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Cancer of the penis – 2016



1.1 Epidemiology

1.1.1 Incidence

Cancer of the penis is rare in Europe. In the period 2000-2007, about 3,900 cases were diagnosed each year. The annual crude incidence rate, based on the total population (male+female), was 0.6 per 100,000, while incidence accounted on the male population was 1.2 per 100,000 (RARECAREnet). There is a geographical variation of incidence (age-adjusted) in Europe: it is the highest in the UK and Ireland (0.60) and the lowest in Central Europe (0.48). Outside Europe, in 2003-2007, sex-specific and age-standardized incidence was about double as in Brazil (Goiana) and in Uganda, higher than 2 per 100,000 (Forman 2014). The peak incidence of penile cancer occurs in men aged 65 or over, when the annual incidence rate was 2.4 per 100,000. About 57% of cases are among men over 65 years of age (RARECAREnet).
In Europe, age-adjusted incidence during the period 1995-2007 slightly increased from 0.50 to 0.56 (RARECAREnet).

1.1.2 Survival

For men diagnosed with penile squamous cell carcinoma in Europe during 2000-2007, relative survival figures at 1-, 3-, and 5-year was 87%, 73%, and 69%, respectively. Prognosis was poorer for adenocarcinoma, less than 1% of the epithelial variant; the corresponding figures were 72%, 57%, and 49%.
Five-year relative survival decreased with the increasing age: from 73% in men 25-64 years old to 63% in men 75 years and over.
There are major differences in survival between Countries for European patients with penile cancer: 5-year survival ranged from 77% (Northern Europe) to 60% (Eastern Europe). In the other European regions, 5-year survival ranged between 69% and 67%. During the period 1999-2007, 5-year survival remained stable (RARECAREnet).

1.1.3 Prevalence

In Europe, slightly more than 33,400 men were living with a diagnosis of penile cancer (RARECAREnet) at the beginning of 2008. Thirty-seven percent of them were patients who had survived 5 years or less after diagnosis (slightly more than 12.000 cases at the beginning of 2008). Long survivors (i.e., people surviving 15 years or more after their diagnosis) were about 29% of the total prevalence.
Prevalence is an important indicator of the burden for the health care system. The proportion of complete prevalence of men with penile cancer at the beginning of 2008 was 6.5 per 100,000 (RARECAREnet). According to the European definition of rare disease (prevalence equal or below 50 per 100,000), penile cancers are a rare disease therefore profitable of the EU Directive on orphan drugs.

1.2 Aetiology and risk factors

Penile cancer is rarely seen in Jewish men who are circumcised at birth (Licklider 1961). Frequently it occurs in uncircumcised men, suggesting an irritative effect of smegma and circumcision performed later in life does not have the same protective potential as circumcision at birth (Maden 1993; Schoen 2000). A history of phimosis has been found in 25% of penile cancer patients (Tsen 2001).
About 50% of people with penile cancer is estimated to be due to HPV infection. The attributable proportion is larger in the less developed regions (70%) than in the more developed ones (30%) (de Martel 2012)
There is a consistent association between penile cancer and smoking (Harish 1995). The relationship is dose-dependent and not explained by the investigated confounding factors such as sexual history (Dillner 2000).
Other potent risk factors are chronic inflammatory conditions (e.g., balanoposthitis and lichen sclerosus et atrophicus), and treatment with psoralen or ultraviolet A photochemotherapy (PUVA) (Dillner 2000).

1.3 Early diagnosis

1.3.1 Screening and case finding

Penile cancer is uncommon in Western Countries, so that screening would only be applied to a selected high-risk population. The most important risk factor is the presence of a phimosis. In high-risk areas as Brazil, Colombia, or African Countries, there are difficulties in organizing screening programmes, especially among lower socioeconomic groups where the disease is more common.

1.3.2 Prevention

Carcinoma of the penis is a preventable disease. All patients with phimosis, which prevents adequate inspection and cleanliness of the glans, should undergo corrective surgery. The rare occurrence of cancer in the circumcised men indicates that neonatal circumcision is a contributing factor in the prevention of penile cancer. When neonatal circumcision has not been performed, attention to other risk factors such as personal hygiene, phimosis, HPV infection, and cigarette smoking may reduce risk.
Referral of penile cancer patients to specialised institutions is generally recommended.


2.1 ICD-O Classification (ICD-0 C60)

2.1.1 Histological types

ICD-O 2000 Classification includes the following histotypes. The ICD-O morphology code is provided in brackets:

Squamous cell carcinoma [8070/3]
Sarcoma [8800/3]
Melanoma [8720/3]
Basal cell carcinoma [8090/3]
Lymphoma [9590/3]

Squamous cell carcinoma (SCC) accounts for more than 95% of cases of penile malignancies.
Traditionally, squamous cell carcinoma has been divided on morphological grounds into two forms: exophytic (fungating, papillary) and endophytic (infiltrating, ulcerating). Exophytic penile carcinoma is commonly located in the glans, may grow into a large polypoid mass, and at the microscopic level, is well differentiated and heavily keratinized. Endophytic carcinoma may occur in the prepuce or the glans and only rarely in the shaft; microscopically it is poorly differentiated. The ulcerating tumour has a higher incidence of lymph node metastases than does the fungating carcinoma. Cubilla et al. (Cubilla 1993) divided penile squamous cell carcinoma into four categories: superficial spreading, vertical growth, verrucous, and multicentric. Superficially spreading squamous cell cancers occur most frequently and inguinal lymph node metastases are present in 42% of cases. Lymph node metastases are reported in 82% of tumours with a deeper vertical growth pattern, 33% of the multicentric tumours, and none of those with a verrucous pattern. Virtually all penile carcinomas are of squamous cell origin and include the following subtypes:

  • usual type;
  • verrucous carcinoma;
  • warty carcinoma;
  • basaloid carcinoma;
  • papillary carcinoma;
  • adenosquamous carcinoma;
  • mixed.

Rare morphologic variants of squamous cell carcinoma are spindle cell (sarcomatoid) carcinoma and adenoid (pseudoglandular) carcinoma.
Currently, because of aetiological and prognostic considerations, two morphologically and molecularly distinctive groups of subtypes of penile SCCs, based on the presence of HPV, were delineated. Warty carcinoma and basaloid carcinoma appear to be highly associated with HPV, particularly HPV16. Tumours negative for the virus are preferentially of lower grade and keratinizing maturing neoplasms, such as verrucous carcinoma, with the exception of sarcomatoid carcinoma (Sanchez 2015a). HPV is detected in research studies by PCR or in situ hybridization (ISH) technologies, but p16 immunohistochemical stain is an adequate and less-expensive surrogate that is useful in the routine practice of pathology. Histological subtypes of penile squamous cell carcinoma are important to determine risk for nodal metastasis and patients’ survival. Recent findings have permitted the grouping of special subtypes of squamous cell carcinomas into prognosis risk groups: low, intermediate, and high:

  • In the first category of excellent prognoses are the usual grade I, verrucous, papillary NOS, pseudohyperplastic and cuniculatum carcinomas.
  • In the second group, there are the grade II usual, mixed and warty carcinomas.
  • The third category of tumours, with the worst prognosis is composed of high grade usual, basaloid, warty-basaloid, papillary basaloid, and sarcomatoid carcinomas (Sanchez 2015b).

Nonsquamous malignancies comprise less than 5% of penile cancers. Among them, sarcomas (including Kaposi’s sarcoma) are the most frequent, followed by melanomas, basal cell carcinomas, Paget’s disease, and lymphomas. Metastatic carcinoma to the penis is rare. Priapism is one form of presentation. The most common sources are prostate, bladder, rectosigmoid colon, kidney, and testis, in decreasing order of frequency.

2.1.2 Premalignant lesions of the penis

Several premalignant lesions have been identified, including leukoplakia, balanitis xerotica obliterans (the penile equivalent of lichen sclerosis et atrophicus), and Buschke-Lowenstein tumour (or giant condyloma acuminatum).

2.1.3 Carcinoma in situ (Erythroplasia of Queyrat, Bowen’s disease)

Erythroplasia of Queyrat refers to carcinoma in situ involving the glans penis, prepuce, or shaft, whereas carcinoma in situ affecting the skin of the penile shaft, scrotum, or perineum is known as Bowen’s disease. Bowen’s disease has been reported to degenerate into invasive carcinoma in 5 to 10% of cases (Schellhammer 1992), while erythroplasia of Queyrat transforms to invasive carcinoma more frequently, in approximately 10 to 33% of cases (Grossman 1992; Wieland 2000).

2.2 Tumour grading

The histopathological grading of penile cancer is based on the WHO grading system, including in 2009 TNM classification for penile cancer (Table 1):

Table 1. WHO histopathological grading of penis cancer.


Gx Grade of differentiation cannot be assessed
G1 Well differentiated
G2 Moderately differentiated
G3-4 Poorly differentiated/undifferentiated

Another grading system of penile cancer is the Broder’s classification System (I-IV) (Lucia 1992) (Table 2).

Table 2. Broder's classification System


Grade Characteristics
Grade I Cells well differentiated with keratinization
Prominent intercellular bridges
Keratin pearls
Grade II-III Greater nuclear atypia
Increased mitotic activity
Fewer keratin pearls
Grade IV Marked nuclear pleomorphism
Numerous mitoses
Lymphatic and perineural invasion
No keratin pearls
Deeply invasive

The tumour grade is a relevant prognostic factor. However, both Broder’s classification and the WHO grading system for grading penile cancer are highly dependent on the observer (Gunia 2013).


3.1 Diagnostic Clues

3.1.1 Symptoms

The most common presenting symptoms of penile carcinoma, in decreasing order of frequency, are: mass lesions, pain or itching, bleeding, palpable groin masses, and urinary symptoms. The glans is the most common site (48%) followed by prepuce (21%), glans and prepuce (9%), coronal sulcus (6%), and shaft (< 2%) (Sufrin 1991).
Phimosis may hide the lesion and create a long period of delay.
Palpable inguinal adenopathy is frequently present at diagnosis (58%) but is often inflammatory in nature, due to ulcerated or infected penile lesion. Only half of patients presenting with palpable lymphadenopathy actually have metastatic disease (Sufrin 1991), the remainder having inflammatory lymphadenopathy that resolves following resection of the primary tumour and a 4-6-week course of antibiotic therapy.

