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18
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CASE
Advanced and metastatic
penile cancer
Hussain Alnajjar
Expert commentary Asif Muneer
Case history
A 69- year- old male presents to hospital with a 6- month history of a progressive phimosis, bleeding, and pain from the distal penis. The phimosis has been present for
several years. There are no other previous comorbidities and he is a non- smoker. On
clinical examination, he was found to have a palpable penile mass affecting the distal
penis and which is extending proximally towards the proximal penile shaft. He had
bilateral impalpable inguinal lymph nodes. His imaging studies include an ultrasound
scan of the groins and computed tomography scan of the chest, abdomen, and pelvis
which were unremarkable. He also underwent penile magnetic resonance imaging
(MRI) with alprostadil (Caverject®) which showed that the tumour was invading into
the tips of the distal corpora with multiple skip lesions more proximally.
The patient was introduced to a specialist cancer nurse specialist and a biopsy of
the lesion was arranged. Subsequently, the penile biopsy and imaging were reviewed
at a penile cancer multidisciplinary meeting which confirmed that the lesion was a
squamous cell carcinoma with a basaloid subtype. The imaging studies showed no
evidence of metastatic disease. The ultrasound of the groins did not detect any morphologically abnormal lymph nodes.
The patient underwent a radical penectomy and perineal urethrostomy and bilateral dynamic sentinel node biopsy.
Learning point Risk factors
Learning point Penile- sparing surgery
● Distal penile tumours which involve the glans penis or distal corporal tips have previously been
managed by performing a partial penectomy. Penile- preserving surgery is now used where
possible which maintains penile length with better cosmetic, functional outcomes and without the
detrimental emasculating effects of partial or radical penectomy.
● Austoni et al. described the anatomical distinction between the corpora cavernosa and corpus
spongiosum and proposed glansectomy as a penile- preserving surgical option for patients with
invasive penile cancer confined to the glans.
● Approximately 80% of all cases of invasive penile carcinoma are potentially amenable to penilesparing surgery.
● The extent of tumour extension is determined on preoperative MRI with intracavernosal
prostaglandin injection used to induce an erection.
The histopathology report confirmed an exophytic grade 3 squamous cell carcinoma,
stage pT3 of basaloid subtype arising from the glans, corona, and inner foreskin and
infiltrates extensively into the lamina propria, spongiosus, tunica, and distal cavernous
erectile tissue with focal obstruction of the distal urethra. There were several skip
3
4
● Risk factors for penile cancer
include the following:
– Phimosis, chronic
inflammation, lichen
sclerosus, smoking, psoralen
and ultraviolet light
A phototherapy, human
papillomavirus infection,1 low
socioeconomic status, and
multiple sexual partners.
● Any suspicious penile lesion
should be biopsied. Even
in clinically obvious cases,
histological confirmation is
mandatory before the primary
surgical treatment.
2
176 Challenging Concepts in Urological Surgery
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lesions throughout the corpus cavernosum. There was widespread lymphovascular
invasion and focal perineural invasion. The tumour extended to the left corporal
margin. The urethral, right corporal, and peripheral skin limits were all free of tumour
by >5 mm. The right sentinel lymph node biopsy detected metastatic disease in one
of two lymph nodes excised with the presence of extracapsular spread. The left sentinel lymph node was free of metastatic disease. The patient subsequently underwent
a right radical inguinal lymphadenectomy. A further eight right inguinal lymph nodes
were removed with metastatic disease present in three of them.
Following surgery, he underwent a further restaging computed tomography scan
of the chest, abdomen, and pelvis which revealed multiple new metastatic pulmonary
lesions.
Discussion
Penile- preserving surgery
The surgical management of penile cancer is largely directed by the grade and stage of
the primary tumour and the extent of involvement of the glans, corpus cavernosum,
and penile skin. Advanced disease involving a significant portion of the corpus cavernosum is still best managed by conventional radical surgery. However, in cases where
lesions are confined to the glans or just extend into the distal corpus cavernosum, the
requirement for radical surgery is no longer a requirement and has resulted in a paradigm shift in surgical practice.
Evidence base Penile- preserving surgery and surgical margins
Previously, clearance margins following surgery required at least 2 cm to be tumour free. However,
a number of studies have challenged this hypothesis. Agrawal et al. examined 64 partial and total
penectomy specimens to determine the microscopic extension of the primary tumour beyond the
macroscopic tumour margin.5 They reported that 81% did not spread beyond the macroscopic
tumour margin and of those that did; only 25% extended more than 5 mm from the margin. They
concluded that a 10 mm clearance was adequate for grade 1 and 2 lesions, and 15 mm for grade 3
tumours.5 A further study reported on 51 cases who underwent penile- sparing surgery and concluded
that despite 90% of patients having a margin <20 mm (48% of which were <10 mm), only three
(6%) patients had positive margins and only two (4%) developed local recurrence within an average
follow- up of 26 months.6 A follow- up study reviewed 179 patients with invasive penile cancer treated
with organ- sparing surgery. Local, regional, and distant metastatic recurrence developed in 16 (8.9%),
19 (10.6%), and nine patients (5.0%). The overall 5- year local recurrence- free rate was 86.3% (95%
confidence interval 82.6– 90.4). They established that penile- conserving surgery is oncologically safe
and a surgical excision margin of <5 mm is adequate.7 By establishing the effect of reducing the
surgical clearance margin on the incidence of local tumour recurrence, these studies have led to the
increasing use of penile- preserving procedures in the management of invasive penile carcinoma.
