Penile cancer is rare, with the global incidence reported at 26,000 cases per year [1]. The majority of these cases occur in areas of South America, Africa, and Asia, accounting for up to 10% of all malignancies in the non-Western world, while penile cancer makes up only 0.4–0.6% of all cancers in men in the United States [2, 3]. It has been well reported in the literature that penile cancer typically plagues those men aged 50 years and older, with a reported incidence as high as 39% in patients greater than 66 years of age based on a Brazilian study [2, 4].

The risk factors for penile carcinoma can largely be divided into behavioral/cultural practices versus infectious causes. Phimosis with its accompanying chronic inflammation and balanitis has been known to have a strong association with penile carcinoma with rates of malignancy reported to be significantly lower in populations and religious groups that practice neonatal circumcision [1, 2]. Poor hygiene and cigarette smoking are other behavioral risk factors for penile cancer with smokers being at a 2.8-fold greater risk than nonsmokers [1, 2]. The human papillomavirus (HPV) is by far the most important and common infectious risk factor for penile carcinoma with its presence reported in 40–50% of cases and HPV-16 and HPV-18 being implicated as the most commonly found subtypes [1, 2, 5].

While 80% of patients are diagnosed with localized penile cancer with a 5-year cancer-specific survival reported at 95%, those patients who present with a primary penile tumor and nodal involvement have a much more dismal prognosis [2, 6, 7]. It has been well documented, therefore, that the presence and extent of lymph node metastasis is by far the most important prognostic factor in determining long-term oncologic outcomes and patient survival [7, 8]. Graafland et al. detected nodal involvement in 16% of cases of penile squamous cell carcinoma (SCC) with a 38% overall survival at 9 years and 0% survival at 10 years in these patients compared to a 90% 10-year overall survival in patients without nodal metastases [7].

The risk of lymph node metastasis is influenced by both the stage of the primary penile tumor and the histologic subtype with an 89% risk of lymph node metastasis reported in sarcomatoid tumors and a 20–30% risk of lymph node metastasis reported in patients with pathologic T2–T3 disease in the primary lesion [2, 9]. Additionally, the number of inguinal lymph nodes involved, extranodal extension, and the presence of pelvic lymph node involvement further dictate disease-specific survival, making accurate determination of lymph node status of paramount importance [6, 10].

Three positive inguinal lymph nodes have been proposed in the literature as an appropriate cutoff point for risk-stratifying patients based on the extent of lymph node involvement [11]. Pandey et al. reported a 75.6% versus 8.4% overall survival at 5 years in patients with one to three versus four to five positive inguinal lymph nodes, respectively [6]. Similarly, Ravi et al. reported a 5-year overall survival of 75% in patients with one to three positive inguinal lymph nodes [12]. Leijte et al. found no statistical difference in survival between penile cancer patients with one versus two or more positive inguinal nodes, but for patients with between one to three positive inguinal lymph nodes versus four or more, the survival difference was statistically better with less than four positive inguinal nodes [13].

Extranodal extension and pelvic lymph node metastases are also very poor prognostic factors [6, 7, 14]. Multiple positive locoregional lymph nodes have been associated with both extranodal extension and pelvic node involvement [11]. Pandey et al. found 5-year survival rates of 8.9% and 0% in penile SCC patients with extranodal extension and positive pelvic lymph node disease [6].

Finally, inguinal lymph node laterality has been reported to have some prognostic value, with bilateral inguinal lymph node disease portending a worse survival rate than unilateral involvement [6, 11, 12]. A study by Zhu et al. found a 3-year recurrence-free survival rate of 59.2% versus 26.7% in unilateral versus bilateral inguinal lymph node disease [11].

The lymphatic drainage of the penis originates from a dense and intricate network of lymphocapillaries within the penile skin, mucous membrane and submucosa of the urethra, septum of the glans, tunica albuginea of the corpora cavernosa, and Buck’s fascia [15]. Thus, penetration of Buck’s fascia or the tunica albuginea by the primary penile tumor allows for dissemination of tumor cells into the lymphatic system [16]. The regional penile lymphatics can be divided into superficial and deep systems, which drain the penile skin, corporal bodies, and glans into the superficial and deep inguinal lymph nodes, respectively [15, 17].

