S. Horenblas, MD, PhD, FEBU, Head of the Department of Urology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, and Professor of Urologic Oncology, Department of Urology, Free University Medical Center, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. e-mail: firstname.lastname@example.org
Of patients presenting with squamous cell carcinoma (SCC) of the penis, 30–60% have enlarged lymph nodes in the groin [1–16]. In about half of these patients this is caused by metastatic invasion and in the other half by inflammatory reactions . Nodal metastasis will develop in 10–15% of patients presenting with no clinical signs of nodal invasion. Treatment strategies are hampered by the inaccuracies of the physical examination and of imaging modalities to reliably identify presence or absence of lymph node metastasis. This review will focus on the anatomy of the regional lymph nodes and the difficulties in staging.
Biology of SCC of the penis and the anatomy of lymphatic drainage
Like all SCCs, penile cancer has a strong tendency for loco-regional growth, with haematogenic spread only in cases with advanced lymphatic invasion. Spread of the local tumour is not a random process. Lymphogenic spread appears to be an orderly sequential process. Metastatic cells follow the anatomical pattern of lymphatics that drain the primary tumour. Tumour cells are caught in so-called ‘first echelon’ lymph nodes, the first nodes reached by efferent lymphatics draining directly into the tumour. From there metastatic spread is to the so-called ‘second echelon’ lymph nodes, i.e. those not draining directly into the tumour. The general assumption is that cancer cells reach the nodes through embolism and not by continuous growth . The well-known adage in urological oncology, that ‘lymph node metastasis is synonymous with systemic spread’ is definitely not true in penile cancer. Therapeutic nihilism is not justified even in advanced lymphogenic spread.
The regional lymph nodes of the penis are located in the inguinal region. Various anatomists have described the anatomy of these nodes [19,20]. Traditionally, the inguinal nodes have been divided into two groups, superficial and deep. The superficial nodes are located beneath the subcutaneous fascia and above the fascia lata covering the muscles of the upper leg; 8–25 nodes are present [5,19,20]. The deep inguinal nodes are those around the fossa ovalis, the opening in the fascia lata where the saphenous vein drains into the femoral vein; 3–5 nodes are present. These nodes form the link to the second-line regional nodes, i.e. the pelvic nodes. The deep nodes receive their afferents from the superficial ones and directly from the deeper structures of the penis. From a clinical perspective this distinction is useless, as the superficial nodes cannot be distinguished from the deep nodes by physical examination. The most constant and usually largest node is that found medial to the femoral vein and just underneath the inguinal ligament, the so-called node of Cloquet or Rosenmuller . It is customary to divide the inguinal region into four sections by drawing a horizontal and vertical line through the point where the saphenous vein drains into the femoral vein. The nodes that are involved primarily in penile cancer are mostly located in the superomedial segment; however, there is individual variation. The penis drains to both inguinal sides in at least 12% of patients, as shown by lymphographic studies, and in 60% in studies with lymphoscintigraphy [22,23]. The pelvic nodes consist of nodes around the iliac vessels and in the obturator fossa; 12–20 nodes can be found. Crossover from one pelvic side to the other has never been observed.
Lymphadenectomy or lymph node dissection refers to the removal of all regional nodes; inguinal lymphadenectomy consists of removal of all regional nodes in the groin and pelvic lymphadenectomy consists of removal of all pelvic nodes, around the iliac vessels and the obturator fossa. The simultaneous removal of first- and second-line nodes is traditionally called ilio-inguinal lymph node resection.