Expert comment Penile- preserving surgery
● Penile- preserving surgery is oncologically safe and a surgical excision margin of <5 mm is adequate.
● Higher local recurrence rates are associated with lesions which have lymphovascular invasion, and
are a higher tumour stage and grade.
● It is important to note that most recurrences after penile- preserving surgery are surgically
salvageable and local recurrence does not impact on long- term cancer- specific mortality rates.
● Dynamic sentinel lymph node biopsy now offers a less morbid technique to remove inguinal lymph
nodes from patients with clinically impalpable inguinal nodes.
177Case 18 Advanced and metastatic penile cancer
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Locally advanced penile tumours
Patients presenting with penile lesions located on the glans penis with a palpable invasion into the distal tunica albuginea and corpus cavernosum can undergo a partial
penectomy procedure. The preoperative evaluation using MRI to assess the extent of
the tumour can aid in the management of these patients as it can demonstrate tumour
involvement of the glans penis extending into the distal corporal tips, in which case a
glansectomy and distal corporectomy will still preserve the penile length. However, if
the tumour shows a more significant proximal extension, then a conventional partial
penectomy is performed.
Radical or total penectomy is usually reserved for cases where extensive tumour
involvement of the penile shaft necessitates complete excision of the penis and crura.
Once more, preoperative MRI is useful in order to demonstrate the proximal extension
of the tumour as there may be skip lesions extending proximally. Hence, adequate tu-
Clinical tip Intraoperative
frozen section
An intraoperative frozen section
at the time of the primary surgery
may help to confirm clear surgical
resection margins and hence avoid
further revision surgery. However,
a 2018 study by Danakas et al.
showed that performing frozen
section during penectomy does
not appear to have any significant
impact on the final surgical margin
status or the long- term oncological
outcomes. Nonetheless, they
reported that routine frozen section
can be beneficial in select cases.
8
mour margins can only be obtained by performing a total penectomy. The surgical dissection does not have to extend to include the crural attachment with the pubic bone
unless there is extensive tumour involvement of the proximal crura whereby a radical
penectomy is required. If possible, the preservation of the crura aids future reconstruction using phalloplasty procedures as they provide support for the proximal ends of
the penile prostheses used during reconstructive surgery. However, in some advanced
cases of penile cancer, the tumour extends proximally to involve the crura and pubic
bones. In these patients, a conventional radical penectomy is required which involves
detaching the crura from the pubic bone. Patients with extensive sarcomas of the penis
or recurrent disease in the penile stump may also require a radical penectomy. Rarely,
metastatic disease from the genitourinary system presents with multiple nodular lesions within the corpus cavernosum and again MRI is useful for diagnostic evaluation
in these situations.
Locally advanced penile cancer with regional metastasis
At first clinical presentation, it has been shown that 28– 64% of men with penile cancer
will have clinically palpable inguinal lymph nodes, with the quoted risk of metastatic
disease being 47– 85% in such individuals (the remainder are due to inflammatory
or infective cause). The probability of pelvic nodal metastases is 22– 56% if inguinal
lymph nodes are involved.
11– 13
The presence of inguinal lymph node metastases is the
single- most important prognostic indicator in penile cancer. Additional important prognostic factors are the number of positive lymph nodes, the presence of extracapsular
spread, and the presence of pelvic node involvement.14 Micrometastatic disease will
occur in about 25% of cases at presentation, where the inguinal lymph nodes are clinically impalpable (cN0), with predictive prognostic factors being tumour stage, grade,
and lymphovascular invasion.
Advanced metastatic inguinal node disease
As originally described by Cabanas, the step- wise metastatic involvement of lymph
Learning point Outcomes
of partial and radical penectomies
● The techniques of partial
penectomy and radical
penectomy have been
employed since the first century
as it was found that excision of
the penile tumour using these
techniques results in adequate
disease control.
● Patients undergoing these
procedures have a low
recurrence rate. The local
recurrence rate following a
partial penectomy is 0– 8%.
● In terms of functional
outcomes, these procedures
are deemed drastic with a
significant psychological impact
related to de- masculinization.
