view, we found a significant improvement on flow parameters (Figure 9) The Qmax registered at the enrollment visit was significantly increased after PROSTAFLOG® treatment This is evidently the effect induced by the reduction of the static and dynamic factors which underlie the typical symptoms of BPH (9)

Conclusions

PROSTAFLOG® treatment employed in case of chronic prostatitis may significantly increase QoL, providing a sig- nificant improvement of symptomatic scores A critical reduction in PSA level may be eventually take into account in clinical decision making PROSTAFLOG® may represent a promising and safe therapeutic agent leading to a reduction of inflammation markers, able to interrupt the pathophysiological mechanism of benign prostatic hyperplasia

References

1 Lloyd GL, Marks JM, Ricke WA Benign Prostatic Hyperplasia and Lower Urinary Tract Symptoms: What Is the Role and Significance of Inflammation? Curr Urol Rep 2019; 20:54

2 Vasavada SR, Dobbs RW, Kajdacsy-Balla AA, et al Inflammation on Prostate Needle Biopsy is Associated with Lower Prostate Cancer Risk: A Meta-Analysis J Urol 2018; 199:1174-1181

3 De Nunzio C, Voglino O, Cicione A, et al Ultrasound prostate parameters as predictors of successful trial without catheter after acute urinary retention in patients ongoing medical treatment for b e n i g n p ro s t a t i c h y p e r p l a s i a : a p ro s p e c t i v e m u l t i c e n t e r s t u d y Minerva Urol Nephrol 2021; 73:625-630

4 Gandaglia G, Briganti A, Gontero P, et al The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH) BJU Int 2013; 112:432-41

5 Vela-Navarrete R, Alcaraz A, Rodríguez-Antolín A, et al Efficacy and safety of a hexanic extract of Serenoa repens (Permixon®) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH): systematic review and metaanalysis of randomised controlled trials and observational studies BJU Int 2018; 122:1049-1065

6 Wang Q, Zhu SR, Huang XP, et al Prognostic value of systemic immune-inflammation index in patients with urinary system cancers: a meta-analysis Eur Rev Med Pharmacol Sci 2021; 25:1302-1310

7 Alazawi W, Pirmadjid N, Lahiri R, Bhattacharya S Inflammatory and Immune Responses to Surgery and Their Clinical Impact Ann Surg 2016; 264:73-80

8 Paulis G Inflammatory mechanisms and oxidative stress in prostatitis: the possible role of antioxidant therapy Res Rep Urol 2018; 10:75-87

9 Cicero AFG, Allkanjari O, Busetto GM, et al Nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer Arch Ital Urol Androl 2019; 91

10 Krieger JN, Nyberg L Jr, Nickel JC NIH consensus definition and classification of prostatitis JAMA 1999 Jul; 282:236-7

11 Hopland-Nechita FV, Andersen JR, Beisland C IPSS "bother

Correspondence

Luca Cindolo, MD, PhD lucacindolo@virgilio it

Daniele Vitelli, MD doc vitelli@gmail com

Filippo Cianci, MD filippocianci3p@hotmail com

Lorenzo Gatti, MD dottor102@gmail com

Nicola Ghidini, MD info@nicolaghidini it

Nikolas Niek Ntep, MD nicolas22it@yahoo fr

Rosario Calarco Piazza, MD iaiiopiazza@gmail com

Giovanni Ferrari, MD giogioferrari@yahoo it

Cure Group, Hesperia Hospital, Modena, Italy

Andrea Fabiani, MD (Corresponding Author) andreadoc1@libero it

Surgery Dpt, Section of Urology ASUR Marche Area Vasta 3, Macerata Hospital, Italy Via Santa Lucia, 2; 62100 Macerata (Italy)

Alessandra Filosa, MD PhD alessandrafilosa@yahoo it

Pathology Unit, ASUR MARCHE Area Vasta 5, Ascoli Piceno (Italy) question" score predicts health-related quality of life better than total IPSS score World J Urol 2022; 40:765-772

12 Giubilei G, Mondaini N, Crisci A, et al The Italian version of the National Institutes of Health Chronic Prostatitis Symptom Index Eur Urol 2005; 47:805-11

13 Brewer ME, White WM, Klein FA, et al Validity of Pelvic Pain, Urgency, and Frequency questionnaire in patients with interstitial cystitis/painful bladder syndrome Urology 2007; 70:646-9

14 Rosen RC, Cappelleri JC, Smith MD, et al Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction Int J Impot Res 199; 11:319-26

