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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 109Neoplasms of the Penis

, MD, , MD, and , MD.

The penis has superficial epithelium similar to that found in the vulva, with a commonality in the histologic type and clinical behavior of tumors in these organs. Both organs present significant primary site and regional nodal problems. The predominant tumor is epidermoid carcinoma, which usually originates in the glans and prepuce and rarely in the urethra (Table 109.1). Transitional cell carcinoma and adenocarcinoma may originate in the urethra or periurethral glands.1

Table 109.1. Penile Malignant Tumors.

Table 109.1

Penile Malignant Tumors.

During the second half of the 20th century, a transformation occurred in the magnitude of this cancer problem, with a reduced incidence and a shift toward earlier recognition of disease stages. Improvements in the socioeconomic level and education have favored these changes. Consequently, the traditional therapeutic approach (based on amputation) has given way to a greater interest in organ preservation, using limited surgery plus radiotherapy, laser surgery, or radiotherapy alone.

The main concern in the management of a primary tumor is adequate local control of the lesion, with maximum organ preservation. A more serious problem, however, is associated with lymph node metastasis to the groin, which occurs in a substantial percentage of cases.

Epidermoid carcinoma constitutes over 97% of all penile lesions. Rosai1 separated the verrucous type of carcinoma from other epidermoid carcinomas and stated that this special type constitutes approximately 5% of all epithelial lesions. Basically, all are squamous cell carcinomas. The major difference may lie in the aggressiveness of the primary lesion and frequency of metastasis. Melanomas of the penis are rare. In a collection of 1,101 cases of invasive cancers of the penis from the SEER (surveillance, epidemiology, and end results) program,2 only 19 were described. Kaposi’s sarcoma of the penis is becoming a more common entity, particularly in patients with acquired immunodeficiency syndrome (AIDS). Less than 3% of Kaposi’s sarcomas in AIDS cases originate in the penis, but among all patients with Kaposi’s sarcoma, almost 20% eventually have a genital manifestation.3

A number of epithelial lesions develop on the penis that are considered to be premalignant and eventually may evolve into invasive carcinoma (Table 109.2). The Buschke-Löwenstein tumor is a verrucous epithelial growth that, when left untreated, may evolve into an invasive lesion. This condyloma acuminata-like lesion, first described in 1925, is considered by some to be a verrucous carcinoma.

Table 109.2. Premalignant Penile Lesions.

Table 109.2

Premalignant Penile Lesions.

Erythroplasia of Queyrat and Bowen’s disease are closely related types of intraepithelial epidermoid carcinoma, and if left untreated, they also may evolve into frank, invasive squamous cell carcinoma.

Paget’s disease of the penis, as in the vulva, may arise from accessory skin glands in the area and eventuate into adenocarcinoma. It may have an underlying adenocarcinoma or develop into it. Leukoplakia, which is a white plaque on the mucosal surface, denotes an abnormality of the epithelium. Its progression to frank invasive squamous cell carcinoma may not be as frequent, however, unless it is accompanied by erythroplasia or balanitis xerotica obliterans.4 A lesion similar to lichen sclerosis et atrophicus of the vulva, balanitis xerotica obliterans may evolve into an invasive squamous cell carcinoma. Although many of these premalignant lesions are clinically recognizable, a persistent lesion requires histologic diagnosis from biopsy, cytologic diagnosis from scrapings, and close follow-up because these are necessary for appropriate management decisions.

Epidemiology

The incidence of penile tumors is higher in communities with recognizable conditions for a high occurrence of uterine cervix epidermoid carcinomas. This is particularly true in populations at a low socioeconomic level. In some communities in Asia, Africa, and Latin America, penile carcinoma has been reported to constitute approximately 12% of all cancers in males.5 In the United States, carcinoma of the penis accounts for only 1% of male genital cancer.2

The registered incidence of penile cancer in Puerto Rico between 1960 and 1987 is shown in Table 109.3. A previous study6 reported that the incidence was maximum in the 80- to 84-year-old group, with 66.3 cases per 100,000 men each year.

Table 109.3. Incidence of Penile Cancer in Puerto Rico*.

Table 109.3

Incidence of Penile Cancer in Puerto Rico*.