3.2 Diagnostic Strategy

3.2.1 Clinical assessment and imaging

The cornerstone of clinical evaluation of penile carcinoma is the physical examination. The assessment of the primary tumour should include the size, number of lesions, location, morphology of lesions, mobility, degree of infiltration, and involvement of the corporal bodies. Inguinal examination is mandatory, as survival is directly correlated with the presence or absence of inguinal metastases.
Imaging procedures such as computed tomography (CT), magnetic resonance imaging (MRI), and/or ultrasound, may also be useful (Agrawal 2000a; Horenblas 1994; Vapnek 1992).
The frequent coexistence of an inflammatory reaction may limit the initial assessment of corporal invasion, and MRI combined with an intracavernosal injection of prostaglandin E1 that causes an artificial erection has been used to identify corporal invasion by the tumour. However, it is unclear whether MRI findings should change clinical management (Van Poppel 2013).
If there are no palpable lymph nodes, the likelihood of micrometastatic disease is about 25%. Imaging studies are not helpful in staging clinically normal inguinal regions, though imaging may be helpful in obese patients in whom palpation is unreliable or impossible. Inguinal US can reveal abnormal nodes with some enlargement. The longitudinal/transverse diameter ratio and absence of the lymph node hilum are findings with relatively high specificity; conventional CT or MRI scans cannot detect micrometastases reliably; imaging with18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) does not detect lymph node metastases <10 mm (Hakenberg 2015).
A meta-analysis of seven studies to evaluate the accuracy of 18F-FDG PET/TC for inguinal lymph node staging in penile SCC demonstrated that PET/TC has relatively low sensitivity (pooled; 56.5%) in cN0 patients (Sadeghi 2012a). However, in patients with non-palpable nodes, dynamic sentinel node biopsy (DSNB) is indicated in intermediate (T1G2) or high-risk (T1G3 or worse) disease.
DSNB is a less morbid approach compared with prophylactic inguinal lymph node resection (Horenblas 2000; Valdes Olmos 2001). A meta-analysis of 17 studies demonstrated that DSNB is a method with a high detection rate of sentinel nodes (pooled; 88.3%) and sensitivity (pooled; 88.0%). The highest detection rate and sensitivity was seen in studies using radiotracer and blue dye for sentinel lymph node mapping and including only cN0 disease (Sadeghi 2012b). If DSNB is not available, ultrasound-guided fine-needle aspiration cytology (FNAC) biopsy of visualised nodes can be used (Van Poppel 2013).
Clinical examination of the groin area is often difficult, and distinguishing between inflammatory and metastatic nodes can be problematic. About 50% of patients with squamous cell carcinoma have palpable inguinal lymph nodes at diagnosis, but in half of these cases, palpable lymph nodes are due only to inflammatory changes associated with ulcerated or infected penile lesions that resolve following a 4-6 week course of antibiotic therapy (Sufrin 1991). If palpable inguinal lymph nodes persist after antibiotic therapy, a percutaneous needle aspiration should be performed. False negatives do occur, however, and a negative aspiration in a patient with palpable adenopathy should rarely alter a decision for inguinal exploration (Horenblas 1991). Lymph nodes not accessible to physical examination, especially those in the pelvis, can be assessed by CT or MRI imaging.
CT scan is used primarily, despite its low sensitivity (36%). The use of 18F-FDG PET/CT remains uncertain. A meta-analysis of seven studies demonstrated that patients with clinically palpable lymph nodes may benefit from 18F-FDG PET/CT, because the sensitivity in this subgroup of patients is high (pooled sensitivity; 96.4%) (Sadeghi 2012a).

3.2.2 Pathologic diagnosis

For small lesions of the prepuce or glans, circumcision or excisional biopsy can confirm the diagnosis and indicate the primary tumour stage. For larger lesions, incisional biopsy should be performed either preoperatively or simultaneously with a planned definitive procedure (by frozen section) for a pathological confirmation of diagnosis.
The pathology report must include the anatomical site of the primary tumour, the histological type/subtypes, grade, perineural invasion, depth of invasion, vascular invasion (venous/lymphatic), irregular growth and front of invasion, urethral invasion, invasion of corpus spongiosum/cavernosum and surgical margins (Hakenberg 2015).


4.1 Staging Classification

4.1.1 Formal stage classification

Penile cancer should preferably be staged according to the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC), 7th edition, TNM classification (Sobin 2009).

4.1.2 TNM Staging Classification
Table 3. TNM staging classification.
Primary tumour (T)
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour invades subepithelial connective tissue
T1a Tumour invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated or undifferentiated (T1G1-2)
T1b Tumour invades subepithelial connective tissue with lymphovascular invasion or is poorly differentiated or undifferentiated (T1G3-4)
T2 Tumour invades corpus spongiosum and/or cavernosum
T3 Tumour invades urethra
T4 Tumour invades other adjacent structures
Regional lymph nodes (N)
Nx Regional lymph nodes cannot be assessed
N0 No palpable or visibly enlarged inguinal lymph node
N1 Palpable mobile unilateral inguinal lymph node
N2 Palpable mobile multiple unilateral or bilateral inguinal lymph nodes
N3 Fixed inguinal nodal mass or pelvic lymphadenopathy, unilateral or bilateral
Distant metastasis (M)
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
4.1.3 Pathological classification

The pT categories correspond to the T categories. The pN categories are based upon biopsy or surgical excision.

Table 4. Pathological classification
Regional lymph nodes (pN)
pNX Regional lymph nodes cannot be assessed
pN0 N0 regional lymph node metastasis
pN1 N1 Intra-nodal metastasis in a single inguinal lymph node
pN2 N2 Metastasis in multiple or bilateral inguinal lymph nodes
pN3 N3 Metastasis in pelvic lymph node(s), unilateral or bilateral or extranodal extension of regional lymph node metastasis
Distant metastasis (pM)
pM0 No distant metastasis
pM1 Distant metastasis
4.1.4 AJCC/UICC stage groupings
Table 5. AJCC/UICC stage groupings
Stage 0 Tis, N0, M0
Ta, N0, M0
Stage I T1, N0, M0
Stage II T1, N1, M0
T2, N0, M0
T2, N1, M0
Stage III T1, N2, M0
T2, N2, M0
T3, N0, M0
T3, N1, M0
T3, N2, M0
Stage IV T4, any T, M0
Any T, N3, M0
Any T, any N, M1


5.1 Natural History

Carcinoma of the penis typically originates as a lesion on the surface of the glans, foreskin, or penile shaft, and often remains localized for prolonged periods. When left untreated, is characterized by progressive tumour growth with local destruction and eventual corporal or urethral invasion. Two-thirds of the patients have an organ-confined disease at the time of initial diagnosis. Dissemination of disease beyond the primary site is via the penile lymphatics that drain into the superficial and deep inguinal lymph nodes (up to 45%, depending on the histological pattern) and later to the lymph nodes (Cabanas 1977). Distant dissemination to the liver, lung, bone, and other sites, usually occurs late in the course of the disease. Delays in diagnosis and treatment are critical because the stage at presentation appears to be the most important prognostic indicator for survival.
Patients with carcinoma of the penis often die of septic complications, erosion of large vessels in the groin, or a combination of the two.

5.2 Prognostic factors

The presence of metastases in the regional lymph nodes is the main factor which predicts an unfavourable prognosis for patients with penile SCC. In patients with pN+ disease, the prognosis varies according to the number of positive lymph nodes, the presence of unilateral or bilateral inguinal extension, pelvic node involvement, and the presence of extranodal extension (Ficarra 2010; Djajadiningrat 2014a). The extent of nodal involvement adversely affects survival: in a study of 201 patients (Ravi 1993a), 5-year survival rates declined from 95% for patients without nodal disease to 81% and 50% when 1-3 or >3 inguinal lymph nodes were positive, respectively. No patient with pelvic nodal disease survived to 5 years.
The incidence of nodal involvement is related to the extent and localisation of the primary lesion. Nodal disease occurs in 20% of T1 tumours and in 47% to 66% of T2-T4 penile cancers (Ornellas 1994). Furthermore, the extent of nodal involvement adversely affects survival: in a study of 201 patients (Ravi 1993a), 5-year survival rates declined from 95% for patients without nodal disease to 81% and 50% when 1-3 or >3 inguinal lymph nodes were positive, respectively. No patient with pelvic nodal disease survived to 5 years.
Tumour differentiation is also an important prognostic factor (McDougal 1995; Solsona 2001). Low-grade lesions (grade 1-2) represent 50% of the reported cases at diagnosis (Lynch 1998). Almost half of the tumours originating in the shaft are poorly differentiated whereas only 10% of tumours located in the prepuce are high-grade tumours (Ro 1996).
Patients can be prognostically stratified based on stage and/or grade into three risk groups, according to the likelihood of harbouring occult node-positive disease:

  • low-risk group;
  • Tis, TaG1-2 or T1G1 (intermediate-risk group);
  • T1G2 (high-risk group);
  • T2-T3 or any G3.

Patients with T1G1 penile SCC do not need further nodal assessment after local treatment, because 0% developing lymph node metastases.
In patients with intermediate T1G2 tumours, 13% up to 29% develop LN metastases during follow-up, in contrast to high-risk pT2/3 G2/3 tumours, with 83% developing lymph node metastases (Hakenberg 2015; Van Poppel 2013).
In a large surgical series of 688 patients, immediate lymphadenectomy (No. 251) was associated with a better 10-year disease-specific survival than delayed (No. 81) lymphadenectomy (71% vs. 30%; p =0.002). The authors reported divergent 10-year disease-specific survivals for low-risk (T1G1-2), intermediate (T2-3G1-2), and high-risk (T1-3G3 and T4G1-3) patients ranging from ∼75% to ∼40%.
The 10-year disease-free survival rates for patients with negative and positive pathological nodal involvement in the immediate lymphadenectomy group were 96% and 35%, respectively (Ornellas 2008). Despite the caveats of a retrospective analysis, these data suggest the powerful favourable impact of inguinal LN dissection.
However, the risk for LN metastasis may be predicted by several tumour characteristics other than T and G categories. Specifically, these risk factors include pathological subtypes, invasion of perineural spaces, lymphovascular invasion, tumour depth or thickness, anatomical site, size of the primary tumour, growth pattern, irregular front of invasion, positive margins of resection and urethral invasion. High histological grade, perineural invasion and lymphovascular invasion appear to be the strongest predictors of metastasis of penile cancer (Van Poppel 2013).