15 Viktrup L, Hayes RP, Wang P, Shen W Construct validation of patient global impression of severity (PGI-S) and improvement (PGII) questionnaires in the treatment of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia BMC Urol 2012; 12:30

16 Kohnen PW, Drach GW Patterns of inflammation in prostatic hyperplasia: a histologic and bacteriologic study J Urol 1979; 121:755-60

17 Cai T, Anceschi U, Tamanini I, et al Soybean Extracts (Glycine Max) with Curcuma, Boswellia, Pinus and Urtica Are Able to Improve Quality of Life in Patients Affected by CP/CPPS: Is the ProInflammatory Cytokine IL-8 Level Decreasing the Physiopathological Link? Uro 2022; 2:40-48 https://doi org/10 3390/ uro2010006

18 Fabiani A, Morosetti C, Filosa A, et al Effect on prostatic specific antigen by a short time treatment with a Curcuma extract: A real life experience and implications for prostate biopsy Arch Ital Urol Androl 2018; 90:107-111

Conflict of interest: The authors declare no potential conflict of interest

Oncological outcomes of papillary versus clear cell renal cell carcinoma in pT1 and pT2 stage: Results from a contemporary Turkish patient cohort

Taha Cetin 1 , Serdar Celik 1 , Sinan Sozen 2 , Bulent Akdogan 3 , Volkan Izol 4 , Guven Aslan 5 , Evren Suer 6 , Yildirim Bayazit 4 , Nihat Karakoyunlu 7 , Haluk Ozen 3 , Sumer Baltaci 6 , Fatih Gokalp 8 , Ilker Tinay 9 ,

Members of Turkish Urooncology Association

1 Izmir Bozyaka Research and Training Hospital Urology Department, Izmir, Türkiye;

2 Gazi University Faculty of Medicine Urology Department, Ankara, Türkiye;

3 Hacettepe University Faculty of Medicine Urology Department, Ankara, Türkiye;

4 Cukurova University Faculty of Medicine Urology Department, Adana, Türkiye;

5 Dokuz Eylul University Faculty of Medicine Urology Department, Izmir, Türkiye;

6 Ankara University Faculty of Medicine Urology Department, Ankara, Türkiye;

7 University of Health Sciences Dıskapi Yildirim Beyazit Research and Training Hospital Urology Department, Ankara, Türkiye;

8 Mustafa Kemal University Tayfur Ata Sokmen Medicine Faculty Urology Department, Hatay, Türkiye;

9 Marmara University Faculty of Medicine Urology Department, Istanbul, Türkiye

Summary

Objectives: To compare overall survival (OS), recurrence free survival (RFS), and cancer-specific survival (CSS) in the long-term follow-up of T1 and T2 clear-cell-Renal Cell Carcinoma (ccRCC) and papillary Renal Cell Carcinoma (pRCC) patients, as well as to determine the risk factors for recurrence and overall mortality.

Material and method: Data of patients with kidney tumors obtained from the Urologic Cancer Database - Kidney (UroCaD-K) of Turkish Urooncology Association (TUOA) were evaluated retrospectively. Out of them, patients who had pathological T1-T2 ccRCC and pRCC were included in the study

According to the two histological subtype, recurrence and mortality status, RFS, OS and CSS data were analyzed

Results: RFS, OS and CSS of pRCC and ccRCC were found to be similar Radiological local invasion was shown to be a risk factor for recurrence in pRCC, and age was the only independent factor affecting overall mortality

Conclusions: There were no differences in survivals (RFS, OS and CSS) of patients with localized papillary and clear cell RCC. While age was the only factor affecting overall mortality, radiological local invasion was a risk factor for recurrence in papillary RCC.

KEY WORDS: Kidney cancer; Renal cell carcinoma; Clear cell RCC; Papillary type RCC; Recurrence, Survival

Submitted 26 January 2023; Accepted 17 February 2023

Introduction

Almost twenty years ago the Heidelberg classification system recognized the histological subtypes of Renal Cell Carcinoma (RCC) as clear cell (cc)-RCC, with a frequency of 70-88% in most series, papillary (p)-RCC accounting for 10-15% and other RCC accounting for less than 10% (1, 2) Several studies have uniformly reported that a pRCC histology is associated with a favorable prognosis compared with clear cell RCC (ccRCC) (3-6) In other studies, pRCC was a significant risk factor (7, 8) However, the results of multivariable analyses assessing the prognostic significance of type2 pRCC histological subtype are incoherent (9, 10) In this context, outcomes may vary depending on the pRCC type and tumor stage

The aim of this study was to compare OS, CSS and RFS of patients diagnosed with pRCC and ccRCC and define the factors affecting survival in the patient population with localized disease

