Although curable, localized or regional squamous cell carcinoma of the penis presents treatment dilemmas
By Sunni Hosemann
Squamous cell carcinoma (SCC) of the penis is treatable and
curable when detected early. However, because the disease is rare, no
large, randomized clinical trials of penile SCC have been conducted.
For this reason, treatment recommendations for this cancer have been
derived from small trials, from retrospective analyses, from what has
been learned about similar cancers—vulvar, cervical, and head and neck
SCCs—and from expert experience.
According to the National Cancer Institute, penile cancer accounts for
less than 1% of cancers in men in the United States. More than half of
penile cancers are diagnosed in men 60 years or older; however, 22%
occur in men younger than 40 years.
Some factors are known to affect the incidence of penile cancer.
According to Curtis Pettaway, M.D., a professor in the Department of
Urology at The University of Texas MD Anderson Cancer Center, the
incidence of penile cancer is highest among men not circumcised in
childhood, men who develop phimosis, men with AIDS or other immune
deficiency disorders, and men treated for psoriasis with ultraviolet
light (alone or with psoralens) without genital protection during
Another potential risk factor is human papillomavirus infection, which
is suspected to play a role in about 40% of penile cancers. Although
melanomas and sarcomas can affect the penis, 95% of penile cancers are
SCCs, and this discussion is confined to potentially curable SCCs,
which include localized disease and disease that has metastasized to
regional lymph nodes but not distant sites (any T, any N, M0).
The 5-year relative survival rate is 85% for men with SCC confined to
the penis, 59% for men whose disease has spread to lymph nodes, and 11%
for men whose disease has spread to distant sites.
Men with limited inguinal lymph node metastases are often cured with
surgery alone, whereas men with bulkier inguinal metastases and pelvic
metastases may be cured by surgery and chemotherapy. However, distant
metastases from penile SCC are not curable and tend to be rapidly
These disparate prognoses are why surgical exploration for potential
occult nodal disease is appropriate for some patients with no clinical
evidence of inguinal spread (i.e., no palpable lymph nodes). However,
inguinal lymph node dissection (ILND) is associated with significant
morbidity. Physicians must therefore determine the risk of regional
One determinant of risk for regionally advanced disease is the
pathological makeup of the primary lesion. Less differentiated tumors
and those with evidence of microvascular or lymphovascular invasion
have an increased risk of metastasis to regional lymph nodes.
According to Dr. Pettaway, treatment decisions are heavily dependent on
a thorough assessment of the extent of disease. This assessment begins
with a clinical evaluation of the primary lesion and regional lymph
nodes. The primary lesion must be clinically assessed for size,
location, involvement of the scrotum or base of the penis, fixation,
depth of invasion, and involvement of corporeal bodies (i.e.,
submucosa, urethra, corpora spongiosum or cavernosum). In addition, the
lymph nodes in the groin are palpated for evidence of involvement,
which is a strong prognostic indicator. In obese patients, whose lymph
nodes are more difficult to palpate, imaging modalities such as
computed tomography can provide useful staging information about the
presence of inguinal or pelvic adenopathy.
The primary lesion must also be biopsied to determine the histological
grade and the presence of vascular invasion. The likelihood of
micrometastases is increased in patients whose primary tumor is poorly
differentiated or found to exhibit lymphovascular invasion. Such tumors
are categorized as T1b or greater according to the American Joint
Committee on Cancer’s TNM staging system. In patients with these
tumors, regional lymph nodes should be assessed to determine whether
regional metastases are present, even if there is no palpable
lymphadenopathy. Such an assessment is usually accomplished by
superficial ILND, dynamic sentinel node biopsy, or inguinal
ultrasonography and biopsy.
Primary tumor treatment options
Penectomy or conservative measures?
The goal of treatment in patients with penile SCC is to eradicate the
cancer with minimal impairment of organ function. “For this cancer,
surgical resection remains the gold standard for the treatment of the
primary tumor,” Dr. Pettaway said. “However, the extent of resection
necessary is a concern for both aesthetic and functional reasons, and
organ-sparing options can be considered in select patients.”
Partial or total penectomy often is necessary for tumors that require
wide surgical excision, including tumors that are grade 3 or higher;
tumors that are 4 cm or larger; tumors that have penetrated the glans,
urethra, or corpus cavernosum; and tumors located on the penile shaft.
For Tis, Ta, and T1 tumors that have no nodal extension and a favorable
histology (i.e., low grade and well differentiated with no vascular
invasion), organ-sparing treatment options may include topical therapy,
laser ablation, or limited surgical excision.