Diagnosis of lymph node metastasis in clinically node-negative patients
An essential problem in managing patients with penile cancer is the unreliability of clinical methods to detect lymph node metastasis at an early stage. With noninvasive methods occult metastasis cannot be detected, whether it be by physical examination (by definition), ultrasonography, CT or MRI. Therefore, the present author does not recommend CT or MRI in those patients who present with no physical signs of node involvement of the groin. About 10% of patients harbour occult metastasis that becomes apparent during the follow-up or will be found at early lymphadenectomy [6,24–27]. Occult metastasis can only be detected by invasive methods. Recent experience in patients with breast cancer or head and neck cancer shows excellent sensitivity and specificity for detecting occult metastasis using ultrasonography with fine-needle aspiration biopsy [28–30]. Modern ultrasonography can reliably show changes in the architecture of impalpable nodes suggestive of invasion by metastasis. Hypoechoic and heterogeneous nodes are suspicious. Using these characteristics ultrasonographically guided fine-needle aspiration biopsy of suspicious nodes should be the first investigation in clinically node-negative patients at high risk for occult metastasis. Dynamic sentinel-node biopsy could then be restricted to cytologically negative patients (see later).
Diagnosis of lymph node metastasis in clinically node-positive patients
What is the reliability of the various investigations in clinically positive patients? Comparing findings at physical examination and histopathology in modern series shows a false-positive rate for the physical examination of ≈50% (specificity 50%) [8,17,31–34]. The easiest way to confirm lymph node metastasis in clinically node-positive patients is by fine-needle aspiration biopsy. Obviously the result is only reliable if positive; false-negative rates are reportedly up to 15% [7,33]. If negative, another fine-needle biopsy is recommended with a brief delay. If negative again and clinical suspicion remains, an excision biopsy is advised. Care must be taken to position the biopsy needle so that the needle tract will be removed with the lymph node dissection, if positive. The same is true for the planning of the incision for biopsy. With these tools there is only a limited place for antibiotic treatment. A 6-week treatment has often been advised before final clinical judgement; this 6-week delay should be abandoned in favour of immediate fine-needle biopsy with or without ultrasonography.
The role of CT or MRI is limited; relevant information can be gained in advanced cases only, identifying those patients with enlarged pelvic or retroperitoneal nodes. With the exception of some rare published cases, all patients with pelvic node involvement always first had symptoms of inguinal node involvement [35,36].
Indicators of lymphatic spread
Analysing the clinical and pathological characteristics of the primary tumour in node-positive and -negative patients provides an insight into the factors that can be considered predictive for the true presence of metastasis. As many of these elements are probably interrelated, only publications with a multivariate analysis should be considered, although there are few such studies.
The grade of the primary tumour and depth of invasion are considered to be the most important indicators for metastatic spread. Grading for SCC is based on the work of Broders . Unfortunately, the criteria for grading differ among pathologists, which partly explains the differences in the published prognostic significance of the grade of the primary tumour [31,38–45]. Another factor is the absence of multivariate analysis. Despite these drawbacks there was a good correlation in some series between the presence of lymph node metastasis and poorly differentiated tumours [3,31,38,46,47]. A minority of patients with well-differentiated tumours present with nodal metastasis (Table 1) [1,2,10,13,16,27,48–52]. Also, non-infiltrating tumours have a low tendency to metastasise; in contrast, deeply infiltrating tumours have a high propensity for nodal spread (Table 1). By combining these factors, high and low probabilities for lymph node metastasis have been identified [3,13,47,49,53–55]. Traditionally, management schedules have used this separation in deciding whether to undertake lymph node dissection in clinically node-negative patients. While this seems reasonable, many unnecessary node dissections are undertaken even in the high-risk group. In almost 60% of cases no lymph node metastases are found in the resection specimen and thus there is ample room for improvement. The growth pattern as described by Cubilla et al. had prognostic value in a large series. No metastasis was found in patients with verrucous carcinoma or superficial spreading grade 1 tumours. By contrast, all patients with grade 3 tumours showing vertical growth presented with metastasis. Vascular and lymphatic invasion was found by some to be the most important prognostic factor for lymph node metastasis . In a study of 48 patients, the strongest independent predictors for node metastasis were pathological stage of the primary tumour, presence of vascular invasion and presence of > 50% of poorly differentiated cells .
