Radiotherapy, in the form of external beam radiotherapy or interstitial brachytherapy, provides an effective penile-sparing option for localized squamous cell carcinoma of the penis. Interstitial brachytherapy is completed in 4 to 5 days and provides 5-year penile preservation rates of 70% to 88%, and at 10 years, 67% to 72%. Surgery provides effective salvage for local failures, maintaining cause-specific survival at 84% to 92% at 10 years. Ideal tumors for brachytherapy should be less than 4 cm without extension onto the shaft. More advanced cases can be considered for external radiotherapy.
Carcinoma of the penis is relatively rare but the incidence shows wide geographic variation. It occurs in about 1 per 100,000 men in North America and Western Europe where it represents less than 1% of cancers in men, but has an incidence as high as 10 to 20 per 100,000 men in parts of Asia, Africa, and South America. Socioeconomic and cultural factors play a role in this disparity. As a rare tumor, most published reports span several decades and often represent experience from a single center, during which time staging systems and management policies have evolved. Apart from the investigation of systemic agents for advanced disease, randomized trials are essentially nonexistent.
Primary surgical management is effective in localized disease but traditional extirpative surgery often results in profound psychosexual consequences. Radiotherapeutic approaches and newer surgical techniques strive to conserve penile function and morphology. Whenever possible, management should be centralized to tertiary referral centers with collective expertise, including expert pathologists, urologists, and radiation and medical oncologists, to deliver a cooperative multidisciplinary approach from the outset. Such an approach should include psychosocial support and counseling. Sexual consequences of treatment should be discussed with the patient and his partner during the decision-making phase.
Cause
Incidence increases with increasing age, being most common in the sixth decade, but earlier where the incidence is higher. Human papillomavirus types (HPV) 16 and 18 are most frequently associated with invasive squamous cell carcinomas. Amplification of DNA by polymerase chain reaction (PCR) can demonstrate viral DNA in about 40% to 45% of tumors, especially those of the basaloid variety but less frequently in squamous or verrucous types. Premalignant conditions including bowenoid papulosis, Bowen disease, and erythroplasia of Queryat show a high incidence of HPV positivity in penile intraepithelial neoplasia, whereas lichen sclerosis is associated with non-HPV variants. The presence of HPV does not confer a worse prognosis whereas p53 positivity, detected in 41% to 75% of invasive cancers, is associated in multivariate analysis with the presence of lymph node metastases.
Circumcision is protective when performed in infancy and is associated with a 3-fold decrease in the risk of penile carcinoma. However, circumcision is not 100% protective and subsequent infection with genital condylomas in adulthood (overall 3–5 times increased risk), presumably in conjunction with oncogenic HPV strains, has been reported to be associated with subsequent development of squamous carcinoma in circumcised men. Lack of circumcision is believed to play a role through association with poor hygiene and chronic infection, with phimosis being a factor in as many as 50% of cases in some series. However, infant circumcision is no longer recommended on these grounds alone; rather the emphasis is on education, hygiene, and correction of phimosis.
Smoking is an additional causal factor that may play a role as a promoter in conjunction with other oncogenic factors.
Staging
Staging systems have evolved in recent decades. The 3 commonly encountered systems, Jackson, TNM 1978, and TNM 1987 are shown in Box 1 . The Jackson system is purely anatomically based with stage 1 tumors limited to the prepuce and glans, stage 2 involving the shaft, and stage 3 confined to the shaft but with malignant operable nodes. Although somewhat simplistic, this system is practical and clinically useful as decisions on management are often made on this basis. In contrast, TNM 1978 was based on tumor size, distinguishing T stages by less than 2 cm, 2 to 5 cm, and greater than 5 cm. Again this system had clinical usefulness because tumor size influences the choice of treatment approach and suitability for penile conservation. The current TNM system has not changed in the past 2 decades and is based on final surgical pathology, distinguishing T1 from T2 by depth of invasion into the erectile tissue. This information, unfortunately, is often not available when planning a penile-conserving approach.
Jackson Classification
Primary tumor:
- 1.
Limited to the glans or prepuce
- 2.
Extending into the shaft or corpora but without nodal involvement
- 3.
Confined to the shaft but with malignant lymph nodes considered operable
- 4.
Invading beyond the shaft, with inoperable lymph nodes or distant metastases
- 1.
