Imaging

The primary landing site for right-sided tumors is the interaortocaval region, whereas left-sided tumors typically land in the para-aortic region. Although no absolute size cutoff exists to define clinical stage II disease (lymphatic metastases to the retroperitoneum), a 1-cm cut point to identify suspicious lymph nodes lacks sensitivity, because clinical understaging may occur in up to 80% of patients. Evidence suggests that a lower size threshold should be used for lymph nodes in the primary landing zone, and we view lymph nodes 6 mm or larger with a high degree of suspicion, particularly when present in the context of other risk factors. In NSGCT, otherwise healthy and young men rarely have significant retroperitoneal adenopathy at baseline. Therefore, patients presenting with visually detectable lymph nodes within the primary landing zone on abdominal computed tomography (CT), even when smaller than 1.0 cm, should be treated with a high degree of suspicion for metastatic disease. Several investigators have shown that using a cutoff of 4 mm in the primary landing zone and 10 mm outside the primary landing zone was associated with a sensitivity and specificity of pathologic stage (PS) II disease of 91% to 93% and 50% to 58%, respectively.

Nevertheless, accurate clinical staging is an imperfect science, as exemplified by the fact that even with the latest imaging technology and risk-stratification techniques, patients with a pristine CT scan of the abdomen and pelvis are understaged up to 20% to 30% of the time and are at risk for relapse. In an attempt to improve rates of understaging, fluorodeoxyglucose (FDG) positron emission tomography (PET) has been investigated as a primary staging tool in patients with newly diagnosed, low-stage (I-II) NSGCT. Although the positive predictive value exceeds 90%, the negative predictive value of FDG-PET is similar to CT, at 67% to 78%. Because teratoma is not FDG-avid, a negative PET result fares no better than CT at ruling out occult retroperitoneal metastatic disease, even when considering malignant GCT elements such as embryonal carcinoma (EC), yolk sac tumor, and choriocarcinoma. Therefore, FDG-PET cannot be recommended as a staging tool for NSGCT.

Histopathologic Risk Factors

Previous work has focused on histopathologic risk factors associated with the presence of occult retroperitoneal disease. Two histologic features in the primary tumor have consistently been shown to confer a greater risk of occult metastatic disease:

• 1.
  

  Lymphovascular invasion (LVI)

  
  
• 2.
  

  Percentage of EC

Other, less reliable predictors of occult metastases include high (T3/T4) histopathologic stage of the primary tumor and MIB-1 staining.

Impressively, 1 series showed that patients with LVI in the primary tumor carry a 48% chance of relapse, whereas those without LVI have a 14% to 22% chance of relapsing. In a series of 267 patients with CSI-IIA NSGCT and who underwent retroperitoneal lymph node dissection (RPLND), the presence of EC predominance and LVI in the primary tumor was associated with a higher rate of PSII disease (54% vs 37%, P = .009).

Therefore, previous consensus meetings have recommended the use of LVI in the primary specimen to risk stratify patients. Meanwhile, the definition of EC predominance is not clearly defined, ranging from 45% to 90%. In addition, presence of occult metastases in patients with CSI NSGCT with LVI and EC predominance varies widely, from 45% to 90% and 30% to 80%, respectively, and underscores the lack of reliability of these characteristics in accurately predicting patients at higher risk of retroperitoneal relapse.

Although contemporary studies have confirmed the prognostic significance of LVI for occult metastatic disease in CSI NSGCT, the rate of metastases in these studies seems to be substantially lower (≤30%–50% relative decrease) compared with the early studies from the 1980s and 1990s analyzing LVI. For example, in a population-based study of patients with LVI on surveillance in the SWENOTECA (Swedish and Norwegian Testicular Cancer Group) study, Tandstad and colleagues reported a probability of relapse of 45%. Likewise, in a study of unselected surveillance patients from Princess Margaret Hospital, Sturgeon and colleagues reported a 49% relapse rate for those with pure EC and LVI. The reason for the lower than expected relapse rate for these patients may be related to stage migration, improved clinical staging, or differences in the pathologic assessment of LVI over time. Thus, when counseling patients about treatment options for CSI NSGCT, urologists should endeavor to counsel patients about the probability of occult disease rather than simply identifying patients as high or low risk from LVI or EC predominance.

Active Surveillance

Data accumulated over many decades have revealed that surveillance for CSI NSGCT achieves long-term survival outcomes that are comparable with adjuvant chemotherapy and RPLND. Although identifying patients at high risk of relapse remains challenging, overall surveillance relapse rates have been consistently reported in the 20% to 30% range. Although most relapses typically occur within 2 years, late relapses beyond 5 years have been documented in approximately 1% to 5% of cases.

Table 1 summarizes the largest trials of active surveillance (AS) to date.

