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CANCER January 1, 1998 / Volume 82 / Number 1
Gray Gy, given 2 – 5 mm beyond the prostate capsule.’’ 1
This claim cannot go unchallenged. There was no
information provided in their article that could support their claim that the minimum dose to the target
volume was 160 Gy consistently, or that it was 160 Gy
even in one patient of the 126 treated. Furthermore,
to my knowledge, they have never published even one
example of a patient whose target volume was shown
to be as they defined, with the isodoses superimposed
to demonstrate coverage by the 160-Gy isodose. Information regarding the minimum target dose is crucial
to judge the efficacy of their technique for irradiation
of the prostate. For example, Ragde et al. reported that
23 of 126 patients manifested tumor progression, but
provided no information regarding what the minimum
target dose was in those 23 patients in comparison
with the 103 who did not manifest tumor progression.
A clarification would be greatly appreciated.
Ragde H, Blasko JC, Grimm PD, Kenny GM, Sylvester JE,
Hoak DC, et al. Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 1997;80:442–53.
Bhadrasain Vikram, M.D.
Department of Radiation Oncology
Montefiore Medical Center and
Albert Einstein College of Medicine
Bronx, New York
Prognostic Risk Factors in Low
Stage Testicular Germ Cell Tumors
Unanswered Questions Regarding
Clinically Useful Prognosticators for
Extratesticular Disease
he counterpoint by Heidenreich et al.1 and the article by Albers et al.2 address the issue of prognostic
risk factors in patients with low stage testicular germ
cell tumors. Both groups agree that new factors should
provide independent prognostic information compared with recognized risk factors and that prospective
validation of new markers predicting the risk of occult
metastasis is needed. The latter point deserves emphasis because both current staging methods and tumor
marker analysis by histopathology and immunohistochemistry inherently are subjective and variable.
The literature is replete with new risk factors identi-
/ 7b9a$$0993
12-17-97 20:46:48
fied on the basis of retrospective analysis that either
have not been validated or fail to fulfill their promise of
segregating populations at risk when they are applied in
rigorous prospective studies.3 For example, retrospective
analysis of our own long term study of 105 Stage I testicular tumor patients on surveillance shows that both vascular space invasion within the primary testicular tumor
and embryonal carcinoma histology significantly predict
the probability of recurrence compared with patients
who do not have these risk factors.4 Conversely, a prospective study in 76 unselected Stage I testicular tumor
patients undergoing retroperitoneal lymph node dissection only shows a trend in favor of vascular invasion
predicting the risk of occult metastasis (48% of patients
with and 33% without vascular invasion had microscopic
lymph node metastasis; P Å 0.24).5 Furthermore,
‘‘newer’’ prognostic factors must be balanced against
improvements in conventional staging methods. For example, two studies5,6 show that revised computed tomography interpretation of retroperitoneal metastasis
based on lymph node size (3–4 mm) and distribution
(anterior vs. posterior) can predict ú 90% of Stage I
testicular tumor patients who harbor occult lymph node
A prognostic factor-based staging system has been
proposed for patients with metastatic germ cell carcinoma7 and a similar model combining clinical, histologic, and tumor markers needs to be devised for patients with low stage testicular carcinoma. Prospective
validation of such a model in multiinstitutional studies
will help to define optimal strategy (observation vs. treatment) for patients with low volume testicular tumors. It
is time to move forward.
Heidenreich A, Sesterhenn IA, Moul JW. Prognostic risk factors in low stage testicular germ cell tumors: unanswered
questions regarding clinically useful prognosticators for extratesticular disease [editorial counterpoint]. Cancer 1997;
Albers P, Bierhoff E, Neu D, Fimmers R, Wernert N, Müller
SC. MIB-1 immunohistochemistry in clinical stage I nonseminomatous testicular germ cell tumors predicts patients
at low risk for metastasis. Cancer 1997;79:1710–6.
Hermanek P, Sobin LH, Fleming ID. What do we need beyond TNM? Cancer 1996;77:815–7.
Perrotti M, Herr HW, Sogani PC. Clinical stage I testis cancer:
long term outcome of patients on surveillance. J Urol. In
Hilton S, Herr HW, Teitcher JB, Begg CB, Castellino RA. CT
detection of retroperitoneal lymph node metastases in patients with clinical stage I testicular nonseminomatous germ
cell cancer: assessment of size and distribution criteria. AJR
Am J Roentgenol In press.
