Key points

Introduction

Improvements in the management of germ cell tumors (GCTs), most notably the introduction of highly effective cisplatin-based chemotherapy, has resulted in dramatically improved rates of overall survival, now exceeding 95% for all patients who receive a diagnosis of testicular cancer and 80% for those with metastatic disease. The multimodal approach to the management of GCT with the integration of surgery, chemotherapy, and radiation serves as a model for the successful management of cancer and provides hope for dramatic improvements in the management and prognosis of other malignancies in the future.

Although the advent of effective chemotherapy provides an adjunct to technically challenging surgery, retroperitoneal lymph node dissection (RPLND) remains an essential component of the treatment algorithm for nonseminomatous germ cell tumors (NSGCT) and serves as both a therapeutic and a diagnostic and staging procedure (see the article by Masterson and colleagues elsewhere in this issue for further exploration of this topic).

Whether done in the primary or postchemotherapy setting (PC-RPLND), it is apparent that complete resection of all metastatic retroperitoneal disease is the key variable related to long-term relapse-free survival. Unfortunately, some patients will relapse in the retroperitoneum or harbor unresected disease after RPLND, and salvage chemotherapy will rarely adequately compensate for an inadequate initial RPLND, as these late recurrences tend to be chemoresistant malignancies or have chemoresistant teratomatous elements. Despite the technical challenges, appropriately selected patients can be effectively managed with reoperative retroperitoneal surgery with an acceptable morbidity rate when performed by experienced surgeons at tertiary care centers.

This review describes the patterns of metastasis of testicular tumors; incidence, distribution, and histologic findings of retroperitoneal recurrences; indications for reoperative retroperitoneal surgery; and postoperative morbidity/complications and clinical outcomes of patients with GCTs with retroperitoneal recurrences following RPLND.

Introduction

Improvements in the management of germ cell tumors (GCTs), most notably the introduction of highly effective cisplatin-based chemotherapy, has resulted in dramatically improved rates of overall survival, now exceeding 95% for all patients who receive a diagnosis of testicular cancer and 80% for those with metastatic disease. The multimodal approach to the management of GCT with the integration of surgery, chemotherapy, and radiation serves as a model for the successful management of cancer and provides hope for dramatic improvements in the management and prognosis of other malignancies in the future.

Although the advent of effective chemotherapy provides an adjunct to technically challenging surgery, retroperitoneal lymph node dissection (RPLND) remains an essential component of the treatment algorithm for nonseminomatous germ cell tumors (NSGCT) and serves as both a therapeutic and a diagnostic and staging procedure (see the article by Masterson and colleagues elsewhere in this issue for further exploration of this topic).

Whether done in the primary or postchemotherapy setting (PC-RPLND), it is apparent that complete resection of all metastatic retroperitoneal disease is the key variable related to long-term relapse-free survival. Unfortunately, some patients will relapse in the retroperitoneum or harbor unresected disease after RPLND, and salvage chemotherapy will rarely adequately compensate for an inadequate initial RPLND, as these late recurrences tend to be chemoresistant malignancies or have chemoresistant teratomatous elements. Despite the technical challenges, appropriately selected patients can be effectively managed with reoperative retroperitoneal surgery with an acceptable morbidity rate when performed by experienced surgeons at tertiary care centers.

This review describes the patterns of metastasis of testicular tumors; incidence, distribution, and histologic findings of retroperitoneal recurrences; indications for reoperative retroperitoneal surgery; and postoperative morbidity/complications and clinical outcomes of patients with GCTs with retroperitoneal recurrences following RPLND.

