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Diagnostic Applications of Nuclear Medicine: Penile Cancer

  • Serena ChiacchioEmail author
  • Abedallatif AlSharif
  • Zia Saad
  • Giampiero Giovacchini
  • Jamshed Bomanji
Living reference work entry

Abstract

Penile carcinomas are rare in most developed countries; in contrast, this cancer is not infrequent in the tropical and subtropical regions of Latin America, Asia, and Africa. In addition, penile cancer is common in regions with high prevalence of human papilloma virus infection. More than 95% of penile carcinomas are of the squamous cell type; other histologic types include basal cell carcinoma, melanoma, and sarcoma. Penile carcinoma usually spreads through lymphatic channels to the superficial and deep inguinal lymph nodes; subsequently iliac lymph nodes are involved. The presence and extent of metastatic disease in inguinal nodes is the single most important prognostic factor in patients with penile cancer. Primary evaluation of penile cancer is based on physical examination including inguinal lymph node palpation. Ultrasound and MRI can provide information on tumor invasion of the corpora cavernosa if organ preservation is planned. Ultrasound can be used to evaluate nonpalpable inguinal lymph nodes, whereas pelvic CT scan can be used to assess pelvic lymph nodes. Lymphoscintigraphy, preferably with SPECT/CT imaging, and subsequently sentinel lymph node biopsy is gaining popularity in clinical practice, especially in patients with nonpalpable lymph nodes; sensitivity reported for this local staging approach ranges from 70% to 86%. Assessment of distant metastases should be performed in patients with positive inguinal nodes; this includes abdomen and pelvis CT, chest X-ray, or thoracic CT. [18F]FDG PET/CT can be used for initial staging of penile cancer with pooled sensitivity and specificity of 80.9% and 92.4% respectively; this staging technique is particularly advocated for patients with positive lymph nodes. [18F]FDG PET/CT can also be employed to monitor the efficacy of induction chemotherapy. Follow-up of penile cancer is based mainly on clinical evaluation, while radionuclide imaging techniques have rarely been used for restaging purposes during regular follow-up.

Keywords

Penile cancer Imaging [18F]FDG PET/CT 

Glossary

Glossary of terms for Chapter “Diagnostic Applications of Nuclear Medicine: Penile Cancer”

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

AIDS

Acquired immune deficiency syndrome

AJCC

American Joint Committee on Cancer

CDKN2A

Gene encoding for cyclin dependent kinase inhibitor 2A, also encoding for proteins p16INK4A and p14ARF

CI

Confidence interval

CpG

5′-C-phosphate-G-3′ sequence in DNA, where cytosine and guanine are separated by only one phosphate

CT

X-ray computed tomography

EAU

European Association of Urology

HPV

Human papilloma virus

KAI1/CD82

Member of the tetraspanin family classified as metastasis suppressor gene

LOH

Loss of heterozygosity

MR

Magnetic resonance

MRI

Magnetic resonance imaging

p53

Tumor protein p53, also known as cellular tumor antigen p53, phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53)

PET

Positron emission tomography

PET/CT

Positron emission tomography/computed tomography

PUVA

Therapy with psoralen plus ultraviolet light to treat atopic dermatitis

Rb

Gene encoding for the retinoblastoma protein

SCC Ag

Squamous cell carcinoma antigen

SCC

Squamous cell carcinoma

SLN

Sentinel lymph node

SLNB

Sentinel lymph node biopsy

SPECT

Single-photon emission computed tomography

SPECT/CT

Single-photon emission computed tomography/computed tomography

TNM

AJCC/UICC staging system based on parameters “T” (tumor status), “N” (lymph node status) and “M” (distant metastasis status)

US

Ultrasonography

WHO

World Health Organization

Epidemiology and Environmental Factors

Penile carcinomas are rare in most developed nations including in Europe and the USA where the rate is less than 1 per 100,000 men per year. Incidence is also affected by race and ethnicity in North America [1, 2], with the highest incidence of penile cancer found in white Hispanics (1.01 per 100,000), followed by a lower incidence in Alaskan, Native American Indians (0.77 per 100,000), blacks (0.62 per 100,000), and white non-Hispanics (0.51 per 100,000), respectively.

In contrast, penile cancer is not infrequent in the tropical or subtropical regions of Latin America, Asia, and Africa. In South America, Southeast Asia, and parts of Africa, the incidence of penile cancer is much higher and can represent 1–2% [2, 3] of all malignant diseases in men. The annual age-adjusted incidence is 0.7–3.0 per 100,000 men in India, 8.3 per 100,000 men in Brazil, and even higher in Uganda, where it is the most commonly diagnosed cancer in men [3, 4].

Penile cancer is common in regions with a high prevalence of human papilloma virus (HPV) infection, and therefore much knowledge about penile cancer comes from research in countries with a high incidence of the disease. HPV infection in the population may account for the wide variability in incidence observed across countries, as the HPV infection prevalence varies considerably worldwide. Whereas at least one third of cases can be attributed to HPV-related carcinogenesis, there are no clear data linking penile cancer to HIV infection or AIDS.

In the USA, the overall age-adjusted incidence rate decreased between 1973 and 2002 from 0.84 per 100,000 in 1973–1982 to 0.69 per 100,000 in 1983–1992 and further declined to 0.58 per 100,000 in 1993–2002 [1, 2]. In European countries, the overall incidence has remained stable from the 1980s until today [5]. Recently, an increased incidence has been reported from Denmark [6] and the UK, where a longitudinal study has confirmed a 21% increase in incidence over the period 1979–2009 [7].

Risk Factors and Association with Other Conditions

The incidence of penile cancer increases with age [3] and have a peak during the sixth decade of life, although this disease can indeed occur in younger men [8].

Infection by the human papilloma virus is an important risk factor in the development of penile cancer. DNA of HPV has been identified in 70–100% of intraepithelial neoplasias and in 40–50% of invasive penile cancer tissue samples. The HPV virus plays an important role in oncogenesis through the interaction with oncogenes and tumor suppressor genes (p53, Rb genes) [9, 10]. The rate of HPV positive differs between different histological subtypes of penile cancer. This suggests that HPV is a cofactor in the carcinogenesis of some variants of penile SCC, while other variants of penile cancer are not related to HPV [2]. HPV subtypes most commonly found associated with penile cancer are types 16 and 18 [11]. The risk of penile cancer is also increased in patients with condyloma acuminata [12]. It is not clear whether HPV-associated penile cancer differs in prognosis from non-HPV-associated penile cancer. A significantly better 5-year disease-specific survival has been reported for HPV-positive versus HPV-negative cases (93% vs. 78%) in one study [13], while no difference in lymph node metastases and 10-year survival rate was reported in another study [14].