Leibovitch I, Foster RS, Kopecky KK, Donohue JP. Improved
accuracy of computerized tomography based clinical staging
in low stage nonseminomatous germ cell cancer using size
criteria of retroperitoneal lymph nodes. J Urol 1995;
W: Cancer
International Germ Cell Cancer Collaborative Group. A
prognostic factor-based staging system for metastatic germ
cell cancer. J Clin Oncol 1997;15:594–603.
Harry W. Herr, M.D.
Urology Service
Department of Surgery
Memorial Sloan-Kettering Cancer Center
New York, New York
Author Reply
e completely agree with Dr. Herr that it is time
to move forward and to evaluate prospectively
risk factors in patients with clinical Stage I nonseminomatous testicular germ cell tumors. Because low stage
testicular carcinoma is highly curable with nerve-sparing retroperitoneal lymph node dissection, primary
chemotherapy, or surveillance, improvements in therapy for this disease could result from more rational,
scientifically based decisions in favor of one of the
therapeutic options for individual patients.
We agree in part that pathohistologic evaluation
of primary testicular carcinoma specimens might be
subjective and variable; however, meticulous pathohistologic evaluation with regard to the presence of vascular invasion and the percentage of germ cell tumor
components is subjective only if certain defined criteria for the correct evaluation are not applied. Invasion
of lymph and blood vessels is correctly identified only
if a sufficient number of tumor blocks of a given tumor
are analyzed. Scherenberg et al.1 demonstrated that
vascular invasion was diagnosed in only 2 cases with
1 – 10 blocks examined but was detected in 33% of
cases with 21 – 30 blocks examined. Furthermore, the
probability of detecting vascular invasion will be increased by appreciating the anatomy of testicular
veins and lymph vessels.1,2 Last but not least, definition of vascular invasion should adhere to strict criteria
as described by Hoeltl et al.3: compact aggregations of
tumor cells within the lumen of blood vessels similar
to thrombotic occlusion and/or definite endothelial
defects from capillary invasion. Isolated tumor cells
within the vascular lumen are caused by artifacts and
are not considered vascular invasion.
The same holds true for the determination of the
percentage of germ cell tumor components within the
primary orchiectomy specimen. The prognostic significance of embryonal carcinoma becomes evident
only if embryonal carcinoma is handled as a continuous variable from 0 – 100%; recognition only of the
mere presence or absence of embryonal carcinoma
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12-17-97 20:46:48
underestimates the prognostic value of embryonal carcinoma, as has been demonstrated previously.4 However, adequate assessment of the percentage of embryonal carcinoma also requires examination of all
available paraffin embedded tissue blocks.
With regard to the prospective study in 76 unselected and 70 analyzed clinical Stage I nonseminomatous germ cell tumors cited by Hilton et al.,5 the aforementioned criteria were not applied for pathohistologic reevaluation, but vascular invasion nevertheless
was associated with a higher risk of occult retroperitoneal disease, emphasizing the significance of this factor. Therefore, we do not agree that quantitative histopathology or immunohistochemistry is subjective and
not useful as a routine parameter but instead believe
that routine examination of the primary tumor has to
be performed systematically.
However, we completely disagree that pathohistologic risk factors in patients with low stage testicular
carcinoma failed to be reproducible in identifying patients at risk when applied in prospective trials. A
number of prospective trials have been published in
the literature with regard to risk-adapted management
in patients with clinical Stage I nonseminomas based
on the presence or absence of vascular invasion and
the presence of embryonal carcinoma.6 – 9 All studies
demonstrated that 1) patients at high risk and low
risk for metastatic disease could be identified, 2) that
embryonal carcinoma and vascular invasion are interrelated because in ú90% of vessel invasion the invading element was embryonal carcinoma, and 3) that
a risk-adapted approach based on these parameters
decreased recurrence rates in the surveillance group
by as much as 4.5%.
With regard to conventional staging methods, we
are aware of the recently published studies performed
on the accuracy of computerized tomography (CT) using new size criteria for retroperitoneal lymph nodes
and cited by Hilton et al. and Leibovitch et al.5,10 However, both studies suffer from the very same problem
criticized by Dr. Herr with regard to the histopathologic and immunohistochemical risk factors: they represent single institution experiences, they are retrospective studies, and they include nonconsecutive patients.10 Although the false-negative rates could be
decreased substantially using variable threshold dimensions to define nonmetastatic lymph nodes, a significant interreader variability in the assessment of
lymph nodes was observed, indicating an inherently
subjective and variable method.5
Furthermore, the lack of uniform techniques for
abdominal CT scans5 certainly represents a limitation
of these studies. Therefore, the results of both studies
must be confirmed in prospective randomized trials.
W: Cancer
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