PRIMER

Penile cancer
Anita Thomas 1,2,3, Andrea Necchi 4, Asif Muneer5,6,7, Marcos Tobias-​Machado 8
,
Anna Thi Huyen Tran9, Anne-​Sophie Van Rompuy 10, Philippe E. Spiess 11 and
Maarten Albersen 1,2 ✉
Abstract | Penile squamous cell carcinoma (PSCC) is a rare cancer with orphan disease
designation and a prevalence of 0.1–1 per 100,000 men in high-​income countries, but it
constitutes up to 10% of malignancies in men in some African, Asian and South American
regions. Risk factors for PSCC include the absence of childhood circumcision, phimosis, chronic
inflammation, poor penile hygiene, smoking, immunosuppression and infection with human
papillomavirus (HPV). Several different subtypes of HPV-​related and non-​HPV-​related penile
cancers have been described, which also have different prognostic profiles. Localized disease
can be effectively managed by topical therapy, surgery or radiotherapy. As PSCC is characterized
by early lymphatic spread and imaging is inadequate for the detection of micrometastatic disease,
correct and upfront surgical staging of the inguinal lymph nodes is crucial in disease management.
Advanced stages of disease require multimodal management. Optimal sequencing of treatments
and patient selection are still being investigated. Cisplatin-​based chemotherapy regimens are the
mainstay of systemic therapy for advanced PSCC, but they have poor and non-​durable responses
and high rates of toxic effects, indicating a need for the development of more effective and less
toxic therapeutic options. Localized and advanced penile cancers and their treatment have
profound physical and psychosexual effects on the quality of life of patients and survivors by
altering sexual and urinary function and causing lymphoedema.

✉e-​mail: maarten.albersen@
uzleuven.be
https://doi.org/10.1038/
s41572-021-00246-5
Penile cancer is a rare cancer with a prevalence of
0.1–1 per 100,000 men in high-​income countries. How­
ever, global incidence varies considerably between
different populations depending on risk factors, such
as human papillomavirus (HPV) infection, smoking
and poor hygiene, or protective factors, such as routine
infant circumcision1,2. Hence, penile cancer can consti-
tute up to 10% of male malignancies in some African,
Asian and South American regions1. Most penile can-
cers (95%) arise from the squamous cells of the glan-
ular and preputial skin and are penile squamous cell
carcinomas (PSCCs). These can further be subdivided
into basaloid, warty, papillary, verrucous, sarcomatoid,
adenosquamous and some other rare types in concord-
ance with WHO recommendations, and can either be
HPV-​driven or not HPV-​related. A meta-​analysis of
global data reported a pooled HPV prevalence of 50.8%
in PSCC2. Other tumours such as mucosal melanoma,
sarcoma and extramammary Paget’s disease can also
occur on the penile and glanular skin but these are not
the focus of the present review.
Penile cancer and its treatment often result in dev-
astating disfigurement, and efforts are underway to
improve disease-​related and treatment-​related qual-
ity of life3. Early diagnosis and staging are imperative,
as lymphatic spread is strongly associated with a poor
prognosis4. Early surgical staging of the groins (the
primary lymphatic landing site of PSCC metastasis)
has been shown to result in a survival advantage, but
adoption rates are low owing to the associated morbidity
and, potentially, the learning curve of this procedure5,6.
The mainstay of systemic therapy for advanced PSCC
is platinum-​based chemotherapy, but response rates are
poor (15–55%) and overall survival does not exceed
12 months7–10. Owing to a shortage of experimental can-
cer tissue samples, difficulties in obtaining funding for
rare cancer research and a poor understanding of the
genomic and molecular composition of metastatic PSCC,
highly effective systemic therapies are not available and
mortality is high. However, new insights into the patho-
physiology and genomic drivers have led to exciting
research in precision oncology and immune therapy.
In this Primer, we describe the epidemiology of and
mechanisms underlying penile cancer with an empha-
sis on the role of HPV infection in the development
of the disease. We explain contemporary and possible
future diagnostic approaches and management options
in localized and advanced penile cancer, and highlight
important considerations around the quality of life of
affected patients. Throughout this Primer, we provide a

NATURE REVIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:11 1

0123456789();:
Primer
Author addresses
1
Laboratory of Experimental Urology, Department of Development and Regeneration,
KU Leuven, Leuven, Belgium.
2
Department of Urology, University Hospitals Leuven, Leuven, Belgium.
3
Department of Urology and Pediatric Urology, University Medical Center Mainz,
Mainz, Germany.
4
Genitourinary Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute,
Milan, Italy.
5
Department of Urology, University College London Hospitals, London, UK.
6
National Institute for Health Research (NIHR) Biomedical Research Centre, University
College London Hospitals, London, UK.
7
Division of Surgery and Interventional Science, University College London, London, UK.
8
Section of Urologic Oncology, Department of Urology, ABC Medical School, Instituto do
Cancer Vieira de Carvalho, São Paulo, Brazil.
9
Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
10
Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
11
Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, USA.
perspective on specific challenges originating from the
rarity of the disease.
Epidemiology
Penile cancer is a rare disease for which only 26,000 cases
are estimated globally per year, accounting for <1% of
newly diagnosed cancers in men11. In high-​income coun-
tries, penile cancer prevalence is 0.1–1 per 100,000 men,
but it is generally more common in low-​income and
middle-​income regions12,13 (Fig. 1). Notably, its incidence
is negligible in Islamic countries and Israel owing to the
practice of religious neonatal circumcision, whereas
3–7 per 100,000 men in Brazil and India are affected14.
The number of new diagnoses in the EU is estimated
at ~3,100 per year15. However, variations between dif-
ferent European regions are relatively large and some
regions have an incidence >1 per 100,000 men (Malta,
some regions in Spain, Neuchatel in Switzerland and
Haute-​Rhin in France)15,16. Owing to disparities in reli-
gious practices or socioeconomic conditions, incidence
rates can vary even within one country. For instance, in
the USA, penile cancer is more common in men with
Hispanic ancestry than those with Asian-​Pacific Islander
ancestry (0.7 versus 0.2 per 100,000 men)17. There are
no conclusive data on inheritable genetic aberrations
or factors relating to ethnicity to explain the observed
regional differences.
Up to 40% of men are diagnosed with localized
penile cancer, which has a 5-​year overall survival of
~90%; however, once the tumour has metastasized the
prognosis worsens dramatically18. Overall survival for
metastatic disease is ~80% for unilateral inguinal lymph
node involvement of ≤2 nodes (stage N1 or limited N2),
10–20% for bilateral or pelvic lymph node involvement
(stage N2 or N3) and <10% in the case of extranodal
extension19. Importantly, the overall prognosis has not
improved in Europe and the USA since 1990, which
may be due to late-​stage initial diagnosis and lim-
ited improvements in care and disease management20.
However, in the UK the overall prognosis of penile
cancer has drastically improved after establishing cen-
tralized health care, with 5-​year survival improving by
~10%, probably as a result of improved detection and
management of inguinal lymph node metastases21,22.
2 | Article citation ID: (2021) 7:11
0123456789();:
Precise tumorigenesis of PSCC is still poorly under-
stood, but several risk factors have been identified. PSCC
mostly affects men of advanced age with a peak in inci-
dence in the sixth decade8. Currently observed trends of
early onset (≤64 years of age) may be partly associated
with changes in sexual practice that increase exposure
to sexual transmitted diseases and prevalence of HPV
infection23. HPV is a non-​enveloped double-​strand DNA
virus existing in >150 different types of which only some
have been clearly shown to be associated with cancer
causality24,25. Infection with HPV types 16, 18, 31 and
33 have been reported in high percentages of PSCC
cases23,26–28. Premalignant lesions that are related to HPV
infection, such as erythroplasia of Queyrat and Bowen’s
disease, are associated with an increased risk of invasive
PSCC27. Overall, 30–50% of invasive PSCCs are esti-
mated to be associated with HPV infection, most nota-
bly with HPV16. Hence, HPV infection is becoming a
crucial focus in the development of preventive and ther-
apeutic strategies, including gender-​neutral vaccination,
aimed to ultimately reduce its prevalence particularly in
high-​risk male populations29.
Furthermore, the presence of a phimosis has been
identified as a risk factor for PSCC development, and
early penile circumcision is considered a strong pro-
tective factor against developing invasive PSCC (odds
ratio 0.33; 95% CI 0.13–0.83)30–32. Chronic inflamma-
tory conditions, such as lichen sclerosus, are commonly
described risk factors for PSCC; penile lichen sclerosis
has an estimated risk of malignant transformation of
4–8%33. The relationship between phimosis, chronic
inflammation and PSCC and the role of circumcision in
prevention are detailed in Box 1.
Some lifestyle factors also increase the risk of PSCC.
Tobacco use is a well-​recognized risk factor for many
malignancies and also has a correlation with PSCC
development34. Of note, obesity and poor penile hygiene
are also associated with an increased risk of developing
PSCC35. In line with this observation, PSCC is more
common in regions with low socioeconomic status and
education, as risk factors such as lack of circumcision,
poor hygiene and HPV infection tend to be more prev-
alent in these locations36. Interestingly, PSCC occurs
more frequently in patients with psoriasis undergoing
psoralen UV-​A phototherapy (PUVA)37. As the male
genitalia are more susceptible to the dose-​dependent
carcinogenic effects of PUVA than nongenital areas,
shielding of the genital area is therefore recommended38.
Mechanisms/pathophysiology
Progression of premalignant lesions to cancer
Several terms have been used for precursor lesions of
penile cancers, such as erythroplasia of Queyrat, penile
Bowen’s disease, penile carcinoma in situ and bowe-
noid papulosis. Multiple different terms for the same
entity can be confusing, particularly if a term does
not describe the grade of the malignant changes and,
thereby, the prognosis of the lesion39. Thus, the stand-
ardized term penile intraepithelial neoplasia (PeIN) is
now favoured over previous terms. PeIN is divided into
two subtypes: a differentiated subtype, which is typically
lichen sclerosus-​associated, and an undifferentiated,
www.nature.com/nrdp
 Primer

Penile cancer
incidence ASR
(world) (per 100,000)
<0.08
0.08–0.43
0.43–0.88
0.88–1.3
≥1.3
Not applicable
No data

Penile cancer
mortality ASR
(world) (per 100,000)
0.00–0.09
0.09–0.27
0.27–0.43
≥0.43
Not applicable
No data

Fig. 1 | Penile cancer incidence and mortality. Estimated incidence (part a) and mortality (part b) rates in 2018 for penile
cancer shown as age-​standardized rates (ASR; adjusted to World Standard Population) to account for differing age
profiles of regions. Data are from the Global Cancer Observatory (https://gco.iarc.fr/today)12,13.

HPV-​associated subtype40,41. In addition to this clas- tissue registry study in 380 patients in the Netherlands
sification based on pathogenesis, in analogy with vul- found that 67% of lesions were PeIN 3 (severe dyspla-
var premalignant lesions, classification of PeIN lesions sia) and progressed to a malignant phenotype in 7% of
into three grades has been proposed39 (Table 1). A 2019 cases; PeIN 2 (moderate dysplasia) was found in 22%

NATURE REVIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:11 3

0123456789();:
Primer
and progressed in 8% and PeIN 1 (mild dysplasia) was
found in 11% and progressed to malignancy in 2%39.
Most lesions were noted on the prepuce (45%) or glans
(38%)39. The majority of PeIN lesions are HPV positive
and they predominantly harbour several HPV genotypes
(HPV6, HPV11 or HPV16)42. A 2019 meta-​analysis
estimated that 98.6% of PeIN 1–2 and 80.5% of PeIN 3
lesions were HPV positive2. Risk factors for PeIN incl­
ude the presence of inflammatory skin diseases, such
as lichen planus, use of immunosuppressive drugs, pre-
vious penile surgical procedures, history of balanitis or
genital warts, and organ transplantation, according to a
large population-​based study from Sweden43.
Undifferentiated PeINs, of which 80% are HPV pos-
itive, are mostly associated with HPV16. Benign penile
condylomas, which predominantly occur within 1 year
after HPV infection, have an increased prevalence of
more indolent forms of HPV, such as HPV6 and HPV11
(ref.27). By contrast, HPV16 is a more concerning geno-
type owing to its frequency and malignant propensity.
Progression of HPV16 infection to PeIN is believed to
occur in up to 2% of cases, and typically occurs over a
longer time period (within 2 years)27. Of note, this area
of penile carcinogenesis is poorly studied and many
additional predisposing factors are not well accounted
for, such as the susceptibility of the host immune system
or the potential synergistic effect of repeated exposure to
either HPV16 and/or other HPV genotypes42.
Box 1 | Phimosis, circumcision and penile cancer
Phimosis and penile circumcision seem to be two opposing risk factors for penile
cancer, and circumcision is widely cited to protect against penile cancer. In East Africa
in the 1960s, penile cancer was more common in traditionally non-​circumcizing ethnic
groups than among those practising circumcision246,247. A 1947 case–control study in the
US military showed that circumcision in childhood was rare in men with penile cancer
compared with controls248. In 2011, a meta-​analysis including 248 cases and 2,959
controls showed a strong protective effect of childhood and adolescent circumcision
on invasive penile cancer (odds ratio (OR) 0.33; 95% CI 0.13–0.83)32.
Several explanations for these epidemiological observations have been put forward.
First, circumcision may lead to increased detection of penile cancer at an early stage if
the tumours would have been located under the foreskin. Second, many penile tumours
arise from the foreskin and circumcision may be preventive by removing a site susceptible
to tumour development65,66. Third, phimosis itself is a strong risk factor for penile cancer
(OR 4.9–37.2)32; hence, the effect of childhood and adolescent circumcision on invasive
penile cancer may be largely mediated through elimination of phimosis. This link is
biologically plausible, as phimosis likely leads to a build-​up of smegma and chronic
inflammation, which may increase the risk of penile cancer50,249,250.
Apparently conflicting with this reasoning is that circumcision in adulthood is associated
with an increased risk of invasive penile cancer (summary OR 2.71; 95% CI 0.93–7.94)32.
A plausible explanation for this increased risk may be reverse causality32, wherein cir-
cumcision may have been performed as a treatment for penile cancer, a cancer precursor
or an underlying medical condition that is a risk factor for penile cancer.
Routine infant circumcision is a controversial topic, as the debate is influenced by strong
cultural, religious and economic sentiments251. Proponents state that circumcision
prevents or reduces the risks of penile cancer, HIV and human papillomavirus (HPV)
infection, whereas opponents highlight the lack of consent and the possible effects
of circumcision on sexuality and sensitivity of the penis252,253. Given the low incidence of
invasive penile cancer and the availability of other preventive strategies, such as HPV
vaccination, condom use and smoking cessation, it is difficult to justify universal
neonatal circumcision as a preventive strategy for penile cancer in infants in areas with
good personal hygiene and low penile cancer prevalence251. However, the combined
effects of circumcision on cancer, HPV and HIV infection may be arguments to advocate
the procedure in developing countries with high prevalence and high mortality rates of
these diseases254.
4 | Article citation ID: (2021) 7:11
0123456789();:
Genes, pathways and microenvironment
PSCC can develop along HPV-​d ependent and
HPV-​independent pathways. The HPV-​related path-
way remains the better understood biological mech-
anism underlying penile carcinogenesis (Fig. 2). The
initial inciting event is thought to be HPV infection
of the penile epithelial mucosal cells via both specific
receptors, including proteoglycans and integrins, and
physical micro-​abrasions likely generated through sex-
ual activity44. Persistent and/or recurrent exposure of the
penile tissue to HPV leads to the integration of HPV
DNA into the host genome and eventual transforma-
tion of the host cell into a malignant phenotype. The
resulting overexpression of viral oncoproteins E6 and E7
elicits cell cycle dysregulation and host genomic instabil-
ity through interaction with p53 and pRb, respectively,
initiating and maintaining malignant propensity45. E7
associates with pRb, resulting in the release of the tran-
scription factor E2F, cell cycle dysregulation and over-
expression of p16INK4a, which is a useful biomarker of
HPV-​related PSCC24,45–47. In addition, E7 leads to down-
regulation of p21 and p27 and upregulation of cyclin A
and cyclin E, which results in proliferation and centriole
amplification, promoting aneuploidy, cellular immor-
talization and carcinogenesis. The carcinogenic effects
of E6 result from inhibition of p53 and BCL-2 homol-
ogous antagonist/killer (BAK), leading to inhibition of
apoptosis and induction of chromosomal instability, and
from activation of telomerase and SRC kinases, leading
to cell proliferation, which results in cell immortali-
zation and dysregulated growth48,49. These drivers of
HPV-​mediated penile carcinogenesis are fairly well
established, but research into targeting these mediators
remains at an early stage and initial results have mostly
been disappointing.
The genomic pathways relating to non-​HPV-​related
penile carcinogenesis and progression are not well
understood and only the clinical aetiological risk factors
and drivers, along with their mechanistic targets, have
been identified. However, gene sequencing studies
have increased our understanding of the genomic path-
ways that drive non-​HPV-​related PSCC, predominantly
through the effects of chronic inflammation and somatic
gene alterations24. Chronic inflammation drives malig-
nant cell transformation via production of reactive oxy-
gen species and reactive nitrogen intermediates that can
induce DNA damage and genomic instability50. Many
chronic penile conditions, including balanoposthitis,
phimosis and lichen sclerosus, which are important
risk factors for the development of penile cancer, share
a common mechanism of inducing cyclooxygenase 2
(COX2) expression, which has been associated with
differentiated PeIN and primary and distant PSCC51.
Studies suggest that COX2 overexpression drives the
overproduction of prostaglandins (most notably pros-
taglandin E2) and thromboxanes, resulting in angiogene­
sis, proliferation and invasion via various molecular
pathways common to HPV-​related PSCC52.
Somatic gene alterations are another proposed
non-​HPV-​mediated genomic pathway of penile carcino-
genesis, occurring through gene copy number amplifica-
tions, deletions, mutations, loss of heterozygosity and/or
www.nature.com/nrdp
 Primer

