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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5511_Библиотеки_им_академика_М_И_Перельмана.pdf
in morbidity and mortality of numerous malignant tumors. Histologic
changes that do not represent overt malignancy but are related to an
abnormal proliferation that increases in severity and/or may become
invasive neoplasms are generally designated as dysplastic (bad molding
in Greek). Dysplastic changes may also be seen in the vicinity of invasive neoplasms in many epithelial tissues such as colon, larynx, vocal
cords, skin (dysplastic nevi and melanomas). In the female genital
tract, the diagnosis of cervical dysplasia represents the most common,
and the best example of a successful prevention of cancer by identifying and removing its precursors. It should be mentioned that the progression from dysplasia to overt cancer is unpredictable and related to
mostly poorly understood factors of host defense. However, it is reasonable to assume that the more severe the degree of dysplastic
change, the more likely the transformation to overt cancerous tissue.
Ovarian dysplasia has first been described in identical twin sisters
of women diagnosed with ovarian cancer who underwent prophylactic oophorectomy.
5
The histologic examination of the grossly normal
appearing ovaries revealed abnormal epithelial stratification, lack of
polarity of the ovarian surface epithelium, and enlarged nuclei with a
coarse chromatin texture (Fig. 1).
178 L Deligdisch
Fig. 1 Dysplastic ovarian epithelium diagnosed in an identical twin sister of a
woman diagnosed with ovarian carcinoma. Note stratification, loss of polarity and
coarse chromatin network. Hematoxylin/eosin, orginal magnification 100×.
The surface epithelium of the ovary is an extension of the peritoneal mesothelium. It is the site of origin of the vast majority of ovarian epithelial tumors (ovarian carcinomas).
Invaginations of the surface epithelium often create inclusion
cysts with papillary proliferation into the cysts. Most ovarian serous
cystadenocarcinomas originate from such cysts and present at a late
stage with solid and cystic components and most often, extension to
the peritoneum. Precursors of serous papillary carcinomas are not easily identifiable because of the hidden location of these intraovarian
cysts often of microscopic dimensions (Fig. 2).
Dysplastic changes of the ovarian surface epithelium and of the
lining of these cysts were identified in two clinical settings:
(1) In apparently normal ovaries, often removed from women
with family history of ovarian and/or breast cancer (incidental
dysplasia).
(2) In the vicinity of overt invasive cancer (adjacent dysplasia). Since the
histologic characteristics of these dysplastic changes were rather
subtle and somewhat subjective, computerized image analysis was
Early Diagnosis of Ovarian Cancer 179
Fig. 2 Ovary “at risk”: multiple small ovarian cysts and psamomma bodies in the
ovarian cortex. Hematoxylin/eosin, orginal magnification 40×.
used to validate the histological changes that turned out to be
intermediate between normal and malignant ovarian epithelium
by using morphometric assessments of architectural (crowding
and stratification) and cellular (nuclear profiles) characteristics of
normal cancerous and dysplastic cells (Figs. 3–6).
180 L Deligdisch
Fig. 3 Ovarian dysplasia: epithelial inclusion cysts with increased nucleo-cytoplasmic
ratio, piling up of epithelial cells with loss of polarity. Hematoxylin/eosin, orginal
magnification 400×.
Fig. 4 (a) Morphometry of normal ovarian surface epithelium. Cells are at regular intervals and equal distance from basement membrane, as demonstrated by lines
tracing the shortest distance from the center of nuclei to the basement membrane.
(b) Morphometry of ovarian epithelial cancer cells: irregular high stratification and
crowding as demonstrated by lines traced by computer from the center of nuclei to
the basement membrane. (c) Morphometry of ovarian dysplasia: epithelial cells
demonstrate cell density and stratification intermediate between normal and cancer.
The architectural characteristics (crowding and piling up of
epithelial cells) and nuclear profiles (area and diameter as well as texture) were evaluated by morphometric measurements and evaluated
by statistical methods that also included neural networks.
