Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5511_Библиотеки_им_академика_М_И_Перельмана.pdf
cytoplasmic vacuoles with pleomorphic nuclei and high mitotic activity
(Fig. 14). They are often mixed with serous carcinomas, tend to be invasive into the myometrium, and metastatic to the regional lymph nodes.
Malignant mixed mullerian tumors (MMMT), also seen in elderly patients, are composed of malignant epithelial and stromal elements.
They are uncommon tumors with occasional early stage presentation in
endometrial polyps.
MOLECULAR BIOLOGY OF ENDOMETRIAL CARCINOMA
Estrogen and progesterone receptors (ER/PR) are present in
most endometrial cancers, being higher in the endometrioid
adenocarcinomas of low grade (Fig. 15). It is generally considered
that ER/PR receptor positivity is predictive of responsiveness to
progesterone therapy and has prognostic significance.
8–10
For the evaluation of the biological behavior of EC, the immune reactivity to various markers for proliferation, apoptosis, tumor suppressor
168 L Deligdisch
Fig. 13 Non-endometrioid serous papillar y endometrial carcinoma, histologically
similar to ovarian serous papillary carcinoma. Hematoxylin/eosin, orginal magnification 40×.
Early Diagnosis of Endometrial Cancer 169
Fig. 14 Non-endometrioid endometrial clear cell carcinoma in a 69 years old
patient. Hematoxylin/eosin, orginal magnification 400×.
Fig. 15 EIN with positive stain for estrogen receptors, 100×.
genes and oncogenes, such as BCL-2, MIB-1, HER2, and especially
p53 and K-ras have yielded results suggestive of a correlation with
metastatic potential and survival.
1
Molecular genetics has confirmed the classification of EC into two
broad groups, endometrioid, and non-endometrioid, based on pathologic, clinical, epidemiological and histochemical features.
11
The most
commonly altered gene in endometrioid carcinoma is the PTEN tumor
suppressor gene mutated in 30%–50% of endometrioid carcinomas and
in 20% of endometrial hyperplasias. The inactivation of this gene
seems to be involved in the early carcinogenesis of endometrioid EC.
It is a marker for detecting endometrial glands predisposed to
progress to malignancy.
Mutation of the p53 tumor suppressor gene is seen in more
advanced grades of endometrioid EC (G2, G3) and therefore may
play a role in the progression and not in the initiation of this tumor.
12
Microsatellite instability, related to a DNA mismatched repair system that results in an increased rate of mutations leading to neoplastic
proliferation of the cells, has been found in both endometrial carcinoma and hyperplasia (and in hereditary non-polyposis colorectal
carcinoma). Other oncogenes such as K-ras, Her2/Neu, bcl-2, and
3 catenins have been found mutated in various proportions in EC.
1
In non-endometrioid EC the mutation of p53 is found in about
75% of serous endometrial carcinomas, in their early stages
accounting for its aggressive behavior, as compared to endometrioid EC in which p53 mutations occur more often later, in G2-G3
lesions.
This marker can be considered as an indicator of aggressive EC.
K-ras and PTEN are rarely found in serous EC. Clear cell EC are
non-endometrioid EC that tend to be high-grade and deeply invasive,
presenting in advanced stages in which p53 mutations are less
frequently expressed than in serous EC.
13
CONCLUSIONS
Endometrial carcinoma is the most common gynecologic cancer in
the USA and in many other countries. Its incidence has increased
170 L Deligdisch
because of the increase of risk factors such as longevity, obesity, nulliparity, hormone replacement therapy. Fortunately, most cases can be
and actually are diagnosed relatively early in their development and
can be cured by surgical and adjuvant therapies. The mortality due to
this neoplasm is relatively low, about 7000 for approximately 40,000
new cases in the USA (estimated for 2006, American Cancer Society).
An early diagnosis is possible due to the frequent association of EC with
endometrial hyperplasia, especially atypical hyperplasia which is associated with the same risk factors as most endometrial cancers. These
cancers are most often histologically endometrioid adenocarcinomas.