No direct association between the incidence of penile cancer and that of cervical cancer has been established yet, except the coexistent link with the prevalence of HPV infections [2, 15, 16]. In particular, female sexual partners of patients with penile cancer do not have an increased incidence of cervical cancer.

Other known risk factors for penile carcinoma include conditions such as phimosis, chronic inflammations leading to balanoposthitis and lichen sclerosus et atrophicus, sexual history (multiple partners, early age at first intercourse), history of condylomata, and smoking [9, 10, 11, 12, 13, 14, 15, 16, 17].

Around 25–60% of phimosis patients develop penile cancer at some stage of their lives [18]. The phimosis causes retention of desquamated epidermal cells and urinary products, collectively called “smegma, ” which leads to chronic inflammation of prepuce and glans penis causing balanitis. Sexual promiscuity which plays a major role in sexually transmitted diseases also poses increased risk of developing penile cancers.

Some, but not all, observational studies also suggest that male newborn circumcision is associated with a decreased risk of penile cancer [19, 20]. According to one study, the risk among uncircumcised men was found to be 3.2 times higher [21], while according to another published data, if the relationship is causal, the number needed to treat is about 909 circumcisions to prevent a single case of invasive penile cancer [22]. In addition, the treatment of psoriasis by ultraviolet light in the region was also found to increase significantly the risk of cancer development [23].

Prevention

Circumcision is a precautionary measure taken by a few healthy adult subpopulations, although no published literature has shown clear advantage in adult circumcision. Similarly, smegma is blamed to be a strong risk factor, but again without any definite correlation having been published so far. Practicing better hygiene, however, has shown to decrease the risk of chronic recurrent inflammation, which is in some situations a precursor of squamous cell carcinoma (SCC).

Raising the awareness regarding sexual health and protective sex can also be considered an effective preventive measure to both privileged and poor socioeconomic countries.

There is at present no recommendation for the use of HPV vaccination in boys due to a different HPV-associated risk pattern in penile and anal cancer; furthermore, the epidemiological effects of HPV vaccination and its acceptance in girls will have to be assessed before any further recommendations can be made [24, 25]. The newer available vaccines against HPV 16 and 18 have shown to be effective with protection for around 5 years; however, their true efficacy in the long term has not yet been established [26].

Due to high rates of developing SCC of the genitalia after psoralen plus ultraviolet light A (PUVA) therapy, genitalia shielding and serial checkups should be in place [27].

Genetic Predisposition

To date no genetic predisposition to penile cancers has been identified.

Underlying Molecular Biological Changes

So far only few datasets are available linking chromosomal abnormalities in penile SCC (the predominant histological type of penile cancer) to biological pattern and patient outcomes [2, 10]. The alterations in DNA copy number found in penile carcinoma are comparable to those found in SCC of other origins. Lower copy numbers and alteration numbers in penile SCC have been linked to poorer survival. Alterations in the locus 8q24 seem to play a major role and have also been assumed to be involved in the carcinogenesis of other neoplasms such as prostate cancer [28, 29]. Telomerase activity has been demonstrated in invasive penile carcinoma [30]. It has also been reported that aneuploidy changes according to tumor grade [31].

Epigenetic alterations evaluating the methylation pattern of CpG islands in CDKN2A have been described as well [32]. CDKN2A encodes for two tumor suppressor proteins (p16INK4A and p14ARF) that control cell growth through the Rb and p53 pathways. Poetsch at al. showed that 62% of invasive SCCs of the penis displayed allelic loss of p16 and 42% promoter hypermethylation. Tumors immunohistochemically negative for p16 showed hypermethylation of and/or copy number neutral loss of heterozygosity (LOH) near the p16INK4A locus; furthermore, p16 negativity was linked to greater probability of lymph node metastasis and to poor prognosis [33]. Allelic loss of the p53 gene is a frequent event in penile SCC (42%) and has been linked to poor prognosis [34]. Another factor influencing lymph node metastasis is the metastasis-suppressor protein KAI1/CD82; in particular, decreased expression of this protein favors lymph node metastasis [35].

Staging and Prognostic Stratification

The TNM classification of penile cancer is shown in Tables 1 and 2. Ultrasound (US) is useful in evaluating suspected penile masses and has been advised for primary penile cancer deemed to invade the corpora cavernosa [36]; SCC usually presents as a hypoechoic lesion with heterogeneous appearance. However, US evaluation is unreliable in the presence of microscopic invasion. On MR imaging, penile carcinoma is often a solitary, ill-defined mass infiltrating the adjacent corpora, hypo-intense on both T1- and T2-weighted images [37]. The local extent, the depth of tumor invasion, and the extension to adjacent structures can be accurately depicted using MRI, and this information is valuable for surgical planning [38].
Table 1

AJCC TNM classification of penile cancer

Definitions of TNM

Primary tumor (T)

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

Ta

Noninvasive verrucous carcinomaa

T1a

Tumor invades subepithelial connective tissue without lymph-vascular invasion and is not poorly differentiated

(i.e., grades 3–4)

T1b

Tumor invades subepithelial connective tissue with lymph-vascular invasion or is poorly differentiated

T2

Tumor invades corpus spongiosum or cavernosum

T3

Tumor invades urethra

T4

Tumor invades other adjacent structures

Regional lymph nodes (N)

Clinical stage definitionb

cNX

Regional lymph nodes cannot be assessed

cN0

No palpable or visibly enlarged inguinal lymph nodes

cN1

Palpable mobile unilateral inguinal lymph node

cN2

Palpable mobile multiple or bilateral inguinal lymph nodes

cN3

Palpable fixed inguinal nodal mass or pelvic lymphadenopathy unilateral or bilateral

Pathologic stage definitionc

pNX

Regional lymph nodes cannot be assessed

pN0

No regional lymph node metastasis

pN1

Metastasis in a single inguinal lymph node

pN2

Metastasis in multiple or bilateral inguinal lymph nodes

pN3

Extranodal extension of lymph node metastasis or pelvic lymph node(s) unilateral or bilateral

Distant metastasis (M)

M0

No distant metastasis

M1

Distant metastasisd

Histopathological grading

GX

Grade of differentiation cannot be assessed

G1

Well differentiated

G2

Moderately differentiated

G3-4

Poorly differentiated/undifferentiated

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Eighth Edition (2014) published by Springer Science and Business Media LLC. www.springer.com

aBroad pushing penetration (invasion) is permitted; destructive invasion is against this diagnosis

bClinical stage definition based on palpation and imaging

cPathologic stage definition based on biopsy or surgical excision

dLymph node metastasis outside of the true pelvis in addition to visceral or bone sites

Table 2

AJCC anatomic stages and prognostic groups for penile cancer

Group

T category

N category

M category

Stage 0

Tis

N0

M0

Ta

N0

M0

Stage I

T1a

N0

M0

Stage II

T1b

N0

M0

T2

N0

M0

T3

N0

M0

Stage IIIa

T1–3

N1

M0

Stage IIIb

T1–3

N2

M0

Stage IV

T4

Any N

M0

Any T

N3

M0

Any T

Any N

M1

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, IL. The original source for this material is the AJCC Cancer Staging Manual, Eighth Edition (2014) published by Springer Science and Business Media LLC. www.springer.com

Both clinical examination and conventional imaging techniques, including US, CT, and MRI, are unreliable in accurately detecting lymph node metastases [36]. Hence, prophylactic inguinal lymphadenectomy is often recommended, particularly in high-risk patients, with the expectation to improve survival. However, the morbidity of groin dissection is high, with complication rates between 30% and 50%, thus stimulating interest in the search for other techniques able to noninvasively assess the lymph node status and possibly reduce the need for groin dissection [39].

