ARTICLE IN PRESS

Seminars article
A 25-year perspective on advances in an understanding of the biology,
evaluation, treatment and future directions/challenges of penile cancer
Timothy A. Masterson, M.D.a, Scott T. Tagawa, M.D., M.S.b,*
a
Department of Urology, Indiana University School of Medicine, Indianapolis, IN
b
Division of Hematology & Medical Oncology, Department of Medicine and Department of Urology, Weill Cornell Medicine, New York, NY
Received 6 March 2021; received in revised form 14 May 2021; accepted 18 May 2021

Abstract
Squamous cell carcinoma of the penis (SCCP) is uncommon in some countries (including the U.S.), but is an important malignancy else-
where. As a rare disease, progress has been slow compared to more common tumor types discussed in this anniversary issue and most often
limited to single-center or retrospective datasets. In this section we describe developments leading to the current standard approach with
current research questions Ó 2021 Elsevier Inc. All rights reserved.

Keywords: Penile cancer; Squamous cell carcinoma; Human papilloma virus; Penectomy; Lymph node dissection

1. Penile cancer: slow, but important progress for a rare
disease
Squamous cell carcinoma of the penis (SCCP) is uncom-
mon in some countries (including the U.S.), but is an impor-
tant malignancy elsewhere. As a rare disease, progress has
been slow compared to more common tumor types dis-
cussed in this anniversary issue and most often limited to
single-center or retrospective datasets. In this section we
describe developments leading to the current standard
approach with current research questions.
2. Biology
The recognition of human papilloma virus (HPV) as a
risk factor for cervical cancer followed by anal and head
and neck cancers paved the way for investigation in penile
carcinoma. Approximately half of penile carcinoma cases
have an association with HPV [1]. As with other HPV-
associated malignancies, HPV subtypes 16 and 18 are
most commonly implicated along with subtypes 31 and
33. Pathogenesis for HPV-associated SCCP may involve
*Corresponding author. Tel.: 646-962-2072, Fax 646-962-1603
E-mail address: stt2007@med.cornell.edu (S.T. Tagawa).
dysregulation of tumor suppressor proteins p53 and retino-
blastoma protein pRb; suppression of pRb leads to upregu-
lation of p16 [2]. With loss of cell cycle arrest,
upregulation of p16 is sometimes used as a surrogate for
HPV infection. A retrospective North American cohort
points towards the prognostic value of p53 and p16 expres-
sion, with good (but not complete) concordance between
p16 and HPV in situ hybridization [3]. Inflammation likely
plays a role in carcinogenesis as well, in particular for
HPV negative tumors.
In addition to epidemiologic and prevention considera-
tions (see vaccine discussion below), the presence or
absence of HPV may have therapeutic implications. While
datasets are limited in penile carcinoma, HPV positive
tumors may have a better prognosis, similar to what has
been observed in other cancers. It is also possible that there
may be predictive considerations, such as more radiosensi-
tivity as seen with SCC of the oropharynx [4]. Using an
international database, a subset of 507 men with penile car-
cinoma who underwent inguinal lymph node dissection
were analyzed [5]. This retrospective study demonstrated
that HPV positivity was associated with lower nodal stage
and independently better outcome with radiation and sup-
port a previous North American dataset providing prognos-
tic associations for p16 and p53 expression [3].

https://doi.org/10.1016/j.urolonc.2021.05.021
1078-1439/Ó 2021 Elsevier Inc. All rights reserved.
 ARTICLE IN PRESS
2 T.A. Masterson and S.T. Tagawa / Urologic Oncology: Seminars and Original Investigations 00 (2021) 1−8
As above, inactivation of cell cycle arrest may be a result
of HPV infection, with sustained expression of viral E6 and
E7 oncogenes, which are the target of vaccines [6]. In a study
from the National Health and Nutrition Examination Surveys,
the prevalence of HPV in male adults is estimated to be
42.2% [95% CI 38.3−46.1], with a 23.4% [95% CI 21.3
−25.6] prevalence of high-risk subtypes (including HPV
types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 59, 66, and 68)
[7]. Prevalence was higher with a greater lifetime number of
sex partners, greater number of sex partners in the last year,
earlier age at first sex, and was highest in non-Hispanic
blacks compared to Asians. There was no difference based
upon socioeconomic status or having same-sex partners.
