Penile Cancer

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EAU GUIDELINES ON PENILE CANCER

(Text update April 2014)

O.W. Hakenberg (Chair), E. Compérat, S. Minhas, A. Necchi, C. Protzel, N. Watkin

Guidelines Associate: R. Robinson

Introduction and epidemiology

The incidence of penile cancer increases with age, peaking during the sixth decade of life. However, the disease does occur in younger men. There are significant geographical variations within Europe as well as worldwide. Penile cancer is common in regions with a high prevalence of human papilloma virus (HPV), which may account for the global incidence variation, as the worldwide HPV prevalence varies considerably. There is at present no recommendation for the use of HPV vaccination in boys.

Risk factors

Recognised aetiological and epidemiological risk factors for penile cancer are:

Risk factors

Relevance

Phimosis

Odds ratio 11-16 vs. no phimosis

Chronic penile inflammation (balanoposthitis related to phimosis)

Balanitis xerotica obliterans (lichen sclerosus)

Risk

Smoking

5-fold increased risk vs. non-smokers

Human papilloma virus infection condylomata acuminata

22.4% in verrucous squamous cell carcinoma 36-66.3% in basaloid-warty

Rural areas, low socio-economic status, unmarried

Multiple sexual partners, early age of first intercourse

3-5-fold increased risk of penile cancer

Pathology

Squamous cell carcinoma (SCC) in different variants accounts for more than 95% of cases of malignant penile disease. Table 1 lists premalignant lesions and Table 2 lists the pathological subtypes of penile carcinomas.

Table 1: Premalignant penile lesions (precursor lesions)

Lesions sporadically associated with squamous cell carcinoma (SCC) of the penis:

Cutaneous horn of the penis

Bowenoid papulosis of the penis

Lichen sclerosus (balanitis xerotica obliterans)

Premalignant lesions (up to one-third transform to invasive SCC):

Intra-epithelial neoplasia grade III

Giant condylomata (Buschke-Löwenstein)

Erythroplasia of Queyrat

Bowen’s disease

Paget’s disease (intradermal ADK)

Table 2: Histological subtypes of penile carcinomas, their frequency and outcome

Subtype

Frequency

(% of cases)

Prognosis

Common squamous cell carcinoma (SCC)

48-65

Depends on location, stage and grade

Basaloid carcinoma

4-10

Poor prognosis, frequently early inguinal nodal metastasis

Warty carcinoma

7-10

Good prognosis, metastasis rare

Verrucous carcinoma

3-8

Good prognosis, no metastasis

Papillary carcinoma

5-15

Good prognosis, metastasis rare

Sarcomatoid carcinoma

1-3

Very poor prognosis, early vascular metastasis

Mixed carcinoma

9-10

Heterogeneous group

Pseudohyperplastic carcinoma

< 1

Foreskin, related to lichen sclerosus, good prognosis, metastasis not reported

Carcinoma cuniculatum

< 1

Variant of verrucous carcinoma, good prognosis, metastasis not reported

Pseudoglandular carcinoma

< 1

High-grade carcinoma, early metastasis, poor prognosis

Warty-basaloid carcinoma

9-14

Poor prognosis, high metastatic potential (higher than in warty, lower than in basaloid SCC)

Adenosquamous carcinoma

< 1

Central and peri-meatal glans, high-grade carcinoma, high metastatic potential but low mortality

Mucoepidermoid carcinoma

< 1

Highly aggressive, poor prognosis

Clear cell variant of penile carcinoma

1-2

Exceedingly rare, associated with Human papilloma virus, aggressive, early metastasis, poor prognosis, outcome is lesion-dependent, frequent lymphatic metastasis

Biopsy

In the management of penile cancer there is need for histological confirmation if:

there is doubt about the exact nature of the lesion (e.g. carcinoma in situ, metastasis or melanoma);

treatment with topical agents, radiotherapy or laser surgery is planned.

Staging and classification systems

The 2016 UICC, Tumour Node Metastasis (TNM) classification should be used for staging and classification (Table 3). The T1 category is stratified into two prognostically different risk groups. The classification T2 denotes invasion of the corpus spongiosum and T3 invasion of the corpora cavernosa, recognising that these two invasion patterns differ prognostically. The current pN1 group consists of one or two inguinal lymph node metastases, pN2 is more than two uni- or bilateral metastatic nodes, and pN3 any pelvic nodes, uni- or bilateral as well as any extranodal extension.