The rationale for surveillance is based on the fact that 70% to 80% of patients are cured by orchiectomy, whereas adjuvant chemotherapy and RPLND are both associated with defined rates of important short-term and long-term toxicity. However, the series presented in Table 1 represent cohorts of mainly low-risk patients. As discussed previously, relapse rates in patients with high-risk features typically exceed 30%, and it is in this subset of patients in whom the rationale for surveillance is less robust. Nevertheless, both low-risk and high-risk patients who relapse on surveillance are cured of their disease in most cases. Thus, surveillance reserves treatments (and potential treatment-related morbidity) to those who need it. Therefore, AS for CSI NSGCT is an attractive strategy and we believe that it should be considered the standard of care in this patient population, regardless of risk factors.

Although there is no validated method of performing surveillance, most protocols involve frequent monitoring in years 1 to 2 with clinical assessment, STM (β human chorionic gonadotropin, α-fetoprotein, and lactate dehydrogenase) determinations, chest imaging, and transaxial abdominal-pelvic imaging. Beyond 2 years, the frequency of these tests is lessened. The low (0.5%–1.0%) but defined risk of relapse beyond 5 years mandates long-term surveillance. For patients with CSIA testicular cancer enrolled in AS, the National Comprehensive Cancer Network (NCCN) guidelines recommend a history, physical examination, and STMs every 2 months in the first year, every 3 months in year 2, every 4 to 6 months in year 3, every 6 months in year 4, and annually thereafter. Abdominal/pelvic CT imaging should be performed every 4 to 6 months in the first year, every 6 to 12 months in year 2, and annually thereafter. Chest radiographs should be performed at months 4 and 12, and annually thereafter. For CSIB patients, the NCCN guidelines recommend a similar surveillance strategy to stage IA, except with an increased frequency of abdominal/pelvic CT imaging and chest radiographs: abdominal/pelvic CT every 4 months in the first year, every 4 to 6 months in year 2, every 6 months in year 3, and annually thereafter, and chest radiographs every 2 months in the first year, every 3 months in year 2, every 4 to 6 months in year 3, every 6 months in year 4, and annually thereafter.

In addition to the NCCN guidelines, other published data on surveillance imaging protocols call for up to 4 to 7 CT scans within the first 2 years after enrollment. Accordingly, the frequent use of CT imaging on surveillance has come under scrutiny because of the association of secondary malignancies with numerous abdominopelvic CT scans and the associated cumulative radiation exposure; the safety threshold seems to be crossed when an individual has received 7 lifetime CT scans. A recent randomized trial of 2 versus 5 CT scans in years 1 to 2 among CSI NSGCT patients on surveillance reported no differences in the relapse rate, the IGCCCG (International Germ Cell Cancer Collaborative Group) risk group at relapse, or treatment required for relapsing patients, with no differences in survival between the 2 arms. Although there were relatively few patients with LVI randomized in this trial, it seems that 2 CT scans in years 1 to 2 on surveillance is safe and effective for a low-risk cohort of patients. With improving technology, low-dose, single-phase CT scanners are becoming increasingly used and show acceptable diagnostic accuracy. Although there is no absolute safe radiation threshold, low-dose scanners may allow for a greater number of abdominopelvic CT scans in high-risk patients and do not necessarily increase the long-term risk of radiation-induced secondary malignancies.

The surveillance protocol used at our institution has been previously reported. Clinical assessment, chest radiograph, and STM measurements are performed every 3 months during the first year, every 4 months in year 2, every 6 months in year 3 to 5, and annually thereafter. We perform low-dose, single-phase CT abdominal-pelvis imaging at 3, 12, 24, and 60 months in otherwise asymptomatic patients with normal STMs. Other investigators have also shown the safety and reliability of low-dose, noncontrast CT imaging and magnetic resonance imaging to survey the retroperitoneum when read by experienced radiologists and clinicians.

Many urologists stipulate that a reliable patient is a prerequisite for AS, and reports of nonadherence to follow-up have been reported. Although it is true that frequent physician visits, along with serum markers, chest radiographs, and abdominopelvic CT imaging are the cornerstones of a surveillance protocol, patients who are lost to follow-up typically present to hospital once symptomatic relapse occurs. In these rare cases, reports of sustainable remission with either chemotherapy or RPLND have been achieved. Thus, although anticipated compliance should be considered when choosing/recommending treatments, anticipated noncompliance should not be the principal reason to deny a patient surveillance. Despite high rates of noncompliance with surveillance protocols, long-term cure rates approach 100%, suggesting that available treatments are able to salvage even those patients who are noncompliant with surveillance and who relapse with advanced disease. Thus, little rationale exists for excluding these patients from surveillance.

In general, remote location or inability to access physicians/hospitals with expertise in GCT management is a relative contraindication to surveillance, and these patients may best be served by either chemotherapy or RPLND.