Table 1 | Classification and features of premalignant penile lesions and squamous cell carcinoma
Disease phenotype Relative HPV Tumour-​specific Histopathological features39,86,240
frequency positivity mortality
(%)24,237,238 (%)24,238,239 (%)87,237,240
Precursor lesions
Non-​HPV-​related PeIN 3: 75 0 NA Thickened epithelium with elongated and anastomosing rete ridges,
(differentiated) severe subtle abnormal maturation, atypical basal layer cells, parakeratosis,
PeIN dysplasia prominent intercellular bridges, basal and suprabasal mitotic figures
Differentiated PeIN is always classified as PeIN 3: severe dysplasia
HPV-​related PeIN 1: 25 100 NA Warty: atypical parakeratosis, squamous maturation, prominent
(undifferentiated) mild pleomorphism and koilocytosis. Basaloid: full-​thickness presence
PeIN (warty, dysplasia of immature, small, monotonous basophilic cells. Warty–basaloid:
basaloid, variable mixture of warty and basaloid cells.
PeIN 2:
warty–basaloid)
moderate Undifferentiated PeIN is graded according to severity of dysplasia.
dysplasia PeIN 1: flat lesion with atypical cells and elevated mitotic activity
PeIN 3: restricted to the basal or lower third of the epithelium, maturation in
severe the upper two-​thirds. PeIN 2: atypical cells involve two-​thirds of the
dysplasia epithelium, mitotic figures confined to the basal two-​thirds. PeIN 3:
full-​thickness presence of atypical cells, mitotic figures at all levels
of the epithelium
Non-​HPV-​related squamous cell carcinoma
Squamous cell carcinoma, 45–75 24–59 20–38 Various degrees of squamous differentiation and keratinization,
usual type diagnosed after exclusion of other variants, three-​tiered WHO/ISUP
grading system
Pseudohyperplastic <1 0 0 Commonly multifocal, flat lesion with downward, irregular
carcinoma proliferation of nests with sharp borders composed of
well-​differentiated cells, simulates pseudoepitheliomatous
hyperplasia
Pseudoglandular carcinoma <1 0 30 Honeycomb appearance, acantholytic pseudolumina filled
with necrotic debris in the centre of nests composed of poorly
differentiated cells
Verrucous carcinoma 3–8 0–23 0 Papillomatosis, hyperorthokeratosis, acanthosis, extreme squamous
differentiation, no koilocytosis, broad-​based and pushing tumour front
Carcinoma cuniculatum <1 0 0 Variant of verrucous carcinoma with burrowing labyrinthine growth
pattern, hyperkeratosis, papillomatosis, acanthosis, endophytic
growth with broad-​based pushing margins, no koilocytosis; irregular
foci of invasive usual squamous cell carcinoma may be present
Papillary carcinoma, NOS 2–15 8–15 0–6 Variable and complex papillae with or without fibrovascular core,
hyperkeratosis, maturing squamous cells with minimal to moderate
atypia, no koilocytosis, irregular and jagged tumour–stromal interface
Adenosquamous carcinoma 1–2 0–14 Mixed neoplasm consisting of predominant squamous tumour nests
intermixed with a minor mucinous glandular component
Sarcomatoid carcinoma 1–7 0–17 45–75 Biphasic epithelial-​spindle cell neoplasm, composed of atypical
spindle cells arranged in fascicles or bundles, with or without foci
of carcinoma, sometimes pleomorphic or giant cells or heterologous
bone and cartilaginous formation
HPV-​related squamous cell carcinoma
Basaloid carcinoma 4–10 70–100 21–67 Nesting pattern, solid or centrally necrotic (comedonecrosis) nests of
small uniform basaloid cells, abrupt keratinization, abundant mitosis
and apoptosis
Papillary-​basaloid carcinoma <1 92 80 Papillary variant of basaloid carcinoma, papillae with central
fibrovascular core, small basophilic tumour cells
Warty carcinoma 5–10 22–100 0–9 Condylomatous papillae with prominent central fibrovascular cores,
(hyper)parakeratosis, clear cells and pleomorphic koilocytosis,
irregular and jagged tumour–stromal interface
Warty–basaloid carcinoma 4 82 30 Variant of warty carcinoma with intermixed warty and basaloid
features
Clear cell carcinoma <1 100 20–30 Variant of warty carcinoma, nests composed of large and polygonal
cells with clear cytoplasm, common comedo-​like and geographical
necrosis
Lymphoepithelioma-​like <1 100 Not known Syncytial growth pattern, poorly differentiated to undifferentiated
carcinoma cells, dense lymphoplasmacytic and eosinophilic infiltrate
HPV, human papillomavirus; ISUP, International Society of Urological Pathology; NA, not applicable; NOS, not otherwise specified; PeIN, penile intraepithelial neoplasia.

NATURE REVIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:11 5

0123456789();:
Primer

HPV-associated carcinogenesis

E6 E7
Cell
p16
death

p53 and Telomerase SRC kinases pRB p21 and p27 Cyclin A and Centriole
BAK cyclin E amplification
E2F

Release

Apoptosis Proliferation E2F Proliferation Aneuploidy

Cell immortalization Cell immortalization

Fig. 2 | Molecular pathways in HPV-associated penile carcinogenesis. Interaction of HPV E6 and E7 oncoproteins with
cellular pathways induces cell immortalization. E6 activates telomerase and proto-​oncogene tyrosine-​protein kinase (SRC
kinases), and inhibits p53 and BCL-2 homologous antagonist/killer (BAK). E7 inhibits the tumour suppressor protein pRb,
with consequent release of the E2F transcription factor, which enables E2F to interact with the cellular transcription
machinery and stimulate upregulation of the tumour suppressor gene cyclin-​dependent kinase inhibitor 2A (CDKN2A),
which encodes the protein p16INK4a (p16). pRb inactivation releases p16 from its negative feedback control, causing a
paradoxical increase in the levels of this protein, which attempts to inhibit uncontrolled cellular replication; in other
words, p16 is overexpressed in HPV-​related tumours in an unsuccessful attempt to stop cell proliferation. E7 stimulates
cyclin A and cyclin E, inactivates cyclin-​dependent kinase inhibitors p21 and p27, which have important regulatory
functions pertaining to cell cycle control, and induces centriole amplification, resulting in excessive cell proliferation
and aneuploidy. Adapted with permission from ref.241, Elsevier.

epigenetic changes53,54. Some of the tumour suppressor
genes implicated in these mechanisms are the p16INK4a–
cyclin D–Rb and the p53 pathways, illustrating the con-
fluence of HPV-​dependent and non-​HPV-​dependent
pathways, which provides unique opportunities to
develop targeted therapies against these mechanisms of
carcinogenesis.
Tumour microenvironment. Understanding the tumour
microenvironment is crucial to understanding how and
why some tumours remain indolent, whereas others are
highly aggressive. Clinical studies of tissue samples have
shown possible unique differences between the tumour
microenvironments of HPV-​positive and HPV-​negative
PSCC. HPV-​positive tumours seem to have a higher
propensity of tumour-​infiltrating T cells with a stronger
polarization towards T helper 1 cells and a more pro-
nounced cytotoxic immune response than HPV-​negative
tumours55; however, why these changes occur and their
effects remain unclear. In HPV-​related malignancies,
alterations in components of the extracellular matrix,
including matrix metalloproteinases, and in some of
its regulators, such as tissue inhibitors, including the
presence of stromal granzyme B, have been found56,57.
In invasive PSCC, peritumoural stromal remodelling
characterized by a focal loss of CD34-​positive fibrocytes
with an associated increase of α-​smooth muscle actin-​
positive myofibroblasts was strongly associated with
cancer-​specific mortality58. Furthermore, some char-
acteristics of the tumour microenvironment of penile
cancer have been associated with the progression of
lymph node metastases, including diffuse programmed
cell death 1 ligand 1 (PDL1) expression on tumour cells,
CD163-​positive macrophage infiltration, non-​classical
HLA class 1 upregulation and low stromal CD8-​positive
T cell infiltration 59. Understanding and targeting
the tumour microenvironment and accounting for the
unique differences between HPV-​positive and HPV-​
negative tumours holds great promise in improving
and personalizing current therapeutic strategies60. An
emerging research area is the effect of the microbiome
on cancer development and progression. A study in men
from South Africa found differences in the penile micro-
biota composition between those with and without HPV
infection and with and without HIV infection61. HPV
infections were strongly associated with relative abun-
dance of Staphylococcus and microorganisms associated
with bacterial vaginosis, notably Prevotella, Peptinophilus
and Dialister.
Immune involvement
Pioneering work by Blank et al. provided a framework to
study the interactions between a cancer and host along
with its incipient immune response using the concept
of a cancer immunogram — a graphic visualization of
the patient-​specific landscape of the tumour micro­
environment that can be used as a clinical biomarker62.
The implementation and adoption of personalized can-
cer immunograms, such as those created for urothelial
cancer63, provides a unique opportunity to optimize a
personalized therapeutic approach to a specific tumour
by potentiating the various elements of a cancer-​specific

6 | Article citation ID: (2021) 7:11 www.nature.com/nrdp

0123456789();:

immune response. Early work has provided insights
into the role of various immune parameters, such as
tumour mutational burden, immune cell infiltration
and immune checkpoint expression such as PDL1
(ref.64). Unfortunately, crucial elements of elucidating a
tumour immune response, such as tumour metabolism
and T cell receptor variability in expression and bind-
ing, remain unclear, limiting our understanding of the
dynamic interactions within a complex PSCC immu-
nogram. An improved understanding of the impor-
tant drivers of host and tumour immune responses in
PSCC should lead to more effective and personalized
therapeutic approaches.
Diagnosis, screening and prevention
Clinical appearance and history
Primary tumours of the penis are clinically obvious
when they present as large exophytic lesions. The diag-
nostic pathway confirms the histological subtype and the
extent of invasion of the primary lesion as well as assess-
ing for metastatic disease to regional or distant lymph
nodes. The majority of penile cancers are squamous
cell carcinomas (SCCs) (95%), which can be suspected
clinically on appearance and location8. The anatomical
location on the penis and the exophytic appearance are
two distinct features that would raise a clinical suspi-
cion and instigate investigations. Penile cancer typically
arises on the mucosal surfaces of the penis and a review
of 2,000 cases showed that tumour location was mainly
on the glans (35–48%) or inner prepuce (13–21%) and
a smaller proportion located on the keratinized penile
shaft (2%)65,66. These lesions are commonly painless
and, under a phimotic foreskin, can be associated with
a purulent discharge67. In contrast to exophytic lesions,
ulcerative lesions on the glans or prepuce have a wider
differential diagnosis and should not be diagnosed as
a penile cancer until histologically proven on either
an incisional or a punch biopsy for larger and glanular
lesions or excisional biopsy, such as radical circumcision,
for foreskin lesions. Ulcerative lesions may be secondary
to inflammatory disorders, such as granulomatosis with
polyangiitis68, pyoderma gangrenosum69, tuberculosis70,
or sexually transmitted diseases, such as syphilis71.
Clinical evaluation of the primary lesion to assess the
extent of local invasion aids in the planning of surgery.
As most invasive lesions located on the prepuce or glans
can be excised using penis-​preserving procedures, pal-
pation of the glans and penile shaft correlates with the
extent of invasion into the corpus spongiosum or corpus
cavernosum72. This enables surgical planning, includ-
ing the requirement for either a glansectomy or partial
penectomy. Lesions can also arise from the anterior ure-
thra and infiltrate into the glans spongiosum without
developing an exophytic glans lesion. Careful examina-
tion of the urethral meatus can detect these tumours,
and palpation of the proximal urethra can ensure that
there are no further lesions that are not contiguous
with the primary lesion (skip lesions). The clinical
examination should assess the lesion size, location (for
example, glans, shaft or foreskin) and morpho­logy
(for example, papillary, nodular, ulcerating, fungating or
flat). Medical photography can be used as an adjunct,
NATURE REVIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:11
0123456789();:
Primer
as it aids multidisciplinary discussions and follow-​up
(Fig. 3).Diagnostic difficulties arise when the cancer is
occluded under the foreskin or originates from within
the distal urethra. Even when visible, the appearance of
small cancers or low-​grade disease may be difficult to
differentiate from that of benign genital dermatoses73.
Owing to poor public awareness and feelings of
shame, the majority of penile cancers have a delayed
presentation and are clinically obvious74. The clini-
cal history should document key risk factors, such as
smoking, previous HPV-​related infections, circumcision
status, lichen sclerosus and immunosuppression75–77. For
large lesions, which can obstruct the urethral meatus, the
duration of complaints and voiding dysfunction are also
relevant and determine the urgency of treatment or the
need for urethral catheterization.
Imaging
Imaging is essential for cancer staging, surgical planning
and identification of skip lesions within the corpora cav-
ernosa. Cross-​sectional imaging, such as CT, enables dis-
ease staging at diagnosis and identification of abnormal
inguinal or pelvic lymphadenopathy as well as distant
metastatic disease. Penile ultrasonography and MRI are
the preferred modalities for the primary lesion.
Ultrasonography. The primary role of ultrasonogra-
phy in the diagnostic work-​up is to assess the inguinal
lymph nodes. Morphologically abnormal lymph nodes
can undergo fine needle aspiration (FNA). As an alter-
native to MRI, ultrasonography also enables imaging of
the primary tumour to visualize the extent of spongiosal
or cavernosal invasion (Fig. 4). On the basis of the final
histological analysis, ultrasonography provides more
accurate assessment of the extent of cavernosal invasion
than clinical palpation78. Although ultrasonography can
delineate the tumour from the normal corpus spongio-
sum and tunica albuginea, it is not as accurate in assess-
ing the extent of corpus spongiosum involvement for
small glans tumours79.
MRI. Clinical and histological assessment of the pri-
mary tumour correlates with penile MRI in the pres-
ence of a pharmacologically induced erection80,81 (Fig. 4).
Comparison with histological analysis shows progres-
sively better stage-​specific sensitivity and specificity of
MRI assessment according to the tumour stage (T1 85%
and 83%, T2 75% and 89% and T3 88% and 98%, respec-
tively)80. A further study showed that preoperative penile
MRI changed the decision for surgical management in
3 of 13 patients, as the tumour stage was changed fol-
lowing penile imaging80. Thus, penile MRI is a useful
adjunct in planning primary surgery, particularly when
the extent of corpus cavernosum invasion is unclear and,
therefore, adjustment of the surgical resection margins
to include the distal corpora is required if the tumour
breaches the tunica albuginea.
CT and PET/CT. Owing to the potential considerable mor-
bidity of inguinal lymphadenectomy (ILND) and pelvic
lymphadenectomy (PLND), the search for an imaging mo­
dality that can accurately identify lymphatic metastases of
7
Primer

a b c d

e f g h

i j k l

Fig. 3 | Clinical appearance of penile cancer. Several premalignant lesions and subtypes of penile squamous cell
carcinoma (SCC) result in various clinical presentations. a | Non-​HPV-​related penile intraepithelial neoplasia (PeIN).
b | HPV-​related PeIN. c | Carcinoma cuniculatum on a background of severe lichen sclerosus of the prepuce (cT1).
d | Usual-​type spinocellular carcinoma on a background of severe lichen sclerosus of the glans (cT2). e | Keratinizing
tumour of the glans and inner prepuce; well-​differentiated hybrid squamous-​verrucous carcinoma (cT1). f | Verrucous
carcinoma of the glans displaying hyperkeratosis (cT1). g | Ulcus of the glans consisting of usual-​type SCC displaying
hyperkeratosis (cT2). h | Warty–basaloid carcinoma (HPV-​driven, cT2) on a background of PeIN 3. i | Exophytic tumour
consisting of usual-​type SCC invading the spongious tissue of the glans (cT2). j | Exophytic tumour consisting of usual-​type
SCC invading the spongious tissue of the glans (cT2) originating from a background of lichen sclerosus. k | Usual-​type SCC
invading the complete glans and the tips of the corpora cavernosa (cT3). l | HIV-​seropositive patient with HPV-​driven
poorly differen­tiated basaloid penile SCC; locally invasive tumour invading the scrotum with bulky lymph nodes fungating
through the skin (cT4N3); associated condyloma accuminata on the penile shaft.

PSCC continues82. A systematic review assessing the role
of 18F-​fluorodeoxyglucose PET/CT (18F-​FDG PET/CT)
in inguinal nodal staging concluded that pooled sensi-
tivity of this imaging modality was 96% for patients with
palpable lymph nodes but 57% for cN0 patients83. Hence,
micrometastases and distinction between reactive and
malignant lymphadenopathy continue to be challeng-
ing, and surgical staging of the groins remains a central
aspect of penile cancer management8. Staging for distant
metastases is recommended in patients with biopsy-​
proven positive inguinal nodes. On the basis of only a few
small studies and case reports, 18F-​FDG PET/CT seems
to be more accurate than contrast-​enhanced CT alone
for pelvic lymph nodes and distant metastases if ingui-
nal metastases are present84. In other malignancies and
lymph node areas, results suggest that 18F-​FDG PET/CT
has higher accuracy than CT alone in staging pelvic
lymph nodes; however, high-​quality comparative data
in large cohorts of patients with penile cancer are lack-
ing to reliably suggest that adding 18F-​FDG PET/CT to
diagnostic contrast-​enhanced CT improves accuracy84.
Penile biopsy
A diagnostic biopsy is deemed mandatory in the man-
agement of solid tumours in general. However, the penis
is an external organ and large exophytic tumours are
clinically obvious. In the presence of palpable inguinal
lymph nodes, FNA confirming PSCC within the lymph
nodes negates the need for a penile biopsy in the pres-
ence of a clinically obvious PSCC, as its results would

8 | Article citation ID: (2021) 7:11 www.nature.com/nrdp

0123456789();:
 Primer

not change the treatment decision-​making in a patient
with metastatic disease. Lesions that appear ulcerative
or inflammatory are sometimes secondary to benign
disease. PSCC lesions on the foreskin can be removed
easily by circumcision, which provides a diagnostic
biopsy as well as a definitive therapy. However, caution is
advised for more extensive lesions affecting the glans or
those invading the corpus cavernosum, so that adequate
surgical planning is performed based on the definitive
biopsy result. In situations in which ablative therapy or
radiotherapy is planned, a pre-​procedure penile punch
or incisional biopsy is mandatory for local staging as
lesions that invade the corpus spongiosum may not be
suitable for ablative therapy and because risk stratifi-
cation is needed to determine the appropriate method
of lymph node assessment. Biopsy specimens obtained
from primary penile lesions need to be deep enough to
include the underlying corpus spongiosum for accurate
local staging. This is particularly important in the con-
text of premalignant disease for which invasive disease is
detected in the final histological analysis in up to 20% of
patients undergoing surgery for premalignant disease85.
Histological analysis and TNM staging
Most classification schemes of PSCC before 2016
were exclusively morphology based. The 2016 WHO
classification presents a new classification based on
clinicopathological distinctiveness and relation to HPV
infection86. An overview of subtypes and histopatho-
logical hallmarks is provided in Table 1 and exemplary
images are shown in Fig. 5. The final pathology report
should include several tumour characteristics: type of
specimen (circumcision, partial or total penectomy),
primary tumour site or sites (glans, coronal sulcus,
foreskin or shaft skin), tumour size, histological sub-
type and grade, tumour thickness, level of invasion
(lamina propria, corpus spongiosum/tunica dartos,
corpora cavernosa/skin) and lymphovascular and per-
ineural invasion8. Immunohistochemistry for p16INK4a
is a helpful tool for identifying HPV-​related cases, as
p16INK4a positivity is strongly associated with high-​risk
HPV infection24. Furthermore, associated lesions, such
as PeIN and lichen sclerosus, should be reported. Finally,
if lymph nodes have been submitted for assessment, the
site, the total number and the number of positive nodes,
as well as the presence of extracapsular extension, should
be reported87,88.
The tumour–node–metastasis (TNM) classification
is the most widely used cancer staging system and was
updated in 2018 (refs89,90) (Box 2). Pathological and clin-
ical staging categories of the primary tumour include Tis
(PeIN) and Ta (noninvasive localized), both of which are
limited to the epidermis, T1 (where the tumour invades
the dermis or subdermal connective tissue; subdivided

a b c
*

CC *
CC

CC
*

d S e f
CC * *
CC
S

Fig. 4 | Imaging in penile cancer diagnosis. Various imaging techniques can be used for staging of the primary tumour
and metastatic sites in penile squamous cell carcinoma. a–c | MRI images of different patients with penile cancer. MRI was
performed after pharmacological erection induction to better discern the corpora cavernosa, the tunica albuginea and the
glans penis. Asterisks indicate tumour, arrow indicates tunica albuginea (black line), CC indicates corpus cavernosum.
The tumour abuts the tunica albuginea, which appears intact, indicating a tumour confined to the glans (part a). The tunica
albuginea is unsharp, correlating to a suspected invasion of the tunica (part b). The tumour grossly invades the vascular
spaces in the corpora cavernosa (part c). d | Ultrasonographic image of a glanular tumour. Arrowheads and arrow indicate
tumour, CC indicates corpus cavernosum, S indicated spongious tissue of the glans. e,f | 18F-​FDG PET/CT images. Inguinal
lymph node metastasis of penile cancer; asterisk indicates necrotic core, whereas the arrow indicates viable tissue with
uptake of 18F-​FDG tracer (part e). A large penile tumour invading the corpora cavernosa and crura of the penis (asterisk);
a skip lesion or skip metastasis is noted more proximal in the bulb of the penis (arrow) (part f). Part a adapted from ref.242,
Springer Nature Limited. Part b is adapted from ref.243, CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).
Parts c and d adapted with permission from ref.244, Springer Nature Limited.