Grading

Tumor grade has been included into the penile cancer TNM classification because of its prognostic relevance. However, tumor grading of penile cancer according to Broder’s classification has been shown to be highly observer dependent and is therefore no longer used, similarly as has occurred for the WHO grading system [40]. The currently recommended grading according to the pTNM system is reported in Table 1.

Pathologic Prognostic Factors

More than 95% of penile malignancies are of the SCC type (see Fig. 1). SCC displays multiple subtypes with different prognostic features. Other histologic types include basal cell carcinoma, melanoma, and sarcoma. The glans penis is the most common site of SCC (48%) [41].
Fig. 1

Penile cancer: typical histopathologic pattern of a squamous cell cancer (also called “spinocellular” cancer) of the penis. Hematoxylin and eosin staining; original magnification approximately 250×

Lymphatic Involvement

Penile carcinoma usually spreads through penile lymphatic channels to regional lymph nodes, especially the superficial and deep inguinal nodes, and subsequently to the iliac nodes. Presence and degree of lymph node involvement is the most important prognostic factor for penile carcinoma. The prevalence of nodal disease is related to the stage of the primary lesion and occurs in 20% of T1 penile cancers and in 47–66% of T2–T4 tumors [42, 43]. Between 30% and 60% of patients with penile carcinoma have palpable inguinal nodes, but nearly half of these are linked to inflammatory reaction [44]. Some tumors metastasize directly to deep inguinal nodes.

Basaloid tumors are poorly differentiated subtypes of SCC, are infiltrative, and frequently metastasize to inguinal lymph nodes. The prognosis for survival in patients with lymph node metastases is closely correlated with the number and location of involved lymph nodes and with the presence of extranodal extension [9, 45]. Involvement of deep inguinal nodes is more ominous than involvement of superficial inguinal nodes. The 5-year overall and disease-free survival rates are as high as 80% for unilateral, superficial inguinal lymph node involvement with no more than one node (N1), only 10–20% for bilateral or pelvic lymph nodes involved (N2/N3), and less than 10% in the presence of extranodal extension [9, 41].

Hungerhuber et al. recommend prophylactic lymphadenectomy for high-risk patients [46]. Chaux et al. proposed a “prognostic index” based on findings in 193 patients; this index incorporates several pathological parameters (such as grade, deepest anatomical level, perineural invasion) and permits scoring in a ranking system that can be used to predict the likelihood of inguinal lymph node metastases and the likelihood of 5-year survival [47]. Low scores confer a 95% chance of 5-year survival, intermediate scores a 65%, and high scores a 45% likelihood of 5-year survival.

Widespread dissemination occurs in 20–40% of the patients; distant metastases occur most frequently in the lung, liver, and skeleton. Histopathologic features affecting patients’ outcome are multiple. Poorer prognosis is related to histological grade, patterns of growth, perineural and vascular invasion, corpus cavernosum invasion, and histological subtype of SCC [41]. For example, verrucous carcinomas are well differentiated, have an expansile border, and are essentially nonmetastatic.

Performance of Diagnostic Imaging Other Than Nuclear Medicine

While penile cancer can be cured in over 80% of all cases, it is a life-threatening disease with poor prognosis once metastatic spread has occurred. Furthermore, local treatment, although potentially lifesaving, can be mutilating and devastating for the psychological well-being of the patient. Therefore, the treatment of patients with penile cancer requires a careful diagnosis and adequate staging before treatment decisions can be made [2].

Primary Lesion

Penile carcinoma is often a clinically obvious lesion, but can be hidden under a phimosis. Physical examination of a patient with penile cancer should include palpation of the penis with a view to examining the extent of local invasion.

Ultrasound can give information about infiltration of the corpora [48, 49]. Magnetic resonance imaging (MRI) in combination with an artificial erection induced by prostaglandin E1 can also be used for excluding tumor invasion of the corpora cavernosa if organ preservation is planned and preoperative decisions are needed [37, 50].

Regional Lymph Nodes

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

    Palpable lymph nodes are highly suspicious for the presence of lymph node metastases. Physical examination should note the number of palpable nodes on each side and whether these are fixed or mobile. Additional inguinal imaging does not alter management and is usually not required. A pelvic CT scan can be performed in order to assess the pelvic lymph nodes.

  • Non-palpable inguinal nodes

    The management of clinically node-positive groin in penile cancer is clear-cut with radical inguinal lymph node dissection being the surgical option. It is known that lymph node metastases have an inverse prognostic outcome for these patients. In clinically node-negative groin with occult metastases, the dilemma remains whether to perform lymphadenectomy (with the associated risk of high morbidity) or to continue close observations. In the absence of palpable abnormalities, the likelihood of the presence of micrometastatic disease is about 25%. However, current imaging techniques are not reliable in detecting micrometastases. Inguinal ultrasound (7.5 MHz) can reveal abnormal lymph nodes with some enlargement. The longitudinal/transverse diameter ratio and the absence of the lymph node hilum have been reported to be relatively specific for lymph node metastasis [51]. Conventional CT or MRI scans similarly cannot detect micrometastases reliably [38]. Imaging studies are therefore not helpful in staging clinically normal inguinal regions. An exception can be represented by obese patients, in whom palpation is unreliable or not possible. The further diagnostic management of patients with normal inguinal nodes should be guided by pathological risk factors. Several series have identified lymph-vascular invasion, local stage, and grade as risk factors predicting the likelihood of lymphatic metastasis [52, 53]. Nomograms are unreliable as they cannot achieve an over 80% accuracy. Invasive lymph node staging is required in patients at intermediate or high risk of lymphatic spread.