The emotional stress and anxiety accompanying the chance of relapse while on surveillance must be balanced against the physical stress and morbidity of either chemotherapy or RPLND. Quality-adjusted survival models have been developed in an attempt to comprehend the patient’s decision-making process when considering cancer outcomes, morbidity, and patient preferences for AS, chemotherapy, and RPLND, and have found that in all scenarios, patients prefer AS to chemotherapy or RPLND, except when the risk of recurrence is greater than 33% to 37%. The predominance of an aversion to the emotional stress associated with AS in a high-risk group may sway the patient toward chemotherapy or RPLND.

For those who relapse on surveillance, the standard approach has been to administer risk-appropriate chemotherapy to all patients regardless of clinical stage and marker status at relapse. In these instances, long-term cure rates approach 100%. We and others have advocated that similar treatments should be offered to similarly staged patients with metastatic NSGCT at diagnosis. Although chemotherapy is the preferred salvage treatment of those who relapse with increased markers or CSIIC-III, select patients with normal STMs and nonbulky retroperitoneal disease (<3 cm) may also be considered for RPLND as the primary intervention. In general, relapses treated with chemotherapy should be risk adapted according to IGCCCG risk group.

Retroperitoneal Lymph Node Dissection

Subclinical metastatic disease in CSI NSGCT is the principal cause of early relapse and is present in approximately 20% to 30% of patients with this clinical stage. In those with occult metastases, malignant GCTs (which may later transform into teratomatous elements at metastatic sites) are usually located in the retroperitoneum ± systemic sites. Metastatic GCT that bypasses the retroperitoneum is an uncommon event, whereas teratoma, when present, is virtually always localized to the retroperitoneum. Therefore, an adjuvant treatment that effectively removes occult metastases (including teratoma) in the retroperitoneum is an ideal choice for those patients in whom surveillance is not the preferred route.

RPLND for CSI NSGCT should be considered for the following reasons:

• 1.
  

  Systemic disease is rare.

  
  
• 2.
  

  Teratoma is chemoresistant and is identified in 15% to 25% of patients with occult PSII disease.

  
  
• 3.
  

  After full, bilateral template RPLND, the risk of abdominopelvic relapse is as low as 2%, thus obviating routine surveillance transaxial imaging of the retroperitoneum, postoperatively.

  
  
• 4.
  

  Patients who relapse after RPLND can be effectively salvaged with chemotherapy.

  
  
• 5.
  

  In patients with pN1 disease, cure rates after RPLND exceed 75%.

  
  
• 6.
  

  In patients with pN2 disease and greater, adjuvant chemotherapy cures virtually 100% of patients.

  
  
• 7.
  

  RPLND is a safe, well-tolerated surgery, with minimal short-term and long-term morbidity, when performed by experienced surgeons at high-volume centers.

  
  
• 8.
  

  RPLND offers the most complete and accurate staging method for the retroperitoneum.

  
  
• 9.
  

  Given the low relapse rates after RPLND alone for patients with PSI (pN0, <5%–10%) and pN1 (<10%–20%), RPLND is associated with the lowest use of chemotherapy (and its associated short-term and long-term toxicity) among the 3 treatment options.

Long-term recurrence after primary RPLND is exceedingly rare, ranging from 1% to 2% beyond 2 years. Predictors of occult metastatic disease and early recurrence are less robust predictors of late recurrence.

In addition to removal of the ipsilateral spermatic cord, a full, bilateral template dissection involves removal of all lymphatic tissue between the boundaries of the renal arteries at the cephalad extent, the ureters laterally, and the crossing of the ureters over the common iliac arteries at the caudal extent, including removal of all lymphatic tissue in the retroaortic and retrocaval locations. Without preservation of the sympathetic trunks, the postganglionic nerves from T10 to L2, and the hypogastric plexus, virtually all patients have ejaculatory dysfunction. To minimize this risk, several modified templates have been proposed to limit contralateral dissection lateral to either the aorta (right-sided templates) or inferior vena cava (left-sided templates) to spare these nerves. When modified templates are used, ejaculation rates up to 75% have been reported. With the development of nerve-sparing techniques that endeavor to dissect the postganglionic sympathetic fibers and hypogastric plexus from the surrounding lymphatic tissue, ejaculation rates of 95% or greater have been reported. Thus, nerve-sparing techniques have obviated modified templates and many centers routinely perform a full, bilateral, nerve-sparing dissection on all patients. If modified templates are performed, they should exclude contralateral dissection only below the inferior mesenteric artery, because lesser templates risk leaving malignant GCT or teratoma behind in up to 25% of patients. Although primary, bilateral template RPLND obviates frequent follow-up abdominopelvic imaging, the risk of recurrence with a modified template RPLND is sufficiently high to require follow-up CT imaging, thus negating one of the principle benefits of RPLND over surveillance. Experts agree that a full, bilateral template, nerve-sparing RPLND is the optimal approach when a surgical avenue is chosen over chemotherapy or surveillance.

Table 2 summarizes the largest reported series of primary RPLND to date.

Table 2

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