Table 3: 2016 TNM clinical and pathological classification of penile cancer

Clinical classification

T - Primary tumour

TX

Primary tumour cannot be assessed

T0

No evidence of primary tumour

Tis

Carcinoma in situ

Ta

Non-invasive verrucous carcinoma*

T1

Tumour invades subepithelial connective tissue

T1a

Tumour invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated (T1G1-2)

T1b

Tumour invades subepithelial connective tissue with lymphovascular invasion or is poorly differentiated (T1G3-4)

T2

Tumour invades corpus spongiosum with or without invasion of the urethra

T3

Tumour invades corpus cavernosum with or without invasion of the urethra

T4

Tumour invades other adjacent structures

N - Regional lymph nodes

NX

Regional lymph nodes cannot be assessed

N0

No palpable or visibly enlarged inguinal lymph nodes

N1

Palpable mobile unilateral inguinal lymph node

N2

Palpable mobile multiple or bilateral inguinal lymph nodes

N3

Fixed inguinal nodal mass or pelvic lymphadenopathy, unilateral or bilateral

M - Distant metastasis

M0

No distant metastasis

M1

Distant metastasis

Pathological classification

The pT categories correspond to the clinical T categories

The pN categories are based upon biopsy or surgical excision

pN - Regional Lymph Nodes

pNX

Regional lymph nodes cannot be assessed

pN0

No regional lymph node metastasis

pN1

Metastasis in one or two inguinal lymph nodes

pN2

Metastasis in more than two unilateral inguinal nodes or bilateral inguinal lymph nodes

pN3

Metastasis in pelvic lymph node(s), unilateral or bilateral or extranodal extension of regional lymph node metastasis

pM - Distant Metastasis

pM0

No distant metastasis

pM1

Distant metastasis

G - Histopathological Grading

GX

Grade of differentiation cannot be assessed

G1

Well differentiated

G2

Moderately differentiated

G3-4

Poorly differentiated/undifferentiated

*Verrucous carcinoma not associated with destructive invasion.

Diagnostic evaluation and staging

Penile cancer can be cured in over 80% of all cases if diagnosed early. Once metastatic spread has occurred, it is a life-threatening disease with poor prognosis. Local treatment, although potentially life-saving, can be mutilating and devastating for the patient’s psychological well-being.

Physical Examination

Careful palpation of both groins for enlarged inguinal lymph nodes must be part of the initial physical examination of patients with penile cancer.

Imaging

Ultrasound (US) can give information about infiltration of the corpora.

Magnetic resonance imaging (MRI) with an artificially induced erection can help to exclude tumour invasion of the corpora cavernosa if preservation of the penis is planned.

In case of non-palpable inguinal nodes, current imaging techniques are not reliable in detecting micrometastases.

A pelvic computed tomography (CT) scan can be used to assess pelvic lymph nodes.

In case of positive inguinal nodes, CT of the abdomen and pelvis and a chest X-ray are recommended; a thoracic CT will be more sensitive than an X-ray.

Recommendations for the diagnosis and staging of penile cancer

GR

Primary tumour

Perform a physical examination, record morphology, extent and invasion of penile structures.

C

Obtain magnetic resonance imaging with artificial erection in cases for which organ-preserving surgery is intended.

Inguinal lymph nodes

Perform a physical examination of both groins, record the number, laterality and characteristics of inguinal nodes and:

if nodes are not palpable, offer invasive lymph node staging in high-risk patients;

if nodes are palpable, stage with a pelvic computed tomography (CT) or positron emission tomography (PET) /CT.

C

Distant metastases

In N+ patients, obtain an abdominopelvic CT scan and chest X-ray for systemic staging. Alternatively, stage with a PET/CT scan.

C

In patients with systemic disease or with relevant symptoms, obtain a bone scan.

Disease management

Treatment of the primary penile cancer lesion aims to remove the tumour completely while preserving as much of the penis as possible without compromising radicality.

Recommendations for stage-dependent local treatment of penile carcinoma

Primary tumour

Use organ-preserving treatment whenever possible

LE

GR

Tis

Topical treatment with 5-fluorouracil or imiquimod for superficial lesions with or without photodynamic control.

3

C

Laser ablation with carbon dioxide (CO2)or neodymium: yttriumaluminum-garnet (Nd:YAG) laser.

Glans resurfacing.

Ta, T1a (G1, G2)

Wide local excision with circumcision, CO2 or Nd:YAG laser surgery with circumcision.

3

C

Laser ablation with CO2 or Nd:YAG laser.

Glans resurfacing.

Glansectomy with reconstructive surgery, with or without skin grafting.

Radiotherapy by external beam or as brachytherapy for lesions < 4 cm.