“The goal of these treatments is to remove the tumor while preserving
glans sensation and retaining the maximum possible penile shaft
length,” Dr. Pettaway said. Fortunately, nearly 80% of SCCs present on
the prepuce, on the glans, or in the coronal sulcus—distal locations
that lend themselves to organ-conserving approaches.
However, these organ-conserving methods carry a higher risk for disease
recurrence than penectomy does. Patients who undergo conservative
procedures should be counseled about the need for increased
self-examination and surveillance, as early detection increases the
likelihood that a locally recurrent lesion also will be amenable to
Limited surgical excision
Low-grade T1a tumors located on the glans may be treated with limited
excision of the glans or glansectomy, sparing the penile shaft; tumors
confined to the prepuce may be treated with circumcision. Conservative
surgery should be done in conjunction with intraoperative pathological
analysis to ensure negative surgical margins.
Mohs micrographic surgery also offers the potential for functional and
aesthetic preservation of the penis for patients with small, distal,
low-grade, early-stage lesions. The Mohs procedure is an excisional
treatment performed by dermatological surgeons in an outpatient
setting. As with limited excisions performed by urologists,
intraoperative pathological analysis is performed to confirm negative
Laser ablation is most useful for superficial penile lesions. CO2-based
lasers have a very small depth of penetration and were commonly used in
the past. But newer, high-energy, neodymium-doped yttrium aluminum
garnet–based lasers have a deeper penetration capability, and the
recent use of these lasers to ablate penile lesions has resulted in
high rates of resumption of sexual activity and patient satisfaction.
Like conservative surgery, laser ablation should be done in conjunction
with frozen section tissue analysis to ensure adequate margins.
Topical cream formulations of 5-fluorouracil or 5% imiquimod used daily
or every other day for 4–6 weeks are options for patients with Tis
penile lesions, especially those who are not good candidates for
surgery. These agents achieve good functional and aesthetic results;
however, many patients do not complete the recommended course of
treatment because the agents irritate the skin.
Radiation therapy (brachytherapy or external beam radiation therapy) is
a treatment option considered for men with T1b or T2 tumors when
technically feasible. Radiation therapy can preserve the penis, but the
high doses of radiation that are necessary to treat SCC can cause acute
edema and desquamation as well as late urethral stricture or tissue
necrosis. Penile preservation rates of 70%–90% have been reported in
appropriately selected patients treated with brachytherapy.
Radiation therapy also may be used to treat T3 or greater tumors in
patients who refuse or who are medically unable to tolerate surgery.
For these patients, radiation is administered concurrently with
chemotherapy. “There are limited data on outcomes after chemoradiation
therapy for penile SCC,” said Karen Hoffman, M.D., an assistant
professor in the Department of Radiation Oncology. “However, definitive
chemoradiation is a proven, effective therapy for other human
papillomavirus–related SCCs, including cervical and anal SCC.”
Regional lymph node treatment options
The spread of penile cancer from the penis to metastatic sites is
orderly and virtually always occurs first in the inguinal lymph nodes.
Thus, a plan for management of the inguinal region should be considered
in the overall management plan when the cancer is first diagnosed.
Surgery, observation, or neoadjuvant therapy?
ILND can offer a cure in many patients whose penile SCC has
metastasized to the inguinal lymph nodes. However, the procedure comes
with significant drawbacks. Although improved surgical techniques and
better perioperative care have reduced the incidence of complications
from ILND, its associated morbidities can include wound infection and
dehiscence, seromas, venous thromboembolic events, and chronic
lymphedema of the scrotum and lower limbs. For these reasons, ILND can
be controversial. Therefore, physicians must determine the best way to
stage the inguinal nodal basin and stratify patients for treatment.
Surveillance is considered for patients who have no palpable lymph
nodes and are considered to be at low risk (i.e., Tis, Ta, grade 1 T1)
or intermediate risk (i.e., grade 2 T1 without lymphovascular invasion)
for inguinal involvement. For all other patients, superficial ILND and
dynamic sentinel node biopsy are the standard staging tools. The
results of these studies then allow physicians to make decisions about
the need for additional procedures.
Palpable inguinal lymph nodes require immediate investigation. Because
30%–50% of enlarged lymph nodes are caused by inflammation, patients in
the past were given a 6-week course of antibiotics before further
investigation of palpable lymph nodes, but this is no longer
recommended. Even when antibiotics are administered for underlying
cellulitis or inflammation, investigation of the lymph nodes should
Superficial ILND with frozen section analysis (followed by complete
ILND if necessary) is recommended for patients with mobile palpable
nodes confined to one side of the groin. Fine needle aspiration
cytology, while not sufficiently sensitive for complete inguinal
staging, can provide information to help determine the next steps in
treatment, especially in patients with bilateral nodal involvement or
fixed palpable nodes.