Testicular tumors and patterns of metastasis

The successful management of testicular GCTs has been facilitated by a predictable pattern of metastatic spread of disease, primarily to the lymph nodes of the retroperitoneum and subsequently to the lung and posterior mediastinum. This process holds true for all histologic subtypes of GCTs, with the notable exception of choriocarcinoma, which has a higher reported incidence of hematogenous distribution. The embryologic origin of the testis in the retroperitoneum and, therefore, lymphatic drainage pattern informs the most common location of metastatic disease; tumors of the right testis are first drained by the interaortocaval area, followed by the precaval and preaortic lymph nodes, whereas tumors of the left testis are first drained by the para-aortic and preaortic lymph nodes, followed by the interaortocaval nodes. Right testis tumors are more commonly associated with contralateral spread, and bulky retroperitoneal disease and lymphatic obstruction can result in more caudal deposition of metastatic disease in the retroperitoneum.

Given the predictable patterns of metastatic spread of testicular cancer, RPLND has a well-established role in the management of NSGCT for several reasons. First, because the retroperitoneum is often the first and only site of metastatic disease, patients can be cured with RPLND as long as the initial surgery is thorough enough to removal all sites of gross or micrometastatic disease. Second, although radiologic imaging continues to improve, clinical staging still underestimates the disease burden in the retroperitoneum, with a reported 20% to 30% incidence of pathologic stage II disease (positive retroperitoneal nodes) despite radiographic suggestion of clinical stage I disease. Third, the uncontrolled retroperitoneum represents a significantly adverse prognostic factor, as untreated retroperitoneal metastases are usually fatal. The management of advanced-stage NSGCT involves the integration of chemotherapy and surgery, and even in the postchemotherapy setting for clinical stage IIA/IIB NSGCT, RPLND reveals a 6% to 8% incidence of viable malignancy and a 31% to 44% incidence of chemoresistant teratoma. Finally, the retroperitoneum is the predominant site of relapse of seminomatous and nonseminomatous GCT for viable malignant tissue, teratoma, or teratoma with malignant transformation.

Incidence, distribution, and histologic findings of retroperitoneal recurrences

Tumor recurrence within the retroperitoneum following RPLND is a relatively rare event, with a reported incidence of approximately 1% to 3%, but incidence of as high as 8.2% has been reported ( Table 1 ). However, there is reason to believe that residual disease within the retroperitoneum following RPLND may be an underreported phenomenon. The use of effective postoperative cisplatin-based chemotherapy, especially in chemo-naïve patients, may eliminate occult micrometastatic disease that was not resected during initial RPLND. In addition, some centers will not perform routine postoperative imaging, and the lack of publications with long-term follow-up likely results in an underreporting of retroperitoneal recurrences.

Except in rare cases, a retroperitoneal recurrence following RPLND should be regarded as a technical failure, which may be due to a variety of factors including inappropriate modifications to the original retroperitoneal dissection template or lack of expertise in performing the challenging initial dissection.

This proposal is supported by the findings of increased retroperitoneal recurrence with left-sided primary testicular tumors, which are associated with a more complex left renal hilar dissection, and the finding that incomplete lumbar ligation, a prerequisite for clearing the posterior lymphatics behind the great vessels, is a common finding at the time of reoperative retroperitoneal surgery.

RPLND has had a well-established role in the management of NSGCT since 1948, but the surgical template, techniques, and decision to implement this strategy has evolved over the past several decades. The initial description of the RPLND involved an extensive template involving all the nodal tissue between both ureters from the suprahilar region down to the bifurcation of the common iliac arteries. Before the advent of cisplatin-based chemotherapy, extensive suprahilar dissection was indicated because of a lack of effective alternative therapy. The discovery of effective systemic chemotherapy, coupled with the relatively low incidence of suprahilar nodal involvement, and significant morbidity associated with suprahilar dissection (including renovascular complications, pancreatic complications, and an increased incidence of chylous ascites), led to one of the first modifications of the RPLND template to exclude the suprahilar region from the standard template. Although less morbid, the bilateral infrahilar RPLND was still associated with loss of antegrade ejaculation caused by damage to the paravertebral sympathetic ganglia, postganglionic sympathetic fibers, or the hypogastric plexus, with the incidence of retrograde ejaculation related to the degree of retroperitoneal dissection. Several modified templates has been proposed to preserve antegrade ejaculation (see the article elsewhere in this issue “The Technique and Evolution of Nerve-Sparing Retroperitoneal Lymphadenectomy”). The mainstay of these nerve-sparing templates is to limit the dissection of the contralateral nodal basin, particularly below the level of inferior mesenteric artery, whereas the interaortocaval nodes are variably resected for left-sided primary tumors. However, as Jewett and Torbey acknowledge of the limitations of modified templates, “all modified dissections introduce a risk of incomplete resection of involved nodes.”

