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Originally published as JCO Early Release 10.1200/JCO.2003.01.094 on October 14 2003 © 2003 American Society for Clinical Oncology Predictors of Occult Metastasis in Clinical Stage I Nonseminoma: A Systematic Review
From the Center for Clinical Decision Sciences, Department of Public Health, Erasmus MC, Rotterdam, The Netherlands; and the Department of Urology, Bonn University, Bonn, Germany. Address reprint requests to Yvonne Vergouwe, PhD, Center for Clinical Decision Sciences, Department of Public Health, Ee20-33, Erasmus MC, PO Box 1738, 3000 DR Rotterdam, The Netherlands; e-mail: y.vergouwe{at}erasmusmc.nl.
Purpose: Patients with clinical stage I nonseminomatous testicular germ cell tumor should ideally receive adjuvant therapy only when they are at high risk for occult metastasis. We aimed to quantify the importance of predictors for occult metastasis by performing a systematic review of the relevant literature. In addition, we reviewed published multivariable models and risk-adapted treatment policies. Patients and Methods: We identified 23 publications between 1979 and 2001, reporting a total of 2,587 patients. Twenty-nine percent of the patients (759 of 2,587 patients) had occult metastases, which was diagnosed either at retroperitoneal lymph node dissection (n = 193) or during follow-up (n = 566). Odds ratios (OR) were pooled using meta-analysis techniques. Results: The presence of vascular invasion of the primary tumor cells had the strongest effect (OR, 5.2; 95% CI, 4.0 to 6.8). Immunohistochemical staining of the primary tumor cells with the MIB-1 monoclonal antibody showing proliferative activity was a promising predictor (OR, 4.7; 95% CI, 2.0 to 11). Intermediate effects were found for embryonal carcinoma in the primary tumor (OR, 2.9; 95% CI, 2.0 to 4.4) and a high pathologic stage of the tumor (OR, 2.6; 95% CI, 1.8 to 3.8). Size of the primary tumor and age of the patient had weaker though also statistically significant associations with occult metastasis. Until now, multivariable models often included vascular invasion and embryonal carcinoma with one or two weaker predictors. None of the published risk-adapted treatment policies included MIB-1 staining. Conclusion: Several strong predictors for occult metastasis were identified. A risk-adapted treatment policy should be developed that incorporates all relevant predictors so that adjuvant therapy is targeted better to those with occult metastases.
MOST PATIENTS with clinical stage I nonseminomatous testicular germ cell tumor (NSGCT) can be cured by orchidectomy alone. Approximately 30% of patients with NSGCT have occult metastatic disease, which can be detected at retroperitoneal lymph node dissection (RPLND) or on surveillance.1–3 Some oncologists consider RPLND as a staging procedure that might be followed by adjuvant chemotherapy if metastases are revealed.4 Others prefer surveillance with chemotherapy administration after detection of relapse.5,6 Both treatment policies have excellent long-term survival rates (98% to 99%), but each approach has important drawbacks. RPLND and chemotherapy can induce morbidity.7 In particular, chemotherapy may have long-term adverse effects.8,9 Conversely, surveillance can lead to detecting relapses at a more advanced disease stage if compliance is poor. Therefore, efforts have been made to select patients at high risk for occult metastasis who can be offered immediate adjuvant treatment.10,11 Additional unnecessary treatment may be avoided in patients at low risk. To distinguish high-risk patients from low-risk patients, many groups studied the associations between tumor and patient characteristics and occult metastasis in clinical stage I NSGCT.2,5,6,12–35 This resulted in a number of well-known predictors, particularly vascular invasion and embryonal carcinoma. Several predictors have been combined in multivariable regression models,17,26,33 and these models underlie risk-adapted treatments. Patients at high or intermediate risk are then offered chemotherapy (often several cycles of bleomycin, etoposide, and cisplatin [BEP]) or RPLND, whereas patients at low risk go on a surveillance protocol without further treatment until relapse.11,36 Several reviews have qualitatively summarized studies on predictors. However, a systematic review is required to quantify the strength of the known predictors more precisely. From the evidence-based literature, systematic reviews have been promoted, which include a comprehensive search for available data and a quantitative summary.37 In addition to a systematic review of predictors for occult metastasis, we reviewed reported multivariable models and proposed risk-adapted treatment policies.
