David B. Mansur
ANATOMY
The basic structural components of the penis include two corpora cavernosa and the corpus spongiosum. These are encased in a dense fascia (Buck’s fascia), which is separated from the skin by a layer of loose connective tissue. Distally, the corpus spongiosum expands into the glans penis, which is covered by a skin fold known as the prepuce. The skin extends over and is firmly attached to the glans.
The male urethra is composed of a mucous membrane and the submucosa. It extends from the bladder neck to the external urethral meatus. The posterior urethra is subdivided into the membranous urethra, the portion passing through the urogenital diaphragm, and the prostatic urethra, which passes through the prostate. The anterior urethra passes through the corpus spongiosum and is subdivided into fossa navicularis (a widening within the glans), the penile urethra, which passes through the pendulous part of the penis, and the bulbous urethra, the dilated proximal portion of the anterior urethra. The prostatic urethra is covered by transitional epithelium only. The distal portion of the anterior urethra is covered by stratified squamous epithelium, which changes proximally to pseudostratified columnar epithelium. The columnar epithelium gradually changes into transitional epithelium in the membranous urethra.
The lymphatic channels of the prepuce and the skin of the shaft drain into the superficial inguinal nodes located above the fascia lata. The rich anastomotic network of the lymphatics within the penis and at the base of the penis means that for practical purposes lymphatic drainage may be considered bilateral. There is some disagreement as to whether the glans and the deep penile structures drain into the superficial or deep inguinal lymph nodes (those under the fascia lata). The so-called sentinel nodes located above and medial to the junction of the epigastric and saphenous veins have been identified as the primary drainage sites in carcinoma of the penis.1 Selective biopsy of this group of nodes is of obvious importance in assessment of tumor extent, because, if they are not involved by tumor, a complete nodal dissection may not be necessary. The reliability of this procedure has not been supported by some.2,3Catalona4 found that biopsy of the sentinel nodes showed false-negative results in 10% of Cabanas’s5 cases who died of carcinoma.
The lymphatics of the fossa navicularis and the penile urethra follow the lymphatics of the penis to the superficial and deep inguinal lymph nodes. The lymphatics of the bulbomembranous and prostatic urethra may follow three routes. Some pass under the pubic symphysis to the external iliac nodes, some go to the obturator and internal iliac nodes, and others end in the presacral lymph nodes. The pelvic (iliac) lymph nodes are rarely involved in the absence of inguinal lymph node involvement.6
EPIDEMIOLOGY
Carcinoma of the penis is rare in the United States, where an estimated 1,100 new cases will be diagnosed each year.7 The annual incidence is estimated to be 1 in 100,000 males, accounting for less than 1% of all cancers in men.6There is increasing evidence that newborn circumcision has a preventive effect in the development of carcinoma of the penis.8 This tumor is extremely rare in circumcised Jewish men;6 circumcision performed early in life protects against carcinoma of the penis, but this is not true if the operation is done in adult life.9 The higher incidence in some areas of South America, Africa, and Asia seems to be related to the absence of the practice of neonatal circumcision. It has been shown that male circumcision is highly effective in preventing the development of penile carcinoma in Nigeria and Uganda.10,11 The high incidence of carcinoma of the penis in American blacks has similarly been attributed to the lower percentage of blacks undergoing neonatal circumcision. Phimosis is common in men suffering from penile carcinoma. Smegma is carcinogenic in animals, yet the component of the smegma responsible for its carcinogenic effect has not been identified.6
Human papilloma virus (HPV) is associated with penile carcinoma. In a systematic review of the literature, Miralles-Guri et al.12 concluded that approximately half of all carcinomas are HPV related, with the most common serotypes being HPV-16 and HPV-18. Boon et al.13 observed an increased incidence of cervical carcinoma and penile carcinoma in Bali in a Hindu population in whom circumcision is rare and phimosis in adult males is high. They suggested that HPV infection, estimated to be present in over 75% of Balinese patients with genital carcinoma, may be a cofactor with impeded postcoital hygiene in genital carcinogenesis. In the Netherlands, where males are usually circumcised, the male is exclusively a vector of HPV but not a victim as in Bali. Martinez14 in Puerto Rico and Graham et al.15 in New York also noted a significantly higher incidence of carcinoma of the cervix in the wives of males with penile carcinoma.