Materials And Methods

Patients with renal cell carcinoma (RCC), who underwent radical or partial nephrectomy due to renal tumors, whose data were obtained from a series of 5300 patients with kidney tumors included in the Urologic Cancer DatabaseKidney (UroCaD-K) of Turkish Urooncology Association (TUOA) were evaluated retrospectively Pathological stage and grade were determined according to the 2002 Union Internationale Contre le Cancer TNM Classification, and Fuhrman classification (G1-G4), respectively Tumor size was measured using the computed tomography (CT) and taking the largest diameter

Histological subtypes were classified according to the Heidelberg classification (1): ccRCC, pRCC, chromophobe, Bellini duct, and unclassified RCC Patients from UroCaD-K database, who had pathological T1-T2 ccRCC and pRCC were evaluated in the study According to the two histological subtype, recurrence and mortality status, recurrence free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) data were analyzed The follow-up protocol of the patients was arranged according to the EAU-RCC guideline

Statistical analysis

Analyses were performed by the using of Statistical Package for the Social Sciences (SPSS) version 22 0 Chi- square and Student t-tests were used to compare categorical and continuous data, respectively The relationship between tumor size and histological subtype was analyzed with logistic regression models The Kaplan-Meier method was used to estimate tumor specific survival, and c o m p a r i s o n w a s p e r f o r m e d b y t h e l o g - r a n k t e s t

Multivariate Cox proportional hazard models were used to detect independent variables with a p < 0 05 considered to indicate statistical significance

1

Results

The clinical, pathological and oncological data of the patients are shown in Table 1 Among 5300 patients, 2129 patients who had pathological T1-T2 ccRCC and pRCC were included in the study The mean age was 57 7 ± 11 8 years and two-thirds of the patients were male There were 1700 patients with ccRCC, while the pRCC was observed in 429 patients

Patients in the ccRCC group were younger and had a higher BMI (p values were < 0 001 and 0 004, respectively)

Radiological tumor size was statistically found to be smaller in pRCC than ccRCC group (mean size were 4 7 cm vs 5cm, p = 0 001)

We detected that radiologically < 4 cm tumors were more frequent in the pRCC group that ccRCC (p = 0 034) The finding of radiological local invasion was also more common in ccRCC, but there was no statistically difference (5 4% vs 3 5%) There was no statistically difference between the groups when we evaluated them in terms of pathological tumor size and Fuhrman grade Considering the postoperative follow-up periods, the mean follow-up time for ccRCC and pRCC were 25 2 months and 26 1 months, respectively (p = 0 613)

Pathological T stage and radiological local invasion were found to be risk factors for recurrence in ccRCC Age, radiological local invasion and Fuhrman grade 3-4 were found to be independent risk factors affecting overall mortality in patients with ccRCC In pRCC patients, radiological local invasion was found to be an independent risk factor for recurrence and age was a risk factor for overall mortality (Table 2)

In addition, RFS, OS and CSS were not statistically different between the groups (Figure 1)

Discussion

Factors affecting recurrence and overall mortality in ccRCC and pRCC groups

We aimed to discuss OS, CSS and RFS of patients diagnosed with pRCC and ccRCC and define the factors affecting survival in patient population with pT1 and pT2 disease It was observed that ccRCC was seen in younger patients and in patients with higher BMI, and that pRCC was more common in males

P a p i l l a r y t y p e p a t h o l o g y w a s r a d i o l o g i c a l l y smaller and was more frequently evaluated as pT1a than clear cell type Radiological local invasion and age were found to be independent risk factors for recurrence and overall mortality, respectively for both groups Pathological stage was also a risk factor for recurrence in ccRCC

In addition, during the follow-up, OS, CSS and RFS were not statistically different for both groups in pT1 and pT2 disease

The two most important factors determining the outcome of RCC are nuclear grade and tumor stage (11) According to some authors, apart from these two factors, histological subtype was also an independent prognostic factor (12)

Type 1 pRCC is associated with MET alteration or trisomy of chromosome 7 where the MET gene is located, while Type2 pRCC shows allelic imbalance on chromosomes 1p, 3p, 5, 6, 8, 9p, 10, 11, 15, 18 and 22 (13, 14)

According to the study shared by Waldert et al 5-year CSS was 94% in type 1 pRCC and 74% in type 2 pRCC (p = 0 027) During the follow-up, the overall CSS for M0 patients with pRCC and ccRCC (90% vs 84% respectively) was not significantly different) Steffens et al evaluated long-term survival of pRCC versus ccRCC In this series, patients with pRCC had significantly higher 5-yr CSS rate (85 1% vs 76 3%; p = 0 001) Notably, at multivariable analysis, the papillary subtype was significantly associated with favorable oncologic outcome in localized RCC but was an independent negative prognostic factor in metastatic patients

