AUA2022: BEST POSTERS Role of the Human Papilloma Virus in the Prostate Cancer Etiology
By: Marco Vella, MD; Cristina Minasola, MD; Gabriele Tulone, MD; Mirko Pinelli, MD; Gianpaolo Di Gregorio, MD; Sonia Maria Agiato, MD; Rosa Giaimo, MD; Nicola Pavan, MD; Carlo Pavone, MD; Giuseppina Capra, MS; Chiara Mascarella, MS; Alberto Abrate, MD; Alchiede Simonato, MD | Posted on: 01 Nov 2022
Chronic inflammation may contribute to the development of several forms of human cancer, including prostate cancer,1 since histological specimens of prostate cancer tissue frequently exhibit unexplained acute and chronic inflammation and inflammation associated lesions.2
The role of human papillomavirus (HPV) and other sexually transmitted infections in prostate cancer is highly controversial.3
There has been speculation about prostate exposition to infectious agents by sexual activity, which may increase the risk of cancer by direct infection with a carcinogenic organism (like the relationship between HPV and cervical cancer) or by initiating an inflammatory response, known as carcinogenic effects.
A sexually transmitted etiology for prostate cancer was first proposed in the 1950s based on a higher prevalence observed in uncircumcised men.5
A meta-analysis by Dennis and Dawson (2002) suggested a high risk of prostate cancer among men with a history of sexually transmitted infections (especially syphilis), frequent sexual activity, and a greater number of sexual partners;6 however, subsequent case-control and cohort studies have not confirmed these observations.7
In the meta-analysis conducted by Russo et al, conducted in 2018 and published in 2020, 30 papers were identified as eligible suggesting that HPV-16 infection may represent a risk factor for prostate cancer, while no association for HPV-18 has been found.3 Medel-Flores et al evaluated the association between prostate cancer and HPV infection in the Mexican population, studying 356 paraffin tissue samples of Mexican men with prostatic carcinoma or benign prostatic hyperplasia (BPH).8 The results showed that high-risk HPV was detected in prostate cancer samples in 19.6% compared to 9.6% of 18 BPH samples, suggesting that high-risk HPV could play an important role in the genesis of prostate cancer. HPV 52 and 58 were the most frequent, 33% and 17%, respectively, genotypes detected.
Our prospective study intended to show the direct relationship between HPV infection and prostate cancer investigating the presence of HPV DNA sequences into the different zones of the prostatic tissue, and eventually correlating it with benign and malignant tissue according to Gleason score.
We selected 59 consecutive outpatients with suspicious prostate cancer based on digital rectal examination and/or prostate specific antigen values. No patient had visible lesions in the anal and perianal zone suspicious for HPV infection. Besides a standard ultrasound transrectal 12-core prostatic biopsy (6 for each lobe, taken for histopathological examination), 3 additional samples (1 in the transitional zone and 1 in the margin of each lobe) were sent for molecular biology investigation for HPV DNA research.
The specimens were obtained fresh, and immediately stored at −20° C until the moment of total DNA extraction.
The QIAamp DNA Mini Kit was used for DNA extraction and purification.
The sample was put in solution with 180 μl of ATL buffer, containing detergents, and 20 μl of proteinase K.
In the subsequent purification step, 200 μl of AL buffer containing chaotropic agents was added to the lysate and the solution was incubated for 10 min at 70° C.
Everything was transferred and absorbed on a column with silica base, which has the advantage of not binding many contaminants present in biological samples or in buffers for cell lysis.
Once the DNA is bound to the silica, repeated washing with ethanol-based solutions is carried out to eliminate unwanted organic components and extraction waste.
The viral DNA research, carried out using the Ampliquality HPV-Type Express v.3.0 (AB Analytica) kit, involves a first phase of nucleic acid amplification and a second phase of detection through a reverse hybridization reaction (reverse dot blot). After extraction of the total DNA, the eluates were subjected to PCR amplification of the L1 region of the HPV viral genome with biotinylated primers.
The L1 region is particularly conserved and can detect the presence of a large number of viral genotypes, both oncogenic high- and low-risk genotypes.4
Histological analysis confirmed the diagnosis of prostate adenocarcinoma in 37 men (62.7%), atypical small acinar proliferation in 4 (6.8%), chronic inflammation in 10 (16.9%), BPH in 7 (11.9%), and high-grade prostatic intraepithelial neoplasia in 1 man (1.7%; see Table). All the molecular analysis for HPV research, performed on a total of 177 prostate biopsy samples, did not show HPV-DNA regardless of the histological nature of the lesion (see Figure).
Table. Examined Population
|Age, median (IQR), y||71 (71-74,5)|
|PSA, median (IQR), y||7.69 (5.77-11.55)|
|DRE prostate consistency, %|
|Hard wooden prostate||17|
|Presence of nodule||20|
|Histological diagnosis, %|
|Abbreviations: ASAP, atypical small acinar proliferation; BPH, benign prostatic hyperplasia; DRE, digital rectal examination; HGPIN, high-grade prostatic intraepithelial neoplasia; PSA, prostate specific antigen.|
These results are different from those reported by other authors who have used samples stored in paraffin, unlike our analysis, made on fresh tissues.8
False-positive results could be due to contamination of the needle going through the perineum or the anus.
Utilizing fresh samples of prostatic biopsy, we minimized the risk of contamination of the samples.
Although many studies and meta-analyses report a high incidence of positive HPV prostate tissue samples, particularly in prostate cancer patients, our study questions the true incidence and prevalence of HPV in the prostate, especially in patients with an oncological pathology, as well as benign or inflammatory prostatic glands. New studies and greater case studies will be needed to study the real tropism of HPV in prostate tissue. These studies will thus also be able to give greater impetus to any vaccination campaign in males.
- Bora G, Scott ML, Thompson IM Jr, et al. Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial. Cancer Epidemiol. Biomarkers Prev. 2014;23(5):847-856.
- Sfanos SK, De Marzo AM. Prostate cancer and inflammation: the evidence. Histopathology. 2012;60(1):199-215.
- Russo G, Calogero A, Condorelli R, et al. Human papillomavirus and risk of prostate cancer: a systematic review and meta-analysis. Aging Male. 2020;23(2):132-138.
- Karlsen F, Kalantari M, Jenkins A, et al. Use of multiple PCR primer sets for optimal detection of human papillomavirus. J Clin Microbiol. 1996;34(9):2095-2100.
- Ravich A. Prophylaxis of cancer of the prostate, penis, and cervix. N Y State J Med. 1951;51(12):1519-1520.
- Dennis LK, Dawson DV. Meta-analysis of measures of sexual activity and prostate cancer. Epidemiology. 2002;13(1):72-79.
- Sutcliffe S. Sexually transmitted infections and risk of prostate cancer: review of historical and emerging hypotheses. Future Oncol. 2010;6(8):1289-1311.
- Medel-Flores O, Valenzuela-Rodríguez VA, Ocadiz-Delgado R, et al. Association between HPV infection and prostate cancer in a Mexican population. Genet Mol Biol. 2018;41(4):781-789.