The quadrivalent vaccine against HPV serotypes 6, 11, 16, and 18 has been approved for females aged 9 to 26 to prevent cervical cancer. Based on the demonstrated ability to significantly decrease the incidence of penile lesions (primarily HPV-6 and HPV-11 associated genital warts) in young men, the U.S. Food and Drug Administration also approved the use of the vaccine in males aged 9 to 26. Because the incidence of penile cancer in the United States is much lower than that of genital warts, the reduction in penile cancer incidence is expected to be low. However, there is potential great benefit to vaccination in countries with much higher penile cancer rates. Perhaps the greatest benefit of vaccination of young men in the United States would be the reduced HPV infection rate in the overall population and subsequent reduced transmission to females at risk for cervical cancer.16 Other etiologic factors, such as other viruses (herpes simplex) and venereal disease (syphilis), have been implicated,17,18 but the evidence remains inconclusive.5
Carcinoma of the male urethra is also rare. There are no recognized racial or geographic predisposing factors. Although the etiology remains unknown, there seems to be some correlation between the incidence of carcinoma of the urethra and chronic irritation (infection, venereal diseases, strictures). Significant past medical history of male urethra cancer patients include venereal disease (24% to 37%), urethral stricture (35% to 54%), urethral trauma (7%), and urethral polyps (2%).19,20 The part of the urethra covered by the transitional epithelium (prostatic and membranous urethra) may be susceptible to the same carcinogenic factors that affect the bladder and the upper urinary tract. Average age at presentation of these tumors is 58 to 60 years, although 10% occur in men younger than 40 years.5,20
NATURAL HISTORY
Most carcinomas of the penis start within the preputial area, arising in the glans, coronal sulcus, or the prepuce itself. Lesions arising in the skin of the shaft are rare. In most patients, carcinoma of the penis is characterized by slow locoregional progression. The penis is handled and observed daily, yet there is often significant debate as to when patient recognition and medical diagnosis should have occurred. The patient experiences fear and embarrassment, which probably contributes to delayed diagnosis. Therefore, expeditious diagnosis of all penile lesions should be the rule. Extensive primary lesions may involve the corpora cavernosa or even the abdominal wall. The inguinal lymph nodes are the most common site of metastatic spread. Pathologic evidence of nodal metastases is reported in about 35% of all patients and in approximately 50% of those with palpable lymph nodes.5,17,21,22
Distant metastases are uncommon (about 10%), even in patients with advanced locoregional disease, and usually occur in patients with inguinal lymph node involvement. These patients often die of septic complications, erosion of large vessels in the groin, or a combination of the two.
The natural history of carcinoma of the anterior urethra in the male is similar to that of carcinoma of the penis. Approximately 40% of tumors originate in the anterior urethra.19 Many tumors are low grade and progress slowly at primary and regional sites rather than spread to distal areas. Tumors of the penile urethra spread to the inguinal lymph nodes first, whereas those of the bulbomembranous and prostatic urethra metastasize first to the pelvic lymph nodes. Approximately one-third of men will present with either clinically or pathologically involved lymph nodes.19
Urethral cancers tend to spread by direct extension to adjacent structures. Invasion into the vascular space of the corpus spongiosum in the periurethral tissues is common. Malignancies beginning in the bulbomembranous urethra often invade the deep structures of the perineum, including the urogenital diaphragm, prostate, and adjacent skin. In the majority of prostatic urethral tumors, the bulk of the prostate gland is invaded at the time of diagnosis. Hematogenous spread is uncommon except in advanced regional disease. Kaplan et al.20 reported distant metastases in about 15% of patients; most had corpora cavernosa invasion at diagnosis.
FIGURE 68.1. Localization of the primary tumor in 259 patients; each circle represents one anatomic compartment. Intersections indicate involvement of two or three compartments. Unknown: two. (From Rozan R, Albuisson E, Giraud B, et al. Interstitial brachytherapy for penile carcinoma: a multicentric survey (259 patients). Radiother Oncol1995;36:83–93, copyright 1995, with permission from Elsevier.)
CLINICAL PRESENTATION
Carcinoma of the penis may present as either an infiltrative-ulcerative or an exophytic papillary lesion. Figure 68.1 demonstrates the localization of penile tumors in 259 patients from 14 cancer institutes in France. The glans and the prepuce were the predominant sites of the primary lesion, whereas tumors of the shaft were rare.23 Assessment of the primary lesion may be obscured by the presence of phimosis. Secondary infection and associated foul smell are quite common. Urethral obstruction is an unusual symptom of carcinoma of the penis. The most common presenting symptom is a mass, which occurs in over two-thirds of patients. Ulceration is also common, occurring in approximately half of patients.22,24 In a collective series of 552 patients with penile carcinoma, the presenting symptoms were mass lesions (78%), pain or itching (12%), bleeding (7%), groin mass (7%), and urinary symptoms (4%).25–27 Inguinal lymph nodes are palpable on presentation in 30% to 45% of patients;5,17,21,26,28,29 however, only half contain tumor.21,22 Enlargement of the lymph nodes is often related to inflammatory (infectious) processes. Administration of antibiotics over several weeks results in regression of inguinal lymph nodes in a substantial proportion of cases and many have advocated this practice before the status of the regional lymph nodes is definitively assessed. Conversely, between 20% and 40% of patients with clinically negative inguinal lymph nodes have occult metastases.3,30–33
Patients with urethral carcinoma most commonly present with obstructive symptoms (43%). Other presenting signs and symptoms include mass (28%), bleeding (20%), abscess (20%), and irritative symptoms (20%).19 These symptoms are often attributed to urethritis or urethral stricture, which may precede the development of urethral carcinoma and may also result in delay in diagnosis. The majority of urethral carcinomas occur in the bulbomembranous (posterior) region (61%), and tumors in this location have a worse prognosis compared with those arising in the anterior urethra.19
DIAGNOSTIC WORKUP
Diagnostic studies are required in the evaluation of patients with suspected or confirmed carcinoma of the penis and urethra. Urethroscopy and cystoscopy are essential for urethral primaries. Inguinal lymph nodes should be thoroughly evaluated. Computed tomography (CT) is useful in the identification of enlarged pelvic and periaortic lymph nodes in patients with involved inguinal lymph nodes.