They usually become symptomatic with irregular vaginal bleeding and
especially postmenopausal bleeding. Patients receiving hormone
replacement therapy for postmenopausal symptoms and Tamoxifen
therapy against breast cancer, as well as those with certain predisposing hereditary conditions, should be screened with sonography, hysteroscopy, and especially endometrial biopsies. The smaller group of
patients without clinical risk factors and without clinical symptoms
such as vaginal bleeding, increased uterine volume who are also generally older and less likely to have frequent gynecologic check-ups,
often present in later stages of the disease, with involvement of pelvic,
abdominal and distant organs by the tumor. Predictably, there is
a higher mortality in this group of patients in whom the histopathologic diagnosis is more often that of non-endometrioid adenocarcinoma. The challenging question is that of an early diagnosis of
EC in women who are elderly, not obese, often multiparous, with no
history of hormone intake, often from a social-economical deprived
background, unlikely to have frequent gynecologic examinations. The
pathologic findings that are revealing in such cases are precancerous
lesions without endometrial hyperplasia and occasionally abnormal
Pap smears. Endometrial intrauterine carcinoma (EIC) may be seen in
atrophic polyps or adjacent to atrophic endometrium. Unfortunatelly,
invasive non-endometrioid EC is not often diagnosed in its early
stages because of the absence of clinical risk factors and often, the
absence of symptoms (vaginal bleeding, tumor mass). These mostly
type 2 EC are often diagnosed in a late stage by the time they become
symptomatic. The natural history of the non-endometrioid EC is
Early Diagnosis of Endometrial Cancer 171
somewhat similar to that of ovarian serous carcinoma, the early diagnosis of which is still elusive.
REFERENCES
1. Ronnett B, Zaino RJ, Ellenson LH, et al., Endometrial carcinoma, in
Blanstein’s Pathology of the Female Genital Tract, 5th edn., Springer
Verlag, New York, Berlin, Heidelberg, pp. 533–537, 2002.
2. Deligdisch L, Hormonal pathology of the endometrium, Mod Pathol
13(3):285–294, 2000.
3. Mutter GL, Zaino RJ, Baak JP, et al., Benign endometrial hyperplasia
sequence and endometrial intraepithelial neoplasisa (review), Int J Gynecol
Pathol 26:103–114, 2007.
4. Mutter GL, Duska L, Crum CP, Endometrial intraepithelial neoplasia,
in Crum CP, Lee K (eds.), Diagnostic Gynecologic and Obstetric
Pathology, Philadelphia PA Saunders, pp. 493–518, 2005.
5. Mutter GL, Lin MC, Fitzgerald JT et al., Altered PTEN expression as a
diagnostic marker for the earliest endometrial precancers, J Natl Cancer
Inst 92:924–930, 2000.
6. Deligdisch L, Kalir T, Cohen CJ, et al., Endometrial histopathology in
700 patients treated with Tamoxifen for breast cancer, Gynecol Oncol
78:181–186, 2000.
7. Deligdisch L, Kase N, Bleiweiss I, Endometrial cancer in elderly women:
a histologic and steroid receptor study, Gerontology 46:17–21, 2000.
8. Fukuda K, Mori M, Uchiyama M, et al., Prognostic significance of
progesterone receptor immunohistochemistry in endometrial carcinoma,
Gynecol Oncol 69:220–225, 1998.
9. Ramirez PT, Frumovitz M, Bodurka DC, et al., Hormonal therapy for
the management of grade I endometrial adenocarcinoma: a literature
review, Gynecol Oncol 95:133–138, 2004.
10. Montz FJ, Bristow RE, Bovicelli A, et al., Intrauterine progesterone
treatment of early endometrial cancer, Am J Obstet Gynecol 186(4):
651–657, 2002.
11. Deligdisch L, Holinka CF, Endometrial carcinoma? Two diseases,
Cancer Detection and Prevention 10:237–246, 1987.
12. Tashiro H, Isacson C, Levine R, et al., p53 mutations are common in
uterine serous carcinoma and occur early in their pathogenesis, Am J
Surg Pathol 150:177–185, 1997.
172 L Deligdisch
13. Baak JP, Mutter GL, Robboy S et al., The molecular genetics and morphometry-based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more
accurately then the 1994 World Health Organization classification system, Cancer 103:2304–2312, 2005.
14. Sherman ME, Sturgeon S, Brinton LA, et al., Risk factors and hormone
levels in patients with serous and endometrial uterine carcinomas, Mod
Pathol 10:963–968, 1997.
Early Diagnosis of Endometrial Cancer 173
This page intentionally left blankThis page intentionally left blank
EARLY DIAGNOSIS
OF OVARIAN CANCER
Liane Deligdisch
INTRODUCTION
Ovarian cancer is not the most common gynecologic cancer but it
is the most lethal. Despite recent progress in the identification of
risk factors, chemotherapy and cytoreductive surgery, the high
lethality due to this neoplasm still represents a major public health
problem.
