AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Penile tumors represent a difficult diagnostic and therapeutic issue to solve, mainly because of their psychological implications. The diagnosis may be delayed because many patients tend to disregard early asymptomatic lesions, and they often seek medical attention in an advanced stage when a conservative surgical approach is no longer feasible (Agarwal, 2005; Jaganmohan, 2004).

Among malignant neoplasms of the penis, squamous cell carcinoma (SCC) is the most common (Micali, 1996; Micali, 2004; Micali, 2006). Verrucous carcinoma, also called Buschke-Löwenstein tumor, is a well-differentiated variant of SCC worthy of special recognition (Schwartz, 1990; Schwartz, 1995).

Pathophysiology

The cause of penile SCC is unclear, though human papillomavirus (HPV) appears to play a major role. In situ carcinomas may progress to invasive lesions. Other associations considered to play a role in the development of the disease include preexisting dermatoses; lack of circumcision; and other factors, including environmental exposures.

In situ carcinomas

If untreated, in situ carcinomas likely evolve to invasive carcinomas. They include Bowen disease, erythroplasia of Queyrat, and bowenoid papulosis. Bowen disease and erythroplasia of Queyrat share similar histologic appearance and biological behavior and therefore are now usually considered different aspects of a single preneoplastic disorder. They are also defined as penile intraepithelial neoplasia, whereas the abbreviation Tis is used in the TNM classification. Classification of bowenoid papulosis is controversial. The disease is probably better considered as a separate entity, owing to its peculiar clinical features, significantly lower rate of malignant progression, and better outcome (Micali, 2006).

Bowen disease

Bowen disease is rare, with the most common occurrence in elderly white men. Bowen disease usually occurs on the shaft and appears as a solitary, dull-red plaque with areas of crusting and oozing. Ulceration or papillomatous growth suggests evolution to invasive SCC, which occurs in approximately 5% of patients. About 37% of the invasive lesions are associated with regional lymph node metastases (Lucia, 1992).

Erythroplasia of Queyrat

Erythroplasia of Queyrat is most common in elderly, noncircumcised white men. It appears as a solitary, sharply defined, bright red, glistening, velvety, nontender, often-eroded plaque on the glans, the inner surface of the prepuce, or the coronal sulcus (see Image 1). Transformation into an invasive SCC is more common in erythroplasia of Queyrat than in Bowen disease, with an incidence of 10-33%. Ulceration and/or papillary outgrowths are clinical signs of the disease. About 20% of patients have regional lymph node metastases (Graham, 1973).

Bowenoid papulosis

Bowenoid papulosis mainly occurs on the shaft in young circumcised men. It appears as multiple, small, slightly elevated, red-to-violet, slightly scaly or warty papules, which sometimes coalesce into large plaques (see Image 2). Extragenital involvement is exceedingly rare (Papadopoulos, 2002). Bowenoid papulosis is a HPV infection with a characteristic bowenoid histology. Lesions may remain static, spontaneously regress, or progress to Bowen disease. Local recurrences after conservative excision and the onset of Bowen disease or SCC are reported in elderly and in immunocompromised patients (Schwartz, 1991; Micali, 1996; Micali, 2004).

Preexisting dermatoses

The true role of previous dermatoses, such as lichen planus, in the pathogenesis of SCC is still unsettled because the available data suggest that, in most cases, penile carcinoma arises de novo. Therefore, further investigations are needed to define the true incidence of the preexisting conditions reported in association with penile SCC.

Leukoplakia

Leukoplakia is a clinical description of lesions appearing as slightly infiltrated, white verrucous plaques on the glans or the prepuce. If ulceration, erosion, or fissuring is present, the likelihood of malignant degeneration is high because 10-20% of these lesions show dysplastic changes on histologic examination (Schellhammer, 1992; Mikhail, 1980).

HPV infections

A role of HPV infections is established but not fully understood. Genital HPV infections mostly affect middle-aged, sexually active individuals. The lesions clinically appear as exophytic, fleshy, fibroepithelial proliferations involving the mucosal and cutaneous surfaces of the anogenital area (anogenital warts) (see Image 3). However, subclinical HPV infections are common, especially in male sexual partners of females with in situ or invasive cervical carcinoma; they may be revealed by local application of an acetic acid solution (Bleeker, 2002).

The evolution of HPV infections is related to the HPV type involved. In recent years, the oncogenic properties of some types (HPV types 16, 18, 31, and 33) have been confirmed. HPV types 6 and 11 are usually found in benign penile lesions, whereas HPV types 16 and 18 are often detected with in situ and invasive carcinomas. HPV sequences have also been found in local and distant metastases of penile SCC (Iwasawa, 1993; Rosemberg, 1991). The existence of 2 etiologically distinct types of penile SCC has been hypothesized: a type with a viral cause and possible sexual transmission more likely to occur in younger individuals and another type of unknown cause affecting older individuals (Nasca, 1999; Rubin, 2001; Micali, 2006).

Penile lichen sclerosus

Penile lichen sclerosus is a chronic, sclerosing, atrophic inflammatory condition that is more often observed in men, although male children may also be affected. Penile lichen sclerosus usually appears as white, atrophic papules on the glans and the prepuce that slowly coalesce into plaques, leading to meatal stenosis and/or phimosis (balanitis xerotica obliterans). On clinical examination, nodules or ulcerated plaques usually reveal malignant transformation (see Image 4).

Although the likelihood of individual lesions of penile lichen sclerosus progressing into an invasive carcinoma is not predictable, this condition has a statistically significant risk of becoming SCC. Malignant changes have been observed in 9.3% of cases of penile lichen sclerosus in some series, and lichen sclerosus adjacent to a tumor has been detected in excision specimens from patients with penile SCC (Nasca, 1999; Micali, 2001; Powell, 2001; Perceau, 2002; Pietrzak, 2006; Barbagli, 2006). Studies have shown that lichen sclerosus is preferentially associated with HPV-negative, low-grade, differentiated, and highly keratinizing penile SCCs (Perceau, 2002; Velazquez, 2003).