Limited prospective data regarding the use of positron emission tomography (PET) with CT are available, but preliminary results show encouraging sensitivity (88%) and specificity (98%) in evaluating inguinal lymph nodes34 and a diagnostic accuracy of 96% in evaluating pelvic lymph nodes in patients with known inguinal metastases.35
TABLE 68.1 AMERICAN JOINT COMMITTEE STAGING SYSTEM FOR CARCINOMA OF THE PENIS
TABLE 68.2 AMERICAN JOINT COMMITTEE STAGING SYSTEM OF CARCINOMA OF THE URETHRA
STAGING
The American Joint Committee on Cancer (AJCC) staging systems for carcinoma of the penis and urethra are shown in Tables 68.1 and 68.2, respectively.36
PATHOLOGIC CLASSIFICATION
Most malignant penile tumors are well-differentiated squamous cell carcinomas.37 Although an apparent adverse prognostic effect of anaplasia has been reported in some series,17 others found no significant correlation between histologic grade and survival.18,26
Bowen disease is squamous cell carcinoma in situ that may involve the shaft of the penis as well as the hairy skin of the inguinal and suprapubic area. Clinically, the lesion is a solitary, dull-red plaque with areas of crusting and oozing. Approximately 25% to 50% of patients with this disease have a concomitant visceral malignancy.6
Erythroplasia of Queyrat is an epidermoid carcinoma in situ that involves the mucosal or mucocutaneous areas of the prepuce or glans.37 It appears as a reddened, elevated, or ulcerated lesion. Graham and Helwig38 reported that 10 of 100 patients presenting with erythroplasia of Queyrat had invasive squamous cell carcinoma at diagnosis. Mikhail39 reported on 5 of 15 patients with the same presentation. Erythroplasia of Queyrat is not as frequently associated with internal malignancies as Bowen’s disease.40
Basal cell carcinoma is infrequently reported, accounting for 1% to 2% of all cases of penile cancers.41,42
Extramammary Paget disease is a rare intraepithelial apocrine carcinoma. The most common sites are the scrotum, inguinal folds, and perineal region.39 The lesion has a propensity to metastasize, necessitating frequent assessment of regional nodes. Radiation therapy has been recommended as palliative treatment.39
Soft tissue tumors are uncommon. Approximately half of the tumors are benign and may include angiomatous, neurogenous, myogenous, fibrous, and lymphoreticular tumors.43,44 Most soft tissue tumors occur on the shaft and are malignant.
Primary lymphoma of the penis was reported in one patient with Peyronie disease, without other evidence of lymphomatous involvement. Five cases of secondary involvement of the penis by lymphoma were reported in the literature.45
Cancers metastatic to the penis are rare and usually represent late, advanced carcinomatosis. The most common neoplasms metastasizing to the penis are from the genitourinary organs, followed by the gastrointestinal and respiratory systems (Table 68.3). The predominant cell type is carcinoma, occurring in 202 of 219 cases.46 Sarcomas and tumors of unknown histologic type are rare. A palpable mass, swelling, nodule, or skin change frequently occurs. Priapism as an initial presenting feature or subsequent development occurs in 40% of patients.46
The histological subtypes in the Memorial Sloan-Kettering Cancer Center series of urethral cancers included squamous cell carcinoma (52%), transitional cell carcinoma (33%), epidermoid carcinoma (11%), adenocarcinoma (2%), and anaplastic carcinoma (2%).19 Primary malignant melanoma arising from the urethra has been reported.47,48 The frequency of histologic type varies with site. Over 90% of carcinomas of the prostatic urethra are of transitional cell type. Adenocarcinomas occur only in the bulbomembranous urethra.
TABLE 68.3 PRIMARY MALIGNANCIES ASSOCIATED WITH SECONDARY CANCERS OF THE PENIS IN 219 PATIENTS
PROGNOSTIC FACTORS
The principal prognostic factors in carcinoma of the penis are extent of the primary lesion and status of the lymph nodes.24,49 The incidence of nodal involvement is related to the size, location, and grade of the primary lesion. Invasion of deep-seated structures (corpora cavernosa) carries a high risk of deep inguinal node involvement.
Tumor-free regional nodes imply an excellent (80% to 90%) long-term survival or cure.21,29,49 Patients with involvement of the inguinal nodes fare considerably worse, and only 40% to 50% survive long term.21,29,49,50 Pelvic lymph node involvement implies a still worse prognosis; less than 20% of these patients survive.5,21,26 Gerbaulet and Lambin51 reported the results of 109 patients with carcinoma of penis at Institut Gustave-Roussy. The actuarial survival rates of patients with negative nodes were 82% at 5 years and 59% at 10 years. For patients with positive nodes, the survival rates were 36% and 18%, respectively. The number of positive lymph nodes has also been reported to have prognostic significance. Brkovic et al.52 reported a 5-year survival rate of 71% in patients with solitary inguinal lymph node metastasis compared with 33% in patients with multiple positive inguinal nodes.
Tumor differentiation was shown to be an important prognostic factor by Fraley et al.53 None of 9 patients with carcinoma in situ, 1 of 20 with well differentiated, 5 of 13 with moderately differentiated, and 3 of 4 with poorly differentiated lesions died of their tumors. Other investigators have confirmed the prognostic significance of tumor grade.24,49,54,55
Carcinoma of the penis has been reported to have greater propensity to metastasize and poorer prognosis in patients younger than 50 years of age53 and patients older than 65 years of age.54 Soria et al.24 reported younger age at presentation adversely affected disease free survival, but not overall survival. Conversely, Marcial et al.56 observed no difference in survival in relation to age.