Distant Metastases

An assessment of distant metastases should be performed in patients with positive inguinal nodes [44, 54, 55]. Computed tomography of the abdomen and pelvis and a chest X-ray are recommended, although thoracic CT will be more sensitive than a plain chest X-ray, and in symptomatic M1 patients a bone scan is also advisable, as per guidelines of the European Association of Urology (EAU) [2, 56].

There is no established tumor marker for penile cancer. The squamous cell carcinoma antigen (SCC Ag) is increased in less than 25% of penile cancer patients. In one study, SCC Ag was not a predictor for occult metastatic disease, but it was a prognostic indicator of disease-free survival in lymph node-positive patients [57].

Performance of Nuclear Imaging for Staging and Prognosis

Due to its low incidence, penile cancer is best managed at specialized centers. Imaging with CT or MRI can neither accurately detect occult metastases nor predict on tumor characteristics reliably. Lymphoscintigraphy to visualize lymphatic drainage, especially its early dynamic sequence to look for sentinel lymph node(s) (the first node in a given lymphatic pathway from the primary tumor), has been a standard technique for over a decade [58, 59]. This imaging procedure (the preliminary phase of sentinel lymph node biopsy) is recommended for patients without palpable inguinal lymph nodes by the latest guidelines both of the EAU [2] and of the National Cancer Comprehensive Network (Version 1.2014, at www.nccn/guideline/urological/english/penile.pdf, last accessed March 5, 2016). However, it has not yet been sufficiently utilized in Europe or the USA in patients with penile cancers to identify non-palpable metastasis, despite the well-known notion that only 20–25% of clinically negative inguinal nodes harbor metastatic disease [60]. Nevertheless, sentinel lymph node biopsy (SLNB) as a diagnostic procedure in patients with malignancies, especially SCC, has proven to be of tremendous advantage for the detection of subclinical lymph node metastases [61, 62]. The technique of SLNB with the primary penile tumor has become standardized for the identification of a patient population with subclinical or clinically negative groin (see Fig. 2); when metastasis is found in sentinel lymph node(s), then elective lymph node dissection is currently recommended [63, 64]. Recent data indicate that correct application of this treatment algorithm can confer an effective survival benefit to patients with penile SCC [65].
Fig. 2

Pictorial sequence of sentinel lymph node biopsy in penile cancer. (a) Interstitial injection of the radiocolloid (99mTc-nanocolloidal albumin) proximally to the primary tumor. (b) Imaging with dual-head gamma camera imaging. (c) Planar imaging: early (top) and delayed (bottom), showing lymphatic drainage to both right and left inguinal lymph nodes. (d) Fused SPECT/CT images in the three axial planes (maximum intensity projection image in the bottom right panel). (e) Intraoperative localization of sentinel lymph node(s) with the gamma probe (after blue dye injection). (f) Probe-positive sentinel node localized (white arrow) demonstrating in-transit blue dye

Staging

Early detection plays a vital role in disease control, and appropriate diagnostic modalities must be used in order to accurately identify the cancer and its progression. The use of imaging in combination with biopsy is an effective mean in determining disease stage and grade [26]. One of the most important factors that affect the outlook for people with penile cancer is whether nearby lymph nodes contain cancer cells or not.

The management of the regional lymph nodes is of critical importance to both quantity and quality of life for these patients. Importance of inguinal and pelvic nodes cannot be overlooked in this uncommon malignancy, and the final management of penile cancer relies on the timely and appropriate management of the inguinal and pelvic lymph nodes. In fact, the presence and extent of metastatic disease in the inguinal lymph nodes is the single most important prognostic indicator in patients with penile cancer. In particular, the 5-year survival rate is approximately 95% when no metastasis is present in inguinal lymph nodes, while it is 80% when metastatic disease is limited to a single inguinal lymph node, and it drops to 40% if there are two or more metastatic inguinal lymph nodes; in addition, the 5-year survival rate is virtually 0% when metastatic disease at diagnosis involves pelvic lymph nodes [66].

Penile lymphatic drainage follows a well-validated pattern, draining to superficial inguinal nodes (above the fascia lata) and to deep inguinal nodes surrounding the saphenofemoral junction. After these two basins/regions, it flows to pelvic nodes following the ipsilateral iliac and obturator vessels. The pattern of lymphatic drainage can be accurately depicted by lymphoscintigraphy following interstitial injection of a suitable radiopharmaceutical (typically a 99mTc-labeled colloid) around the tumor. This imaging procedure constitutes an essential component of radioguided biopsy of the sentinel lymph node (SLN). Seminal work with SLN biopsy was originally described by Cabañas in the late 1970s [67]; nevertheless, his pioneering intuition of the clinical relevance of the SLN tumor status was based on the incorrect assumption of a fixed anatomic location of the SLN, a concept that was later corrected after lymphoscintigraphic demonstration of a certain degree of variability in lymphatic drainage patterns from the penis and following the currently accepted definition of the SLN as the first lymph node encountered on a direct drainage pathway from the primary tumor [68, 69]. In this regard, there can be more than one single pathway of direct lymphatic drainage from the penis. In fact, both unilateral (Fig. 3) and bilateral drainage patterns are recognized and could be either a physiological variant, secondary to previous inguinal surgeries, or could be due to extensive metastatic infiltration (a recent concept) [70]. The advanced hybrid SPECT/CT systems are at present gaining popularity in clinical practice. The value of lymphoscintigraphy can be greatly enhanced by performing a tomographic acquisition 2 h postinjection and by correlating scintigraphic findings to regional morphology assessed with CT; with this combined approach, the sensitivity of SPECT may be as high as 95% [38, 70].
Fig. 3

Dynamic sentinel lymph node biopsy following intradermal peri-tumoral injection of 99mTc-nanocolloidal albumin in a patient with penile cancer. (a) Dynamic acquisition for approximately 15 min, showing unilateral lymphatic drainage to the right groin. (b) Fused SPECT/CT images in the axial, coronal, and sagittal planes (upper left, upper right, and lower left images, respectively), confirming visualization of a single lymph node in the right groin

The eventual survival criteria in patients presenting with penile cancer rests with the detection and complete resection of nodal metastases. This resection can be curative even in advanced disease, but carries with it a significant burden of morbidity that has led the thrust to develop protocols and techniques to maximize detection and minimize morbidity and unnecessary surgery.

The sensitivity of sentinel lymph node (SLN) biopsy in patients with penile cancer with non-palpable lymph nodes ranges between 70% and 86% [71, 72]. In patients with clinically palpable nodes, SLN biopsy is less useful due to the possibility of false-negative results as a result of massive invasion of lymphatic pathways by cancer cells.