Polymerase chain reaction (PCR) testing has shown the presence of oncogenic HPVs in some cases of penile carcinoma arising on lichen sclerosus. Patients with lichen sclerosus may be more susceptible to cancer development following infection by oncogenic HPV types than healthy subjects. Alternatively, HPV infection may hasten lichen sclerosus progression towards cancer, resulting in a shorter lag-time. However, further investigations on the prevalence of HPV infection in patients with genital lichen sclerosus are needed to confirm these hypotheses (Micali, 2006).

Pseudoepitheliomatous, keratotic, and micaceous balanitis

Pseudoepitheliomatous, keratotic, and micaceous balanitis (PKMB) is an uncommon condition that occurs mainly in elderly men who are circumcised later in life. The lesion appears as a solitary, well-demarcated, hyperkeratotic plaque on the glans (see Image 5). Once considered benign, it is now regarded as a tumor with a low-grade malignancy potential similar to that of verrucous carcinoma (Gray, 1990). Degeneration into SCC clinically appears as a nodular lesion within the plaque.

Penile horn

A penile horn is a rare condition that usually appears as a hard and conical keratotic mass with a bulging erythematous base that develops on the glans (see Image 6). These clinical features are not diagnostic because penile horns may microscopically reveal a benign epidermoid outgrowth, such as warts; keratoacanthomas; or in situ, verrucous, or invasive carcinomas (Solivan, 1990; Cruz Guerra, 2005). Therefore, obtaining a biopsy sample of the base is mandatory, and clinical evolution and management depend on the underlying condition.

Relapsing chronic balanitis of a different etiology

Relapsing chronic balanitis of a different etiology (eg, bacterial, mycotic, viral) may be a preexisting condition. According to some observations, chronic balanitis may, in time, lead to cancer development (Micali, 1996; Micali, 2004).

Factors resulting from the lack of circumcision

Epidemiologic data have demonstrated that penile SCC is exceedingly rare in men who are circumcised at birth. The prophylactic effect of circumcision on penile carcinoma is likely related to the lack of retained smegma that has been proven to be carcinogenic in animals (Pratt-Thomas, 1956). Smegma retention may cause irritation and recurrent infections, leading to phimosis.

One study also demonstrated an increased risk of HPV infection in uncircumcised men (19.6%) compared with circumcised men (5.5%) (Castellsague, 2002). On the other hand, phimosis itself is a risk factor for penile SCC development (Tsen, 2001), as it has been experimentally shown to induce histologic changes in the epithelium of the preputial sac.

Poor genital hygiene in uncircumcised males, even in the absence of phimosis, may also play a role, leading to the retention of smegma. This finding is confirmed by the lower incidence of penile SCC in countries with good hygienic standards (Micali, 1996; Micali, 2004; Micali, 2006). However, a recent study failed to detect any correlation between personal hygiene habits (frequency and method of bathing and/or cleaning of the anogenital area) and risk of penile cancer development (Tsen, 2001).

Other factors

Occasional factors that have been reported in association with penile SCC include the following:

• Prolonged exposure to different chemical compounds (eg, insecticides, fertilizers, styrene, acrylonitrile), together with poor hygiene practice (Rogus, 1987), traumas (Tsen, 2001; Thomas, 2004), or chronic irritation (Kakinuma, 1994).
• Late ritual circumcision followed by herbal treatments to control bleeding performed in the Southwestern Saudi region is associated with extensive scarring and may result in the development of invasive tumors proximally and dorsally located on the shaft (Seyam, 2006).
• Cigarette smoking, which has been found to show a clear-cut association with penile SCC related to the nicotine intake and independent of phimosis or balanitis; whether tobacco products concentrate in smegma has not been proven in humans (Hellberg, 1987; Tsen, 2001).
• UV radiation that may enhance the development of penile SCC, as observed in patients with psoriasis treated with psoralen plus UV-A (PUVA) or with UV-B (Stern, 2002)
• Immune suppression, due to either transplantation or HIV infection, which has a greater risk of SCC development on the penis as well as on other skin sites (Poblet, 1999)
• Reconstructive surgery for sex reversal, though whether the heterotopic penile skin within the neovagina may be at an increased risk of cancer development is unclear (Harder, 2002)
• Penile verrucous carcinoma has been linked to HPV infection; HPV types 6 and 11 are most frequently isolated (Schwartz, 1990; Schwartz, 1995; Micali, 1996; Micali, 2004; Micali, 2006). Because HPV types 6 and 11 are usually isolated from benign lesions, other co-factors may be involved, including genomic alterations enhancing the oncogenic properties of these low-risk viruses; immunosuppression; co-infections by other viruses; the synergistic effect of environmental factors; poor hygiene; lack of circumcision; chronic irritation (Micali, 1996; Micali, 2004; Micali, 2006); and previous dermatoses involving the genital area, such as genital lichen sclerosus (Nasca, 1999; Micali, 2001), lichen planus (Bain, 1989), or PKMB (Child, 2000).

  Evolution of a verrucous carcinoma to SCC is possible, especially following irradiation. Invasive growth has been linked in some patients to the high-risk HPV types 16 and 18 (Schwartz, 1990; Schwartz, 1995; Micali, 1996; Micali, 2004; Micali, 2006).

Frequency

United States

SCC accounts for at least 95% of all penile malignancies (Burgers, 1992). It represents about 2% of all cancers of the male genitalia and is found in 0.3-0.5% of the cancer-bearing male population (Narayana, 1982; Carver, 2002).

International

The incidence of SCC varies in different geographic areas, ranging from 1% of all malignancies in male patients in the Western countries to 10-20% in some parts of Asia, Africa, and South America. Higher incidences are reported in tropical areas, such as Puerto Rico, Mexico, Paraguay, Venezuela, Vietnam, Ceylon, Thailand, China, Uganda, and parts of India (Burgers, 1992; Micali, 1996; Micali, 2004; Micali, 2006).

