Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors

INTRODUCTION — Germ cell tumors, which arise from germ cell elements within the seminiferous tubules, account for 90 to 95 percent of all testicular tumors (table 1). Approximately one-half of these cases are seminomas, and the other half constitute nonseminomatous germ cell tumors (NSGCTs).

Historically, testicular cancer accounted for 11 percent of all cancer deaths in men between the ages of 25 and 34 with a five-year survival rate of 64 percent [1]. With a better understanding of the natural history of testicular tumors, improved staging and surgical techniques, and the introduction of effective platinum-based combination chemotherapy, approximately 410 deaths from testicular cancer occur in the United States per year, and five-year overall survival rates are consistently over 95 percent [2]. The high probability of cure for men with early-stage disease has shifted the focus toward reducing treatment-related effects on sexual and reproductive function and reducing the pulmonary, neural, and renal toxicities associated with chemotherapy. (See "Approach to the care of long-term testicular cancer survivors".)

Given the greater risk for nodal involvement for men with NSGCTs, these men are more likely to undergo a retroperitoneal lymph node dissection (RPLND) as part of their treatment. However, this procedure should only be performed by surgeons with appropriate technical expertise. The rationale and techniques for RPLND in men with early-stage (ie, stage I and IIA) NSGCTs will be reviewed here (table 2 and table 3). Further details on the treatment on advanced testicular germ cell tumors are discussed separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

OVERVIEW OF TREATMENT OPTIONS AFTER ORCHIECTOMY — Following orchiectomy, men with early-stage nonseminomatous germ cell tumors (NSGCTs) are candidates for active surveillance, a short course of chemotherapy, or retroperitoneal lymph node dissection (RPLND). Staging should include abdominal computed tomography (CT) scan, chest radiograph, and repeat tumor markers. If the tumor markers are rising or not decreasing by appropriate half-life, chemotherapy is the primary treatment. In general, the approach to management depends on the likelihood of relapse, relative importance of different toxicities for an individual patient, and ability of the patient to adhere to active surveillance protocols. Given the overall excellent prognosis of men with early-stage NSGCTs, all of these options should be discussed with the patient. However, an RPLND should only be performed by experienced surgeons (ie, surgeons who perform at least 24 procedures annually).

RATIONALE FOR RPLND — For men with early-stage nonseminomatous germ cell tumors (NSGCTs), retroperitoneal lymph node dissection (RPLND) is the only reliable method to identify nodal micrometastases, which may be an important factor in some patients. In addition, it is associated with low short- and long-term morbidity [3]. There are several advantages to the performance of RPLND rather than surveillance or adjuvant chemotherapy in men with stage I or II NSGCTs:

●RPLND permits the selection of those who may benefit from postoperative chemotherapy [4]. (See "Management of stage I nonseminomatous germ cell tumors" and "Management of stage II nonseminomatous germ cell tumors".)

●For men with pathologically confirmed stage I disease, surveillance after RPLND involves only tumor markers and chest radiographs because the incidence of retroperitoneal relapse is less than 1 percent [5]. In contrast, men who do not undergo RPLND require more intensive surveillance protocols that include imaging of the abdomen and pelvis because the relapse risk ranges from 25 to 30 percent. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors".)

●The chance of future successful pregnancies may be higher for men who have an RPLND compared with those who do not undergo RPLND [6]. A possible explanation of this observation is that men managed with surveillance are at a greater risk for relapse, which would require chemotherapy, which would place them at a greater risk for infertility.

INDICATIONS — For men with early-stage nonseminomatous germ cell tumors (NSGCTs) who are considering retroperitoneal lymph node dissection (RPLND), the procedure should only be performed at centers where the technical expertise is available. At our institution, appropriate indications for RPLND include:

●Stage I NSGCT in the presence of at least one risk factor – For these patients, an increased risk for retroperitoneal lymph node involvement includes vascular invasion or a predominant embryonal component to the primary tumor. However, chemotherapy and active surveillance are reasonable alternatives. (See "Management of stage I nonseminomatous germ cell tumors", section on 'Retroperitoneal lymph node dissection'.)

