Diagnosis and Management of Penile Cancer

Diagnosis and management of penile cancer

CLARE KANE, LAURA SELLERS AND ROWAN MILLER

Cancer of the penis is rare, but if caught early has a good prognosis. In this article the authors discuss the epidemiology, risk factors, presentation features and management of penile cancer.

enile cancer is rare, representing less Pthan 1% of all UK cancer diagnoses. It most commonly presents in the fifth decade and involves the glans or prepuce in over 80% of cases.1 While squamous cell carcinoma (SCC) is the dominant pathology, other subtypes including basaloid, warty and adenosquamous also exist.2 Human papillomavirus (HPV) and phimosis are the most important Figure 1. Presenting features of penile cancer. Any new lesion present on the penis for more risk factors for the development of than four weeks is suspicious and warrants an urgent referral for further investigation penile cancer. over 65 years.3 The increased incidence is The prognosis is highly dependent on explained by changes in sexual practice stage at diagnosis, ranging from 90% (resulting in higher exposure to HPV), five-year survival with localised disease, decreasing rates of circumcision and an to 40% with more than two lymph ageing population.4 nodes involved. Due to the rarity of the disease, there is limited level 1 evidence RISK FACTORS for the management of penile cancer, and A number of risk factors for penile cancer guidelines are often based on retrospective, have been identified, including HPV single-centre studies. infection, smoking, circumcision state, phimosis, poor hygiene and low socio- EPIDEMIOLOGY economic status.5 HPV infection, which is Although penile cancer is rare, with associated with an increased number of Clare Kane, Specialist Registrar; Laura approximately 620 cases diagnosed in the sexual partners, a history of genital warts Sellers, Clinical Fellow; Rowan Miller, UK annually, the incidence is increasing. and concomitant sexually transmitted Specialist Registrar, Department of Over the last decade the incidence in diseases, is a strong risk factor for penile Medical Oncology, University College the UK has increased by 25%, with the cancer. As many as 60–80% of penile London Hospital, London majority of cases diagnosed in those cancers are associated with HPV infection,5

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although the link with HPV is dependent cancer have a history of phimosis.4,5 Other area of the penis or foreskin. This then on cancer subtype, being highest in warty/ conditions causing inflammation, such as develops into a non-healing rash, lump or basaloid cancers at around 70–100%, in balanitis, paraphimosis and lichen sclerosis, ulcer. Lesions may present as a flat growth comparison to 30% in other types of penile also increase the risk of penile cancer, as do with a bluish-brown colour or red rash, a cancer. The predominant genotypes found iatrogenic causes such as treatment with wart or small crusty bumps or an ulcer or are HPV16 and 18.6 Concurrent infection PUVA and psoralen for psoriasis.4 Other risk blister (Figure 1). These changes are often with HIV or immunosuppression increases factors known to increase the risk of penile painless and may only be visible when the the rates of malignant transformation of cancer include tobacco use (2.8–4.5% foreskin is pulled back. Any new lesion HPV lesions. increase), and low socio-economic and present on the penis for more than four educational status.5,8 weeks is suspicious and warrants an urgent It has been suggested that HPV status referral for further investigation. Later may have both a prognostic and predictive PATHOLOGY symptoms include bleeding or discharge, role in determining treatment response, SCC is the most common type of penile which is often malodorant. Alternatively, although the results are conflicting. While cancer, representing 90% of cases.9 penile cancer may present with new onset some studies have demonstrated a clear SCC normally develops on the foreskin phimosis. Occasionally, patients present beneficial effect for HPV positivity on or the head of the penis, and can be with non-specific symptoms due to prognosis, others have been unable to further classified based on appearance, metastatic disease, such as fatigue, weight confirm this.7 Expression of HPV predicts eg basaloid, warty, mixed warty-basaloid, loss, abdominal pain or symptoms of bony treatment response in other HPV-related verrucous and papillary. Less common metastases, such as pain. cancers, such as head and neck cancer, subtypes include adenocarcinomas, which although it remains to be seen whether arise from the sweat glands in the skin of INVESTIGATIONS this is the case in penile cancer. the penis, melanoma, basal cell cancers Initial investigations include physical and sarcoma. examination with recording of the Phimosis and poor hygiene are important morphological and physical characteristics risk factors for penile cancer. Both lead PRESENTING FEATURES AND of the lesion and examination of both to the accumulation of smegma, leading INVESTIGATIONS groins. Cytological and/or histological to chronic inflammation and irritation. The initial signs of penile cancer are often diagnosis is required and any palpable As many as 90% of patients with penile a thickening or a change in colour of an lymph nodes should also be biopsied. Pelvic imaging should be performed Prognosis and a PET-CT (or standard CT if PET-CT Stage (five-year survival) is not available) in those with evidence Stage 0 (Tis, Ta, N0, M0: carcinoma in situ or 90–100% of metastatic inguinal lymph nodes. non-invasive verrucous carcinoma) A bone scan should be performed in patients with symptoms suggestive of Stage 1 (T1a, N0, M0: no evidence of LVI) 90–100% bony metastatic disease. Stage 2 (T1b/T2/T3, N0, M0: LVI/poorly differentiated/ 90–100% undifferentiated/tumour invades corpus spongiosum/ STAGING AND PROGNOSIS corpora cavernosa or urethra) Penile cancer should be staged according to the American Joint Committee on Stage 3A (T1–3, N1, M0) 80% Cancer (AJCC) tissue, nodes and metastases Single, unilateral lymph node (TNM) classification (Table 1), with 10 Stage 3B (T1–3, N2, M0) 40% presenting stage important for prognosis. Multiple unilateral or bilateral inguinal lymph nodes Broadly, patients are divided into those with localised or metastatic disease. Stage 4 (any T4, any N3, any M1) 11% Localised disease is highly curable and T4 – invades adjacent structures, N3 – fixed inguinal or further subdivided into Stage 0, 1 or 2. pelvic lymph nodes, or metastatic disease Stage 0 represents cancer on the surface of Tis, tumour in situ; Ta, verrucous (wart-like) carcinoma that is only in the top layers of the skin only, Stage 1 where the cancer has skin (non-invasive); LVI, lymphovascular invasion. invaded connective tissue but not lymph nodes or blood vessels, and Stage 2 where Table 1. Staging of penile cancer10 the cancer has spread to local connective

