Laboratory Studies
No specific laboratory studies or tumor markers are diagnostic for penile cancer. A general evaluation, which includes a complete blood cell count; a chemistry panel with liver function tests; and an assessment of cardiac, pulmonary, and renal status, is helpful as a baseline and in the detection of any unsuspected problems.
Patients with advanced penile cancer may be anemic, with leukocytosis and hypoalbuminemia. Hypercalcemia has been found in some patients in the absence of metastases.
Imaging Studies
Magnetic resonance imaging (MRI) and ultrasonography are useful for local cancer staging and for assessing the inguinal lymph nodes. These studies may be helpful for detecting tumor invasion into the corpora. MRI produces sharp images of the penile structures, is accurate for demonstrating invasion of the corpora, and can help the physician determine the extent of the cancer along the surface of the penis in patients with tumors larger than 2 cm. [26]
Both MRI and computed tomography (CT) scanning can demonstrate enlarged pelvic and retroperitoneal lymph nodes. Positron emission tomography (PET) and CT scanning have not been studied extensively but may be helpful and should be obtained in patients with high-grade and extensive local disease and in those with evidence of inguinal node involvement.
CT images in men with proven unilateral or bilateral cancer with central node necrosis and/or irregular nodal borders of the regional nodes are very useful to identify high-risk patients. Graafland et al demonstrated an association between these unfavorable pathologic features and poor prognosis, with a sensitivity of 95%, a specificity of 82% and a diagnostic accuracy of 87%. [27]
Rarely, chest radiography can help detect metastases. However, CT is the preferred study to evaluate for metastases.
A technique to identify lymph node metastases using MRI following the intravenous injection of ferromagnetic particles has shown a high degree of sensitivity. Tabatabaei et al studied 7 patients with this imaging and found a sensitivity of 100%, a specificity of 97% and a positive predictive value of 81.2% in the ability to detect micrometastatic disease. [28] Further study are necessary to determine the tumor burden needed for this imaging modality to be effective, but current results indicate that it is more accurate than conventional CT scanning.
Positron emission tomography (PET)/CT imaging using 18F-fluorodeoxyglucose (18F-FDG) was used to study 42 patients with nonpalpable inguinal nodes. Five of these patients had micrometastatic disease but the PET/CT found tumor in only one patient. [29] Another study using 18F-FDG-PET/CT scan imaging conducted by Schlenker et al on 35 patients with invasive penile carcinoma found that integrating PET/CT scanning into preoperative procedures could avoid surgical staging in selected patients. [30]
Naumann et al reported that in patients with penile cancer who do not have palpable inguinal nodes, preoperative sentinel lymph node (SLN) imaging with single photon emission computed tomography/CT (SPECT/CT) provided clear and precise anatomical localization of SLNs. These authors recommend SPECT/CT to enhance the safety and feasibility of SLN biopsy in such cases. [31]
Diagnostic Procedures
The most important diagnostic test is a biopsy. This may be an excisional biopsy if the cancer is small or the lesion is confined to the prepuce and a circumcision is acceptable. The biopsy should contain tissue beneath the tumor, if this is feasible, in order to help stage the disease.
CT-guided or ultrasound-guided fine-needle aspiration of enlarged lymph nodes may aid the urologist in planning therapy. Aspiration biopsies of sentinel nodes using the identification techniques described below have also been reported. A study by Kroon et al of ultrasound-guided fine-needle aspiration in patients with clinically node-negative penile squamous cell carcinoma found that although the procedure had 100% specificity for detection of tumor cells in nodes, sensitivity was 39%; of the 23 cases confirmed by subsequent lymph node dissection, only nine had been positive on aspiration biopsy. [32]
Sentinel node biopsy may be of assistance in determining the need for extensive inguinal lymphadenectomy. Various methods have been used to identify the sentinel node. One method involves intradermal injection of 2 mL of patent blue dye around the tumor. Approximately 15 minutes later, the node can be identified and removed for histologic assessment.
