The association between penile cancer and HIV infection: A literature review

Abstract

Penile cancer is a rare malignancy which HIV infection appears to increase the risk of. The magnitude of this risk and the pathogenesis remain unclear. A comprehensive review of the literature was undertaken using conventional search strategies. Twenty-four publications were identified by this methodology, of which nine were case reports and 15 were observational studies. These studies were highly heterogeneous, with varying study designs, populations, and objectives. The risk of penile cancer within HIV-positive individuals is significantly greater than in those without HIV (RR = 3 .7 to 5.8, 3 studies; SIR = 3.8 to 11.1, 4 studies). HIV is also shown to influence disease characteristics, with a four-fold increased risk of death from penile cancer. Moreover, progression from intraepithelial neoplasia occurs earlier in HIV, six years sooner than in HIV-negative men. HIV-positive men have a higher prevalence of HPV infection. Ethnicity is also shown to modulate the relationship between HIV and penile carcinoma, with a higher risk of cancer in Hispanic, compared with Caucasian, HIV-positive men. This review has collated data from diverse sources to improve understanding of the relationship between HIV and penile cancer. This relationship has been quantitatively and qualitatively characterised and highlights areas deserving further enquiry.

Keywords

AIDS < Viral disease HIV (Human immunodeficiency virus) < Viral disease HPV (Human papillomavirus) < Viral disease Men < Other

Introduction

Penile cancer is a rare cancer, the majority (95%) being squamous cell carcinoma (SCC) although other types are seen.^1,2 Recognised risk factors for penile (Pe)SCC include omission of neonatal circumcision, human papillomavirus (HPV) infection, lichen sclerosus (LSc) and phimosis, HIV, tobacco use, and poor penile hygiene, of which circumcision status is probably the most important.^1,3–6 In the uncircumcised the most significant drivers seem to be HPV and LSc with a dichotomous but sometimes overlapping carcinogenetic pathway analogous to vulval cancer.^4,5,7

HIV is known to increase the risk of a number of cancers e.g. Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), and invasive cervical cancer, i.e. those that together constitute the AIDS-defining cancers (ADC).⁶ Although AIDS‐related cancers are decreasing in incidence, non‐AIDS‐defining cancers (NADC) are on the increase, particularly non‐melanoma skin cancer (NMSC) and ano‐oro‐genital cancer.⁸ Specific risk factors for SCC of the skin in HIV-positive individuals include low CD4 nadir and viral load.^9,10

As with all NMSC, HIV also appears to increase the risk of developing PeSCC, despite antiretroviral treatment.^4,11,12 At present, the exact nature of this relationship, the risk ratio (RR) and mechanisms that lead HIV-positive men to develop PSCC, remain unclear.

We have undertaken a literature review to determine what is known and published about the relationship and interplay of HIV with PeSCC.

Methods

We searched Medline, EMBASE and the Cochrane Library using a prespecified search criteria. The search terms used were HIV, AIDS, HIV-1, HIV-2, human immunodeficiency virus, acquired immunodeficiency syndrome, AND penile cancer, penis cancer, penile neoplasm, penile carcinoma, non-melanoma.

Titles, abstract and full texts were imported into Mendeley reference manager. Titles and abstracts were screened by two independent reviewers to assess if they met our prespecified inclusion and exclusion criteria. Any discrepancies in findings were resolved by a third reviewer. Relevant data from the manuscripts were extracted and tabulated.

Inclusion and exclusion criteria

We included published articles concerning PeSCC amongst patients with known HIV infection, in any language, country and publication date. Articles that mentioned penile cancer alone, without reference to HIV/AIDS, were excluded. Articles about HPV-associated, anogenital, or non-melanoma cancers, without clarification of the specific site of cancer, were excluded. Case reports and case series were included, but literature reviews were excluded. Articles about penile carcinoma in situ/penile intraepithelial neoplasia (PeIN) were also excluded. Wherever it was possible so to determine, articles relating to non-PeSCC penile cancer were excluded.

Results

A total of 303 articles were identified through our search across all three databases. Nineteen additional articles were identified by screening the citations of these papers. All 322 articles were scrutinised through their abstract and 232 papers were excluded. The 90 remaining articles were then assessed for relevance based on their full text. A total of 24 studies were deemed eligible for inclusion (Figure 1). The studies included in this review were highly heterogeneous, with varying study designs, populations, and objectives.

Figure 1.

PRISMA chart showing literature search and study selection.