TNM Staging UICC 1978
Tis: Carcinoma in situ
T1: ≤2 cm
T2: >2 cm and ≤5 cm
T3: >5 cm or deep invasion including urethra
T4: Invades adjacent structures
Positive inguinal lymph nodes
N1: Unilateral
N2: Bilateral
N3: Fixed
TNM Staging UICC 1987–2009
Tis: Carcinoma in situ
Invasive tumor involving:
T1: Subepithelial connective tissue
T2: Corpus spongiosum or cavernosum
T3: Urethra/prostate
T4: Other adjacent structures
Positive lymph nodes
N1 1 superficial inguinal
N2 Multiple/bilateral superficial inguinal
N3 Deep inguinal or pelvic
One of the difficulties in determining tumor stage in the current TNM system is that diagnostic biopsies are often superficial, with only enough tissue to establish the diagnosis of malignancy, but not enough to determine the depth of invasion, or to reliably determine grade or rule out lymphovascular invasion (LVI). In 1 study, 30% of tumors were upgraded on final pathology compared with biopsy, and only 1/8 of biopsies correctly identified LVI. Imaging such as ultrasound (US) or magnetic resonance imaging with prostaglandin-induced artificial erection may help to distinguish invasion of the corpora when clinical examination is uncertain.
Evaluation of lymph nodes is important as nodal involvement is the strongest predictor of survival. Although clinical examination of the inguinal regions may be sufficient for Tis-T1, grade 1 to 2 lesions, for G3 lesions or T2 disease, computed tomography (CT) staging should be performed as an initial step; US-guided fine-needle aspiration cytology is useful for nodes that are clinically suspicious. For tumors that are less than well differentiated, showing LVI, or higher than stage T2, surgical staging is recommended with either modified inguinal lymph node dissection or dynamic sentinel lymph node mapping, which uses a gamma probe after intradermal injection of technetium 99m around the primary tumor. Centers with expertise report low false-negative rates, ranging from 2% to 11%, suggesting that this is an adequate substitute for groin dissection in experienced hands.
Staging
Staging systems have evolved in recent decades. The 3 commonly encountered systems, Jackson, TNM 1978, and TNM 1987 are shown in Box 1 . The Jackson system is purely anatomically based with stage 1 tumors limited to the prepuce and glans, stage 2 involving the shaft, and stage 3 confined to the shaft but with malignant operable nodes. Although somewhat simplistic, this system is practical and clinically useful as decisions on management are often made on this basis. In contrast, TNM 1978 was based on tumor size, distinguishing T stages by less than 2 cm, 2 to 5 cm, and greater than 5 cm. Again this system had clinical usefulness because tumor size influences the choice of treatment approach and suitability for penile conservation. The current TNM system has not changed in the past 2 decades and is based on final surgical pathology, distinguishing T1 from T2 by depth of invasion into the erectile tissue. This information, unfortunately, is often not available when planning a penile-conserving approach.
Jackson Classification
Primary tumor:
- 1.
Limited to the glans or prepuce
- 2.
Extending into the shaft or corpora but without nodal involvement
- 3.
Confined to the shaft but with malignant lymph nodes considered operable
- 4.
Invading beyond the shaft, with inoperable lymph nodes or distant metastases
- 1.
TNM Staging UICC 1978
Tis: Carcinoma in situ
T1: ≤2 cm
T2: >2 cm and ≤5 cm
T3: >5 cm or deep invasion including urethra
T4: Invades adjacent structures
Positive inguinal lymph nodes
N1: Unilateral
N2: Bilateral
N3: Fixed
TNM Staging UICC 1987–2009
Tis: Carcinoma in situ
Invasive tumor involving:
T1: Subepithelial connective tissue
T2: Corpus spongiosum or cavernosum
T3: Urethra/prostate
T4: Other adjacent structures
Positive lymph nodes
N1 1 superficial inguinal
N2 Multiple/bilateral superficial inguinal
N3 Deep inguinal or pelvic
One of the difficulties in determining tumor stage in the current TNM system is that diagnostic biopsies are often superficial, with only enough tissue to establish the diagnosis of malignancy, but not enough to determine the depth of invasion, or to reliably determine grade or rule out lymphovascular invasion (LVI). In 1 study, 30% of tumors were upgraded on final pathology compared with biopsy, and only 1/8 of biopsies correctly identified LVI. Imaging such as ultrasound (US) or magnetic resonance imaging with prostaglandin-induced artificial erection may help to distinguish invasion of the corpora when clinical examination is uncertain.
Evaluation of lymph nodes is important as nodal involvement is the strongest predictor of survival. Although clinical examination of the inguinal regions may be sufficient for Tis-T1, grade 1 to 2 lesions, for G3 lesions or T2 disease, computed tomography (CT) staging should be performed as an initial step; US-guided fine-needle aspiration cytology is useful for nodes that are clinically suspicious. For tumors that are less than well differentiated, showing LVI, or higher than stage T2, surgical staging is recommended with either modified inguinal lymph node dissection or dynamic sentinel lymph node mapping, which uses a gamma probe after intradermal injection of technetium 99m around the primary tumor. Centers with expertise report low false-negative rates, ranging from 2% to 11%, suggesting that this is an adequate substitute for groin dissection in experienced hands.