Lymphoscintigraphy is another method used to identify the sentinel node. This technique, developed at The Netherlands Cancer Center Institute, involves injecting technetium-99m nanocolloid around the primary tumor. Following the injection, dynamic images are taken with a gamma camera to visualize lymphatic drainage. Static scintigrams are obtained 2 hours after the injection. A hot spot in the inguinal area is considered to be a sentinel node, and its position is marked on the skin. In some instances, both techniques are used to identify the sentinel node. Kroon et al found that that the size of the metastasis was predictive of nonsentinel node metastasis. They reported that, in groins with only micrometastases in the sentinel node, none of the other nodes were involved. [33]
Tabatabaei and McDougal reported on their results using lymphotrophic nanoparticle-enhanced MRI and found that this technique yielded 100% sensitivity and 97% specificity. [34, 35]
The major limitation of these techniques is the need to perform the test in all patients regardless of the presence of clinically normal nodes and histologic features of the primary tumor. Another possible concern is thrombosis of the lymphatic vessels cause by inflammation. Finally, inexperience with these techniques is an obstacle. It has been estimated that experience with 25 patients is needed to achieve the 4.8% false-negative rate reached by the Netherlands group, [36] and few centers see enough patients to become proficient.contained tumour cells and this was confirmed by subsequent lymph node dissection
Histologic Findings
Most penile cancers are squamous cell carcinomas that demonstrate keratinization, epithelial pearl formation, and various degrees of mitotic activity. The normal rete pegs are disrupted, and invasive lesions penetrate the basement membrane and surrounding structures.
Erythroplasia of Queyrat, a red, velvety, well-marginated lesion usually occurring on the glans, is characterized by atypical hyperplastic cells that appear disoriented and vacuolated and have hyperchromatic nuclei and multiple mitotic figures. The submucosa shows capillary proliferation and ectasia with a surrounding inflammatory infiltrate rich in plasma cells.
Campos et al studied E-cadherin (cell adhesion molecules involved in the metastatic process), matrix metalloproteinase (MMP)–2, and MMP-9 (part of a group of enzymes that degrade collagen type IV in the basement membrane). In the 125 available tumor specimens and clinical records, they found that low levels of E-cadherin and high expression of MMP-9 represented independent risk factors for nodal disease. [37]
Guimaraes et al examined the value of proliferating cell nuclear antigen (PCNA) and MIB-1/Ki-67 to determine if these might serve as prognostic factors in predicting nodal metastasis. PCNA was an independent factor in univariate and multivariate analysis (RR, 2.94; 95% confidence interval, 1.1-7.7). Unexpectedly, a high expression of MIB-1/Ki-67 reactivity correlated with a decreased incidence of nodal metastases. [38] Although these markers did have predictive value, they added little to the predictive value of tumor stage and grade and the presence of vascular invasion.
Stankiewicz et al found that Ki-67 was only a moderate surrogate marker for HPV infection in patients with penile squamous cell carcinoma. Ki-67 did not show prognostic value for cancer-specific survival or overall survival. [39]
Staging
No universal staging system has been established for penile cancer. A detailed and accurate assessment of the primary tumor, including identification of regional and distant metastatic disease, is important for selecting appropriate therapy and for assessing and communicating results.
The Jackson and tumor-node-metastasis (TNM) systems are used, although the TNM system is preferable. The Jackson system does not include characteristics of the primary lesion, such as size and confinement to the epidermis (superficial or invasive). The presence and extent of nodal metastases is not addressed. Histologic criteria are not used, even though the grade and extent of invasion is important.
Solsona et al presented the European Association of Urology (EAU) guidelines on penile cancer. They proposed 3 risk groups for patients with clinically negative or occult nodal metastases: low risk, stage T1, grade 1; intermediate, stage T1, grade 2 or 3; and high, T2-T3, grade 2-3. [40] Most patients with positive sentinel node biopsy findings tend to fall into the high-risk category.
Most penile cancers are low grade, but correlation between grade and survival is lacking. High-grade disease is associated with regional lymph node metastases. The strongest predictor for survival is the presence or absence of nodal metastases.
