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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5511_Библиотеки_им_академика_М_И_Перельмана.pdf
focused on finding molecular or genetic markers that may triage this
morphologically difficult group in order to achieve the goal of early
detection and early management of ovarian cancers.
Ascites fluid, especially large amount of bloody fluid, is often associated with ovarian malignancy, most frequently metastatic ovarian
papillary serous carcinoma in elderly patients (Fig. 12). Serous papillary tissue fragments with borderline nuclear features can also be seen
in ascites fluid when borderline papillary tumor involves the surface of
the ovary. This kind of atypical cell groups can be confused with
reactive/hyperplastic mesothelial cells. In such uncertain situation,
immunocytochemical studies with markers such as calretinin, Ca 125,
CEA, etc. may be helpful. Malignant acites is often cellular and the
sample can be spun down to make cell block (Fig. 13) that can be
used for immunocytochemical or molecular studies.
Peritoneal washings are generally associated with gynecological
cancer/tumor surgery for the purpose of staging. While positivity for
malignant cells is often consistent with metastatic carcinoma, mechanical
258 M Wu
Fig. 12 A three-dimensional cluster of malignant cells with marked nuclear pleomorphism and clear cytoplasm. This is an example of metastatic ovarian serous papillary carcinoma to the peritoneal fluid. Pap stained ThinPrep slide, original
magnification 100×.
seeding can also be seen in less advanced cases. Mechanical seeding
refers to (1) rupture of an ovarian tumor (which should be avoided
during surgery) and (2) transportation of endometrial tumor cells
through the fallopian tubes. In these situations, it is recommended to
the cytopathologist to correlate the case with the corresponding surgical pathology. For example, atypical cells in peritoneal washing seen
in a patient with superficially invasive endometrial carcinoma as well
as free floating tumor cells in the fallopian tube should not be signed
out as positive; if an ovarian tumor was ruptured during surgery,
cytopathologist should be informed or at least a note should be put
on the requisition form. It is also important not to overtreat a patient
since some side effects of chemotherapy and/or radiation can be devastating to the patient.
Although efforts have been made over the years in attempts for
early detection of ovarian cancer, the results are disappointing so far.
Annual surveillance, by trans-vaginal ultrasound scanning and serum
Ca 125 measurements in women at increased familial risk of ovarian
cancer was shown to be ineffective in detecting tumors at a sufficiently
Cytology for Early Diagnosis of Gynecologic Cancer 259
Fig. 13 A cell block slide showing numerous malignant cells that can be potentially
used useful for immunocytochemical or malicular studes. Hematoxylin & Eosin
stained cell bock slide, original magnification 40×.
early stage to substantially influence survival in BRCA1/2 carriers.
42,43
While early detection of ovarian cancer continues to be a challenge,
further understanding of the pathogenesis of ovarian tumors and
maximizing advantages of cytopathology in combination with current
molecular technologies may offer some hope for progress.
Updated Ovarian Carcinogenesis and Molecular Studies
Based on Kurman et al.
44
a new model of ovarian carcinogenesis
based on clinical, pathological, and molecular genetic studies that may
enable more targeted screening and therapeutic intervention should
be developed in order to detect disease when confined to the ovary
(stage I) and thereby prolong survival. The model divides ovarian
cancer into types I and II.
Type I tumors are slow growing, generally confined to the ovary at
diagnosis and develop from well-established precursor lesions, the socalled borderline tumors. Type I tumors include low-grade micropapillary serous carcinoma, mucinous, endometrioid, and clear cell
carcinomas. They are genetically stable and are characterized by mutations in a number of different genes including KRAS, BRAF, PTEN,
and beta-catenin.
Type II tumors are rapidly growing, highly aggressive neoplasms that
lack well-defined precursor lesions; most are detected at an advanced
stage at, or soon after, their inception. These include high-grade
serous carcinoma, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas. The type II tumors are
characterized by mutation of TP53 and a high level of genetic instability. Screening tests that focus on stage I disease may detect lowgrade type Ineoplasms but miss the more aggressive type II tumors,
which account for most ovarian carcinomas. Crum et al.
45
have studied the fallopian tubes and found a relatively high frequency of early
cancer in the fimbria in unselected women with ovarian and peritoneal
serous carcinoma, raising the distinct possibility that a significant proportion of these tumors have a fimbrial origin. This finding, if further
260 M Wu
verified, may alter our strategies in early detection and management
of ovarian cancers.
A study
46
of microarray gene expression in serous epithelial ovarian cancer (SEOC) compared with bulk normal ovarian tissue and
ovarian surface scrapings revealed that gene expression profiling and
sequential statistical analysis of gene subsets can identify new genes and
molecular pathways affecting the development of SEOC. The genes of
interest are potential targets for future research of SEOC. According
to a recent review by Nossov et al. proteomics may offer some hope in
early detection of ovarian cancer.
47
MicroRNAs (miRNAs), an abundant class of small noncoding RNAs that function as negative gene
regulators have also been studied in ovarian cancer.
48
The results indicated that miRNAs may offer new biomarkers and therapeutic targets
in epithelial ovarian cancer. Autoantibody profile of ovarian cancer
related genes (TM4SF1, C1D, TIZ, BARD1, FXR1, OV-189) may
also potentially serve as markers in ovarian cancer detection.
49
SUMMARY
Cytopathology screening programs have been serving well in early
detection of gyneocological cancers, in perticular cervical squamous
cell carcinoma. As the field progresses, the pathology and clinical
teams have to realize that morphology alone is insufficient to detect
gynecological cancers such as ovarian carcinomas in the early stages.
Pathogenesis related factors such as HPV in cervical cancer, immunocytochemical studies of tumor markers, and molecular testing of
genetic abnormalities will have to merge into the daily practice in
addition to cytomorphology.
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Cytology for Early Diagnosis of Gynecologic Cancer 265
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MOLECULAR AND BIOLOGICAL
DIAGNOSIS OF EARLY
GYNECOLOGIC CANCERS
Frederique Penault-Llorca
Recently, molecular diagnostic assays have been developed for
gynecologic cancer, mostly for ovarian and uterine (cervix or endometrial) cancers. The markers are different for the two types of cancers.
For ovarian cancer, the molecular diagnosis is serial and aimed to
detect an early lesion of invasive cancer. For uterine cancer, the markers are mainly tissue based and tailored to predict the biological outcome of a preinvasive lesion.
OVARIAN CANCER
The development of useful markers for the detection of ovarian
cancer is crucial because of the high mortality associated with the disease and the lack of reliable symptoms, biomarkers and mechanisms
of early diagnosis. Effective early diagnosis could change the clinical
spectrum of the disease and should have a direct impact on mortality.
267
8
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