Introduction
It is estimated that in 1996, there will be 6,600 new cases of
testicular cancer in the United State and 63% of these will be
clinically localized at initial diagnosis.[1] If half of the new
cases are nonseminomas, approximately 2,050 cases of clinical
stage I nonseminomatous germ-cell tumor (NSGCT) will be diagnosed.
Major controversy persists over the care of these patients. Inexact
staging does not permit true stage I disease, ie, that confined
to the testis, to be distinguished from occult stage II/III retroperitoneal
or distant disease.[2] Because up to 30% of men will have occult
retroperitoneal disease that is not appreciated on initial staging
studies, the standard of care in the United States continues to
be orchiectomy followed by retroperitoneal lymph node dissection
(RPLND) rather than by surveillance (observation).[3] Based on
the numbers above, some might argue that over 1,400 patients (2,050
× .7) per year are being subjected to an unnecessary major
abdominal procedure. In fact, this has been the major argument
given by those who favor surveillance as initial treatment for
clinical stage I NSGCT.[4]
Prognostic factors for testicular cancer patients have only become
relevant over the last 20 years with the advent of cisplatin (Platinol)-based
curative chemotherapy. Prior to this, the majority of patients
died, and the value of prognostic markers was moot.
Over the last decade a number of primary tumor prognostic factors
have been discovered that may be useful in stratifying clinical
stage I patients as to their likelihood of harboring occult disease.
Clinical use of these markers may help identify which patients
are best managed by RPLND as opposed to observation or even primary
chemotherapy. Use of these markers to guide therapy, termed "risk-adaptive"
management, may allow for a more rational scientifically based
decision in favor of RPLND or surveillance for individual patients.
The following sections will examine the value of individual histologic,
clinical, and molecular and proliferative prognostic factors for
stratifying the clinical stage I patient.
Histologic Factors
Vascular Invasion
The utility of vascular invasion (VI) as a prognostic marker in
clinical stage I NSGCT was first recognized in a 1983 surveillance
study by Peckham et al. These authors noted that 6 of 8 patients
who had VI and/or lymphatic invasion (LI) relapsed, as compared
with only 5 of 19 patients without these features.[5] However,
not all early studies recognized the importance of VI. For example,
in another study of 1,058 testicular cancer patients examined
for prognostic factors in 1984, no mention of VI was made.[6]
With studies conducted in the mid-1980s, however, the potential
importance of VI became more obvious.[7-10] The studies by Fugime
et al[7] and Moriyama et al[8] were limited by small numbers of
patients, the inclusion of all stages of disease, and the failure
to perform multivariate analysis. Javadpour and Young studied
165 NSGCT patients for prognostic factors and found VI to be correlated
with clinical stage I staging error and recurrence after negative
RPLND.[9]
The main problem with these early studies, which still plagues
some studies performed recently, is the failure to clearly define
what constitutes VI. Some investigators have found it difficult
to differentiate blood vessel from lymph vessel invasion[7-11]
or simply failed to specify exactly what was included as VI.[12]
Multivariate and Surveillance Studies--Studies conducted
in the late 1980s shed more light on the subject by carefully
defining vascular and lymphatic invasion and by performing multivariate
analyses on prognostic factors.[13-19] Hoskin et al were the first
to carefully define VI as tumor within a luminal space lined by
endothelium and containing a smooth muscle wall; LI was tumor
in an endothelial-lined space but without a smooth muscle wall.[13]
These investigators also were the first to carry out multivariate
analysis.[13] In their multivariate prognostic factor study of
clinical stage I nonseminomas, Dunphy et al even provided a photomicrograph
to demonstrate the difference between VI and LI.[15]
Table 1 summarizes those factors proven by multivariate statistical
testing to have prognostic importance in clinical stage I NSGCT.
Both Hoskin et al[13] and Dunphy et al[15] did not find VI to
be significant on multivariate analysis; however, LI was felt
to be important. In the multivariate analysis of Freedman et al,
both VI and LI maintained significance.[14] These three studies[13-15]
used relapse on a surveillance protocol as an end point of the
prognostic capability of VI.
In contrast, Fung et al[16] and Moul et al[19] used pathologic
stage II disease at RPLND or later recurrence as end points, and
noted that VI alone, but not LI, remained significant by multivariate
testing. The largest study (279 patients) by Klepp et al, which
also used positive RPLND and/or recurrence after RPLND as end
points, did not examine VI and LI individually. However, both
variables analyzed together were predictive in their multivariate
analysis.[17]
Table 2 lists surveillance studies that have commented on factors
predictive of recurrence. Some studies evaluated VI and LI individually,
whereas others combined VI and LI. Most of these surveillance
studies did find VI to be important.
Prospective Study--From the preceding discussion, it is
clear that VI is an exceedingly important prognostic factor in
clinical stage I nonseminoma with regard to predicting both recurrence
on surveillance and occult disease found at RPLND. A study by
Pont et al prospectively utilized VI to stratify patients between
surveillance and primary chemotherapy.[20] When this single prognostic
factor was used, relapses occurred in only 3 (7.5%) of 40 patients,
1 in the surveillance arm and 2 in the chemotherapy arm.
These authors were very careful in defining VI as: "(1) compact
aggregation of tumor cells within the lumen similar to or associated
with a thrombotic occlusion and/or (2) definite endothelial destruction
by tumor invasion. Isolated tumor cells or tumor cell aggregation
in the vascular space without actual attachment to the wall cannot
be accepted for vascular invasion, since they are possibly artifacts
resulting from specimen processing. Lymphatic invasion is not
evaluated since to our pathologists it appears impossible to define
invasion into lymphatic spaces on a histological basis without
misinterpreting artifacts."[20]
Areas of Controversy--Despite the critical importance of
VI, there is still controversy, particularly over the use of VI
alone, LI alone, the combination of VI and LI, and even, as Pont
et al[20] noted, the validity of diagnosing LI. Since the average
small- or medium-sized hospital does not see an abundance of testicular
cancer cases, and even many medical centers are hampered by a
similar problem, it is essential to have an experienced reference
pathologist review these cases.[21] This point is illustrated
in the Testicular Cancer Intergroup Study.[22] The central laboratory
detected VI in 179 (43%) of 414 specimens, whereas the local pathologist
found VI in only 59 (14%) of 414 specimens. There were even more
striking differences in recurrence rates comparing VI determined
by local vs reference pathologists. When VI was assessed locally,
recurrence rates were 35% and 19% in patients with and without
VI. In contrast, these rates were 40% and 8%, respectively, when
VI was assessed by the reference pathologist.[22]
Because of differences in the definition of VI and the ability
to detect it, Stephenson has pointed out that VI rates vary between
16% to 53% even among institutions that care for significant numbers
of testicular cancer patients.[23] These data further emphasize
the need for an experienced reference pathologist to examine all
testicular cancer orchiectomy specimens for VI.
Neovascularization--A related concept to VI, neovascularization,
has recently been described as a prognostic marker in clinical
stage I NSGCT.[24] When factor VIII staining was used to determine
microvascular counts in 65 patients with clinical stage I disease,
none of the patients with pathologic stage I disease had microvessel
counts > 400 per high power field. Neovascularization did not
remain a significant predictor of occult disease in multivariate
analysis, however. Further prospective work with larger numbers
of patients is needed to determine whether this prognostic marker
has clinical value.