NATURE REVIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:11 9

0123456789();:
Primer

a b c d

Precursor
*

e f g h
* *
* * * *
*
*
Non-HPV related

* *
*
i j k l
*
* *
*

m n o p
*
HPV-related

*
* *
*

q r s
p16INK4a immunostaining

Fig. 5 | Histology of penile carcinomas. This figure illustrates the histopathological appearance of precursor lesions, non-​HPV-​
related invasive penile squamous cell carcinoma (PSCC) and HPV-​related invasive PSCC in haematoxylin and eosin stains
(upper panel) and different p16INK4a immunostaining patterns (lower panel). a | Differentiated penile intraepithelial
neoplasia (PeIN) with elongated and anastomosing rete ridges (arrow) and atypical basal layer cells (magnification ×10).
b | Warty PeIN with squamous maturation, atypical parakeratosis, pleomorphism and koilocytosis (magnification ×10).
c | Basaloid PeIN with a full-​thickness presence of immature, small, monotonous basophilic cells in the epithelium (asterisk)
(magnification ×10). d | Warty–basaloid PeIN with koilocytic changes in the upper epithelial cell layer (asterisk) and basaloid
cells in the lower half of the epithelium (arrow) (magnification ×10). e | Usual PSCC, well-​differentiated, grade I with well-​
delineated tumour nests with minimal atypia and central keratinization (asterisks) (magnification ×5). f | Usual PSCC,
moderately differentiated, grade II with irregular tumour nests with more atypia, but maintained squamous maturation
(asterisks) (magnification ×5). g | Usual PSCC, poorly differentiated, grade III with infiltrating tumour nests with minimal
squamous maturation (asterisks) (magnification ×5). h | Pseudoglandular carcinoma with honeycomb appearance and
acantholytic pseudolumina (asterisks) (magnification ×5). i | Verrucous carcinoma with papillomatosis, hyperorthokeratosis
(asterisks) and broad-​based pushing tumour front (arrow) (magnification ×20). j | Carcinoma cuniculatum with burrowing
labyrinthine growth pattern (arrows) (magnification ×0.5). k | Adenosquamous carcinoma with squamous nests (asterisk)
intermixed with a glandular component (arrows) (magnification ×10). l | Sarcomatoid carcinoma with atypical spindle cells
(asterisk) (magnification ×5). m | Warty PeIN (asterisk) with microinvasion (arrow) (magnification ×10). n | Warty carcinoma
with clear cells and pleomorphic koilocytes (arrows) (magnification ×10). o | Basaloid carcinoma with irregular nests of
small uniform basaloid cells (asterisks) (magnification ×10). p | Warty–basaloid carcinoma with tumour nests with clear
and koilocytic cell warty features in the centre (asterisk) and basaloid features in the periphery (arrow) (magnification ×10).
q | Example of strong and diffuse p16INK4a immunostaining in a HPV-​related carcinoma (magnification ×20). r | Negative
p16INK4a immunostaining in a non-​HPV-​related carcinoma (magnification ×20). s | Patchy and focal staining is considered
negative for p16INK4a overexpression and indicative for a non-​HPV-​related carcinoma (magnification ×20).

into T1a and T1b depending on the presence or absence
of lymphovascular or perineural invasion and high grade,
respectively), T2 (invasion into corpus spongiosum), T3
(invasion into corpora cavernosa including tunica albug-
inea) and T4 (invasion into scrotum, prostate or pubic
bone). Clinical regional (inguinal) lymph node stages
include cN0 (no enlarged nodes), cN1 (palpable mobile
unilateral node), cN2 (≥2 palpable mobile unilateral
nodes or bilateral nodes), cN3 (unilateral or bilateral
palpable fixed nodal mass or pelvic lymphadenopathy)

10 | Article citation ID: (2021) 7:11 www.nature.com/nrdp

0123456789();:
 Primer

and pathological stages include pN0 (no metastasis), Screening

pN1 (≤2 unilateral metastases, no extranodal extension),
pN2 (≥3 unilateral metastases or bilateral metastases, no
extranodal extension) and pN3 (extranodal extension
or pelvic lymph node metastases). Distant metastasis
status is expressed as cM0 and cM1 for the absence or
presence of distant metastasis, respectively, and pM1 if
distant metastasis has been microscopically confirmed.
Histological grades of penile cancer include G1, G2 and
G3, denoting well, moderately and poorly differentiated/
high-​grade tissues, respectively.
Changes to the previous editions include the addi-
tion of perineural invasion as a prognostic indicator for
T1a and T1b lesions; T2 lesions include glans or ure-
thral spongiosum involvement; T3 refers to corpus cav-
ernosum involvement; pN1 is defined as ≤2 unilateral
inguinal metastases with no extranodal extension; and
pN2 refers to ≥3 unilateral inguinal metastases or bilat-
eral metastases. These amendments provide improved
discrimination of prognostic groups.
No dedicated screening programme for PSCC currently
exists. In countries with screening programmes for other
cancers, the low prevalence of penile cancer means that
it does not meet criteria for a screening programme.
Early detection and referral can be achieved by educat-
ing allied medical specialties, including primary care
providers, sexual health physicians, dermatologists and
urologists. In some countries, government and chari-
table campaigns promote regular self-​examination of
the male genitalia and encourage HPV vaccination for
schoolchildren, but these efforts are relatively new and
their effect will likely only be seen after several years.
Prevention
Until 2014 only a bivalent (HPV16 and HPV18) and
a quadrivalent (HPV6, HPV11, HPV16 and HPV18)
vaccine were available, whereas the nonavalent vaccine
(HPV6, HPV11, HPV16, HPV18, HPV31, HPV33,
HPV45, HPV52 and HPV58) is the current standard

Box 2 | Management recommendations for PSCC

According to current guidelines7,8,75, penile squamous cell carcinoma (PSCC) can be managed according to disease
classification following the American Joint Committee on Cancer (AJCC) prognostic stage group system89,255.
Stage 0 (Tis, N0, M0) tumours are non-​invasive lesions limited to the epithelium and can be treated with excision, ablation
and/or topical therapy. As these tumours usually do not metastasize, clinical examination of the groins combined with
definitive pathology is sufficient to stage the disease.
Stage I (T1a, N0, M0) tumours are invasive in the stroma but do not present with risk factors for metastasis, such as
lymphovascular or perineural invasion or poor differentiation grade. These lesions can be treated with organ-​sparing
surgery, laser ablation or radiotherapy. Low-​grade cases are staged by clinical groin examination, whereas
intermediate-​grade cases should undergo surgical inguinal staging procedures.
Stage II (T1b–T3, N0, M0) tumours are lesions invasive into the stroma with high-​risk features, in the corpus spongiosum or
in the corpora cavernosa, without palpable lymph nodes. These tumours are at high risk of micrometastasis and patients
should undergo surgical inguinal staging. The primary tumour can be treated with organ-​sparing surgery, partial penectomy,
radical penectomy or radiotherapy.
Stage III (T1–3, N1–2, M0) tumours are characterized by inguinal lymph node metastasis without extracapsular extension
and confer poor survival but are still considered for treatment with curative intent. Management is often multimodal,
including upfront surgery of the inguinal and, in select cases, pelvic lymph nodes, and adjuvant radiotherapy. Neoadjuvant
chemotherapy is an option in N2 disease. Cases with ≤2 lymph nodes without extracapsular extension are commonly
treated with surgery alone. As these patients are at high risk of systemic spread, staging using CT or PET/CT is recommended
to exclude metastatic disease.
Stage IV (T4 and/or N3 and/or M1) disease is characterized by locally advanced tumours growing into surrounding
structures (such as the scrotum or the pubic bone), bulky and/or fixed inguinal lymph nodes or inguinal nodes with
extrapelvic extension, involved pelvic lymph nodes or distant metastasis. Some patients can be cured with radical
multimodal approaches, but most have very poor prognosis and supportive care is paramount. Inclusion in clinical trials
investigating novel therapeutic options is an option for selected patients.

Skin Prognostic stage groups

Corpus Stage 0is or 0a: Tis or Ta, N0, M0
cavernosum Stage I: T1a, N0, M0
Corpus Stage IIA: T1b–T2, N0, M0
spongiosum
Stage IIB: T3, N0, M0
Stage IIIA: T1–3, N1, M0
Stage IIIB: T1–3, N2, M0
Stage IV: T4 or N3 or M1

NATURE REVIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:11 11

0123456789();:
Primer
of care91,92. Previously, these have been exclusively
administered to girls and women aged 9–26 years but
gender-​neutral vaccination has now been adopted in
some countries to prevent oropharyngeal, cervical,
vulvar, anal and penile SCC93–95. Data on the efficacy of
HPV vaccination are primarily derived from studies on
cervical cancer96,97. These data indicate >90% efficacy of
an early bivalent vaccine and the quadrivalent vaccine
against cervical intraepithelial neoplasia and reduced
prevalence of HPV16 and HPV18 in vaginal swabs
(reduction from 17.6% to 4% at 4–5 years after introduc-
tion of vaccination)97,98. However, initial data also suggest
poor efficacy against active or established infection; thus,
vaccination should be timed before the onset of sexual
activity.
During the past decade, gender-​neutral vaccina-
tion programmes using the nonavalent HPV vaccine
have been implemented as part of public health pro-
grammes, after studies in boys and men have clearly
shown a reduction in external genital lesions fol-
lowing vaccination. In a randomized, multicentre,
placebo-​controlled, double-​blind trial in 4,065 male
volunteers aged 16–26 years without signs or history
of HPV infection at enrolment, vaccination using
the quadrivalent vaccine reduced the incidence of
lesions related to HPV6, HPV11, HPV16 and HPV18
by 90% compared with those who received a placebo
injection99. Subgroup analysis of 602 men who have sex
with men showed that the vaccine reduced the inci-
dence of HPV-​related high-​grade anal intraepithelial
neoplasia by 75%. Notably, vaccine efficacy at prevent-
ing PeIN or PSCC could not be assessed owing to the
low incidence of the disease in the study population100.
However, although adoption of male vaccination may
not be cost-​effective in preventing PSCC itself, the dis-
cussion has to be placed in a broader context. Shabbir
and colleagues illustrated that a female-​only vaccina-
tion programme has disadvantages101. First, immunity
against infection in women, although providing some
benefit to the male population, will not provide as
much protection as vaccination of both sexes. Second,
vaccinating both sexes prevents stigmatization of HPV
infection as a problem that only affects women. Finally,
vaccination of women alone does not provide herd
immunity for men who have sex with men. Some evi-
dence exists that HPV vaccination of boys and men in
a population in which girls and women already receive
the vaccine would have a positive effect on future
costs of treating HPV-​related disease and on quality
adjusted life years102. However, the economic benefits
are reduced where the uptake of HPV vaccination by
girls and women is high owing to the increased general
protection via herd immunity103.
Management
Premalignant disease can be treated with topical
agents, whereas surgical excision with curative intent
is the standard of care for surgically resectable invasive
PSCC7,8,75. Disease stage at diagnosis dictates which
resection technique is used. To ensure maximal pres-
ervation of penile tissue and function, organ-​sparing
techniques have been developed for cT0–2 disease104.
12 | Article citation ID: (2021) 7:11
0123456789();:
Larger tumours invading the corpora cavernosa or
adjacent organs (T3–4) require disfiguring options, such
as partial or total penectomy7. As an alternative to sur-
gery, radiotherapy to the primary tumour is offered, but
this approach has the disadvantage of incomplete local
staging and lack of detailed histopathological prognos-
tic information of a resected specimen7,8,75,105. PSCC is
characterized by early lymphatic dissemination; hence,
surgical staging and resection of the inguinal and pelvic
basins have a central role in multidisciplinary manage-
ment, where neoadjuvant and adjuvant chemother-
apy and radiotherapy may aid in improving survival
in patients with bulky and multiple nodal metastases
(N2–3)106–108. Patients with metastatic PSCC are offered
palliative care or clinical trial participation7,8,75. An
overview of possible treatment strategies for PSCC is
provided in Box 2.
Premalignant diseases
Treatment options depend on the location and extent
of premalignant lesions (Fig. 5). PeIN can progress to
invasive lesions in up to 35% of cases; hence, defin-
itive eradication and diligent follow-​up monitoring
are important109. Most PeIN lesions are located on the
mucosal surfaces of the glans or prepuce and lichen
sclerosus also affects the prepuce39. Thus, circumcision
should be the primary surgical option110. Following cir-
cumcision, the glans mucosa keratinizes over a period
of 3–6 months and any residual PeIN or lichen scle-
rosus often resolves. Close monitoring before starting
additional therapy has been advocated110. Taking into
account a median time to progression to malignancy of
13 months, this approach seems feasible and would spare
patients from unnecessary additional therapies39,110.
For persisting lesions, topical, ablative or surgical
therapies are available. Topical therapies include chemo-
therapy with 5-​fluorouracil (5-​FU) and immunother-
apy with imiquimod, which are both suitable for PeIN
or small lesions on the penile shaft. The evidence for
these treatments is heterogeneous and no randomized
or comparative data are available. Overall, up to 57%
complete response and a low number of serious adverse
events have been reported111. Protocols for application
vary and optimal administration has yet to be deter-
mined for either option. Topical 5-​FU exerts its effects
through inhibition of the enzyme thymidylate synthase
and a 4-​week treatment course is often recommended
in reported series of PeIN therapy112. Imiquimod acts
through several pathways including activation of
immune cells via toll-​like receptor 7, creates an inflam-
matory response and is commonly used for 12 weeks,
although the treatment regime can be tailored to the
individual patient by using less-​frequent applications
and treatment breaks if required to aid tolerance113.
Various monotherapy or combination therapy protocols
have been used with complete response rates of up to
63% and non-​response rates of up to 29%113. Establishing
standard protocols of topical therapy requires a multi-
centre trial but the low prevalence of PSCC would limit
the recruitment.
Laser ablation therapy has been used with good
functional outcomes for superficial lesions 104,114.
www.nature.com/nrdp
 Primer

Typically a CO 2 laser (penetration 2–2.5 mm) or
a neodymium-​d oped yttrium aluminium garnet
(Nd:YAG) laser (penetration 4–6 mm) is used115. Treated
sites typically heal after 4–6 weeks but larger treatment
areas may require 3 months. Initial reports were rela-
tively positive but multi-​institutional data show that
19–50% of patients experience local disease recurrence
or upstaging to invasive cancer115–117. For cryotherapy,
with or without topical therapy, and photodynamic ther-
apy, which induces photo-​selective cell death, there are
limited data for the treatment of PeIN. Reports show
high rates of local recurrence possibly owing to inad-
equate penetration, difficulties in assessing borders of
affected areas and missing lesions that have invaded the
subepithelial tissue118,119.
Extensive PeIN, residual PeIN after circumcision or
recurrent disease can be treated by surgical excision. As
the lesions are non-​invasive, the glans epithelium can
be surgically excised and the denuded glans spongio-
sum covered with a split thickness skin graft in a proce-
dure called glans resurfacing. The reported outcomes of
recurrence (4%) and cosmesis are excellent85,120 (Fig. 6).
Compared with initial biopsy, ~20% of patients will be
upstaged to more invasive PSCC on definitive patholog-
ical examination and may require further surgery with
a resection of deeper tissues, such as a glansectomy,
depending on margins85. However, complete surgical
excision, rather than topical or ablative treatment, ena-
bles correct staging of the primary lesion and minimizes
the risk of overlooking more invasive disease85.

a b c

d e f

g h i

Fig. 6 | Organ-sparing surgical options for penile cancer. a–f | Glans resurfacing for extensive penile intraepithelial
neoplasia (PeIN). Clinical appearance with foreskin covering the glans (part a). b | Clinical appearance with foreskin
retracted showing extensive lesions suspect for PeIN; pathological analysis of a biopsy specimen showed extensive poorly
differentiated PeIN (part b). c,d | Glans mucosa removed and replaced with a split-​thickness skin graft; the donor site on
the right thigh can be seen in part d. e | Post-​operative appearance at 10 days. f | Long-​term postoperative appearance
at 6 months. g–i | Brachytherapy for T1a grade 2 penile squamous cell carcinoma. Pre-​treatment appearance (part g).
Appearance 1 month after completion of therapy showing diffuse moist desquamation (part h). Appearance 2 months
after completion of therapy, healing is complete (part i). Parts g–i adapted with permission from ref.245, Elsevier.