6.1 Treatment Strategy

6.1.1 General considerations

The rarity of penile carcinoma has contributed to the lack of a standardized approach to the management of patients. There are no randomized trials in this rare tumour that assist in making clinical decisions. Therefore, the evidence is only based on selected series or small prospective and retrospective studies. When diagnosed early (stage I-II) the favourable natural history of penile cancer means that cure is achievable in most patients.
Surgical resection is the mainstay of treatment with attention directed to both the primary tumour and the regional lymph nodes.
Surgical intervention at the primary site involves removal of the lesion with adequate margins to minimize the risk of local recurrence and may range from wide local excision and epithelial ablative techniques to partial or total penectomy. The ideal surgical procedure should eliminate the disease and preserve sexual and urinary function, although this is not always possible because of the extent of disease. Approximately 20% of patients are under 40 years of age, and radical procedures, especially total penectomy, may be psychologically devastating to the patient.
Wide local excision, microscopically controlled surgery, laser therapy, external beam radiation therapy and brachytherapy have all been used in an attempt to provide organ-sparing alternatives. Local recurrence, as high as 56%, more commonly occurs after organ-preserving procedures applied for T2 or T3 tumours (Brkovic 1997; Ficarra 1999).

6.2 Carcinoma in situ (Tis)

For carcinoma in situ (also referred to as erythroplasia of Queyrat or Bowen’s disease), the standard therapeutic options on a type 3 level of evidence include: microscopically controlled surgery (Mohs 1985) or topical applications of 5-fluorouracil cream or imiquimod (Alnajjar 2012). Laser ablation using a neodymium:yttrium-aluminum garnet (Nd:YAG) or carbon dioxide (CO2) laser has also been employed successfully (Schlenker 2010; Bandieramonte 2008; van Bezooijen 2001). However, close and long-term surveillance and patient self-examination is mandatory.

6.3 Treatment of The Primary Tumour

6.3.1 T1 tumours

An organ-sparing approach has been recommended for patients with stage T1 disease, according to the 2009 TNM clinical and pathological classification system, in national and international guidelines.

  • LESIONS LIMITED TO THE FORESKIN: a penis-preserving strategy is recommended for small and localized invasive lesions (T1). For tumours confined to the prepuce, wide local excision with circumcision may be adequate, and is indicated as the standard treatment on a type C basis. Negative surgical margins are imperative when using penile-conserving treatments, and a margin of 5 mm is considered adequate for most tumours (Minhas 2005). The recurrence rate of patients with resection margins of 5 mm or less could still be <5%. For all surgical treatment options, the intraoperative assessment of surgical margins by frozen section is recommended, because tumour-positive margins lead to local recurrence. However, proper patient selection is crucial for a successful outcome, because circumcision alone, especially with tumours in the prossimal foreskin, may be associated with a recurrence rate of 32% (McDougal 1986). These high recurrence rates underscore the need for careful follow-up of patients treated by circumcision alone and.adequate patient education.
  • LESIONS INVOLVING THE GLANS: For glandular and distal penile tumours, it is now possible to preserve much more length, and cosmetic and functional results are far superior to conventional partial penectomy. The choice of therapy is dictated by tumour size, localization, histology, extent of infiltration, degree of tumour destruction of normal tissue and patient preference, as there are no documented differences in long-term local recurrence rates between surgery, laser and radiation therapy. Standard therapeutic options on a type 3 level of evidence include:1) partial penile amputation; 2) local tumour excision; 3) irradiation (external-beam, brachytherapy with iridium-192 moulds or wires). There are no randomized trials comparing different treatment options. Partial or total penectomy (PE) has historically been considered the standard treatment for invasive disease. Although the local control rate of PE is ~95%, it has a significant negative impact on the patient’s sexual function, quality of life, social interactions, self-image, and self-esteem. During the past decade, there has been a change in the management of primary tumours with an emphasis on penile sparing surgery (PSS), and significantly more penile preservation therapies were performed in more recent years. PSS has been previously reported to produce excellent cosmetic and functional results without sacrificing oncological outcomes in certain patients with early-stage penile tumours. In some retrospective studies reported in the literature, local disease control was achieved in 40-80% of the cases following PSS. Although PSS was associated with an increased risk of local failure compared with penile amputation, it did not appear to compro¬mise long term cancer specific survival and local recurrence can be treated accurately in most cases (Feldman 2011; Schlenker 2011; Shindel 2007; Lont 2006b; Pietrzak 2004; Ficarra 1999). A recent published study described the use of PSS in a population-based cohort, and also examined the role of PSS on penile cancer-specific mortality (PCSM) (Zhu 2015). Data from the Surveillance, Epidemiology, and End Results (SEER) database were used to identify individuals that were diagnosed with penile squamous cell carcinoma between 1998 and 2009 and treated with surgery. Patients were sorted into two groups: local tumour excision (LTE) and partial/total penectomy (PE). Of the 1,292 eligible patients, 24.2% underwent LTE. For stage T1 disease, the rates of LTE increased moderately from 29 to 40% over the last decade. With a median follow-up period of 55 months, the four-year PCSM rate was 9.8% in patients treated with LTE. In older age, a tumour size of 3-4 cm and regional/distant disease were significant predictors of PCSM. Furthermore, in matched cohorts with stage T1 disease, the four-year PCSM rates were 8.9 and 10.0% for patients that received LTE or PE, respectively (p =0.93). In a recent report, the records of 1,000 patients treated for invasive tumours were analysed. The 5-year cumulative incidence of local recurrence as the first event after penile preservation was 27% (95% CI 23-32) while after (partial) penectomy it was 3.8% (95%CI 2.3-6.2; p <0.0001). Patients treated with penile preservation showed no significant difference in survival compared to patients treated with (partial) amputation. Factors associated with cancer specific survival were pathological T stage, pathological N stage and lymphovascular invasion on multivariable analysis. In the penile preservation group local recurrence as a time dependent variable in a Cox model was not associated with cancer specific survival (HR 0.52; 95%CI 0.21-1.24; p =0.13). Although patients treated with penile preservation experienced more local recurrences, 5-year cancer specific survival was not jeopardized (Djajadiningrat 2014b). Radiation therapy is an appealing alternative to surgical treatment in early stage penile cancer, preserving a functional organ. Radiotherapy may be delivered as external-beam therapy or brachytherapy. External radiation therapy can be delivered with a conventional energy X-ray device or with high-energy photons. In many reported series, fraction sizes have ranged from 2 to 3.5 Gy up to a total dose of 50-55 Gy. However, a correlation exists between large fraction size and late tissue damage, therefore a smaller daily fraction size (1.8 to 2.0 Gy), five fractions per week during 6-7 weeks to a higher total dose (65-70 Gy) is preferable (Chao 1997). External beam treatment as single treatment modality has been used in only a small number of studies, reporting on limited numbers of patients (McLean 1993; Neave 1993). One exception is a study by Gotsadze et al. analysing results in 155 patients. Reported local control rates for stages I and II range from 65% to 90% (Gotsadze 2000). Brachytherapy can be performed with either an external isotope-mould technique or by interstitial radiotherapy. Iridium 192 is preferred to radium 226 sources and low-dose rate interstitial brachytherapy is more often used (Gerbaulet 2002). A typical brachytherapy schedule consists of 55-60 Gy given in 4-6 days. All these techniques may effectively treat selected patients with distal penile T1 lesions with long-term (5-10 years) local control rates ranging in several series between 78% and 90% (Akimoto 1997; Chaudhary 1999; Crook 2005; de Crevoisier 2009; El-Demiry 1984; Gerbaulet 1994; Grabstald 1980; Kiltie 2000; Neave 1993; Petera 2004; Rozan 1995). According to 2013 American Brachytherapy Society-Groupe Européen de Curiethérapie-European Society of Therapeutic Radiation Oncology (ABS-GEC-ESTRO) consensus statement for penile brachytherapy, the good tumour control rates, acceptable morbidity, and functional organ preservation warrant recommendation of brachytherapy as the initial treatment for invasive T1, T2 and selected T3 penile cancers (Crook 2013). Reported penile preservation rate is 70% at 10 years postimplant. Several investigations have demonstrated that local relapses (10 to 20%) after radiotherapy can be salvaged with surgery without apparently affecting the prognosis (Zouhair 2001). Approximately 20% of patients with low-stage lesions require subsequent amputation after radiation therapy as a result of recurrent disease or iatrogenic complications, with a secondary control of about 85% of the recurrences (Grabstald 1980; Rozan 1995). The most important predictors for successful brachytherapy seem to be tumour size (less than 4 cm) and tumour location limited to the glans or the prepuce without corpus cavernosum involvement. Concurrent chemotherapy may enhance the effectiveness of radiotherapy in achieving tumour control (Edsmyr 1985; Modig 1993) and its use is under evaluation in clinical trials. Laser therapy is an alternative option still under clinical evaluation. Laser ablation using a neodymium:yttrium-aluminum garnet (Nd:YAG) or carbon dioxide (CO2) laser has been used successfully in selected patients with small superficial or superficially invasive penile cancers (Schlenker 2010; Bandieramonte 2008). The risk of local control using the Nd-Yag laser is significantly related to T category, with 10% of local recurrences in stage I tumours in contrast to 32% and 100% in T2 and T3 tumours, respectively (Horenblas 1992). Therefore, in T1 tumours YAG laser therapy offers excellent local control with preservation of cosmetic appearance and sexual function. Conversely, invasive lesions (T2 or greater) cannot be adequately controlled with laser therapy alone. On a type 3 level of evidence, organ preservation may be preferred for T1 lesions ≤4 cm with a risk of local relapse but a possibility of surgical salvage if local recurrence occurs.
6.3.2 T2-T4 tumours

In patients with deeply invasive lesions, organ preservation is rarely achievable. For these lesions penile amputation is considered the standard option on a type C basis. Total penectomy is preferred for ≥T2 tumours, although some T2 tumours are amenable to partial penectomy based on location if surgical margins of 5- to 10-mm can be achieved. For larger or proximal tumours, total amputation may be required with perineal urethrostomy. In ≥T2 tumours, radiation therapy with surgical salvage may be an alternative approach (McLean 1993; Zouhair 2001; Crook 2013), if organ preservation is a major therapeutic aim on a type 3 level of evidence.

6.4 Treatment of regional lymph nodes

Survival of patients with penile cancer is directly related to the presence and extent of nodal metastases. Several studies reveal 5-year disease-free survival rates of 95-100% in surgically staged patients with negative lymph nodes. This rate decreases to 80% when a single inguinal lymph node is involved, to 50% when multiple inguinal nodes are positive, and to virtually 0% when perinodal extension or pelvic lymph node metastases occur (Lynch 1998; Ravi 1993a).
However, clinical examination of regional lymph nodes may not be reliable. About 50% of patients with squamous cell carcinoma have palpable inguinal lymph nodes at diagnosis, but in one-half of these patients, palpable lymph nodes are indicative of inflammatory changes associated with ulcerated or infected penile lesions that will resolve following a 4-6 week course of antibiotic therapy. Only 50% of patients with palpable lymphadenopathy actually have metastatic disease; conversely, 25% of patients with clinically non-palpable lymphadenopathy have occult metastases (Burgers 1992).
Accurate staging of regional nodes becomes paramount when one considers that lymphadenectomy can be curative in about 50% of patients with histologically confirmed lymph node metastases. At the base of the penis, the lymphatics of the prepuce and penile skin decussate toward the right or left (Cabanas 1977; Rouviere 1938).
That means that lymphatic drainage may be considered bilateral. Thus, ipsilateral penile lesions can give rise to controlateral inguinal metastases and a bilateral lymphadenectomy should be performed.