●Stage IIA NSGCT – This includes men with radiographically evident (especially if nodal metastases measure 2 cm or less) or histologically confirmed metastases involving the retroperitoneal nodes (during RPLND). (See "Management of stage II nonseminomatous germ cell tumors".)

●Early-stage metastatic seminoma – Testicular seminoma with isolated retroperitoneal lymphadenopathy is typically treated with external beam radiation or systemic chemotherapy, which can be associated with long-term morbidities (eg, secondary malignancy, cardiovascular diseases). Several retrospective studies have shown promising results when RPLND surgery is performed for seminomas with low-volume retroperitoneal metastases (stage I or II) [7]. Two active phase 2 clinical trials (SEMS [NCT 02537548] and PRIMETEST [NCT 02797626]) are investigating the recurrence-free survival after RPLND for early-stage metastatic seminoma.

The standard of care for men with more advanced or disseminated NSGCTs (stage IIB or higher) is to administer chemotherapy. In general, any patient with one or more residual retroperitoneal lymph nodes larger than 1 cm following chemotherapy should undergo RPLND. In addition, these patients should undergo resection of any residual masses identified after chemotherapy (eg, pulmonary or hepatic lesions). RPLND may also be an option for some men with early-stage NSGCTs. Centers that are not accustomed to performing RPLNDs should refer the patient to a center of excellence with extensive experience in resecting postchemotherapy residual germ cell tumor masses whenever possible.

SURGICAL PRINCIPLES — For men with testicular cancer, the goal of a retroperitoneal lymph node dissection (RPLND) is to provide accurate pathologic staging information and to remove any disease involving the retroperitoneal nodes. However, given the excellent prognosis for men with testicular cancer, preservation of fertility and sexual function are also important objectives of surgery.

The classic (open) bilateral RPLND has been largely replaced with template nerve-sparing dissections for both right- and left-sided disease, resulting in the preservation of sexual function and fertility for the vast majority of patients; over 90 percent of men can expect to maintain or recover antegrade ejaculation with a nerve-sparing RPLND [8]. Laparoscopic/robotic techniques may further reduce the morbidity associated with RPLND. Surgical expertise is required to minimize the morbidity of this procedure without compromising the cancer-specific outcomes. (See 'Laparoscopic/robotic RPLND' below.)

Metastatic pattern — The approach to RPLND for nonseminomatous germ cell tumors (NSGCTs) is guided by a well-described pattern of metastatic nodal involvement. This is illustrated by a study that involved 100 patients with pathologic stage II NSGCTs [9]:

●Right-sided tumors involved the interaortocaval nodes in 93 percent of patients, while left-sided tumors metastasized to the pre- and paraaortic nodes in 88 and 86 percent, respectively.

●For men with stage IIA disease, 14 percent had ipsilateral common iliac node involvement. However, suprahilar retroperitoneal lymph node involvement was rare.

●Although contralateral node involvement was uncommon in patients with early-stage disease, it was more common in patients with right-sided tumors, likely due to the right-to-left-sided flow of lymphatic drainage.

●Inguinal node metastases may result by retrograde spread from extensive retroperitoneal nodes, scrotal invasion, or a scrotal rather than inguinal orchiectomy. Pelvic node involvement may signify locally advanced disease, including epididymal involvement.

Of note, choriocarcinoma is the exception to this pattern of spread and tends to metastasize hematogenously. (See "Anatomy and pathology of testicular tumors", section on 'Choriocarcinoma'.)

Anatomic considerations — Because RPLND increases the risk for sexual dysfunction and infertility, an understanding of the pelvic anatomy underlying normal sexual and erectile function is important. Normal (ie, antegrade) propulsion of semen through the urethra requires coordination of three separate events: seminal emission, closure of the bladder neck, and ejaculation. (See 'Complications following RPLND' below.)