Verrucous carcinoma represents 5-16% of all SCCs, and its incidence varies from 5-24% among all penile malignancies (Schwartz, 1990).

Mortality/Morbidity

• SCC is the cause of less than 1-2% of all deaths from cancer in men in the United States (Narayana, 1982).
• A statistically significant decreased survival has been found in African American men, who tend to present with a high stage of disease (Rippentrop, 2004).

Race

• A racial predilection is unlikely, but statistical data are controversial because of possible confounders.
• SCC is rare among some religious communities who practice circumcision, such as Jewish and Moslem groups and the Ibos of Nigeria (Micali, 1996; Micali, 2004).

Age

• The age at onset of penile SCC is 20-90 years, with a peak around the sixth and seventh decades (Aynaud, 2000; Carver, 2002).
• A few cases have been reported in childhood (Burgers, 1992).
• Penile verrucous carcinoma may occur at any age (18-88 y), but two thirds of all cases occur before the age of 50 years (Schwartz, 1990; Schwartz, 1995).

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Primary SCC may occur at any anatomic site on the penis.

• In most cases, the earliest symptoms are itching or a burning sensation under the foreskin, and ulceration of the glans or the prepuce, which, if untreated, may progress to a mass or a nodule.
• With time, the tumor destroys the glans and the prepuce and infiltrates the corpora cavernosa (Velazquez, 2004).
• When the urethra is invaded, obstruction and fistulae may develop.
• Lymphatic metastases first occur in the superficial or deep inguinal lymph nodes, then in the regional lymphatics of the pelvis.
• Distant metastases resulting from vascular dissemination (most commonly to the lungs and the liver, followed by the bone, the brain, and the skin) are rare and usually late (Micali, 1996; Giesler, 2001; Khandpur, 2002; Micali, 2004; Micali, 2006).
• With regard to penile Verrucous carcinoma, its apparent clinical benignity may lead to lengthy periods of misdiagnosis during which it is not likely to spread to distant lymph nodes, but rather, to the penis as it slowly but relentlessly extends into underlying tissue (Schwartz, 1990; Schwartz, 1995).

Physical

Penile SCC most often occurs on the glans (48%), though it may also develop on the prepuce (21%), both the glans and the prepuce (9%), the coronal sulcus (6%), and the shaft (<2%). Invasion of the shaft by a tumor originating from more distant sites may also be observed (14%) (Burgers, 1992).

• The clinical presentation varies from slightly elevated areas of induration, erythema, or warty growth to an extensive tumor with sloughing and autoamputation of the phallus.
• Two growth patterns have been described: papillary and flat.
• • Papillary tumors usually originate as single or multiple coalescing, elevated, and warty lesions that may subsequently undergo necrosis and ulceration (see Image 7).
  • Flat tumors extend on the surface and infiltrate deeper tissues. They usually appear as small, superficial, round ulcers on a slightly elevated and indurated base (see Image 8).
• Secondary infection, with a purulent, foul-smelling discharge, is often present. Pain is usually slight in comparison with the extent of the local destruction (Micali, 1996; Micali, 2004; Micali, 2006).
• Palpable inguinal lymphadenopathy is present at diagnosis in 58% of patients.
• • Of these patients, 45% have cancer in the nodes, and the remainder have inflammatory lymphadenopathy secondary to infection of the primary tumor.
  • Of nonpalpable lymph nodes, about 20% contain metastases (Burgers, 1992).
  • The extent of penile shaft involvement, tumor grading, and the growth pattern are correlated with the frequency of regional lymph node metastases.
  • Unlike patients with superficially invasive (<2 cm) or well-differentiated tumors, those with high-grade SCCs, extensive (>75%) penile shaft involvement, and a flat growth pattern have an increased incidence of involvement of the inguinal lymph nodes (Burgers, 1992; Solsona, 2001; Slaton, 2001).
• Penile verrucous carcinoma usually involves the glans and the prepuce and rarely the shaft.
• • Penile verrucous carcinoma frequently appears as an exophytic cauliflowerlike mass that may be foul smelling and sometimes ulcerated, or it may resemble a penile horn in rare cases (see Images 9-11).
  • Swelling of the regional lymph nodes as a result of secondary infection is frequent, whereas local metastases are infrequently reported (Schwartz, 1990; Schwartz, 1995).

Causes

See Pathophysiology.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Imaging Studies

• Imaging techniques recommended for a more accurate staging of neoplastic disease and for periodic follow-up of treated patients include ultrasonography, CT scanning, and MRI (Misra, 2004).
• • Ultrasonography has the advantages of low cost, noninvasiveness, easy availability, and reliability in assessing extension of the primary tumor and of lymph nodes. Sonographic evaluation may also have a role in determining whether metastatic nodes are resectable.
  • CT is widely performed in the staging of lymph nodes, but is of limited help in the assessment of penile lesions.
  • MRI improves soft tissue contrast and provides multiplanar high-resolution images, yielding the greatest accuracy in the evaluation of both the penile primary tumor and the lymph nodes.
• Autofluorescence study and 5-aminolevulinic acid–induced fluorescence study have been suggested as promising tools for planning adequate laser ablation of superficial tumors (Frimberger, 2002). However, none of these techniques is able to detect occult lymph node micrometastases.
• Lymphangiography and cavernosography tend to be abandoned because of their invasiveness.
• Lymphoscintigraphy may be performed to identify sentinel nodes and to establish the need for lymph node dissection (Burgers, 1992; Vapnek, 1992; Valdes Olmos, 2001; Tanis, 2002).

Other Tests

• Initial biopsy of the primary penile lesion is necessary to confirm the diagnosis and to assess the grade and the invasiveness of the tumor, although a recent study has shown that it may fail to correctly assess the histologic grade (30% of cases) and deepest point of tumor invasion (91% of cases) when used alone (Velazquez, 2004). Biopsy usually consists of a 1-cm elliptical wedge excision centered on the margin of the lesion. The mucosal application of 1% toluidine blue may aid in the identification of the best area to biopsy (Micali, 2006).
• In the diagnosis of long-standing, ulcerating condylomata, the identification of HPV DNA by using molecular hybridization techniques (eg, Southern blotting, dot blotting, in situ hybridization, PCR) may be a useful diagnostic adjunct because lesions harboring oncogenic HPVs are reported to be at high risk of malignant degeneration.
• Because these investigations are expensive, their use should be reserved for selected cases.

