The most important prognostic factor for germ-cell
tumors of the testis is the tumor stage. The presence of
lymphoid infiltration suggests a good prognosis in clear
granulomatous reaction seminomas [
1]. Mitotic activity is
not a valid measure in seminoma prognosis. In NSGCTs,
on the other hand, prognostic factors include vascular
invasion and extratesticular pathology, lymph-node involvement,
tumor components, the presence of EC and CC
(particularly within the tumor), and high S-phase and proliferation indicators in flow cytometry [
1,
4-
8,
10,
22-
24]. Pathology reports in testicular tumors must include
the status of the tumor in the testis, extratesticular pathology,
the presence of lymphovascular invasion, and the ratios of
tumor subtypes.
p53 gene mutation has been demonstrated in a number
of human tumors, including testicular tumors [2-9,15].
Lewis et al. [4] demonstrated p53 protein expression at a
rate of 90% in seminomas, and of 94% in NSGCTs. In this
study, p53 mutation was shown in 100% of CSI seminomas,
and 98% of CSI NSGCTs, and as the clinical stage progressed,
the p53 overexpression percentage decreased,
more markedly in seminomas (50% in clinical stage III
seminomas, 88% in clinical stage III NSGCTs) [4]. p53
expression was observed in all components in NSGCTs,
but a strong correlation with clinical stage was observed
in ECs. In this study, it was asserted that VI and the
intratumor EC ratio were more useful clinical parameters
for prognosis [4]. In a study by Eid et al. (8), p53 expression
was observed in all tumors except differentiated teratomas
in 77 untreated GCTs, and the strongest p53 expression
was determined in seminomas and ECs. Moreover, a negative
correlation was observed between clinical stage and
p53 expression. In this study, a positive correlation was
determined between p53 expression and response to treatment;
nonetheless, in another study by Eid et al. [9], no
correlation was determined by multidrug-resistanceassociated
protein (MRP) between metastatic behavior and
p53 expressions. In contrast, p53 and Ki-67 expression
were not found to be of prognostic significance in Heidenreich
et al.'s [22] 149 NSGCT cases. According to our
results, p53 is not a useful marker to discriminate pathologic
stages. Similar to our results, DeRiese et al. [24] in their
study found similar p53 expression in both stage I and
stage II tumors. On the other hand, p53 protein overexpression is shown in most testicular tumors but mutations are
rare [25]. In our study, no significant correlation was
determined between p53 expression and necrosis or VI.
In a study on 76 stage-A germ-cell tumors without
lymph-node metastasis, Albers et al. [17] found that Ki-67
was a good prognostic parameter, and that it could be used
even to classify patients with low metastatic risk. However,
in patients with a risk so high as to be clinically demonstrable,
no valid classification has been achieved by assessment
of tumor-cell proliferation [17]. In Heidenreich et
al.’s studies [22,23], Ki-67 expression did not correlate
with pathological stage in CSI, NSGCTs. In these studies,
the presence of VI and the intratumor EC ratio were determined
as significant risk factors for occult nodal disease
and prognosis [22,23].
In our study, the correlation between pathologic stage
and Ki-67 expression was found to be significant (p<0.05).
While the Ki-67 correlation was stronger between stages
1 and 2 and stages 1 and 3 in seminomas, significant
differences in Ki-67 expression were observed at all stages
in NSGCTs. These results suggest that Ki-67 is not useful
in discriminating between advanced stages in seminomas.
Nonetheless, Ki-67 expression appears to be an important
indicator in discriminating between stages in NSGCTs,
while p53 expression is not a good indicator in advanced
stages. In NSGCTs, the positive correlation between vascular
invasion and Ki-67 staining intensity suggests that Ki-67’s
correlation in pathologic staging is no coincidence.
Fas receptor and Fas ligand can be shown immunohistochemically
in normal and tumoral tissues, including the
testes [18,19]. Fas-Fas ligand expression has been determined
in Leydig, Sertoli, and germ cells in the testis.
Sugihara et al. [18] obtained positive staining immunohistochemically
in 23 seminomas, 8 ECS and 3 YSTs with
the Fas-Fas ligand, and they found a single major band
heavier than 47.5 kilodaltons, to which antibodies were
bound for Fas and Fas ligand. These researchers asserted
that the Fas system had a role other than signal producing for apoptosis in testicular tumors. Braenstrup et al. [19]
did not determine Fas-fas ligand secretion in invasive
testicular tumors, but they did demonstrate its presence in
normal seminiferous tubules and occasionally in carcinoma
in situ (CIS) areas. We observed Fas expression in intratumoral
lymphocytes in normal seminiferous tubules, Leydig
cells, and teratomas, and ECs. We observed that immunoreactivity
with Fas is generally weak and there is a low
number of cells. In NSGCTs, although a significant correlation
was determined between stage and Fas expression
in tumor cells, the scattered and weak Fas expression was
not considered to be a good indicator in the staging of
testicular tumors.
Wishnow et al [24] were first to do a quantitative
analysis of the percentage of EC and in their study, it was
reported that percentage of EC was an important prognostic
factor for relapse. The studies of Lewis et al. [4] and
Heidenreich et al. [10,22,23] have also suggested this result.
In contrast, in one of the largest studies of prognostic factors
in CSI, NSGCT, Klepp et al. [27] did not confirm the
importance of EC. In our study, significant correlations
were found between EC% and pathological stage, VI and
necrosis. But, we could not determine the correlation
between EC% and p53, Ki-67 and Fas expressions.
In conclusion, the high p53 expression in germ-cell
tumors, especially in CIS and at low pathologic stages,
supports the idea that p53 mutation in these tumors occurs
at the early stages. Correlation between pathologic stage,
VI and Ki-67 in NSGCTs suggest that Ki-67 plays a role
at all stages of tumorogenesis and that it could be used as
an auxiliary to other parameters in tumor prognosis. However,
in the evaluation of apoptosis in germ-cell tumors,
we think that, besides immunohistochemical findings, more
advanced techniques would be more specific and enlightening.
We recommend that in orchiectomy specimens of
all patients with CSI, NSGCT evaluated for EC% and the
presence of VI to determine their risk for occult retroperitoneal
metastasis.
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