Emission is the movement of semen into the posterior urethra immediately prior to ejaculation. Emission is mediated by sympathetic nerves from spinal segments T12 to L3 and affected by contractions of the vas deferens, prostate, and seminal vesicles. Ejaculation is the passage of semen distally through the urethra; it results from tightening of the closed bladder neck (sympathetic reflex), relaxation of the external sphincter (parasympathetic reflex), and contraction of the bulbocavernosus muscle (somatic innervation via the pudendal nerve). Thus, ejaculation is mediated by combined autonomic and somatic innervation originating at the sacral and lumbar spinal cord levels.

Neuroanatomy — The sympathetic nerves responsible for emission and bladder neck closure during ejaculation leave the spinal cord with the ventral roots of the 12^th thoracic (T12) to the third lumbar (L3) spinal nerves. These nerves extend to the paravertebral sympathetic ganglion chain, located beneath the medial edge of the vena cava on the right, the aorta on the left, and between the gutter formed by the vertebral bodies and the psoas muscle. Within the mid-retroperitoneum, these nerve fibers converge toward midline after leaving the sympathetic trunk and form the hypogastric plexus, which is situated in front of the body of the fifth lumbar vertebra and the bifurcation of the abdominal aorta and behind the left common iliac vein. From the superior hypogastric plexus, the right and left hypogastric nerves pass into the pelvic plexuses, which are situated on either side of the rectum, seminal vesicles, bladder, and prostate.

Lymphatics — For men undergoing RPLND, the retroperitoneal, pelvic, and inguinal nodes should be evaluated. The spermatic cord contains lymphatic channels that ascend into the retroperitoneal lymph node chain. The right testis drains into the interaortocaval node, which is located at the level of the second lumbar vertebral body. In contrast, the left testis drains into lymph nodes located in the paraaortic region in an area bounded by the renal vein superiorly, the aorta medially, the ureter laterally, and the origin of the inferior mesenteric artery inferiorly. In contrast, the epididymis drains into the external iliac nodes and pelvic nodes.

SURGICAL APPROACHES — Retroperitoneal lymph node dissection (RPLND) can be performed as an open surgical procedure or laparoscopically. These techniques are described briefly below. Regardless of the approach, a good understanding of the anatomy involved and a careful dissection technique are critical to the preservation of the efferent sympathetic nerve fibers.

Open RPLND — RPLND may be limited (RPLND-I) or require a more extended (RPLND-II) dissection. This depends on the clinical and intraoperative assessment:

RPLND-I — An RPLND-I is typically performed in men with nonseminomatous germ cell tumors (NSGCTs) who have normal serum tumor markers and no radiographic features of retroperitoneal involvement but who have at least one risk factor for micrometastases in retroperitoneal lymph nodes (eg, vascular invasion or a predominant embryonal component to the primary tumor). The surgical technique is usually a template nerve-sparing RPLND. This entails an ipsilateral node dissection below the level of the inferior mesenteric artery. This approach preserves the sympathetic nerves responsible for emission and antegrade ejaculation in the majority of patients, thus preserving sexual function and future fertility [3,10]. (See 'Neuroanatomy' above and 'Complications following RPLND' below.)

RPLND-II — An RPLND-II is typically indicated for men with clinical stage IIA NSGCTs or those with intraoperative evidence of retroperitoneal node involvement. The surgical boundaries are wider than in the RPLND-I and include bilateral dissection above the renal arteries and below the inferior mesenteric artery. Every attempt should be made to preserve both the lumbar sympathetics and the hypogastric plexus. (See 'Anatomic considerations' above.)

Laparoscopic/robotic RPLND — Low-quality data suggest that laparoscopic/robotic RPLND is a feasible option, especially for men at low risk of nodal involvement. However, this procedure should be considered a staging procedure rather than one performed with therapeutic intent. Therefore, most men found to have positive nodes on laparoscopic or robotic RPLND are treated automatically with adjuvant chemotherapy. In contrast, those who undergo open RPLND with resection of all gross disease are candidates for active surveillance rather than chemotherapy, provided they have a limited volume of nodal disease (eg, N1 disease (table 2)). (See "Management of stage II nonseminomatous germ cell tumors".)