6–8
The objective methods of quantifying subtle differences in the tissue structure of dysplastic ovarian epithelium yielded accurate values
Early Diagnosis of Ovarian Cancer 181
Fig. 5 Morphometric evaluation of nuclear surface, perimeter, and diameter of a
dysplastic cell.
Fig. 6 Diagram of nuclear profiles. Normal nuclei distribution: 10 µm–35 µm.
Malignant nuclei: 10 µm–100 µm. Dysplastic nuclei: Intermediate.
characterizing tissue and cell changes intermediate between benign
and malignant ovarian epithelium (Table 2). Interestingly, the histologic changes of incidental dysplasia diagnosed in grossly normal
appearing ovaries were similar to the histologic changes in dysplastic
epithelium adjacent to overt ovarian carcinoma, as measured with the
most discriminating methods of multivariate statistical analysis and
neural networks (Fig. 7).
8
At the present time, there is no screening program for ovarian
cancer. Serum tumor markers have not proven to be sensitive or specific enough for an early ovarian cancer screening. With the advent
182 L Deligdisch
Fig. 7 Neural network architecture. Dysplastic nuclei in incidental dysplasia are
indistinguishable from those of adjacent dysplasia.
Table 2. Criteria for Diagnosis of Ovarian Dysplasia
Architectural: Stratification, crowding, loss of polarity.
Cytological: Cellular atypia, enlarged nuclei and increased nucleo-cytoplasmic ratio,
prominent nucleoli, changes in chromatin pattern (nuclear texture).
Morphometric data evaluated by statistical and artificial neural network analysis for
validation.
of advanced laparoscopic techniques, the ovary becomes more
accessible and asymptomatic precursors or low-stage ovarian cancer
may be detected more readily. The routine histologic descriptions
and the measurements performed by interactive methods of computerized image analysis have revealed changes that are recognizable and reproducible by the practicing pathologist. The structural
changes of the ovarian epithelial tissue diagnostic for dysplasia were
correlated with antigenic expression of certain tumor markers, such
as p53 and Ki67.
9
More tumor marker studies are presently studied
in order to gain an insight into the molecular biologic events occurring in histologically and morphometrically identified ovarian dysplastic changes.
PROPHYLACTIC OOPHORECTEMY AND THE OVARY AT RISK
The most effective prevention of ovarian carcinoma is prophylactic
oophorectomy (PO), which is now considered a valid option for
women at risk for ovarian cancer. PO is recommended for carriers
of BRCA1 and 2 mutations offering them a dramatic 90%–98%
chance of reduction of ovarian and peritoneal cancer risk, and a
50% reduction of later breast cancer hazard.
10,11
Other potential
benefits include the discovery of an occult ovarian cancer
12,13
and
the possibility of studying pathobiological changes that may represent potential precursors of ovarian neoplasm in these ovaries “at
risk”.
9,14,15
The prophylactically removed ovaries are generally described as
grossly and most often microscopically normal. A number of recent
studies, however, have challenged the notion of “normal” by submitting the grossly normal appearing ovaries to a thorough histologic analysis consisting of multiple sections of the organ;
examination of histologic changes associated with neoplastic and
preneoplastic features; morphometric studies including a novel
approach of a tri-dimensional assessment of nuclear texture; and
immunohistochemical identification of tumor markers using
microdissection.
9,14
Early Diagnosis of Ovarian Cancer 183
A “cancer prone” phenotype has been described in ovaries removed
by PO. It consists of inclusion cysts, surface papillomatosis, epithelial
hyperplasia and deep invaginations of the surface epithelium into the
ovarian stroma.
15
The study of nuclear texture by computerized image analysis
revealed changes in the size and texture of the ovarian surface epithelial nuclei in a statistically significant high proportion of ovarian tissue
removed by PO from Ashkenazi Jewish women. These females also
have genetic mutations predisposing to breast/ovarian carcinoma.