Classically, the superficial inguinal lymph nodes have been divided into five quadrants or zones named the superomedial, superolateral, inferomedial, inferolateral, and central zones [18]. Cadaveric and anatomic studies have shown that there are approximately 4–25 superficial inguinal lymph nodes in these five regions with more recent studies reporting 5–17 lymph nodes in this area [17, 18]. In a study of the lymphangiographic patterns of penile cancer patients, Cabanas et al. showed that injection into the dorsal penile vasculature consistently drained into a node anterior or medial to the superficial epigastric vein or superomedial to the sapheno-epigastric junction with subsequent drainage into the deep inguinal lymph nodes and iliac nodes. Each patient in the study showed metastasis to this sentinel node [19]. A study using single-photon emission computed tomography (SPECT) scanning to assess lymphatic drainage patterns found sentinel lymph nodes to be present in the superior and central zones, which suggested that all modified inguinal lymph node dissections should include these two regions [20].

The deep inguinal lymph nodes are separated from the superficial nodes by the fascia lata, and they have been noted to be fewer in number with one cadaveric study reporting only zero to five lymph nodes in the deep system located medial to the saphenous vein and draining into the pelvic nodes (namely, the external iliac, internal iliac, and obturator nodes) [17, 21]. There have been no anatomic or lymphangiographic studies demonstrating direct lymphatic drainage to the pelvic lymph nodes from the penis, which is evidenced by the lack of metastatic spread to the pelvic lymph nodes from a primary penile tumor in the absence of metastatic spread to the inguinal lymph nodes [15, 20, 21]. It has been well documented, however, that lymphatic drainage of penile SCC can be unilateral or bilateral to the groins with lymphatic spread of penile carcinoma to unilateral or bilateral inguinal lymph nodes seen [20].

Palpable inguinal lymph nodes in the setting of penile SCC is considered to be secondary to metastatic spread as a trial of antibiotics is no longer advised since it can delay oncologic diagnosis and treatment [22]. Surgical staging with radical inguinal lymph node dissection is warranted in the setting of fixed inguinal lymph nodes (cN3) on physical examination, often requiring neoadjuvant chemotherapy prior to lymphadenectomy [22]. Palpable inguinal lymph nodes have been noted to harbor metastatic spread in 60–80% of cases, and diagnostic modalities such as fine needle aspiration or 18F-flurodeoxyglucose positron emission tomography/computerized tomography (PET/CT) can be used to confirm the presence of penile carcinoma in suspicious regions, but this does not obviate the need for inguinal lymph node dissection for adequate oncologic diagnosis and staging [22–24].

Fine needle aspiration has been shown to have a sensitivity of 93% in detecting carcinoma in clinically positive lymph nodes [23]. A meta-analysis also reported PET/CT to have a pooled sensitivity of 96.4% for patients with palpable or clinically positive inguinal lymph nodes [25]. Similarly, a study by Schlenker et al. found PET/CT to have a sensitivity and specificity of 88.2% and 98.1%, respectively, in all clinically node-positive penile cancer patients with a false-negative rate of 11.8% [24]. While PET/CT can be used as an adjunct in diagnosing metastatic involvement in clinically positive lymph nodes, it has shown less utility in clinically negative inguinal lymph node cases [26, 27]. A study by Rosevear et al. reported PET/CT to have a sensitivity of 0% and a false-negative rate of 100% in detecting carcinoma patients with clinically negative inguinal lymph nodes [26]. While the study had a small population, it demonstrated that PET/CT had limited utility in the setting of nonpalpable lymph nodes that may harbor micrometastatic disease, thus ought not to be used solely to rule out the presence of inguinal nodal involvement. It must be noted, however, that in this same study, the patients who later developed palpable lymph nodes had positive PET/CT scans, which were confirmed histologically [26]. Thus, it is the management of clinically negative inguinal lymph nodes with the identification of micrometastasis that is the most problematic aspect of penile cancer staging.

Approximately 25% of clinically normal groins have micrometastatic disease, and cross-sectional imaging studies such as CT and magnetic resonance imaging (MRI) are unable to accurately detect these cases and thus are only largely used to assess for the presence of pelvic lymph node involvement [22, 26]. Patients with noninvasive, well-differentiated penile tumors (i.e., low-grade or pathologic stage Ta, Tis, or T1 without LVI (lymphovascular invasion) [T1a]) and clinically negative groins warrant surveillance as this group is at low risk for inguinal nodal spread and are unlikely to benefit from lymphadenectomy [22].