Laparoscopic/robotic RPLND is a technique that may reduce morbidity compared with the classic RPLND [11]. Both procedures appear to result in equivalent cancer control rates [12-15]. In one series, 87 men with stage I germ cell tumors underwent a laparoscopic RPLND for pathologic staging of the retroperitoneum; men with pathologically involved nodes received adjuvant chemotherapy [15]. With a median follow-up of 84 months, the distant relapse rate was 9 and 0 percent among men with pathologically node-negative and node-positive disease, respectively. Of note, only men with node-positive disease were treated with adjuvant chemotherapy. Postoperative complications were seen in 9 percent of cases, including pulmonary embolus (n = 1), development of a lymphocele (n = 1), ureteral injury (n = 5), and retrograde ejaculation (n = 1). Short-term data show equivalence to open RPLND; however, long-term data without adjuvant chemotherapy are lacking [16,17].

Surgical template — For men with early-stage NSGCTs, the template for RPLND depends on the laterality of the tumor:

●For right-sided tumors, the dissection extends from:

•The right ureter laterally

•The anterior aspect of the infrarenal abdominal aorta medially

•The anterior aspect of the right common iliac artery all the way to its bifurcation caudally

•The renal vessels within the left and right margins of this template in the cephalad direction

●For left-sided tumors, the dissection extends from:

•The left ureter laterally

•The medial aspect of the infrarenal inferior vena cava medially

•The anterior aspect of the left common iliac artery all the way to its bifurcation caudally

•The renal vessels within the left and right margins of this template in the cephalad direction

For both templates, the cephalad extent is to the renal vessels within the left and right margins of the template. Posteriorly, the dissection extends all the way onto the psoas muscles and anterior spinous ligament.

Prospective nerve sparing coupled with template dissection can result in improved preservation of ejaculation [18].

COMPLICATIONS FOLLOWING RPLND — For men with testicular cancers, retroperitoneal lymph node dissection (RPLND) can cause a number of immediate surgical complications, as well as subsequent sexual dysfunction and infertility.

Surgical complications — RPLND following chemotherapy includes both resection of residual disease and a full bilateral node dissection. In patients who undergo RPLND following chemotherapy for advanced disease, surgery can entail a combined abdominal and thoracic approach, depending upon the distribution of residual masses.

In the best of hands, RPLND is associated with an 18 percent complication rate due to the technically demanding nature of the surgery and patient comorbidity. Depending upon the site and extent of the tumor mass, postoperative absence of ejaculation occurs in a significant percentage of patients [19,20]. Resection of the infrarenal vena cava is necessary in some patients [21,22], and aortic tube grafts may be necessary to replace aortic segments that are damaged by subadventitial dissection [23].

Men who have received bleomycin as part of their chemotherapy regimen may have restrictive lung disease, a greater risk of lung toxicity in response to high concentrations of inspired oxygen, and sensitivity to volume replacement both intraoperatively and postoperatively [24]. Intraoperative central venous pressure monitoring and close attention to fluid volume are recommended in these patients. (See "Bleomycin-induced lung injury" and "Treatment-related toxicity in testicular germ cell tumors", section on 'Pulmonary'.)

In one review, pulmonary complications were the most frequent cause of severe morbidity after RPLND [24]. Among 125 such patients, six developed acute respiratory distress syndrome, and five needed prolonged ventilatory support. The underlying cause was a combination of bleomycin-induced lung toxicity and resection of large retroperitoneal and lung volumes in patients with both intrathoracic and retroperitoneal residual masses. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors", section on 'Lung lesions'.)

Because of the fibrosis and intense desmoplastic reaction after chemotherapy, minimally invasive RPLND has generally been associated with higher complications, up to 42 percent in some series [25]. Other series still report minor complications in 7 of 16 patients [26].

Sexual dysfunction — Men undergoing primary RPLND are at risk for sexual dysfunction, which ranges from 1 to 15 percent with modern nerve-sparing techniques [3,27,28]. The neuroanatomy that underlies the risk to sexual function for men who undergo RPLND is discussed above. (See 'Anatomic considerations' above.)