The potential influence of HPV on prognosis was studied retrospectively in a cohort of patients treated surgically. HPV DNA was detected in paraffin-embedded specimens in 30% of patients. The presence of HPV had no prognostic significance with regard to lymph node metastasis or overall survival.57
Overall prognosis in males with carcinoma of the urethra varies considerably with location of the primary lesion.19,58–63 Distal lesions generally have a prognosis similar to that of carcinoma of the penis. Lesions of the bulbomembranous urethra are usually quite extensive and are associated with a dismal prognosis. Dalbagni et al.19 reported a 5-year overall survival of 69% in patients with anterior tumors compared with 26% in patients with posterior tumors. Other prognostic factors included lymph node status and histology (superficial vs. invasive). Tumors of the prostatic urethra show prognostic features similar to those in bladder carcinoma. Superficial lesions have a good prognosis and may be managed with transurethral resection.61 Deeply invasive tumors have a greater tendency to develop inguinal or pelvic lymph node and distant metastases.
GENERAL MANAGEMENT
Carcinoma of the Penis
Conservative Therapies
Treatment for carcinoma in situ and very small penile carcinomas includes topical imiquimod and 5-fluorouracil (5-FU).64 For larger lesions, conservative laser surgery65 or Mohs micrographic surgery is used.66
Surgery
Treatment of patients with carcinoma of the penis is generally performed in two phases: initial management of the primary tumor and later treatment of the regional lymphatics. Surgical intervention at the primary site may range from local excision, including circumcision, or laser surgery67 in a small group of highly selected patients, especially those with small lesions of the prepuce, to partial or total penectomy.22,52,54 In very advanced proximal tumors, more aggressive resections such as total emasculation (penectomy, scrotectomy, orchiectomy) or cystoprostatectomy may be indicated.68 Although surgical resection is a highly effective and an expedient treatment modality in most cases, it may not be acceptable to sexually active patients. Radical surgery, especially total penectomy, may be psychologically devastating to the patient. The ideal surgical procedure removes the disease with adequate margins while preserving sexual and urinary function, although this is not always possible because of the extent of disease. The high local recurrence rates described in some reports with limited surgery69,70 illustrate the need for careful patient selection in choosing a surgical approach. Lesions confined to the prepuce may be treated with wide circumcision. Microsurgical techniques have shown local excision to be an acceptable and desirable option with small superficial lesions. A local control rate of 92% was achieved in 29 patients with a 5-year survival rate of 81% for stage I and 57% for stage II lesions.71 Lesions on the glans penis have traditionally been treated by partial penectomy. Larger or more invasive lesions (stage III) can be treated by partial or total penectomy. Partial penectomy is the procedure of choice if surgical margins of 2 cm can be achieved. If an adequate margin cannot be achieved, total penectomy with perineal urethrotomy is warranted. Local (stump) recurrence is quite rare.5 It is possible for some patients to remain sexually active after partial penectomy. Jensen72 reported 45% of patients with 4 to 6 cm and 25% of patients with 2 to 4 cm of penile stump could perform sexual intercourse. D’Ancona et al.73 evaluated the quality of life in 14 patients treated with partial penectomy. Sexual function was reported to be normal or only slightly decreased in 64% of patients. Complete loss of sexual function was reported in 14% of patients.
Surgical Treatment of Inguinal Lymph Nodes
The clinical evaluation of inguinal lymph nodes in men with cancer of the penis is unreliable. Several series have shown the sensitivity of clinical staging of the nodes to be 40% to 60% and false-negative rates to be 10% to 20%.3,4McDougal et al.74 reported the correlation between clinical findings and pathologic positivity of inguinal nodes in patients with penile carcinoma. For tumors with no invasion or superficial invasion, moderately or well differentiated, only 12% of clinically enlarged inguinal nodes were pathologically positive. However, 78% to 88% of invasive or poorly differentiated tumors metastasized to inguinal nodes regardless of clinical findings. In a prospective study involving 37 patients with clinically negative groins, Solsona et al.33 have demonstrated the predictive value of histologic grade and T stage in predicting the likelihood of occult positive lymph nodes. Three groups were identified: low, intermediate, and high risk with an incidence of occult positive nodes of 0%, 33%, and 83%, respectively (Table 68.4). Given the unreliability of clinical assessment, a rationale exists to submit all patients to the staging and therapeutic benefits of radical inguinal lymph node dissection. However, this procedure is associated with considerable morbidity. Up to one-half of patients will experience complications including wound necrosis or dehiscence, infection, lymphocele, erosion of femoral vessels, chronic lymphedema, thrombophlebitis, or pulmonary embolism.50,68 The morbidity of radical lymphadenectomy and the relative small percentage of patients with pathologic involvement of inguinal nodes have resulted in surveillance as the initial management of regional lymph nodes in clinically negative patients at some centers.
Of concern, however, are reports describing poor salvage rates after regional failure. McDougal et al.74 reported a 5-year disease-free survival rate of 88% for patients with clinical stage II disease who underwent immediate lymphadenectomy compared with 38% if delayed lymphadenectomy was performed. Johnson and Lo75 reported that only one of eight patients undergoing late inguinal node dissection survived 5 years. Fraley et al.53 noted an 88% 5-year survival rate with immediate lymphadenectomy compared with 8% with a delayed procedure. Sentinel node biopsy has been advocated as a less morbid means of evaluating inguinal nodes by some,4 but its reliability has been questioned by others.2,76 Catalona4 and Colberg et al.77 described a modified inguinal lymphadenectomy for patients with penile cancer and clinically negative groins. Long-term follow-up of nine patients reveals significantly less morbidity than the classic groin dissection designed by Daseler et al.78 Extension of the nodal dissection into the pelvis to cover the iliac lymph nodes is justified in patients with evidence of inguinal involvement (positive biopsy of Cloquet’s node). Approximately 20% of patients with pelvic lymph node involvement can be salvaged by radical pelvic lymphadenectomy.5,79
As demonstrated in other anatomic sites, such as the head and neck, uterine cervix, vagina, and vulva, patients with clinically negative lymph nodes who are at risk for microscopic nodal metastases (primary tumor beyond stage I or less than well-differentiated histology) can receive elective irradiation to the inguinal lymph nodes with a high probability of tumor control and low morbidity.