A 9-valent vaccine targeting HPV types 6, 11, 16, 18, 31,
33, 45, 52, and 58 is available in the U.S., with others
(quadrivalent and bivalent) available elsewhere. The vac-
cine is indicated for the prevention of anal, oropharyngeal
and other head and neck cancers, anal precancerous and
dysplastic lesions, and genital warts in males. In addition to
direct risk-reduction, there may be an additional effect in
augmenting herd immunity with vaccination of boys in
addition to girls [8-10]. In the NHANES study, a compari-
son of prevalence of HPV types covered by vaccination in
sexually active males aged 14 to 19 years, no HPV was
detected in those with history of vaccination as opposed to
4.6% in unvaccinated [7]. Therapeutic vaccines are being
studied for the treatment of men with SCCP (discussed
below).
Other strategies to prevent transmission of HPV include
circumcision in high-risk populations. In a prospective ran-
domized study, almost 3900 men were assigned to either
undergo circumcision at initiation of the study versus at the
end of 24 months [11]. Rates of HPV and HSV sero-positivity
were assessed. Overall, HPV rates were 35% lower among
the cohort treated with upfront circumcision. Similarly, HSV
seroconversion rates were 28% lower than controls. Although
prophylactic circumcision has not been advocated for across
the board in this regards, its public health benefits among
high risk populations should be considered.
3. Evaluation
3.1. To image, or not to image in penile cancer
In most solid malignancies, radiographic imaging serves
a vital importance for assessing local and distant extent of
disease. Penile cancer may be one of the few exceptions. In
the late 1980’s and early 1990’s, penile ultrasonography
(US) was initially reported to provide a more accurate
means of assessing the primary tumor when compared to
physical exam (PE) alone [12]. In the 1990’s, magnetic res-
onance imaging (MRI), in contrast to computed tomogra-
phy (CT), offered similar benefits to US of greater soft
tissue resolution when evaluating for local invasion of dis-
ease [13]. While preliminary results were promising, others
reported comparative data that questioned its widespread
benefit in evaluating local disease. In a study published in
2003, Lont and colleagues compared PE to both MRI and
US among 33 patients with penile cancer undergoing surgi-
cal resection to identify which modality best predicts inva-
sion into the corpus cavernosum [14]. Surprisingly, PE was
associated with the best overall performance when assess-
ing positive predictive value, sensitivity and specificity.
Conclusions from that study suggest imaging is most help-
ful only when physical exam is hindered due to body habi-
tus or associated barriers. For small tumors, PE alone
serves as a reliable means of assessing local stage. In cir-
cumstances of equivocal PE findings or associated barriers
to examination of the primary tumor (obesity, buried penis,
large tumor size), contrast enhanced MRI with gadolinium
along with induction of an artificial erection has been
shown help evaluate local disease for invasion [15,16]. This
can also be particularly helpful when organ preserving tech-
niques are being considered.
For assessment of regional spread of disease to the ingui-
nal lymph nodes, similar findings prevail. As seen in testic-
ular malignancies, positron emission tomography (PET)
using radioactively labelled fluorodeoxyglucose (FDG) can
be associated with high rates of false-positivity and poor
sensitivity among clinically node negative patients [17,18].
Therefore, initiation of surgical staging with inguinal lym-
phadenectomy in clinically node negative patients remains
based upon PE findings and primary tumor characteristics.
In patients with clinically positive inguinal lymph nodes,
cross-sectional imaging remains an important means for
assessing radiographically evident distant spread to pelvic
lymph nodes and beyond [19]. FDG-PET may have value
in the assessment of those with at least regionally advanced
disease on standard cross-sectional imaging for the assess-
ment of metastatic disease [20].