Another method for staging the inguinal nodal basin is dynamic sentinel
lymph node biopsy, in which a radioactive dye is injected near the
tumor to visualize the draining (i.e., sentinel) inguinal nodes. Recent
data suggest that dynamic sentinel lymph node biopsy may be less morbid
than superficial ILND, but this finding requires further validation.
If cancer is found in the inguinal nodes, the next consideration is the
pelvic nodes. “We never see pelvic involvement without inguinal
disease,” Dr. Pettaway said, “and distant disease is always in the
setting of high-volume disease in the inguinal and pelvic nodes.”
According to Dr. Pettaway, patients found during ILND to have two or
more involved inguinal nodes, evidence of extension into extranodal
tissue, or poorly differentiated histologies should undergo pelvic
lymph node dissection. If pelvic disease is found prior to ILND,
neoadjuvant chemotherapy should be considered.
According to Lance Pagliaro, M.D., a professor in the Department of
Genitourinary Medical Oncology, men with metastases in three or fewer
unilateral inguinal nodes and no pelvic nodal involvement who are
treated with surgery alone have a disease recurrence rate of 10%–20%.
But in patients who have bulky or bilateral inguinal nodal involvement,
pelvic nodal involvement, or extension into extranodal tissue and who
are treated with surgery alone, the recurrence rate is 80%–90%. Dr.
Pagliaro said that in these patients, neoadjuvant chemotherapy,
radiation therapy, or chemoradiation should be considered.
Neoadjuvant chemotherapy followed by consolidation surgery is the
preferred treatment for patients who have regional disease involvement
beyond two unilateral lymph nodes and are willing and able to undergo
surgery. A prospective, nonrandomized phase II trial reported in 2010
by Drs. Pagliaro and Pettaway and their colleagues established the
efficacy of neoadjuvant chemotherapy with paclitaxel, ifosfamide, and
cisplatin in patients with SCC of the penis classified as any T, N2–3,
“The results surprised us,” Dr. Pagliaro said. “We found that 50% of
the patients had a response to chemotherapy—that’s more than we
expected—and 37% of the patients experienced progression-free survival
for a median follow-up period of 34 months, compared with the 10%–15%
that would be expected with surgery alone.”
The study also revealed that the preoperative chemotherapy did not
increase surgical complications and that the paclitaxel, ifosfamide,
and cisplatin regimen was as effective as but less toxic than a
combination previously used in a larger multicenter study by the
cooperative trial group SWOG.
For patients who cannot tolerate or whose tumors do not respond to
neoadjuvant chemotherapy, radiation therapy can be used to improve the
resectability of nodal masses. Preoperative chemoradiation also can
improve lymph node tumor resectability and is particularly useful in
patients with fixed or bulky nodes.
“We also use radiation adjuvantly, usually with concurrent
chemotherapy, when concerning features such as multiple involved nodes
or gross extranodal extension are found at lymph node dissection,” Dr.
Hoffman said. “It is important to achieve local disease control in the
pelvis to prevent morbid local recurrence.”
Chemoradiation is also used as a definitive therapy in patients who refuse or are medically unable to tolerate surgery.
Toward better answers
An international collaborative research initiative of the U.S. National
Cancer Institute, the United Kingdom clinical trial system, and the
European Organization for Research and Treatment of Cancer is likely to
clarify treatment options for penile SCC. This collaborative, called
the International Rare Cancer Initiative, was formed in 2011 to provide
a research infrastructure and recruit sufficient numbers of study
participants from multiple international sites to help direct the
treatment of rare cancers, including penile cancer. As part of this
initiative, MD Anderson will participate in a collaborative study of
metastatic penile cancer.
Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010.
National Comprehensive Cancer Network. Clinical Practice Guidelines in
Oncology, Penile Cancer, V1.2013. [PDF]
Pagliaro LC, Williams DL, Daliani D, et al. Neoadjuvant paclitaxel,
ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a
phase II study. J Clin Oncol. 2010;28:3851–3857.
Pettaway CA, Davis JW. Contemporary management of penile carcinoma.
Part I: overview of epidemiology, diagnosis, staging and management of
the primary tumor. AUA Update Series. 2012;15:149.
Pettaway CA, Pagliaro LC. Penile squamous carcinoma. Part II:
contemporary management of the inguinal region. AUA Update Series.
The University of Texas MD Anderson Cancer Center
Karen Hoffman, M.D.
Assistant Professor, Radiation Oncology
Lance C. Pagliaro, M.D.
Professor, Genitourinary Medical Oncology
||Curtis A. Pettaway, M.D.
For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.
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