Although modifications to the RPLND template have resulted in reduced morbidity, there is reason to question the adequacy of the anatomic mapping studies of retroperitoneal metastases on which these reduced templates are based. Landmark studies by Ray and colleagues and Donohue and colleagues lack follow-up information, which is a major limitation, as sample error by the surgeon or pathologist cannot be assessed. Without adequate postoperative follow-up the rate of extratemplate recurrence cannot be estimated. Furthermore, it is not possible to accurately determine adequacy of a surgical dissection template, when all patients receive adjuvant chemotherapy. In addition, there is a concern for the potential impact of renal and renovascular anatomic variation on the lymphatic drainage pattern of the testicles, an area of research that has yet to be explored. As such, Eggener and colleagues compared the impact of using 5 modified RPLND templates (Testicular Tumor Study Group [TTSG], Memorial Sloan-Kettering Cancer Center [MSKCC], Indiana, Johns Hopkins University [JHU], Innsbruck) on 500 patients with clinical stage I to IIA NSGCT who underwent primary RPLND at MSKCC. Of the 191 patients with positive nodes, the incidence of extratemplate disease ranged from 3% to 23% depending on the particular node dissection template. For right-sided testicular primary tumors, the most common sites of extratemplate disease were the para-aortic nodes (included in only the MSKCC template) and preaortic nodes (excluded only in the JHU template). Excluding the para-aortic and periaortic nodes would have resulted in unresected disease in 34 (6.8%) patients. For left-sided testicular primary tumors, the most common sites of extratemplate disease were in the interaortocaval regions for those templates which excluded this region (TTSG, Innsbruck). Excluding the interaortocaval nodes for left-sided testicular tumors would have resulted in unresected disease in 23 (4.6%) patients.

Beyond inappropriate reductions in the dissection template, the other main source of retroperitoneal recurrence is lack of expertise or appropriate surgical resolve during the initial RPLND. Recent data suggest that the quality of RPLND is highly correlated with relapse-free survival. Data from Europe, which has largely adopted a model of centralization of health care for complex operations, suggest that patients undergoing RPLND for GCT at higher volume hospitals have significantly improved survival. In the United States, a review of case logs of 8545 urologists certifying between 2003 and 2013 revealed that just 3.4% (290) of urologists logged all the 553 RPLNDs. The median number of RPLNDs logged annually was 1, with just 3 of the 290 urologists performing 23% of all RPLNDs. Three-fourths of urologists logged only a single RPLND. This finding, coupled with data from the American Board of Urology Residency Review Committee, which reports urology residents performed an average of approximately 5 RPLNDs during their 4-year training from 2000 to 2004, and the finding that most recurrences are found within the field of the surgical template, is compelling evidence to suggest that the quality of RPLND may be compromised by inexperienced surgeons.