Case reports and case series

Of the 24 studies, nine (38%) were case reports or case series, with a combined total of 12 patients. Relevant data from these cases were extracted and are presented in Table 1. Median age at diagnosis of PeSCC was 49 years (range 32–78). At the time of presentation with PeSCC, six patients (50%) had a known diagnosis of HIV, and three patients (25%) had AIDS. The remaining three patients (25%) were diagnosed with HIV at the time of PeSCC presentation.

Table 1.

Case reports included in the study.

Author and publication date	Country	Patient demographics and presentation	HIV status (±where available viral load/CD4 count at diagnosis) and treatment	Cancer type, stage and treatment	Outcome
Aboulafia and Gibbons, 2001¹³	USA	64-year-old, uncircumcised, Caucasian MSM, smoker (60 pack years), COPD, DM, PVD, IHD. 6-months history of a ulcerating, foul-smelling lesion on the glans, phimosis, several nodules on the glans, and bilateral indurated tumours of the distal corpus cavernosa HPV18 found in both penile tumour and metastatic specimens	HIV diagnosed in 1994 In 1997, CD4 <500 cells/mm³ and viral load >5000 copies/ml, started on zidovudine and lamivudine In 1998, SCC diagnosis, CD4 550 cells/mm³ and viral load <500	Well-differentiated PeSCC. Treated with radical penectomy10 months later, transbronchial biopsy revealed lung metastasis.	Died from complications of a respiratory arrest and myocardial infarction
Binny et al., 2019¹⁴	India	51-year-old uncircumcised, heterosexual Presented with multiple inguinal and pubic ulcerative, painful and purulent nodules of 2 months’ duration History of unprotected penovaginal intercourse with multiple partners, history of phimosis of 2 months’ duration	Known HIV-positive diagnosed 3 years prior to PeSCC diagnosis, on zidovudine, lamivudine and nevirapine CD4 count at diagnosis of PeSCC: 312 cells/mm³	PeSCC. Bilateral lung metastases, metastatic scrotal deposits and metastatic inguino-pelvic lymphadenopathy Treated with palliative chemotherapy	Died following two cycles of chemotherapy
Diallo et al., 2017¹⁵	Guinea	46-year-old with 6 cm tumour of the glans penis 5 other cases were reported though were HIV-negative	Diagnosed with HIV at presentation, started on ART	PeSCC T2N3M0, grade 3 Treated via total penectomy and ART.	Died after 12 months
Konan et al., 2015¹⁶	Ivory Coast	Pt. 1: 47-year-old, circumcised when 17 years old, smoker (20 pack years) presented with a hard and painless tumour infiltrating glans penis and 3 cm of cavernous body, evolving over 2 years. No superficial inguinal LN. History of unprotected intercourse with multiple partners Pt. 2: 56-year-old non-smoker presented with spontaneous amputation of the glans, left suppurative inguinal adenitis, acute urinary retention. Wife died 4 years prior from cervical cancer Pt. 3: 40-year-old non-smoker presented with paraphimosis. History of unprotected intercourse with multiple partners	All 3 were diagnosed with HIV at presentation	All three had mature, invasive differentiated PeSCC Pt. 1: T4N0M0, no treatment Pt. 2: T4N+M0, treated with antibiotics and IV fluids Pt. 3: T3N0M0, no treatment	Pt. 1: Lost to follow up Pt. 2: Died 10 days post admission Pt. 3: Died 15 days post admission
Poblet et al., 1999¹⁷	Spain	Pt. 1: 56-year-old man presented with papular lesions on the inner prepuce and glans that did not respond to treatment with podophyllotoxin HPV 16 positive Pt. 2: 78-year-old uncircumcised man presented with painful and suppurative tumour of the penis. HPV 6b and 11 positive	Both previously diagnosed with HIV.	Pt. 1: Diagnosed with PeSCC after lesions rapidly evolved to form tumour on glans penis. Treated with partial penectomy Pt. 2: Diagnosed with PeSCC on biopsy. Partial penectomy performed	Pt. 1: Died 8 months post-initial presentation from miliary TB, no evidence of metastases Pt. 2: Died 1-year post-initial presentation, no evidence of metastases
Sanders et al., 1997¹⁸	Zimbabwe	32-year-old man presented with condylomata acuminata of >2 years duration with phimotic foreskin, and a necrotic penile ulcer present for 3 months Patient also had widespread seborrheic dermatitis, oral candidiasis and generalised lymphadenopathy, pulmonary TB 2 years prior	Diagnosed with HIV at presentation	Diagnosed with invasive PeSCC following biopsy	Lost to follow up
Theodore et al., 2002¹⁹	France	37-year-old married heterosexual Caucasian man, non-smoker. 1980 phimosis, 1993 condylomatous balanitis occupying 40% of surface of glans penis Oct 1995 diagnosed with Zoon’s plasma cell balanitis, Sept 1996 diagnosed with PeSCC in situ, Dec 1996 spread to L inguinal node chain, 1998 to right inguinal node chain, Mar 1999 developed lung metastases	Diagnosed with AIDS in 1995 following a PCP pneumonia, CD4 count 47 cells/mm³. Started on zidovudine and zalcitabine (latter replaced by lamivudine, and indinavir added)CD4 <100 cells/mm³ at SCC diagnosis in 1996 1998 CD4 253 cells/mm³, viral load 200,000 copies/ml When diagnosed with lung metastases, CD4 count was 150 cells/mm³ with viral load of 300,000 copies/ml	PeSCC in situ (T1N0M0) treated with surgical excision and CO₂ laser coagulation, 1997 had external beam radiotherapy to inguinal chain, 1997 partial amputation of penis due to urethral stenosis. External beam radiotherapy to right inguino-iliac field in 1998. Placed on cisplatin chemotherapy following lung metastases diagnosis in 1999	Died following two cycles of chemotherapy in Jun 1999, with evidence of extensive disease (pleuro-pericardiac effusion, bone and lung metastases)
Yeolekar et al., 1998²⁰	India	51-year-old heterosexual male presented with fever and productive cough, 25-years smoking history 2cm ulcer on glans penis with blood-stained discharge	Diagnosed with HIV at presentation	PeSCC on biopsy	Referred to tertiary hospital, no further information
Yoganathan, et al., 1995²¹	United Kingdom	44-year-old uncircumcised Caucasian MSM, non-smoker. Presented with a polypoid ulcer in coronal sulcus and bilateral lymphadenopathy. HPV 16 positive	Previously diagnosed with HIV in 1985. 1988, commenced on zidovudine and aerosol pentamidine, CD4 count <200 cells/mm³. 1990 developed PCP pneumonia, CD4 count <20 cells/mm³. Later developed oral candidiasis and eosinophilic folliculitis. Stated that CD4 count <100 cells/mm³ from 1987–1992	Diagnosed with well-differentiated PeSCC in Nov 1992. T1N0. Treated via circumcision and radiotherapy	Not stated