NATURE REVIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:11 13

0123456789();:
Primer
Localized invasive disease
Localized invasive PSCC, TNM stages cT1–3 or
American Joint Committee on Cancer (AJCC) prog-
nostic stage groups 1–2, is treated with curative intent
by surgical excision; alternatively, radiotherapy to the
primary lesion, possibly in combination with systemic
chemotherapy, can be offered. In patients with lymph
node or distant metastases, treatment of the primary
lesion follows the same principles as those detailed in
this section.
Surgery. Surgery is the mainstay of treatment of locally
invasive PSCC. Resection of the primary lesion not only
eradicates all disease in localized invasive tumours but
also provides definitive pathological staging without the
risk of understaging and of missing intratumour heter-
ogeneity encountered with incisional or punch biopsy.
Until two decades ago, surgery predominantly consisted
of either partial or total penectomy with division of the
urethra and corpora cavernosa at the level of the shaft or
the base of the penis, respectively, to create a resection
margin of ≥2 cm121. However, contemporary guidelines
of the European Association of Urology (EAU) now rec-
ommend the use of organ-​sparing surgery (OSS) when-
ever possible8. In OSS, the primary tumour is completely
removed leaving as much functional length and anatom-
ical structures of the penis intact as possible to preserve
three important functions of the penis: voiding stand-
ing upright; sexual pleasure and sensation; and aesthetic
aspects and masculinity104.
The concept of OSS is based on observations of how
the distance between tumour and resection margin affects
local recurrence104. A study in 2000 found that most
lesions do not spread >5 mm beyond the macro­scopic
margin and, in line with this finding, subsequent reports
show that an excision margin of between 5 mm and
10 mm results in acceptably low recurrence rates122–124.
A study in 2018 found that local recurrence rates increa­
sed considerably only when the distance from tumour
to margin was <1 mm121. Hence, the EAU guidelines
currently recommend a minimal margin beyond the
macroscopic aspect of the tumour8.
The second principle supporting the concept of OSS
is the observation that the occurrence of local recur-
rence, although more frequent in OSS series than more
radical surgery, does not affect cancer-​specific survival
(CSS) according to retrospective multivariate analysis
of 1,000 patients undergoing OSS125. This observation
is being challenged by new data from a patient cohort
enriched for high-​stage and high-​grade tumours in
whom local recurrence conferred worse survival, indi-
cating that in higher-​risk patients, local recurrence is
a manifestation of underlying aggressive disease 126.
The same has been found to be true for partial penec-
tomy which has been commonly used for higher-​risk
tumours, illustrating that local recurrence may be a
result of (lympho)vascular invasion and cell seeding in
vascular spaces of the penis, rather than direct epithe-
lial spread in more advanced tumours where the glan-
ulopreputial mucosa has been completely resected121,125.
Hence, a debate is ongoing about whether OSS should
be used whenever possible or with caution in suspected
14 | Article citation ID: (2021) 7:11
0123456789();:
aggressive tumours, in line with the recommendation of
the National Comprehensive Cancer Network (NCCN)
guidelines to limit the use of OSS in patients with more
aggressive primary PSCC7.
In terms of outcomes, OSS results in similar survival
to partial penectomy127. Reported local recurrence rates
after OSS vary greatly from 4% to >27%104. Series that
include laser ablation typically show high recurrence
rates, which are likely a result of suboptimal ablation
techniques, also in invasive lesions115,125,128. As poor
tumour differentiation and high T stage are independ-
ent predictors of local recurrence, series enriched in
high-​grade and/or high-​stage tumours show increased
local recurrence rates, whereas series excluding patients
with positive margins on definitive pathology and
those with cohorts enriched for low-​grade and low-​stage
tumours typically show trends towards low recurrence
rates121,124,129. Hence, appropriate patient selection is key
and, in the absence of definitive data and in the light of
conflicting guidelines, patients should be well informed
of their individualized treatment options and the bal-
ance of oncological risks and quality of life should be
considered before reaching a joint decision. The risk of
local recurrence based on final pathology can be used
to tailor follow-​up monitoring after treatment of the
primary PSCC lesion.
Several OSS techniques are available. In patients
with extensive PeIN (Tis) or limited invasion into the
stroma (T1), glans resurfacing can be offered115,130,131.
For invasive tumours (T1–2) several options are avail-
able, including Moh’s micrographic surgery, wide local
excision, hemiglansectomy or total glansectomy with or
without reconstruction of a neoglans using, for example,
a split-​thickness skin graft132. Tumours arising from the
meatus or distal urethra can be excised with reconstruc-
tion of the meatus using buccal mucosa autografts or
other types of graft133. Radical circumcision is the option
of choice for tumours limited to the preputium or cor-
onal groove and is often used as an adjunct procedure
in all other types of resection132. Radical circumcision
is also often advised before starting penile radiotherapy
for full exposure of the lesion, to prevent possible par-
aphimosis due to swelling of the foreskin and to avoid
post-​radiotherapy necrosis or foreskin contracture and
subsequent phimosis7,8.
Radiotherapy. Primary penile surgery can be associated
with considerable psychosexual morbidity, especially
if OSS cannot be used. Increased rates of depression
and suicide have been reported following penectomy,
making radiotherapy a compelling option as an organ-​
sparing treatment134,135. For localized cases (such as
cT1–3, AJCC stage 1–2), treatment options include
external beam radiotherapy (EBRT) and interstitial
brachytherapy (BT). Radiotherapy choice depends on
the size and location of the lesion as well as the avail-
ability of expertise, as BT is not widely offered. Small
distal lesions can be considered for BT, whereas those
>4 cm or involving the shaft are better suited for EBRT.
For BT, large retrospective series of patients with
early-​stage disease found local control rates of 86–87%
and 72–80% and penile preservation rates of 88% and
www.nature.com/nrdp

67–72% at 5 years and 10 years, respectively136–138. CSS
was 84–88% at 5 years and 92% at 10 years136–138. For
EBRT, disease control rates were lower: 5-​year local con-
trol, penile preservation and CSS were 41–70%, 36–66%
and 56–86%, respectively135,139–141. This difference may
reflect patient selection bias, as those receiving EBRT
were likely to be older, have more comorbidities and
more advanced disease than those receiving BT105.
Transient acute adverse effects of radiotherapy
include erythema, moist desquamation and oedema
(Fig. 6). Meatal stenosis and soft tissue necrosis can occur
several months and up to 3 years after radiotherapy.
Meatal stenosis and tissue necrosis rates of 10–45% and
of up to 23% for BT136–138 and 7–14% and 1–3% for EBRT,
respectively, have been reported135,140–142.
To date, data from prospective, randomized, con-
trolled trials comparing radiotherapy with surgery in
PSCC are lacking. Such a randomized trial is highly
unlikely, given the vastly different consequences of
the two approaches. Hence, in the absence of a direct
comparison, both options should be weighed in multi-
disciplinary team discussions, patient counselling and
decision-​making. A meta-​analysis of 2,178 patients
(1,505 received surgery and 673 received BT) demon-
strated no statistical difference in 5-​year local control
rate or overall survival between the two groups for
stage I/II disease143. Local control and overall survival for BT
was 84% and 79% and for surgery was 86% and 80%,
respectively. For stage III and IV disease, overall survival
did not differ between treatment groups, suggesting that
recurrences following BT are surgically salvageable with
no detriment to overall survival.
Current NCCN, ESMO and EAU guidelines support
radiotherapy as a penis-​preserving strategy in early-​stage
PSCC7,8,75. Evidence from randomized trials from other
SCC sites, such as the oropharynx, cervix, vulva and
anal canal, has clearly demonstrated that SCC is radio­
sensitive and potentially radiocurable144. Although these
results cannot be extrapolated to all PSCCs, a large
proportion of PSCCs share common pathophysiologi-
cal drivers with other SCCs and, for locally advanced
presentations or for patients not amenable to surgical
resection, good clinical outcomes have been achieved
using a combination of chemotherapy and radiotherapy
according to some reports, indicating that this strategy
needs further exploration105,145.
Lymph node staging
PSCC displays a predictable stepwise lymphatic dissem-
ination from the primary tumour to inguinal lymph
nodes, which can occur on both or either side, and then
to the ipsilateral pelvic nodes before widespread meta-
static disease occurs. Staging and treatment options are
based on this pattern of spread to identify those patients
with cN0 disease who require radical ILND without
unnecessarily subjecting up to 77% of patients to this
radical surgery, which has a high morbidity rate146. It is
widely accepted that metastatic disease in the inguinal
or pelvic lymph nodes is a poor prognostic factor147,148.
The probability of palpable (cN+) inguinal lymph nodes
harbouring metastatic disease is 80% and the need for
ILND is, therefore, undisputed149,150. However, patients
NATURE REVIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:11
0123456789();:
Primer
with impalpable inguinal lymph nodes (cN0) and risk
features in the primary tumour have a high probability
of harbouring occult disease, but the currently available
imaging modalities do not offer an acceptable sensitivity
to detect micrometastatic disease151,152. In large cohorts,
the risk of lymph node metastasis at initial staging or
during surveillance was 9% in EAU intermediate-​risk
(T1G2) cN0 tumours153, whereas the risk was up to
23% in EAU high-​risk (T1G3 or >T1) cN0 tumours154.
Poor differentiation and lymphovascular invasion were
predictive factors in the high-​risk cohort154. The 5-​year
CSS of patients with pN0, pN1, pN2 and pN3 disease
is 85–100%, 79–89%, 17–60% and 0–17%, respectively,
highlighting the need for accurate lymph node staging147.
Subjecting all cN0 patients to prophylactic open
radical ILND would clearly lead to overtreatment and
unacceptable morbidity. Close surveillance can lead to a
delay in detection of occult metastases in 15–25% of cN0
patients, but elective ILND is still considered unneces-
sary owing to the absence of metastatic disease in most
cases155,156. Unfortunately, although it has been clearly
shown that early surgical staging is of vital importance in
patients at high risk of occult micrometastasis157, adop-
tion of surgical staging is low, which can at least par-
tially be attributed to fear of surgery-​related morbidity
and complications5. To overcome this problem, patients
with nonpalpable lymph nodes harbouring risk factors
for micrometastatic disease, such as poor differentiation
and lymphovascular invasion, are offered less-​invasive
staging methods as part of a so-​called risk-​adapted
approach7,8.
Physical examination of the inguinal area can detect
large palpable nodes but will fail to detect those with
micrometastatic disease. Multiple modalities have
been used for noninvasive staging of inguinal nodes.
Ultrasonography combined with FNA cytology of mor-
phologically abnormal nodes has a sensitivity and spec-
ificity of 39% and 100%, respectively, which improves
to 93% and 91% for palpable nodes158,159. CT, MRI and
PET/CT are not recommended as initial staging tools
for inguinal nodes in cN0 disease, as suspicious lymph
nodes are detected according to size, shape and cen-
tral necrosis. The spatial resolution of these imaging
modalities is limited to 2 mm, which is insufficient for
the detection of micrometastatic disease83,152.
In most European high-​volume centres, dynamic
sentinel node biopsy (DSNB) is used for surgical staging
of the groins. DSNB involves preoperative peritumoural
injection of both nanocolloid radioisotope 99mTc and a
dye, such as patent blue, to localize the sentinel node160.
Alternatively, a hybrid fluorescent and radioactive
tracer161 can be used, which demonstrated better optical
sentinel node detection than patent blue162. If DSNB is
performed after primary tumour removal, the injection
is performed in the coronal sulcus or close to the tumour
resection site. A single-​photon emission CT (SPECT)/CT
is used for anatomical reference of the location of the
sentinel node. All nodes of the first echelon, determined
by preoperative SPECT/CT, that contain dye, γ-​radiation
or both are potential sentinel nodes and are removed
and pathologically assessed. To further improve the
sensitivity of the procedure, preoperative inguinal
15
Primer

ultrasonography and FNA of morphologically abnormal
lymph nodes has been incorporated, as well as serial sec-
tioning and immunostaining of the specimen to detect
micrometastatic disease151,163. Combination of DSNB
with PET/CT has also shown good results164. Prospective
multicentre data of >600 clinically node-​negative groins
show that DSNB is a reproducible and reliable method
with sensitivity of 93%, specificity of 100% and compli-
cation rate <5% in high-​volume centres160,165,166. However,
DSNB has not been uniformly adopted owing to con-
cerns of high false-​negative and complication rates in
non-​centralized health-​care systems and those with poor
access to nuclear medicine167. In these cases, modified or
superficial lymphadenectomy with a reduced dissection
template and saphenous vein sparing or minimally inva-
sive video-​endoscopic prophylactic radical ILND can be
offered (Fig. 7).
Inguinal and pelvic lymphadenectomy
ILND can provide important prognostic information
and serves as a staging tool and therapeutic option.
However, this procedure has been characterized by high
complication rates (42–57% or higher) and considerable
effects on long-​term quality of life owing to the develop-
ment of lymphoedema146,168,169. Various techniques have
been described to reduce this morbidity.
Superficial ILND is a staging procedure and consists
of removal of the subcutaneous lymph nodes that are
located between the subcutaneous tissue and the fascia
lata inside the boundaries of the femoral triangle: the
inguinal ligament, the medial border of the sartorius
muscle and the lateral border of the adductor longus
muscle146,167,170 (Fig. 7). These nodes are evaluated intra-
operatively using frozen section analysis and, if positive
for malignancy, dissection of the deep inguinal nodes,
which lie medial to the femoral vein under the cribri-
form fascia, is performed7,8,75. Modified ILND is used
as either a staging or prophylactic surgical procedure
and consists of using a smaller incision, medializing the
lateral border of the template to the lateral border of
the femoral artery, and preservation of Scarpa’s fascia
and the saphenous vein, suggesting that this would
decrease the lymphatic complications to 10–36%171,172.
Radical ILND is performed if intraoperative frozen
section analysis shows malignancy.
Video-​endoscopic and robot-​assisted ILND (VEIL)
has been explored with the intention of promoting a
radical-​template dissection with reduced morbidity by
making smaller skin incisions and using laparoscopic
instruments, while preserving fluid drainage through
uninterrupted subcutaneous lymphatics173–177. A sys-
tematic review based on small series and including a
total of 307 patients that compared VEIL with open
radical surgery found reduced hospital stay and mor-
bidity (especially reduced wound healing disorders and
lymphoedema) with similar lymphocele and recurrence
rates178. Lymph node yields and oncological outcomes
are comparable to those of open radical ILND in the

Sentinel
node

Penile
injection
Radical ILND site
template
Modified ILND
template

Fig. 7 | Surgical staging and treatment of the groins in penile cancer. Lymph node metastases are frequent in penile
cancer. The extent of lymph node dissection should be adapted to clinical stage, as this corresponds to metastatic spread.
For low-​risk disease (pTis, pTa and pT1G1) without palpable lymph nodes and with good compliance, a surveillance strategy
may be chosen. For other patients without palpable lymph nodes (including intermediate-​risk pT1G2 disease), a modified
bilateral inguinal lymphadenectomy (ILND) is recommended with a reduced template (blue dashed line) compared with
radical ILND (red dashed line) to reduce complications. Alternatively, dynamic sentinel lymph node biopsy (DSNB) can
be used in specialized high-​volume centres, as false-​negative rates can be high in centres with less experience. In DSNB,
a radioactive nanocolloid and dye are injected close to the penile primary tumour or resection site and the sentinel node
is detected by combined SPECT/CT and intra-​operative γ-​probe-​assisted localization. All patients with histologically
proven lymph node metastases should undergo radical ILND.

16 | Article citation ID: (2021) 7:11 www.nature.com/nrdp

0123456789();:

