The incidence is 1:100,000 men in the West, which represents less than 1% of male maligmant tumours. It is commonest in men in their 60's, and in Asia, Africa and S. America where it can reach rates of 10-20%.

It can be caused by phimosis and poor genital hygiene. Circumcisions in newborns (e.g. Jews) results in almost 100% protection, and with adolescent circumcision (e.g. Muslims) there is a slightly lower degree of protection.

It can be associated with HPV e.g. PCR studies have identified a 50% incidence of HPV type 16 (most common type) in invasive SCC, 90% in CIS (most contain E6 - E7 portions).

Psoralens and UV radiation treatment also results in increased risk.

• Cutaneous horn
  A hyperkeratotic lesion that may be associated with pre-existing wart/trauma. Excise and watch.
• Balanitis Xerotica Oblitarans (lichen sclerosis et atropicus)
  A patchy white lesion involving the glans, prepuce and urethra. Histologically it has an atrophic epidermis with loss of rete pegs. It should be treated with local steroid application, circumcision and meatotomy for meatal stenosis.

Balanitis Xerotica Oblitarans - pathology

• Leukoplakia
  A hyperkeratotic lesion associated with chronic irritation. Histologically hyperkeratosis and hypertrophy of rete pegs. The source of irritation should be removed and if this does not resolve it then local excision.

• Bowenoid papulosis
  First described in 1977, it consists of violaceous papules on the glans or shaft of the penis. It is often seen in younger patients (teens - 20's), the circumcised, the sexually promiscuous and is also associated with HPV. It is similar histologically to CIS but with a lesser degree of atypia. It is completely benign BUT is associated with cervical cancer in sexual partners. It can be treated with laser therapy, 5FU cream or excision with skin grafting.
• Condyloma acuminatum
  Venereal/genital warts - a STD caused by Human Papilloma Virus. It is also the main agent causing cervical dysplasia and dysplasia. Often found on the penis after first diagnosing in the female. It can be treated by application of 1% Podophyllin or trichloroacetic acid, electrocautery, local excision, laser therapy (CO2, Nd:YAG, KTP) and flurouracil cream (meatal and intraurethral disease).
• Karposi's Sarcoma
  A tumour of the reticuloendothelial system. Eighteen percent of patients with AIDS have penile/genital lesions.These show as dark coloured bleeding tender papules of skin. There are four subcategories:
  • Classical Karposi's - in patients without immunodeficiency, indolent course.
  • Immunosupressive treatment related Karposi's (transplants etc.), often reversed with dose modification.
  • African Karposi's (epidemic) - young men, aggressive or indolent.
  • AIDS-related Karposi's (epidemic), associated with Negroes with HIV.
• Buscheke-Lowenstein tumour
  Giant condyloma acuminatum which causes pressure erosion into surrounding tissues. It is extremely well differentiated and superficial, invading the underlying tissues in a broad front. It can be locally aggressive, but does not metastasise. It can also contain HPV types 6 and 11and is known as a 'verrucous' carcinoma of the penis. When found in other sites (e.g. larynx, vulva) it does metastasise.
  

• Erythroplasia of Queyrat
  First described in 1911 it is multiple or solitary shiny, erythematous velvety plaques on the glans or prepuce. Fifty percent note pain/itching. It is treated with circumcision and 5-FU cream (2/12 trial, alternating 2 weeks on 2 weeks off - need to wear condom to protect scrotum).
• Bowens disease
  First described in 1912 in 2 patients with non-genital skin CIS. The development of invasive SCC is rare, but up to 25% have simultaneous systemic tumours. This is not the case in Bowen's disease of the penis, which affects the shaft. It is treated with local excision.
  

SCC is usually well to moderately differentiated. It metastases by lymphatic embolisation to regional lymph nodes. The penile skin/prepuce/glans drain to the superficial inguinal, the glans and corpora to the deep inguinal and pelvic (usually obturator fossa) nodes. The depth of invasion and tumour grade are the best predictors of nodal involvement. 40% - 50% of patients will develop nodal metastases during the course of the disease. 50% have palpable inguinal nodes at presentation but only 50-60% have metastasis within them, others are reactive/infective.