A gradual reduction in incidence, both in crude and age-adjusted rates, has occurred, which may have been a consequence of improved socioeconomic conditions. When one compares the incidence of penile carcinoma in Puerto Rico with the rest of the United States, on the basis of data from the SEER program of the National Cancer Institute (NCI) for the period 1975 to 1977, the incidence was five times higher and mortality approximately eight times higher in Puerto Rico (Table 109.4). In 1990, mortality from cancer of the penis in Puerto Rico was less than 4 cases per 1 million men.7 In Western European countries, the reported yearly frequency is 4 to 9 cases per million.8

Table 109.4. Penile Cancer in the United States and Puerto Rico, 1973 to 1977*.

Table 109.4

Penile Cancer in the United States and Puerto Rico, 1973 to 1977*.

A shift toward early stages has been noted in the United States. During the period 1973 to 1987, regional stage fell from 18% to 10% of cases.2

Etiology

Carcinoma of the penis seldom occurs in circumcised males. It is extremely rare in Israel, where neonatal circumcision is practiced; only 10 cases of carcinoma of the penis were reported in a 20-year period.9 It has been postulated that early circumcision helps prevent carcinoma of the penis, but when practiced later in life, circumcision does not confer protection. In a review of 500 patients with carcinoma of the penis (Table 109.5), Puras and colleagues10 found only 5 who had been circumcised early in life. An unretractable prepuce impairs adequate penile hygiene; as a consequence, smegma accumulates in the preputial sac. The maximum accumulation of smegma in the preputial sac occurs in phimosis; in our past experience, 92% of patients with penile carcinoma showed phimosis.6

Table 109.5. Circumcision and Penile Carcinoma.

Table 109.5

Circumcision and Penile Carcinoma.

Smegma itself no longer is considered to be carcinogenic, but it does serve as a marker of failed penile hygiene. It is generally accepted that adequate hygiene, with prepuce retraction and cleansing from an early age, is equivalent to circumcision for the prevention of penile cancer.

It has been reported that women whose spouses suffer from carcinoma of the penis have up to an eight-fold higher incidence of cervical carcinoma compared with women married to healthy men;11 however, this finding has been challenged by other reports.12,13 The possible association of these two types of cancer has raised the strong suggestion of a sexually transmitted agent. Human papilloma virus (HPV) types 16 and 18 have been associated with carcinoma of the penis14 and the cervix.

Men with psoriasis treated with oral methoxsalen and ultraviolet A photochemotherapy develop a higher incidence of penile carcinoma than the normal population.15

Anatomic Pathogenesis

The epithelium of the glans penis may undergo macroscopic changes similar to those observed in the vulva, lower lip, and buccal mucosa, which are characterized by color change, thickening of the mucosa, keratotic accumulation, and superficial ulcerations. Biopsy may reveal intraepithelial carcinoma or invasive epidermoid carcinoma, but other histologies, such as adenocarcinoma, melanoma, Kaposi’s sarcoma, or benign processes also may be found.

Intraepithelial Epidermoid Carcinoma

Epidermoid carcinoma can manifest as an in situ form or a more aggressive, invasive tumor. Bowen’s disease and erythroplasia of Queyrat are forms of epidermoid carcinoma in situ that are characterized by full-thickness cellular alteration of the epithelium, large hyperchromatic nuclei, multi-nucleated cells, dyskeratosis, vacuolization, and numerous typical and atypical mitoses. Bowen’s disease appears as a sharply demarcated, scaly, erythematous plaque in the penile skin, whereas erythroplasia of Queyrat appears as a shiny, velvety, erythematous plaque, typically arising on the glans and foreskin of uncircumcised men. Both these conditions should be regarded as one, with the same prognostic and therapeutic implications.4

Erythroplasia of Queyrat has been associated with a 10 to 20% incidence of invasive squamous cell carcinoma.1 Bowenoid in situ lesions may be precusor lesions for penile cancer.4 Histologically, Bowenoid papulosis may look like an intraepithelial neoplasm, although it has a completely benign course.16

Invasive Epidermoid Carcinoma

Invasive epidermoid carcinoma of the penis may manifest as an exophytic tumor with papillary appearance, good histologic differentiation, heavy keratinization, and low incidence of inguinal node metastasis. It also may manifest as an ulcerating, endophytic neoplasm that tends to be poorly differentiated and to metastasize. Lesions in the glans tend to be exophytic and those of the prepuce more of the infiltrating type (Fig. 109.1). The degree of histologic differentiation of the primary tumor profoundly influences the course of the disease. Among 23 patients with well-differentiated tumors, only 1 developed metastasis, while among 35 patients with moderate to poorly differentiated disease, 31 developed metastases to the groin.17

Figure 109.1. Infiltrating squamous cell carcinoma of the penis in a patient with phimosis.