PET/CT with [18F]FDG has also been used for initial staging of penile cancer [73, 74, 75]. In a systematic review and meta-analysis of the literature, overall pooled sensitivity and specificity of [18F]FDG PET/CT were 80.9% (95% CI: 69.589.4%) and 92.4% (95% CI: 86.8–96.2%), respectively. However, sensitivity for clinically negative patients was only 56.5% (95% CI: 34.5–76.8%), considerably lower than in patients with palpable inguinal lymph nodes (96.4%, with 95% CI 81.7–99.9%) [76]. The authors concluded therefore that the routine use of [18F]FDG PET/CT is not justified in patients without palpable inguinal lymph nodes, while patients with palpable lymph nodes may benefit from this imaging procedure. Nevertheless, [18F]FDG PET/CT can occasionally be useful to evaluate also sub-centimeter lymph nodes that would be deemed as negative both clinically and on morphological imaging alone (Fig. 4). A more recent study has explored the diagnostic performance of combined [18F]FDG PET/CT and sentinel lymph node biopsy in a group of 129 patients, showing a combined sensitivity of 94.4% (95% CI: 81–99%) and a false-negative rate as low as 5.6% (95% CI: 1–11.9%) [77].
Fig. 4

[18F]FDG PET/CT in a 61-year-old patient with newly diagnosed penile SCC (T2; G3) with clinically negative inguinal lymph nodes. Axial sections at the level of the groin: (a) PET component; (b) CT component; (c) fused PET/CT image. Despite the small size (maximum diameter was 8 mm by CT estimate), metastasis in a left inguinal lymph node showed distinct focal [18F]FDG uptake (arrows) (Reprinted with permission of the Society of Nuclear Medicine)

Since distant metastasis is detected in 20% of the patients with cytological positive inguinal disease, routine use of [18F]FDG PET/CT at initial staging has been advocated for patients with positive lymph nodes (see Fig. 5), as integration of PET/CT scanning into preoperative staging algorithms may avoid surgical staging in selected patients [74, 76]. Since bone metastases are rare, bone scintigraphy is not yet commonly used in newly diagnosed penile SCC.
Fig. 5

Fused images obtained at various plane levels after i.v. injection of [18F]FDG and PET/CT performed for staging purposes in a 48-year-old patient with newly diagnosed penile carcinoma. (a) Besides increased metabolic activity at the primary tumor site (axial section shown in lower right panel), this patient had clinically silent metastatic disease in left common iliac lymph nodes (axial section shown in upper left panel, coronal section in upper right panel, and sagittal section in lower left panel). (b) Coronal sections of the CT component (left panel), of the PET component (center panel), and corresponding fused PET/CT image (right panel) demonstrating metastatic disease in mediastinal and para-hilar lymph nodes (bilaterally). (c) Coronal sections of the CT component (left panel), of the PET component (center panel), and corresponding fused PET/CT image (right panel) demonstrating a pulmonary metastasis in the right anterior costophrenic space

Follow-Up and Restaging

Most relapses are seen during the first 2 years after primary treatment, while late recurrences are uncommon [41]. Conservative treatment and surveillance are recommended for pN0 disease, at 2–4 month intervals in the first 2 years, 3–6 months in the third year, and 6–12 months thereafter. Follow-up is based mainly on clinical evaluation, while radionuclide imaging techniques have rarely been used for restaging purposes during regular follow-up. Whereas it has been shown that [18F]FDG PET may be used for assessing the metabolic response to induction chemotherapy in patients with positive inguinal lymph nodes, in fact, changes in glucose metabolism preceded morphological changes, thus indicating that functional assessment is more sensitive than morphological assessment. However, the implications of such findings on long-term survival are still unknown [52].

Treatment Options for Penile Cancer

The primary tumor and regional lymph nodes are usually treated separately [78]. The front-line treatment for managing the primary lesion remains surgical; however, the options are corresponding to the stage and grade of the disease. The gold standard remains partial or total penectomy with local control rates of above 90%, but carries very high psychosexual morbidity [79]. In the light of the new EAU guidelines, margins of up to 1–2 cm are enough to provide the same control rates [2].
  • Treatment option for carcinoma in situ

    It ranges from topical use of 5% 5-fluorouracil cream for 6 weeks, laser, circumcision, resurfacing glans penis to total glansectomy in case of urethral involvement [79].

  • Treatment options for T1

    This group requires careful selection of patients and close surveillance as it involves wide local excision with primary closure or split skin graft (depending on the size of lesion) in case where there is no urethral involvement and complete amputation for recurrences [80].

  • Treatment options for T2

    According to the new TNM stage classification, the previous two T2 stages (T2a, involvement of corpus spongiosum, and T2b, involvement of corpus cavernosa) have been amalgamated into one stage, which is T2. T2 has higher lymph node metastases, and if corpus cavernosa is involved, then conservative surgery is not an option. Therefore, in most cases partial penectomy is carried out unless the tumor has proximal extension warranting total penectomy with phalloplasty.

  • Radiotherapy

    Radiotherapy either by conventional external beam therapy or brachytherapy is commonly indicated for patients with tumors of less than 4 cm in size. Due to their high rate of complications and morbidity secondary to urethral stenosis, fibrosis, or even penile necrosis leading to amputation, the EAU guidelines restricted its use for T1–T2 tumors of glans penis or penile sulcus and for palliative use in advanced metastatic disease [56, 80].

  • Chemotherapy

    Chemotherapeutic regimens such as combination of bleomycin, methotrexate, and cisplatin have played positive role when used as neoadjuvant therapy. A new agent, cetuximab, has shown its promise in head and neck SCC, and due to close cross resemblance of SCC prevalent in penis, anal canal, and vulva, the efficacy of this agent is presumed to be high [81].

Since tumors are often localized in the penis at the time of diagnosis, they can be treated either by local excision or circumcision, laser ablation, brachytherapy, external radiation, or partial penectomy. Preservation of the penis is a concern for most patients, but more proximal or advanced lesions require total penectomy. With adequate treatment of the primary tumor, however, the rate of local recurrence is very low [82].

The management of inguinal metastasis is crucial, as distant metastases are rare in the absence of inguinal metastases. The standard recommendation for patients with palpable lymph nodes is bilateral inguinal lymphadenectomy. Inguinal lymphadenectomy, however, is associated with high morbidity, including severe lymphedema, wound infection, etc. The decision to opt either for imaging coupled with minimally invasive sentinel lymph node sampling or to predict nodal disease on the basis of primary tumor characteristics and pathology imposes significant challenge.

In patients with non-palpable lymph nodes, decision-making is based on risk stratification and recommendations that vary between surveillance, SLN biopsy, and radical inguinal lymph node dissection. Patients with high risk of distant disease are treated using a multimodality approach. Possible strategies in this setting include neoadjuvant chemotherapy followed by surgery (penectomy and bilateral groin dissection), or chemoradiotherapy, either cytoreductive or adjuvant.