4. Evolution in staging of primary disease, risk
stratification
A lot has changed from the AJCC fourth edition on
penile cancer staging that was in use in 1995. After the fifth
edition was published in 1997, three subsequent versions
were circulated, including the most recent publication of
the eighth edition that was released in 2016 [21]. Important
elements of change over time have incorporated the stratifi-
cation of subepithelial involvement (T1) into two sub-cate-
gories (T1a & T1b) according to the presence or absence of
lymphovascular invasion (LVI) and grade (low grade ver-
sus high grade) in the seventh edition. For the eighth edi-
tion, the presence of perineural invasion was added to the
T1b classification, along with sarcomatoid differentiation
as higher risk features, with discrimination based upon ana-
tomical location of the primary tumor on the penis (glans,
foreskin, or penile shaft). Additionally, the T2 category that
historically included both corpus spongiosum and caverno-
sum invasion was modified, allowing for invasion of the
urethra (previously T3) and excluding corpus cavernosum
 ARTICLE IN PRESS
T.A. Masterson and S.T. Tagawa / Urologic Oncology: Seminars and Original Investigations 00 (2021) 1−8
involvement (now T3 designation). This was based upon
findings that survival outcomes with conventional staging
(7th edition and earlier) poorly discriminated between T2
and T3 disease. Rather, those with urethral involvement
had better outcomes than those with corpus cavernosum
involvement (5-yr DSS 68% vs. 53%) [22]. Others have
corroborated these findings, demonstrating higher rates of
inguinal LN metastases and cancer specific mortality for
those with corpus cavernosum involvement compared to
corpus sponsiosum involvement, irrespective of urethral
invasion [23].
PITaged mportant changes have been made over the past 25 years
in nodal staging as well. Traditional stratifications were
based upon LN involvement equal to or greater than one,
laterality, and location. While this hierarchy was preserved
for much of the past quarter century, modifications based
upon the presence or absence of extranodal extension (7th
edition) were incorporated, minimizing the significance of
nodal involvement above (superficial) or below (deep) the
fascia lata. More recently, further refinements in the eighth
edition improved risk stratification for disease specific sur-
vival based upon number of nodes involved (≤2 versus 3 or
more) and laterality (unilateral versus bilateral) for pN1
and pN2 disease [23-25]. Currently, HPV status does not
play a role in altering the risk stratification schemes for
penile cancers like they have in other squamous cancers,
such as those of the head and neck [26]. Although, evidence
suggesting improved prognostic stratification has been pub-
lished [27] and it is likely that future editions will incorpo-
rate the presence or absence of HPV into their revisions.
5. Dynamic sentinel lymph node biopsy (DSNB)
In 1977 sentinel lymph node biopsy was first described,
documenting the predictable pattern of penile cancer spread
lymphatically to a primary landing zone along the greater
saphenous vein inserting into the femoral vein. While ini-
tially believed to be reliably consistent enough to limit the
staging of clinically node-negative invasive penile cancers
to sampling of this region, several investigators demon-
strated the poor accuracy in several subsequent publications
(false negative rate range 10%−50%) [29-35]. As such, any
variation of the sentinel lymph node biopsy based purely
upon a limited anatomic template fell to the wayside.
However, advances were noted in sentinel LN mapping
through the utilization of injectable blue dye and gamma
emitting emulsions into the primary lesion and tracking its
course to the sentinel lymph node in other malignancies (i.e.,
melanoma, breast, vulvar) [36-39]. This dynamic approach to
identify the initial site of metastatic deposition into regional
LN’s offers significant advantages in the staging of penile
malignancies, and potentially limiting the need and hence
reducing the morbidity of templated inguinal LN dissections.
Preliminary results of investigative studies assessing the accu-
racy of DSNB have demonstrated modest improvements in
the false negative rate to 18%−25% [40,41]. Subsequent
3
understanding of the risk of lymphatic obstruction in sub-clin-
ically involved lymph nodes resulting in shunting of the tracer
and dyes away from the “sentinel” node have resulted in
modifications of technique. Among centers experienced in
these techniques, false negative rates have improved to 7% in
one series among 323 patients evaluated with modified
DSNB [17]. However, half of those relapsing patients were
unable to be salvaged and progressed to metastatic disease
beyond the groin or died of disease. As such, DSNB remains
a tool that should largely be reserved for high volume centers
experienced in these techniques and have a full understanding
of their limitations. Some have suggested that centralization
of care will lead to improved outcomes and this practice has
started in certain countries [42-44].