6.4.1 Clinically N0

The primary controversy concerns the role of lymph node dissection if there is no clinically involved inguinal disease. The morbidity of inguinal lymphadenectomy may be considerable with infection, skin necrosis, seromas, wound breakdown, and chronic lymphoedema. Rarely, venous thromboembolism and death have been also reported. Therefore, some investigators propose surveillance for patients with clinically uninvolved inguinal nodes and recommended lymphadenectomy only after the nodes became palpable (“watch and wait” approach). However, several other studies, on a type 3 level of evidence, suggested improved survival in patients with microscopic metastases who undergo early “prophylactic” inguinal lymphadenectomy compared with those with initially non palpable inguinal nodes who subsequent developed recurrent disease and received delayed “therapeutic” inguinal dissection (Fraley 1989; Johnson 1984a; McDougal 1986; Ornellas 1994; Ornellas 2008). Of patients with initially clinically negative inguinal nodes McDougal et al. (McDougal 1986) found an 5-year survival rate of 83% for those with confirmed nodal metastases at prophylactic lymphadenectomy compared to a 5-year survival rate of 42% for patients undergoing therapeutic lymphadenectomy after initial surveillance. In a large surgical series of 688 patients, immediate lymphadenectomy (No. 251) was associated with a better 10-year disease-specific survival than delayed (No. 81) lymphadenectomy (71% vs. 30%, P =0.002) (Ornellas 2008). However, randomized studies of “prophylactic” versus “therapeutic” dissection are lacking and about 75% of patients with non-palpable inguinal lymph nodes have been found not to develop microscopic inguinal metastases. Thus, lymphadenectomy applied to all patients would expose many to the morbidity of inguinal dissection with benefit for only a minority of patients. The selection of patients with no palpable nodes for prophylactic inguinal lymphadenectomy is aided by determining the pathologic stage, the grade of the primary tumour and the presence or absence of vascular invasion on a type 3 level of evidence. For tumours with no or only superficial invasion, which are moderately or well differentiated, only 12% of clinically non-enlarged inguinal nodes are pathologically positive, whereas 78 to 88% of invasive or poorly differentiated tumours metastasize to inguinal nodes, regardless of clinical findings (McDougal 1995). Both EAU and ESMO guidelines suggest a risk adapting management of lymph node. Generally, for low-risk compliant patients (pTis, pTa and pT1G1) without palpable lymph nodes, surveillance was recommended. For all other patients (intermediate risk: pT1G2 and high-risk: pT1G3 or greater) without palpable lymph nodes, a bilateral inguinal lymphadenectomy or sentinel lymph node dissection was recommended on a type 3 level of evidence (Van Poppel 2013; Hakenberg 2015; Protzel 2009; Sonpavde 2013). Whether a more limited dissection (Colberg 1997; Catalona 1988; Jacobellis 2003) or a video endoscopic inguinal lymphadenectomy (Tobias-Machado 2007) will decrease morbidity while maintaining efficacy needs further study in prospective clinical trials. Some reports of small retrospective series of patients suggest that these techniques may decrease postoperative morbidity without compromising oncological outcome, although the false-negative rate might be ≤25%. However, a larger experience and longer follow-up are necessary before routine adoption. Prophylactic radiation therapy is not recommended in patients without cytologically or histologically proven metastases nor in those with micrometastases.

6.4.2 N1-N2

In patients with cytologically or histologically proven inguinal metastases, complete inguinal lymphadenectomy should be performed ipsilaterally, on a type 3 level of evidence. In patients with histologically confirmed inguinal metastases involving ≥2 nodes on one side, contralateral limited inguinal lymphadenectomy with frozen section analysis can be performed, with complete inguinal lymphadenectomy if the frozen section analysis findings are positive. If clinically suspicious inguinal metastases develop during surveillance, complete inguinal lymphadenectomy should be performed on that side only, and sentinel lymph node dissection or limited inguinal lymphadenectomy with frozen section analysis on the contralateral side can be considered, on a type 3 level of evidence. Pelvic lymph node dissection is recommended if ≥2 proven inguinal metastases, grade 3 tumour in the lymph nodes, extranodal extension, or large (2-4 cm) inguinal nodes are present, or if the femoral (Cloquet’s) node is involved on a type 3 level of evidence. In patients with numerous or large inguinal metastases, CT or MRI should be performed. If grossly enlarged iliac nodes are present, neoadjuvant chemotherapy should be given and the response assessed before proceeding with pelvic lymph node dissection. Antibiotic treatment should be started before surgery to minimize the risk of wound infection. Perioperative low-dose heparin to prevent thromboembolic complications can be used, although it might increase lymph leakage. Elastic stockings or sequential compression devices are advisable to minimize the risk of lymphedema and thromboembolism. Radiation therapy can be considered in patients with large (>4cm) or fixed nodes as neoadjuvant therapy to surgery (Gerbaulet 1992; Ravi 1994), although lymphadenectomy after irradiation may be associated with severe complications. Adjuvant radiotherapy after complete inguinal lymphadenectomy may decrease the incidence of locoregional recurrences, especially in cases of multiple or large inguinal metastases or extranodal extension or capsular rupture (Chao 1997; Gerbaulet 1992; Franks 2011) on a type 3 level of evidence. Secondary fibrosis resulting from combined lymphadenectomy and radiotherapy can lead to oedema, pain, and difficulty in walking. These complications are reported in more than 30% of patients receiving both surgery and irradiation (Gerbaulet 1992). Adjuvant chemotherapy after complete inguinal lymphadenectomy can be used in patients with ≥2 inguinal metastases, large nodes, extranodal extension, or pelvic metastases (Heyns 2010).
In patients who are not candidates for surgery, radiation therapy may be considered as an alternative to lymph node dissection (Chao 1997; Gerbaulet 1992) on a type 3 level of evidence.

6.5 Advanced disease

Patients with advanced disease have a very poor prognosis and early consideration of palliative care is recommended. There is no standard curative therapy for patients with advanced or metastatic disease and treatment is directed at palliation. Palliative surgery may be considered for control of local penile lesions in patients with advanced ulcerated or infiltrating tumours providing temporary tumour regression and decreasing pain and bleeding. Radiation therapy may be also been used for palliation of the primary tumour, regional lymph nodes, and bone metastases.
Due to the low incidence of penile carcinomas, there are only a few studies concerning chemotherapy with mostly inhomogeneous patient groups. So far, chemotherapeutic options are limited to single-centre experiences or case reports, on a type 3 level of evidence. Active agents include methotrexate, bleomycin, cisplatin, 5-fluorouracil, vincristine, paclitaxel used as single drug therapy or in various combinations.
Responses to chemotherapy occur in ≤50% of patients; most of these responses are partial responses of short duration (Ahmed 1984).
The role of combination chemotherapy has also been explored, but always in small studies. Different drugs have been used in combination, usually including cisplatin. Cisplatin can be combined with bleomycin, 5-fluorouracil, vinblastine, vincristine, irinotecan, etoposide and/or methotrexate. Methotrexate-based regimens have also been used.
Combination chemotherapy with methotrexate, bleomycin and cisplatin has been the most extensively studied (Corral 1998; Dexeus 1991; Haas 1999). In the M.D. Anderson Cancer Centre experience an overall response rate of 72% (with 14% complete responses) was first reported in 14 patients with inoperable or metastatic squamous cell carcinoma of the male genital tract (in 12 patients the primary tumour site was the penis); the median response duration was 6 months (Dexeus 1991). Corral et al. subsequently reported an overall response rate of 57% in 21 evaluable patients with squamous penile cancer; the overall median survival was 11 months (Corral 1998). In the patients who achieved disease-free status by chemotherapy alone or by chemotherapy followed by surgery or radiotherapy, the median survival was 34 months. The Southwest Oncology Group (Haas 1999) evaluated the same three-drug regimen in 40 patients with locally advanced or unresectable disease. A complete response was seen in 12.5% of patients and the overall response rate was 32.5%; the median duration of response was 16 weeks, with a median survival of 28 weeks. Unfortunately, in this study, five treatment-related deaths occurred and six other patients had one or more life threatening toxic episodes. The toxic effects of bleomycin-containing regimens have been recognized and considered to be prohibitive.
Other studies have reported the activity of cisplatin and 5-fluorouracil. Hussein et al. reported one complete response and 5 partial responses in six men with recurrent or unresectable squamous cell carcinoma of the penis (Hussein 1990). Shammas et al. treated 8 patients with advanced squamous cell carcinoma of the penis, two of whom achieved a partial response, 1 requiring surgery and the other requiring surgery and radiotherapy to achieve a complete response (Shammas 1992). These 2 patients were disease-free at 32 and 58 months.
In the largest retrospective study, cisplatin and 5-fluorouracil were used in 25 patients with metastatic penile cancer. Partial responses were observed in 8 patients (32%). The median progression-free survival and overall survival was 20 weeks and 8 months, respectively. Severe neutropenia was the most important grade 3-4 side effect observed, occurring in 20% of patients (Di Lorenzo 2012). One trial investigated the combination of cisplatin and irinotecan in locally advanced or metastatic disease. This nonrandomized, prospective phase II study involved six centres belonging to the EORTC Genito-Urinary Tract Cancer Group. Patients were treated in the neoadjuvant setting for T3 or N1-N2 disease either with up to four cycles before surgery or up to eight cycles for T4 or N3 or M1 disease. There were eight clinical responses in 26 assessable patients (30.8%) including two complete clinical responses. Three patients treated in the neo-adjuvant setting underwent a lymphadenectomy after chemotherapy and no evidence of malignancy was found at the pathological examination. Major adverse events were grade 3 diarrhoea in 3 cases and grade 4 neutropenic fever in 2 cases, of which 1 stopped treatment after pneumonia (Theodore 2008). Paclitaxel in combination with carboplatin may provide an alternative regimen in patients who are ineligible for cisplatin treatment. Paclitaxel showed promising activity in chemotherapy-pretreated metastatic penile cancer. Twenty-five patients were enrolled in a single-arm phase 2 multicentre study and treated with 175 mg/m² paclitaxel at 3-week intervals until disease progression or irreversible toxicity. Partial responses were observed in 20% (5 of 25 patients). Grade 1-2 neutropenia, nausea, and oral mucositis were the most common side effects. Grade 3-4 neutropenia was reported in seven patients (28%). Median PFS was 11 weeks; median OS was 23 weeks (Di Lorenzo 2011).
In order to deliver higher concentrations of drugs to the affected areas, intra-arterial administration of chemotherapy has been attempted, with promising results in patients with locally advanced or recurrent disease (Roth 2000).
A phase II trial of combined biological therapy with 13-cis-retinoic acid and interferon alpha showed low efficacy in advanced carcinoma of the penis, with one complete response in 16 eligible patients (Skeel 2003).

