In contrast to many cancers, squamous cell carcinoma of the penis can be cured despite the presence of lymph node metastases. This characteristic is shared with testicular cancer. But unlike testicular cancer, penile carcinoma is not chemosensitive and, therefore, the focus of management has been on surgery. This article addresses all aspects of imaging and minimally invasive methods of detecting lymph node involvement. It focuses on the indications of surgical management of the regional nodes, the extent of the surgery, and its complications. Also, neoadjuvant therapy is covered.
Most penile cancers are squamous cell carcinomas (∼95%), which typically show a stepwise lymphogenic spread before hematogenic dissemination. The primary draining lymph nodes are invariably located within the inguinal lymphatic region. Thereafter, dissemination usually continues to the pelvic nodes or distant sites. At initial presentation, distant metastases are present in only 1% to 2% of patients and are virtually always associated with clinically evident lymph node metastases.
The presence of nodal involvement is the single most important prognostic factor. Because the currently available noninvasive staging modalities have a low sensitivity in detecting the regional lymph node status (ie, missing micrometastatic disease), the optimal management of patients who are clinically node negative (cN0) has been the subject of debate ; approximately 20% to 25% of these patients have occult metastasis. Some clinicians manage these patients with close surveillance, whereas others will perform an inguinal lymphadenectomy.
Other approaches are dynamic sentinel node biopsy, modified lymphadenectomy, and the concept of lymphadenectomy in those patients considered to be at risk for occult metastases, the so-called risk-adapted approach. Although close surveillance may lead to an unintentional delay because of outgrowth of occult metastases in 20% to 25% of patients with cN0 disease, elective and risk-adapted inguinal lymphadenectomy is considered unnecessary in 75% to 80% of such cases because of the absence of metastases. Furthermore, lymphadenectomy is associated with a high morbidity rate. Up to 35% to 70% of patients have short- or long-term complications.
Anatomy of the inguinal lymph nodes
The lymph nodes in the inguinal lymphatic region are the first draining nodes for the penis, and the anatomy has been described by various investigators. Historically, the inguinal lymphatic region was divided into 2 groups: the superficial and deep lymph nodes. The superficial inguinal lymph nodes are located beneath the Camper fascia and above the fascia lata covering the muscles of the thigh. The deep inguinal nodes are located deep to the fascia lata and medial to the femoral vein. These nodes intercommunicate with each other and then drain into the pelvic nodes. From a clinical perspective, this anatomic distinction is not useful because the superficial nodes cannot be distinguished from the deep nodes by physical examination or imaging. Daseler and colleagues divided the inguinal region into 5 sections by drawing a horizontal and a vertical line through the point where the saphenous vein drains into the femoral vein with one central zone directly overlying the junction. A recent lymphoscintigraphic study by Leijte and colleagues showed that most of the first draining lymph nodes are located in Daseler’s superomedial segment, although there is individual variation.
Assessment of inguinal lymph nodes
The key issue in lymph node staging is the unreliability of the currently available modalities that detect occult nodal involvement. However, given that early resection of the inguinal lymph nodes is associated with a therapeutic benefit, it is imperative that those patients with metastatic disease in the inguinal lymph nodes undergo an inguinal lymphadenectomy at the earliest possible time. Unfortunately, the high morbidity rate associated with performing an elective inguinal lymphadenectomy makes the operation unsuitable for every patient with penile cancer who does not have inguinal nodal involvement. Hence, there is uncertainty about the timing of lymphadenectomy and identifying those patients who would benefit. However, 3 clinical groups can be identified: those with cN0 groins, those with palpable inguinal lymph nodes (cN+), and those with immobile (fixed) inguinal lymph nodes.
Assessment of inguinal lymph nodes
The key issue in lymph node staging is the unreliability of the currently available modalities that detect occult nodal involvement. However, given that early resection of the inguinal lymph nodes is associated with a therapeutic benefit, it is imperative that those patients with metastatic disease in the inguinal lymph nodes undergo an inguinal lymphadenectomy at the earliest possible time. Unfortunately, the high morbidity rate associated with performing an elective inguinal lymphadenectomy makes the operation unsuitable for every patient with penile cancer who does not have inguinal nodal involvement. Hence, there is uncertainty about the timing of lymphadenectomy and identifying those patients who would benefit. However, 3 clinical groups can be identified: those with cN0 groins, those with palpable inguinal lymph nodes (cN+), and those with immobile (fixed) inguinal lymph nodes.