Figure 109.1

Infiltrating squamous cell carcinoma of the penis in a patient with phimosis. (Courtesy of A. Puras.)

Verrucous Carcinoma

Verrucous carcinoma, a form of exophytic carcinoma, has its own particular characteristics, and it accounts for approximately 5% of all penile cancers. It is an extremely welldifferentiated, papillary squamous cell carcinoma, with the same characteristics as its corresponding lesion in the oral cavity. It produces no nodal metastasis. The giant condyloma acuminata of BuschkeLöwenstein is considered to be identical to verrucous carcinoma, and it is highly associated with the HPV etiology.1,18

Other Histologies

Adenocarcinomas of the periurethral glands or the bulbourethral (i.e., Cowper’s) glands have been reported. Transitional cell carcinomas may arise in the penile urethra as they can in the prostatic urethra.

Malignant melanomas may arise in the glans or prepuce and usually have a high incidence of metastases, both to the inguinal lymph nodes and distantly. When malignant melanomas arise in the urethra, the prognosis is extremely poor.1

Kaposi’s sarcoma may be of the classic type (Fig. 109.2), or the AIDS-related variety. The former can be cured with local therapy, but the latter presently is considered to be incurable.

Figure 109.2. Nonepidemic Kaposi’s sarcoma.

Figure 109.2

Nonepidemic Kaposi’s sarcoma. A. Before treatment. B. After radiotherapy. The patient remained well until death from cardiovascular disease 12 years after therapy. (Courtesy of V. Marcial.)

Molecular Pathogenesis

Using the highly sensitive polymerase chain reaction (PCR) test, which enables the identification of minimal amounts of nuclear DNA from both known and unknown DNA sequences, DNA of HPV 16 was found in 40% of cases.8 Evidence of HPV 18 also has been found in carcinoma of the penis.14

Natural History and Diagnosis

Any persistent ulcer or growth over the glans, sulcus, or preputial sac should be subjected to biopsy. Swelling of the distal penis in the presence of phimosis should be viewed with suspicion. A dorsal slit of the prepuce (or circumcision) will permit adequate examination of the preputial sac and glans, as well as biopsy, when appropriate. The histologic diagnosis of intraepithelial carcinoma, a verrucous hyperkeratotic process, or an inflammatory condition does not exclude the possibility of underlying invasive carcinoma.

Intraepithelial carcinomas will evolve into invasive carcinomas in a significant percentage of cases. Invasive carcinoma may remain superficial for a time or invade deeply. When left untreated, invasive carcinoma may destroy the glans, shaft, and invade the scrotum. Lymph node metastases are first observed in the inguinal area, but “skip” metastasis to the pelvic nodes also may occur. Distant metastases occur in invasive carcinoma of the penis but seldom are seen during the early stages of the disease.

The processes of diagnosis and therapy for carcinoma of the penis are shown in Figure 109.3.

Figure 109.3. Decision tree in carcinoma of the penis.

Figure 109.3

Decision tree in carcinoma of the penis.

Staging

When invasive carcinoma is diagnosed, the patient must be adequately staged with complete physical examination to exclude metastasis to the inguinal lymph nodes and other pertinent tests to rule out tumor elsewhere in the body. Recommended imaging procedures include chest radiography, computed tomography (CT) of the pelvis, and, sometimes, lymphography. Ultrasonography may help determine the thickness and extent of the primary tumor and the presence or absence of gross inguinal node metastases.19 The more recent technology, magnetic resonance imaging (MRI), may permit determination of the true depth of penile invasion by the tumor. In addition, MRI can be helpful in detecting ilioinguinal metastasis and tumor vascular infiltration.

The accepted staging classification for carcinoma of the penis is shown in Table 109.6 for the primary tumor, lymph nodes, distant metastasis, and stage grouping. Ultimate evaluation of true invasion by the primary tumor or the regional lymph node status requires surgical intervention and histopathologic evidence. When the penis is conserved and the groins not surgically explored, staging will be entirely clinical.