Table 1. Incidence of lymph node metastasis related to tumour stage and grade (% lymph node metastasis)
There is scanty information on the use of DNA-ploidy for identifying risk groups. In two studies using multivariate analysis, DNA-ploidy was not an independent prognostic factor [3,57].
Role of sentinel node biopsy
Recent technical improvements have renewed the interest in the role of the sentinel node. Based on the assumption that lymphatic spread is a stepwise process, absence of metastasis in the first node draining the tumour is indicative of the absence of lymphatic spread in the whole lymphatic basin. The question is how to find this node reliably. On the basis of lymphangiography performed via dorsal lymphatics of the penis, Cabanas labelled the node close to the superficial epigastric vein as the sentinel node . The removal of this node was recommended, based on static anatomical landmarks and disregarding individual variation in lymphatic drainage patterns, as being one source of false-negative findings [2,58–63]. Anatomical studies show that the sentinel node area has up to seven lymph nodes located between the superficial epigastric vein and the external pudendal vein . Even by extending the area of dissection and removing all lymphatic tissue in the area of the superficial epigastric vein, and all the nodes medial to the saphenous vein, the true sentinel node can be missed. In 20 patients treated at the MD Anderson Cancer Center in Houston, five recurrences were found after extended resection of the sentinel node area, with negative findings . More recently, Morton et al. took the sentinel node concept one step further in patients with melanoma. They identified the sentinel node through individual visualization of lymphatic channels originating in the primary tumour, using a blue dye . In addition to the blue dye technique, the detection of the sentinel node is improved by lymphoscintigraphy with 99mTc-nanocolloid as a tracer for the preoperative evaluation and a gamma detection probe for intraoperative guidance (Fig. 1). The authors group termed this procedure ‘dynamic sentinel node biopsy’, in contrast to the static method described by Cabanas . To date, after assessing 90 patients, the dynamic sentinel node procedure has resulted in an unsatisfactory outcome in three patients presenting with clinically palpable inguinal recurrences 4, 14 and 27 months after the procedure. At least three reasons for failure can be proposed. The first is a false-negative pathology report; the sentinel node should be serially sectioned and immunohistochemistry always used in addition to routine staining. The second reason is the inability to visualize the sentinel node on one side or both, possibly for technical reasons (e.g. inadequate intradermal injection of the radioactive tracer) or anatomical reasons (blockage of the lymphatic flow). Finally, the occurrence of a false-negative sentinel node may be explained by the presence of a metastasis blocking the lymphatic flow. The tracer is then diverted to another node that is falsely labelled as the sentinel node. From the author's experience it is unclear whether this occurs only in patients who have clinically detectable metastatic invasion or whether clinically undetectable microscopic invasion may have the same effect. This underscores that sentinel node biopsy should not be used to determine whether node dissection is needed in patients with evident clinically positive nodes and should only be used in those with no clinical signs of nodal involvement. The probability of false-negative results underlines the need for a strict follow-up scheme. During the first 2 years after a dynamic sentinel node procedure patients are seen every second month, and in the third year every third month. Salvage procedures can then be undertaken at the earliest possible moment. Patients who cannot comply with this follow-up should not be submitted to this procedure. The reliability of ultrasound-guided fine needle aspiration biopsy of impalpable nodes has led to a change in the staging. Dynamic sentinel node biopsy is preceded by ultrasonography with biopsy only in patients with negative findings.
Contemporary imaging modalities are unable to detect clinically occult metastasis from cancer of the penis; only invasive procedures can identify reliably the presence of lymph node metastasis. A promising first-line investigation is ultrasound-guided fine needle aspiration biopsy. If this is negative dynamic sentinel node biopsy is a reliable second-line investigation. Clinically node-positive patients should undergo immediate fine-needle aspiration biopsy. Understandably, only a positive outcome is useful; no time should be wasted with the often-advised antibiotic treatment for 6 weeks.