OncoLog

 

From OncoLog, July 2013, Vol. 58, No. 7

Compass: Penile Cancer
Although curable, localized or regional squamous cell carcinoma of the penis presents treatment dilemmas

By Sunni Hosemann

Introduction

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 treatment.

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.

Prognostic factors

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 fatal.

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 spread.

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.

Disease evaluation

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 conservative treatment.

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 surgical margins.

Laser ablation

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 therapy

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

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 proceed immediately.

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.

Neoadjuvant therapy

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, M0.

“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.

References

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. 2012;16:157.

Contributing Faculty
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.
Professor, Urology

For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.

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