9,10
nodes in patients with penile cancer begins at the level of the inguinal lymph nodes.15
In advanced disease, the lymph nodes may develop into large palpable lesions which
may infiltrate into the overlying skin or become fixed to the underlying fascia or
muscle. Unsurprisingly, these large masses are associated with extracapsular extension of tumour and therefore require excision of overlying skin and subcutaneous
tissue in order to achieve local control. With metastatic lymph nodes deep to the skin,
primary closure of the defect may still be possible by mobilization of the superior
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and inferior skin flaps. However, larger defects following resection of bulky inguinal
metastatic nodes associated with skin ulceration often requires the use of pedicled
skin flaps (e.g. vertical rectus abdominis muscle or tensor fascia lata flaps) in order to
cover the resulting large defect. Bulky ulcerating inguinal N3 disease can be managed
by palliative resection of the tumour and overlying skin followed by coverage of the
defect using a pedicled skin flap.16 This allows palliation with better symptom control
such as pain, mobility, and sepsis and reduces the risk of fatal vascular invasion due to
malignant infiltration. When circumstances demand a large area of inguinal soft tissue
sacrifice, primary closure may be obtained by using scrotal skin17 or an abdominal
Expert comment
Management of fixed
nodal mass
The options for patients with penile
tumours and a fixed nodal mass are
limited. Current chemotherapeutic
regimens show a promising yet
limited response in the neoadjuvant
setting. These patients often present
with a poor performance status
and are unlikely to tolerate the side
effects of chemotherapy. Surgical
resection with reconstruction may
offer both symptom control and a
chance of cure in the absence of
distant metastasis.
wall advancement flap.
The role of neoadjuvant and adjuvant chemotherapy/ radiotherapy
in advanced and metastatic disease
There is a paucity of data related to preoperative chemoradiation regimens in penile
cancer prior to surgery in cases of advanced disease. As a result, clear guidelines are
not available and a case- by- case approach is currently used to manage these challenging cases. It is clear that treatment of the primary lesion with radiotherapy is not
recommended due to the high local recurrence rates and complications. Neoadjuvant
radiotherapy does not appear to improve the overall survival according to limited
data and may also lead to a delay in surgery in cases which have a limited window
of opportunity before vascular or skin infiltration. However, it is often used in other
squamous cell carcinoma sites such as head and neck cancers and has led to the development of a multinational trial called InPACT (International Penile Advanced Cancer
Trial) to investigate the role of neoadjuvant radiotherapy in penile cancer.
18
Learning point Metastatic lymph nodes and radiotherapy
Metastatic lymph nodes which have extensively progressed through the skin and present as ulcerating
lesions can be managed using external beam radiotherapy to the inguinal regions. Ravi et al.19 studied
41 patients (66 groins) who were treated with palliative radiotherapy to the inguinal regions for fixed
inguinal lymph nodes. They reported that 56% of the patients attained a relief in symptoms. However,
the 5- year disease- free survival was only 1%. Additionally, 33 patients were treated with neoadjuvant
radiotherapy (40 Gy) over a 4- week period. The incidence of extranodal disease was only 8% with
a further 3% suffering recurrence in the groins. This indicates that preoperative radiotherapy can
improve local disease control in cases with extensive disease. Although, radiotherapy relieved painful
bony metastases, it was deemed ineffective for pelvic node metastases.
Small retrospective case series have shown some advantage in preoperative chemotherapy prior to undergoing surgery. Shammas et al.20 reported a 28% response using
a combination of cisplatin and 5- fluorouracil (FU). Ahmed et al.21 investigated singleagent use of methotrexate, cisplatin, or bleomycin. They reported overall response
rates in 39 with 1.5%, 25%, and 21% for methotrexate, cisplatin, and bleomycin,
respectively. Bleomycin and methotrexate showed treatment- related deaths of 7% and
12%, respectively.
In a Southwest Oncology Group Study (SWOG) study, 26 patients were administered single- agent cisplatin at a dose of 50 mg/ m2 (days 1 and 8 of 28- day cycle).22
The overall response rate obtained in the SWOG study was 15%, with no treatmentrelated deaths. The aforementioned two studies led to the prospect of combined
chemotherapeutic agents in advanced penile cancer. In 1999, a phase II prospective
study utilizing bleomycin, methotrexate, and cisplatin was reported.23 In this study,
https://t.me/med1917
45 patients were recruited, of whom 40 were evaluable. The overall response rate
was 32.5%, with five treatment- related deaths (12.5%). The median overall survival
in this group was 28 weeks. However, the study was discontinued due to the high
toxicity rates.