6.6 Neoadjuvant and adjuvant chemotherapy

In patients with multiple, fixed or bulky inguinal lymph node metastasis or involved pelvic lymph nodes, multimodality approach including neoadjuvant chemotherapy followed by surgery and node resection is preferred on a type 3 level of evidence. There is very little information about adjuvant treatment concepts after radical resection of lymph node metastasis, because there are no prospective trials of adjuvant chemotherapy, but only small retrospective series. Recently, in a large retrospective study adjuvant chemotherapy was associated with improved overall survival in patients with penile carcinoma who have positive pelvic lymph nodes after lymph node dissection. 141 patients with positive pelvic lymph nodes were identified across 4 centres from 1978 to 2013 and 84 of them met inclusion criteria. Adjuvant chemotherapy was used in 36 (43%) patients. Estimated median overall survival was 21.7 months in patients who received adjuvant chemotherapy versus 10.1 in those who did not (p =0.048) (Sharma 2015). In a pilot study 12 weekly courses of vincristine, bleomycin and methotrexate were administered to 12 patients with radically resected inguinal lymph node metastases and to 5 patients with fixed inguinal nodes before lymphadenectomy. Of the patients treated with adjuvant therapy only 1 relapsed after a median follow-up of 42 months. Neoadjuvant therapy produced partial responses in 3 of the 5 patients, permitting radical lymphadenectomy. There was no evidence of disease at 20, 27 and 72 months (Pizzocaro 1988). Subsequent experience at the National Tumour Institute of Milan, showed a relapse rate of 45% in the 31 patients treated only surgically in the 1964-77 period, versus a relapse rate of 16% in the 25 patients given adjuvant chemotherapy between 1978 and 1990 (Pizzocaro 1996). Nine (56%) of the 16 patients treated with neoadjuvant chemotherapy underwent successful surgical resection, and 5 (31%) achieved 5-year disease-free survival. By contrast, only one of the 10 patients treated with radiotherapy alone could undergo subsequent surgery and all 10 patients died of cancer within 3 years. Cisplatin plus continuous infusion of 5-fluorouracil has also been shown to be effective as neoadjuvant therapy (Fisher 1990). In a phase II trial four cycles of neoadjuvant paclitaxel in combination with cisplatin and ifosfamide chemotherapy has been shown to be well tolerated and effective in patients with bulky regional disease (any T, N2 or N3). Thirty men received chemotherapy of whom 15 (50.0%) had an objective response and 22 (73.3%) subsequently underwent surgery. A pathologic complete response was observed in three patients (13.6%) who completed chemotherapy and underwent surgery. Nine patients (30%) remained alive and disease-free at a median follow-up of 34 months and two patients died of other causes without recurrence (Pagliaro 2010). Also four cycles of paclitaxel, cisplatin, and 5-fluorouracil may provide an attractive neoadjuvant regimen. Preliminary data of this combination for salvage of primarily unresectable or relapsed nodal metastases from penile cancer was reported by Pizzocaro et al. from the National Tumour Institute of Milan. Six consecutive patients were treated for unresectable (two cases) or recurrent nodal metastases (four cases). Two patients had pathologically documented complete remission, and they are alive and disease free >2 years after chemotherapy (Pizzocaro 2009). These limited experiences suggest that neoadjuvant chemotherapy can render resectable approximately 50% of patients with fixed or recurrent inguinal metastases. A larger series is necessary to confirm preliminary results. However, the roles of neoadjuvant and adjuvant chemotherapy need to be explored further in larger prospective studies. Concurrent chemotherapy may enhance the effectiveness of radiotherapy in achieving tumour control (Edsmyr 1985; Modig 1993) and its use is under evaluation in clinical trials.

6.7 Recurrent penile carcinoma

Locally recurrent disease can be treated with surgery or radiotherapy. Local relapses after radiation therapy as initial treatment can be salvaged by surgery.
Recurrent disease may progress to distant sites, such as the liver, lung, bone, and brain. Metastatic disease is uncommon at presentation and is usually subsequent to initial treatment failure. No curative therapy exists for these patients and treatment is directed at palliation.
The role of chemotherapy has not been extensively explored and is limited to small series.


7.1 Late sequelae related to surgery

Total penectomy followed by perineal urinary diversion results in the loss of both sexual function and the ability to urinate in the standing position, requiring a readjustment of the patient’s body image. Appropriate counselling should be available and physicians should discuss the expected outcome and consequences of the different treatment options with the patient before treatment commences.
The morbidity of inguinal lymphadenectomy may be considerable, with lymphocele, chronic lymphangitis, and a 30-50% incidence of severe lymphoedema and skin flap necrosis (Horenblas 1993; Johnson 1984b; Ornellas 1994; Ravi 1993b). Lymphoedema can be bothersome with respect to ambulation, difficulty standing for prolonged periods and recurrent bouts of cellulitis.
Rarely venous thromboembolism and death have been also reported.

7.2 Late sequelae related to radiotherapy

Radiation therapycan induce adverse effects and complications such as teleangiectasia, atrophy, hyperpigmentation of the skin, fibrosis, urethral stenosis, ulcerations and necrosis. Most serious complications are necrosis or urethral stenosis resulting in a non-functioning penis. The frequency and degree of these complications depend on the type of radiation, fraction dose, total dose, extent of tumour invasion, and irradiated volume.
Urethral stenosis is reported in 10 to 20% of patients (Chao 1997) and dilatation may results in a symptomatic relief in about 90% of affected patients (Gerbaulet 1992).
Necrosis of the glans is also reported in 10 to 20% of patients and may lead to a high risk of infection and pain. The reported incidence of penectomy for radiation complications varies from 0% to 5% (Crook 2005; Sarin 1997).
Sexual function seems better preserved after radiation therapy than after organ-preserving surgery, although a reduction of erectile function is reported in 20-30% of patients treated with radiotherapy (Opjordsmoen 1994).
In the groin, radiation therapy, alone or combined with surgery, may result in severe oedema and pain (Gerbaulet 1992).


There is no standard follow-up for patients with penile cancer. Nevertheless, close surveillance is essential and must be supervised by a team with experience in this rare tumour.
The follow-up interval and strategies should be closely related to the initial treatment of the primary lesion and regional lymph nodes.
A large retrospective study based on a two-centre analysis of 700 patients with penile cancer showed that 74.1% and 92.2% of all recurrences occurred within the first 2 and 5 years, respectively (Leijte 2008). Long-term follow-up is therefore recommended. Follow-up is based essentially on physical examination.
Chest radiographs and computed tomography (CT) may be useful in patients with positive regional lymph nodes to identify lymphadenopathy or distant metastases. Other diagnostic tests (e.g., bone scan) should be used only in symptomatic patients.


Agrawal A, Pai D, Ananthakrishnan N, Smile SR, Ratnakar C. Clinical and sonographic findings in carcinoma of the penis. J Clin Ultrasound 2000a; 28(8): 399-406. [Medline]

Agrawal A, Pai D, Ananthakrishnan N, Smile SR, Ratnakar C. The histological extent of the local spread of carcinoma of the penis and its therapeutic implications. BJU Int 2000b; 85(3): 299-301. [Medline]

Ahmed T, Sklaroff R, Yagoda A. Sequential trials of methotrexate, cisplatin and bleomycin for penile cancer. J Urol 1984; 132(3): 465-8. [Medline]

Akimoto T, Mitsuhashi N, Takahashi I, Yonome I, Takahashi M, Hayakawa K et al. Brachytherapy for penile cancer using silicon mold. Oncology 1997; 54(1): 23-7. [Medline]

Alnajjar HM, Lam W, Bolgeri M, Rees RW, Perry MJ, Watkin NA. Treatment of carcinoma in situ of the glans penis with topical chemotherapy agents. Eur Urol 2012; 62(5): 923-8. [Medline]

Bandieramonte G, Colecchia M, Mariani L, Lo Vullo S, Pizzocaro G, Piva L et al. Peniscopically controlled CO2 laser excision for conservative treatment of in situ and T1 penile carcinoma: report on 224 patients. Eur Urol 2008; 54(4): 875-82. [Medline]

Bermejo C, Busby JE, Spiess PE, Heller L, Pagliaro LC, Pettaway CA. Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol 2007; 177(4): 1335-8. [Medline]

Berrino F, Capocaccia R, Coleman MP, Esteve J, Gatta G, Hakulinen T et al. Survival of cancer patients in Europe: the EUROCARE-3 study. Ann Oncol 2003; 14 Suppl 5: v1-155.

Bezerra AL, Lopes A, Santiago GH, Ribeiro KC, Latorre MR, Villa LL. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer 2001; 91(12): 2315-21. [Medline]

Brkovic D, Kälble T, Dörsam J, Pomer S, Lötzerich C, Banafsche R et al. Surgical treatment of invasive penile cancer –the Heidelberg experience from 1968 to 1994. Eur Urol 1997; 31(3): 339-42. [Medline]

Brown CT, Minhas S, Ralph DJ. Conservative surgery for penile cancer: subtotal glans excision without grafting. BJU Int 2005; 96(6): 911-2. [Medline]

Burgers JK, Badalament RA, Drago JR. Penile cancer. Clinical presentation, diagnosis, and staging. Urol Clin North Am 1992; 19(2): 247-56. [Medline]

Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977; 39(2): 456-66. [Medline]

Cabanas RM. Anatomy and biopsy of sentinel lymph nodes. Urol Clin North Am 1992; 19(2): 267-76. [Medline]

Carter JJ, Madeleine MM, Shera K, Schwartz SM, Cushing-Haugen KL, Wipf GC et al. Human papillomavirus 16 and 18 L1 serology compared across anogenital cancer sites. Cancer Res 2001; 61(5): 1934-40. [Medline]

Catalona WJ. Modified inguinal lymphadenectomy for carcinoma of the penis with preservation of saphenous veins: technique and preliminary results. J Urol 1988; 140(2): 306-10. [Medline]

Chao KS, Perez CA. Penis and male urethra. In: Perez CA, Brady LW, editors. Principles and Practice od Radiation Oncology. 3rd ed. Philadelphia (PA), Lippincott-Raven Publishers, 1997; pp. 1717-32.