short term, but long-​term oncological safety required
further evaluation178.
Finally, radical ILND is a therapeutic or palliative
procedure that includes removal of all nodes super-
ficial and deep to the fascia lata and within the lateral
and superior borders described above146,170. Cloquet’s
or Rosenmuller’s node, which is the node between the
inguinal and external iliac basins, is the highest node
removed during this surgery. Previous advice was to
resect the saphenous vein and skeletonize the femo-
ral vessels, but it is now increasingly recognized that
manoeuvres to preserve Scarpa’s fascia, the fascia lata,
the saphenous vein and leaving a limited layer of adi-
pose tissue, containing deep lymphatic channels, on
the vessels (if not obviously affected by metastasis) may
help to reduce complications146,179. In the case of bulky
or fixed nodes, neoadjuvant chemotherapy is recom-
mended, and in extensive nodal disease or nodes fun-
gating through the skin, resection of a large skin island
may require coverage of the defect using myocutaneous
flap reconstruction180,181.
Radical ILND is likely over-​used in PSCC. In breast
cancer, detection of micrometastasis on DSNB does
not necessitate formal radical axillary dissection182,183.
Evaluation of this approach is needed for PSCC to
spare patients from ILND-​related morbidity. Ipsilateral
prophylactic or PLND up to the iliac bifurcation can
be performed via a midline laparotomy, laparoscopic
surgery or robot-​assisted surgery and is advised if risk
factors for pelvic nodal disease exist, such as extraca-
psular extension or involvement of ≥2 inguinal nodes
on one side7,8,184. Cross-​over of metastatic spread from
the contralateral inguinal basins has not been reported
and bilateral PLND is, therefore, only indicated if risk
factors for pelvic nodal metastases are found bilaterally
during ILND. PLND is also performed in patients who
present with cN3 disease, often following neoadjuvant
chemotherapy7,8,75.
Neoadjuvant and adjuvant therapy strategies
In PSCC, the occurrence of metastatic lymph node
spread marks the boundary between curable disease
and high-​risk disease, which easily becomes incurable
depending on the extent of lymph node involvement107.
Evidence on systemic therapy in this patient group is
limited by a predominance of retrospective data and a
lack of randomized studies, restricting particular ther-
apeutic recommendations. Despite these limitations,
expert consensus supports the use of neoadjuvant com-
bination chemotherapy including cisplatin and a taxane
in patients with locally advanced or cN2–3 disease7,8.
The two most widely used regimens are the combination
of paclitaxel, ifosfamide and cisplatin (TIP) and the com-
bination of docetaxel, 5-​FU and cisplatin (TPF)9,185–188.
Overall, neoadjuvant chemotherapy achieves patholog-
ical complete responses in 15% of patients and an objec-
tive response rate (ORR) of 50%106,189. Reports of survival
outcomes are scarce and indicate a poor 5-​year overall
survival of <50% in patients with cN1–3 disease190. One
multicentre retrospective study reported improved sur-
vival following adjuvant chemotherapy particularly in
patients with pelvic lymph node metastasis190.
NATURE REVIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:11
0123456789();:
Primer
Primary radiotherapy is the modality of choice in
other ano-​genital SCC (for example, anal canal and
vulvar SCC), suggesting a role for radiotherapy of
lymph node metastases from PSCC. In a randomized,
controlled trial in patients with vulvar cancer follow-
ing ILND, adjuvant radiotherapy to the inguinal and
pelvic basins has been shown to improve survival191,192.
However, its role in PSCC is debated and guidelines are
conflicting. The NCCN endorses the radiotherapy as
a definitive treatment, whereas the EAU only recom­
mends radiotherapy for palliation 7,8. A systematic
review of seven retrospective series failed to demon-
strate a benefit of adjuvant inguinal radiotherapy fol-
lowing ILND. Possible toxic effects remain unquantified
owing to inconsistent reporting108. Data from retrospec-
tive series on adjuvant pelvic nodal radiotherapy are
contradictory, highly heterogeneous and have a high
risk of bias108,193–197. This paucity of robust data leaves
the optimal role for radiotherapy to PSCC lymph node
metastases uncertain. Intriguing preliminary findings
in a large retrospective study of perioperative (mainly
adjuvant) nodal radiotherapy in locally advanced,
HPV-​positive PSCC indicate that HPV-​positive can-
cer may be more radiosensitive than HPV-​negative
cancer198.
Going forward, clinical research needs include the
optimal timing and sequencing of chemotherapy and
radiotherapy, as well as investigation of the necessary
extent of lymph node dissection. These points are an
ongoing source of debate and mark a breaking point
between the evidence-​based guidelines recommen-
dations and what is performed in clinical practice in
high-​volume centres. The ongoing InPACT trial aims
to evaluate the efficacy of various therapeutic modal-
ities, including the extent of regional lymph node dis-
section and the role of perioperative chemotherapy and
radiotherapy199. At present, the use of other systemic
treatments, such as targeted therapies or immuno-
therapy, in PSCC has not been established, but these
strategies are being tested in ongoing clinical trials.
Metastatic disease
Palliative systemic therapy options are currently offered
to patients who present with de novo metastatic PSCC
or who develop disease recurrence after regional
lymph node dissection, with or without systemic ther-
apies. Distant metastasis without concurrent lymph
node involvement is rarely observed in penile cancer.
In these patients, therapeutic options are limited and
no standard-​of-​care chemotherapy exists. The usual
first-​line therapy regimens in these patients are the
same as those in the perioperative setting, that is, com-
bination chemotherapies, preferably including a taxane
and cisplatin (for example, TIP or TPF chemotherapy).
To improve outcomes of these patients through the
use of more tolerable chemotherapy, the phase II trial
VinCaP trial evaluated the use of vinflunine, adminis-
tered as neoadjuvant or first-​line therapy in patients with
locally-​advanced or metastatic PSCC200. In 25 pati­
ents, the ORR was 27% and the clinical benefit rate
(including stable disease) was 45.5%. In a prospective
phase II non-​randomized clinical trial (EORTC 30992),
17
Primer
cisplatin was combined with irinotecan201. In 26 patients,
the ORR was 30.8% and treatment was associated with
considerable grade 3/4 neutropenia and diarrhoea. Data
from older, small retrospective studies of single-​agent
and various combinations of chemotherapy options
as palliative therapy could still be considered on a
case-​by-​case basis, depending on patient performance
status and organ function tests. In patients who have
received platinum-​based combination chemotherapy,
single-​agent chemotherapy is generally advisable if the
patient is motivated to receive further therapy. Cisplatin
alone, if not used in first-​line therapy, can be consid-
ered, but weekly paclitaxel monotherapy is likely to
be the most suitable option, as it resulted in an initial
response rate of 20% with minimal toxicity in a phase II
study202. In addition, radiotherapy to slow disease pro-
gression and for local and metastatic symptom control
can be employed in patients with bulky or symptomatic
disease7,8,105.
Thus, evaluating whether a patient with metastatic
PSCC can be included in a clinical trial should be the
first consideration to provide potentially more effective
and better tolerated treatment options. In the absence
of clinical trials, palliative care administration is likely
to be the primary focus in discussion with the patient.
Quality of life
Survivorship after penile cancer diagnosis and treat-
ment holds numerous challenges, as survivors try to
maintain quality of life while navigating the immedi-
ate and late adverse effects of surgery and other forms
of treatment203. Penile cancer can be a devastating
disease with a considerable effect on quality of life3.
Nevertheless, the literature on this aspect is scarce
and consists mainly of focus group investigations and
semi-​structured interview-​based qualitative research in
small cohorts of patients3.
Box 3 | Patient experience
In life, there is often a point that marks a difference resulting in a life before and one
after the event. Being diagnosed with a cancer with poor prognosis is such an event.
One cannot help thinking about the end of life and once in follow-​up, the fear of
recurrence will never completely go away. A cancer diagnosis can also lead to feelings
of letting others down … instead of taking care of others, one becomes needy in the
blink of an eye.
Patients with penile cancer face several specific problems. Amputation of the penis
interferes with sexual and urinary function. Although a partial amputation initially
seems to be less disabling than full amputation, this is not completely true. Urinating is
easier after complete amputation with reconstruction compared with partial amputation.
There is no doubt that sexuality changes dramatically after amputation. Sexuality should
always include a mixture of physical and emotional components. After amputation of
the penis, there is a clear shift towards the emotional side. Intimacy becomes far more
important, for both the patient and their partner.
The effect of inguinal node dissection cannot be overestimated. Even in the absence
of debilitating lymphoedema, the constant concern of preventing it changes the way of
life. Every single day, there are a few situations in which cancer slaps you in the face and
asks “You didn’t think of forgetting me, did you?” At meetings, all of a sudden, hearing
impairment due to chemotherapy appears and makes it difficult to follow conversations.
The most difficult thing to handle as a patient with cancer with a limited prognosis
is the lack of comprehension by some others. “You have had surgery, radiation therapy
and chemotherapy, so you’re cured and can move on.” Can we, really?
This statement was provided by an anonymous patient who survived stage IV penile cancer.
18 | Article citation ID: (2021) 7:11
0123456789();:
Patients suffer from mental stress originating from
their diagnosis, outlook on their prognosis and muti-
lating treatment modalities3,204 (Box 3). In patients with
penile cancer, mental illness, avoidance behaviour,
impaired well-​b eing and post-​t raumatic stress dis-
order are frequently encountered205. Surgery-​related
and radiotherapy-​related changes in the sensitivity,
appearance and length of the penis have implications
for sexual function, identity, personality and inter-
personal relationships3. Organ-​sparing approaches
can help in reducing these deleterious effects with
often satisfactory preservation of the aesthetic aspects
of the penis, sensitivity, and erectile and orgasmic
function132. Maximal preservation of glanular tissue
and neo-​glans reconstruction have been shown to lead
to better outcomes as perceived by both patients and
their partners206,207. By contrast, partial and total penec-
tomy are severely mutilating and have profound effects
on sexual function, overall well-​being and masculinity.
In addition, urinary function can be drastically altered
owing to the deviation of urine flow through a perineal
urethrostomy208. In particular, patients with advanced
or bulky primary disease with enlarged inguinal and
pelvic lymph nodes often undergo extensive surgery,
sometimes necessitating flap advancement for recon-
struction of defects, and highly toxic combinations of
chemotherapy and radiotherapy regimens, which leads
to a drastic reduction in quality of life both during
therapy and subsequently8.
In patients and survivors of penile cancer, lymphoe-
dema frequently occurs in the legs, scrotum, penis or
penile stump after ILND or PLND and can be aggra-
vated by adjuvant radiotherapy146. Symptoms of this
debilitating condition include difficulty walking, pain,
puffiness, weakness, frequent infections and impaired
wound healing203. Hence, lymphoedema substantially
impairs normal daily activities. Patients often need to
wear bothersome compression garments or require
manual lymph drainage. For severe cases of scrotal lym-
phoedema, surgical scrotectomy might be required209.
Survivors of penile cancer benefit from multidisci-
plinary follow-​up assessment of their functional sta-
tus tailored to their individual needs204. At this point
case managers, specialist nurses, physical therapists,
psychologists and sexologists are key care providers.
Self-​help groups and inter-​patient contact provide sup-
port mechanisms that can help in coping throughout
all phases of the disease. In a centralized health-​care
approach for penile cancer, the health-​care provider may
facilitate the development of these groups.
Outlook
Owing to the lack of standard therapeutic options for
patients with advanced PSCC, tumour biomarkers that
are suitable for new therapies or patient selection for
personalized therapeutic strategies are a huge clinical
need. Current knowledge is limited, but some intriguing
possibilities may stimulate translational research in this
field. A patient’s perspective on research needs in penile
cancer is highlighted in Box 4 and open research ques-
tions throughout the diagnostic and treatment pathways
are summarized in Box 5.
www.nature.com/nrdp

Box 4 | Needs for future research: patient perspective
Penile cancer is a rare cancer. Although aetiologically related to cervical cancer in
women, fewer efforts are made in prevention and screening of penile cancer. In many
countries, girls are vaccinated against human papillomavirus (HPV). However,
prevention would be a lot more effective if boys were also vaccinated.
The use of sentinel node procedures to omit the need for complete inguinal lymph
node dissection would be a major progress in penile cancer surgery. Sentinel node
procedures are more widespread in breast cancer, where the gained experience has
led to more conservative approaches. In penile cancer, criteria to identify in whom
a complete inguinal procedure can be safely omitted are lacking.
Personalized treatments for various types of cancer are becoming available, but
unfortunately penile cancer seems to garner much less attention. The number of
patients that might benefit from these treatment options seems too low to be an
incentive. Further research to identify which new treatments are effective in certain
patient populations should be promoted. These new treatments are often reserved as
last resources, but they should also be tested in earlier phases of the disease, to prevent
recurrences or distant metastases.
Every cancer patient should have the same rights, including research to develop
new strategies in prevention, screening and treatment in all phases and stages of
the disease.
This statement was provided by an anonymous patient who survived stage IV penile cancer.
Biomarkers
In PSCC, data on the role of molecular biomarkers that
inform a patient’s prognosis or guide patient selection for
specific therapeutic approaches are limited210.
HPV infection is certainly the predominant bio-
marker for prognostic workup and therapeutic aims.
In contrast to HPV-​negative disease, HPV positivity
generally confers a more indolent clinical course and
better prognosis, and preventive or therapeutic HPV
vaccination may be useful additions to the therapeutic
strategies against PSCC211.
Apart from HPV infection, genomic profiling of
metastatic PSCC revealed potential targeted therapy
opportunities, such as alterations in the MTOR pathway
(alterations of NF1 in 7% and PTEN in 4%) and in the
DNA repair pathway (alterations of BRCA2 in 7% and
ATM in 7%) and tyrosine kinase pathways (alterations
of EGFR in 6%, FGFR3 in 4% and ERBB2 in 4%)212. In
addition, intriguing differences between PSCC and other
SCCs have been reported that are likely due to the role
of ultraviolet light exposure in the case of cutaneous
tumours. In a study that focused on RNA expression
in tumours of patients receiving first-​line cisplatin-​based
chemotherapy, upregulation of MAML2, KITLG and
JAK1 was associated with poor outcome, and upreg-
ulation of FANCA was associated with improved sur-
vival, suggesting a role for gene expression signatures in
patient selection for cisplatin chemotherapy213.
PDL1 expression has been reported in a varying pro-
portion of PSCCs214,215. In two large retrospective stud-
ies, tumour or stromal PDL1 expression independently
identified patients with PSCC at increased risk of poor
clinical outcomes216,217. However, conflicting data have
been reported in another cohort in which PDL1 expres-
sion did not correlate with tumour location, histologi-
cal subtype, tumour stage, depth of invasion or tumour
grade218.
Finally, in a single-​centre retrospective study, the
expression of p53 in lymph node metastases was asso-
ciated with a clinical benefit from the use of adjuvant
NATURE REVIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:11
0123456789();:
Primer
cisplatin-​based chemotherapy in terms of disease-​free
survival and overall survival219.
Translational research and ongoing trials
PSCC is a rare cancer and few therapeutic options
are available owing to a lack of efficacy data from
well-​designed randomized, controlled trials. The dis-
ease is characterized by an aggressive clinical course
and, although platinum-​based regimens are the current
standard of care for advanced and metastatic disease,
their efficacy is poor and treatment resistance develops
early220. Consequently, development of novel and effec-
tive personalized treatment options for PSCC is required.
The rarity of PSCC affects the set-​up of clinical trials to
investigate the activity of new treatment strategies220.
Knowledge of prognosis-​relevant altered molecular
pathways is growing, opening paths to identify poten-
tial therapeutic targets212,221. Knowledge translation from
other types of SCC may also guide research in PSCC,
although disease drivers and mutational load may differ
depending on the site of the primary disease212. More
than a quarter of patients with metastatic PSCC may
benefit from existing and available therapies targeting
MTOR, DNA repair and tyrosine kinase pathways that
are currently being investigated in skin SCCs212. Disease
models have been scarce but, in the past 5 years, several
cell lines have been characterized and genetically modi-
fied or patient-​derived tumour xenograft mouse models
have been established with potential for the development
of promising novel therapeutic strategies222–226.
Multicentre clinical trials in the setting of central-
ized PSCC care are warranted to establish effective
marker-​based individualized treatment strategies. The
InPACT trial, an ongoing large, international, multi-
centre study, addresses many of the open questions
in the management of regionally advanced PSCC
(NCT02305654). InPACT includes patients with a
diagnosis of PSCC and evidence of enlarged regional
lymph nodes at clinical staging (that is, cTany, cN1–3,
M0 disease). Its set-​up is based on a Bayesian design
implicating two randomization nodes. Neoadjuvant
chemotherapy and ILND versus chemoradiotherapy and
ILND versus therapeutic ILND alone is the first rand-
omization. If ILND shows a high risk for pelvic involve-
ment, patients are randomized to receive adjuvant
chemoradiotherapy to the pelvis with or without PLND
in chemotherapy-​naive patients or surveillance versus
PLND alone in patients previously treated with neoad-
juvant therapy. The trial aims to answer important ques-
tions on the efficacy of stepwise surgical management
and perioperative radiotherapy and chemotherapy199.
Inclusion of patients in InPACT is certainly valuable for
investigators and will hopefully improve management
and outcomes of patients with PSCC.
In chemotherapy-​naive patients with advanced or
metastatic PSCC, a phase II trial is currently testing the
combination of pembrolizumab (targeting programmed
cell death protein 1 (PD1)) and cisplatin-​based chemo-
therapy in the first-​line setting (LACOG 0218 Hercules;
NCT04224740). Another trial is evaluating the role of
maintenance immunotherapy with avelumab (targeting
PDL1) after the completion of first-​line chemotherapy in
19
Primer
Box 5 | Open research questions in penile cancer
• Will a detailed characterization of genomic drivers, the tumour microenvironment
and role of the microbiome generate novel biomarkers and treatment strategies?
• Should we perform organ-​sparing surgery or approaches (like brachytherapy, laser or
topical therapy) whenever technically feasible?
• Which imaging strategy will enable accurate staging including of micrometastatic
disease?
• Does every positive sentinel node require inguinal lymph node dissection (ILND) or
is there a subset of patients with micrometastatic disease who can be spared this
morbid surgery?
• Does minimally invasive ILND reduce complications whilst preserving oncological
benefit?
• Which patient should receive neoadjuvant or adjuvant radiotherapy, chemotherapy
and radiochemotherapy combined with ILND, and what is their optimal sequence?
The InPACT trial is recruiting to help answer these questions.
• Data on quality of life and problems of survivors of penile cancer are lacking. How can
we better guide patients through the disease and therapy landscape, and how do we
standardize outcome measures in this field?
• Should we differentiate staging and treatment based on human papillomavirus
(HPV)-driven versus non-​HPV-​driven pathophysiology and tumour subytpes?
• Can we personalize optimal systemic therapy based on individual patient and tumour
hallmarks?
• What are the effects of immune checkpoint blockade or other immune targeting
approaches, such as tumour-​infiltrating lymphocytes (TILs) and chimeric antigen
receptor (CAR) T cell therapy, in penile cancer, and who will likely benefit from them?
• How do we best organize clinical research in penile cancer, along with other rare
genitourinary cancers?
patients with advanced PSCCs, and may provide data on
the role of therapeutic chemo-​immunotherapy sequenc-
ing (PULSE; NCT03774901). The PERICLES trial inves-
tigates atezolizumab (targeting PDL1) and radiotherapy
versus atezolizumab monotherapy in patients with unre-
sectable advanced penile cancer (NCT03686332). An
international, phase II trial will evaluate the activity of
retifanlimab (targeting PD1), which has demonstrated a
favourable preclinical profile in various solid tumours,
in chemotherapy-​naive and chemotherapy-​t reated
patients with advanced or metastatic PSCC (ORPHEUS;
NCT04231981).
For patients with more advanced disease and who
have generally failed cisplatin-​based chemotherapy,
inclusion in umbrella or basket trials that evaluate
immuno­therapy combinations or various targeted com-
pounds is possible. Preliminary results of the combina-
tion of ipilimumab (targeting cytotoxic T lymphocyte
protein 4 (CTLA4)) and nivolumab (targeting PD1)
from a phase II basket trial (NCT03333616) included
one partial response among three evaluable patients with
PSCC227. Other combination treatments that are availa-
ble in basket trials for patients with relapsed advanced
disease are atezolizumab with bevacizumab (target-
ing vascular endothelial growth factor A (VEGFA))
(NCT03074513), atezolizumab with valproic acid
(NCT03357757) and nivolumab with ipilimumab and
cabozantinib (a multikinase inhibitor) (NCT02496208).
Among the enrolling immunotherapy studies that are
exclusively focused on patients with PSCC, two phase II
trials are evaluating the role of PDL1 and PD1 inhibition,
using avelumab (NCT03391479) and pembrolizumab
(NCT02837042), respectively, both with ORR as the
20 | Article citation ID: (2021) 7:11
0123456789();:
primary end point. In summary, research on immuno-
therapy in PSCC is in its infancy. Although some initial
reports indicate therapeutic efficacy, translation into
clinical practice will certainly require additional studies
and higher numbers of included patients.
Finally, historically, HPV has been one of the most
intriguing targets in PSCC, and multiple trials are
currently testing different therapeutic approaches
in HPV-​p ositive cancers, including in oropharyn-
geal, cervical, anal and vulvar carcinoma, and PSCC
(NCT02379520, NCT03427411, NCT03418480,
NCT03912831 and NCT03439085). Among these stud-
ies, a promising 50% response rate for cellular therapy
(gene-​engineered T cell therapy targeting HPV16 E7)
in HPV16-​associated malignancies has been reported,
including vulvar, anal, head and neck, and cervical
cancer228.
Centralized health care and rare disease networks
The very low case load of penile cancer per practitioner
poses specific challenges. Survey data show that guide-
line knowledge is poor and adherence to guidelines
is suboptimal5,229,230. Possibly owing to fear of compli-
cations and poor guideline knowledge, use of often
life-​saving lymphadenectomy in patients at high risk
of micrometastatic disease has been shown to be as
low as 25% and even lower in non-​academic facilities5.
Optimal outcomes require expertise not only in surgery,
radiotherapy and medical oncology but also in allied
services, such as psychological support, pathological
reporting and advanced imaging, amounting to true
multidisciplinary cancer management22. Treatment of
penile cancer in high-​volume referral centres has been
shown to improve management through correct patho-
logical reporting231, to stimulate adoption of OSS232 and
to increase utilization of invasive lymph node staging in
high-​risk patients5,233,234, resulting in increased survival
rates. For example, 5-​year mortality rates were reduced
by ≥7% in the UK after implementation of centralized
care, and 5-​year CSS of patients with high-​risk cN0
disease improved by 9% in the Netherlands after the
introduction of sentinel node biopsy within a central-
ized care setting18,21,235,236. Centralization and collabo-
ration in rare cancer management also provide further
possibility of research, for example, through biobank-
ing and improved participant numbers in outcomes
research. In the UK and certain Scandinavian countries,
government-​imposed centralization has been realized21.
In the USA, academic centres treat higher-​stage can-
cers and manage more cases per year than community
centres, suggesting a limited trend towards informal
centralization5. Similar informal academic-​driven cen-
tralization occurs in the Netherlands and Belgium149.
The concept of expert care for rare diseases has been fun-
damental in the development of the European Reference
Networks (ERN), an EU initiative. The ERN eUROGEN
workstream includes penile cancer and greatly facilitates
cross-​centre tumour boards, collaborative research and
education22.
In spite of the obstacles posed by the low preva-
lence of penile cancer, valuable data on disease drivers
and potential biomarkers are now emerging. This new
www.nature.com/nrdp