T1b (G3) and T2 confined to the glans

Wide local excision plus reconstructive surgery, with or without skin grafting.

3

C

Laser ablation with circumcision.

Glansectomy with circumcision and reconstruction.

Radiotherapy by external beam or brachytherapy for lesions < 4 cm in diameter.

T2 with invasion of the corpora cavernosa

Partial amputation and reconstruction or radiotherapy by external beam or brachytherapy for lesions < 4 cm in diameter.

3

C

T3 with invasion of the urethra

Partial penectomy or total penectomy with perineal urethrostomy.

3

C

T4 with invasion of other adjacent structures

Neoadjuvant chemotherapy followed by surgery in responders.

Alternative: palliative external beam radiation.

3

C

Local recurrence after conservative treatment

Salvage surgery with penis-sparing treatment in small recurrences or partial amputation.

3

C

Large or high-stage recurrence: partial or total amputation.

Management of inguinal lymph nodes

The treatment of regional lymph nodes is crucial for the survival of the patient. A surveillance strategy carries considerable risk as regional lymph node recurrence dramatically reduces the chance of long-term survival. Invasive staging by modified inguinal lymphadenectomy or dynamic sentinel node biopsy is recommended for penile cancers pT1G1 and higher.

Recommendations for treatment strategies for nodal metastases

Regional lymph nodes

Management of regional lymph nodes is fundamental in the treatment of penile cancer

LE

GR

No palpable inguinal nodes (cN0)

Tis, Ta G1, T1G1: surveillance.

2a

B

> T1G2: invasive lymph node staging by bilateral modified inguinal lymphadenectomy or dynamic sentinel node biopsy.

2a

B

Palpable inguinal nodes (cN1/cN2)

Radical inguinal

lymphadenectomy.

Fixed inguinal lymph nodes (cN3)

Neoadjuvant chemotherapy followed by radical inguinal lymphadenectomy in responders.

Pelvic lymphadenopathy

Ipsilateral pelvic lymphadenectomy if two or more inguinal nodes are involved on one side (pN2) and if extracapsular nodal metastasis (pN3) is confirmed.

2a

B

Adjuvant chemotherapy

In pN2/pN3 patients after radical lymphadenectomy.

2b

B

Radiotherapy

Do not use for the treatment of nodal disease in penile cancer.

Recommendations for chemotherapy in penile cancer patients

LE

GR

Treat patients with pN2-3 tumours with adjuvant chemotherapy (3-4 cycles of cisplatin, 5-florouracil, paclitaxel or docetaxel).

2b

C

Treat patients with non-resectable or recurrent lymph node metastases with neoadjuvant chemotherapy (four cycles of a cisplatin and taxane-based regimen) followed by radical surgery.

2a

B

Treat patients with systemic disease and a limited metastatic load with chemotherapy.

3

C

Follow-up

Follow-up after curative treatment in penile carcinoma, as in any malignant disease, is important for two reasons:

early detection of recurrence allows for potentially curative treatment;

the detection and management of treatment-related complications.

Local recurrence does not significantly reduce long-term survival if successfully treated, while inguinal nodal recurrence leads to a drastic reduction in the probability of long-term disease-specific survival.

Quality of life

Overall, nearly 80% of penile cancer patients of all stages can be cured. Partial penectomy has negative consequences for the patients’ self-esteem and sexual function. Organ-preserving treatment allows for better quality of life and sexual function and should be offered to all patients whenever feasible. Referral to centres with experience is recommended and psychological support is very important for penile cancer patients.

Recommendations for follow-up in penile cancer

Interval of follow-up

Examinations and investigations

Minimum duration of follow-up

GR

Years 1-2

Years 3-5

Recommendations for follow-up of the primary tumour

Penile-preserving

treatment

3 months

6 months

Regular physician or self-examination.

Repeat biopsy after topical or laser treatment for carcinoma in situ.

5 years

C

Amputation

3 months

1 year

Regular physician or self-examination.

5 years

C

Recommendations for follow-up of the inguinal lymph nodes

Surveillance

3 months

6 months

Regular physician or self-examination.

5 years

C

pN0 at initial treatment

3 months

1 year

Regular physician or self-examination.

Ultrasound with fine-needle aspiration biopsy optional.

5 years

C

pN+ at initial treatment

3 months

6 months

Regular physician or self-examination.

Ultrasound with fine-needle aspiration cytology optional, computed tomography/magnetic resonance imaging optional.

5 years

C

This short booklet text is based on the more comprehensive EAU Guidelines (ISBN 978-90-79754-91-5), available to all members of the European Association of Urology at their website: http://www.uroweb.org/guidelines/.

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