Histologic Findings

Histopathologic examination is essential to establish the diagnosis and to provide information about the extension of the tumor in deeper tissues (Cubilla and Reuter, 2001; Cubilla and Piris, 2001).

On microscopy, SCC may have different histologic features according to the degree of differentiation.

Broders has described a classification of 4 groups with increasing aspects of atypia (Lucia, 1992). The grading of SCC in the Broders systems is as follows:

• Grade I
  • Cells well differentiated with keratinization
  • Prominent intercellular bridges
  • Keratin pearls
• Grade II-III
  • Greater nuclear atypia
  • Increased mitotic activity
  • Fewer keratin pearls
• Grade IV
  • Marked nuclear pleomorphism
  • Numerous mitoses
  • Necrosis
  • Lymphatic and perineural invasion
  • No keratin pearls
  • Deeply invasive

Low-grade (grades I-II), well-differentiated lesions show a thickened, hyperkeratotic, and papillomatous epidermis, with a downward, fingerlike projection of atypical squamous cells, which often appear as concentrically arranged nests of cells surrounding keratin accumulations (keratin pearls). Epithelial cells show intact desmosomes and slight atypia, with enlarged and pleomorphic nuclei and 1 or more prominent nucleoli. Mitotic figures are present. Individual cells may become dyskeratotic, appearing deeply eosinophilic. In the dermis, a dense lymphocytic or mixed inflammatory infiltrate may be present (Lucia, 1992).

Poorly differentiated SCC (grades III-IV) shows little or no keratinization, increased nuclear pleomorphism and hyperchromasia, and deeper invasion, and it may have areas of necrosis or superinfection (Lucia, 1992).

Several histologic subsets of SCC have been identified (Micali, 2006). These include, beside the usual variant (most common subtype, accounting for almost 60%) (Cubilla and Reuter, 2001); the verruciform variant (including the warty/condylomatous, the papillary/not otherwise specified and verrucous types) (Cubilla, Velazquez and Reuter, 2001), the pseudohyperplastic variant (Cubilla, Velazquez and Young, 2001), the basaloid variant (Cubilla, Velazquez and Reuter 2001; Cubilla 1998), sarcomatoid or spindle cell carcinoma (Manglani, 1980; Shimamoto, 2005), the adenosquamous variant (Cubilla, 1996; Romero, 2006), and the mixed variant. Identification of more unusual variants on biopsy is often challenging, and they are usually identified only in penectomy specimens (Velazquez, 2004).

The histologic type seems to be correlated to its biologic behavior. HPV DNA positivity is only weakly associated (11%) with typically keratinizing SCC and strongly correlated histopathologically with basaloid changes (75%) (Dillner, 2000; Velazquez, 2003; Gross, 2004). Moreover, well-differentiated, low-grade keratinizing tumors, including the papillary/NOS, and pseudohyperplastic variants, occur in older patients and are usually associated with preexisting lichen sclerosus (Cubilla, 2004) and a low risk of metastatic spread. Conversely, warty and/or condylomatous and basaloid tumors are consistently associated with HPV infection and with an aggressive growth and poor prognosis. SCC of the usual type holds an intermediate position with regard to depth of invasion, metastasizing potential and prognosis (Cubilla, Velazquez and Reuter, 2001; Bezerra, 2001).

In verrucous carcinoma, morphologically warty or verrucous, the relatively bland histologic features are often more suggestive of verruca vulgaris or pseudoepitheliomatous hyperplasia than of SCC to those unfamiliar with the diagnosis (Schwartz, 1990; Schwartz, 1995). Histologic examination shows massive hyperplasia of the epidermis, with marked hyperkeratosis and parakeratosis. The granular layer is prominent, with vacuolated cells that resemble the koilocytes of condyloma acuminatum. The individual keratinocytes have a large amount of cytoplasm and a large nucleus with prominent nucleoli. Atypical mitotic figures, individual cell necrosis, dyskeratosis, and multinucleated keratinocytes are rare.

Intracytoplasmic glycogen is scant. Tumor projections appear as blunt masses that extend into the dermis and the deep structures to form sinuses and keratin-filled cysts. Centripetal keratinization is often present, but horn pearls are not present. A marked inflammatory lymphohistiocytic infiltrate is usually observed. Tumor cells are not found in blood vessels or lymphatics; this finding is presumably correlated with the lack of metastases (Schwartz, 1990; Schwartz, 1995; Micali, 1996).

Staging

Assessment of histologic grade and infiltration or invasion of the adjacent deep or lateral tissues aids in planning treatment.

Clinical staging is not always reliable because tumors apparently limited to the glans and the prepuce can be understaged on histologic examination. Moreover, a comparison of relevant pathologic parameters between incisional biopsy and penectomy specimens from the same patients with penile SCC showed that the former may be insufficient for correctly assessing the histologic grade and deepest point of tumor invasion (Velazquez, 2004). Therefore, additional information obtained with complementary imaging techniques should be evaluated for accurate staging of neoplastic disease.

Clinical assessment of inguinal node metastases is often difficult as well. When inguinal lymph node enlargement persists after a course of oral antibiotics, thorough imaging and histologic examination are suggested.

The staging systems currently used are the Jackson classification and the tumor, nodes, metastases (TNM) system (Union Internationale Contre le Cancer) (Das, 1992; Vapnek, 1992).