In another study where a combination of paclitaxel, ifosfamide, and cisplatin (TIP)
was utilized, 20 patients were evaluated, with an overall response rate of 55% and
median overall survivals of 11 months.24 Therefore, cisplatin or paclitaxel- based combinations seem to provide a good overall response rate with much less toxicity. The
TPF study, one of the first national, multicentre, phase II chemotherapy trials in the UK,
used docetaxel, cisplatin, and 5- FU. The primary endpoint in this study was response
rates in all patients recruited with metastatic or locally advanced disease. Docetaxel,
cisplatin, and 5- FU did not reach the predetermined threshold for further research and
caused significant toxicity leading to a premature study discontinuation.
25
The Netherlands Cancer Institute has reported a series of 19 retrospective cases of
unresectable penile cancer which were treated with varying regimens, including singleagent bleomycin and cisplatin, and 5- FU, but no Taxol®- based regimen.26 Overall, 12
patients responded (63%) with two complete and ten partial responses. Of the 12
responders, nine underwent further surgery and eight of these showed no evidence of
disease at a median follow- up of 20.4 months. All three patients who did not respond
to chemotherapy died within 8 months. The chemotherapy- related deaths were mainly
in those patients receiving bleomycin. Pizzocaro et al. undertook a prospective study
using paclitaxel, cisplatin, and 5- FU. Of the six patients treated, four patients had a
complete response of whom three underwent consolidative surgery with a good outcome.27 Pagliaro et al. from MD Anderson24 studied a total of 30 patients with stage N2
or N3 disease who underwent neoadjuvant treatment using paclitaxel, ifosfamide, and
cisplatin. Fifty per cent had an objective response with a total of 22 patients (73%)
undergoing surgery following chemotherapy. After a median follow- up of 34 months,
9 (30%) patients remained free of recurrence. To date, cisplatin- based chemotherapy
has been shown to have a role in the management of patients with advanced penile
cancer with reasonable patient responses and furthermore, it may allow advanced
disease with skin and muscle involvement deemed irresectable to become resectable.
However, there is currently no accepted optimum regimen and further multicentre
trials are required to novel targeted therapies.
179Case 18 Advanced and metastatic penile cancer
Evidence base Postoperative
radiotherapy for positive
lymph nodes
● There is limited evidence
in favour of postoperative
radiotherapy for prophylaxis in
node- positive penile cancer,
and its use is controversial
although it is offered on a caseby- case basis.
● While a few case series have
proposed a survival benefit,
particularly in pN3 disease, the
data are from extremely small
case series. Larger series and/ or
prospective multicentre studies
are needed before its use can
receive an evidence- based
recommendation.
A final word from the expert
Penile cancer is a rare genital malignancy and advances in surgical techniques and research
related to the disease have primarily been aided by the centralization of services in centres
throughout Europe. In the UK, this was driven by the Improving Outcomes Guidance which
proposed 12 national centres would manage penile cancer. Not only has this allowed a cohort
of urological surgeons to become experts in managing the primary tumour using penilepreserving surgical techniques, it has also ensured that dynamic sentinel lymph node biopsy is
now the standard of care for patients with clinically impalpable inguinal lymph nodes which has
reduced the morbidity associated with open inguinal lymphadenectomy.
Epidemiological studies have also demonstrated that over a 30- year period, the 5- year
cancer- specific mortality has remained relatively unchanged.1 This is largely due to the
180 Challenging Concepts in Urological Surgery
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unresponsiveness of patients with advanced or metastatic disease to the currently available
chemotherapy regimens and despite a number of studies which have used multiple agents,
advanced disease is relatively chemoresistant.
Research relating to rare disease is often hampered by the lack of funding opportunities,
low number of patients available for recruitment, and limited resources such as tissue
biorepositories. With the increasing centralization of services, there has now been progress
mainly related to whole- exome sequencing and methylation studies which will help to identify
key therapeutic targets.
The establishment of international groups such as the International Rare Cancers Initiative
and the eUROGEN workstream as part of the European Reference Network has also aided in
developing collaborative trials to help recruit patients with advanced disease.
Future research will aim to develop targeted treatment options and investigate the role of
immunotherapy focusing on the programmed cell death- 1 (PD- 1)/ programmed death- ligand 1
(PD- L1) immune checkpoint inhibitors.
References
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lymphadenectomy for penile cancer using an abdominal cutaneous advancement flap.
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19. Ravi R, Chaturvedi HK, Sastry DV. Role of radiation therapy in the treatment of carcinoma
of the penis. Br J Urol. 1994;74(5):646– 651.
20. Shammas FV, Ous S, Fossa SD. Cisplatin and 5- fluorouracil in advanced cancer of the penis.
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22. Gagliano RG, Blumenstein BA, Crawford ED, et al. Cis- diamminedichloroplatinum in the
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181Case 18 Advanced and metastatic penile cancer
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SECTION 8
Testicular cancer
Case 19 Growing teratoma syndrome in testis cancer
Case 20 Metastatic testicular cancer: post-chemotherapy residual
mass and cancer survivorship
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