In case of inoperable advanced penile cancer with distant metastasis, [18F]FDG PET/CT has been employed to monitor the efficacy of induction chemotherapy, by performing the scan at baseline, then after two cycles of therapy [83]; although a relatively small group of patients was studied, the [18F]FDG PET/CT findings were compared with CT data and with histopathological analysis. The preliminary results so obtained suggest that the metabolic tumor response is more reliable than morphologic imaging with CT to monitor the efficacy of induction chemotherapy in patients with penile cancer.

References

  1. 1.
    Backes DM, Kurman RJ, Pimenta JM, et al. Systematic review of human papillomavirus prevalence in invasive penile cancer. Cancer Causes Control. 2009;20:449–57.CrossRefPubMedGoogle Scholar
  2. 2.
    Hakenberg OW, Comperat E, Minhas S, et al. Guidelines on penile cancer. European Association of Urology 2014. https://uroweb.org/guidelines/. Last accessed 5 Mar 2016.
  3. 3.
    Parkin DM, Whelan SL, Ferlay J, et al. Cancer incidence in five continents, IARC scientific publications. No. 155, vol. VIII. Lyon: IARC; 2002.Google Scholar
  4. 4.
    Parkin DM, Bray F. The burden of HPV-related cancers. Vaccine. 2006;24 Suppl 3:S3/11–25.Google Scholar
  5. 5.
    Chaux A, Netto GJ, Rodríguez IM, et al. Epidemiologic profile, sexual history, pathologic features, and human papillomavirus status of 103 patients with penile carcinoma. World J Urol. 2013;31:861–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Baldur-Felskov B, Hannibal CG, Munk C, et al. Increased incidence of penile cancer and high-grade penile intraepithelial neoplasia in Denmark 1978–2008: a nationwide population-based study. Cancer Causes Control. 2012;23:273–80.CrossRefPubMedGoogle Scholar
  7. 7.
    Arya M, Li R, Pegler K, et al. Long-term trends in incidence, survival and mortality of primary penile cancer in England. Cancer Causes Control. 2013;24:2169–76.CrossRefPubMedGoogle Scholar
  8. 8.
    Barnholtz-Sloan JS, Maldonado JL, Pow-sang J, et al. Incidence trends in primary malignant penile cancer. Urol Oncol. 2007;25:361–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Bleeker MC, Heideman DA, Snijders PJ, Horenblas S, Dillner J, Meijer CJ. Penile cancer: epidemiology, pathogenesis and prevention. World J Urol. 2009;27:141–50.CrossRefPubMedGoogle Scholar
  10. 10.
    Kayes O, Ahmed HU, Arya M, et al. Molecular and genetic pathways in penile cancer. Lancet Oncol. 2007;8:420–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Muñoz N, Castelisague X, de Gonzalez AB, et al. HPV in the etiology of human cancer. Vaccine. 2006;24 Suppl 3:S3/1–10.Google Scholar
  12. 12.
    Nordenvall C, Chang ET, Adami HO, et al. Cancer risk among patients with condylomata acuminata. Int J Cancer. 2006;119:888–93.CrossRefPubMedGoogle Scholar
  13. 13.
    Lont AP, Kroon BK, Horenblas S, et al. Presence of high risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer. 2006;119:1078–81.CrossRefPubMedGoogle Scholar
  14. 14.
    Bezerra AL, Lopes A, Santiago GH, et al. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer. 2001;91:5–21.CrossRefGoogle Scholar
  15. 15.
    Philippou P, Shabbir M, Ralph DJ, et al. Genital lichen sclerosus/balanitis xerotica obliterans in men with penile carcinoma: a critical analysis. BJU Int. 2013;111:970–6.CrossRefPubMedGoogle Scholar
  16. 16.
    D’Hauwers KW, Depuydt CE, Bogers JJ, et al. Human papillomavirus, lichen sclerosus and penile cancer: a study in Belgium. Vaccine. 2012;30:6573–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Dillner J, von Krogh G, Horenblas S, Meijer CJ. Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl. 2000;34:89–93.CrossRefGoogle Scholar
  18. 18.
    Pow-Sang MR, Ferreira U, Pow-Sang JM, Nardi AC, Destefano V. Epidemiology and natural history of penile cancer. Urology. 2010;76(2 Suppl 1):S2–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Schoen EJ, Oehrli M, Colby C, et al. The highly protective effect of newborn circumcision against invasive penile cancer. Pediatrics. 2000;105:E36.CrossRefPubMedGoogle Scholar
  20. 20.
    Fetus and Newborn Committee, Canadian Paediatric Society. Neonatal circumcision revisited. CMAJ. 1996;154:769–80.Google Scholar
  21. 21.
    Maden C, Sherman KJ, Beckmann AM, et al. History of circumcision, medical conditions, and sexual activity and risk of penile cancer. J Natl Cancer Inst. 1993;85:19–24.CrossRefPubMedGoogle Scholar
  22. 22.
    Christakis DA, Harvey E, Zerr DM, et al. A trade-off analysis of routine newborn circumcision. Pediatrics. 2000;105(1 Pt 3):246–9.PubMedGoogle Scholar
  23. 23.
    Stern RS. Genital tumors among men with psoriasis exposed to psoralens and ultraviolet A radiation (PUVA) and ultraviolet B radiation. The photochemotherapy follow-up study. N Engl J Med. 1990;322:1093–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Newman PA, Logie CH, Doukas N, et al. HPV vaccine acceptability among men: a systematic review and meta-analysis. Sex Transm Infect. 2013;89:568–74.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Fisher H, Trotter CL, Audrey S, et al. Inequalities in the uptake of human papillomavirus vaccination: a systematic review and meta-analysis. Int J Epidemiol. 2013;42:896–908.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lawindy SM, Rodriguez AR, Horenblas S, Spiess PE. Current and future strategies in the diagnosis and management of penile cancer. Adv Urol. 2011;2011:593751.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Minhas S, Manseck A, Watya S, Hegarty PK. Penile cancer – prevention and premalignant conditions. Urology. 2010;76(2 Suppl 1):S24–35.CrossRefPubMedGoogle Scholar
  28. 28.
    Fromont G, Godet J, Peyret A, et al. 8q24 amplification is associated with Myc expression and prostate cancer progression and is an independent predictor of recurrence after radical prostatectomy. Hum Pathol. 2013;44:1617–23.CrossRefPubMedGoogle Scholar