Abbreviations: HIV, human immunodeficiency virus; AIDS, acquired immune deficiency syndrome; (Pe)SCC, (penile) squamous cell carcinoma; HPV, human papilloma virus; ART, antiretroviral therapy; LN, lymphadenopathy; MSM, men who have sex with men; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; PVD, peripheral vascular disease; IHD, ischaemic heart disease; Pt., patient.

Observational studies

A total of 15 observational studies were included in this review, which are summarised in Table 2.

Table 2.

Observational studies included in the study. *These studies form part of the NIH HIV/AIDS cancer match Study.

Author and year of publication	Study period	Study design	Country	Setting	Study objective	Study population	Age in years (of patients with PeSCC)	Outcome(s) relating to penile cancer
Chalya et al., 2015²²	2004–2013	Retrospective cohort	Tanzania	Tertiary hospital	Demographics and outcomes of patients with penile cancer, including their statistical associations	236 patients with penile cancer, of which 104 with known HIV status	21–78 (median 47)	7 penile cancer cases were HIV-positive (6.7%); CD4 count, at cancer diagnosis, was known in 4 cases (126–712, median 234 cells/μl); HIV positivity was a predictor of death (OR = 4.4, p = 0.011); surgical site infection was higher in HIV-positive cases (p = 0.003)
Chaturvedi et al., 2009*²³	1980–2004	Retrospective cohort	USA	Multicentre	Investigate the risk of HPV-associated cancers in AIDS; characterise the relationship between this risk and immunosuppression	499,230 people diagnosed with AIDS during the study period	N/A	20 cases of penile cancer were reported (SIR = 5.3); comparing HIV exposure groups, risk of penile cancer was significantly increased amongst MSM and heterosexual groups (SIR = 4.4, and = 14.7, respectively) but not in IVDUs; no statistically significant trend in risk of penile cancer across the 10-year period before AIDS diagnosis and the same period after diagnosis was observed, although the same trend was statistically significant for PeIN.
Engels et al., 2006*²⁴	1980–2002	Retrospective cohort	USA	Multicentre	Identify trends in cancer risk in people with AIDS, grouped by year of AIDS diagnosis across three periods: Pre-ART era; ART monotherapy and dual therapy era; and HAART era	375,933 people with AIDS.	N/A	The incidence of penile cancer was greater in those diagnosed with AIDS during the HAART era (5 cases; SIR = 8.0) compared to the ART monotherapy and dual therapy era (8 cases; SIR = 5.6; p for trend <0.05); No penile cancer cases were observed in patients diagnosed with AIDS during the pre-ART era
Frisch et al., 2000*¹¹	1978–1996	Cross-sectional	USA	Multicentre	Determine whether increased HPV-associated cancer burden in AIDS patients is related to common lifestyle factors between HIV and HPV infection, or to HIV-related immunosuppression	309,365 people diagnosed with AIDS during the study period	25–67 (mean 41.0)	14 cases of penile cancer observed (1.9 per 100,000 person-years; RR = 3.7); the mean age difference between diagnosis of in situ and invasive penile cancer was 1.7 years in people with AIDS, compared with 7.6 years in the general population; penile cancer occurred in particular excess in those diagnosed with AIDS under 30 years old (RR = 37.2); risk of penile cancer in Black and Hispanic patients was fivefold higher (RR = 5.3 and = 5.4, respectively) while the RR was not statistically significant amongst white patients; comparing HIV exposure groups, risk increased sevenfold in IVDUs (RR = 7.1), but was not statistically significant amongst other groups; RR of penile cancer increased significantly from pre-AIDS to post-AIDS diagnosis (finding was not robust after sensitivity analysis)
Frisch et al., 2001*⁶	1978–1996	Cross-sectional	USA	Multicentre	Examine the pattern of cancer in patients with AIDS and distinguish immunosuppression-associated cancers from other cancers occurring in excess in this group	302,834 people diagnosed with AIDS during the study period	N/A	14 cases of penile cancer observed (RR = 3.9); risk of penile cancer increased from pre-AIDS diagnosis (14 cases; RR = 3.9) to post-AIDS diagnosis (5 cases; RR = 5.1; p for trend <0.046) although this trend failed to reach statistical significance during sensitivity analysis