TABLE 68.4 T STAGE AND GRADE PREDICT THE RISK OF OCCULT POSITIVE LYMPH NODES
Radiation Therapy
The primary advantage of radiation therapy is organ preservation. In the past, radiation therapy often utilized insufficient total dose and high-dose per fraction along with poor technique, resulting in underdosage or overdosage and a high incidence of injury to normal tissues. Although historically a wide variation of techniques, doses, and fractionation schemes have been used,17,80–84 improvement in the tumor control rate in some modern series employing adequate total doses and small daily doses is noteworthy, resulting in a decreased incidence of treatment-related sequelae. Most patients who experience local failure after radiation therapy can be salvaged surgically. Several radiation modalities are used to deliver radiation to the penis including megavoltage external-beam irradiation, iridium-192 (192Ir) mold plesiotherapy, and interstitial implant using 192Ir wires.67,84–85,86,87
Inguinal lymph node irradiation for clinically negative nodes is an integral component of successful radiotherapeutic management of this disease. Regional control has been achieved in 95% of cases. Without irradiation to the inguinal lymph nodes, as many as 20% of patients can be expected to develop positive nodes later.17,81 For palpable nodes, groin dissection may be necessary, accepting the likelihood of postoperative morbidity. Postoperative radiation therapy to the groin adds little to the morbidity but contributes significantly to locoregional tumor control. If the inguinal lymph nodes are treated, a CT scan helps define the depth and location of the inguinal lymph node, femoral artery, and veins, which is crucial, as indicated in Chapter 74 on the vulva.
Chemotherapy
The use of systemic chemotherapy either as an adjuvant or concomitantly with radiation therapy has not been fully investigated in patients with penile cancer. Chemoradiotherapy of squamous cell carcinoma of the anus (another HPV-related carcinoma) has been used with great success, resulting in high tumor control rates and organ preservation. Similar data in penile carcinoma are lacking, however. Modern multiagent chemotherapy regimens have overall response rates ranging from 15% to 55% in patients with advanced disease (Table 68.5). The agents most commonly used include platinum, methotrexate, and bleomycin. Additional clinical trials are needed to adequately define the role of chemotherapy in the management of cancer of the penis.
TABLE 68.5 MULTIAGENT CHEMOTHERAPY IN ADVANCED PENILE CARCINOMA
FIGURE 68.2. A: View from above of plastic box with central cylinder for external irradiation of the penis. Patient is treated in the prone position. The penis is placed in the central cylinder, and water is used to fill the surrounding volume in the box. Depth dose is calculated at the central point of box. B:Lateral view.
Carcinoma of the Male Urethra
The primary mode of therapy for carcinoma of the male urethra is surgical excision. Because of the rarity of this disease, comparison of the cure rates with radiation therapy or surgery is difficult. The principal advantage of irradiation is organ preservation. Noninvasive carcinoma of the proximal urethra can be treated with transurethral resection. In lesions of the distal urethra, results with either penectomy or radiation therapy are similar to those for carcinoma of the penis, and the 5-year survival rates are comparable (50% to 60%).88 Involved regional lymph nodes are treated with lymphadenectomy.
Most patients, however, present with advanced invasive lesions, which are difficult to manage with either radical surgery or radiation therapy. The major problem is the high rate of local recurrence. In an attempt to improve the locoregional control rate, extended resections encompassing the inferior pubic rami, prostate, bladder, and perineum have been performed after preoperative radiation therapy. After a dose of 20 to 60 Gy, Klein et al.60 performed an extended resection in seven patients with proximal urethral lesions. Locoregional failure was observed in two patients (29%).
Chemotherapy
Concomitant chemoradiotherapy has been investigated in only a few patients. However, these preliminary data are encouraging. Gheiler et al.47 reported their experience with multimodality treatment of 21 patients (10 women, 11 men) with urethral carcinoma. Treatment consisted of cisplatin- and 5-FU-based chemotherapy for squamous cell carcinoma and concomitant external-beam irradiations. Patients with transitional cell carcinoma were treated with concomitant methotrexate, vinblastine, Adriamycin (doxorubicin), and cisplatin. Some patients underwent surgical resection following chemoradiation. With a median follow-up of 42 months, the overall disease-free survival rate was 62%. Of significance is the pathological complete response rate of 87.5% in eight women undergoing resection following chemoradiation.
RADIATION THERAPY TECHNIQUES
Carcinoma of the Penis
If indicated, circumcision must be performed before radiation therapy is initiated. The purpose of this procedure is to minimize radiation therapy–associated morbidity: swelling, irritation of the skin, moist desquamation, and secondary infection.
Although external-beam therapy has become prevalent in the treatment of the primary lesion in carcinoma of the penis, plastic molds or interstitial implants are still used.
External-Beam Radiation Therapy
External-beam therapy requires specially designed accessories (including bolus) necessary to achieve homogeneous dose distribution to the entire penis. Frequently, a plastic box with a central circular opening that can be fitted over the penis is used. The space between the skin and the box must be filled with tissue-equivalent material (Fig. 68.2). This box can then be treated with parallel opposed megavoltage beams. An alternative to the box technique is the use of a water-filled container to envelop the penis while the patient is in a prone position.89
Another more complex device consists of a Perspex tube attached to a baseplate resting on the skin.90 This is placed as close as possible to the base of the penis, and a flexible tube is connected to a vacuum pump. The suction effect keeps the penis in a fixed position during treatment. Appropriate bolus is placed outside the tube. The patient can also be treated in the prone position, with the penis hanging through a small hole placed in the Perspex’s cylinder.