Table 109.6. Staging Classification for Penile Carcinoma.

Table 109.6

Staging Classification for Penile Carcinoma.

Therapy

Some type of surgery for the primary tumor and lymph node metastasis is the most commonly employed therapy for carcinoma of the penis. In a select number of patients, however, amputation may represent overtreatment.

Approximately 20% of patients are under 40 years of age. Therefore, radical procedures, such as penectomy, may cause considerable mental distress, even to the point of suicide.6

Surgical excision is an adequate and expeditious treatment for small patches of carcinoma in situ; however, laser surgery, electrodissection and curettage, topical 5-fluorouracil, and superficial radiation therapy give good results in superficial, noninvasive neoplasms.4,16,20Figure 109.4 shows a carcinoma in situ managed with superficial radiation therapy using Grenz rays.

Figure 109.4. Bowen’s disease of the penis.

Figure 109.4

Bowen’s disease of the penis. A. Before treatment. B. After Grenz ray radiotherapy. (Courtesy of G. Panizzon.)

Invasive carcinomas can be managed by organ conservation, either using radiotherapy alone after biopsy (Fig. 109.5) or postoperative radiotherapy following surgery restricted to removal of the gross lesion. Patients with deeply invading tumors, tumors that destroy the glans and invade the shaft, or tumors that cause considerable scar tissue in the glans are not considered good candidates for organ preservation with irradiation. Newer combinations of radiation with concurrent chemotherapy, such as those presently used in cancer of the anus, may, however, be considered in select advanced lesions.

Figure 109.5. Invasive squamous cell carcinoma of the penis.

Figure 109.5

Invasive squamous cell carcinoma of the penis. A. Before therapy. B. After radiotherapy. (Courtesy of J. Vaeth.)

Surgery

The primary therapeutic role in the management of penile carcinoma should be complete tumor removal with adequate surgical margins, regional lymphatic control, and a functional penis.

Primary Lesion

Superficial, noninvasive lesions of the foreskin can be treated with a wide circumcision. Excisional biopsy of this lesion is associated with a high recurrence rate.10,21,22 Superficial lesions may be managed and excised using a CO2 laser or by micrographic surgery.20,23

Invasive tumors involving the glans or distal shaft of the penis are adequately managed by partial penectomy, excising 1.5 to 2.0 cm of normal tissue proximal to the margin of tumor infiltration (Fig. 109.6). This should leave a functional penis that can allow directable micturition and often enough rigidity and length for penetration during intercourse. The recurrence rate in patients with tumor-free surgical margins should be less than 10%.10,24 Recent analysis demonstrates that margins of 10 mm are adequate for tumor control following excision.25

Figure 109.6. Partial penectomy for invasive squamous cell carcinoma of the penis.

Figure 109.6

Partial penectomy for invasive squamous cell carcinoma of the penis. (Courtesy of A. Puras.)

Patients with large, extensive, and infiltrating tumors involving the glans and midshaft of the penis should be managed with a radical penile amputation and perineal urethrostomy. For lesions involving the scrotum, perineum, and anterior abdominal wall, complete removal of the neoplasm, with total emasculation, is necessary. In some instances, cystoprostatectomy with urinary diversion will be needed.

All penile lesions should be cultured, and prompt antibiotic therapy established before any surgical procedure. Following surgery, we continue antibiotic therapy for a period of 4 weeks.

Regional Lymph Nodes

The lymphatics of the penis leave the ventral surface from the median raphe and course laterally to the dorsum; here, they may be joined by lymphatics channeled from the prepuce. At the base of the penis, lymphatic trunks from the skin divide and decussate toward the right or left. These trunks drain into the superficial inguinal nodes.26 Together with the saphenous vein and its tributaries, these nodes are situated beneath the integument and surrounded by two layers of superficial fascia of the thigh. The superficial inguinal nodes vary in number from 4 to 25, with an average of 8.25 lymph nodes per extremity.27

The first metastatic site of penile cancer is to the superficial inguinal lymph nodes. Clinical staging of the lymph nodes on the basis of palpation is inaccurate. Puras and colleagues10 compared their experience between clinical findings and histologic examination of the inguinal nodes in 165 patients who underwent inguinal femoral lymphadenectomy. They found that 33% of patients were understaged and 48% overstaged. A composite review of the literature28–30 revealed microscopic lymph node metastasis in 26% of patients with clinically negative groins and no evidence of metastatic disease in 48% with palpable groin lymph nodes.