Fuchs et al., 2016²⁵	2008–2011	Prospective cohort	Germany	Outpatient clinic, teaching hospital	Determine prevalence of genital and anal condylomata, intraepithelial neoplasia and cancer in HIV-positive men	400 HIV-positive men attending a screening programme	Mean 43.1	1 case of penile cancer was diagnosed at baseline (0.25%); no additional cases of penile cancer were diagnosed during 3 years of follow-up
Mpunga et al. 2020²⁶	2012–2018	Cross-sectional	Rwanda	Multicentre	Determine prevalence of HPV-associated cancers	738 patients with HPV-associated cancer	Mean 56 (SD 16.9)	Of 81 penile cancer cases, HIV status was only known in 60. Of these, 10 were HIV-positive (16.7%) and 50 were HIV-negative (83.3%). Statistical analysis was not performed for this finding
Newnham et al., 2005²⁷	1985–2001	Retrospective cohort	UK	Multicentre	Determine the risk of cancer in HIV-positive people	26,080 HIV-positive men, including 10,522 with AIDS	—	3 cases of penile cancer were identified, 2 of which in AIDS (SIR = 11.1) and 1 in HIV infection alone (SIR = 1.7; non-significant)
Newton et al. 2001²⁸	1994–1999	Case-control	Uganda	Multicentre	Examine the association of HIV infection and cancers of infectious aetiology, compared with those of non-infectious aetiology	302 patients presenting with any cancer	N/A	There were 5 cases of penile cancer, of which 4 were in HIV-positive patients (80%; OR = 13.0; p = 0.03)
Ngendahayo et al., 2018²⁹	2015–2016	Prospective cohort	Rwanda	Multicentre	Demographics and management of patients with penile cancer, newly presenting due to a public health campaign	30 patients with penile cancer	33–83 (median 60)	6 patients were HIV-positive (20%), all on ART for at least 2 years; there was no difference in disease presentation or progression between HIV-positive and HIV-negative patients
Ortiz et al. 2018*³⁰	1996–2012	Cross-sectional	USA	Multicentre	Quantify the ethnic disparities in HPV-related cancer risk in Hispanic HIV-positive patients, compared to non-Hispanic americans	864,067 person-years of follow-up among HIV-positive Hispanic men (including AIDS)	N/A	39 cases of penile cancer were reported amongst HIV-positive Hispanic patients, a higher incidence compared to the general Hispanic population (SIR = 3.78); Hispanic HIV-positive patients were significantly more likely to develop penile cancer than HIV-positive white patients (aIRR = 2.60); there was no statistically significant difference in 5-year survival between HIV-positive Hispanics and non-Hispanics with penile cancer
Parkin et al., 1999³¹	1960–1997	Retrospective cohort	Uganda	Multicentre	Compare incidence of viral-associated cancers to the timeline of the AIDS epidemic	7312 people diagnosed with viral-associated cancers	N/A	100 cases of penile cancer were reported, without reference to HIV status; there was no trend observed between incidence of penile cancer and the timeline of the AIDS epidemic
Santos et al. 2002³²	1989–2001	Retrospective cohort	Spain	Tertiary teaching hospital	Determine prevalence of non-AIDS-defining malignancies amongst HIV-positive patients	2560 HIV-positive patients	N/A	2 cases of penile cancer were reported in 2560 HIV-positive patients (0.08%); penile cancer represented 4.7% of non-AIDS-defining malignancies in this population and 0.9% of malignancies of any site
Silverberg et al., 2009³³	1996–2007	Case-control	USA	Multicentre	Compare incidence of cancers in HIV-positive and matched HIV-negative controls	20,277 HIV-positive patients (including AIDS) and 203,313 matched HIV-negative controls	N/A	4 cases of penile cancer occurred in the HIV-positive group at an almost six-fold greater rate compared with the HIV-negative group (RR = 5.8, p = 0.006)
Wentzel et al., 2018³⁴	2000–2008	Retrospective cohort	South Africa	Tertiary teaching hospital	Determine prevalence of HIV-positivity in patients with penile cancer, and its relationship to age at presentation and HPV infection	65 patients with penile cancer	28–89 (mean 50.9)	Of 48 patients with known HIV status, 27 (56.2%) were HIV-positive (p = 0.05); the HIV-positive group, compared with the HIV-negative group, had a significantly lower mean age at presentation (43.7 vs 57.2 years) and higher prevalence of HPV infection (55.6% vs 23.8%); 52 patients had SCC, 10 had verrucous carcinoma, 1 undifferentiated, and 2 mixed carcinoma - there was no relationship between HIV status and histological type of carcinoma