knowledge enables exploration of the potential for pre-
cision oncology to overcome the disappointing results
of chemotherapy-​b ased treatments, specifically in
advanced disease. Trials such as InPACT are underway
and immune checkpoint inhibitors have revolutionized
the management of other SCC types both in combi-
nations and as monotherapy. Preclinical evidence and
early clinical reports indicate that this strategy may also
1. Douglawi, A. & Masterson, T. A. Penile cancer
epidemiology and risk factors: a contemporary review.
Curr. Opin. Urol. 29, 145–149 (2019).
2. Olesen, T. B. et al. Prevalence of human papillomavirus
DNA and p16(INK4a) in penile cancer and penile
intraepithelial neoplasia: a systematic review and
meta-​analysis. Lancet Oncol. 20, 145–158 (2019).
3. Dräger, D. L., Milerski, S., Sievert, K. D. &
Hakenberg, O. W. Psychosocial effects in patients
with penile cancer: a systematic review. Urologe A
57, 444–452 (2018).
4. Novara, G., Galfano, A., De Marco, V., Artibani, W.
& Ficarra, V. Prognostic factors in squamous cell
carcinoma of the penis. Nat. Clin. Pract. Urol. 4,
140–146 (2007).
5. Woldu, S. L. et al. Usage and survival implications
of surgical staging of inguinal lymph nodes in
intermediate- to high-​risk, clinical localized penile
cancer: a propensity-​score matched analysis.
Urol. Oncol. 36, 159.e7–159.17 (2018).
6. Ross, G. L. et al. The learning curve for sentinel node
biopsy in malignant melanoma. Br. J. Plast. Surg. 55,
298–301 (2002).
7. Flaig, T. W. et al. NCCN Guidelines Version 2.2020
Penile Cancer (NCCN, 2020).
8. Hakenberg, O. W. et al. EAU guidelines on penile
cancer: 2014 update. Eur. Urol. 67, 142–150
(2015).
9. Pagliaro, L. C. et al. Neoadjuvant paclitaxel,
ifosfamide, and cisplatin chemotherapy for metastatic
penile cancer: a phase II study. J. Clin. Oncol. 28,
3851–3857 (2010).
10. Agarwal, G., Gupta, S. & Spiess, P. E. Novel targeted
therapies for the treatment of penile cancer.
Expert Opin. Drug Discov. 9, 959–968 (2014).
11. Montes Cardona, C. E. & García-​Perdomo, H. A.
Incidence of penile cancer worldwide: systematic
review and meta-​analysis. Rev. Panam. Salud Publica
41, e117 (2017).
12. Bray, F. et al. Global cancer statistics 2018:
GLOBOCAN estimates of incidence and mortality
worldwide for 36 cancers in 185 countries.
CA Cancer J. Clin. 68, 394–424 (2018).
13. Ferlay, J. et al. Estimating the global cancer incidence
and mortality in 2018: GLOBOCAN sources and
methods. Int. J. Cancer 144, 1941–1953 (2019).
14. Favorito, L. A. et al. Epidemiologic study on penile
cancer in Brazil. Int. Braz. J. Urol. 34, 587–593
(2008).
15. Visser, O. et al. Incidence and survival of rare
urogenital cancers in Europe. Eur. J. Cancer 48,
456–464 (2012).
16. Rando Sous, A. et al. A review of penile cancer.
Adv. Urol. 2009, 415062 (2009).
17. Goodman, M. T., Hernandez, B. Y. & Shvetsov, Y. B.
Demographic and pathologic differences in the
incidence of invasive penile cancer in the United
States, 1995-2003. Cancer Epidemiol. Biomarkers
Prev. 16, 1833–1839 (2007).
18. Djajadiningrat, R. S. et al. Contemporary management
of regional nodes in penile cancer — improvement of
survival? J. Urol. 191, 68–73 (2014).
19. Pagliaro, L. C. & Crook, J. Multimodality therapy in
penile cancer: when and which treatments? World J.
Urol. 27, 221–225 (2009).
20. Verhoeven, R. H. A. et al. Population-​based survival of
penile cancer patients in Europe and the United States
of America: no improvement since 1990.
Eur. J. Cancer 49, 1414–1421 (2013).
21. Ayres, B. et al. Has centralisation of penile cancer
services in the United Kingdom improved survival?
Eur. Urol. Suppl. 13, e50 (2014).
22. Vanthoor, J., Thomas, A., Tsaur, I. & Albersen, M.
Making surgery safer by centralization of care:
impact of case load in penile cancer. World J. Urol. 38,
1385–1390 (2020).
23. Hansen, B. T., Orumaa, M., Lie, A. K., Brennhovd, B. &
Nygard, M. Trends in incidence, mortality and survival
NATURE REVIEWS | DISeASe PRIMeRS | Article citation ID:
be useful in PSCC. A setting of centralized care in this
context not only provides more opportunities to study
promising therapies but also results in improvements of
care quality and survival. This approach has been pio-
neered in several European regions and is now being
developed in other parts of the world.
Published online xx xx xxxx
of penile squamous cell carcinoma in Norway
1956-2015. Int. J. Cancer 142, 1586–1593 (2018).
24. Emmanuel, A., Nettleton, J., Watkin, N. &
Berney, D. M. The molecular pathogenesis of penile
carcinoma-​current developments and understanding.
Virchows Archiv. 475, 397–405 (2019).
25. Leto, M., Santos Junior, G. F., Porro, A. M. &
Tomimori, J. Human papillomavirus infection:
etiopathogenesis, molecular biology and clinical
manifestations. An. Bras. Dermatol. 86, 306–317
(2011).
26. Mosconi, A. M., Roila, F., Gatta, G. & Theodore, C.
Cancer of the penis. Crit. Rev. Oncol. Hematol. 53,
165–177 (2005).
27. Spiess, P. E., Dhillon, J., Baumgarten, A. S.,
Johnstone, P. A. & Giuliano, A. R. Pathophysiological
basis of human papillomavirus in penile cancer: key
to prevention and delivery of more effective therapies.
CA Cancer J. Clin. 66, 481–495 (2016).
28. Alemany, L. et al. Role of human papillomavirus in
penile carcinomas worldwide. Eur. Urol. 69, 953–961
(2016).
29. Flaherty, A. et al. Implications for human
papillomavirus in penile cancer. Urol. Oncol. 32,
53.e1–53.e8 (2014).
30. Ornellas, A. A. & Ornellas, P. Should routine neonatal
circumcision be a police to prevent penile cancer?
Opinion: Yes. Int. Braz. J. Urol. 43, 7–9 (2017).
31. Minhas, S., Manseck, A., Watya, S. & Hegarty, P. K.
Penile cancer — prevention and premalignant
conditions. Urology 76, S24–S35 (2010).
32. Larke, N. L., Thomas, S. L., dos Santos Silva, I.
& Weiss, H. A. Male circumcision and penile cancer:
a systematic review and meta-​analysis. Cancer Causes
Control 22, 1097–1110 (2011).
33. Clouston, D., Hall, A. & Lawrentschuk, N. Penile lichen
sclerosus (balanitis xerotica obliterans). BJU Int. 108,
14–19 (2011).
34. Harish, K. & Ravi, R. The role of tobacco in penile
carcinoma. Br. J. Urol. 75, 375–377 (1995).
35. Barnes, K. T. et al. Obesity is associated with
increased risk of invasive penile cancer. BMC Urol.
16, 42 (2016).
36. Vieira, C. B. et al. Profile of patients with penile cancer
in the region with the highest worldwide incidence.
Sci. Rep. 10, 2965 (2020).
37. Clark, P. E. et al. Penile cancer. J. Natl Compr. Cancer
Netw. 11, 594–615 (2013).
38. Stern, R. S., Bagheri, S. & Nichols, K. The persistent
risk of genital tumors among men treated with
psoralen plus ultraviolet A (PUVA) for psoriasis.
J. Am. Acad. Dermatol. 47, 33–39 (2002).
39. Hoekstra, R. J., Trip, E. J., Ten Kate, F. J., Horenblas, S.
& Lock, M. T. Penile intraepithelial neoplasia:
nomenclature, incidence and progression to
malignancy in the Netherlands. Int. J. Urol. 26,
353–357 (2019).
40. Ingles, D. J. et al. Human papillomavirus virus (HPV)
genotype- and age-​specific analyses of external genital
lesions among men in the HPV Infection in Men (HIM)
study. J. Infect. Dis. 211, 1060–1067 (2015).
41. Sudenga, S. L. et al. Genital human papillomavirus
infection progression to external genital lesions:
the HIM study. Eur. Urol. 69, 166–173 (2016).
42. Akogbe, G. O. et al. Race and prevalence of human
papillomavirus infection among men residing in Brazil,
Mexico and the United States. Int. J. Cancer 131,
E282–E291 (2012).
43. Kristiansen, S. et al. Risk factors for penile
intraepithelial neoplasia: a population-​based register
study in Sweden, 2000-2012. Acta Derm. Venereol.
99, 315–320 (2019).
44. Yoon, C. S., Kim, K. D., Park, S. N. & Cheong, S. W.
alpha(6) Integrin is the main receptor of human
papillomavirus type 16 VLP. Biochem. Biophys. Res.
Commun. 283, 668–673 (2001).
45. Yugawa, T. & Kiyono, T. Molecular mechanisms
of cervical carcinogenesis by high-​risk human
(2021) 7:11
0123456789();:
Primer
papillomaviruses: novel functions of E6 and E7
oncoproteins. Rev. Med. Virol. 19, 97–113 (2009).
46. Ferreux, E. et al. Evidence for at least three alternative
mechanisms targeting the p16INK4A/cyclin D/Rb
pathway in penile carcinoma, one of which is mediated
by high-​risk human papillomavirus. J. Pathol. 201,
109–118 (2003).
47. Steinestel, J. et al. The role of histologic subtype,
p16(INK4a) expression, and presence of human
papillomavirus DNA in penile squamous cell
carcinoma. BMC Cancer 15, 220 (2015).
48. Klingelhutz, A. J., Foster, S. A. & McDougall, J. K.
Telomerase activation by the E6 gene product of
human papillomavirus type 16. Nature 380, 79–82
(1996).
49. Gewin, L., Myers, H., Kiyono, T. & Galloway, D. A.
Identification of a novel telomerase repressor that
interacts with the human papillomavirus type-16 E6/
E6-AP complex. Genes Dev. 18, 2269–2282 (2004).
50. Khansari, N., Shakiba, Y. & Mahmoudi, M. Chronic
inflammation and oxidative stress as a major cause of
age-​related diseases and cancer. Recent Pat. Inflamm.
Allergy Drug Discov. 3, 73–80 (2009).
51. De Paula, A. A. et al. The impact of cyclooxygenase-2
and vascular endothelial growth factor C
immunoexpression on the prognosis of penile
carcinoma. J. Urol. 187, 134–140 (2012).
52. Greenhough, A. et al. The COX-2/PGE2 pathway:
key roles in the hallmarks of cancer and adaptation
to the tumour microenvironment. Carcinogenesis 30,
377–386 (2009).
53. Poetsch, M. et al. Alterations in the tumor suppressor
gene p16(INK4A) are associated with aggressive
behavior of penile carcinomas. Virchows Archiv. 458,
221–229 (2011).
54. Afonso, L. A. et al. Human papillomavirus, Epstein-​
Barr virus, and methylation status of p16(ink4a) in
penile cancer. J. Med. Virol. 89, 1837–1843 (2017).
55. Lohneis, P. et al. Human papilloma virus status of
penile squamous cell carcinoma is associated with
differences in tumour-​infiltrating T lymphocytes.
Virchows Archiv. 466, 323–331 (2015).
56. Herbster, S., Paladino, A., de Freitas, S. &
Boccardo, E. Alterations in the expression and activity
of extracellular matrix components in HPV-​associated
infections and diseases. Clinics 73, e551s (2018).
57. Chu, C. et al. Immunophenotypes based on the tumor
immune microenvironment allow for unsupervised
penile cancer patient stratification. Cancers 12, 1796
(2020).
58. Gunia, S. et al. Diagnostic and prognostic impact
of peritumoral stromal remodeling in patients with
surgically treated invasive penile squamous cell
cancer. Hum. Pathol. 45, 1169–1176 (2014).
59. Ottenhof, S. R. et al. The prognostic value of immune
factors in the tumor microenvironment of penile
squamous cell carcinoma. Front. Immunol. 9, 1253
(2018).
60. Aydin, A. M. et al. Understanding genomics and the
immune environment of penile cancer to improve
therapy. Nat. Rev. Urol. 17, 555–570 (2020).
61. Onywera, H. et al. The penile microbiota of Black South
African men: relationship with human papillomavirus
and HIV infection. BMC Microbiol. 20, 78 (2020).
62. Blank, C. U., Haanen, J. B., Ribas, A. &
Schumacher, T. N. Cancer immunology. The “cancer
immunogram”. Science 352, 658–660 (2016).
63. van dijk, N. et al. The cancer immunogram as a
framework for personalized immunotherapy in
urothelial cancer. Eur. Urol. 75, 435–444 (2019).
64. de Vries, H. M., Ottenhof, S. R., Horenblas, S.,
van der Heijden, M. S. & Jordanova, E. S. Defining
the tumor microenvironment of penile cancer by
means of the cancer immunogram. Eur. Urol. Focus.
5, 718–721 (2019).
65. Hernandez, B. Y. et al. Burden of invasive squamous
cell carcinoma of the penis in the United States,
1998–2003. Cancer 113, 2883–2891 (2008).
21
Primer
66. Barnholtz-​Sloan, J. S., Maldonado, J. L., Pow-​sang, J.
& Giuliano, A. R. Incidence trends in primary
malignant penile cancer. Urol. Oncol. 25, 361–367
(2007).
67. Favorito, L. A. et al. Epidemiologic study on penile
cancer in Brazil. Int. Braz. J. Urol. 34, 587–591
(2008).
68. Dufour, J. F. et al. Urogenital manifestations in
Wegener granulomatosis: a study of 11 cases and
review of the literature. Medicine 91, 67–74 (2012).
69. Lee, D. K., Hinshaw, M., Cripps, D. & Jarrard, D. F.
Pyoderma gangrenosum of penis. J. Urol. 170,
185–186 (2003).
70. Khan, D., Choudhary, A., Dutta, A. & Khan, I.
