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Cancer of the penis – 2016

UPDATED JANUARY 2016

1. GENERAL INFORMATION

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. PATHOLOGY AND BIOLOGY

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
Necrosis
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. DIAGNOSIS

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. STAGING

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. PROGNOSIS

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. TREATMENT

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. LATE SEQUELAE

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).

8. FOLLOW-UP

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.

INDEX

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Dr. Claudia Caserta (Author)
Azienda ospedaliera Santa Maria – Terni, Italy
mail: caserta_claudia@libero.it

Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: gatta@istitutotumoti.mi.it

Dr. Anna Maria Mosconi (Author)
Policlinico Monteluce – Perugia, Italy
mail: amarmosc@unipg.it

Dr. Fausto Roila (Associate Editor)
Ospedale Policlinico Monteluce – Perugia, Italy
mail: faroila@unipg.it

Dr. Christine Theodore (Reviewer)
Hôpital Foch – Suresnes, France
mail: c.theodore@hopital-foch.org