The possibility of groin metastasis relates to the histopathologic aggressiveness of the tumor, its size, and its thickness.6 Luciani and colleagues31 suggested use of lymphangiography with percutaneous regional lymph node aspiration cytology to improve accuracy while avoiding unnecessary surgery. The main disadvantages of this approach are that negative aspiration does not rule out metastatic disease and careful follow-up with repeat biopsies is necessary. This can increase the possibility of tumor seeding along the needle tract, with contamination of the skin.32

In 1977, Cabañas33 reported a specific lymph node center called the sentinel lymph node. He postulated that this node represents the first site of metastasis from penile carcinoma. This node is adjacent to the superficial epigastric vein in the superomedial region of the groin, and in all 15 patients who had lymph node metastasis in his study, the sentinel lymph node was found to contain tumor. In addition, in 12 patients, the sentinel lymph node was the only one involved. Therefore, Cabañas suggested performing bilateral sentinel lymph node biopsies in patients with squamous cell carcinoma of the penis. If the nodes are free of tumor, no further surgical therapy is indicated; however, the reliability of this approach has not been totally established. Sentinel lymph nodes were free of tumor in 31 patients, but the 5-year survival rate was only 90%. Also, it was not specified if these patients died of or with penile cancer, and there have been reports of patients in whom lymph node metastasis developed after negative bilateral sentinel lymph node biopsies.34,35

Clinical studies of patients with carcinoma of the penis have demonstrated that 40 to 60% with biopsy-proven regional lymph node metastasis can be cured with radical groin lymphadenectomy,10,22,36 whereas if left untreated, most patients die within 3 years.22,37,38 A major controversy is whether to perform regional lymphadenectomy in patients with clinically negative nodes or to delay lymphadenectomy until the nodes become palpable (i.e., “watch and wait”). Baker and colleagues39 reviewed 122 cases and found no difference in survival between patients who had superficial only or superficial and deep lymph node dissection prophylactically versus those in whom dissection was not performed until the nodes were clinically positive. They concluded that prophylactic lymph node dissection cannot be justified because of its high morbidity and 5-year survival statistics. Several retrospective series,30,40,41 however, have provided data suggesting that early prophylactic lymphadenectomy may offer advantages over the “wait and watch” approach. A randomized study comparing both alternatives should give the most reliable answer.

Some authors believe that metastatic penile cancer can bypass the inguinal nodes and drain directly to the iliac nodes.42,43 Recent clinical studies have demonstrated that lymphatic channels usually do not lead directly from the penis to the pelvic nodes, and that patients do not have iliac metastasis without inguinal lymph node involvement. In our own series,37 we were not able to find a patient with iliac metastasis and negative groins; similar findings have been reported by other authors.32,41,44 We do not recommend iliac node dissection in the presence of histologically confirmed negative groins.

We have had two patients with negative “sentinel node” biopsies who later developed metastatic inguinal lymph node involvement without recurrence in the penis. This experience also has been reported by other authors.35,36,41,44 The present policy at the University of Puerto Rico Urology Service is to submit all patients with penile carcinoma to a modified superficial inguinal lymphadenectomy. Usually, this is performed 4 weeks after treatment of the primary lesion. The purpose of this policy is to accumulate experience for future evaluation of results. Some institutions withhold inguinal node dissection until the nodes are clinically positive;30 however, to wait for the lymph node metastasis to become clinically evident may reduce survival.

The experiences reported in the medical literature are not entirely convincing in their support of early elective node dissection. In favor of observing clinically negative inguinal nodes is the fact that inguinal node dissection may be associated with high morbidity (e.g., flap necrosis, wound infection, seromas, lymphocele, persistent leg edema, chronic lymphangitis), and that only 18% of sampled nodes will be histologically positive.30

A modified lymph node dissection (as practiced at the University of Puerto Rico) is associated with less morbidity than is a total lymphadenectomy.48 If a frozen section of suspicious nodes shows tumor, however, we proceed with a complete inguinal lymphadenectomy.