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tissue, lymphatics or blood vessels, or to KEY POINTS the erectile tissue or urethra. Metastatic disease includes Stage 3A, which involves • Penile cancer is a rare cancer a single unilateral groin node, Stage 3B where ≥1 lymph node is involved • Incidence is increasing in the UK (including bilateral groin nodal disease) • Prognosis is highly dependent on stage at diagnosis and Stage 4, which can represent invasion of local structures such as the prostate, • Most tumours are squamous cell cancers and can be cured if detected pelvic lymph node involvement or distant early enough 11 metastatic disease. The overall survival of • Early diagnosis is essential patients with metastatic disease (beyond the pelvic nodes) is 0% at five years and • Early signs to recognise include a new rash or lesion on the penis present <10% at two years.11 for four weeks or longer • Some lesions may be painless and may not be visible unless the foreskin MANAGEMENT is retracted Treatment is dependent on tumour stage, size and location. Treatment • New bleeding or discharge and new onset phimosis are warning signs options include surgery, radiotherapy, chemotherapy and novel therapies. ulcer following radiotherapy should be CONCLUSIONS Surgical resection is an important part biopsied to exclude recurrent disease. Due to the rarity of penile cancer, of treatment. For localised disease, Circumcision is routinely performed prior treatment should be managed in a tertiary conservative treatment such as to radiotherapy treatment. centre using a multidisciplinary approach. cryotherapy, laser surgery and Mohs Early diagnosis gives the best chance of microsurgery can be considered. Mohs Chemotherapy is used in metastatic long-term survival and maintenance of microsurgery is a technique where disease and in conjunction with surgery function. In order to improve outcomes for the tumour is cut from the skin in thin for those with local-regional disease, patients, concerted efforts are required for layers and examined microscopically either in a neoadjuvant setting or multicentre, international collaborations during surgery to ensure clear margins. postoperatively.11 The evidence for to increase our understanding of this For more extensive disease, a partial chemotherapy in penile cancer is limited rare disease. or total penectomy is required, which to small studies and retrospective analysis, may also include surgical removal which makes it difficult to draw any Declarations of interest: none declared. of the lymph nodes in the groin for definite conclusions regarding optimal high-risk tumours. Radical iliac lymph regimes. Chemotherapy regimes commonly Acknowledgements node dissection is recommended for combine two or three chemotherapy With thanks to Professor Peter Malone, involved nodes. In the presence of drugs due to the relative resistance of Consultant Urologist, Royal Berkshire metastatic inguinal node disease, penile cancer to chemotherapy and the Hospital for providing the photographs. superficial dissection of the contralateral majority contain a cisplatin backbone. side is also required, with complete Neoadjuvant chemotherapy followed REFERENCES dissection performed in the presence of by surgery is recommended for patients 1. Pizzocaro G, Algaba F, Horenblas S, et al. positive nodes on frozen section. with unresectable inguinal lymph nodes.11 EAU penile cancer guidelines 2009. Eur Urol Adjuvant therapy is recommended for 2010;57:1002–12. Radiotherapy has the advantage of those with N2 or N3 disease. Combination 2. Downes MR. Review of in situ and providing durable local control with the therapy such as cisplatin/fluorouracil invasive penile squamous cell carcinoma preservation of functional anatomy. External or paclitaxel/carboplatin is used for and associated non-neoplastic beam radiotherapy and brachytherapy can metastatic disease. Due to the rarity of dermatological conditions. J Clin Path be used alone or in combination to treat penile cancer, few studies have examined 2015;68:333–40. the primary tumour. Radiotherapy is not the effects of novel targeted or biological 3. Cancer Research UK. Penile cancer statistics without toxicity; this includes skin toxicity, therapies for its management, although (www.cancerresearchuk.org/health- soft-tissue ulceration and meatal stenosis, the association with HPV suggests that professional/cancer-statistics/statistics- and less commonly urethral fistulae, penile immunotherapy may represent a promising by-cancer-type/penile-cancer; accessed necrosis and oedema. Any slow-healing treatment option. 1 August 2016).

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