Clinical examination
Most patients diagnosed with penile cancer in Western countries present without any palpable abnormalities in the groins; only 20% present with palpable nodes. Inguinal lymph nodes that become palpable during follow-up are due to metastasis in nearly 100% of cases. Physical examination of the inguinal region is of limited value in accurate detection, especially of small metastases. Approximately 20% to 25% of patients with cN0 disease will harbor occult metastases. These occult metastases are, by definition, not detected by physical examination. In the patients with cN+ disease, approximately 70% will actually have metastatic inguinal nodal involvement. The remainder will have enlarged inguinal nodes secondary to infection of the primary tumor. Traditionally, antibiotic treatment was advised for 6 weeks to treat the inflammation, with a further reassessment of the inguinal lymph nodes thereafter. However, to avoid a delay in diagnosis, this is no longer recommended. Patients with lymph node involvement should undergo inguinal lymphadenectomy.
Investigations
The currently available noninvasive staging techniques that can be used to stage the groin besides physical examination include ultrasonography combined with fine-needle aspiration cytology (FNAC) of morphologically suspicious-looking nodes, computed tomography (CT) scanning, magnetic resonance (MR) imaging, and positron emission tomography (PET)/CT scanning. These modalities are especially useful in patients who are obese or those who are difficult to examine because additional imaging may identify metastases not found by physical examination.
Ultrasound with fine-needle aspiration cytology
Ultrasound is noninvasive, quick, and inexpensive and can easily be combined with FNAC of morphologically suspicious-looking lymph nodes. In a series of 43 patients with 83 cN0 groins, ultrasound-guided FNAC had a sensitivity and specificity of 39% and 100%, respectively. Ultrasound-guided FNAC has been used preoperatively to screen cN0 groins and to further analyze the groins of patients with palpable inguinal lymph nodes (cN+). In a series of 16 patients staged cN+ and not having antibiotic treatment, FNAC alone (without ultrasonography) showed a sensitivity and specificity of 93% and 91%, respectively. False-negative rates for FNAC have been reported in up to 15%. If the clinician remains suspicious, repeat FNAC is indicated, and if it is still inconclusive, then excisional biopsy can be performed. Care must be taken when performing an open biopsy such that in the event of a malignant node, the site of the biopsy can be excised during the subsequent lymphadenectomy.
CT imaging
The role of CT in staging the inguinal lymph nodes is poorly understood because of a paucity of studies. One report published in 1991 described a small series of 14 patients who underwent preoperative CT scanning. A sensitivity and specificity of 36% and 100% were found, respectively. None of the occult metastases in the cN0 groins were identified. However, these results are a reflection of the CT technology available at the time of the study. Currently, with the use of multi-slice CT scanners and increased spatial resolution, results are probably better. Nevertheless, the problem of missing a small metastasis still remains. The diagnostic accuracy regarding the pelvic lymph nodes is poor, in accordance with the experience recently reported by other centers. Therefore, CT imaging is not recommended as the initial staging tool for staging in patients with cN0 disease, although it is suitable in those who are difficult to examine (eg, patients who are obese). By contrast, CT scanning can be useful in patients with cN+ disease to determine the extent of disease, and this is discussed later.
MR imaging
MR imaging with lymphotropic nanoparticles (LN-MRI), such as coated ultrasmall particles of iron oxide and ferrumoxtran-10, has shown promising results in identifying occult metastasis in a study of 7 patients with penile cancer. MR imaging was performed before and also 24 hours after intravenous ferumoxtran-10 administration. In this small series, LN-MRI has shown a sensitivity of 100% and a specificity of 97%. This imaging technique has also revealed high diagnostic accuracies in staging lymph nodes in prostate cancer and bladder cancer. However, ferrumoxtran-10 is not approved by the Food and Drug Administration, hence, it is not commercially available. Furthermore, the manufacturer has withdrawn the application for marketing authorization for lymphotropic nanoparticles in Europe. In addition, conventional MR imaging is also limited by its spatial resolution. Thus, its use is also limited for staging the cN0 groin.
PET/CT scan
PET instrumentation detects subnanomolar concentrations of radioactive tracer in vivo. Following malignant transformation, a range of tumors can be characterized by elevated glucose metabolism and subsequent increased uptake of the intravenously injected radiolabelled glucose analog [F18]-fluorodeoxyglucose. PET combined with low-dose CT imaging (PET/CT) in a single scanner fuses the acquired data into 1 image containing both functional and anatomic information. The accuracy of the combined images is reported to be higher than separate PET and CT images.
