Risk assessment

Considerable attention has been devoted to identifying clinical and pathologic parameters associated with the presence of occult metastasis in the retroperitoneum or at distant sites to better select patients for additional therapy after orchiectomy. The retroperitoneum continues to be the most difficult area to stage clinically and a consistent 25% to 35% rate of clinical under-staging has been reported over the last 4 decades for CS I NSGCT despite the advent of third- and fourth-generation computed tomography (CT) scanners. In contrast, pulmonary metastases 5 mm in size are easily identified by contemporary imaging modalities. There is no consensus regarding size criteria for retroperitoneal lymph nodes that constitute a "normal" abdominal CT scan. A size cutoff of 10 mm is frequently used to identify enlarged lymph nodes, but false-negative rates up to 63% have been reported when this size criterion is used.

An understanding of the primary drainage sites for left- and right-sided tumors has led to efforts to increase the sensitivity of abdominal CT imaging by decreasing the size criteria for clinically positive lymph nodes in the primary landing zone and size criterion as small as 4 mm have been proposed. Leibovitch and colleagues [3] showed that using a size cutoff of 4 mm in the primary landing zone and 10 mm outside this region was associated with a sensitivity and specificity for pathologic stage II disease of 91% and 50%, respectively. in a similar study, Hilton and colleagues [4] reported a sensitivity and specificity of 93% and 58%, respectively, using a cutoff of 4 mm for lymph nodes in the primary landing zone that were anterior to a horizontal line bisecting the aorta. Based on this evidence, patients who have retroperitoneal lymph nodes greater than 4 mm in the primary landing zone, particularly if they are anterior to the great vessels on transaxial CT images, should be considered for additional therapy after orchiectomy given the high probability of regional metastasis. of note, investigations of positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) in the staging of patients who have low-stage NSGCT have been disappointing and there is currently no role for FDG-PET in the routine staging of CS I NSGCT.

The most commonly reported risk factors for occult metastasis are the presence of lymphovas-cular invasion (LVI) and a predominant component of embryonal carcinoma (EC). The definition of EC predominance in the literature varies from 45% to 90%. The reported rate of relapse or pathologic stage II for patients who have LVI and EC predominance varies from 50% to 90% and 30% to 80%, respectively [5-14]. In the absence of these two risk factors, the reported rate of occult metastasis is less than 20%. Other identified risk factors include advanced pT stage, absence of mature teratoma, absence of yolk sac tumor, presence of EC, percentage of MIB-1 staining, increasing primary tumor size, and older patient age. In a pooled analysis of 23 studies assessing predictors of occult metastasis in CS I NSGCT, Vergouwe and colleagues [14] identified LVI (odds ratio [OR] 5.2), MIB-1 staining greater than 70% (OR 4.7), and EC predominance (OR 2.8) as the strongest predictors, and these factors were present in 36%, 55%, and 51% of CS I patients, respectively.

Numerous risk groups and prognostic indices have been proposed based on the presence or absence of several of these risk factors, most commonly on the basis of LVI and EC predominance. These risk stratification schemes classify patients as low, intermediate, or high risk based on the presence of none, some, or all of these parameters. A summary of these risk stratification tools is listed in Table 1 [15]. These risk stratification tools are most useful for predicting a low risk for occult metastasis to identify patients who are optimal candidates for surveillance. Between 18% and 64% of patients are classified as low-risk in these series and the metastasis rate for these patients is less than 20% in all reported series (range, 0% to 19%).

The usefulness of these tools to guide treatment decisions in patients who have intermediate-and high-risk features is less clear. In most of the models in which 25% or more of patients are identified as high risk, the reported relapse rate ranges from 48% to 64%. Mandating treatment for all high-risk patients would expose 36% to 52% of patients to potential treatment-related toxicity unnecessarily. Some models predict a risk for relapse greater than 70% for patients who have adverse features, although often only a small proportion of patients (<10%) are classified as such. The usefulness of these models for intermediate-risk patients is even less clear. In general, between 30% and 50% of patients are classified as intermediate risk on the basis of one or two risk factors, and the reported occult metastasis rate ranges from 23% to 48%.

Caution must be exercised when using these models to guide treatment decisions for the individual patient, particularly if he is classified as intermediate or high risk. Data from prospective studies of patients staged and evaluated in a standardized and rigorous fashion are needed to develop optimal prediction tools for CS I NSGCT and they must be based on all potentially important variables. External validation of these

Table 1

Summary of published risk stratification models for occult metastasis in clinical stage I nonseminomatous germ cell testicular cancer and the proportion of patients classified as low, intermediate, and high risk

Table 1

Summary of published risk stratification models for occult metastasis in clinical stage I nonseminomatous germ cell testicular cancer and the proportion of patients classified as low, intermediate, and high risk

Low risk

Intermediate risk

High risk

Mets

Cohort

Mets

Cohort

Mets

Cohort

Features

(%)

(%)

Features

(%)

(%)

Features

(%)

(%)

Albers

No LVI, EC

19

18

53

LVI, EC

64

29

et al [5]

<50%, MIB <70%

>50%, MIB >70%

Alexandre

No LVI,

0

31

LVI or no

29

39

LVI, no

61

26

et al [6]

teratoma

teratoma

teratoma

Freedman

0-1 of LI,

9

38

2 risk factors

24

38

3-4 risk factors

58

24

et al [47]

VI, EC, or no YS

Heidenreich

No LVI,

8

48

LVI or EC

48

18

LVI, EC

91

38

et al [7]

EC <45%

>45%

>45%

Hermans

No LVI,

16

31

LVI or EC

29

37

LVI, EC

62

33

et al [8]

EC < 50%

>50%

> 50%

Leibovitch

EC volume,

2

45

EC volume,

88

55

LN size

MIB-1, LN size

Nicolai

No LVI,

14

54

LVI or EC

30

32

LVI, EC

48

14

et al [9]

EC < 90%

>90%

>90%

Read

0-1 of LI,

17

39

2 risk factors

23

39

3-4 risk factors

48

23

et al [46]

VI, EC, or no YS

Sogani

No LVI,

12

64

LVI or EC

44

30

LVI, EC

71

7

et al [11]

EC < 50%

> 50%

> 50%

Stephenson

No LVI,

35

LVI or EC

47

45

LVI, EC

63

20

et al [12]

EC < 50%

>50%

> 50%

Abbreviations: EC, embryonal carcinoma; LI, lymphatic invasion; LN, lymph node; LVI, lymphovascular invasion; Mets, regional or distant metastasis; VI, vascular invasion; YS, yolk sac.

Abbreviations: EC, embryonal carcinoma; LI, lymphatic invasion; LN, lymph node; LVI, lymphovascular invasion; Mets, regional or distant metastasis; VI, vascular invasion; YS, yolk sac.

models in independent cohorts is essential to reliably assess their anticipated performance in future patients.

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