• Jackson classification for SCC of the penis
• • Stage I - Tumor confined to the glans or the prepuce
  • Stage II - Invasion into the shaft or the corpora; no nodal or distant metastases
  • Stage III - Tumor confined to the penis; operable metastases of the inguinal nodes
  • Stage IV - Tumor involves adjacent structures; inoperable inguinal nodes and/or distant metastasis or metastases
• TNM classification for SCC of the penis
• • Tumor
    • TX - Not defined
    • T0 - No evidence of primary tumor
    • Tis - Carcinoma in situ (Bowen disease, erythroplasia of Queyrat)
    • Ta - Noninvasive verrucous carcinoma
    • T1 - Tumor invading the subepithelial connective tissue
    • T2 - Tumor invading the corpus spongiosum or cavernosum
    • T3 - Tumor invading urethra or prostate
    • T4 - Tumor invading other adjacent structures
  • Node
    • NX - Not defined
    • N0 - No evidence of regional node involvement
    • N1 - Involvement of a single superficial inguinal node
    • N2 - Involvement of multiple or bilateral superficial inguinal nodes
    • N3 - Involvement of deep inguinal or pelvic nodes, unilateral or bilateral
  • Metastasis
    • MX - Not defined
    • M0 - No evidence of distant metastasis
    • M1 - Distant metastasis present
    • M1a - Occult metastasis (biochemical and/or other tests)
    • M1b - Single metastasis in a single organ
    • M1c - Multiple metastasis in a single organ
    • M1d - Metastasis in multiple organ sites

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

The treatment of penile SCC varies according to the clinical stage. Treatment includes radiation therapy, medical therapy, and surgery (see Surgical Care below), alone or in combination. However, because of the generally limited experience with SCC of the penis, considerable controversy exists as to the best form of treatment, specifically treatment for regional lymph nodes (McDougal, 2005; Micali, 2006).

• Radiation therapy
• • Radiation therapy with external beams or mould techniques (cesium Cs 137, iridium Ir 192) (Crook, 2002; Azrif, 2006) may be an option to treat small, superficial, exophytic lesions in young individuals, allowing for the preservation of sexual function with a high cure rate. In case of relapse, salvage surgery may be required (Sanchez-Ortiz, 2003).
  • Circumcision before therapy is recommended.
  • The advantage of radiation therapy over excision has not been definitively demonstrated (Zouhair, 2001; Ozsahin, 2006), and major complications, such as urethral stenosis, fistulas, and penile necrosis, may occur.
  • Radiation therapy is not indicated in the treatment of verrucous carcinoma because it may result in anaplastic changes and metastases (Guillet, 1988).
  • Radiation therapy may also be used to treat advanced SCCs of lymph node metastases in patients with unresectable or recurrent lymph node disease or in patients in whom a surgical approach is not feasible.
  • Adjuvant inguinal radiation therapy may be performed after surgical resection of metastatic lymph nodes, whereas prophylactic groin irradiation should be avoided; in irradiated groins, detecting metastases is clinically more difficult, and a high rate of complications occur after lymphadenectomy.
• Medical treatment includes local and systemic chemotherapy.
• • Early premalignant and in situ changes can be treated with topical chemotherapy (5-FU), as pioneered by Klein (Klein, 1968).
  • Systemic chemotherapy may be used according to the stage of the disease with 3 distinct modalities (Micali, 1996; Micali, 2004), as follows:
    • Palliative chemotherapy is suggested for local recurrences and for metastases when other treatments fail. It is usually delivered systemically by means of intramuscular or intravenous injection (depending on the agent used) as monochemotherapy with bleomycin, methotrexate, or cisplatin alone or combined with other drugs for a synergistic effect. Drugs used in combination include vincristine, bleomycin, and methotrexate (VBM therapy); cisplatin and fluorouracil (PF therapy); and cisplatin, bleomycin, and methotrexate. Generally, better results are obtained with combination chemotherapy (Misra, 2004).
    • Adjuvant combined chemotherapy (VBM therapy) may be used to reduce the incidence of metastases in patients with involved nodes after surgical resection of the lymph nodes.
    • Neoadjuvant combined chemotherapy may be attempted for locally invasive tumors (stages T3-T4) or for fixed regional node enlargement (stage N3) to reduce the neoplastic mass before surgical excision (downstaging). This approach may allow for a more conservative surgical procedure than what would otherwise be needed.
  • Other medical treatments include the following:
    • Chemotherapy (bleomycin) and radiation therapy
    • Regional intra-arterial chemotherapy (methotrexate and mitomycin C)
    • Systemic or intralesional interferon-alpha either alone or combined with surgical shaving (for relapsing verrucous carcinoma)

Surgical Care

Surgical procedures consist of local excision, circumcision, glansectomy, partial penectomy, total penectomy, and demasculinization. The last 3 procedures may be performed in conjunction with lymph node dissection (Kroon, 2005; Micali, 2006; Loughlin, 2006).

• Local excision

  Small and superficial lesions on the glans or the shaft (<2 cm) may be treated with wide wedge resection, extending the surgical margin 2 cm beyond the proximal end of the lesion. Obtaining multiple deep and lateral biopsy samples at the time of surgery is strongly recommended.

• Circumcision

  Small carcinomas of the distal foreskin without deep infiltration can be treated with wide circumcision with a 2-cm margin of clearance. Without adequate margins, the incidence of local recurrence is high (40%).

• Mohs surgery

  Local excision with Mohs micrographic surgery has been performed with good results for small and superficial invasive carcinomas located on the glans or near the preputial sulcus. It has the advantage of preserving large amounts of healthy tissue and normal functions.

• Laser therapy

  Destructive therapy can be administered with a carbon dioxide or a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, alone or in combination or with an argon and potassium-titanyl-phosphate (KTP) laser, although this last option is least common (Tietjen, 1998; Frimberger, 2002). Laser therapy has the advantage of providing a bloodless field (Windahl, 2003), but it does not allow for histopathologic sampling and local recurrences can be frequent (>50%), especially with the carbon dioxide laser. Better results are obtained with the Nd:YAG laser, which penetrates deeper and allows coagulation of larger vessels. For this reason, accurate preoperative staging of the tumor by means of multiple deep biopsies is recommended to establish the adequacy of the depth of laser destruction (Misra, 2004).

