The aim of the work described in this thesis is to improve the
understanding of the pathobiology of testicular cancer (type II Germ
Cell Tumors) to create possibilities for optimalization of diagnosis for
this type of malignancy in routine pathology laboratories. The
different studies presented here show valuable additional information on
the microscopic diagnostics in daily practice. This enables proper and
complete diagnosis of this relative rare variant of cancer ensuring the
best possible treatment for the patient. A number of novel sensitive and
specific immunohistochemical markers are presented, of value for
(early) diagnostics. In addition an enzymhistochemical method is
presented informative to detect the presence of (pre-)malignant cells
during a surgical intervention. Based on these data, a decision can be
made regarding a testis sparing procedure. The studies included in this
thesis are part of a diagnostically decision tree in which immuno- and
enzymhistochemistry plays an important role.
General
Testicular cancer is a relative rare variant of cancer with raising
incidence in the Western population, in contrast to the rest of the
world. Within the Netherlands, about 750 new patients are diagnosed each
year. In particular this affects young males between the age of 15 – 45
years The current treatment possibilities is successful in
approximately 95% of the patients. It consists of removing of the
affected testicle (radical orchiectomy) and possibly additional
treatment using irradiation and/or chemotherapy. In spite of the
excellent prognosis, patients often will suffer from long-term side
effects of the treatment like fatigue, disorders of the metabolism,
heart diseases, neurotoxicity and infertility. A small group of patients
(5%) will shows an insensitivity of the cancer treatment given, and
will possibly die of the disease. An early and accurate diagnosis can
prevent under- or overtreatment, ensure an optimal balance between the
pro and conts of the treatment. This will have significant impact on
their quality of life, for both short- and long term.
Specific
The cell of origin from which testicular cancer arises is already
present during the first months of pregnancy (embryogenesis), as
demonstrated in Chapter 3. It is a primitive germ cell formed after the
first month after fertilization, which provide spermatozoa after puberty
by spermatogenesis. In case this primitive germ cell does not maturate
completely and keeps the properties of the embryonal cell. This cell can
become carcinoma in situ (CIS), being the progenitor of testicular
cancer. These CIS cell is located in the testis on the same place as the
spermatogonium, below the Sertoli cells on the basal lamina. These
cells start to
CHAPTER 14
multiply in an uncontrolled manner after puberty and finally they can
develop cancer. In chapter 4 the totipotent character of this cancer is
described for the first time in literature, shown by the presence of new
formed germ cells. In other words testicular cancer is the only real
totipotent cancer that can give rise to different germ lines the same as
in embryogenesis. The application of a unique panel of immunological
markers permitted this finding. In chapter 5 the value of the presence
of OCT3/4 in CIS, seminoma and embryonal carcinoma is for the first time
described. This study was initiated by the presence of this marker in
embryonal cells and germ cells of the mouse. The diagnostic significance
of this extremely sensitive and specific marker is huge as described in
chapter 6. Diagnostics of testicular germ cell tumors requires in most
cases surgical removed tissue. In chapter 7 a new method is described
that offers the possibilities to detect OCT3/4 positive cells in semen.
This method introduces the possibility to screen men with a higher risk
for developing testicular germ cell tumor for CIS cells without surgical
intervention. The robustness of this detection method for OCT3/4, even
in sub optimal material, is illustrated in chapter 8. The malignant germ
cells in the here described patient where only detectable by the
presence of OCT3/4.
The two groups of testicular cancer: seminomatous and nonseminomatous
tumors, differs in sensitivity for irradiation and chemotherapy.
Therefore differentiation of these two groups is of great importance for
an optimal treatment. The nonseminomas can be subdivided in different
groups of which embryonal carcinoma is the stem cell population. In
chapter 9 detection of two SOX proteins (SOX2 and SOX17) is shown to be
informative. Seminoma cells show expression of OCT3/4 and SOX17,
embryonal carcinoma cells of OCT3/4 and SOX2. The other subgroups of the
nonseminomas (yolk sac tumor, choriocarcinoma and teratoma) show a more
heterogeneous expression.
A chance of overdiagnosis of CIS in the testicle based on the presence
of OCT3/4 is risk in young children, especially in the first year after
birth, a result of a possible delay in maturation of the normal
developing germ cells. This is Important because maturation delay is
common also in cases of an increased risk for the development of
testicular cancer, for instance an undescended testicle. In chapter 10
it is demonstrated how to distinguish a germ cell with maturation delay
from a (pre-) malignant germ cell (CIS). Because SCF is only present in
the direct neighbourhood of (pre-)malignant germ cells. This finding has
an additional value in case of possible maturation delay when OCT3/4
positive cells are present. There is also a significant value for this
finding concerning that specific DNA variants related to this gene,
associated with an increased risk for development of testicular cancer
in the entire population.
SUMMARY/SAMENVATTING
Organ sparing surgery may be preferred for different reasons, even so in
cases of testicular cancer. Prevention of a second surgical
intervention requires proper histopathological examination of frozen
sections. In testis cancer this is mainly based on the detection of the
presence of CIS. Unfortunately morphologic analysis of frozen material
is not that easy, therefore formalin fixed tissue is needed which
excludes often a single operation procedure. In chapter 11 a direct
enzymhistochemical method is described which makes it possible to detect
the presence of these CIS cells in a few minutes on frozen tissue. By
using this direct alkaline phosphatase (dAP) technique it is possible to
have certainty about the presence of CIS cells in the available tissue.
Based on these results a decision is possible about performing a testis
sparing operation.
Chapter 12 describes the low DNA methylation status of both CIS cells
and embryonal germ cells in their natural environment. This is performed
by the use of immunohistochemistry. Interesting is the possible
connection between cancer cells which are sensitive to cisplatin and the
status of methylation. DNA of the resistant tumors seems to be
hypermethylated compared to sensitive tumors. Analysis of cultured cell
lines indicates c-FLIP gene as a potential candidate. This gene
regulates the sensitivity of cells for a programmed cell death
(apoptosis).
Conclusions
The studies presented give possibilities to perform optimal diagnostics
of testicular cancer, eventually in certain circumstances, even in a
non-invasive set up. These findings demonstrate that understanding of
the normal development of germ cells, especially during embryogenesis,
is of importance to carry out these kind of studies. The results give a
solid base for implementation in a diagnostic set up and for further
translational research.
http://repub.eur.nl/res/pub/30598/111130_Stoop%2CJohannes%20Adrianus.pdf
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