Fraction size in many of the reported series has been 2.5 to 3.5 Gy (total dose of 50 to 55 Gy), although a smaller daily fraction size (1.8 to 2.0 Gy) and a higher total dose are preferable. There is a well-established association between large fraction size and late tissue damage (Chapter 1). A total of 60 to 65 Gy, with the last 5 to 10 Gy delivered to a reduced portal, should result in a reduced incidence of late fibrosis.
Regional lymphatics may be treated with external-beam megavoltage irradiation. Both groins should be irradiated. The fields should include inguinal and pelvic (external iliac and hypogastric) lymph nodes (Fig. 68.3). The posterior pelvis may be partially spared by anterior loading of the beams. Depending on the extent of the nodal disease and the proximity of the detectable tumor to the skin surface or the presence of skin invasion, application of a bolus to the inguinal area should be considered. If clinical and radiographic evaluation show no gross enlargement of the pelvic lymph nodes, the dose to these nodes may be limited to 50 Gy. In patients with palpable lymph nodes, doses of approximately 75 to 70 Gy over 7 to 8 weeks (1.8 to 2.0 Gy per day) with reducing fields (after 50 Gy) are advised. Alternatively, grossly involved nodes can be removed surgically either before or after inguinal radiation therapy.
Brachytherapy
A mold is usually built in the form of a box or cylinder with a central opening and channels for placement of radioactive sources (needles or wires) in the periphery of the device. The cylinder and sources should be long enough to prevent underdosage at the tip of the penis. A dose of 60 to 65 Gy at the surface and approximately 50 Gy at the center of the organ is delivered over 6 to 7 days. The mold can be applied either continuously, in which case an indwelling catheter should be in place, or intermittently. Intermittent application requires precise time record keeping. Alternatively, single- or double-plane implants can be used to deliver 60 to 70 Gy in 5 to 7 days.87 Salaverria et al.55 point out that molds should be reserved for stage I and II tumors. The author believes the same is true for interstitial implants. In more extensive lesions involving the shaft of the penis, it is technically difficult to obtain an adequate margin with brachytherapy procedures, similar to the problem in performing a partial penectomy.
Carcinoma of the Male Urethra
Radiation therapy for carcinoma of the anterior (distal) urethra is quite similar to that for carcinoma of the penis; lesions of the bulbomembranous urethra can be treated with a set of parallel opposed fields covering the groins and the pelvis, followed by perineal and inguinal boost. Lesions of the prostatic urethra can be treated with techniques and doses similar to those used for carcinoma of the prostate.
FIGURE 68.3. Portals encompassing inguinal and pelvic lymph nodes.
TABLE 68.6 SURGICAL RESULTS IN PATIENTS WITH CARCINOMA OF THE PENIS
RESULTS
Carcinoma of the Penis
At many institutions patients with carcinoma of the penis are treated surgically. A summary of selected modern surgical series is presented in Table 68.6. Ornellas et al.32 reported the results of 350 patients treated with surgery alone. Five-year disease-free survival was 62% for patients treated with immediate lymphadenectomy versus 8% for those treated with delayed lymphadenectomy. For all node-negative patients, 5-year disease-free survival was 87% compared with 29% for node-positive patients. Boon et al.91 reported tumor control in 13 of 16 patients (81%) with carcinoma in situ or T1 and T2 tumors treated with wide local excision and lasers.
Radiation therapy has yielded comparable results at several institutions. Engelstad,81 Cade,93 Paterson et al.,93 Lederman,94 and Thurgar95 reported 5-year survival rates ranging from 45% to 68% in groups of patients ranging from 41 to 57 years treated with various irradiation techniques (mold, interstitial, external beam). The ability of irradiation to control the tumor is closely associated with the stage of the disease.
The 20-year experience of the Institut Gustave-Rousy was reported by Soria et al.24 One hundred and two patients with tumors <4 cm in diameter with <1 cm corpora cavernosa invasion were treated with a conservative approach consisting of limited surgery (biopsy, local excision, or therapeutic circumcision) and interstitial brachytherapy (65 to 70 Gy delivered over 5 to 7 days). Regional lymph nodes were not treated electively but were dissected in patients with clinically enlarged nodes. With a median follow-up of 111 months, local tumor recurrence rate was 25%. A regional nodal recurrence developed in 21% of patients. Disease-free survival at 5 and 10 years was 56% and 42%, respectively. Overall survival at 5 and 10 years was 63% and 50%, respectively.
Grabstald and Kelley31 reported 90% local tumor control in 10 patients with stage I lesions treated with external-beam irradiation for 51 to 52 Gy over 6 weeks. Another series from the MD Anderson Cancer Center demonstrated 80% local control and retention of the phallus in early-stage disease.25 Duncan and Jackson96 also reported 90% local control for stage I lesions treated with a megavoltage treatment unit delivering 50 to 57 Gy over 3 weeks.
Irradiation of the involved regional lymph nodes in patients with carcinoma of the penis results in permanent control and cure in a substantial proportion of patients. In the classic series of Staubitz et al.,18 13 patients with proven involvement of regional lymph nodes received radiation therapy to these nodes. Five of 13 (38%) survived 5 years. Narayana et al.26 reported 2 of 16 patients (12%) with histologically proven lymph node metastases cured with radiation therapy. No data on radiation therapy are given for either series, precluding an assessment of the doses and fields.