14
The nuclear texture analysis is based on the autocorrelation procedure
which is a powerful discriminant especially when combined with
nuclear measurements illustrated by three-dimensional images. These
images represent the relationship between neighboring pixels. Normal
nuclei with a homogenous chromatin network generate a flat surface
reflecting the homogeneity of the nuclear chromatin. The nuclei of cancer cells with their characteristic irregularly clumped chromatin reflecting
the out of control DNA replication have a markedly non-homogenous
tri-dimensional image. In dysplastic nuclei, the tri-dimensional image is
intermediate, that is less homogenous than the normal and less irregular
than the carcinoma nuclei (Figs. 8(a)–(c)).
The size of the nuclei correlates with their texture being also
intermediate for the dysplastic cells (31
µ
m versus 18 µm for normal
and 51
µ
m for cancer cell nuclei).
184 L Deligdisch
Fig. 8 (a) Tri-dimensional image of normal ovarian epithelial nucleus: flat surface
reflects homogenous texture. Area: 18 µm. (b) Tri-dimensional image of malignant
nucleus: high spikes and deep depressions due to markedly irregular chromatin texture. Area: 51 µm. (c) Dysplastic nucleus: irregularity of the tri-dimensional image is
intermediate between benign and malignant. Area: 31 µm.
Further studies of prophylactic oophorectomy specimens identified a number of histologic changes significantly more common when
compared to oophorectomies performed for reasons unrelated to
ovarian carcinoma risk.
9
These histologic changes include the following: deep invaginations of the surface epithelium into the ovarian hyperplastic
cortical stroma; multiple, often clustering, epithelial inclusion
cysts; and psammoma bodies (concentric calcifications around a
proteinaceous central body) often seen in ovarian serous papillary
carcinomas and considered to represent a “burnt-out” papillary
proliferation. Surface papillations, hyperplasia of the surface
epithelium and of the epithelium lining the inclusion cyst, and the
presence of dysplastic changes of this epithelium (piling up, loss
of polarity, nuclear size increase and irregular texture) are histologic changes that are found in the “ovaries at risk” removed by
PO in significantly higher proportion than in control ovaries
(Fig. 9). Immunohistologic analysis revealed a significantly higher
immunoreactivity for tumor markers such as p53, MIB-1 (Ki67)
Early Diagnosis of Ovarian Cancer 185
Fig. 9 Papillations next to psammoma bodies (concentric calcifications) often
encountered in “ovaries at risk”. Hematoxylin/eosin, orginal magnification 400×.
and Ca 125 in the ovarian tissue removed by PO as compared to
the control specimens.
9
The abnormal histologic, morphometric and immunohistologic findings in apparently normal ovaries removed by PO justify more detailed
studies of this tissue. The thorough examination of multiple ovarian sections from PO specimens may occasionally reveal unsuspected, clinically
silent, cancer tissue, associated with dysplastic epithelium (Fig. 10).
Overexpression of Ki67 proliferation marker (Fig. 11) and of the
p53 tumor suppressor gene product (Fig. 12) in the ovarian epithelium suggest a proliferation abnormality and the loss of cell cycle
control, clonal expansion and acquisition of potential invasive
growth properties. Since it is unlikely that multiple mutations of such
occur within the same cell cycle within the same cell, it is reasonable
to assume the existence of preneoplastic changes in the ovarian
epithelium.
10
Recent reports of morphometric studies of nuclear
abnormalities in “high-risk” ovaries support their significance for
early detection and prevention of ovarian cancer.
16,17
With the advent of laparoscopy, the ovaries become more accessible for study; the analysis of structural and molecular changes in the
“ovaries at risk” may offer an unique insight into the early preneoplastic changes of these tissue (Tables 3 and 4).
186 L Deligdisch
Fig. 10 Normal ovarian surface epithelium (above), dysplastic changes (left lower
corner) and frankly malignant tissue (carcinoma, right lower corner). Hematoxylin/
eosin, orginal magnification 100×.
Early Diagnosis of Ovarian Cancer 187
Fig. 11 Ki67 immunopositivity of ovarian epithelial inclusion cysts in “ovary at
risk.” Hematoxylin/eosin, orginal magnification 100×.
Fig. 12 p53 immunopositivity of ovarian surface epithelium in “ovary at risk”.