• Cryosurgery

  The use of cryosurgery, either alone or combined with 5-fluorouracil, has been suggested for verrucous carcinoma (Michelman, 2002).

• Glansectomy and penectomy

  Glansectomy may be performed in verrucous carcinoma limited to the glans (Hatzichristou, 2001; Davis, 2001), whereas partial penectomy is the procedure of choice for tumors (SCC or verrucous carcinoma) at a low stage (stage I, T1-T2) that involves most of the glans or the distal third of the penis (Das, 1992). Total penectomy is necessary when the lesion is in the proximal portion of the penis or when the tumor is at an advanced stage (stages II-III, T3-T4) (Das, 1992).

  Reconstruction techniques may help in preserving acceptable function and appearance of the penis (Mazza, 2001). Conservative organ-sparing surgical techniques for penile SCC are currently under evaluation (Pietrzak, 2004; de Fonseca, 2003).

• Demasculinization

  Penectomy plus scrotectomy and bilateral orchidectomy with wide en bloc excision of the involved abdominal wall and bilateral lymphadenectomy may be required for infiltrating masses at the base of shaft (Das, 1992).

• Lymph node dissection

  Because of the significant morbidity of inguinal and pelvic node dissection (Bevan-Thomas, 2002) and because of the high incidence of reactive nodes, surgical dissection of the lymph nodes is necessary only if they are enlarged and do not regress after adequate antibiotic therapy (Laughlin, 2006). In general, if positive nodes are found during dissection of the superficial lymph nodes, bilateral dissection of the deep nodes is suggested. Bilateral pelvic lymphadenectomy should also be performed because about 30% of these nodes harbor tumor metastases when the inguinal lymph nodes are involved.

  As an alternative, some authors perform ipsilateral inguinal (superficial and deep) and pelvic lymphadenectomy with contralateral superficial inguinal node dissection to decrease the incidence of complications due to a radical approach (Sanchez-Ortiz, 2003). Extensive surgical dissection is not justified if involvement of the para-aortic lymph nodes is present (stage N4) because improved survival is not likely (Abi-Aad, 1992). Surgical techniques to reduce the morbidity of inguinal node dissection, including the use of a spermatic cord patch and saphenous vein sparing, have been proposed (Szostak, 2001; Coblentz, 2002).

  The time and extension of lymph node dissection is controversial because histologic investigations have demonstrated that 10-20% of clinically normal nodes contain unsuspected metastases. The 5-year survival rate is as high as 84-88% in patients undergoing prophylactic inguinal lymphadenectomy compared with 35-42% in patients undergoing therapeutic lymph node dissection (McDougal, 1986; Kroon, 2005). A disease-specific 3-year survival rate of 84% was reported in patients who underwent early lymph node resection compared with 35% in those with positive lymph nodes detected during surveillance (Kroon, 2005).

  Histopathologic variables considered to be strong predictors of inguinal metastases are vascular invasion and the grade and stage of the primary tumor (Solsona, 2001; Slaton, 2001; Sanchez-Ortiz, 2003; Ficarra, 2005; Ficarra, 2006). Other factors that have been found to correlate with a higher risk of inguinal metastases are an infiltrating growth pattern of invasion (Guimaraes, 2006) and a low E-cadherin expression (Campos, 2006) of the primary tumor.

  Watchful waiting is advised in patients who are not obese, those in whom accurate clinical assessment is possible, and those for are compliant and reliable for follow-up. Patients should also have impalpable lymph nodes and superficially invasive (<2 cm) tumors. Patients with poorly differentiated and deep, invasive tumors (stage T2 or higher) are considered at high risk, especially if the tumor is proximal on the shaft and shows vascular invasion on histology; these patients are more likely than others to benefit from prophylactic dissection of the lymph nodes (Misra, 2004).

  Dynamic mapping of lymph nodes with technetium Tc 99m as a tracer plus blue dye followed by targeted biopsy has been introduced to restrict surgical dissection to sentinel nodes. The aim is to avoid the complications of unnecessary elective regional groin dissection, which can be reserved for patients with positive sentinel nodes (Valdes Olmos, 2001; Tanis, 2002; Kroon, 2005; Izawa, 2005; Perdona, 2005). The size of metastasis in the sentinel node has been found to predict additional nodal involvement (Kroon, 2006). Dynamic lymphotrophic nanoparticle-enhanced MRI with iron oxide is another promising technique that may be helpful in the evaluation of patients with palpable groin adenopathy (Tabatabaei, 2005) in which standard sentinel node biopsy is considered of low value for the detection of lymphatic spread (Hungerhuber, 2006). However, the reliability of identifying sentinel nodes needs further studies and follow-up data.

  The development of groin metastases after a negative result on sentinel node biopsy has been observed. Moreover, micrometastases may bypass the superficial nodes of the groin and drain directly into the deep groin or the iliac nodes. Preoperative sonography with fine-needle aspiration cytology, groin exploration with intraoperative wound palpation, and serial sectioning with immunohistochemical staining have been suggested as adjunctive tools to increase the reliability of sentinel-node identification (Kroon, 2004; Biedrzycki, 2006; Saisorn, 2006).

  Bilateral biopsy of sentinel lymph nodes or percutaneous fine-needle aspiration may be performed. When the result is positive, percutaneous fine-needle aspiration is useful; however, if the result is negative, involvement of metastatic nodes should not be excluded (Abi-Aad, 1992).

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Treatment for penile SCC includes medical and surgical procedures and radiation therapy. Medical therapy consists of local and systemic therapy.

Drug Category: Antineoplastic agents

These agents inhibit cell growth and proliferation.