  29. 29.
    Alves G, Heller A, Fiedler W, et al. Genetic imbalances in 26 cases of penile squamous cell carcinoma. Genes Chromosom Cancer. 2001;31:48–53.CrossRefPubMedGoogle Scholar
  30. 30.
    Alves G, Fiedler W, Guenther E, et al. Determination of telomerase activity in squamous cell carcinoma of the penis. Int J Oncol. 2001;18:67–70.PubMedGoogle Scholar
  31. 31.
    Kayes OJ, Loddo M, Patel N, et al. DNA replication licensing factors and aneuploidy are linked to tumor cell cycle state and clinical outcome in penile carcinoma. Clin Cancer Res. 2009;15:7335–44.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Gunia S, Erbersdobler A, Hakenberg OW, et al. p16(INK4a) is a marker of good prognosis for primary invasive penile squamous cell carcinoma: a multi-institutional study. J Urol. 2012;187:899–907.CrossRefPubMedGoogle Scholar
  33. 33.
    Poetsch M, Hemmerich M, Kakies C, et al. Alterations in the tumor suppressor gene p16(INK4A) are associated with aggressive behavior of penile carcinomas. Virchows Arch. 2011;458:221–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Gunia S, Kakies C, Erbersdobler A, et al. Expression of p53, p21 and cyclin D1 in penile cancer: p53 predicts poor prognosis. J Clin Pathol. 2012;65:232–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Protzel C, Kakies C, Kleist B. et al J. Down-regulation of the metastasis suppressor protein KAI1/CD82 correlates with occurrence of metastasis, prognosis and presence of HPV DNA in human penile squamous cell carcinoma. Virchows Arch. 2008;452:369–75.CrossRefPubMedGoogle Scholar
  36. 36.
    Kochhar R, Taylor B, Sangar V. Imaging in primary penile cancer: current status and future directions. Eur Radiol. 2010;20:36–47.CrossRefPubMedGoogle Scholar
  37. 37.
    Kayes O, Minhas S, Allen C, Hare C, Freeman A, Ralph D. The role of magnetic resonance imaging in the local staging of penile cancer. Eur Urol. 2007;51:1313–8.CrossRefPubMedGoogle Scholar
  38. 38.
    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;18:105–10.CrossRefPubMedGoogle Scholar
  39. 39.
    Spiess PE, Izawa JI, Bassett R, et al. Preoperative lymphoscintigraphy and dynamic sentinel node biopsy for staging penile cancer: results with pathological correlation. J Urol. 2007;177:2157–61.CrossRefPubMedGoogle Scholar
  40. 40.
    Gunia S, Burger M, Hakenberg OW, 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;90:207–13.CrossRefPubMedGoogle Scholar
  41. 41.
    Misra S, Chaturvedi A, Misra NC. Penile carcinoma: a challenge for the developing world. Lancet Oncol. 2004;5:240–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Hughes B, Leijte J, Shabbir M, Watkin N, Horenblas S. Noninvasive and minimally invasive staging of regional lymph nodes in penile cancer. World J Urol. 2009;27:197–203.CrossRefPubMedGoogle Scholar
  43. 43.
    Hughes BE, Leijte JA, Kroon BK, et al. Lymph node metastasis in intermediate-risk penile squamous cell cancer: a two-centre experience. Eur Urol. 2010;57:688–92.CrossRefPubMedGoogle Scholar
  44. 44.
    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;151:1244–9.PubMedGoogle Scholar
  45. 45.
    Pandey D, Mahajan V, Kannan RR. Prognostic factors in node-positive carcinoma of the penis. J Surg Oncol. 2006;93:133–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Hungerhuber E, Schlenker B, Karl A, et al. Risk stratification in penile carcinoma: 25-year experience with surgical inguinal lymph node staging. Urology. 2006;68:621–5.CrossRefPubMedGoogle Scholar
  47. 47.
    Chaux A, Caballero C, Soares F, et al. The prognostic index: a useful pathologic guide for prediction of nodal metastases and survival in penile squamous cell carcinoma. Am J Surg Pathol. 2009;33:1049–57.CrossRefPubMedGoogle Scholar
  48. 48.
    Bertolotto M, Serafini G, Dogliotti L, et al. Primary and secondary malignancies of the penis: ultrasound features. Abdom Imaging. 2005;30:108–12.CrossRefPubMedGoogle Scholar
  49. 49.
    Lont AP, Besnard AP, Gallee MP, et al. A comparison of physical examination and imaging in determining the extent of primary penile carcinoma. BJU Int. 2003;91:493–5.CrossRefPubMedGoogle Scholar
  50. 50.
    Petralia G, Villa G, Scardino E, et al. Local staging of penile cancer using magnetic resonance imaging with pharmacologically induced penile erection. Radiol Med. 2008;113:517–28.CrossRefPubMedGoogle Scholar
  51. 51.
    Krishna RP, Sistla SC, Smile R, et al. Sonography: an underutilized diagnostic tool in the assessment of metastatic groin nodes. J Clin Ultrasound. 2008;36:212–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Graafland NM, Lam W, Leijte JA, et al. Prognostic factors for occult inguinal lymph node involvement in penile carcinoma and assessment of the high-risk EAU subgroup: a two-institution analysis of 342 clinically node-negative patients. Eur Urol. 2010;58:742–7.CrossRefPubMedGoogle Scholar
  53. 53.
    Alkatout I, Naumann CM, Hedderich J, et al. Squamous cell carcinoma of the penis: predicting nodal metastases by histologic grade, pattern of invasion and clinical examination. Urol Oncol. 2011;29:774–81.CrossRefPubMedGoogle Scholar
  54. 54.
    Horenblas S, van Tinteren H, Delemarre JF, et al. Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol. 1993;149:492–7.PubMedGoogle Scholar
  55. 55.
    Zhu Y, Zhang SL, Ye DW, et al. Predicting pelvic lymph node metastases in penile cancer patients: a comparison of computed tomography, Cloquet’s node, and disease burden of inguinal lymph nodes. Onkologie. 2008;31:37–41.CrossRefPubMedGoogle Scholar
  56. 56.
    Pizzocaro G, Algaba F, Horenblas S, et al. EAU penile cancer guidelines 2009. Eur Urol. 2010;57:1002–12.CrossRefPubMedGoogle Scholar
  57. 57.
    Zhu Y, Ye DW, Yao XD, et al. The value of squamous cell carcinoma antigen in the prognostic evaluation, treatment monitoring and followup of patients with penile cancer. J Urol. 2008;180:2019–23.CrossRefPubMedGoogle Scholar