6. Management
6.1. Organ preservation with penile sparing techniques
In 1995, surgeons managing tumors of the penis advo-
cated for partial amputative surgery when a 2 cm proximal
margin of clearance could be achieved, and radical penec-
tomy when a 2 cm margin could not be reached without
impacting one’s ability to stand to urinate or engage in sex-
ual intercourse [45]. While penectomy can be highly effec-
tive for local management of tumors, the importance of
organ preservation has been established in select patients,
noting improved functional and psychological outcomes in
patients without negatively impacting oncologic survival.
Over the last 25 years, expansion of organ-preserving and
glans-preserving approaches have been incorporated.
Whether through Mohs micrographic surgery, laser ablation,
topical treatments with 5-FU or imiquimod, radiation, or lim-
ited resections +/- resurfacing techniques, maintaining penile
length and glans sensation are important to minimizing the
negative aspects of penile cancer treatment on the patient’s
sexual quality of life. This has been able to be achieved
through better patient selection, and a greater understanding
of the impact local recurrences have on survival and salvage-
ability. Favorable histologic characteristics based upon grade
(AJCC Grade 1 & 2) and stage (CIS, Ta, T1a) have a low
metastatic potential and have been shown to correlate with
less risk of microscopic spread [46,47].
Local recurrences (LR) can be predicted based upon surgi-
cal margin status, tumor grade, extent of local invasion (T2 or
greater) and the presence of lymphovascular invasion (LVI)
[48,49]. In a study by Sri and colleagues, among 332 penile
preserving procedures associated with negative surgical mar-
gins, LR rates were 15% if the margins were within <1mm
and <5% when >1mm, with the average time to LR being 6
months [48]. Rates of LR are certainly higher with organ-
sparing techniques as compared to amputative approaches;
however, the impact of LR has been shown in several studies
not to adversely affect survival rates [50,51]. Rather, survival
outcomes in these patients are tied to the presence of nodal
involvement and beyond [50].
 ARTICLE IN PRESS
4 T.A. Masterson and S.T. Tagawa / Urologic Oncology: Seminars and Original Investigations 00 (2021) 1−8
Many have also demonstrated high rates of local surgical
salvage with repeated penile sparing approaches to address
LR in these patients [52-54]. As such, goals of local man-
agement have certainly evolved over the last quarter cen-
tury, focusing more on balancing factors that negatively
affect survivorship while improving cancer control and
overall quality of life.
7. Surgical management of inguinal lymphadenopathy
Significant change has also occurred in the assessment
and management of inguinal lymph node metastases since
the mid 1990’s. Gone are the days of empiric antibiotics for
inguinal lymphadenopathy to assess for resolution of palpa-
ble disease. In the setting of non-palpable disease, manage-
ment is determined by risk stratification based upon
primary staging and grading of the penile lesion. Low risk
patients (pTis, Ta, T1a) can be observed safely with serial
physical exams and selective use of imaging among patients
with altered anatomy due to prior therapy and/or obesity
[19]. Higher risk patients with non-palpable disease should
be surgically staged. These factors include poorly differen-
tiated tumors (grade 3 or 4), invasive disease (stage T2 or
greater), or the presence of LVI [55]. Among these patients,
occult inguinal lymphatic metastases are detected in 50%
−80% of cases. Patients exhibiting any of these factors
despite the absence of clinically evident lymph node
involvement are appropriate for bilateral inguinofemoral
lymph node dissections. Acceptable alternative strategies at
centers experienced in the approach would be to perform
DSNB and/or incorporate minimally invasive approaches
with or without robotic assistance to the lymph node dissec-
tion. Modified inguinal lymph node dissection may
decrease morbidity while retaining efficacy at centers of
excellence [56].
Palpable disease has been categorized based upon clini-
cal size and fixation. For tumors that are less than 4 cm and
mobile, diagnostic fine needle aspiration or excisional
biopsy is recommended. Positive findings for regional
extension of penile cancer is an indication for radical bilat-
eral inguinofemoral node dissections [19,57]. For bulky
patients and those with fixed nodes, diagnostic biopsy is
again recommended to confirm the diagnosis. However, the
major paradigm shift that has taken place over the past two
decades is the incorporation of multimodal therapy. Similar
to disease like bladder and colon cancers, neoadjuvant sys-
temic chemotherapy (as discussed further below) is recom-
mended followed by consolidative surgical resection of
patients with a favorable response. Additionally, the pres-
ence of two or more positive ipsilateral inguinal lymph
nodes has been associated with a greater risk of pelvic
lymph node spread, and an ipsilateral pelvic dissection is
indicated [55,58]. Radical bilateral pelvic LN dissections
are recommended if 4 or more inguinal LN are positive for
disease [59].
