33.1.2.1 Incidence and Prevalence

Malignant neoplasms of the penis are rare in Europe (Figure 33.2) and North America, but they are more common in developing nations. The UK age‐standardised incidence for 2008–2010 was 1.3–2.0 per 100 000 males. The mortality rate in the UK is 0.3–0.4 per 100 000 males [5]. In Paraguay, Brazil, Angola, and India, the incidence varies between 2.3 and 8.3 per 100 000 males [6] and can account for 10–20% of male cancers.

The incidence of penile cancer has increased over the last four decades, although the overall five‐year relative survival rate has increased [7]. Between 1979 and 2009, there has been a 21% increase in incidence in the UK [8]. The reasons for this are most likely to be due to better understanding of the natural history and more aggressive management. Despite this, there is often a delay in diagnosis with men reluctant to seek advice. If left untreated, most men will succumb to their disease within two years, and the sequelae from metastases are significant. Prompt management can result in five‐year survival rates approaching 70% in the UK [8].

33.1.2.2 Aetiology and Risk Factors

The most common histological type in malignant neoplasms of the penis is squamous cell carcinoma (SCC), which accounts for more than 95% of all cases. The remaining 5% are made up of malignant melanoma, basal cell carcinoma, sarcomas, and rarely metastasis from the prostate, colorectal, or other tissue cancers.

Risk factors for penile cancer:

• Age: The incidence of penile cancer increases with age [9]. The peak age is during the sixth decade of life, but around 20% of all new cases are in men younger than 50 years of age [10].
  
• Presence of the foreskin. Penile cancer is rarely seen in a man who is uncircumcised.
  
• Phimosis is strongly associated with penile cancer. The mechanism is probably secondary to chronic infection and inflammation rather than the carcinogenic effect of retained smegma [11]. The role of BXO is more controversial and is not thought to represent a precancerous condition. However, BXO can cause phimosis so the conditions often coexist.
  
• Human papilloma virus (HPV) infection is an important risk factor. HPV is seen in the majority of penile intraepithelial neoplasia and is found in 30–40% of invasive penile SCC [12]. HPV subtypes 16 and 18 are most common. It is unclear whether HPV confers a worse prognosis. However, penile cancer is more prevalent in areas of high HPV infection, which are also often areas of low socioeconomic status.
  
• Premalignant conditions of the penis are associated with SCC and may be found in up to 40% of patients. The common premalignant conditions are as follows.

HPV related:

• Erythroplasia of Queyrat: Penile intraepithelial neoplasia (PeIN) or carcinoma in situ (CIS) of the glans or inner prepuce, associated with up to a 30% increased risk. Initially presenting as a velvety bright red painless lesion which eventually ulcerates and once infected is painful. Treatment is by excision, 5‐flourouracil or imiquimod topical use, or photodynamic therapy or cryotherapy.
  
• Bowen’s disease: PeIN of the keratinising genital (penile shaft) or perineal skin. Presents with a gradually enlarging, well‐demarcated erythematous plaque with an irregular border and surface crusting or scaling. Treatment is by excision, 5‐flourouracil or imiquimod topical use, or photodynamic therapy or cryotherapy.
  
• Buschke–Löwenstein tumour (giant condyloma acuminatum): a rare disease characterised by aggressive, wart‐like growths, verrucous carcinoma. It is an aggressive locally invasive tumour but rarely metastasises. The warty‐like lesions coalesce into a large cauliflower‐looking exophytic mass. Treatment is by wide local excision.
  
• Bowenoid papulosis: discrete pigmented verrucous papules on the penile skin. It is highly contagious and appears as multimaculopapular brown‐red lesions. It can be self‐limiting, but if it persists, treatment is by excision.

Non‐HPV related:

• Extramammary Paget disease: a rare intraepithelial adenocarcinoma. Present with velvety‐red, soft areas with scattered white islands of hyperkeratosis (i.e. a strawberry and cream appearance). The lesions become erythematous, plaque like, and desquamating especially when located in dry areas which can ulcerate. Symptoms are of itching and burning but when ulcerated become painful. Treatment is by excision.
  
• Cutaneous horn of the penis an unusual keratinising skin tumours with the appearance of horns protruding from the skin (Figure 33.3). Treatment is by excision.
  
• Lichen sclerosis

• Immunosuppression can increase the risk of SCC.
  
• There is a fivefold increase risk in smokers and tobacco chewers [13].
  
• HIV infection [14] due to either immunosuppression or increased risk of synergistic HPV infection or increased risk of reticuloendothelial tumours such as Kaposi sarcoma. Kaposi sarcoma presents as a painful, raised, bleeding papule or ulcer. Treatment is by excision, laser ablation, cryotherapy, or in advanced disease palliation.

33.1.2.3 Clinical Features

The presentation of penile cancer can range from an incidental finding (e.g. during a circumcision) to a large fungating destructive mass in the genital area (Figures 33.4 and 33.5). However, isolated lesions of lumps are the most common presentation. Lesions are found on the glans (48%); prepuce (21%); glans and prepuce (9%); glans, prepuce, and shaft (14%); coronal sulcus (6%); and shaft only (2%) [15].

Lesions can be flat red areas, papillary growths, or ulcerative. These can be painful and prone to infections. If ulcerated, they may cause significant bleeding. Palpable inguinal lymph nodes might also be present.

33.1.2.4 Diagnosis and Investigations

A physical examination should include a thorough inspection of the penis. This includes retraction of the prepuce to expose the glans. The shaft of the penis should be palpated along its length, tracing it back to the division of the corpora cavernosa if possible. Both inguinal regions should be carefully examined for any evidence of lymphadenopathy.