Pelvic lymphadenectomy is performed as a second-stage procedure, usually 4 weeks later, for staging purposes. Metastatic pelvic nodes have not been observed in the absence of metastasis to the superficial inguinal nodes. No patient with proven pelvic node metastasis has survived 5 years. If the pelvic nodes are positive, additional nonsurgical treatment is indicated.

The chances of recurrence in the surgical area after lymphadenectomy have been reported to be 14% (3 of 22 patients) at the M.D. Anderson Cancer Center,41 but if more than two nodes are found histologically to be involved, the chances of recurrence, which can be very troublesome, are much higher. Nodal metastasis reduces patient survival significantly.49

Radiotherapy

If preservation of sexual function is a concern, radiotherapy should be considered the treatment of choice in early cancer of the penis. It can be used as the main therapy modality, thus reserving surgery for the salvage of failures, or combined with a surgical procedure that is restricted to resection of the gross portion of the tumor. The value of radiotherapy for eliminating subclinical tumor is well recognized in cancer of the head and neck, rectum, anus, female pelvis, breast, and soft tissue. The same principles apply to carcinomas of the penis. As in the previously stated tumor sites, however, when the neoplasm is very advanced or it has caused considerable destruction of normal tissue, organ preservation may not be advisable because functional results are not satisfactory and tumor control with radiotherapy may be compromised. Concurrent chemotherapy may enhance the effectiveness of radiotherapy in achieving tumor control, and partial or total penectomy is not hindered by prior radiotherapy to the penis, which usually is restricted to the glans and prepuce. Therefore, whenever possible, organ preservation should be attempted, particularly in a sexually active person.

The choice of radiotherapy technique depends greatly on the radiotherapist’s preference; this usually is conditioned by past experiences, expertise, and available radiation sources. Principles of managing penile tumors are similar to those prevailing in radiotherapy of similar lesions in the skin or lower lip. Very superficial in situ carcinomas are treatable with low-energy Grenz rays (see Fig. 109.4). Invasive superficial lesions (0.3-mm thick) can be managed by low-energy x-rays (50–100 kV), intermediate-energy electrons (3–6 MeV), or mold brachytherapy. Interstitial brachytherapy with iridium-192 or cesium-137 is useful for boosting the dose in hard, thick (0.5-mm) lesions that persist after a base external dose of 3,000 to 5,000 cGy. Field reduction should be done during the external irradiation to restrict the high-dose volume to the minimum.

Small-diameter (1–2 cm), superficial tumors can be treated with 50 to 100 kV x-rays using short (15–20 cm) focal skin distance, a single direct field, fraction doses of 250 to 300 cGy, and total doses that may range from 4,500 to 5,000 cGys in 3 to 4 weeks, calculated at 3- to 5-mm deep to the mucosa. Electron-beam therapy with 3- to 6-MeV energy and a compensator, when needed, may substitute for superficial photon therapy. Mold brachytherapy also can be substituted for superficial x-rays in superficial tumors involving most of the glans.

These tumors also can be treated with orthovoltage x-rays. If tumors are bulky, exophytic, or deeply penetrating, they can be managed well with cobalt teletherapy, or 4- to 6-MeV x-rays, with the penis enclosed in a wax compensator and using opposing fields to cover all of the glans and sulcus with a 2-cm margin of normal tissue proximal to the tumor. Large-field radiotherapy will require higher doses than those stated for small superficial tumors; consequently, more dose fractionation will be required. The usual doses for teletherapy of bulky lesions range from 6,000 to 6,600 cGy in 6.0 to 6.5 weeks, with fractions of 180 to 200 cGy each. The most often used radiotherapy prescription at the Princess Margaret Hospital in Toronto is 50 Gy in 20 fractions over 4 weeks.50 Brachytherapy doses will range from 5,000 to 7,000 cGy, with dose rates of 40 to 60 cGy per hour.