8. Surveillance strategies following treatment
Unfortunately, advances in imaging which have become
standard following treatment for multiple malignancies
have not clearly changed overall survival for previously
treated penile cancer. However, identification of recurrent/
progressive local or regional disease may be amenable to
salvage therapy. As above, cross sectional imaging with
CT/MRI remains the standard of care with FDG PET/CT
sometimes useful to assess abnormalities seen on initial
standard imaging [60]. In the setting of abnormal findings
on physical examination, the use of ultrasound plus fine-
needle aspiration or biopsy has utility. In the setting of
recurrent or regionally advanced disease, FDG PET may
add value in the assessment of metastatic disease. In a study
of FDG-PET/CT of 48 men with mostly recurrent disease,
42 were evaluable for full analysis with either serial cross-
sectional imaging or biopsy [20]. Sensitivity of FDG-PET
for metastatic disease beyond lymph nodes was 85% with
specificity of 84% (for lung) to 100% (for bone, liver, adre-
nal, and kidney), potentially adding value in the assessment
of metastatic disease.
9. Challenges & future directions
9.1. InPACT trial
As a rare disease, it has been difficult to prospectively
address many questions. Fortunately, the modern era allows
collaboration across countries and disciplines, such as
InPACT (International Penile Advanced Cancer Trial,
NCT02305654). This study examines multiple simulta-
neous issues, including neoadjuvant chemotherapy, prophy-
lactic lymph node dissection, and chemoradiotherapy.
Patients with locally advanced penile cancer including posi-
tive lymph nodes undergo initial randomization to therapeu-
tic inguinal lymph node dissection, neoadjuvant
chemotherapy followed by inguinal lymph node dissection,
or chemo-radiation followed by inguinal lymph node dis-
section. The results of the randomization in this group with
intermediate risk features will provide evidence if inguinal
lymph node dissection alone is sufficient or whether pre-
operative therapy (either combination chemotherapy or
chemo-radiation) is superior. Those with high-risk patho-
logic features undergo a second randomization as follows.
Those with high-risk pathology following prior chemo-radi-
ation are randomized to surveillance vs pelvic lymph node
dissection to assess whether chemo-radiation is sufficient in
management of pelvic lymph nodes. Those with no prior
chemo-radiation and high-risk pathology following inguinal
lymph node dissection are randomized to adjuvant chemo-
radiation or pelvic lymph node dissection (followed by
chemo-radiation if significant pathology exists). It is hoped
that the results of this randomized portion of the study will
provide evidence whether pre-operative combination che-
motherapy or chemo-radiation prior to inguinal lymph node
 ARTICLE IN PRESS
T.A. Masterson and S.T. Tagawa / Urologic Oncology: Seminars and Original Investigations 00 (2021) 1−8
dissection is superior. It should be noted that while this
study will address multiple clinically important issues, it
cannot address the question of adjuvant chemotherapy or
definitive chemo-radiation based upon the surgical design.
9.2. Systemic & targeted therapeutics
Much of our current standard of care for this rare disease
has evolved based upon extrapolated experience with simi-
lar cancers. The most common regimens utilized today for
advanced disease are platinum-based regimens. Most data
comes from institutional or retrospective studies, but coop-
erative groups have occasionally studied this disease,
including an important study that did not support single-
center utility of a bleomycin containing regimen [61]. Sys-
temic therapy has not made a major impact in the treatment
of localized disease in terms of clear survival benefit, but a
subset of those with unresectable tumors become resect-
able, and bulky lymph node metastases may be downstage.
Current consensus is that for patients healthy enough to tol-
erate, combination chemotherapy with regimens such as
cisplatin, ifosfamide, and paclitaxel is warranted for locally
advanced disease [62]. In addition, chemotherapy may be
used concurrently with radiation as a radiosensitizer in
organ-sparing strategies.