In 2005, Scher and colleagues published the first results of PET/CT scanning in penile cancer. They found promising results with a sensitivity of 80% and specificity of 100% on a per-patient basis, respectively. However, these results may be a little optimistic. The limitations of MR imaging regarding spatial resolution are also true for PET/CT. In a recent prospective study of 42 cN0 groins that underwent preoperative PET/CT scanning without pretreatment antibiotics, PET/CT missed 1 out of 5 occult metastases. In addition, 3 false-positive results were found among the 37 remaining groins, leading to a specificity of 92%. The false-positive findings were associated with inflammatory responses within the lymph nodes.
Management of the inguinal lymph nodes in patients with cN0 disease
Several risk-adapted management approaches have been used and advocated during the last decades ( Table 1 ). Basically, these management policies can be divided into noninvasive management (surveillance), minimally invasive staging (dynamic sentinel node biopsy/modified inguinal lymphadenectomy), or invasive staging techniques (complete inguinal lymphadenectomy). The fact that approximately 20% of the patients with cN0 disease have occult metastases indicates that inguinal lymphadenectomy is an unnecessary procedure in approximately 80% of patients. Furthermore, lymphadenectomy is associated with risks and prone to several complications that are discussed later. In general, a lymphadenectomy in all patients with cN0 disease (sometimes described as early, prophylactic, or preemptive) is not recommended.
| Advantages | Disadvantages | |
|---|---|---|
| 1. Close surveillance | No morbidity in patients without occult metastasis | Survival disadvantage compared with early dissection; some patients develop inoperable inguinal recurrences |
| 2. Nomogram/risk-adapted lymphadenectomy | Reduction in number of inguinal node dissections and, hence, decreased overall morbidity | Significant overtreatment despite risk adaptation |
| 3. Minimally invasive staging | ||
| a) Modified inguinal lymphadenectomy | High incidence of detection of micrometastasis and lower risk of complications than radical surgery | Significant overtreatment (>80% of inguinal specimens will be benign) |
| b) Dynamic sentinel node biopsy | Patients are pathologic staged with minor morbidity Only patients with pN+ disease suffer from (completion) lymph node dissection morbidity | In some patients, metastases are missed (ie, false negative) and develop inguinal recurrences Some patients cannot be salvaged hereafter |
| 4. Elective bilateral radical lymphadenectomy | No occult metastases are missed | Unnecessary in 80% of patients and severe short- and long-term morbidity |
Close Surveillance
The basis of close surveillance involves a regular clinical examination of patients proceeding to lymphadenectomy when lymph node metastases become clinically evident. This surveillance avoids the morbidity associated with lymphadenectomy and, therefore, patients with cN0 disease who subsequently are unlikely to develop inguinal lymph node metastases are not overtreated. Although this has been advocated in the past with seemingly good results, recent nonrandomized retrospective studies indicates that this approach is associated with a negative effect on survival rates.
Predictive Nomogram for Occult Metastasis/Risk-Adapted Lymphadenectomy
Another noninvasive approach is the use of a preoperative nomogram predictive of inguinal metastases. In one nomogram, the following parameters were used for risk assessment: tumor thickness (≤5 mm vs >5 mm), growth pattern (vertical vs horizontal), grade (well vs intermediate vs poor), lymphovascular invasion (absent vs present), corpora cavernosa infiltration (absent vs present), corpora spongiosum infiltration (absent vs present), urethral infiltration (absent vs present), cN status (cN0 vs cN+). In clinical practice, this particular nomogram may be a useful tool but still requires validation. It remains to the discretion of the doctor in collaboration with patients to determine at which cut-off point to embark on a lymphadenectomy.
The basis of risk-adapted approaches is risk assessment of lymph node metastases based on histopathologic factors of the primary tumor, such as tumor stage (T stage), tumor grade (ie, grade [G] 1, 2, or 3), presence of lymphovascular (LVI), perineural invasion, and depth of infiltration. The European Association of Urology (EAU) guidelines have included tumor stage, grade, and absence or presence of LVI into a risk-adapted approach for the management of the inguinal regions. Three risk groups have been identified: low risk tumors (pTis, pTa, pT1G1), intermediate risk tumors (pT1G2, no LVI), and high-risk tumors (pT1G3, pT2-3G1-3, or presence of LVI). If patients are considered suitable for surveillance, the 2009 EAU guidelines advise follow-up in patients with low-risk tumors only, and surgical staging in intermediate and high-risk patients with cN0 disease. In a prospective study of 100 patients managed according to these EAU guidelines, none of the patients considered low risk developed lymph node metastases during a mean follow-up of 29 months. On the other hand, elective lymphadenectomy was unnecessary in 82% of the patients with high-risk features because no evidence of metastatic spread was found with histopathology. In another series of 118 patients, it was estimated that 63% of the high-risk patients will be subjected to unnecessary lymphadenectomy. Both studies indicate that current EAU high-risk stratification is not accurate enough to stratify these patients. It seems that the risk of occult nodal involvement in patients with cN0 disease with low risk (T1G1) is low and these patients can still be subjected to close surveillance with subsequently inguinal lymphadenectomy when metastases become clinically evident.