There were about 165,000 cases of ovarian cancer annually, world-
wide, and about 23,000 new cases in the US in 2007. It is the sixth
most common cancer in women in the US. Ovarian cancer results in
more deaths than all the other gynecologic cancers combined.
Only a small percentage of the cases are known to be related to an
inherited mutated gene while most cases are considered to be sporadic, with mostly unknown risk factors. There is no implementation
of a systematic screening for ovarian cancer at the present time; such
175
5
CHAPTER
screening for other malignancies, especially for cervical cancer,
resulted in spectacular declines in their morbidity and mortality.
The high mortality due to ovarian cancer is related to the
fact that the vast majority of cases (70%–75%) are diagnosed in late
stages of the disease, when the tumor is spread beyond the ovary
(ies) and the pelvis. The reason for this is the paucity or absence of
specific clinical symptoms during the early stages of the tumor.
RISK FACTORS, GENETIC RISK
Non-Hereditary Risk
The incidence of ovarian cancer is considerably higher in industrialized countries in which there is high consumption of animal fat. This
was evident in women who immigrated from countries with low incidence of ovarian cancer such as Japan to the US.
A controversial but much studied risk factor is ovarian epithelial injury
by chemical carcinogens such as talcum powder or asbestos fibers. The
injuries due to incessant ovulation that elicits a defective DNA repair may
result in mutations leading to ovarian cancer. The use of fertility drugs
with subsequent hyperovulation may promote an enhancement of errors
in DNA replication and repair. There is no consensus on this subject
because of a number of conflicting reports about the relationship
between the effect of fertility drugs and ovarian cancer.
1
Conversely, it seems that high parity, lactation, tubal ligation and
the use of oral contraceptives have a significant protective effect, especially the latter. The low risk to develop ovarian cancer in women
using contraceptives is related to the suppression of ovulation and
thus the decrease of pituitary stimulation of the ovary by
gonadotropins. Progestins were also shown to induce cell apoptosis in
monkeys, thus having a protective effect.
2
Hereditary Risk
Approximately 10% of ovarian carcinomas are related to mutations in specific inherited genes, namely BRCA1 and 2. These genes are also respon-
sible for greatly increasing the risk of early-onset breast cancer. Mutations
176 L Deligdisch
of other genes responsible for hereditary colorectal cancer and endometrial cancer may also be involved in some cases of ovarian cancer.
The risk of developing ovarian cancer due to mutations of BRCA1
and 2 is about 28% to 44% by the age of 70.
3
Women already diagnosed with breast cancer due to the mutations of these genes have a
ten-fold increase in their risk of ovarian cancer compared to other
women with early onset breast cancer.
4
Mutations of BRCA1 and 2 genes confer cancer risk in autosomal
dominant fashion, with offsprings having an equal chance of either being
at greatly increased risk of cancer or being at the general population risk.
Most hereditary ovarian cancers are invasive serous papillary carcinomas (OSPC). The mutated suppressor genes BRCA1 and 2 are also identified in families with tumors of other sites, often with one or more relatives
diagnosed with breast cancer before the age of 50, or less commonly, with
colorectal or endocervical cancer diagnosed before the age of 50.
Assessment of family history can identify the possibility of one’s
hereditary risk of ovarian cancer but cannot confirm whether the
woman herself is at risk (Table 1).
OVARIAN DYSPLASIA
The histologic identification of precursors of epithelial cancer has contributed significantly to the screening for gynecologic cancers of the
breast, cervix, and endometrium. The concept of a preinvasive oncogenic transformation of epithelial tissues, as a result of hormonal influences in endometrial or breast neoplasms, or as a result of infectious
(viral) factors in cervical cancer, and the identification of actual tissue
change precursors of malignancy has resulted in spectacular decreases
Early Diagnosis of Ovarian Cancer 177
Table 1. Hereditary Ovarian Cancer
About 10% of invasive serous papillary carcinomas.
Hereditary breast/ovarian cancer (HBOC syndrome) have BRCA1 and 2 gene
mutations.
Germplasm BRCA1 gene mutations: 70%.
Germplasm BRCA2 gene mutations: 20%.
Highly penetrant autosomal dominant mutations.
HBOC associated with 75%–90% hereditary ovarian and 30%–70% breast cancer.