Unfortunately, outcome for advanced SCCP with pro-
gressive disease following platinum combination therapy
has been dismal [63]. During the lifetime of this journal,
there have been forays into prospective clinical trials. A
U.S. cooperative group trial (described above) was com-
pleted and importantly was negative for the addition of
bleomycin, while another led by the EORTC was negative
for the doublet of cisplatin and irinotecan [64]. Others using
docetaxel (SWOG S0224) and pazopanib plus paclitaxel
(SOGUG) were closed early due to poor accrual. A pro-
spective trial of cabazitaxel was negative, [65] while the
VinCaP study of vinflunine demonstrated potential activity
at the cost of some toxicity [66].
The advent of precision medicine in multiple tumor
types has led to some research in penile carcinoma. In addi-
tion to the work on biologic importance of HPV discussed
above, interrogation of tumor profiles has started and may
lead to future improvements in the management of penile
carcinoma [67,68]. Initial analyses of copy number altera-
tions in SCCP seemed similar to cutaneous SCC. More
recently, a large panel of targeted next generation sequenc-
ing (NGS) of DNA from SCCP was compared to metastatic
cutaneous SCC [69]. SCCP had a lower tumor mutational
burden than metastatic cutaneous SCC, but not surprisingly
a higher viral DNA content for HPV. Alterations in the
mTOR or DNA repair pathways were found in a significant
minority (11% and 14% respectively), with alterations in
tyrosine kinase pathways including EGFR, FGFR, and
ERBB2 also seen. Comparison to SCC of the urethra has
also been performed.[70] HPV types 16 and 18 tended to be
more common with SCC of penile origin as compared to
5
urethral. Inactivation of CDKN2A, amplification of
CCND1, TERT promoter mutations, and NOTCH1 altera-
tions were more common with SCCP, with no difference in
TP53, EGFR, FGFR, BRCA1, or BRCA2. Tissue microar-
ray analysis has demonstrated that PTEN was downregu-
lated in the majority (75%) and phospo-AKT was
upregulated in approximately half (47%) [71]. In addition
to potential targeting of this pathway, up-regulation of the
PI3K-AKT-mTOR pathway along with HPV positivity
were associated with better prognosis.
To date, epidermal growth factor receptor (EGFR) has
been found to be overexpressed and/or amplified in a subset
of tumors. EGFR overexpression has been associated with
survival (independent of HPV) [72]. While randomized
studies have not been completed, pilot data point towards
the utility of targeting this pathway in advanced disease
[73].
Programmed death-ligand 1 (PD-L1) expression appears
relatively common in small studies of penile carcinoma
tumor tissue, with a North American cohort demonstrating
40% positivity for PD-L1 [74] and another with 62% posi-
tivity [75]. In the comparison of SCCP vs SCC of urethra
demonstrated that high levels of PD-L1 staining was more
common in penile vs urethral origin of SCC [70]. Efforts
are underway to evaluate the utility of immune checkpoint
inhibition in advanced tumors. However, early research
into the frequency of mismatch repair (with associated
FDA-approval of the anti-PD-1 antibody pembrolizumab)
has been disappointing [69,76] and a prospective clinical
trial of single-agent pembrolizumab was closed early due to
poor accrual.[NCT02837042] However, there is ongoing
optimism for immunotherapy with several prospective clin-
ical trials ongoing at the time of this manuscript, including
a cohort in the A031702 ICONIC study (NCT03866382,
ipilimumab, nivolumab, cabozantinib), ORPHEUS study
(NCT04231981, atezolizumab +/- radiation), durvalu-
mab + HPV DNA plasmid vaccine (NCT03439085), and
phase two study of avelumab (NCT03391479). A mouse
model of SCCP may be useful in assessment of combina-
tion immunotherapy and targeted therapy [77].
10. Conclusion
As a rare disease, challenges exist in optimizing care for
affected men. Over the last quarter century, much knowledge
has been gained in the risk stratification and patient selection
criteria used for consideration for local, regional and systemic
therapies. Acknowledgment of the negative effects of ampu-
tative surgery among patients has brought awareness and
important change in our strategies in treating early-stage dis-
ease. Incorporation of multimodal therapies in advance staged
disease will hopefully continue to improve survivorship.
Lastly, discovery of the associations between HPV positivity
and penile carcinogenesis, along with the creation of the HPV
vaccination program, will hopefully result in substantial
reductions in this disease over time.
 ARTICLE IN PRESS
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