Abbreviations: HIV, human immunodeficiency virus; AIDS, acquired immune deficiency syndrome; SCC, squamous cell carcinoma; HPV, human papilloma virus; ART, antiretroviral therapy; HAART, highly active antiretroviral therapy; SIR, standardised incidence ratio; RR, risk ratio; aIRR, adjusted incidence rate ratio; OR, odds ratio; MSM, men who have sex with men; IVDU, intravenous drug user.

Prevalence of PeSCC amongst HIV-positive individuals

A three-year study by Fuchs and colleagues attempted to determine the prevalence of anogenital disease, including PeSCC, within 400 HIV-positive individuals through the use of a screening programme.²⁵ One case of PeSCC was observed at baseline (0.25%) and no additional cases were diagnosed within 3 years of regular follow up.

In another study of 2560 HIV-positive men, two cases of PeSCC were identified in a retrospective chart review, representing a prevalence of 0.08%.³²

Risk of PeSCC amongst HIV-positive individuals

Seven articles published data on the risk of PeSCC in HIV-positive, compared with HIV-negative, individuals (Table 3). Three articles reported risk ratios (RR, the ratio of incidence of PeSCC amongst HIV-positive individuals to that of matched HIV-negative controls within the same study).^6,11,33 Four reported standardised risk ratios (SIR, the ratio of incidence of PeSCC amongst HIV-positive individuals to the expected incidence in the general population).^23,24,27,30 All seven articles demonstrated an increased rate of PeSCC in HIV-positive men. It should be noted that five of these articles include data from the National Institutes of Health (NIH) HIV/AIDS Cancer Match (HACM) Study and are likely to have utilised overlapping datasets.^6,11,23,30

Table 3.

Risk of PeSCC in HIV/AIDS, represented as *standardised incidence ratios (SIR) or **risk ratio (RR).