Drug Category: Interferons

These agents are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha, beta, and gamma interferons may be given topically, systemically, or intralesionally.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• If patients do not undergo prophylactic dissection of lymph nodes, careful follow-up of the inguinal regions are required for 3 years.
• • In view of the natural history of this disease, examining patients monthly during the first year of follow-up and then bimonthly during the subsequent 2 years, with quarterly pelvic and abdominal CT scans, is strongly recommended (Lerner, 1994).
  • A different schedule for physical examination has also been suggested: monthly for the first year, every 6 months for the second year, yearly for the third and fourth years, and every 5 years (Montie, 1994).
• Patients with an early diagnosis of a tumor at a favorable stage and with prognostic features may probably be followed less strictly than those described above, unless conservative procedures are used for treatment.
• Risk-based surveillance schedules tailored to the characteristics of the neoplastic disease (stage, grade, vascular invasion, inguinal metastases), of the patient (obesity, previous inguinal surgery), and to the treatment protocol (penectomy vs surgical or nonsurgical phallus-sparing options, regional lymphadenectomy vs watchful waiting) have been suggested (Sanchez-Ortiz 2003). However, the timing and methods of choice for periodical posttherapeutic examinations are still controversial, and no uniform guidelines are available (Micali, 2006).

Deterrence/Prevention

• Circumcision in infancy and a good standard of sexual hygiene are recognized as good prophylactic measures.
• Future directions in the prevention of penile SCC (as for cervical and vulvar carcinoma) should include further elucidation of the role of preexisting conditions, including HPV infections and genital lichen sclerosus, in the pathogenesis of the disease.

Complications

• Common complications of penile SCC and verrucous carcinoma are ulceration, bleeding, and secondary infection.
• Urethral obstruction and fistulae may also develop as a result of neoplastic infiltration and destruction of underlying tissues.

Prognosis

• In the absence of inguinal metastases, patients with invasive SCC of the penis involving the glans or the distal part of the shaft who undergo adequate partial amputation have a long-term survival rate of 70-80%.
• Of patients with involved lymph nodes, 40-50% can be cured with lymph node dissection, whereas untreated patients usually die within 2-3 years (Das, 1992).
• HPV infection does not seem to negatively influence the prognosis of patients with invasive SCC (Bezerra, 2001; van Doornum, 2003; Lont, 2006).
• Genetic factors may have a role; however, the findings deserve further evaluation to be considered for staging and therapeutic planning for penile SCC.
• • Studies have shown that overexpression of p53 in tumoral tissue is associated with an increased risk of tumor progression and mortality (Martins, 2002; Lopes, 2002).
  • Alterations in DNA sequence copy number, as evaluated by means of comparative genomic hybridization may also be correlated with the clinical outcome (Alves, 2001).
• The thickness, depth of invasion, degree of cell differentiation of the primary tumor (Garcia Rodriguez, 2003), and presence of vascular and lymphatic invasions have been identified as significant predictors of cancer progression (Emerson, 2001; Kattan, 2006).
• The clinical stage of the inguinal lymph nodes is the most powerful predictor of prognosis (Kattan, 2006). In a study of 118 patients with penile SCC, survival appeared to be strictly related to lymph node status (Leewansangtong, 2001). The 5-year survival rate was 93% for stage I, T1-3, N0, M0; 55% for stage II, T1-3, N1-2, M0; and 30% for stage III, T4 or N3 or M1 (Horenblas, 1994). The risk increases according to the number and size (>2 cm) of enlarged lymph nodes or if fixation, extranodal extension, or ulceration is present. Another factor adversely influencing survival is bilateral involvement (Pandey, 2006).

Patient Education

• Early diagnosis is essential to allow for conservative treatment; therefore, patients should be advised to promptly seek medical attention in case of the onset of any penile lesion, especially if they have preexisting conditions that increase the risk of genital cancer (eg, penile lichen sclerosus and the other disorders mentioned in Pathophysiology), In such events, periodic follow-up care should be recommended for the early detection of any malignant changes.
• For excellent patient education resources, visit eMedicine's Men's Health Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Cancer: What You Need to Know, Skin Cancer, and Skin Biopsy.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to examine the genitalia can lead to missing a penile SCC.
• Failure to perform histopathologic examination is a pitfall. The diagnosis of cancer is always a histologic diagnosis; therefore, no such diagnosis should be rendered without suitable histopathologic examination.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Erythroplasia of Queyrat.
	View Full Size Image
Media type:  Photo

Media file 2:  Bowenoid papulosis. Lesions at the base of the shaft.
	View Full Size Image
Media type:  Photo

Media file 3:  Condylomata acuminata.
	View Full Size Image
Media type:  Photo

Media file 4:  Squamous cell carcinoma arising on genital lichen sclerosus.
	View Full Size Image
Media type:  Photo

Media file 5:  Pseudoepitheliomatous, keratotic, and micaceous balanitis.
	View Full Size Image
Media type:  Photo

Media file 6:  Penile horn.
	View Full Size Image
Media type:  Photo

Media file 7:  Papillary squamous cell carcinoma on the penis.
	View Full Size Image
Media type:  Photo

Media file 8:  Ulcerated squamous cell carcinoma on the glans.
	View Full Size Image
Media type:  Photo