Infertility — Men are also at risk for infertility following RPLND, although it is lower with the use of nerve-sparing approaches [27,29]. In one series of almost 300 men, the fertility rate was 37 and 62 percent among men treated with a non-nerve-sparing or a nerve-sparing RPLND, respectively [29]; in contrast, the fertility rate was 77 percent in men who did not undergo an RPLND. Due to the risk of infertility, we discuss sperm banking with patients prior to RPLND.

SURVEILLANCE AFTER RPLND — Following retroperitoneal lymph node dissection (RPLND), all men should undergo postoperative surveillance. For these men, the disease often recurs at distant sites rather than within the retroperitoneum. In one series of over 300 patients with clinical stage I nonseminomatous germ cell tumors (NSGCTs) treated by RPLND (20 percent with pathologically confirmed nodal involvement), 43 of the 49 relapses were distant, predominantly involving the lungs [30].

The posttreatment follow-up for men with NSGCTs is discussed separately. (See "Posttreatment follow-up for testicular germ cell tumors".)

TREATMENT OF RELAPSE — For men with pathologically node-negative or node-positive disease after retroperitoneal lymph node dissection (RPLND), the incidence of distant metastases is approximately 10 and 28 percent, respectively [30]. This is likely due to the direct communication between the testicular lymphatics and the thoracic duct, which bypasses the retroperitoneal lymph nodes.

Testicular cancer metastasizes to the lung most commonly, with subsequent spread to the liver, viscera, and brain; bone metastases are generally a late and rare complication. Fortunately, for most patients, relapse is generally curable with systemic therapy. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Testicular cancer".)

SUMMARY AND RECOMMENDATIONS

●Germ cell tumors, which arise from germ cell elements within the seminiferous tubules, account for 90 to 95 percent of all testicular tumors. Men with early-stage seminoma are likely cured by orchiectomy. In contrast, men with nonseminomatous germ cell tumors (NSGCTs) have a higher risk of nodal involvement. Therefore, a retroperitoneal lymph node dissection (RPLND) is an option for the treatment of men with stage I and II NSGCTs. (See 'Introduction' above.)

●For men with early-stage NSGCTs, reasonable options following orchiectomy include active surveillance, chemotherapy, and RPLND. In the absence of a uniform standard of care, all of these options should be discussed with patients. For men who are considering RPLND, the procedure should only be performed by experienced surgeons (ie, surgeons who perform at least 24 procedures annually). (See 'Overview of treatment options after orchiectomy' above.)

●RPLND is the only reliable method to identify nodal micrometastases and is the gold standard for providing accurate pathologic staging of the retroperitoneum. Our approach is as follows (see 'Rationale for RPLND' above):

•For men with clinical stage I NSGCTs with at least one risk factor for relapse (ie, lymphovascular invasion or a predominant embryonal carcinoma component), we proceed with RPLND. However, treatment with two cycles of a cisplatin-based regimen is a reasonable alternative to surgery and is frequently the treatment of choice in Europe. (See 'Indications' above and "Management of stage I nonseminomatous germ cell tumors".)

•For men with clinical stage IIA NSGCTs with low-volume nodal disease (metastasis ≤2 cm), we suggest RPLND rather than chemotherapy. (See 'Indications' above and "Management of stage II nonseminomatous germ cell tumors".)

●Nerve-sparing RPLND results in a lower risk of sexual dysfunction and infertility compared with non-nerve-sparing approaches. Therefore, expertise in the technique of RPLND is required to minimize the morbidity of this procedure without compromising the cancer-specific outcomes for men with NSGCTs. (See 'Complications following RPLND' above.)

●The rate of relapse following RPLND for early-stage NSGCTs is approximately 15 percent, and relapse is predominantly distant rather than retroperitoneal. Therefore, all men require post-treatment follow-up. (See "Posttreatment follow-up for testicular germ cell tumors".)