	Study demographic	Number of cancers	Risk (95% CI)
Chaturvedi et al., 2009²³	499,230 people with AIDS	20	5.3 (3.2–8.2)*
Engels et al., 2006²⁴	189,129 people with AIDS (diagnosed 1990–1995)	5	5.6 (1.8–13.1)*
Engels et al., 2006²⁴	107,417 people with AIDS (diagnosed 1996–2002)	4	8.0 (2.2–20.6)*
Frisch et al., 2000¹¹	309,365 people with AIDS	14	3.7 (2.0–6.2)**
Frisch et al., 2001⁶	302,834 people with AIDS	14	3.9 (2.1–6.5)**
Newnham et al., 2005²⁷	26,080 people with HIV and AIDS	3	3.9 (0.8–11.5)*
Newnham et al., 2005²⁷	10,522 people with AIDS	2	11.1 (1.3–40.0)*
Ortiz et al., 2018³⁰	864,067 Hispanic people with HIV	39	3.8 (2.7–5.2)*
Silverberg et al., 2009³³	20,277 people with HIV	4	5.8 (1.7–19.8)**

Two of these studies were based upon a sample of HIV-positive men (with and without AIDS, without differentiating between the two groups) and found the risk of PeSCC ranged from 3.8 to 5.8 times that of HIV-negative individuals.^30,33

One study explored HIV-positive men (stratified by AIDS status) and found that only those with AIDS had an increased SIR of developing PeSCC (SIR = 11.1).²⁷

Another four studies were concerned only with patients diagnosed with AIDS. In these, the risk of PeSCC ranged from 3.7 to 8.0 times that of HIV-negative individuals.^6,11,23,24

Within these studies, the risk of developing PeSCC was highly variable between different population subgroups. In one such study, the risk of PeSCC was increased in men who have sex with men (MSM) and heterosexual men (SIR = 4.4 and = 14.7, respectively), but failed to reach statistical significance in the intravenous drug user (IVDU) group.²³ Conversely, in another study, IVDUs were the only exposure group to reach statistical significance (RR = 7.1).¹¹ In the same study, the increased risk of PeSCC was only significant in Black and Hispanic patients (RR = 5.3 and = 5.4, respectively) but not amongst White patients.

Characteristics of PeSCC amongst HIV-positive individuals

Some studies included in this review provided further qualitative and quantitative findings to characterise PeSCC as it appears in HIV-positive individuals.

In the study by Ngendahayo and colleagues, out of 30 Rwandan men with PeSCC, six were HIV positive and undergoing antiretroviral therapy (ART) for at least two years.²⁹ In them, HIV infection showed no relationship to disease presentation or progression.

In contrast, other studies did demonstrate HIV as a variable for PeSCC. Chalya et al. demonstrated that HIV positivity increased the risk of death from PeSCC four-fold.²² Additionally, HIV-positive patients undergoing surgical management of PeSCC were more likely to experience surgical site infections.

Frisch et al. published data on the age difference at the point of PeIN and PeSCC diagnoses. In the general population, the average age of diagnosis of PeSCC was 7.6 years older than that of PeIN. In contrast, in the AIDS group, the age difference was reduced to only 1.7 years, thus suggesting an accelerated progress to invasive disease. Moreover, the risk of PeSCC was greatest in those diagnosed with AIDS below the age of 30 (RR = 37.2), with the risk decreased with increasing age of AIDS onset.¹¹

Three articles, all based upon the HACM Study, compared the risk of developing PeSCC prior to AIDS diagnosis with that of post-AIDS diagnosis.^6,11,23 Although a positive trend was observed, this trend was marginally non-significant. In another study, Parkin et al. did not observe a trend linking the incidence of PeSCC to the timeline of the AIDS epidemic.³¹

A large study of HIV-positive Hispanic men found them to be at 2.6 times greater risk of PeSCC than non-Hispanic White men with HIV.³⁰ Moreover, there was no difference in PeSCC risk between Hispanic men and Black men with HIV. Finally, no difference was found in the five-year survival between Hispanic and non-Hispanic patients with PeSCC.

In a study of 65 patients with PeSCC, by Wentzel et al., HIV-positive men had a significantly lower age at presentation compared with HIV-negative men (mean difference 13.5 years).³⁴

Amongst nine case reports and series, data regarding HPV status were included for four patients;^13,17,21 all were of high-risk HPV subtypes, except one.¹⁷ Similarly, in the study by Wentzel et al., HIV-positive men had a higher prevalence of HPV infection, compared to those without HIV (55.6% vs 23.8%).³⁴