TABLE 68.7 RESULTS OF EXTERNAL-BEAM IRRADIATION FOR CARCINOMA OF THE PENIS
TABLE 68.8 RESULTS OF BRACHYTHERAPY WITH OR WITHOUT EXTERNAL-BEAM IRRADIATION FOR CARCINOMA OF THE PENIS
Jackson97 reported a 66% 5-year survival rate and 86% tumor control rate in 58 patients with stage I carcinoma of the penis treated with irradiation compared with a 70% 5-year survival rate and 81% tumor control rate in 27 surgically treated patients. In stage II, he observed 6 of 11 patients surviving 5 years and 7 exhibiting tumor control in contrast to 6 surviving and 8 showing tumor control in 12 surgically treated patients. In stage III, four of seven irradiated patients survived 5 years with tumor control in contrast to two surviving and three with tumor control in seven treated with surgery only. Radium or cobalt molds produced the best sterilization of primary tumor; if irradiation had not controlled the primary lesion after 6 months, amputation of the penis was carried out, with a significant proportion of the patients salvaged. Two patients required amputation because of necrosis of the penis, and four developed severe phimosis, which was treated with meatotomy. Three of 37 patients (8%) initially treated surgically and 14 of 69 (20%) initially treated with irradiation developed inguinal lymph node metastases. Overall, 8% of patients treated surgically and 10% of those irradiated died of inguinal lymph node metastases and subsequent tumor spread.
Almgard and Edsmyr80 reported tumor control in 12 of 17 patients treated with irradiation alone (superficial x-rays). Four patients underwent local radical excision for recurrence and survived from 10 to 30 years. In 17 additional patients, local irradiation was followed by amputation of the penis, and 16 had been free of recurrence for 5 to 32 years. Marcial et al.56 noted 5-year survival in 4 of 6 patients who received irradiation alone, in 6 of 11 who were given irradiation for frank persistence after limited surgery to the penis, and in 6 of 8 to whom irradiation was administered postoperatively. Sixteen of 25 patients (64%) survived 5 years.
In a series of 145 patients reported by Knudsen and Brennhovd,98 99 (68%) had recurrence, as did 5 of 14 patients (36%) treated by Johnson et al.99 and 24 of 63 patients (38%) reported by Murrell and Williams.82 Haile and Delclos85 reported tumor control and conservation of the penis in 16 of 20 patients (80%) treated with conservative radiation therapy methods. Whereas irradiation alone or combined with a lymph node dissection controlled lymph node metastases smaller than 2 cm in four patients, radiation therapy was successful in controlling lymph node metastases in only one of seven patients with N2 or N3 lymph nodes.
Sagerman et al.89 reported tumor control in six of nine patients with stage I, two of three with stage II, and one of three with stage IV disease treated with irradiation alone. Two patients with stage I disease and one with stage II disease were surgically salvaged. Doses ranged from 45 Gy (15 fractions in 3 weeks) to 64 Gy (32 fractions in 6.5 weeks) with either orthovoltage x-rays or cobalt-60 and appropriate bolus. Good palliation was described in four of nine patients treated for inguinal lymph node metastases to doses ranging from 20 (5 fractions in 1 week) to 64 Gy. None of these patients survived more than 18 months.
Mazeron et al.86 described tumor control in 8 of 9 patients with stage T1, 21 of 27 with T2, and 10 of 14 with T3 tumors treated with 192Ir, using the Paris dosimetry system, to deliver doses of 60 to 70 Gy to the 85% minimal tumor isodose. The tumor-free 5-year actuarial survival rate was 63%. The penis was preserved in 75% of patients with a follow-up of 8 years. Thirty-seven patients received no prophylactic treatment to the inguinal nodes, and only two (one with a T2 and another with a T3 lesion) later developed inguinal lymph node metastases treated by inguinal node dissection and postoperative irradiation. One patient was alive with no evidence of disease at 10 years. Five patients with metastases to the lymph nodes at the time of diagnosis were treated with therapeutic nodal dissection and postoperative irradiation. Four patients had uncontrolled lymph node metastases, and all five died with distant disease.
Duncan and Jackson96 discussed the superiority of external-beam irradiation compared with mold therapy, with 3-year tumor control rates of 90% and 47%, respectively. Salaverria et al.55 reported a 92% 5-year survival rate in 13 stage I and II patients treated with radium-226 or 192Ir molds. This compared with 10 of 13 (77%) patients who survived after partial penectomy. In stage II, four of six patients survived 5 years after 192Ir mold treatment. Ten patients with stage III disease were treated with radical amputation, and eight survived 5 years. Kearsley et al.59 described a patient with locally advanced penile carcinoma and metastatic inguinal lymph nodes who was cured with irradiation alone, a remarkable achievement because most patients with stage IV die with locoregional and disseminated disease.
Tables 68.7 and 68.8 summarize tumor control rates achieved with external-beam irradiation alone or brachytherapy plus external-beam irradiation. Worth mentioning are the results of a multicenter report from France.23 With interstitial brachytherapy, no relationship was found between increasing dose and increasing local control, with doses ranging from 60 to 65 Gy. Two variables have a significant impact on tumor recurrence: the maximum diameter of the tumor and deep infiltration of the disease.