Study Identification We searched the MEDLINE database from 1979 to 2001 to identify all English-language studies on predictors of occult metastasis for clinical stage I NSGCT patients. Search text words were "testicular neoplasms," "neoplasm staging or neoplasm metastasis," and "risk factors or prognosis." Relevant references in articles were also considered. Studies were included if the association between occult metastasis or patient and tumor characteristics was quantified. The clinical staging procedure had to be described and had to contain determination of the serum tumor markers alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) after orchidectomy, and radiologic examination of chest and abdomen.38 If two studies included patients from the same center with overlapping time periods, we included the study with the largest population or with the longest follow-up period. In some cases, both studies were included because different characteristics were studied.
Outcome
Histologic and Clinical Characteristics Vascular invasion was defined as the presence of tumor cells within a well-defined endothelium-lined space. Some studies distinguished venous invasion and lymphatic invasion. If those types were not explicitly mentioned, we assumed that vascular invasion included venous and lymphatic invasion. Most studies classified the tumor histology according to the WHO system: mature teratoma, immature teratoma, embryonal carcinoma, yolk sac tumor, teratocarcinoma, choriocarcinoma, and seminoma.40 Associations with the presence or absence of mature teratoma, embryonal carcinoma, and yolk sac were determined. A pooled estimate could also be determined for the percentage of embryonal carcinoma at a cutoff value of 50%. Furthermore, the British definition of differentiated teratoma was analyzed.41 The pathologic stage of the primary tumor was considered when determined according to the tumor-node-metastasis system classification:42 pT1 was then compared with pT2 to pT4. Size of the primary tumor was dichotomized in all studies. One study used a cutoff value of 3.5 cm,26 whereas the other studies used 3.0 cm.16,19,20,22 Because we could not identify heterogeneity between the studies, they were pooled. Preorchidectomy levels of AFP and HCG were classified as normal or elevated. Patient age was twice dichotomized at a cutoff value of 30 years.20,43 Two other studies used a cutoff value of 29 years.16,22 The results were pooled, given that no heterogeneity was present.
Tumor Proliferative Activity
Multivariable Odds Ratios and Risk-Adapted Treatments In addition, we searched for reports on risk-adapted treatment protocols. We were interested in protocols with only RPLND or cisplatin-based chemotherapy as adjuvant treatment. Reports were included if the outcomes of the protocol were evaluated.
Statistical Analysis We examined whether the predictor effects depended on differences in study characteristics.46 The following characteristics were considered: the treatment (RPLND or surveillance), study perspective (retrospective or prospective), and study size. Study size was used to identify possible publication bias. This bias may be relevant because statistically significant results usually have a greater chance of being published than insignificant results, leading to, on average, greater effect estimates in smaller studies. The heterogeneity of an effect was tested for statistical significance by fitting a weighed linear regression model of ln (study OR) on the study characteristics, for which each study OR was weighed by the reciprocal of its variance. Study size was included in the model as the square root of the total number of patients. If important heterogeneity was found (P < .10), the pooled OR was calculated for each category of the study characteristic.
We included 23 studies (Table 1  ), of which four included more than 150 patients.17,26,33,43 Five studies performed RPLND, 17 studies observed patients until disease relapse, and one study randomly assigned patients to either RPLND or risk-adapted treatment.39 One of the six studies that performed RPLND monitored relapse in PS I patients to find misclassified patients.26 The reported median follow-up times in the studies with surveillance varied between 30 and 139 months. A longer follow-up time did not result in a higher proportion of identified occult metastases (Fig 1). This confirms that follow-up in this study was sufficient to detect occult metastasis. The studies involved 2,587 patients; 193 of 621 patients (31.1%) had PS II disease at RPLND, and 566 of 1,966 patients (28.8%) experienced disease relapse during follow-up. This difference was not statistically significant (P = .27). Overall, the percentage of patients with occult metastasis was 29.3% (759 of 2,587 patients).