Discussion

Penile cancer is a rare malignancy, especially in Europe and the USA where it occurs with an incidence of 0.1–0.9 per 100,000 males.¹ In contrast, the incidence of penile cancer is markedly higher in South America, Southeast Asia, and Africa where it can account for up to 10% of male cancers and tends to affect younger patients compared with the Western world.^1,2 The vast majority (over 95%) of penile cancers are histologically classified as PeSCC, followed by less common types, such as adenocarcinoma, melanoma, Kaposi sarcoma, and true sarcoma.^2,35,36

A number of risk factors have been identified for PeSCC, most importantly the presence of a foreskin (i.e. omission of neonatal or childhood circumcision), HPV infection, LSc and phimosis, HIV, tobacco use, and poor penile hygiene. Omission of neonatal circumcision is probably the single biggest risk factor for developing PeSCC and neonatal circumcision, therefore, is an effective prophylactic measure.^3,37 However, circumcision in later life is thought to reduce the risk of cancer only partially and less so if circumcision is performed for the treatment of penile disease.⁴ LSc also predisposes to PeSCC, with one small study indicating a past history and/or evidence of LSc in over half of PeSCC patients.⁵ HPV is also recognised as a principal risk factor for penile cancer, having been identified in 22–45% of penile tumours.⁴ Unlike cervical cancer, where HPV is the principal aetiological agent, but more like vulval cancer, PeSCC is thought to arise from PeIN via two distinct carcinogenic pathways: HPV-related (undifferentiated PeIN) and non-HPV-related (differentiated PeIN), the latter being associated with LSc.⁷ Histologically, HPV-related PeSCC is largely of basaloid and warty or condylomatous subtypes, while the non-HPV, or LSc-related pathway, most often gives rise to the ‘usual’ and verrucous subtypes.⁴

The primary objective of this study was to determine what is currently known and published in the literature about the relationship with, and interplay between, HIV and PeSCC. Particular attention has been given to addressing epidemiology, patient characteristics, aetiology, and outcomes. A broad, heterogeneous range of evidence has been uncovered and explored to synthesise a summary of this topic. Given this heterogeneity, it has not been possible to perform a formal meta-analysis, yet some important conclusions can nonetheless be drawn.

We present multisource evidence to demonstrate categorically the significantly increased risk of PeSCC in those with HIV. Although this relationship is already generally accepted, this review adds rigour to the claim. It also shows the range of magnitude of the actual risk that has been calculate (RR = 3.7 to 5.8, three studies; SIR = 3.8 to 11.1, four studies). Estimates of risk are markedly variable between studies, most likely because penile cancer is a rare malignancy. Therefore, analysis of risk is based only on a small number of cases, despite large HIV-positive study populations.

Ethnicity is also found to be a variable that appears to modulate the relationship between HIV infection and PeSCC. Most notably, Ortiz and colleagues reported Hispanic men to be at almost 3 times greater risk of PeSCC than White American men living with HIV.³⁰ This may be attributed to differences in rates of circumcision in White and Hispanic Americans (reported to be 91% and 44%, respectively), or to disparity in healthcare between ethnic and socioeconomic groups.³⁸ Further studies addressing ethnicity would be necessary to improve our understanding of the risk factors for PeSCC in different ethnic populations.

Beyond increasing the risk of developing PeSCC, HIV infection may also give rise to different phenotypes of penile disease. Wentzel et al. indicated that HIV-positive men with PeSCC present at a significantly earlier age than HIV-negative men.³⁴ Similarly, Frisch et al. observed a shorter interval between diagnosis of PeIN and PeSCC in those with HIV infection, suggesting more rapid transformation to invasive disease in HIV.¹¹ HIV infection is therefore likely to drive oncogenesis and transformation to PeSCC at an earlier age, a phenomenon also seen in other SCCs, such as those of the cervix and lung.³⁴

Furthermore, HIV status seems to affect clinical outcomes: HIV increased the risk of mortality from PeSCC four-fold in one study.²² Conversely, another study found no effect of HIV status (in patients undergoing ART for more than 2 years) on disease characteristics or progression.²⁹ These findings highlight the varying phenotypic spectrum of HIV disease, from undetectable viral load to AIDS, variability that has not been controlled for in this review. Indeed, the question of whether effective ART negates the effect of HIV on PeSCC is an intriguing area for further research.

Regarding the aetiopathogenesis of penile cancer in the context of HIV, review of the literature shows that it is difficult to make generalisations or come to conclusions, but does allow the generation of hypotheses. What can be said ensues.