Biopsy is mandatory if a suspicious lesion is found (whether incisional or excisional). However, if the lesion is a large fungating or destructive mass, then primary surgery can be undertaken without preceding biopsy to speed up definitive treatment.

Tumour markers include overexpression of p53 and SCC antigens, however, are rarely used for clinical purposes.

Whilst ultrasound may be used to determine the extent of invasion in the primary lesion [16], penile magnetic resonance imaging (MRI) is more commonly used and accurate, accompanied by an intracorporeal injection of alprostadil to induce an erection [17]. This is particularly relevant if penile‐conserving therapy is being considered and allows better definition of the tunical margin and to assess possible invasion through it (Figures 33.6 and 33.7).

Confirmation of suspicious lymph nodes can be delineated with an ultrasound in the inguinal regions and a chest, abdominal, and pelvic computed tomography (CT) scan for distant metastases.

33.1.2.5 Histopathology

There have been a number of histological subtypes described in penile SCC (Table 33.1). The usual type accounts for about 60% of cases.

The verrucous variant has a number of varieties that have been described, all with a relatively good prognosis and very low rate of metastasis [18]. Furthermore, there are many tumours that show a mixed histology (Table 33.1) [7].

The grade of tumours is based on cellular differentiation from original tissue: G1, well differentiated tumours; G2, moderately differentiated; and G3 and G4, poorly differentiated and undifferentiated.

The single‐most important prognostic variable appears to be the presence of metastases in the lymph nodes [19, 20]. Other prognostic factors also play a role, including histological grade, depth of invasion, tumour thickness, and the presence of vascular or perineural invasion [21]. Vascular or perineural invasion are often seen in the specimens of high risk SCC [22].

33.1.2.6 Staging

Invasion can be to the corpora cavernosa and corpus spongiosum, including the urethra.

Metastases usually follow a stepwise progression along the lymphatic chain. Spread is normally to the superficial and deep inguinal lymph nodes, then to the obturator and iliac lymph nodes. Some subtypes (i.e. basaloid) are thought to be able to develop skip lesions further up the lymphatic chain or present with unusual distant metastases (e.g. cutaneous or mediastinal).

The current staging uses the tumour, node, and metastasis (TNM) classification (Table 33.2) (Figure 33.8) [23].

T (Primary Tumour)
TX	Primary tumour cannot be assessed
T0	No evidence of primary tumour
Tis	Carcinoma in situ or PeIN
Ta	Noninvasive verrucous carcinoma, not associated with destructive invasion
T1  T1a  T1b	Tumour invades subepithelial connective tissue Tumour invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated or undifferentiated (G1–2 T1) Tumour invades subepithelial connective tissue with lymphovascular invasion or is poorly differentiated or undifferentiated (G3–4 T1)
T2	Tumour invades corpus spongiosum with or without invasion of the urethraa
T3	Tumour invades corpus cavernosum
T4	Tumour invades other adjacent structures
N (Regional lymph nodes)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1  pN1	Palpable mobile unilateral inguinal lymph node Intranodal metastasis in up to two regional lymph nodes
N2  pN2	Palpable mobile multiple unilateral or bilateral inguinal lymph nodes Metastasis in three or more unilateral lymph nodes or bilateral inguinal lymph nodes
N3  pN3	Fixed inguinal nodal mass or pelvic lymphadenopathy, unilateral or bilateral Metastasis in pelvic node(s), unilateral or bilateral or extranodal extension of any regional lymph node metastasis
M (Distant metastasis)
M0	No distant metastasis
M1	Distant metastasis

^a PEIN, penile intraepithelial neoplasia; TNM, tumour, node, and metastasis.

33.1.2.7 Management

33.1.2.7.3 Surgical Management of Invasive Disease

Curative surgery can be achieved with tumours confined to the prepuce with a radical circumcision.

For lesions on the glans or penis, consideration is needed to determine the extent of the penile‐preserving surgery. Although radiotherapy has been performed in the past, it is now rarely used for primary disease.

For T1 and T2 lesions localised to the glans, a number of techniques can be used with curative intent. Wide local excisions can be used for small lesions. These can be either closed primarily or covered with a split skin graft. For larger lesions, penile‐preserving techniques, such as glansectomy, can be employed. This involves the removal of the glans cap with sparing of the corporal bodies. The area left exposed can then be covered with a split skin graft (Figure 33.9). A frozen section can be used to ensure negative margins. It is good practice to include a ‘doughnut’ of urethra as a separate biopsy for frozen section [25]. Good oncological outcomes have been reported with the local recurrence rate to be less than 10% [31].

Partial penectomy can be considered in tumours that involve the corpora or the urethra. Again, frozen can be used at the time of surgery, but it may not be necessary if the patient is not concerned with penile preservation or has significant erectile dysfunction. Depending on the resultant penile length, split skin grafts may be used or primarily closure with penile shaft skin. The penectomy should give the patient an adequate penile stump to allow directable voiding when standing in addition to adequate length to allow for sexual intercourse. The local recurrence rate in partial penectomy varies widely in the published literature but is generally accepted to be lower than other penile‐conserving techniques.

For more advanced tumours, a total or radical penectomy is required to ensure negative surgical margins. Total penectomy should also be considered when not enough length remains to direct micturition (i.e. if the partial penectomy results in the penile stump being flush with the skin of the scrotum and ammoniacal dermatitis likely). The aim of the surgery is remove the tumour and the penis completely that classically involved the detachment of the crura from the pubic bones. The scrotum and testes are usually preserved, avoiding bone demineralization and the need for testosterone‐replacement therapy. Obviously some form of urinary diversion is required. Dependent of the resultant length of the urethra, a perineal urethrostomy can be fashioned or the urethra can be closed and a suprapubic catheter inserted (Figure 33.10).