Dynamic sentinel lymph node biopsy (DSNB) is a minimally invasive diagnostic tool which can serve as an intermediary between noninvasive imaging modalities and surgical resection when identifying those patients with clinically negative groins who would benefit from inguinal lymphadenectomy [28]. Dynamic sentinel lymph node biopsy is based on the assumption that penile cancer cells will initially spread unilaterally or bilaterally to a single inguinal lymph node before disseminating to adjoining lymph nodes and that this sentinel lymph node can have a variable position among individuals [29]. DSNB involves injecting technetium-99m-labeled nanocolloids and patent blue dye around the primary penile tumor usually on the same day as lymph node biopsy. Lymphoscintigraphic images are obtained using a gamma-ray detection probe intraoperatively to identify the first lymph node that drains the primary tumor (i.e., the sentinel lymph node), which is subsequently resected [28, 30]. The sensitivity of dynamic sentinel lymph node biopsy has been reported at 93% by Leijte et al. and 88% by Lam et al. with false-negative rates of 7% and 5%, respectively. Additionally, the morbidity of dynamic sentinel lymph node biopsy is significantly less than that of a modified inguinal lymph node dissection or a standard lymphadenectomy, with complication rates ranging between 7.6 and 4.7% [28, 30]. The use of fine needle aspiration with ultrasonographic imaging has been shown to further improve the diagnostic yield of DSNB and decrease the rate of false negatives [29, 30]. Although its utility has been well documented, widespread use of DSNB remains limited and generally restricted to high-volume centers [30].

Stage and grade of the primary penile tumor have been known to dictate the management of penile SCC with nonpalpable inguinal lymph nodes. The 2014 European Association of Urology penile cancer guidelines recommend the surgical staging of clinically negative inguinal lymph nodes in penile cancer patients with high-grade, pT1 with LVI (pT1b), or pT2–T4 tumors using a bilateral modified inguinal lymph node dissection or DSNB since this group is considered to be intermediate to high risk for locoregional metastasis [22]. Graafland et al. reported occult nodal metastases in 23% of patients with clinically negative groins who had undergone complete inguinal lymphadenectomy and who had high-grade disease, pT2–T4 penile carcinoma, or when lymphovascular invasion was noted within the primary tumor [31].

A modified inguinal lymph node dissection has been described as a method to stage clinically negative groins in penile SCC and diagnose nodal involvement with less morbidity compared to standard radical inguinal lymph node dissection, but it is important to note that a modified dissection should be converted to a radical inguinal lymphadenectomy if positive inguinal lymph nodes are present on frozen section [22, 32].

Clinically positive groins (cN1 or cN2) warrant bilateral radical inguinal lymphadenectomy, while fixed or bulky groin disease (i.e., >4 cm inguinal lymph nodes) is managed with neoadjuvant chemotherapy and subsequent radical lymphadenectomy in those patients that respond clinically [21, 22, 33]. The boundaries of a radical inguinal lymph node dissection are the inguinal ligament superiorly, the sartorius muscle laterally, the adductor longus muscle medially, and the junction at which these two muscles cross serving as the inferior boundary [21, 34]. Draseler et al. also described the superior boundary as a 12-cm line parallel to that of the inguinal ligament beginning from the pubic tubercle and extending laterally, the lateral boundary as a 20-cm line beginning at the anterior superior iliac spine extending inferiorly, and the medial border beginning at the pubic tubercle and extending inferiorly 15 cm [18].

A skin incision is made 2–3 cm below the inguinal crease that is parallel to the inguinal ligament, and skin flaps are subsequently raised. The dissection begins with exposing the inferior border of the inguinal ligament, spermatic cord, and external oblique aponeurosis. Lymphatic tissue is then removed above the fascia lata. The dissection is deepened through the fascia lata overlying the sartorius muscle laterally and the adductor longus muscle medially. Additionally, lymphatic tissue is removed around the femoral artery and vein until these vessels are skeletonized. The saphenous vein is ligated at the saphenofemoral junction. The sartorius muscle is then released from its attachment to the anterior superior iliac spine and transposed over the femoral vessels to serve as a myocutaneous flap for coverage. A suction drain is then placed in the wound with reapproximation of the skin and subcutaneous tissues [34, 35].

Catalona et al. first described a modified inguinal lymph node dissection involving resection of lymphatic tissue from the superomedial quadrant of the groin, preservation of the saphenous vein, limiting resection of deep inguinal nodes to those medial to the femoral vein, avoiding dissection lateral to the femoral vein or caudal to the fossa ovalis, and eliminating transposition of the sartorius muscle [32, 36]. This technique can also preserve vasculature to the groin that runs parallel to the inguinal ligament, which can decrease the risk of flap necrosis. Jacobellis et al. described minimizing the dissection beneath the superficial layer of the fascia lata since the superficial branches of the inferior epigastric, external pudendal, and circumflex iliac arteries run in this region and supply the skin of the groin [37]. Avoiding the removal of lymphatic tissue in this area can further preserve arterial blood supply and reduce risk of skin breakdown and wound dehiscence [37].