eMedicine Specialties > Dermatology > Malignant Neoplasms
Penile Squamous Cell Carcinoma
Updated: Mar 5, 2009
Introduction
Background
Penile tumors present a difficult diagnostic and therapeutic issue, 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 at an advanced stage when a conservative surgical approach is no longer feasible.1,2
Among malignant neoplasms of the penis, squamous cell carcinoma (SCC) is the most common.3,4,5 Verrucous carcinoma, also called Buschke-Löwenstein tumor, is a well-differentiated variant of SCC worthy of special recognition.6,7,8
Pathophysiology
The cause of penile SCC is unclear, although 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 penile SCC 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.5
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. Approximately 37% of the invasive lesions are associated with regional lymph node metastases.9
Erythroplasia of Queyrat
Erythroplasia of Queyrat is most common in elderly, uncircumcised 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.
Erythroplasia of Queyrat.
Transformation into an invasive SCC is more common in erythroplasia of Queyrat than in Bowen disease, with a prevalence of 10-33%. Ulceration and/or papillary outgrowths are clinical signs of the disease. Approximately 20% of patients have regional lymph node metastases.10,11
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.
Bowenoid papulosis. Lesions at the base of the shaft.
Extragenital involvement is exceedingly rare.12 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.3,4,13
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 upon histologic examination.14,15
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).
Condylomata acuminata.
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.16
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.17,18 HPV sequences have also been found in local and distant metastases of penile SCC.19,20 The existence of 2 etiologically distinct types of penile SCC has been hypothesized: (1) a type with a viral cause and possible sexual transmission more likely to occur in younger individuals and (2) another type of unknown cause affecting older individuals.5,21,22
Penile lichen sclerosus
Penile lichen sclerosus is a chronic, sclerosing, atrophic inflammatory condition that is more often observed in men, although boys 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). Upon clinical examination, nodules or ulcerated plaques usually reveal malignant transformation.
Squamous cell carcinoma arising on genital lichen sclerosus.
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.21,23,24,25,26,27 Studies have shown that lichen sclerosus is preferentially associated with HPV-negative, low-grade, differentiated, and highly keratinizing penile SCCs.25,28
Polymerase chain reaction (PCR) testing has shown the presence of oncogenic HPVs in some cases of penile carcinoma arising on lichen sclerosus.29 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 to 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.5
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.
Pseudoepitheliomatous, keratotic, and micaceous balanitis.
Once considered benign, PKMB is now regarded as a tumor with a low-grade malignancy potential similar to that of verrucous carcinoma.30 Degeneration into SCC clinically appears as a nodular lesion within the plaque.
Penile horn
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.
Penile horn.
These clinical features are not diagnostic because penile horns may microscopically reveal a benign epidermoid outgrowth (eg, warts); keratoacanthomas; or in situ, verrucous, or invasive carcinomas.31,32 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.3,4
Factors resulting from the lack of circumcision
Epidemiologic data have demonstrated that penile SCC is exceedingly rare in men who are circumcised at birth.33 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.34 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%).35 On the other hand, phimosis itself is a risk factor for penile SCC development,36 because 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.3,4,5 However, a 2001 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.36
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,37 traumas,36,38 or chronic irritation,39 can be factors contributing to penile SCC.
- 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.40
- Cigarette smoking has been found to show a clear-cut association with penile SCC; this association is related to the nicotine intake and is independent of phimosis or balanitis. Whether tobacco products concentrate in smegma has not been proven in humans.36,41
- UV radiation may enhance the development of penile SCC, as is observed in patients with psoriasis treated with psoralen plus UV-A or with UV-B.42,43
- Immune suppression, due to either transplantation or HIV infection, is associated with a greater risk of SCC development on the penis and on other skin sites.44
- Reconstructive surgery for sex reversal can be factor, although whether the heterotopic penile skin within the neovagina may be at an increased risk of cancer development is unclear.45
- Penile verrucous carcinoma has been linked to HPV infection; HPV types 6 and 11 are most frequently isolated.3,4,5,6,7
- 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 irritation3,4,5 ; and previous dermatoses involving the genital area, such as genital lichen sclerosus,21,23 lichen planus,46 or PKMB.47
- 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 18.3,4,5,6,7
Frequency
United States
- SCC accounts for at least 95% of all penile malignancies.48 It represents approximately 2% of all cancers of the male genitalia and is found in 0.3-0.5% of the cancer-bearing male population.49,50 The overall incidence of primary malignant penile cancers (mean: 0.69 case per 100,000 population) has been constantly decreasing from 1973 to 2002.51
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.3,4,5,48 An incidence of 0.6 case per 100,000 population per year was recorded in the United Kingdom in 2007.52
- Verrucous carcinoma represents 5-16% of all SCCs, and its prevalence varies from 5-24% among all penile malignancies.6
Mortality/Morbidity
- SCC is the cause of less than 1-2% of all deaths from cancer in men in the United States.49
- Statistically significant decreased survival has been found in African American men, who tend to present with a high stage of disease.53
Race
- A racial predilection is unlikely, but statistical data are controversial because of possible confounders. In the United States, the highest prevalence of penile cancer is reported among Hispanics.54
- SCC is rare among some religious communities who practice circumcision, such as Jewish and Moslem groups and the Ibos of Nigeria.3,4
Age
- The age at onset of penile SCC is 20-90 years, with a peak around the sixth and seventh decades.50,55
- A few cases have been reported in childhren.48
- Penile verrucous carcinoma may occur at any age (18-88 y), but two thirds of all cases occur before age 50 years.6,7
Clinical
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.56
- 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.3,4,5,57,58
- 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.6,7
Physical
Penile SCC most often occurs on the glans (48%), although 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%).48
- 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.
Papillary squamous cell carcinoma on the penis.
- 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
Ulcerated squamous cell carcinoma on the glans.
- Secondary infection, with a purulent, foul-smelling discharge, is often present. Pain is usually slight in comparison with the extent of the local destruction.3,4,5
- 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, approximately 20% contain metastases.48
- 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.48,59,60
- 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, in rare cases, it may resemble a penile horn. Swelling of the regional lymph nodes as a result of secondary infection is frequent, whereas local metastases are infrequently reported.6,7
Verrucous carcinoma.
Verrucous carcinoma.
Verrucous carcinoma.
Causes
See Pathophysiology.
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Further Reading
Keywords
penile squamous cell carcinoma, penile SCC, SCC, penile cancer, genital cancer, penile tumor, epidermoid carcinoma of the penis, verrucous carcinoma, Buschke-Loewenstein tumor, penile malignant neoplasm, Bowen's disease, Bowen disease, erythroplasia of Queyrat, bowenoid papulosis, leukoplakia, HPV infection, human papillomavirus infection, penile lichen sclerosus, balanitis, PKMB