Minimally Invasive Staging Techniques
To circumvent the previously mentioned dilemmas of the timing of lymphadenectomy, minimally invasive staging techniques have been developed. The basis of these techniques is to limit the morbidity in patients with pathologic node-negative (pN0) groins and to identify occult metastases at the earliest moment. Only patients with proven lymphatic spread undergo a completion therapeutic lymphadenectomy. In the last 2 decades, 2 approaches have been introduced worldwide: modified inguinal lymphadenectomy (MIL) and dynamic sentinel node biopsy (DSNB).
Modified inguinal lymphadenectomy
Catalona proposed the MIL in 1988 after being performed in 6 patients with invasive carcinoma of the penis or distal urethra. The aim of this approach is to remove all of the lymph nodes that are at the most probable location of first-line lymphatic invasion and excluding the regions lateral to the femoral artery and caudal to the fossa ovalis. The lymph node packet can be analyzed by frozen section, and if it confirms metastatic disease then a complete inguinal lymphadenectomy can be performed. The anatomic location of these lymph nodes was based on earlier lymphatic drainage studies. The medial margin of MIL was the adductor longus muscle, the lateral margin was the lateral border of the femoral artery, the superior margin was the external oblique muscle above the spermatic cord, and the inferior margin was the fascia lata just distal to the fossa ovalis. The advantages of this MIL are a smaller skin incision and a smaller node dissection resulting in reduced morbidity compared with standard lymphadenectomy. However, limiting the dissection field led to a high number of false-negative findings as reported by several other investigators.
Dynamic sentinel node biopsy
Cabañas first reported sentinel node biopsy for penile cancer in 1977. This report was based on lymphangiograms of the penis and the lymph node medial to the superficial epigastric vein and was identified as being the first echelon lymph node or the so-called sentinel node. It was assumed that a negative sentinel node indicated the absence of further lymphatic spread and, therefore, no lymphadenectomy was indicated. Sentinel node surgery consisted of identification and removal of this lymph node with completion lymphadenectomy only in those with a tumor-positive lymph node. However, this initial static procedure, based on anatomic landmarks only, did not take into account individual drainage patterns. Several false-negative results were reported, and the technique was largely abandoned. The sentinel node procedure was revived by Morton and colleagues in 1992 by using patent blue V or isosulfan blue dye as a tracer enabling individual lymphatic mapping. This technique, with the addition of a preoperative radioactive tracer (technetium-99m-labeled nanocolloid 99m Tc), forms the basis of the modern sentinel node biopsy era and is also used in, for example, breast cancer and melanoma.
In 2001, Horenblas and colleagues described the DSNB procedure for penile cancer in a report of 55 patients with T2 or greater tumors. With this dynamic approach, a sensitivity of 80% was reported. However, the false-negative rates raised concerns about its diagnostic accuracy. Furthermore, patients with negative sentinel nodes remained on rigid follow-up. During the years, the DSNB protocol has been modified after detailed analysis of the false-negative cases. The initial procedure was extended by the pathologic examination of the sentinel node by serial sectioning and immunohistochemical staining instead of routine paraffin sections, and the addition of preoperative ultrasonography with FNAC to detect pathologically enlarged nodes, that fail to pick up radioactivity. Furthermore, exploration of groins with nonvisualization on preoperative lymphoscintigram (occurring in approximately 4%–6% of cN0 groins) and intraoperative palpation of the wound have been introduced. The current modified procedure has evolved into a reliable minimally invasive staging technique with an associated sensitivity of 93% to 95% together with low morbidity and is comparable with the results in breast cancer and melanoma. In a large prospective series of 323 patients from 2 tertiary referral hospitals that use essentially the same protocol, DSNB has shown to be a reliable method with a low complication rate. The combined sensitivity of this procedure was 93% with a specificity of 100%. Complications occurred in less than 5% of explored groins and almost all were transient and could be managed conservatively.
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