Media file 9:  Verrucous carcinoma.
	View Full Size Image
Media type:  Photo

Media file 10:  Verrucous carcinoma.
	View Full Size Image
Media type:  Photo

Media file 11:  Verrucous carcinoma.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Abi-Aad AS, deKernion JB. Controversies in ilioinguinal lymphadenectomy for cancer of the penis. Urol Clin North Am. May 1992;19(2):319-24. [Medline].
• Agarwal P, Sharma D. Autodestruction of penis due to carcinoma. J Eur Acad Dermatol Venereol. Mar 2005;19(2):220-2. [Medline].
• Alves G, Heller A, Fiedler W, et al. Genetic imbalances in 26 cases of penile squamous cell carcinoma. Genes Chromosomes Cancer. May 2001;31(1):48-53. [Medline].
• Anderson PC, Summerton DJ, Terry TR, Bracka A. Surgical management of penile carcinoma: the primary lesion. BJU Int. Aug 2006;98(2):464-5. [Medline].
• Aynaud O, Asselain B, Bergeron C, et al. [Intraepithelial carcinoma and invasive carcinoma of the vulva, vagina and penis in Ile-de-france. Enquete PETRI on 423 cases]. Ann Dermatol Venereol. May 2000;127(5):479-83. [Medline].
• Azrif M, Logue JP, Swindell R, et al. External-beam radiotherapy in T1-2 N0 penile carcinoma. Clin Oncol (R Coll Radiol). May 2006;18(4):320-5. [Medline].
• Bain L, Geronemus R. The association of lichen planus of the penis with squamous cell carcinomain situ and with verrucous squamous carcinoma. J Dermatol Surg Oncol. Apr 1989;15(4):413-7. [Medline].
• Barbagli G, Palminteri E, Mirri F, et al. Penile carcinoma in patients with genital lichen sclerosus: a multicenter survey. J Urol. Apr 2006;175(4):1359-63. [Medline].
• Bevan-Thomas R, Slaton JW, Pettaway CA. Contemporary morbidity from lymphadenectomy for penile squamous cellcarcinoma: the M.D. Anderson Cancer Center Experience. J Urol. Apr 2002;167(4):1638-42. [Medline].
• Bezerra AL, Lopes A, Santiago GH, et al. Human papillomavirus as a prognostic factor in carcinoma of the penis:analysis of 82 patients treated with amputation and bilaterallymphadenectomy. Cancer. Jun 15 2001;91(12):2315-21. [Medline].
• Biedrzycki OJ, Hadway P, Cooke A, et al. Immunohistochemical analysis of negative inguinal lymph nodes in men with squamous cell carcinoma of the penis: are we missing micrometastases which could predict recurrence?. BJU Int. Jul 2006;98(1):70-3. [Medline].
• Bleeker MC, Hogewoning CJ, Van Den Brule AJ, et al. Penile lesions and human papillomavirus in male sexual partners of women with cervical intraepithelial neoplasia. J Am Acad Dermatol. Sep 2002;47(3):351-7. [Medline].
• Burgers JK, Badalament RA, Drago JR. Penile cancer. Clinical presentation, diagnosis, and staging. Urol Clin North Am. May 1992;19(2):247-56. [Medline].
• Campos RS, Lopes A, Guimaraes GC, et al. E-cadherin, MMP-2, and MMP-9 as prognostic markers in penile cancer: analysis of 125 patients. Urology. Apr 2006;67(4):797-802. [Medline].
• Carver BS, Mata JA, Venable DD, Eastham JA. Squamous cell carcinoma of the penis: a retrospective review of forty-five patients in northwest Louisiana. South Med J. Aug 2002;95(8):822-5. [Medline].
• Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervicalcancer in female partners. N Engl J Med. Apr 11 2002;346(15):1105-12. [Medline].
• Child FJ, Kim BK, Ganesan R, et al. Verrucous carcinoma arising in pseudoepitheliomatous keratotic and micaceous balanitis, without evidence of human papillomavirus. Br J Dermatol. Jul 2000;143(1):183-7. [Medline].
• Coblentz TR, Theodorescu D. Morbidity of modified prophylactic inguinal lymphadenectomy for squamous cell carcinoma of the penis. J Urol. Oct 2002;168(4 Pt 1):1386-9. [Medline].
• Crook J, Grimard L, Tsihlias J, et al. Interstitial brachytherapy for penile cancer: an alternative to amputation. J Urol. Feb 2002;167(2 Pt 1):506-11. [Medline].
• Cruz Guerra NA, Sáenz Medina J, Ursúa Sarmiento I, et al. [Malignant recurrence of a penile cutaneous horn]. Arch Esp Urol. Jan-Feb 2005;58(1):61-3. [Medline].
• Cubilla AL, Reuter V, Velazquez E, et al. Histologic classification of penile carcinoma and its relation to outcome in 61 patients with primary resection. Int J Surg Pathol. Apr 2001;9(2):111-20. [Medline].
• Cubilla AL, Piris A, Pfannl R, et al. Anatomic levels: important landmarks in penectomy specimens: a detailedanatomic and histologic study based on examination of 44 cases. Am J Surg Pathol. Aug 2001;25(8):1091-4. [Medline].
• Cubilla AL, Velazques EF, Reuter VE, et al. Warty (condylomatous) squamous cell carcinoma of the penis: a report of 11 cases and proposed classification of ''verruciform'' penile tumors. Am J Surg Pathol. Apr 2000;24(4):505-12. [Medline].
• Cubilla AL, Velazquez EF, Young RH. Pseudohyperplastic squamous cell carcinoma of the penis associated with lichen sclerosus. An extremely well-differentiated nonverruciform neoplasm that preferentially affects the foreskin and is frequently misdiagnosed: a report of 10 cases. Am J Surg Pathol. Jul 2004;28(7):895-900. [Medline].
• Cubilla AL, Reuter VE, Gregoire L, et al. Basaloid squamous cell carcinoma: a distinctive human papilloma virus-related penile neoplasm: a report of 20 cases. Am J Surg Pathol. Jun 1998;22(6):755-61. [Medline].
• Cubilla AL, Ayala MT, Barreto JE, et al. Surface adenosquamous carcinoma of the penis. A report of three cases. Am J Surg Pathol. Feb 1996;20(2):156-60. [Medline].
• Das S. Penile amputations for the management of primary carcinoma of the penis. Urol Clin North Am. May 1992;19(2):277-82. [Medline].
• Davis JW, Schellhammer PF. Glansectomy: an alternative surgical treatment for Buschke-Lowensteintumours of the penis. BJU Int. Oct 2001;88(6):647. [Medline].
• Dennis EJ, Heins HC, Latham E. The carcinogenic effect of human smegma: an experimental study. I. Preliminary report. Cancer. Jul-Aug 1956;9(4):671-80. [Medline].
• Dillner J, von Krogh G, Horenblas S, Meijer CJ. Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl. 2000;189-93. [Medline].
• Emerson RE, Ulbright TM, Eble JN, et al. Predicting cancer progression in patients with penile squamous cellcarcinoma: the importance of depth of invasion and vascular invasion. Mod Pathol. Oct 2001;14(10):963-8.