Analysis of reoperative retroperitoneal series further suggests that surgical technique may play a key role in most retroperitoneal recurrences. In their series, Heidenreich and colleagues noted that a significant proportion of retroperitoneal recurrences were located in the para-aortic and interaortocaval regions. The investigators state that complete resection of this area requires mobilization of the pancreas to expose the cranial aspect of the renal vessels and ligation of the lumbar veins entering the left renal vein, both technically challenging maneuvers. This statement is corroborated by the findings of several studies that identified the left renal hilum and left para-aortic regions as the most common sites of relapse following initial RPLND. Furthermore, Pedrosa and colleagues reported their findings of predictors of retroperitoneal recurrence in 188 patients with unilateral testicular tumors following RPLND. As an indicator of potentially incomplete initial resection, they found incomplete ligation of the lumbar vessels in 56.7% and absent ipsilateral gonadal vein resection in 21.3% of cases at the time of repeat RPLND. Taken together, these studies corroborate the hypothesis that surgical technique during initial RPLND has a significant impact on the rate of retroperitoneal recurrence.

Clearly, the extent of the dissection template will influence the location of possible retroperitoneal recurrences. Pedrosa and colleagues report the Indiana experience of the largest series of reoperative retroperitoneal surgery to date. More than half of their patients had tumors found within the primary landing zone, which should have been resected during the initial RPLND. There were notable differences between the site of recurrence based on the side of the primary testicular tumor. For the 100 patients with primary left-sided testicular tumors who underwent initial RPLND, the most common sites of retroperitoneal recurrence were the periaortic region (53%), followed by the retrocrural (26%), intra-aortocaval (24%), pelvic (19%), suprahilar (17%), and paracaval regions (16%). Of the 88 patients with primary right-sided testicular tumors, the retroperitoneal recurrence site was also most common in the paracaval region (37.5%), followed by the periaortic (35.2%), intra-aortocaval (26.1%), retrocrural (23.8%), pelvic (13.6%), and suprahilar regions (12.5%). These findings correspond with those of the MSKCC series, which found that the left para-aortic and/or hilar region was the most common site of retroperitoneal recurrence (53%). There are 2 reasons for this: as previously noted, this region is often excluded in modified templates for right-sided testicular primary tumors. In addition, the aforementioned technical difficulties of exposure in this region likely contributed to the preponderance of retroperitoneal recurrence within this region. Importantly the investigators from Indiana note that the suprahilar region was the site of recurrence in 12.5% to 17% of cases, a region outside the modern standard RPLND template, and presumably cannot be attributed to surgeon error.

Histologic findings at reoperative retroperitoneal surgery

The histology of retroperitoneal recurrences is an important consideration, as this affects the required therapies and survival. Just as the surgical template will influence the site of potential recurrence, the previous use of chemotherapy before reoperative retroperitoneal surgery will influence the histopathologic findings afterward. The problem in interpretation of the data is that most patients who undergo reoperative retroperitoneal surgery for recurrence will receive chemotherapy before their resection, either between the initial RPLND and the reoperative surgery, or the initial RPLND will be performed in the postchemotherapy setting. In the MSKCC series, 86% of patients who underwent reoperation after a primary RPLND received chemotherapy between operations, and 50% of patients who underwent reoperation after a PC-RPLND received additional chemotherapy between operations. In the Indiana series, 97.5% of patients received chemotherapy before reoperative retroperitoneal surgery.

The most common histologic finding in the reoperative setting is teratoma (or teratoma with malignant transformation [TMT]), which makes intuitive sense given that most reoperative retroperitoneal surgeries are performed following chemotherapy, either before the initial RPLND or following it, and teratoma is considered chemotherapy resistant ( Table 2 ). Although it is a histologically benign entity, the clinical potential of unresected teratoma is unpredictable; it may grow, obstruct, or invade adjacent structures in what has been called growing teratoma syndrome. In addition, teratoma may undergo malignant/somatic transformation with a change to a non-GCT entity (ie, sarcoma or carcinoma). Unresected teratoma is also the main culprit of “late” relapses, defined as occurring after a 2-year disease-free period. The clinical implications of residual teratoma are significant, as it necessitates complete surgical extirpation; however, if mature teratoma is the only histology found in the reoperative surgical specimen, the chances of long-term survival are favorable (see the section on clinical outcomes).

Table 2

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