Tuberculosis of the glans penis mimicking as
carcinoma. Int. J. Mycobacteriol. 5, 341–342 (2016).
71. Tsaur, I., Ochsendorf, F. R., Bug, R. & Jonas, D.
Primary syphilitic lesion mimicking penile cancer.
Atypical manifestation with an unconventional
diagnostic approach. Urologe A 48, 1210–1213
(2009).
72. Lont, A. P., Besnard, A. P., Gallee, M. P., van Tinteren, H.
& Horenblas, S. A comparison of physical examination
and imaging in determining the extent of primary
penile carcinoma. BJU Int. 91, 493–495 (2003).
73. Shim, T. N., Ali, I., Muneer, A. & Bunker, C. B. Benign
male genital dermatoses. Br. Med. J. 354, i4337
(2016).
74. Lucky, M. A., Rogers, B. & Parr, N. J. Referrals into
a dedicated British penile cancer centre and sources
of possible delay. Sex. Transm. Infect. 85, 527–530
(2009).
75. Van Poppel, H. et al. Penile cancer: ESMO clinical
practice guidelines for diagnosis, treatment and
follow-​up. Ann. Oncol. 24, vi115–vi124 (2013).
76. Maden, C. et al. History of circumcision, medical
conditions, and sexual activity and risk of penile
cancer. J. Natl Cancer Inst. 85, 19–24 (1993).
77. Daling, J. R. et al. Penile cancer: importance of
circumcision, human papillomavirus and smoking
in in situ and invasive disease. Int. J. Cancer 116,
606–616 (2005).
78. Agrawal, A., Pai, D., Ananthakrishnan, N., Smile, S. R.
& Ratnakar, C. Clinical and sonographic findings in
carcinoma of the penis. J. Clin. Ultrasound 28,
399–406 (2000).
79. Horenblas, S., Kröger, R., Gallee, M. P., Newling, D. W.
& van Tinteren, H. Ultrasound in squamous cell
carcinoma of the penis; a useful addition to clinical
staging? A comparison of ultrasound with
histopathology. Urology 43, 702–707 (1994).
80. Kayes, O. et al. The role of magnetic resonance
imaging in the local staging of penile cancer. Eur. Urol.
51, 1313–1318 (2007).
81. Petralia, G. et al. Local staging of penile cancer using
magnetic resonance imaging with pharmacologically
induced penile erection. Radiol. Med. 113, 517–528
(2008).
82. Rosevear, H. M. et al. Utility of ¹-F-​FDG PET/CT in
identifying penile squamous cell carcinoma metastatic
lymph nodes. Urol. Oncol. 30, 723–726 (2012).
83. Sadeghi, R., Gholami, H., Zakavi, S. R., Kakhki, V. R.
& Horenblas, S. Accuracy of 18F-​FDG PET/CT for
diagnosing inguinal lymph node involvement in
penile squamous cell carcinoma: systematic review
and meta-​analysis of the literature. Clin. Nucl. Med.
37, 436–441 (2012).
84. Ottenhof, S. R. & Vegt, E. The role of PET/CT imaging
in penile cancer. Transl. Androl. Urol. 6, 833–838
(2017).
85. Shabbir, M. et al. Glans resurfacing for the treatment
of carcinoma in situ of the penis: surgical technique
and outcomes. Eur. Urol. 59, 142–147 (2011).
86. Moch, H., Cubilla, A. L., Humphrey, P. A., Reuter, V. E.
& Ulbright, T. M. The 2016 WHO classification of
tumours of the urinary system and male genital
organs — part a: renal, penile, and testicular tumours.
Eur. Urol. 70, 93–105 (2016).
87. Chaux, A., Velazquez, E. F., Algaba, F., Ayala, G. &
Cubilla, A. L. Developments in the pathology of penile
squamous cell carcinomas. Urology 76, S7–S14
(2010).
88. Velazquez, E. F. et al. Protocol for the examination of
specimens from patients with carcinoma of the penis.
Arch. Pathol. Lab. Med. 134, 923–929 (2010).
89. Paner, G. P. et al. Updates in the eighth edition of
the tumor-​node-metastasis staging classification for
urologic cancers. Eur. Urol. 73, 560–569 (2018).
90. Amin, M. B. et al. AJCC Cancer Staging Manual 8th
edn (Springer, 2017).
91. Dadar, M. et al. Advances in designing and developing
vaccines, drugs and therapeutic approaches to counter
22 | Article citation ID: (2021) 7:11
human papilloma virus. Front. Immunol. 9, 2478
(2018).
92. Schiffman, M. et al. Carcinogenic human
papillomavirus infection. Nat. Rev. Dis. Prim. 2,
16086 (2016).
93. Stanley, M. HPV vaccination in boys and men.
Hum. Vaccin. Immunother. 10, 2109–2111 (2014).
94. Ng, S. S., Hutubessy, R. & Chaiyakunapruk, N.
Systematic review of cost-​effectiveness studies of
human papillomavirus (HPV) vaccination: 9-valent
vaccine, gender-​neutral and multiple age cohort
vaccination. Vaccine 36, 2529–2544 (2018).
95. Powell, N., Hibbitts, S. & Evans, M. Gender neutral
vaccination against HPV. Br. Med. J. 362, k3837
(2018).
96. Markowitz, L. E. et al. Reduction in human
papillomavirus (HPV) prevalence among young women
following HPV vaccine introduction in the United
States, National Health and Nutrition Examination
Surveys, 2003-2010. J. Infect. Dis. 208, 385–393
(2013).
97. Schiller, J. T., Castellsagué, X. & Garland, S. M. A
review of clinical trials of human papillomavirus
prophylactic vaccines. Vaccine 30, F123–F138
(2012).
98. Mesher, D., Panwar, K., Thomas, S. L., Beddows, S. &
Soldan, K. Continuing reductions in HPV 16/18 in a
population with high coverage of bivalent HPV
vaccination in England: an ongoing cross-​sectional
study. BMJ Open 6, e009915 (2016).
99. Giuliano, A. R. et al. Efficacy of quadrivalent HPV
vaccine against HPV infection and disease in males.
N. Engl. J. Med. 364, 401–411 (2011).
100. Palefsky, J. M. et al. HPV vaccine against anal HPV
infection and anal intraepithelial neoplasia. N. Engl.
J. Med. 365, 1576–1585 (2011).
101. Shabbir, M., Barod, R., Hegarty, P. K. & Minhas, S.
Primary prevention and vaccination for penile cancer.
Ther. Adv. Urol. 5, 161–169 (2013).
102. Olsen, J. & Jørgensen, T. R. Revisiting the cost-​
effectiveness of universal HPV-​vaccination in Denmark
accounting for all potentially vaccine preventable
HPV-​related diseases in males and females. Cost. Eff.
Resour. Alloc. 13, 4 (2015).
103. Canfell, K. et al. Modeling preventative strategies
against human papillomavirus-​related disease in
developed countries. Vaccine 30, F157–F167 (2012).
104. Raskin, Y., Vanthoor, J., Milenkovic, U., Muneer, A. &
Albersen, M. Organ-​sparing surgical and nonsurgical
modalities in primary penile cancer treatment.
Curr. Opin. Urol. 29, 156–164 (2019).
105. Crook, J. Contemporary role of radiotherapy in the
management of primary penile tumors and metastatic
disease. Urol. Clin. North Am. 43, 435–448 (2016).
106. Chipollini, J., Necchi, A. & Spiess, P. E. Outcomes for
patients with node-​positive penile cancer: impact of
perioperative systemic therapies and the importance
of surgical intervention. Eur. Urol. 74, 241–242
(2018).
107. Bandini, M., Pederzoli, F. & Necchi, A. Neoadjuvant
chemotherapy for lymph node-​positive penile cancer:
current evidence and knowledge. Curr. Opin. Urol. 30,
218–222 (2020).
108. Robinson, R. et al. Risks and benefits of adjuvant
radiotherapy after inguinal lymphadenectomy in
node-​positive penile cancer: a systematic review by
the european association of urology penile cancer
guidelines panel. Eur. Urol. 74, 76–83 (2018).
109. Ashley, S. et al. Human papilloma virus (HPV) status
may impact treatment outcomes in patients with
pre-​cancerous penile lesions (an eUROGEN Study).
Int. J. Impot. Res. https://doi.org/10.1038/s41443-
020-0327-4 (2020).
110. Kravvas, G. et al. The management of penile
intraepithelial neoplasia (PeIN): clinical and
histological features and treatment of 345 patients
and a review of the literature. J. Dermatol. Treat.
https://doi.org/10.1080/09546634.2020.1800574
(2020).
111. Manjunath, A., Brenton, T., Wylie, S., Corbishley, C. M.
& Watkin, N. A. Topical Therapy for non-​invasive
penile cancer (Tis)-updated results and toxicity.
Transl. Androl. Urol. 6, 803–808 (2017).
112. Alnajjar, H. M. et al. Treatment of carcinoma in situ
of the glans penis with topical chemotherapy agents.
Eur. Urol. 62, 923–928 (2012).
113. Deen, K. & Burdon-​Jones, D. Imiquimod in the
treatment of penile intraepithelial neoplasia:
an update. Australas. J. Dermatol. 58, 86–92
(2017).
114. Bandieramonte, G. et al. Peniscopically controlled CO2
laser excision for conservative treatment of in situ and
0123456789();:
T1 penile carcinoma: report on 224 patients.
Eur. Urol. 54, 875–882 (2008).
115. Tang, D. H. et al. Laser ablation as monotherapy for
penile squamous cell carcinoma: a multi-​center cohort
analysis. Urol. Oncol. 36, 147–152 (2018).
116. van Bezooijen, B. P., Horenblas, S., Meinhardt, W.
& Newling, D. W. Laser therapy for carcinoma in situ
of the penis. J. Urol. 166, 1670–1671 (2001).
117. Protzel, C. & Hakenberg, O. W. Local treatment
of penile cancer. Urologe A 57, 423–427 (2018).
118. Shaw, K. S., Nguyen, G. H., Lacouture, M. & Deng, L.
Combination of imiquimod with cryotherapy in the
treatment of penile intraepithelial neoplasia.
JAAD Case Rep. 3, 546–549 (2017).
119. Paoli, J. et al. Penile intraepithelial neoplasia: results
of photodynamic therapy. Acta Derm. Venereol. 86,
418–421 (2006).
120. Chipollini, J. et al. Surgical management of penile
carcinoma in situ: results from an international
collaborative study and review of the literature.
BJU Int. 121, 393–398 (2018).
121. Sri, D. et al. A study into the association between local
recurrence rates and surgical resection margins in
organ-​sparing surgery for penile squamous cell cancer.
BJU Int. 122, 576–582 (2018).
122. Agrawal, A., Pai, D., Ananthakrishnan, N., Smile, S. R.
& Ratnakar, C. The histological extent of the local
spread of carcinoma of the penis and its therapeutic
implications. BJU Int. 85, 299–301 (2000).
123. Minhas, S. et al. What surgical resection margins are
required to achieve oncological control in men with
primary penile cancer? BJU Int. 96, 1040–1043
(2005).
124. Philippou, P. et al. Conservative surgery for squamous
cell carcinoma of the penis: resection margins and
long-​term oncological control. J. Urol. 188, 803–808
(2012).
125. Djajadiningrat, R. S. et al. Penile sparing surgery for
penile cancer — does it affect survival? J. Urol. 192,
120–125 (2014).
126. Roussel, E. et al. Predictors of local recurrence and its
impact on survival after glansectomy for penile cancer:
time to challenge the dogma? BJU Int. https://doi.org/
10.1111/bju.15297 (2020).
127. Kamel, M. H. et al. Survival outcomes of organ sparing
surgery, partial penectomy, and total penectomy in
pathological T1/T2 penile cancer: Report from the
National Cancer Data Base. Urol. Oncol. 36, 82.
e87–82.e15 (2018).
128. Baumgarten, A. et al. Penile sparing surgery for penile
cancer: a multicenter international retrospective
cohort. J. Urol. 199, 1233–1237 (2018).
129. Albersen, M. et al. Predictive factors for local
recurrence after glansectomy and neoglans
reconstruction for penile squamous cell carcinoma.
Urol. Oncol. 36, 141–146 (2018).
130. Alnajjar, H. M., Randhawa, K. & Muneer, A. Localized
disease: types of reconstruction/plastic surgery
techniques after glans resurfacing/glansectomy/partial/
total penectomy. Curr. Opin. Urol. 30, 213–217
(2020).
131. Pérez, J. et al. Oncological and functional outcomes
after organ-​sparing plastic reconstructive surgery
for penile cancer. Urology 142, 161–165.e1 (2020).
132. Burnett, A. L. Penile preserving and reconstructive
surgery in the management of penile cancer.
Nat. Rev. Urol. 13, 249–257 (2016).
133. Kitamura, Y. et al. Penile-​preserving surgery for male
distal urethral carcinoma followed by buccal mucosa
urethroplasty. IJU Case Rep. 2, 198–201 (2019).
134. Ficarra, V. et al. General state of health and
psychological well-​being in patients after surgery
for urological malignant neoplasms. Urol. Int. 65,
130–134 (2000).
135. Sarin, R., Norman, A. R., Steel, G. G. & Horwich, A.
Treatment results and prognostic factors in 101 men
treated for squamous carcinoma of the penis. Int. J.
Radiat. Oncol. Biol. Phys. 38, 713–722 (1997).
136. Rozan, R. et al. Interstitial brachytherapy for penile
carcinoma: a multicentric survey (259 patients).
Radiother. Oncol. 36, 83–93 (1995).
137. Crook, J., Ma, C. & Grimard, L. Radiation therapy
in the management of the primary penile tumor:
an update. World J. Urol. 27, 189–196 (2009).
138. de Crevoisier, R. et al. Long-​term results of
brachytherapy for carcinoma of the penis confined to
the glans (N- or NX). Int. J. Radiat. Oncol. Biol. Phys.
74, 1150–1156 (2009).
139. McLean, M. et al. The results of primary radiation
therapy in the management of squamous cell
carcinoma of the penis. Int. J. Radiat. Oncol. Biol.
Phys. 25, 623–628 (1993).
www.nature.com/nrdp