Up to 20% of patients with impalpable nodes have pelvic nodal involvement. Death is often due to local complications of nodal disease e.g. infection or haemorrhage. Cachexia from distant dissemination is rare, 10% develop metastases during the course of the disease.

There is often a significant delay in presentation - 50% present at least 6 months after the first onset of symptoms. The usual presentation is a painless sore or ulcer on the prepuce or glans. Otherwise it can be balanoposthitis and discharge, or rarely lymphadenopathy. Assessment of the primary disease is via a biopsy and local invasion assessment can be assisted by US or MRI.

If palpable, assessment of lymph nodes is by FNA (if negative the patient should be re-examined 4-6 weeks after treatment of primary and given a course of antibiotics).CT and bipedal lymphangiography adds little clinical information beyond that of examination when detecting inguinal nodes. A CT of the abdomen may detect pelvic nodal involvement.

Jackson staging

Primary tumour
Controversial - local control important but survival is dependent on nodal involvement.

Non-organ preserving
Good local control can be achieved and usually local recurrence rates are less than 10%. However, when it does occur, nodal metastases also present so prognosis is poor.

• Partial amputation - standard surgical treatment of TNM87 T1 disease is a guillotine resection 2cm from the proximal margin of the tumour.
• Partial penectomy - also performed for T2 disease where a 2cm resection margin is possible, otherwise total amputation.
• Emasculation - performed for T4 tumours with bilateral inguinal lymphadenopathy. Pelvic nodes are removed extraperitoneally.

Organ conserving
Although local recurrence rates are high when compared to radical surgery, most are not concomitant to nodal metastasis and so can safely proceed to surgical resection. It is recommended that T1 and small (less than 4cm) T2G1/2 lesions are suitable for penis conservation (Horenblas et al. 1992 and European Board of Urology recommendation 1994).

• Circumcision
  This is occasionally sufficient for T1NO tumours limited to the foreskin. It has a 30% recurrence rate.
• Wedge resection
  Used for small lesions on the shaft. It has recurrence rates of 50%.
• Laser surgery
  Used for pre-malignant lesions and CIS. It can be used for small T1 tumours, but there is a 5-15% recurrence rate. CO2,Nd:YAG and KTP lasers are used under LA. Resect to a 5mm margin and ensure margin is clear of tumour. If not, DXT can be given. Large exophytic lesions may be given primary chemotherapy to shrink, then laser surgery to widely resect the base.
• Moh's micrographic surgery
  Used for small glanular lesions. Layers of malignant cutaneous tissue are removed under LA. Each shaving is fixed and microscopically examined until cancer free plain is reached. It results in glandular deformity.
• Radiotherapy
  Local recurrence occurs in 45% at 10 years (40% with T1 disease, Sarin et al. 1997). T1NO tumours less than 4 cm in diameter without local invasion are usually selected. Some will treat Jackson II, but local control after salvage is 60%. Circumcision is always performed first.
  • Brachytherapy (external isotope mould and interstitial DXT) - not used now.
  • External beam DXT
    Colbalt or Cesium units or linear accelerators are used. High energy photons give dose ranges of 45-60 Gy in 15-30 fractions over a 3-8 week period. The penis is treated in a perspex block to ensure uniform dose distribution. Selection depends on body habitus to ensure 2 cm clearance (e.g. thin patient with long penis is good).
    Complications are common:
    • Immediate - mucositis, prepucial oedema and infection.
    • Delayed - meatal stenosis in up to 30%, fistulae, penile necrosis (superficial 40%).
• Combined treatment modalities
  SCC is responsive to chemotherapy to some extent. Most active agents are bleomycin, methotraxate and cisplatin. It can be given in combination with DXT or laser surgery to improve the cosmetic result.

Inguinal lymphadectomy

Lymph node metastasis develops in 30-50% and up to 20% occur in the initial NO disease. In the latter case progression is rapid when they do occur (this may be due to poor/non-existent surveillance).

A lymphadectomy is the only hope of cure (80% longterm survival with small volume metastasis), but complications are high. There is major morbidity in 30-50% and flap necrosis, seroma, lymphocoele and infection lead to delayed healing. Lymphodoema of the lower limb and external genitalia is common and permanent. There is also 3% mortality.