Pathologic prognostic factors
Tumor differentiation, stage (or depth of invasion), the presence of lymphovascular invasion and p53 positivity are the most important predictors of outcome. These may be difficult to assess on biopsy as many biopsies are too superficial to assess the depth of invasion and may miss other important prognostic features. Lymph node involvement has been reported in 30% of well-differentiated tumors and 81% of moderately or poorly differentiated tumors. Similarly G3 lesions with invasion of the corpora had a 78% rate of lymph node positivity after inguinal dissection, whereas for G1 to G2 T1, the rate of nodal involvement was only 4%.
Early disease
A 2001 survey of practice confirmed the preference for amputative surgery for distal lesions that is still prevalent in many centers. European Association of Urology guidelines direct urologists away from amputative surgery toward penile conservation whenever possible. A penile-sparing approach is recommended for Ta-T1, grade 1 to 2 tumors. For grade 3 T1 or grade 1 to 2 T2, penile sparing may be considered provided the lesion takes up less than half the glans and the patient is reliable for follow-up. This represents a significant change in philosophy away from traditional surgical approaches involving partial or total penectomy. The literature contains reports of suicide or attempted suicide following surgery, and although some men may be willing to sacrifice their sexual function for a treatment that may offer a better chance of survival, the converse is also true. The sexual sequelae of partial penectomy are almost as severe as for total penectomy and although the capacity for erection of the penile stump and orgasm may be retained, only one-third of men continue to enjoy the same frequency and quality of sexual encounters as before surgery.
Penile conservation
Surgical
The first steps are to obtain a biopsy for diagnosis and to perform a circumcision to permit full exposure of the lesion and prevent complications such as radiation balanitis and phimosis if a radiotherapeutic approach is chosen. Because more than one-third of penile cancers involve the prepuce, with or without involvement of the glans, circumcision also removes a portion of the tumor.
Several surgical approaches exist for penis conservation. Mohs surgery involves removal of successive thin layers of tissue until microscopically verified clear margins are obtained. Generally tumors that involve the corpora, urethra, or urethral meatus are not considered suitable for Mohs surgery. Other options for superficial disease (Tis, T1) include carbon dioxide or neodynium-yttrium-aluminum-garnet laser resection. Results are poor for T2 disease and long-term close follow-up is required because 30% of recurrences occur between 6 and 10 years and 15% after 10 years. Glansectomy and reconstruction can be considered as a limited partial penectomy but with a better functional result and preservation of penile length. The traditional surgical approach requiring a 2-cm margin does not leave much of an option for functional preservation, but recent reports of successful outcomes with margins of 1 cm or less have challenged the old dogma. Closer margins, however, do impart a higher risk of local recurrence and necessitate closer follow-up.
Radiation
Radiation is an organ-conserving modality that can be delivered by an external beam approach (EBRT) or as interstitial brachytherapy (BT). Both are locally effective and spare amputation in a significant proportion of cases ( Tables 1 and 2 ). The choice of modality depends on patient selection factors and the availability of expertise. Either modality must be preceded by a full circumcision.
| Author | Year | No. of Patients | Dose (Gy) | Follow-up, Months (Range) | 5-Year Local Control a | 5-Year Cause-Specific Survival a | Necrosis/Stenosis | Penile Preservation |
|---|---|---|---|---|---|---|---|---|
| Chaudhery et al | 1999 | 23 | 50 | 21 (4–117) | 70% (8 y) | — | 0/9% | 70% (8 y) |
| Crook et al | 2009 | 67 | 60 | 48 (6–194) | 87% 72% (10 y) | 83.6% | 12%/9% | 88% (5 y) 67 (10 y) |
| DeCrevoisier et al | 2009 | 144 | 65 | 68 (6–348) | 80% (10 y) | 92% (10 y) | 26%/29% | 72 (10 y) |
| Delannes et al | 1992 | 51 | 50–65 | 65 (12–144) | 86% crude | 85% | 23%/45% | 75% |
| Kiltie et al | 2000 | 31 | 64 | 61.5 | 81% | 85.4% | 8%/44% | 75% |
| Mazeron et al | 1984 | 50 | 60–70 | 36–96 | 78% crude | — | 6%/19% | 74% |
| Rozan et al | 1995 | 184 | 59 | 139 | 86% | 88% | 21%/45% | 78% |
| Sarin et al | 1996 | 102 | 61–70 | 111 | 77% | 72% | Not stated | 72% (6 y) |
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