The stated radiotherapy described above will cause an acute, wet epithelitis of the irradiated tissues, with resulting local tenderness and burning on urination if the urethra receives a substantial dose of radiation. These acute reactions should disappear shortly after the irradiation is ended. Late effects of irradiation may include hyperpigmentation, telangectasia, and atrophy of the submucosal tissues. Fibrosis may occur when the dose is too high or the tumor has caused a substantial destruction of normal tissue before treatment. Both the frequency and degree of these late effects will depend on the type of radiation, fraction dose, total dose, extent of tumor invasion, pre-existent normal tissue changes, and individual susceptibility. A treated penis may look normal years after radiotherapy (see Figs. 109.2, 109.4B, and 109.5B). As the high-dose volume is limited to the glans, the patient’s capacity to attain erection should not be affected by curative radiotherapy.

Table 109.7 shows results of irradiation in various reported series. Local control is approximately 80% or higher for the early stages but is lower in more advanced (T3) lesions. Radiotherapy can spare amputation in at least 50% of patients. For stage I patients, it has been reported that response rates and actuarial disease-free survival are comparable for both the iridium brachytherapy and external-beam groups.54 Patients with carcinoma in situ of the penis can achieve close to 100% control with radiotherapy. In a series of 11 patients treated with radiotherapy at the Princess Margaret Hospital in Toronto, all lesions were cured with radiotherapy.50 Penile and scrotal manifestations of AIDS-related Kaposi’s sarcoma can show a complete response in 69.4% (34 of 49 patients) managed by radiotherapy.55

Table 109.7. Results of Radiation Alone for Penile Carcinoma (Primary Lesion).

Table 109.7

Results of Radiation Alone for Penile Carcinoma (Primary Lesion).

Radiotherapy should be the treatment of choice in limited penile cancer if preservation of sexual function is a major therapeutic aim. In a group of 30 men with penile cancer, radiotherapy gave the least alteration of sexual function.56 In T1 and T2 patients, local control rates can be 91% with radiotherapy.57 In 49 T1 and T2 tumors treated at the Netherlands Cancer Institute, no difference in the local recurrence rate (18%) was observed with surgery, laser, and external-beam radiation.59 They emphasize that long-term follow-up is needed after penile conservation because local recurrences may appear as late as 8 years after primary treatment and can be salvaged with surgery.59,60

Radiotherapy has been advocated for lymph node metastasis.57,60 An external irradiation dose of 4,500 to 5,000 cGy, with fractions of 180 to 200 cGy, directed to the clinically negative nodes in the inguinofemoral–low iliac areas should reduce the appearance of tumor at this site to less than 5% of patients with controlled primary neoplasms. Postoperative irradiation to the groin also reduces recurrences in this location. In 51 patients subjected to surgery and external irradiation of the inguinal and iliac lymph nodes, 6 (12%) developed nodal and/or metastatic disease after therapy.57

Chemotherapy

Chemotherapy does not have an established role in the primary therapy of penile carcinoma. An objective response of 15%, with 1 complete response in 14 patients, has been reported after multi-drug combination chemotherapy in advanced penile cancer managed at the Institut Gustave-Roussy in Paris.61 Used concurrently with irradiation, chemotherapy has shown value in the treatment of squamous carcinoma of the esophagus and anal canal, and it has been extensively investigated in carcinoma of the head and neck, cervix, and vulva. Consequently, one would expect that this approach may have future applicability in cancer of the penis. Combined/concurrent treatment with bleomycin administration and radical irradiation has been used to increase chances of organ sparing in carcinoma of the penis.62 In 35 patients managed with 5,800 cGy in 38 days, together with 225 mg bleomycin, a complete response was achieved in 33 patients, with a high percentage (17 of 24) living free of tumor longer than 5 years. In 25 patients with stage T1-2 N0 squamous cell carcinoma of the penis who were treated with a combination of irradiation and bleomycin, the result was equivalent to that achieved in 19 patients managed with surgery.64 Bilateral ulcerated lymph node metastases also have been treated successfully with combination of chemotherapy and radical radiotherapy.65 A recently completed Southwest Oncology Group (SWOG) study reported a 32.5% response rate (5 of 40), compared with cisplatin, methotrexate, and bleomycin. However, toxicity was high.66

Prognosis

When untreated or unsuccessfully treated, carcinoma of the penis has the potential to cause self-amputation of the organ, bilateral life-threatening inguinal metastases, and distant dissemination to the liver, lung, skeleton, and even regions of the body such as the distal extremities. The overall 5-year observed survival rate in partial response reported for the years 1973 to 1979 (Table 109.8) was 56% for all stages, 69% for localized disease, and 36% for advanced disease.7 The national SEER 5-year relative survival rate for 1973 to 1987 in a sample of 1,101 patients with invasive cancer was 70% for all stages and over 95% for carcinoma in situ.2 Relative survival was 80% for localized tumor, 52% for regional extension, and 18% for distant disease.67

Table 109.8. Observed Survival of Patients with Penile Cancer in Puerto Rico, 1973 to 1979.