Modifications have been suggested to decrease morbidity, but all miss metastases:

• Sentinel node biopsy (node superior and lateral to the inferior epigastric vein) - misses groin metastasis in 20%
• Most medial inguinal node (MIN) sampling misses 10% (Kumar et al. 1998)
• Bilateral modified inguinal lymphadenectomy - dissection is limited to thelateral margin femoral artery, saphenous vein is preserved and the sartorious muscle is not transposed. It again misses metastatic disease in 15% (Lopes et al. 1996).

A lymphadanectomy is recommended when chances of metastasis are high. Most are recommended with T2N0G3, T2-T4 disease (European Board of Urology recommendation 1994). Others advise a watch and wait policy in all compliant N0 patients. Others advise dissection in all G1 tumours (Theodorescu et al. 1996), as even in watched G1 tumours, 30% may develop groin recurrence.

Penile amputation together with lymphadanectomy is only recommended when there is proven nodal involvement (FNA). In all other cases the regional nodes can be re-evaluated after primary the tumour is surgicall staged/graded and a 6 week course of anti-biotics given. 86% of the remaining palpable nodes will be metastatic.

If more than one node is involved on one side, contralateral dissection is advocated because 50% of impalpable contralateral nodes have metastases.

If inguinal nodes are involved it may be possible to proceed with pelvic dissection BUT the prognosis is dismal - 20% 2 year survival (0% at 5 years) and death is due to metastatic disease.

If lymphadanectomy develops after a period of surveillance, only ipsilateral lymphadanectomy is required.

Combined treatment modalities

Neo-adjuvant and adjuvant radiotherapy is not used because of worsening wound healing and oedema. It may be used in palliation for fixed nodes.

Neoadjuvant chemotherapy is suggested by some for treatment of inoperable fixed inguinal nodes. A combination of bleomicin, methotrexate, cisplatin or cisplatin plus 5FU is used.

It may be possible to give adjuvant therapy if lymph nodes positive/treatment in metastatic disease. Cisplatin, bleomicin and methotrexate were evaluated in a Phase II study (SWOG). There was a 32% response rate (12% complete). However, the toxicity is considerable - 10% mortality, 30% grade 4 morbidity (Crawford et al. 1999).

Nodal involvement is the most important prognostic factor. The tumour grade and depth of invasion is significantly related to nodal metastases.

• 5 year survival is 85% if node negative, 30% if nodes present (Srivinas et al. 1987). Survival is better for a subset with limited nodal involvement - 55% survival if unilateral inguinal nodes, no extra nodal extension and no iliac nodes. Prophylactic lymph node dissection appears to improve survival in T1G3 and T2 disease.
• 5 year survival for 1978 TNM N0, N1 and N2 disease was 93%, 80% and 50% (Horenblas et al. 1993). T1, T2 and higher tumours had 80% and 50% chance of nodal spread. G1/G2 and G3 tumours had 40% and 80% chance of nodal spread.

References

Crawford et al. (1999) J. Urol. 161, 1823-1825
Horenblas S et al. (1991) J. Urol. 147, 1279-1283
Horenblas S et al. (1992) J. Urol. 147, 1533-1538
Horenblas S et al. (1993) J. Urol. 149, 492-497
Krieg R & Hoffman R (1999) Oncology, Oct. 1347-1352
Lopes et al. (1996) Cancer 77, 2099-2102
Magoha GAO (1995) East African Medical Journal, Sept. 547-550
Mellon JK & Thorpe AC (1998) Synopses in Urology. Blackwell Science Ltd. pp. 110-115
Pizzocaro G, Piva L, Bandieramonte G & Tana S (1997) European Urology 32, 5-15
Resnick IR & Novick AC (1999). Squamous cell carcinoma of the penis and pre-malignant lesions of the penis. Urological Secrets. 2nd Edition. Hanley & Belfus Inc.
Sarin et al. (1997) Int. J. Radiat. Oncol. Biol. Phys. 38, 713-722
Theodorescu et al. (1996) J. Urol. 155, 1626-1631