TABLE 68.9 LOCAL TUMOR CONTROL OF MALE URETHRAL CARCINOMA WITH RADIATION THERAPY OR EN BLOC RESECTION
FIGURE 68.4. A: Squamous cell carcinoma of the balanopreputial region with extension into the glands (stage I). Patient was treated with 120 kVp x-rays, 0.3 mm Cu half-value layer, receiving 60-Gy skin dose in 5 weeks. B: Same patient 4 years later with no evidence of disease. Telangiectasis in present.
Carcinoma of the Male Urethra
Historically, men with urethral carcinoma have been treated surgically. Dalbagni et al.19 have reported the outcome of 46 patients with carcinoma of the anterior and bulbar urethra treated at the Memorial Sloan-Kettering Cancer Center. The majority of patients were treated with definitive surgery. With a median follow-up of 125 months, the local control rate was 51%. The 5-year overall survival was 42%. Improved survival was seen in patients with anterior lesions (69%) compared with those with posterior lesions (26%).
Bracken et al.100 described results in 11 patients with tumors at or anterior to the penoscrotal junction, 8 of which were epidermoid carcinoma, 2 transitional cell carcinoma, and 1 melanoma. Three of four patients treated with total penectomy and perineal urethrostomy had tumor control. Partial penectomy controlled the local tumor in two patients. The patient with melanoma had a local recurrence after operation. Two patients were treated with radiation therapy and a third with a combination of preoperative irradiation (45 Gy) and total penectomy. In all of these patients, tumor recurred locally. In four patients with inguinal lymph node metastases, the regional disease was controlled by bilateral lymphadenectomy. All six patients in whom local and regional tumor was controlled remain alive and disease free at 1 to 20 years. In 16 patients, the urethral tumors arose posterior to the penoscrotal junction: 13 lesions were squamous cell carcinoma, 2 transitional cell, and 1 adenocarcinoma. Penectomy was performed in five patients, all of whom had tumor control and no evidence of recurrence 5 to 29 months after therapy. Two patients treated with local excision died of disease 14 and 18 months after surgery. Irradiation was used in three patients unsuccessfully, and all died of cancer 13 to 31 months after therapy.
Kaplan et al.20 reported on 29 patients treated at Northwestern University and reviewed the literature. In their analysis, lesions of the distal urethra carried the best prognosis and those in the bulbomembranous urethra the worst. Five-year survival rates were 22% (16 of 71 patients) with tumors in the distal urethra, 10% (10 of 99 patients) with bulbomembranous urethra lesions, and 25% (4 of 16 patients) with prostatic urethra tumors. Radiation therapy was infrequently used for these patients. Table 68.9 demonstrates equivalent local tumor control with either definitive radiation therapy or en bloc resection.
The combination of radiation therapy and chemotherapy using 5-FU and mitomycin-C has been reported for urethral carcinoma for organ preservation in locally advanced tumors. Reports by Baskin and Turzan,101 Johnson et al.,102 Licht et al.,103 and Shah et al.104 support the efficacy of this combination for squamous cell carcinoma of the male and female urethra. Cleveland Clinic103 reported results of patients with locally advanced squamous cell carcinoma of the urethra treated with concomitant chemoirradiation including 5-FU (1 g/m2 intravenous infusion on days 1 to 4 and days 29 to 32) and mitomycin-C (50 mg/m2 bolus intravenous injection on day 1). External-beam irradiation (30 Gy in 15 fractions) to the pelvis and inguinal lymph nodes began on day 1. An additional 20-Gy tumor boost was given. Complete response was obtained in three patients, who remained disease free after 43 months of follow-up. A patient with a T2N2M0 lesion treated with 30 Gy died of myocardial infarction several months after radiation therapy. Chemotherapy was well tolerated and required no dose reduction or delay in treatment. One grade 3 acute toxicity (skin reaction) occurred that did not compromise the therapeutic plan. One patient developed urethral stricture that was managed successfully with urethral dilatation.
As previously described in this chapter, the largest chemoradiation experience for urethral carcinoma is the Wayne State experience.47 Concomitant 5-FU and cisplatin were used for squamous cell carcinoma, while concomitant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were used for transitional cell carcinoma. A pathological complete response was reported in 87.5% of women undergoing resection following chemoradiation. With a median follow-up of 42 months, the overall disease-free survival rate was 62%.
SEQUELAE OF TREATMENT
Irradiation of the penis produces a brisk erythema, dry or moist desquamation, and swelling of the subcutaneous tissue of the shaft in virtually all patients. Although quite uncomfortable, these are reversible reactions that subside with conservative treatment within a few weeks. Telangiectasia is a common late consequence of radiation therapy and is usually asymptomatic (Fig. 68.4).
In the reported radiotherapy series, meatal-urethral strictures occur with a frequency of 0% to 40%.62,83,85,104,105 This incidence compares favorably with the incidence of urethral stricture following penectomy.22 Most strictures following radiation therapy are at the meatus.
Ulceration, necrosis of the glans, and necrosis of the skin of the shaft are rare complications in a modern series.104 Lymphedema of the legs has been reported following inguinal and pelvic radiation therapy, but the role of irradiation in the development of this complication remains controversial. Many patients with this symptom have active disease in the lymphatics that may be responsible for lymphatic blockage.
Of all male genitourinary cancers, penile cancer poses the greatest threat to sexual function and carries the most devastating psychological impact of penectomy. Despite recent advances in treatment, sexual function is not likely to be adequately preserved in some patients. These patients and their partners need information about the physical impairments after surgical intervention and should be taught adjustment skills prior to undertaking treatment. Referral to a trained sexual consultant or therapist for help is indicated.
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