The optimum surgical margin has been reduced from the classical 2 cm to 1 cm or, in some instances, to 0.5 cm, without any adverse consequences related to cancer recurrence or survival. The advantage of a smaller margin is important because nearly 80% of penile squamous cell carcinomas are distal, presenting on the prepuce, glans, or in the coronal sulcus. These lesions can be managed with local excision and reconstruction.
The Jackson classification is as follows:
-
Stage I (A): The tumor is confined to the glans, prepuce, or both.
-
Stage II (B): The tumor extends onto the shaft of the penis.
-
Stage III (C): The tumor has inguinal metastasis that is operable.
-
Stage IV (D): The tumor involves adjacent structures and is associated with inoperable inguinal metastasis or distant metastasis.
The TNM classification of the primary tumor (T) is below. Note that the following description is devoid of N (node) and M (metastasis) descriptions. These stages simply relate the presence or absence of nodal and distant metastases.
-
TX: Primary tumor cannot be assessed.
-
T0: Primary tumor is not evident.
-
Tis: CIS is present.
-
Ta: Noninvasive verrucous carcinoma is present.
-
T1: Tumor invades subepithelial connective tissue.
-
T2: Tumor invades corpora spongiosum or cavernosum.
-
T3: Tumor invades the urethra or prostate.
-
T4: Tumor invades other adjacent structures.
The WHO histopathological classification is as follows:
-
Grade 1 - Well differentiated, with 33% undifferentiated cells
-
Grade 2 - Moderately differentiated, with 33%-66% undifferentiated cells
-
Grade 3 - Poorly differentiated, with more than 66% undifferentiated cells
Novara and colleagues from the GUONE Penile Cancer Project compared the prognostic accuracy of the Solsona and European Association of Urology (EAU) risk groups in predicting lymph node metastases. They studied clinical and pathology data from 175 patients with squamous cell carcinoma from 1980-2002. Both groups used variations of the pathologic features and primary tumor stage. Although both risk groups could predict the probability of nodal metastases, their prognostic accuracy was poor when the data were analyzed according to the ROC curve analysis. [41]
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Penile cancer. Squamous cell carcinoma (Image courtesy of Hon Pak, MD).
Tables
Level of Evidence |
||||
Stage |
Treatment |
NCCN [5] |
ESMO [72] |
EAU |
Tis or Ta |
Penile-preserving techniques:
|
2A |
IVC |
3C |
|
2B |
IIIC |
3C |
|
|
2A |
IVC |
3C |
|
|
2B |
3C |
||
|
IIIC |
3C |
||
T1 G1-2 |
Penile-preserving techniques:
|
2A |
IIIC |
3C |
|
2B |
IVC |
3C |
|
|
2B |
IVC |
3C |
|
T1 G3-4 |
Wide local excision |
2A |
IIIB |
3C |
Glansectomy |
2A |
IIIB |
3C |
|
Partial penectomy |
2A |
IIIB |
||
Total penectomy |
2A |
IIIB |
||
Radiotherapy |
2B |
IIIC |
3C |
|
Chemoradiotherapy |
3 |
IIIC |
||
T2 or greater |
Partial penectomy |
2A |
IIIB |
3C |
Total penectomy |
2A |
IIIB |
3C |
|
Radiotherapy |
2B |
IIID |
3C |
|
Chemoradiotherapy |
3 |
IIID |
||
Non-palpable lymph nodes |
Surveillance:
|
2A |
B B |
2aB |
Dynamic sentinel node biopsy (DSNB):
|
2A 2A 2A |
B B |
2aB 2aB |
|
Inguinal lymph node dissection (ILND):
|
2A 2A |
IIIB IVC |
2aB 2aB |
|
Palpable inguinal nodes |
Inguinal lymph node dissection (ILND):
|
2A |
|
|
Palpable inguinal nodes (cN1/cN2): Radical inguinal lymphadenectomy Fixed inguinal lymph nodes (cN3): Neoadjuvant chemotherapy followed by radical inguinal lymphadenectomy in responders Pelvic lymph nodes: Ipsilateral pelvic lymphadenectomy if two or more inguinal nodes are involved on one side (pN2) or if extracapsular nodal metastasis (pN3) reported |
Strong
Weak
Strong |
|||
