Renal cell carcinoma and viral infections: A dangerous relationship?

Table 1 Studies about viruses in renal cell carcinoma

Ref.	Study type	Analyzed specimens		Virus investigated	Analysis method	Positive specimens
		No. of cases and tumor type	No. of controls and tissue type			No. of positive cases and tumor type	No. of positive controls and tissue type
Kim et al[18], 2005	Retrospective	73 RCC (22 clear cell; 18 papillary; 20 chromophobe; 10 sarcomatoid; 3 oncocytoma)	18 non-neoplastic kidneys	EBV	EBER-ISH and PCRs (for EBNA-1 and EBNA-3C)	5/73 (all sarcomatoid histology) (EBER-ISH)2; 4/73 (all sarcomatoid histology) showed amplification of EBNA-1	0/18
Neirynck et al[17], 2012	Case report	1 RCC1	1 peritumoral tissue	BKV	IHC (for SV40 T antigen)	65%-70% neoplastic cells	< 1% non-neoplastic cells
Salehipoor et al[19], 2012	Retrospective	49 RCC	16 non-neoplastic kidneys	HPV; EBV; BKV; JCV	Nested PCR (virus DNA)	7/49 HPV (5 clear cell; 1 chromophobe 1 mixed type) 0 EBV, BKV JCV	0/16
Bulut et al[16], 2013	Retrospective	50 RCC	45 non-neoplastic kidneys	BKV	Nested PCR (BKV DNA) and RT-PCR (BKV mRNA)	10/50 (Nested PCR) 8/50 (RT-PCR)	2/45 non neoplastic kidneys (nested PCR, RT-PCR)
Farhadi et al[20], 2014	Retrospective	122 RCC (77 conventional; 26 papillary; 14 chromophobe; 1 collecting duct; 4 unclassified)	96 peritumoral tissues, 19 non-neoplastic kidneys	HR-HPV	Nested PCR (HR-HPV DNA). IHC (for p16INK4a and L1 Capsid Protein); CSAC-ISH	37/122 (17 clear-cell; 13 papillary; 4 chromophobe; 3 unclassified) (PCR). 24/118 (IHC for p16INK4a3) 0/118 (IHC for L1 capsid protein); 18/122 (CSAC-ISH)	4/96 peritumoral tissues; 0/19 non-neoplastic kidneys (PCR); 16/94 peritumoral tissue (IHC for p16INK4a); 0/94 peritumoral tissue (IHC for L1 capsid protein); NA (CSAC-ISH)

¹Allograft kidney.

²EBER-positive signals were located only in the tumor-infiltrating lymphocytes.

³Human papillomavirus capsid protein.

RCC: Renal cell carcinoma; BKV: BK virus; EBV: Epstein-Barr virus; HPV: Human papillomavirus; JCV: JC virus; HR-HPV: High-risk human papillomavirus; Nested PCR: Nested polymerase chain reaction; RT-PCR: Real-time polymerase chain reaction; IHC: Immunohistochemistry; EBER-ISH: EBV-encoded RNAs in situ hybridization; EBNA-1 and EBNA-3C: EBV-encoded nuclear antigen 1 and EBV-encoded nuclear antigen 3C; CSAC-ISH: Catalyzed signal-amplified colorimetric in situ hybridization; NA: Not available.

Table 2 Studies reporting the relationship between chronic viral infections and the occurrence of renal cell carcinoma

Ref.	Study type	Type of chronic viral infection	Study population	RCC histology	Mean age (yr)	Aim	Main results/conclusions
Gaughan et al[43], 2008	Case series	HIV infection	9 HIV-associated RCC1	2 papillary, 1 collecting duct, 6 clear cell	48	To describe the risk factors, clinical findings, pathology, and response to therapy in RCC patients infected with HIV	The clinical presentation and behavior of RCC in patients with HIV infection appeared similar to that of the HIV-negative population and that chronic immunosuppression plays a lesser role than age and exposure to risk factors
Gordon et al[38], 2010	Retrospective study	HCV infection	67063 HCV-tested patients: 3057 HCV+ and 64006 HCV-	17 RCC HCV+: 8 clear cell, 6 papillary, 2 mixed clear cell/papillary, 1 undifferentiated/other; 117 HCV-: 92 clear cell, 43 papillary, 9 mixed clear cell/papillary, 26 undifferentiated/other	54 in HCV+, 63 in HCV-	To determine whether HCV infection confers an increased risk for developing RCC	RCC was diagnosed in 0.6% (17/3057) of HCV+ and 0.3% (117/64006) of HCV- patients. HCV infection confers a risk for the development of RCC: Overall HR for RCC among HCV patients 1.77 (95% confidence interval, 1.05-2.98; P = 0.0313)
Wiwanitkit[42], 2011	Bioinformatics analysis	HCV infection	NA	NA	NA	To assess the cause–outcome relationship between HCV infection and RCC using the bioinformatics network analysis technique	There might be a cause–outcome relationship between HCV infection and RCC via NY-REN-54 (the only one common protein)
Gonzalez et al[39], 2015	Prospective study	HCV infection	140 RCC and 100 colon cancer patients (control)	NA	56.7 in RCC patients with viremia, 61.8 in aviremic patients	To determine whether chronic HCV is associated with an increased risk of RCC	11/140 RCC and 1/100 colon cancer patients were HCAB+. Of the HCAB+ patients, 9/11 RCC and 0/1 controls had detectable HCV RNA. In the multivariable logistic regression analysis, being HCV RNA positive was a significant risk factor for RCC (P = 0.043)
Wijarnpreecha et al[40], 2016	Systematic review and meta-analysis	HCV infection	196826 patients from 7 observational studies (4 cohort and 3 case-control studies). Individuals without HCV infection were used as comparators in cohort studies, individuals without RCC as comparators in the cross-sectional and case-control studies	NA	NA2	To assess the risk of RCC in patients with HCV infection	Significantly increased risk of RCC in HCC+ with the pooled risk ratio of 1.86 (95%CI: 1.11-3.11)
Ong et al[44], 2016	Case series	HIV infection	7 HIV-associated RCC1	5 clear cell, 1 papillary, 1 unknown	56	To report presentation, management and outcomes of RCC patients with HIV infection	RCC patients with HIV infection should be offered all treatment options in the same manner as the general population
Tsimafeyeu et al[41], 2020	Retrospective study	HCV infection	44 mRCC patients: 22 HCV+, 22 HCV-	Clear cell	62 in mRCC HCV+, 63 in mRCC HCV-	To evaluate Nivolumab efficacy and safety in mRCC patients with or without chronic HCV infection (OS primary endpoint, PFS, ORR and rate of grade 3–4 adverse events secondary endpoints)	HCV-infected patients had significantly longer OS (27.5 vs 21.7, P = 0.005) and PFS (7.5 vs 4.9, P = 0.013), no difference in ORR. Grade 3–4 adverse events were observed in 5 (23%) HCV+ patients and in 3 (14%) HCV- patients

¹Human immunodeficiency virus infection before renal cell carcinoma (RCC) diagnosis.

²Mean age not specified, but hepatitis C virus (HCV)+ RCC patients were significantly younger than HCV-RCC patients.

HCV: Hepatitis C virus; RCC: Renal cell carcinoma; mRCC: Metastatic renal cell carcinoma; HR: Hazard ratio; NA: Not available; HCAB: Hepatitis C antibody; RNA: Ribonucleic acid; OS: Overall survival; PFS: Progression-free survival; ORR: Objective response rate; HIV: Human immunodeficiency virus.