Across cancer types, HIV and AIDS are most signally associated with cancers of infectious origin; this implicates susceptibility to oncogenic viruses as the driver of the excess burden of malignancy in the HIV-positive population.¹² HIV infection is associated with increased HPV incidence, higher rates of co-infection with multiple HPV genotypes, reduced HPV clearance, and greater progression to pre-neoplastic lesions.^39,40 Moreover, HIV-positive men diagnosed with PeSCC are significantly more likely to be co-infected with HPV, when compared with HIV-negative men.³⁴ Whether the relationship between HIV and HPV infection is causal or simply due to common lifestyle factors that give rise to both HIV and HPV is debated in the literature.^6,12 The largest study to date, a meta-analysis of cancer in people with HIV/AIDS compared with immunosuppressed transplant recipients, demonstrated similar patterns of excess HPV-associated cancers in both groups.¹² Given that lifestyle-related cancer risk factors likely differ between the two groups, increased cancer risk may in fact be attributed to immunocompromise.

We have noted a paucity of findings relating to HPV status. Wentzel and colleagues reported HIV-positive men to have a greater likelihood of HPV positivity, a finding in keeping with existing literature and the conclusions made above.³⁴ To further this line of enquiry, future research could explore the relationships with oncogenic high risk HPV types and undifferentiated PeIN; we have not specifically addressed the literature relating to PeIN in HIV and this itself may be a fruitful endeavour.

Further characterising the nature of immunocompromise and its relation to cancer risk is challenging. Immune status varies considerably during the course of HIV infection and AIDS, and it would be helpful to identify parameters of immune function that contribute to cancer risk. In PeSCC, Frisch et al. showed a correlation between the age of AIDS onset and the RR of PeSCC, with the greatest risk in those diagnosed with AIDS below the age of 30; the risk of PeSCC was significantly elevated during the first 4–27 months post-AIDS diagnosis, when compared with the pre-AIDS period.¹¹ But another study by the same group failed to find an association between CD4 count at the time of AIDS diagnosis and PeSCC risk.⁶ Yet, CD4 nadir has been suggested to be a risk factor for NMSC.^9,10 A retrospective study of HIV-positive patients found an inverse relationship between SCC risk and most recent CD4 count.⁴¹ Moreover, a prospective study of HIV-positive patients in Denmark found the risk of SCC to be related to nadir, but not most recent, CD4 count thus highlighting the importance of the history of immune status.¹⁰ These findings are congruent with work on transplant recipients where the degree of pharmacological immunosuppression has been shown to correlate with SCC risk.^42,43

The conflicting data regarding the relationship of CD4 nadir to PeSCC risk are intriguing. The topic is being further researched by us in our small but slowly growing cohort of patients. Intuitively, an important working hypothesis is that the risk of penile cancer must be related to the profundity and duration of immunocompromise. But immune function is a complex entity that is difficult to measure; a single CD4 count provides only a snapshot proxy marker of immune function. Instead, assessing the CD4 count (and other parameters) through the course of disease may prove more valuable, albeit investigationally challenging in retrospect. Nonetheless, future research could employ study designs that better characterise and measure immune function. Also, there is a scarcity of research concerning the immunopathogenesis of penile cancer in general that further limits our understanding of the drivers of PeSCC in HIV-positive individuals. For example, oncogenic HPV infection is probably more prevalent than appreciated, yet penile cancer is rare. There is no evidence that LSc is more prevalent in HIV and LSc does not emerge from the literature as risk factor for PeSCC in HIV, although we have seen cases, probably because the topic has not been addressed.

We have performed a comprehensive review of what has been published about HIV and penile cancer, embracing a range of study designs and settings. A limitation is that it is not a formal meta-analysis. Given the heterogeneity of relevant studies, we decided to conduct a literature review to ensure a comprehensive range of qualitative and quantitative data were obtained for consideration. Furthermore, while inclusion of both HIV and AIDS populations was necessary given the existing literature, it makes interpretation of results complex. The most pertinent findings are that the risk of penile cancer is indeed higher in HIV/AIDS (RR = 3.7 to 5.8, 3 studies; SIR = 3.8 to 11.1, 4 studies) and four times more lethal; progression from PeIN occurs ∼6 years sooner; certain ethnic groups (e.g. Hispanic) are more at risk.

More work is needed to understand the risk of cancer amongst the two populations, namely people living with HIV and people with AIDS, as well as in those undergoing effective ART.

We intend this study to be a useful reference for the relationship of HIV and PeSCC. We anticipate that it will be of utility in hypothesis-generation for further research into the aetiology and characteristics of penile cancer and other skin cancers, or indeed all cancers, in people living with HIV and AIDS.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Amir Pooya Amini

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