Table 109.8

Observed Survival of Patients with Penile Cancer in Puerto Rico, 1973 to 1979.

Our previously reported experience with 216 patients followed up for a minimum of 5 years showed an observed survival rate of 49.5%.6 Of 17 patients who received no treatment, only 2 (11.8%) survived 5 years. When patients dying from other causes are eliminated from the analysis, 66% of treated patients survived 5 years. Grading of the tumor affected the survival; grade I tumors showed a 64% (61 of 95) observed 5-year survival, compared with 38% (27 of 71) in grade 2 and 3 lesions. Extent of the primary tumor also influenced the survival; patients with lesions limited to the glans had the best prognosis, with a 73% (33 of 45) observed 5-year survival versus 27% (3 of 11) when the scrotum was invaded.

In our early series,6 the presence of histologically positive metastatic lymph nodes in the groin lowered the 5-year survival; only 21.6% of 51 patients treated with groin dissection lived 5 years. Horenblas and colleagues60 reported that when no nodes were clinically present, 5-year survival was 93%, compared with 50% for clinically positive nodes. When the nodes were fixed, 5-year survival was 17%. In general, invasion of the corpora cavernosa and spongiosa increases the chance of lymph node metastasis; tumor differentiation also influences the incidence of nodal metastases (5% in grade 1 versus 40% in grade 2 and 3 lesions).6 In a series from the University of Iowa Hospital,68 65% of patients with no palpable nodes at initial diagnosis lived 6 or more years, whereas only 15% of patients with palpable nodes survived 6 years. In a series from Memorial Sloan-Kettering Cancer Center in New York,38 the crude 5-year survival rate for all patients with proven inguinal nodal metastasis was 28% (22 of 78). For minimal nodal disease (N1 and N2), there was a 50 to 80% 5-year survival; but the prognosis was poor (4–12% 5-year survival) for N3b and N4. N0 patients had a 74% 5-year survival.

When the pelvic lymph nodes are involved by tumor, the prognosis is ominous.36 Palliative surgery for advanced groin metastases has resulted in death from the disease in all cases.30

Prevention

Carcinoma of the penis is a preventable disease. All patients with phimosis, which prevents adequate inspection and cleanliness of the glans, should undergo corrective surgery.

The growing practice of circumcising male infants should enhance the chances for good penile hygiene. Theoretically, this should be associated with less possibility of developing carcinoma of the penis.

Further knowledge of the interaction of the HPVs with this tumor may bring better understanding of the possibility of prevention.

Conclusions

Carcinoma of the penis is a preventable disease, the incidence and morbidity of which should decrease with improvement of socioeconomic conditions and the practice of circumcision early in life. Currently, the earlier recognition of lesions (23% of cases in 1973 were in situ versus 38% in 1987)2 should favor a reduction in mortality, less need for amputation, and better quality of life.

Use of radiotherapy, with or without limited surgery, permits organ sparing in over 50% of all diagnosed patients with invasive lesions, over 80% of those with early invasive lesions, and close to 100% of those with intraepithelial (in situ) penile tumors. Future research into concurrent chemotherapy and radiotherapy should aim at increasing primary tumor control and organ sparing with high quality of life in patients with more advanced lesions. The addition of hyperthermia may present more possibilities for organ preservation in patients with advanced penile cancer.69

Prophylactic irradiation of clinically negative inguinal lymph nodes in high-risk patients (i.e., those with poor differentiation, large lesions, deep invasion) should reduce the activation of tumor in the groin. This conclusion is based on the experience with squamous cell carcinoma of the head and neck, carcinoma of the anus, and the published experience of several authors who have followed this approach. When histologically proven positive nodes are subjected to surgical dissection, the addition of regional radiotherapy, with or without systemic chemotherapy, should improve prognosis by reducing the chances of recurrence at the surgical site.

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