Chaudhary AJ, Ghosh S, Bhalavat RL, Kulkarni JN, Sequeira BV. Interstitial brachytherapy in carcinoma of the penis. Strahlenther Onkol 1999; 175(1): 17-20. [Medline]

Colberg JW, Andriole GL, Catalona WJ. Long-term follow-up of men undergoing modified inguinal lymphadenectomy for carcinoma of the penis. Br J Urol 1997; 79(1): 54-7. [Medline]

Corral DA, Sella A, Pettaway CA, Amato RJ, Jones DM, Ellerhorst J. Combination chemotherapy for metastatic or locally advanced genitourinary squamous cell carcinoma: a phase II study of methotrexate, cisplatin and bleomycin. J Urol 1998; 160(5): 1770-4. [Medline]

Crocetti E, Capocaccia R, Casella C, Ferretti S, Guzzinati S, Rosso S et al. Cancer trends in Italy: figures from the cancer registries (1986-1997). Epidemiol Prev 2004; 28(2) Suppl 2: 1-6. [Medline]

Crook J, Jezioranski J, Grimard L, Esche B, Pond G. Penile brachytherapy: results for 49 patients. Int J Radiat Oncol Biol Phys 2005; 62(2): 460-7. [Medline]

Crook JM, Haie-Meder C, Demanes DJ, Mazeron JJ, Martinez AA, Rivard MJ. American Brachytherapy Society-Groupe Européen de Curiethérapie-European Society of Therapeutic Radiation Oncology (ABS-GEC-ESTRO) consensus statement for penile brachytherapy. Brachytherapy 2013; 12(3): 191-8. [Medline]

Cubilla AL, Barreto J, Caballero C, Ayala G, Riveros M. Pathologic features of epidermoid carcinoma of the penis. A prospective study of 66 cases. Am J Surg Pathol 1993; 17(8): 753-63. [Medline]

Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M et al (eds). Cancer Incidence in Five Continents, Vol. IX. Lyon, IARC Scientific Publications No. 160, 2007.

Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera KA, Wurscher MA et al. Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer 2005; 116(4): 606-16. [Medline]

de Crevoisier R, Slimane K, Sanfilippo N, Bossi A, Albano M, Dumas I et al. Long-term results of brachytherapy for carcinoma of the penis confined to the glans (N- or NX). Int J Radiat Oncol Biol Phys 2009; 74(4): 1150-6. [Medline]

de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 2012; 13(6): 607-15. [Medline]

Dexeus FH, Logothetis CJ, Sella A, Amato R, Kilbourn R, Fitz K et al. Combination chemotherapy with methotrexate, bleomycin and cisplatin for advanced squamous cell carcinoma of the male genital tract. J Urol 1991; 146(5): 1284-7. [Medline]

Dillner J, von Krogh G, Horenblas S, Meijer CJ. Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl 2000; (205): 189-93. [Medline]

Djajadiningrat RS, Graafland NM, van Werkhoven E, Meinhardt W, Bex A, van der Poel HG et al. Contemporary management of regional nodes in penile cancer-improvement of survival? J Urol 2014a; 191(1): 68-73. [Medline]

Djajadiningrat RS, van Werkhoven E, Meinhardt W, van Rhijn BW, Bex A, van der Poel HG et al. Penile sparing surgery for penile cancer-does it affect survival? J Urol 2014b; 192(1): 120-5. [Medline]

Di Lorenzo G, Buonerba C, Federico P, Perdonà S, Aieta M, Rescigno P et al. Cisplatin and 5-fluorouracil in inoperable, stage IV squamous cell carcinoma of the penis. BJU Int 2012; 110(11 Pt B): E661-6. [Medline]

Di Lorenzo G, Federico P, Buonerba C, Longo N, Cartenì G, Autorino R et al. Paclitaxel in pretreated metastatic penile cancer: final results of a phase 2 study. Eur Urol 2011; 60(6): 1280-4. [Medline]

Edsmyr F, Andersson L, Esposti PL. Combined bleomycin and radiation therapy in carcinoma of the penis. Cancer 1985; 56(6): 1257-63. [Medline]

El-Demiry MI, Oliver RT, Hope-Stone HF, Blandy JP. Reappraisal of the role of radiotherapy and surgery in the management of carcinoma of the penis. Br J Urol 1984; 56: 724-728. [Medline]

ENCR. European Network of Cancer Registries. Eurocim version 4.0. European incidence database V2.2 (1999). Lyon 2001.

Feldman AS, McDougal WS. Long-term outcome of excisional organ sparing surgery for carcinoma of the penis. J Urol 2011; 186(4): 1303-7. [Medline]

Ficarra V, D’Amico A, Cavalleri S, Zanon G, Mofferdin A, Schiavone D et al. Surgical treatment of penile carcinoma: our experience from 1976 to 1997. Urol Int 1999; 62(4): 234-7. [Medline]

Ficarra V, Galfano A. Should the dynamic sentinel node biopsy (DSNB) be considered the gold standard in the evaluation of lymph node status in patients with penile carcinoma? Eur Urol 2007; 52(1): 17-9. [Medline]

Ficarra V, Akduman B, Bouchot O, Palou J, TTobias-Machado M. Prognostic factors in penile cancer. Urology 2010; 76(2) Suppl 1: S66-73. [Medline]

Fisher HA, Barada JH, Horton J, et al. Neoadjuvant therapy with cisplatin and 5-fluorouracil for stage III squamous cell carcinoma of the penis. J Urol 1990; 143 Suppl 4: 352A.

Forman D, Bray F, Brewster DH, Gomba Mbalawa C, Kohler B,  Pineros M et al (eds). Cancer Incidence in Five Continents. Volume X. IARC Scientific Publication No. 164. Lyon, Iternational Agency for Research on Cancer, 2014.

Fraley EE, Zhang G, Manivel C, Niehans GA. The role of ilioinguinal lymphadenectomy and significance of histological differentiation in treatment of carcinoma of the penis. J Urol 1989; 142(6): 1478-82. [Medline]

Franks KN, Kancherla K, Sethugavalar B, Whelan P, Eardley I, Kiltie AE. Radiotherapy for node positive penile cancer: experience of the Leeds teaching hospitals. J Urol 2011; 186(2): 524-9. [Medline]

Friedman GD, Quesenberry CP Jr. Spousal concordance for cancer incidence: A cohort study. Cancer 1999; 86(11): 2413-9. [Medline]

Gerbaulet A, Lambin P, Haie-Meder C, Lartigau E, Gery B, Marsiglia H et al. Brachytherapy in cancer of the penis. Ann Urol (Paris) 1994; 28(6-7): 306-11. [Medline]

Gerbaulet A, Lambin P. Radiation therapy of cancer of the penis. Indications, advantages, and pitfalls. Urol Clin North Am 1992; 19(2): 325-32. [Medline]

Gerbaulet A. Tumours of the penis. In: Souhami RL, Tannock I, Hohenberger P, Horiot P, editors. Oxford Textbook of Oncology. 2nd edition. New York, Oxford University Press, 2002; pp. 2047-56.

Goodman MT, Hernandez BY, Shvetsov YB. Demographic and pathologic differences in the incidence of invasive penile cancer in the United States, 1995-2003. Cancer Epidemiol Biomarkers Prev 2007; 16(9): 1833-9. [Medline]

Gotsadze D, Matveev BB, Zak B, Mamaladze V. Is conservative organ-sparing treatment of penile carcinoma justified? Eur Urol 2000; 38(3): 306-12. [Medline]

Grabstald H, Kelley CD. Radiation therapy of penile cancer: six to ten-year follow-up. Urology 1980; 15(6): 575-6. [Medline]

Grossman HB. Premalignant and early carcinomas of the penis and scrotum. Urol Clin North Am 1992; 19(2): 221-6. [Medline]

Gunia S, Burger M, Hakenberg OW, May D, Koch S, Jain A et al. Inherent grading characteristics of individual pathologists contribute to clinically and prognostically relevant interobserver discordance concerning Broders’ grading of penile squamous cell carcinomas. Urol Int 2013; 90(2): 207-13. [Medline]

Haas GP, Blumenstein BA, Gagliano RG, Russell CA, Rivkin SE, Culkin DJ et al. Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the penis: a Southwest Oncology Group study. J Urol 1999; 161(6): 1823-5. [Medline]

Hadway P, Smith Y, Corbishley C, Heenan S, Watkin NA. Evaluation of dynamic lymphoscintigraphy and sentinel lymph-node biopsy for detecting occult metastases in patients with penile squamous cell carcinoma. BJU Int 2007; 100(3): 561-5. [Medline]

Hakenberg OW, Compérat EM, Minhas S, Necchi A, Protzel C, Watkin N; European Association of Urology. EAU Guidelines on penile cancer: 2014 update. Eur Urol 2015; 67(1): 142-50. [Medline]

Harish K, Ravi R. The role of tobacco in penile carcinoma. Br J Urol 1995; 75(3): 375-7. [Medline]

Hellberg D, Valentin J, Eklund T, Nilsson S. Penile cancer: is there an epidemiological role for smoking and sexual behaviour? Br Med J (Clin Res Ed) 1987; 295(6609): 1306-8. [Medline]

Heyns CF, Fleshner N, Sangar V, Schlenker B, Yuvaraja TB, van Poppel H. Management of the lymph nodes in penile cancer. Urology 2010; 76(2) Suppl 1: S43-57. [Medline]

Horenblas S, van Tinteren H, Delemarre JF, Moonen LM, Lustig V, Kröger R. Squamous cell carcinoma of the penis: accuracy of tumor, nodes and metastasis classification system, and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology. J Urol 1991; 146(5): 1279-83. [Medline]

Horenblas S, van Tinteren H, Delemarre JF, Boon TA, Moonen LM, Lustig V. Squamous cell carcinoma of the penis. II. Treatment of the primary tumor. J Urol 1992; 147(6): 1533-8. [Medline]

Horenblas S, van Tinteren H, Delemarre JF, Moonen LM, Lustig V, van Waardenburg EW. Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol 1993; 149(3): 492-7. [Medline]

Horenblas S, Kroger R, Gallee MP, Newling DW, van Tinteren H. Ultrasound in squamous cell carcinoma of the penis; a useful addition to clinical staging? A comparison of ultrasound with histopathology. Urology 1994; 43(5): 702-7. [Medline]

Horenblas S, Jansen L, Meinhardt W, Hoefnagel CA, de Jong D, Nieweg OE. Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure. J Urol 2000; 163(1): 100-4. [Medline]

Hussein AM, Benedetto P, Sridhar KS. Chemotherapy with cisplatin and 5-fluorouracil for penile and urethral squamous cell carcinomas. Cancer 1990; 65(3): 433-8. [Medline]

Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM et al (eds). ICD-O. International Classification of Diseases for Oncology, 3rd ed. Geneva, World Health Organization, 2000.