140. Neave, F., Neal, A. J., Hoskin, P. J. & Hope-​Stone, H. F.
Carcinoma of the penis: a retrospective review of
treatment with iridium mould and external beam
irradiation. Clin. Oncol. 5, 207–210 (1993).
141. Gotsadze, D., Matveev, B., Zak, B. & Mamaladze, V.
Is conservative organ-​sparing treatment of penile
carcinoma justified? Eur. Urol. 38, 306–312 (2000).
142. Zouhair, A. et al. Radiation therapy alone or combined
surgery and radiation therapy in squamous-​cell
carcinoma of the penis? Eur. J. Cancer 37, 198–203
(2001).
143. Hasan, S. et al. The role of brachytherapy in organ
preservation for penile cancer: a meta-​analysis and
review of the literature. Brachytherapy 14, 517–524
(2015).
144. Crook, J. Radiotherapy approaches for locally
advanced penile cancer: neoadjuvant and adjuvant.
Curr. Opin. Urol. 27, 62–67 (2017).
145. Korzeniowski, M. A. & Crook, J. M. Contemporary role
of radiotherapy in the management of penile cancer.
Transl. Androl. Urol. 6, 855–867 (2017).
146. Leone, A., Diorio, G. J., Pettaway, C., Master, V. &
Spiess, P. E. Contemporary management of patients
with penile cancer and lymph node metastasis.
Nat. Rev. Urol. 14, 335–347 (2017).
147. Ficarra, V., Akduman, B., Bouchot, O., Palou, J. &
Tobias-​Machado, M. Prognostic factors in penile
cancer. Urology 76, S66–S73 (2010).
148. Horenblas, S. & van Tinteren, H. Squamous cell
carcinoma of the penis. IV. Prognostic factors of
survival: analysis of tumor, nodes and metastasis
classification system. J. Urol. 151, 1239–1243
(1994).
149. Djajadiningrat, R. S. et al. Contemporary management
of regional nodes in penile cancer-​improvement of
survival? J. Urol. 191, 68–73 (2014).
150. Srinivas, V., Morse, M. J., Herr, H. W., Sogani, P. C. &
Whitmore, W. F. Jr. Penile cancer: relation of extent of
nodal metastasis to survival. J. Urol. 137, 880–882
(1987).
151. Kroon, B. K., Horenblas, S., Deurloo, E. E., Nieweg, O. E.
& Teertstra, H. J. Ultrasonography-​guided fine-​needle
aspiration cytology before sentinel node biopsy in
patients with penile carcinoma. BJU Int. 95, 517–521
(2005).
152. Graafland, N. M., Teertstra, H. J., Besnard, A. P.,
van Boven, H. H. & Horenblas, S. Identification of
high risk pathological node positive penile carcinoma:
value of preoperative computerized tomography
imaging. J. Urol. 185, 881–887 (2011).
153. Hughes, B. E. et al. Lymph node metastasis in
intermediate-​risk penile squamous cell cancer:
a two-​centre experience. Eur. Urol. 57, 688–692
(2010).
154. Graafland, N. M. et al. Prognostic factors for occult
inguinal lymph node involvement in penile carcinoma
and assessment of the high-​risk EAU subgroup: a two-​
institution analysis of 342 clinically node-​negative
patients. Eur. Urol. 58, 742–747 (2010).
155. Hegarty, P. K. et al. A prospective study of 100 cases
of penile cancer managed according to European
Association of Urology guidelines. BJU Int. 98,
526–531 (2006).
156. Ercole, C. E., Pow-​Sang, J. M. & Spiess, P. E. Update
in the surgical principles and therapeutic outcomes
of inguinal lymph node dissection for penile cancer.
Urol. Oncol. 31, 505–516 (2013).
157. Kroon, B. K. et al. Patients with penile carcinoma
benefit from immediate resection of clinically occult
lymph node metastases. J. Urol. 173, 816–819 (2005).
158. Ornellas, A. A. et al. Prognostic factors in invasive
squamous cell carcinoma of the penis: analysis of
196 patients treated at the Brazilian National Cancer
Institute. J. Urol. 180, 1354–1359 (2008).
159. Kirrander, P., Sherif, A., Friedrich, B., Lambe, M.
& Håkansson, U. Swedish National Penile Cancer
Register: incidence, tumour characteristics,
management and survival. BJU Int. 117, 287–292
(2016).
160. Lam, W. et al. Dynamic sentinel lymph node biopsy in
patients with invasive squamous cell carcinoma of the
penis: a prospective study of the long-​term outcome
of 500 inguinal basins assessed at a single institution.
Eur. Urol. 63, 657–663 (2013).
161. Brouwer, O. R. et al. Comparing the hybrid
fluorescent-​radioactive tracer indocyanine
green-99mTc-​nanocolloid with 99mTc-​nanocolloid for
sentinel node identification: a validation study using
lymphoscintigraphy and SPECT/CT. J. Nucl. Med. 53,
1034–1040 (2012).
162. Dell’Oglio, P. et al. Hybrid indocyanine green–(99m)
Tc–nanocolloid for single-​photon emission computed
NATURE REVIEWS | DISeASe PRIMeRS | Article citation ID:
tomography and combined radio- and fluorescence-​
guided sentinel node biopsy in penile cancer: results
of 740 inguinal basins assessed at a single institution.
Eur. Urol. 78, 865–872 (2020).
163. Kroon, B. K. et al. How to avoid false-​negative dynamic
sentinel node procedures in penile carcinoma. J. Urol.
171, 2191–2194 (2004).
164. Jakobsen, J. K. et al. DaPeCa-3: promising
results of sentinel node biopsy combined with
(18)F-​fluorodeoxyglucose positron emission
tomography/computed tomography in clinically lymph
node-​negative patients with penile cancer – a national
study from Denmark. BJU Int. 118, 102–111 (2016).
165. Kroon, B. K., Lont, A. P., Valdés Olmos, R. A.,
Nieweg, O. E. & Horenblas, S. Morbidity of dynamic
sentinel node biopsy in penile carcinoma. J. Urol. 173,
813–815 (2005).
166. Leijte, J. A. et al. Two-​center evaluation of dynamic
sentinel node biopsy for squamous cell carcinoma
of the penis. J. Clin. Oncol. 27, 3325–3329 (2009).
167. Spiess, P. E. et al. Preoperative lymphoscintigraphy
and dynamic sentinel node biopsy for staging penile
cancer: results with pathological correlation. J. Urol.
177, 2157–2161 (2007).
168. Nabavizadeh, R. et al. Inguinal lymph node dissection
in the era of minimally invasive surgical technology.
Urol. Oncol. https://doi.org/10.1016/j.urolonc.
2020.07.026 (2020).
169. Nabavizadeh, R. et al. Utility of minimally invasive
technology for inguinal lymph node dissection in
penile cancer. J. Clin. Med. 9, 2501 (2020).
170. Protzel, C. et al. Lymphadenectomy in the surgical
management of penile cancer. Eur. Urol. 55,
1075–1088 (2009).
171. Catalona, W. J. Modified inguinal lymphadenectomy
for carcinoma of the penis with preservation of
saphenous veins: technique and preliminary results.
J. Urol. 140, 306–310 (1988).
172. Niyogi, D., Noronha, J., Pal, M., Bakshi, G. &
Prakash, G. Management of clinically node-​negative
groin in patients with penile cancer. Indian J. Urol. 36,
8–15 (2020).
173. Tobias-​Machado, M. et al. Single-​site video endoscopic
inguinal lymphadenectomy: initial report. J. Endourol.
25, 607–610 (2011).
174. Tobias-​Machado, M. et al. Can video endoscopic
inguinal lymphadenectomy achieve a lower morbidity
than open lymph node dissection in penile cancer
patients? J. Endourol. 22, 1687–1691 (2008).
175. Kumar, V. & Sethia, K. K. Prospective study comparing
video-​endoscopic radical inguinal lymph node
dissection (VEILND) with open radical ILND (OILND)
for penile cancer over an 8-year period. BJU Int. 119,
530–534 (2017).
176. Russell, C. M. et al. Minimally invasive inguinal
lymphadenectomy in the management of penile
carcinoma. Urology 106, 113–118 (2017).
177. Tobias-​Machado, M. et al. Video endoscopic
inguinal lymphadenectomy: a new minimally invasive
procedure for radical management of inguinal nodes in
patients with penile squamous cell carcinoma. J. Urol.
177, 953–957 (2007).
178. Hu, J. et al. Comparison of clinical feasibility and
oncological outcomes between video endoscopic and
open inguinal lymphadenectomy for penile cancer:
a systematic review and meta-​analysis. Medicine 98,
e15862 (2019).
179. Yao, K. et al. Fascia lata preservation during inguinal
lymphadenectomy for penile cancer: rationale and
outcome. Urology 82, 642–647 (2013).
180. Ottenhof, S. R. et al. Surgical and oncological
outcomes in patients after vascularised flap
reconstruction for locoregionally advanced penile
cancer. Eur. Urol. Focus. 5, 867–874 (2019).
181. Alnajjar, H. M. et al. Long-​term outcomes for penile
cancer patients presenting with advanced N3 disease
requiring a myocutaneous flap reconstruction or
primary closure-​a retrospective single centre study.
Transl. Androl. Urol. 8 (Suppl. 1), S13–S21 (2019).
182. Yegiyants, S., Romero, L. M., Haigh, P. I. &
DiFronzo, L. A. Completion axillary lymph node
dissection not required for regional control in patients
with breast cancer who have micrometastases in a
sentinel node. Arch. Surg. 145, 564–569 (2010).
183. Fournier, K., Schiller, A., Perry, R. R. & Laronga, C.
Micrometastasis in the sentinel lymph node of
breast cancer does not mandate completion
axillary dissection. Ann. Surg. 239, 859–863
(2004).
184. Lont, A. P. et al. Pelvic lymph node dissection for
penile carcinoma: extent of inguinal lymph node
involvement as an indicator for pelvic lymph node
(2021) 7:11
0123456789();:
Primer
involvement and survival. J. Urol. 177, 947–952
(2007).
185. Necchi, A. et al. Clinical outcomes of perioperative
chemotherapy in patients with locally advanced penile
squamous-​cell carcinoma: results of a multicenter
analysis. Clin. Genitourin. Cancer 15, 548–555.e543
(2017).
186. Nicolai, N. et al. A combination of cisplatin and
5-fluorouracil with a taxane in patients who underwent
lymph node dissection for nodal metastases from
squamous cell carcinoma of the penis: treatment
outcome and survival analyses in neoadjuvant and
adjuvant settings. Clin. Genitourin. Cancer 14,
323–330 (2016).
187. Nicholson, S. et al. Phase II trial of docetaxel, cisplatin
and 5FU chemotherapy in locally advanced and
metastatic penis cancer (CRUK/09/001). Br. J. Cancer
109, 2554–2559 (2013).
188. Djajadiningrat, R. S., Bergman, A. M.,
van Werkhoven, E., Vegt, E. & Horenblas, S.
Neoadjuvant taxane-​based combination
chemotherapy in patients with advanced penile
cancer. Clin. Genitourin. Cancer 13, 44–49 (2015).
189. Azizi, M. et al. Systematic review and meta-​analysis-is
there a benefit in using neoadjuvant systemic
chemotherapy for locally advanced penile squamous
cell carcinoma? J. Urol. 203, 1147–1155 (2020).
190. Necchi, A. et al. Nomogram-​based prediction of
overall survival after regional lymph node dissection
and the role of perioperative chemotherapy in penile
squamous cell carcinoma: a retrospective multicenter
study. Urol. Oncol. 37, 531.e7–531.e15 (2019).
191. Homesley, H. D., Bundy, B. N., Sedlis, A. & Adcock, L.
Radiation therapy versus pelvic node resection for
carcinoma of the vulva with positive groin nodes.
Obstet. Gynecol. 68, 733–740 (1986).
192. Kunos, C., Simpkins, F., Gibbons, H., Tian, C. &
Homesley, H. Radiation therapy compared with
pelvic node resection for node-​positive vulvar cancer:
a randomized controlled trial. Obstet. Gynecol. 114,
537–546 (2009).
193. Tang, D. H. et al. Adjuvant pelvic radiation is associated
with improved survival and decreased disease
recurrence in pelvic node-​positive penile cancer after
lymph node dissection: a multi-​institutional study.
Urol. Oncol. 35, 605.e17–605.e23 (2017).
194. Kulkarni, J. N. & Kamat, M. R. Prophylactic bilateral
groin node dissection versus prophylactic radiotherapy
and surveillance in patients with N0 and N1-2A
carcinoma of the penis. Eur. Urol. 26, 123–128
(1994).
195. Graafland, N. M. et al. Inguinal recurrence following
therapeutic lymphadenectomy for node positive penile
carcinoma: outcome and implications for management.
J. Urol. 185, 888–893 (2011).
196. Franks, K. N. et al. Radiotherapy for node positive
penile cancer: experience of the Leeds teaching
hospitals. J. Urol. 186, 524–529 (2011).
197. Winters, B. R. et al. Is there a benefit to adjuvant
radiation in stage III penile cancer after lymph
node dissection? Findings from the National
Cancer Database. Urol. Oncol. 36, 92.e11–92.e16
(2018).
198. Giannatempo, P. et al. Impact of human
papillomavirus (HPV) infection on the outcome of
perioperative treatments for penile squamous-​cell
carcinoma (PSCC). J. Clin. Oncol. 38, 5088–5088
(2020).
199. Canter, D. J., Nicholson, S., Watkin, N., Hall, E. &
Pettaway, C. The International Penile advanced cancer
trial (InPACT): rationale and current status. Eur. Urol.
Focus. 5, 706–709 (2019).
200. Pickering, L. M. et al. VinCaP: a phase II trial
of vinflunine chemotherapy in locally-​advanced and
metastatic carcinoma of the penis (CRUK/12/021).
J. Clin. Oncol. 36, 4514–4514 (2018).
201. Theodore, C. et al. A phase II multicentre study of
irinotecan (CPT 11) in combination with cisplatin
(CDDP) in metastatic or locally advanced penile
carcinoma (EORTC PROTOCOL 30992). Ann. Oncol.
19, 1304–1307 (2008).
202. Di Lorenzo, G. et al. Paclitaxel in pretreated metastatic
penile cancer: final results of a phase 2 study. Eur. Urol.
60, 1280–1284 (2011).
203. Brown, J. C., Chu, C. S., Cheville, A. L. & Schmitz, K. H.
The prevalence of lymphedema symptoms among
survivors of long-​term cancer with or at risk for lower
limb lymphedema. Am. J. Phys. Med. Rehabil. 92,
223–231 (2013).
204. Dräger, D. L., Protzel, C. & Hakenberg, O. W.
Identifying psychosocial distress and stressors
using distress-​screening instruments in patients with
23
Primer
localized and advanced penile cancer. Clin. Genitourin.
Cancer 15, 605–609 (2017).
205. Maddineni, S. B., Lau, M. M. & Sangar, V. K.
Identifying the needs of penile cancer sufferers:
a systematic review of the quality of life, psychosexual
and psychosocial literature in penile cancer. BMC Urol.
9, 8 (2009).
206. Parnham, A. S. et al. Glansectomy and split-​thickness
skin graft for penile cancer. Eur. Urol. 73, 284–289
(2018).
207. Yang, J. et al. Glans preservation contributes to
postoperative restoration of male sexual function:
a multicenter clinical study of glans preserving
surgery. J. Urol. 192, 1410–1417 (2014).
208. Yu, C. et al. Sexual function after partial penectomy:
a prospectively study from China. Sci. Rep. 6, 21862
(2016).
209. Alnajjar, H. M. et al. A novel ‘Batman’ scrotectomy
technique for the management of scrotal
lymphoedema following treatment for penile cancer.
Transl. Androl. Urol. 8, 448–456 (2019).
210. Kayes, O., Ahmed, H. U., Arya, M. & Minhas, S.
Molecular and genetic pathways in penile cancer.
Lancet Oncol. 8, 420–429 (2007).
211. Sand, F. L., Rasmussen, C. L., Frederiksen, M. H.,
Andersen, K. K. & Kjaer, S. K. Prognostic significance
of HPV and p16 status in men diagnosed with penile
cancer: a systematic review and meta-​analysis. Cancer
Epidemiol. Biomarkers Prev. 27, 1123–1132 (2018).
212. Jacob, J. M. et al. Comparative genomic profiling
of refractory and metastatic penile and nonpenile
cutaneous squamous cell carcinoma: implications for
selection of systemic therapy. J. Urol. 201, 541–548
(2019).
213. Necchi, A. et al. Gene expression profiling of advanced
penile squamous cell carcinoma receiving cisplatin-​
based chemotherapy improves prognostication and
identifies potential therapeutic targets. Eur. Urol.
Focus. 4, 733–736 (2018).
214. De Bacco, M. W. et al. PD-​L1 and p16 expression
in penile squamous cell carcinoma from an endemic
region. Clin. Genitourin. Cancer 18, e254–e259
(2020).
215. Ahmed, M. E., Falasiri, S., Hajiran, A., Chahoud, J. &
Spiess, P. E. The immune microenvironment in penile
cancer and rationale for immunotherapy. J. Clin. Med.
9, 3334 (2020).
216. Davidsson, S. et al. PD-​L1 expression in men
with penile cancer and its association with clinical
outcomes. Eur. Urol. Oncol. 2, 214–221 (2019).
217. Ottenhof, S. R. et al. Expression of programmed death
ligand 1 in penile cancer is of prognostic value and
associated with HPV status. J. Urol. 197, 690–697
(2017).
218. Cocks, M. et al. Immune-​checkpoint status in penile
squamous cell carcinoma: a North American cohort.
Hum. Pathol. 59, 55–61 (2017).
219. Necchi, A. et al. Prognostic factors of adjuvant taxane,
cisplatin, and 5-fluorouracil chemotherapy for patients
with penile squamous cell carcinoma after regional
lymphadenectomy. Clin. Genitourin. Cancer 14,
518–523 (2016).
220. Thomas, A., Vanthoor, J., Vos, G., Tsaur, I. &
Albersen, M. Risk factors and molecular characterization
of penile cancer: impact on prognosis and potential
targets for systemic therapy. Curr. Opin. Urol. 30,
202–207 (2020).
221. McDaniel, A. S. et al. Genomic profiling of penile
squamous cell carcinoma reveals new opportunities
for targeted therapy. Cancer Res. 75, 5219–5227
(2015).
222. Huang, T. et al. Effective combinatorial immunotherapy
for penile squamous cell carcinoma. Nat. Commun. 11,
2124 (2020).
223. Muñoz, J. J. et al. A comprehensive characterization
of cell cultures and xenografts derived from a human
verrucous penile carcinoma. Tumour Biol. 37,
11375–11384 (2016).
224. Chen, J. et al. Establishment and characterization
of a penile cancer cell line, penl1, with a deleterious
24 | Article citation ID: (2021) 7:11
TP53 mutation as a paradigm of HPV-​negative penile
carcinogenesis. Oncotarget 7, 51687–51698 (2016).
225. Zhou, Q. H. et al. Molecular characterization and
integrative genomic analysis of a panel of newly
established penile cancer cell lines. Cell Death Dis.
9, 684 (2018).
226. Thomas, A. et al. Establishment, characterization,
and imaging of a first platinum-​resistant penile cancer
patient-​derived xenograft in nude mice: a eUROGEN
project. Eur. Urol. 78, 294–296 (2020).
227. McGregor, B. A. et al. Phase II study of nivolumab and
ipilimumab for advanced rare genitourinary cancers.
J. Clin. Oncol. 38, 5018–5018 (2020).
228. Norberg, S. et al. Safety and clinical activity of
gene-​engineered T-​cell therapy targeting HPV-16 E7
for epithelial cancers. J. Clin. Oncol. 38, 101–101
(2020).
229. Campbell, R. A. et al. Disparity between pre-​existing
management of penile cancer and NCCN guidelines.
Urol. Oncol. 35, 531.e9–531.e14 (2017).
230. Bada, M. et al. Adherence to the EAU guidelines
on penile cancer treatment: European, multicentre,
retrospective study. J. Cancer Res. Clin. Oncol. 145,
921–926 (2019).
231. Tang, V. et al. Should centralized histopathological
review in penile cancer be the global standard?
BJU Int. 114, 340–343 (2014).
232. Bayles, A. C. & Sethia, K. K. The impact of improving
outcomes guidance on the management and outcomes
of patients with carcinoma of the penis. Ann. R. Coll.
Surg. Engl. 92, 44–45 (2010).
233. Breen, K. J. et al. Penile cancer — guideline adherence
produces optimum results. Surgeon 13, 200–206
(2015).
234. Joshi, S. S. et al. Treatment trends and outcomes for
patients with lymph node-​positive cancer of the penis.
JAMA Oncol. 4, 643–649 (2018).
235. Williams, S. B. et al. Impact of centralizing care for
genitourinary malignancies to high-​volume providers:
a systematic review. Eur. Urol. Oncol. 2, 265–273
(2019).
236. Kamel, M. H. Should the care of penile cancer be
confined to centralized centers of excellence?
Eur. Urol. Focus. 5, 735–736 (2019).
237. Hakenberg, O. W. et al. The diagnosis and treatment
of penile cancer. Dtsch. Arztebl. Int. 115, 646–652
(2018).
238. Chaux, A. & Cubilla, A. L. Advances in the pathology
of penile carcinomas. Hum. Pathol. 43, 771–789
(2012).
239. Cubilla, A. L. et al. Basaloid squamous cell carcinoma
of the penis with papillary features: a clinicopathologic
study of 12 cases. Am. J. Surg. Pathol. 36, 869–875
(2012).
240. Cubilla, A. L. et al. The World Health Organisation
2016 classification of penile carcinomas: a review and
update from the International Society of Urological
Pathology expert-​driven recommendations.
Histopathology 72, 893–904 (2018).
241. Boulet, G., Horvath, C., Vanden Broeck, D., Sahebali, S.
& Bogers, J. Human papillomavirus: E6 and E7
oncogenes. Int. J. Biochem. Cell Biol. 39, 2006–2011
(2007).
242. Summerton, D. J., Campbell, A., Minhas, S. &
Ralph, D. J. Reconstructive surgery in penile trauma
and cancer. Nat. Clin. Pract. Urol. 2, 391–397
(2005).
243. Hadway, P., Sahdev, V., Arya, M. & Muneer, A. Recent
developments and current management of penile
cancer. Clin. Pract. 11, 169–181 (2014).
244. Kirkham, A. P. S. in Textbook of Penile Cancer
(eds Muneer, A. & Horenblas, S.) 89-114
(Springer, 2016).
245. Crook, J. Organ preserving radiation strategies for
penile cancer. Urol. Oncol. https://doi.org/10.1016/
j.urolonc.2020.06.025 (2020).
246. Dodge, O. G., Linsell, C. A. & Davies, J. N.
Circumcision and the incidence of carcinoma of the
penis and the cervix. a study in Kenya and Uganda
Africans. East Afr. Med. J. 40, 440–444 (1963).
0123456789();:
247. Wolbarst, A. Circumcision and penile cancer. Lancet
219, 150–153 (1932).
248. Schrek, R. & Lenowitz, H. Etiologic factors in
carcinoma of the penis. Cancer Res. 7, 180–187
(1947).
249. Reuter, S., Gupta, S. C., Chaturvedi, M. M. &
Aggarwal, B. B. Oxidative stress, inflammation, and
cancer: how are they linked? Free Radic. Biol. Med.
49, 1603–1616 (2010).
250. Elinav, E. et al. Inflammation-​induced cancer: crosstalk
between tumours, immune cells and microorganisms.
Nat. Rev. Cancer 13, 759–771 (2013).
251. Dave, S., Afshar, K., Braga, L. H. & Anderson, P.
Canadian Urological Association guideline on the care
of the normal foreskin and neonatal circumcision in
Canadian infants (full version). Can. Urol. Assoc. J. 12,
E76–E99 (2018).
252. Castellsagué, X. et al. Male circumcision, penile
human papillomavirus infection, and cervical cancer
in female partners. N. Engl. J. Med. 346, 1105–1112
(2002).
253. Doyle, S. M., Kahn, J. G., Hosang, N. & Carroll, P. R.
The impact of male circumcision on HIV transmission.
J. Urol. 183, 21–26 (2010).
254. Schenker, I. Cutting-​edge success in preventing
heterosexual HIV transmission in Africa: voluntary
medical male circumcision has reached 15 million
men. AIDS Educ. Prev. 30, 232–242 (2018).
255. Amin, M. B. et al. The eighth edition AJCC cancer
staging manual: continuing to build a bridge from a
population-​based to a more “personalized” approach
to cancer staging. CA Cancer J. Clin. 67, 93–99
(2017).
Acknowledgements
The authors thank a patient who kindly contributed with his
disease experience to this article. M.A. holds a mandate of
the Foundation Against Cancer.
Author contributions
Introduction (M.A., A.Th. and A.-​S.V.R.); Epidemiology (M.A.
and A.Th.); Mechanisms/Pathophysiology (M.A., A.Th. and
P.E.S.); Diagnosis, screening and prevention (M.A., A.Th.,
A.M. and A.-​S.V.R.); Management (M.A., A.Th., A.N., A.M.,
M.T.-​M. and A.Tr.); Quality of life (M.A., A.Th. and A.M.);
Outlook (M.A., A.Th., A.N. and A.M.).
Competing interests
M.A.: eUROGEN clinical lead on rare urogenital cancer work-
stream (WS3); Nature Reviews Urology advisory board mem-
ber; European Urology Associate Editor; EAU Scientific Office
member; EAU–ASCO penile cancer guideline panel member.
A.Th.: EUSP scholar. A.M.: eUROGEN research lead on rare
urogenital cancer workstream (WS3); ESMO penile cancer
guideline panel member; editorial board BJU International.
A.N.: EAU–ASCO penile cancer guideline panel member,
penile cancer research funding to institute by Ipsen and
Pfizer. P.E.S.: NCCN penile cancer guideline discussion writing
committee member; EAU–ASCO penile cancer guideline
panel member; Nature Reviews Urology advisory board
member. M.T.-​M.: coordinator of Penile Cancer Collabo­rative
Coalition – Latin America. All other authors declare no
competing interests.
Informed consent
The authors affirm that human research participants provided
informed consent for publication of the images in Figure 3
and Figure 6.
Peer review information
Nature Reviews Disease Primers thanks O. Brouwer, J. Crook,
O. Hakenberg, G. Netto, F. Zhou and the other, anonymous,
reviewer(s) for their contribution to the peer review of this
work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
© Springer Nature Limited 2021
www.nature.com/nrdp