Predictors Twenty-one studies reported the effect of vascular invasion. For the other predictors, smaller numbers of studies were available (Table 2 ). The pooled ORs of all three definitions of vascular invasion (venous, lymphatic, and venous or lymphatic) were high (4.7, 5.4, and 5.2, respectively). The presence of differentiated teratoma in the primary tumor strongly decreased the risk of having occult metastasis (pooled OR, 0.13), although the 95% CI was wide (0.02 to 0.85; ie, the absence of differentiated teratoma increased the risk between 1.2 and 50). This predictor was present in only 6% of the patients, which implies that it will not be helpful in identifying the 70% patients without occult metastases. Other predictors indicating the histology of the primary tumor had more moderate effects, such as the presence of embryonal carcinoma (OR, 2.9) and the presence of mature teratoma (OR, 0.48), as did the pathologic stage of the primary tumor (OR, 2.6 for pT2–4 v pT1). A larger primary tumor and older age also increased the risk of occult metastasis. Furthermore, MIB-1 staining of the primary tumor was a promising predictor (OR, 4.7 for > 70% v  70% stained cells). No associations were found for yolk sac histology and serum levels of AFP and HCG before orchidectomy. Both positive and negative effects were found in the individual studies for these characteristics.
Some indication of heterogeneity of effect was found for the pathologic stage of the tumor in relation to the definition of occult metastasis (P = .053). The overall pooled OR was 2.4 (95% CI, 1.7 to 3.5), but the ORs were somewhat higher in studies with RPLND treatment (OR, 4.0; 95% CI, 2.5 to 7.7) and lower in studies where surveillance was the standard procedure (OR, 2.1; 95% CI, 1.4 to 3.4). Several studies reported the mean difference in continuous characteristics between patients with and without occult metastasis. The pooled mean difference was 42% (range of differences, 35% to 49%) for the percentage of primary tumor cells containing embryonal carcinoma24,35,54 and 12% (range of differences, 6.8% to 18%) for the percentage of primary tumor cells staining for MIB-1.35,54,55 The percentages of positive cells were greater in the patients with occult metastasis.
Multivariable ORs
Vascular invasion showed the strongest effect. Two studies, which possibly included some of the same patients,47,54 reported high estimates (OR, 8.2 and 13.5, respectively). The other ORs were approximately 4.0, compared with a pooled univariable OR of 5.2. In eight of the 10 studies, the presence of embryonal carcinoma was used to describe the histology of the primary tumor. In two other studies, absence of teratoma elements was used for this purpose. In none of the models were embryonal carcinoma and teratoma included together.
The percentage of embryonal carcinoma was included linearly47 in one of the four reported models, with an OR of 1.03. This may seem small, but it becomes substantial for higher percentages because the variable was analyzed continuously. A model constructed with reported data24 containing the percentage of embryonal carcinoma and vascular invasion resulted in a similar OR (1.03) for embryonal carcinoma. A model with percentage of embryonal carcinoma categorized ( Several studies reported that embryonal carcinoma and vascular invasion were correlated.53 This is confirmed by the decrease in the ORs for embryonal carcinoma and vascular invasion when estimated together in a multivariable model. However, in most studies the factors remained independent predictors, indicating that the correlation was not high.
The contradictory multivariable estimates for serum AFP level (< 1.026 and > 1.024; Table 3
Risk-Adapted Treatment
Overall, four of the six policies considered at least embryonal carcinoma and vascular invasion. Low-risk patients went on surveillance protocol, and high-risk patients were offered chemotherapy, mainly two courses of BEP. Two studies also defined an intermediate-risk group. Those patients underwent RPLND and subsequent chemotherapy if positive lymph nodes were present. If we combine all results of the treated high-risk patients, irrespective of the differences in definition of high risk, 3% of the patients (seven of 273 patients) experienced relapse after chemotherapy. In contrast, 16% of the low-risk patients (32 of 199 patients) experienced relapse, and 13% of the intermediate-risk patients (14 of 104 patients) experienced relapse after PS I diagnosis, whereas 17% of the intermediate-risk patients (16 of 104 patients) had PS II disease.