Iversen T, Tretli S, Johansen A, Holte T. Squamous cell carcinoma of the penis and of the cervix, vulva and vagina in spouses: is there any relationship? An epidemiological study from Norway, 1960-92. Br J Cancer 1997; 76(5): 658-60. [Medline]

Jackson SM. The treatment of carcinoma of the penis. Br J Surg 1966; 53(1): 33-5. [Medline]

Jacobellis U. Modified radical inguinal lymphadenectomy for carcinoma of the penis: technique and results. J Urol 2003; 169(4): 1349-52. [Medline]

Johnson DE, Lo RK. Complications of groin dissection in penile cancer. Experience with 101 lymphadenectomies. Urology 1984b; 24(4): 312-4. [Medline]

Johnson DE, Lo RK. Management of regional lymph nodes in penile carcinoma. Five-year results following therapeutic groin dissections. Urology 1984a; 24(4): 308-11. [Medline]

Kattan J, Culine S, Droz JP, Fadel E, Court B, Perrin JL et al. Penile cancer chemotherapy: twelve years’ experience at Institut Gustave-Roussy. Urology 1993; 42(5): 559-62. [Medline]

Kayes O, Ahmed HU, Arya M, Minhas S. Molecular and genetic pathways in penile cancer. Lancet Oncol 2007; 8(5): 420-9. [Medline]

Kiltie AE, Elwell C, Close HJ, Ash DV. Iridium-192 implantation for node-negative carcinoma of the penis: the Cookridge Hospital experience. Clin Oncol (R Coll Radiol) 2000; 12(1): 25-31. [Medline]

Kochen M, McCurdy S. Circumcision and the risk of cancer of the penis. A life-table analysis. Am J Dis Child 1980; 134(5): 484-6. [Medline]

Kroon BK, Horenblas S, Lont AP, Tanis PJ, Gallee MP, Nieweg OE. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol 2005a; 173(3): 816-9. [Medline]

Kroon BK, Horenblas S, Meinhardt W, van der Poel HG, Bex A, van Tinteren H, et al. Dynamic sentinel node biopsy in penile carcinoma: evaluation of 10 years experience. Eur Urol 2005b; 47(5): 601-6. [Medline]

Leijte JA, Kroon BK, Valdés Olmos RA, Nieweg OE, Horenblas S. Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma. Eur Urol 2007; 52(1): 170-7. [Medline]

Leijte JA, Kirrander P, Antonini N, Windahl T, Horenblas S. Recurrence patterns of squamous cell carcinoma of the penis: Recommendations for follow-up based on a two- centre analysis of 700 patients. Eur Urol 2008; 54(1): 161-8. [Medline]

Leis PF, Stevens KR, Baer SC, Kadmon D, Goldberg LH, Wang XJ. A c-rasHa mutation in the metastasis of a human papillomavirus (HPV)-18 positive penile squamous cell carcinoma suggests a cooperative effect between HPV-18 and c-rasHa activation in malignant progression. Cancer 1998; 83(1): 122-9. [Medline]

Levi JE, Rahal P, Sarkis AS, Villa L. Human papillomavirus DNA and p53 status in penile carcinomas. Int J Cancer 1998; 76(6): 779-83. [Medline]

Licklider S. Jewish penile carcinoma. J Urol 1961; 86: 98. [Medline]

Lont AP, Kroon BK, Horenblas S, Gallee MP, Berkhof J, Meijer CJ et al. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer 2006a; 119(5): 1078-81. [Medline]

Lont AP, Gallee MP, Meinhardt W, van Tinteren H, Horenblas S. Penis conserving treatment for T1 and T2 penile carcinoma: clinical implications of a local recurrence. J Urol 2006b; 176(2): 575-80. [Medline]

Lucia MS, Miller GJ. Histopathology of malignant lesions of the penis. Urol Clin North Am 1992; 19(2): 227-46. [Medline]

Lynch FL Jr, Schellhammer PF. Tumors of the penis. In: Walsh PC, Retik AB, Vaughan ED, Wein AJ (eds). Campbell’s Urology. 7th ed. Philadelphia, WB Saunders Co, 1998; pp. 2453-85.

Maden C, Sherman KJ, Beckmann AM, Hislop TG, Teh CZ, Ashley RL et al. History of circumcision, medical conditions, and sexual activity and risk of penile cancer. J Natl Cancer Inst 1993; 85(1): 19-24. [Medline]

McDougal WS, Kirchner FK Jr., Edwards RH, Killion LT. Treatment of carcinoma of the penis: the case for primary lymphadenectomy. J Urol 1986; 136(1): 38-41. [Medline]

McDougal WS. Carcinoma of the penis: improved survival by early regional lymphadenectomy based on the histological grade and depth of invasion of the primary lesion. J Urol 1995; 154(4): 1364-6. [Medline]

McLean M, Akl AM, Warde P, Bissett R, Panzarella T, Gospodarowicz M. The results of primary radiation therapy in the management of squamous cell carcinoma of the penis. Int J Radiat Oncol Biol Phys 1993; 25(4): 623-8. [Medline]

Meijer RP, Boon TA, van Venrooij GE, Wijburg CJ. Long-term follow-up after laser therapy for penile carcinoma. Urology 2007; 69(4): 759-62. [Medline]

Micheli A, Francisci S, Krogh V, Rossi AG, Crosignani P. Cancer prevalence in Italian cancer registry areas: the ITAPREVAL study. ITAPREVAL Working Group. Tumori 1999; 85(5): 309-69. [Medline]

Minhas S, Kayes O, Hegarty P, Kumar P, Freeman A, Ralph D. What surgical resection margins are required to achieve oncological control in men with primary penile cancer? BJU Int 2005; 96(7): 1040-3. [Medline]

Modig H, Duchek M, Sjodin JG. Carcinoma of the penis. Treatment by surgery or combined bleomycin and radiation therapy. Acta Oncol 1993; 32(6): 653-5. [Medline]

Mohs FE, Snow SN, Messing EM, Kuglitsch ME. Microscopically controlled surgery in the treatment of carcinoma of the penis. J Urol 1985; 133(6): 961-6. [Medline]

Mohs FE, Snow SN, Larson PO. Mohs micrographic surgery for penile tumors. Urol Clin North Am 1992; 19(2): 291-304. [Medline]

Mueller-Lisse UG, Scher B, Scherr MK, Seitz M. Functional imaging in penile cancer: PET/computed tomography, MRI, and sentinel lymph node biopsy. Curr Opin Urol 2008; 18(1): 105-10. [Medline]

Neave F, Neal AJ, Hoskin PJ, Hope-Stone HF. Carcinoma of the penis: a retrospective review of treatment with iridium mould and external beam irradiation. Clin Oncol (R Coll Radiol) 1993; 5(4): 207-10. [Medline]

Opjordsmoen S, Fosså SD. Quality of life in patients treated for penile cancer. A follow-up study. Br J Urol 1994; 74(5): 652-7. [Medline]

Ornellas AA, Seixas AL, Marota A, Wisnescky A, Campos F, de Moraes JR. Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol 1994; 151(5): 1244-9. [Medline]

Ornellas AA, Kinchin EW, Nóbrega BL, Wisnescky A, Koifman N, Quirino R. Surgical treatment of invasive squamous cell carcinoma of the penis: Brazilian National Cancer Institute long-term experience. J Surg Oncol 2008; 97(6): 487-95. [Medline]

Pagliaro LC, Williams DL, Daliani D, Williams MB, Osai W, Kincaid M et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study. J Clin Oncol 2010; 28(24): 3851-7. [Medline]

Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB (eds). Cancer Incidence in Five Continents. Volume VIII. IARC Scientific Publication No. 155. Lyon, International Agency for Research on Cancer, 2002.

Perdonà S, Autorino R, De Sio M, Di Lorenzo G, Gallo L, Damiano R et al. Dynamic sentinel node biopsy in clinically node-negative penile cancer versus radical inguinal lymphadenectomy: a comparative study. Urology 2005; 66(6): 1282-6. [Medline]

Persky L. Commentary: problems and management of squamous cell carcinoma of the penis. In: Whitehead ED, Leiter E (eds). Current Operative Urology. 2nd ed. Philadelphia, Harper&Row, 1984; pp. 1180-3.

Petera J, Odrázka K, Zouhar M, Bedrosová J, Dolezel M. High-dose-rate interstitial brachytherapy for the treatment of penile carcinoma. Strahlenther Onkol 2004; 180(2): 123-5. [Medline]

Pettaway CA, Pisters LL, Dinney CP, Jularbal F, Swanson DA, von Eschenbach AC et al. Sentinel lymph node dissection for penile carcinoma: the M. D. Anderson Cancer Center experience. J Urol 1995; 154(6): 1999-2003. [Medline]

Pietrzak P, Corbishley C, Watkin N. Organ-sparing surgery for invasive penile cancer: early follow-up data. BJU Int 2004; 94(9): 1253-7. [Medline]

Pizzocaro G, Piva L, Nicolai N. Treatment of lymphatic metastasis of squamous cell carcinoma of the penis: experience at the National Tumor Institute of Milan. Arch Ital Urol Androl 1996; 68(3): 169-72. [Medline]

Pizzocaro G, Piva L. Adjuvant and neoadjuvant vincristine, bleomycin, and methotrexate for inguinal metastases from squamous cell carcinoma of the penis. Acta Oncol 1988; 27(6b): 823-4. [Medline]

Pizzocaro G, Nicolai N, Milani A. Taxanes in combination with cisplatin and fluorouracil for advanced penile cancer: preliminary results. Eur Urol 2009; 55(3): 546-51. [Medline]

Protzel C, Alcaraz A, Horenblas S, Pizzocaro G, Zlotta A, Hakenberg OW. Lymphadenectomy in the surgical management of penile cancer. Eur Urol 2009; 55(5): 1075-88. [Medline]

RARECAREnet project. Available at:

Ravi R. Correlation between the extent of nodal involvement and survival following groin dissection for carcinoma of the penis. Br J Urol 1993a; 72(5 Pt 2): 817-9. [Medline]

Ravi R. Morbidity following groin dissection for penile carcinoma. Br J Urol 1993b; 72(6): 941-5. [Medline]

Ravi R, Chaturvedi HK, Sastry DV. Role of radiation therapy in the treatment of carcinoma of the penis. Br J Urol 1994; 74(5): 646-51. [Medline]

Ro JY, Amin MB, Ayala AG. Pathology of penis and scrotum. In: Bostwick DG, Eble JN (eds). Urologic Surgical Pathology. 3rd edition. St. Louis (MO), Mosby, 1996.