These results could be evaluated separately for papillary type 1 and type 2, but this was not evaluated in the study (14)

In addition, authors have shown that type 1 and type 2 RCC have similar clinical and histopathological features, but lymphovascular invasion (LVI) in type 2 pRCC worsened CSS rate, compared to type1 pRCC (5)

In a multicenter study involving more than four thousand patients from eight international centers, patients with pRCC had better 5-year CSS than patients with ccRCC in univariate analysis (73% versus 79% respectively) In multivariate analysis, the histological subtype was not an independent prognostic factor (15)

Five studies with 32 158 patients indicated that pRCC had a better prognosis than ccRCC (3, 6, 16-18), while other 5 studies including 3674 patients showed that pRCC was an independent predictor of poor outcomes (4, 7, 8, 19, 20) According to the results of the metaanalysis including these studies, pRCC was associated with better outcomes than ccRCC in patients with nonmetastatic disease, but not in patients with metastatic disease Type 2 pRCC had worse prognosis than ccRCC, but no significant difference was found with type 1 pRCC

In this study, it was observed that the tumor size was smaller in pRCC In the study of Waldert et al tumor size was also smaller in pRCC (mean 4 5 cm) compared to ccRCC (mean 5 5 cm) (p = 0 013) (14)

Traditionally, p-RCC is divided into 2 types: type 1 is characterized by a basophilic cytoplasm and is classified as a low-grade tumor, while type 2 displays a bulky eosinophilic cytoplasm and pseudostratified tumor cell nuclei and is considered a high-grade tumor (3)

Compared to type 1 p-RCC, type 2 p-RCC presents more frequently as a locally advanced disease and is associated with more aggressive clinicopathologic features and significantly worse outcome (9, 10, 14, 21)

Our study had some limitations Most important limitations are the retrospective analysis and the multi-centered design with pathological evaluation not performed in a single centre Evaluation of the patients by experts in urooncology may reduce the disadvantage of multi-center data analysis In addition, not taking into the account the pRCC subtypes can be considered among the limitations of the study

Conclusions

In conclusion, RFS, OS and CSS were similar between p R C C a n d c c R C C p a t i e n t s w i t h l o c a l i z e d d i s e a s e Although it was not statistically significant, it is obvious that the histopathological and therefore cancer biology of the most common RCC subtypes are different The management of patients should be planned according to the stage and subtype of the disease

References

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11 Gudbjartsson T, Hardarson S, Petursdottir V, et al Histological subtyping and nuclear grading of renal cell carcinoma and their implications for survival: a retrospective nation-wide study of 629 patients Eur Urol 2005; 48:593-600

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Correspondence

Taha Cetin, MD, FEBU (Corresponding Author) tahacetin88@gmail com

Serdar Celik, MD serdarcelik84@hotmail com

Izmir Bozyaka Research and Training Hospital Urology Department, Izmir, Türkiye

Sinan Sozen, MD sinansozen@usa net

Gazi University Faculty of Medicine Urology Department, Ankara, Türkiye

Bulent Akdogan, MD blntakdogan@yahoo com

Haluk Ozen, MD drhalukozen@gmail com

Hacettepe University Faculty of Medicine Urology Department, Ankara, Türkiye

Volkan Izol, MD volkanizol@yahoo com

Yildirim Bayazit, MD ybayazit@yahoo com

Cukurova University Faculty of Medicine Urology Department, Adana, Türkiye

Conflict of interest: The authors declare no potential conflict of interest

Guven Aslan, MD drguvenaslan@gmail com

Dokuz Eylul University Faculty of Medicine Urology Department, Izmir, Türkiye

Evren Suer, MD drevrensuer@gmail com

Sumer Baltaci, MD baltacisumer@gmail com

Ankara University Faculty of Medicine Urology Department, Ankara, Türkiye

Nihat Karakoyunlu, MD nkarakoyunlu@gmail com

University of Health Sciences Dıskapi Yildirim Beyazit Research and Training Hospital Urology Department, Ankara, Türkiye

Fatih Gokalp, MD fatihgokalp85@gmail com

Mustafa Kemal University Tayfur Ata Sokmen Medicine Faculty Urology Department, Hatay, Türkiye

Ilker Tinay, MD ilker tinay@yahoo com

Marmara University Faculty of Medicine Urology Department, Istanbul, Türkiye