We systematically combined evidence on predictors for occult metastasis of NSGCT. We confirmed the strong effect of vascular invasion. The proliferative activity of the primary tumor cells was a promising predictor. Intermediate effects were found for the histology of the primary tumor and the pathologic stage of the primary tumor. Other predictors were size of the primary tumor and age. However, a risk-adapted treatment policy that takes into account at least the three strongest predictors (vascular invasion, proliferative activity of the primary tumor cells, and histology of primary tumor) was not considered. Several definitions were used for the predictors. Therefore, not all publications, though they studied the same underlying phenomenon, could be combined. The meta-analysis showed that all definitions for vascular invasion (venous and lymphatic alone or together) resulted in similar estimates of effect size. This confirms that the distinction between venous and lymphatic vessels does not add information on the risk of occult metastasis. The predictor venous or lymphatic is, therefore, the best one to use. Histologic differences in the primary tumor were initially studied by the presence of embryonal carcinoma and the absence of mature teratoma or differentiated teratoma. In stepwise regression analyses, one of the two predictors was often included. Inclusion of embryonal carcinoma seems to exclude mature teratoma or differentiated teratoma and vice versa.26,47 This was illustrated by a backward stepwise analysis;33 among patients with complete values for all considered predictors (n = 135), mature teratoma was selected together with vascular invasion and preoperative serum level of HCG. The analysis was repeated after omission of the only predictor with missing values; that is, the maximum diameter of the primary tumor. In this analysis (n = 154), embryonal carcinoma was selected instead of mature teratoma, together with vascular invasion. Because the absence of mature teratoma has a weaker association with occult metastasis than the presence of embryonal carcinoma, and differentiated teratoma is not a common definition, embryonal carcinoma is the most accurate predictor for the histology of the primary tumor.
More recently performed studies reported the percentage of embryonal carcinoma in the primary tumor often in two or three categories ( In several tumors, the proliferative activity of the primary tumor is associated with metastatic behavior.64,65 The association of proliferative activity with occult metastasis in NSGCT has been determined with several techniques, such as cytophotometry, flow cytometry, and immunohistochemistry. The first two techniques are time consuming and expensive, whereas immunohistochemistry is rather simple and inexpensive. Examples of immunohistochemical assessments are staining primary tumor cells for proliferating cell nuclear antigen or MIB-1. A high percentage of tumor cells stained for proliferating cell nuclear antigen or MIB-1 was associated with a high risk of occult metastasis.35,66 Combining three studies on MIB-1 showed that more than 70% positive-stained tumor cells was associated with an increased risk of occult metastasis (OR, 4.7).35,39,49 However, the analysis was based on only 212 patients, and the cutoff value of 70% was data driven in two of the three studies. Additional study on this predictor is necessary.
All predictors for occult metastasis were frequently found in clinical stage I patients (Table 2 We found four multivariable models predicting the risk of occult metastasis in the literature. All included histology of the primary tumor and vascular invasion. Characteristics such as serum level of AFP56 and yolk sac in the primary tumor17,36 were considered in several models, but their effects are not important according to our review. These chance findings can be explained by a limited sample size.
We used the reported data of Leibovitch et al57 to estimate the combined effects of embryonal carcinoma and MIB-1 staining. MIB-1, categorized as more than 80% staining versus
As suggested by the risk-adapted treatment policies shown in Table 4
A limitation of the presented meta-analysis is that we combined studies with different definitions for the outcome variable "occult metastasis" (relapse after surveillance and pathologic stage II after RPLND). Moreover, we used the OR as measure of association instead of the statistically more appropriate hazard ratio. Our rationale was that few occult metastases would have been missed in the surveillance studies, given that the follow-up time was often long enough to identify occult metastasis (Fig 1 Another limitation is the lack of a central pathology review, which is impossible in the analysis of published data. This may have caused variation in the interpretation of specific pathologic indices. In conclusion, present models can define a high-risk group with an approximately 50% risk of occult metastasis and low-risk groups with an approximately 16% risk. A model with more variables and that also considers continuous variables (percentage of embryonal carcinoma and MIB-1) may be able to identify patients at higher and lower risks. Such an evidence-based model can then be the basis for improved risk-adapted treatment policies.
The authors indicated no potential conflicts of interest.
We thank S. Horenblas and L.H. Looijenga for critical comments on an earlier version of this article.
Supported by the Netherlands Organization for Scientific Research (Y.V.) and a fellowship from the Royal Netherlands Academy of Arts and Sciences (E.W.).
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
80%) with vascular invasion showed ORs of 2.1 and 8.2 for the categories 46% to 79% and 
D, Hornak M: Orchiectomy alone for clinical stage I nonseminomatous germ cell tumors of the testis (NSGCT): A minimum follow-up period of 5 years. Tumori 80:362–364, 1994