Roth AD, Berney CR, Rohner S, Allal AS, Morel P, Marti MC et al. Intra-arterial chemotherapy in locally advanced or recurrent carcinomas of the penis and anal canal: an active treatment modality with curative potential. Br J Cancer 2000; 83(12): 1637-42. [Medline]

Rouviere H. Anatomy of the Human Lymphatic System. Ann Arbor (MI), Edward Bros, 1938.

Rozan R, Albuisson E, Giraud B, Donnarieix D, Delannes M, Pigneux J et al. Interstitial brachytherapy for penile carcinoma: a multicentric survey (259 patients). Radiother Oncol 1995; 36(2): 83-93. [Medline]

Rubin MA, Kleter B, Zhou M, Ayala G, Cubilla AL, Quint WG et al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol 2001; 159(4): 1211-8. [Medline]

Sadeghi R, Gholami H, Zakavi SR, Kakhki VR, Horenblas S. Accuracy of 18F-FDG PET/TC for diagnosing inguinal lymph node involvement in penile squamous cell carcinoma: systematic review and meta-analysis of the literature. Clin Nucl Med 2012a; 37(5): 436-41. [Medline]

Sadeghi R, Gholami H, Zakavi SR, Kakhki VR, Tabasi KT, Horenblas S. Accuracy of sentinel lymph node biopsy for inguinal lymph node staging of penile squamous cell carcinoma: systematic review and meta-analysis of the literature. J Urol 2012b; 187(1): 25-31. [Medline]

Sanchez DF, Cañete S, Fernández-Nestosa MJ, Lezcano C, Rodríguez I, Barreto J et al. HPV- and non-HPV-related subtypes of penile squamous cell carcinoma (SCC): Morphological features and differential diagnosis according to the new WHO classification (2015). Semin Diagn Pathol 2015a; 32(3): 198-221. [Medline]

Sanchez DF, Soares F, Alvarado-Cabrero I, Cañete S, Fernández-Nestosa MJ, Rodríguez IM et al. Pathological factors, behavior, and histological prognostic risk groups in subtypes of penile squamous cell carcinomas (SCC). Semin Diagn Pathol 2015b; 32(3): 222-31. [Medline]

Sarin R, Norman AR, Steel GG, Horwich A. Treatment results and prognostic factors in 101 men treated for squamous carcinoma of the penis. Int J Radiat Oncol Biol Phys 1997; 38(4): 713-22. [Medline]

Schellhammer PF, Jordan GH, Robey EL, Spaulding JT. Premalignant lesions and nonsquamous malignancy of the penis and carcinoma of the scrotum. Urol Clin North Am 1992; 19(1): 131-42. [Medline]

Scher B, Seitz M, Reiser M, Hungerhuber E, Hahn K, Tiling R et al. 18F-FDG PET/CT for staging of penile cancer. J Nucl Med 2005; 46(9): 1460-5. [Medline]

Schlenker B, Tilki D, Seitz MM, Bader MJ, Reich O, Schneede P et al. Organ-preserving neodymium-yttrium-aluminium-garnet laser therapy for penile carcinoma: a long-term follow-up. BJU Int 2010; 106(6): 786-90. [Medline]

Schlenker B, Tilki D, Gratzke C, Seitz M, Reich O, Schneede P et al. Intermediate-differentiated invasive (pT1 G2) penile cancer – oncological outcome and follow-up. Urol Oncol 2011; 29(6): 782-7. [Medline]

Schoen EJ, Oehrli M, Colby C, Machin G. The highly protective effect of newborn circumcision against invasive penile cancer. Pediatrics 2000; 105(3): E36. [Medline]

Shammas FV, Ous S, Fossa SD. Cisplatin and 5-fluorouracil in advanced cancer of the penis. J Urol 1992; 147(3): 630-2. [Medline]

Sharma P, Djiajadiningrat R, Zargar-Shoshtari K, Catanzaro M, Zhu Y, Nicolai N et al. Adjuvant chemotherapy is associated with improved overall survival in pelvic node-positive penile cancer after lymphnode dissection: A multi-institutional study. Urol Oncol 2015; pii: S1078-1439(15)00231-8. [Medline]

Shindel AW, Mann MW, Lev RY, Sengelmann R, Petersen J, Hruza GJ et al. Mohs micrographic surgery for penile cancer: management and long-term followup. J Urol 2007; 178: 1980-1985. [Medline]

Singh AK, Gonzalez-Torrez P, Kaewlai R, Tabatabaei S, Harisinghani MG. Imaging of penile neoplasm. Semin Ultrasound CT MR 2007; 28(4): 287-96. [Medline]

Skeel RT, Huang J, Manola J, Wilding G, Dreicer R, Walker P et al. A phase II study of 13-cis retinoic acid plus interferon alpha-2a in advanced stage penile carcinoma: an Eastern Cooperative Oncology Group study (E3893). Cancer Invest 2003; 21(1): 41-6. [Medline]

Slaton JW, Morgenstern N, Levy DA, Santos MW Jr, Tamboli P, Ro JY et al. Tumor stage, vascular invasion and the percentage of poorly differentiated cancer: independent prognosticators for inguinal lymph node metastasis in penile squamous cancer. J Urol 2001; 165(4): 1138-42. [Medline]

Smith Y, Hadway P, Biedrzycki O, Perry MJ, Corbishley C, Watkin NA. Reconstructive surgery for invasive squamous carcinoma of the glans penis. Eur Urol 2007; 52(4): 1179-85. [Medline]

Sobin LH, Gospodariwics M, Wittekind C (eds). TNM Classification of Malignant Tumours. UICC International Union Against Cancer, 7th edition. Willy-Blackwell 2009; pp. 239-42.

Solsona E, Iborra I, Rubio J, Casanova JL, Ricós JV, Calabuig C. Prospective validation of the association of local tumor stage and grade as a predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative inguinal lymph nodes. J Urol 2001; 165(5): 1506-9. [Medline]

Sonpavde G, Pagliaro LC, Buonerba C, Dorff TB, Lee RJ, Di Lorenzo G. Penile cancer: current therapy and future directions. Ann Oncol 2013; 24(5): 1179-89. [Medline]

Sufrin G, Huber R. Benign and malignant lesions of the penis. In: Gillenwater JY, Howards SS, Duckett JW (eds). Adult and Pediatric Urology. 2nd edition. St. Louis, Mosby, 1991; pp. 1643-62.

Tanis PJ, Lont AP, Meinhardt W, Olmos RA, Nieweg OE, Horenblas S. Dynamic sentinel node biopsy for penile cancer: reliability of a staging technique. J Urol 2002; 168(1): 76-80. [Medline]

Tewari M, Kumar M, Shukla HS. Nd:YAG laser treatment of early stage carcinoma of the penis preserves form and function of penis. Asian J Surg 2007; 30(2): 126-30. [Medline]

Theodore C, Skoneczna I, Bodrogi I, Leahy M, Kerst JM, Collette L et al. A phase II multicentre study of irinotecan (CPT 11) in combination with cisplatin (CDDP) in metastatic or locally advanced penile carcinoma (EORTC PROTOCOL 30992). Ann Oncol 2008; 19(7): 1304-7. [Medline]

Tobias-Machado M, Tavares A, Ornellas AA, Molina WR, Juliano RV, Wroclawski ER. Video endoscopic inguinal lymphadenectomy: a new minimally invasive procedure for radical management of inguinal nodes in patients with penile squamous cell carcinoma. J Urol 2007; 177(3): 953-7. [Medline]

Tsen HF, Morgenstern H, Mack T, Peters RK. Risk factors for penile cancer: results of a population-based case-control study in Los Angeles County (United States). Cancer Causes Control 2001; 12(3): 267-77. [Medline]

Valdes Olmos RA, Tanis PJ, Hoefnagel CA, Jansen L, Nieweg OE, Meinhardt W et al. Penile lymphoscintigraphy for sentinel node identification. Eur J Nucl Med 2001; 28(5): 581-5. [Medline]

van Bezooijen BP, Horenblas S, Meinhardt W, Newling DW. Laser therapy for carcinoma in situ of the penis. J Urol 2001; 166(5): 1670-1. [Medline]

Van Poppel H, Watkin NA, Osanto S, Moonen L, Horwich A, Kataja V; ESMO Guidelines Working Group. Penile cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24 Suppl 6: vi115-24. [Medline]

Vapnek JM, Hricak H, Carroll PR. Recent advances in imaging studies for staging of penile and urethral carcinoma. Urol Clin North Am 1992; 19(2): 257-66. [Medline]

Verdecchia A, Francisci S, Brenner H, Gatta G, Micheli A, Mangone L et al. Recent cancer survival in Europe: a 2000-02 period analysis of EUROCARE-4 data. Lancet Oncol 2007; 8(9): 784-96. [Medline]

Werness BA, Levine AJ, Howley PM. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 1990; 248(4951): 76-9. [Medline]

Wespes E. The management of regional lymph nodes in patients with penile carcinoma and reliability of sentinel node biopsy. Eur Urol 2007; 52(1): 15-6. [Medline]

Wieland U, Jurk S, Weissenborn S, Krieg T, Pfister H, Ritzkowsky A. Erythroplasia of queyrat: coinfection with cutaneous carcinogenic human papillomavirus type 8 and genital papillomaviruses in a carcinoma in situ. J Invest Dermatol 2000; 115(3): 396-401. [Medline]

Zhu Y, Gu WJ, Wang HK, Gu CY, Ye DW. Surgical treatment of primary disease for penile squamous cell carcinoma: A Surveillance, Epidemiology, and End Results database analysis. Oncol Lett 2015; 10(1): 85-92. [Medline]

Zouhair A, Coucke PA, Jeanneret W, Douglas P, Do HP, Jichlinski P et al. Radiation therapy alone or combined surgery and radiation therapy in squamous-cell carcinoma of the penis? Eur J Cancer 2001; 37(2): 198-203. [Medline]



Dr. Claudia Caserta (Author)
Azienda ospedaliera Santa Maria – Terni, Italy

Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy

Dr. Anna Maria Mosconi (Author)
Policlinico Monteluce – Perugia, Italy

Dr. Fausto Roila (Associate Editor)
Ospedale Policlinico Monteluce – Perugia, Italy

Dr. Christine Theodore (Reviewer)
Hôpital Foch – Suresnes, France