  58. 58.
    Leijte JAP, Kroon BK, Valdés Olmos RA, Nieweg OE, Horenblas S. Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma. Eur Urol. 2007;52:170–7.CrossRefPubMedGoogle Scholar
  59. 59.
    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;100:561–5.CrossRefPubMedGoogle Scholar
  60. 60.
    Ficarra V, Zattoni F, Cunico SC, et al. Lymphatic and vascular embolizations are independent predictive variables of inguinal lymph node involvement in patients with squamous cell carcinoma of the penis: Gruppo Uro-Oncologico del Nord Est (Northeast Uro-Oncological Group) Penile Cancer data base data. Cancer. 2005;103:2507–16.CrossRefPubMedGoogle Scholar
  61. 61.
    Saad Z, Buscombe J. Sentinel lymph node: established and new areas of use. Clin Transl Imaging. 2015;3:225–36.CrossRefGoogle Scholar
  62. 62.
    Belhocine T, Pierard G, De Labrassinne M, Lahaye T, Rigo P. Staging of regional nodes in AJCC stage I and II melanoma: 18FDG PET imaging versus sentinel node detection. Oncologist. 2002;7:271–8.CrossRefPubMedGoogle Scholar
  63. 63.
    Protzel C, Alcaraz A, Horenblas S, Pizzocaro G, Zlotta A, Hakenberg OW. Lymphadenectomy in the surgical management of penile cancer. Eur Urol. 2009;55:1075–88.CrossRefPubMedGoogle Scholar
  64. 64.
    Horenblas S. Sentinel lymph node biopsy in penile carcinoma. Semin Diagn Pathol. 2012;29:90–5.CrossRefPubMedGoogle Scholar
  65. 65.
    Djajadiningrat RS, Graafland NM, van Werkhoven E, et al. Contemporary management of regional nodes in penile cancer – improvement of survival? J Urol. 2014;191:68–73.CrossRefPubMedGoogle Scholar
  66. 66.
    Zhu Y, Ye D-W. Lymph node metastases and prognosis in penile cancer. Chin J Cancer Res. 2012;24:90–6.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Cabañas RM. An approach for the treatment of penile carcinoma. Cancer. 1977;39:456–66.CrossRefPubMedGoogle Scholar
  68. 68.
    Ollila DW, Brennan MB, Giuliano AE. The role of intraoperative lymphatic mapping and sentinel lymphadenectomy in the management of patients with breast cancer. Adv Surg. 1999;32:349–64.PubMedGoogle Scholar
  69. 69.
    Nieweg OE, Tanis PJ, Kroon BBR. The definition of a sentinel node. Ann Surg Oncol. 2001;9:538–41.CrossRefGoogle Scholar
  70. 70.
    Leijte JA, van der Ploeg IM, Valdés Olmos RA, Nieweg OE, Horenblas S. Visualization of tumor blockage and rerouting of lymphatic drainage in penile cancer patients by use of SPECT/CT. J Nucl Med. 2009;50:364–7.CrossRefPubMedGoogle Scholar
  71. 71.
    Spiess PE, Hernandez MS, Pettaway CA. Contemporary inguinal lymph node dissection: minimizing complications. World J Urol. 2009;27:205–12.CrossRefPubMedGoogle Scholar
  72. 72.
    Crawshaw JW, Hadway P, Hoffland D, et al. Sentinel lymph node biopsy using dynamic lymphoscintigraphy combined with ultrasound-guided fine needle aspiration in penile carcinoma. Br J Radiol. 2009;82:41–8.CrossRefPubMedGoogle Scholar
  73. 73.
    Scher B, Seitz M, Reiser M, et al. 18F-FDG PET/CT for staging of penile cancer. J Nucl Med. 2005;46:1460–5.PubMedGoogle Scholar
  74. 74.
    Graafland NM, Leijte JA, Valdés Olmos RA, Hoefnagel CA, Teertstra HJ, Horenblas S. Scanning with 18F-FDG-PET/CT for detection of pelvic nodal involvement in inguinal node-positive penile carcinoma. Eur Urol. 2009;56:339–45.CrossRefPubMedGoogle Scholar
  75. 75.
    Schlenker B, Scher B, Tiling R, et al. Detection of inguinal lymph node involvement in penile squamous cell carcinoma by 18F-fluorodeoxyglucose PET/CT: a prospective single-center study. Urol Oncol. 2012;30:55–9.CrossRefPubMedGoogle Scholar
  76. 76.
    Sadeghi R, Gholami H, Zakavi SR, Kakhki VR, Horenblas S. Accuracy of 18F-FDG PET/CT for diagnosing inguinal lymph node involvement in penile squamous cell carcinoma: systematic review and meta-analysis of the literature. Clin Nucl Med. 2012;37:436–41.CrossRefPubMedGoogle Scholar
  77. 77.
    Jakobsen JK, Alslev L, Ipsen P, et al. DaPeCa-3: promising results of sentinel node biopsy combined with 18F-fluorodeoxyglucose positron emission tomography/computed tomography in clinically lymph node-negative patients with penile cancer – a national study from Denmark. BJU Int. 2016;118:102–11.CrossRefPubMedGoogle Scholar
  78. 78.
    Pagliaro LC, Crook J. Multimodality therapy in penile cancer: when and which treatments? World J Urol. 2009;27:221–5.CrossRefPubMedGoogle Scholar
  79. 79.
    Rossari JR, Vora T, Gil T. Advances in penile cancer management. Curr Opin Oncol. 2010;22:226–35.CrossRefPubMedGoogle Scholar
  80. 80.
    Horenblas S, van Tinteren H. Squamous cell carcinoma of the penis. IV. Prognostic factors of survival: analysis of tumor, nodes and metastasis classification system. J Urol. 1994;151:1239–43.PubMedGoogle Scholar
  81. 81.
    Gold KA, Lee H-Y, Kim ES. Targeted therapies in squamous cell carcinoma of the head and neck. Cancer. 2009;115:922–35.CrossRefPubMedGoogle Scholar
  82. 82.
    Culkin DJ, Beer TM. Advanced penile carcinoma. J Urol. 2003;170:359–65.CrossRefPubMedGoogle Scholar
  83. 83.
    Graafland NM, Valdés Olmos RA, Teertstra HJ, Kerst JM, Bergman AM, Horenblas S. 18F-FDG PET/CT for monitoring induction chemotherapy in patients with primary inoperable penile carcinoma: first clinical results. Eur J Nucl Med Mol Imaging. 2010;37:1474–80.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Serena Chiacchio
    • 1
    Email author
  • Abedallatif AlSharif
    • 2
  • Zia Saad
    • 3
  • Giampiero Giovacchini
    • 4
  • Jamshed Bomanji
    • 3
  1. 1.Regional Center of Nuclear MedicineUniversity of Pisa Medical SchoolPisaItaly
  2. 2.Department of Radiology and Nuclear MedicineUniversity of JordanAmmanJordan
  3. 3.Institute of Nuclear MedicineUniversity College London Hospitals, NHS Foundation Trust, University College HospitalLondonUK
  4. 4.Department of Radiology and Nuclear MedicineStadtspital TriemliZurichSwitzerland

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