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
158 L Deligdisch
Fig. 6 Same patient as in Fig. 5. Note severely atypical nuclei with prominent
nucleoli, papillary proliferation and detached clusters of tumor cells. Hematoxylin/
eosin, orginal magnification 400×.
Fig. 5 Endometrial intraepithelial carcinoma (EIC) in a 72 years old patient with
metastatic spread to pelvic lymph nodes and peritoneum. Hematoxylin/eosin,
orginal magnification 100×.
Early Diagnosis of Endometrial Cancer 159
Fig. 7 Endometrial intraepithelial carcinoma (EIC) positive immune reaction
to p53 mutation. Despite the focal endometrial lesion there were metastases in the
peritoneum and pelvic lymph nodes 40.
Fig. 8 EIC with positive stain for p53 mutation proteins.
endometrioid and non endometrioid EC (Table 1). Overlapping of
those characteristics in individual patients is of course possible.
Endometrioid adenocarcinoma is more often diagnosed early.
EARLY ENDOMETRIAL CARCINOMA
The high risk for developing endometrial carcinoma in women
exposed to continuous estrogenic stimulation is similar to that for
endometrial hyperplasia which can be considered as a precursor
especially the atypical glandular hyperplasia (EIN). Progression
from hyperplasia to carcinoma is not always predictable only
from histologic criteria. Hormonal therapy with substitution estrogen therapy and tamoxifen therapy for breast carcinoma may
have a profound influence on the natural history of endometrial
carcinogenesis.
2,6
A relatively less common group of endometrial carcinomas
arise in a non-hyperestrogenic clinical context, independently
from risk factors such as obesity, nulliparity, chronic anovulation
or exogenous hormone intake. These cancers are usually nonendometrioid and seen in older patients as compared to the endometrioid carcinomas.
7
Tamoxifen (a non-steroidal synthetic triethylene estrogen derivative) has been widely and successfully used in the adjuvant therapy
and prophylaxis of breast cancer. Tamoxifen binds to the estrogen
160 L Deligdisch
Table 1. Pathogenetic and Clinical Classification of Endometrial Carcinoma
Type I Type II
Unopposed estrogen effect Hormonal-independent
Peri-menopausal and post-menopausal Post-menopausal
Precursor: Atypical glandular hyperplasia Precursor: Endometrial intraepithelial
and intraepithelial neoplasia (EIN) carcinoma (EIC)
Variable myometrial invasion, often focal Myometrial invasion, often deep
Endometrioid histologically Non-endometrioid histologically
PTEN and K-ras mutations p53 mutations
Favorable prognosis Poor prognosis
Various degrees of differentiation Poor differentiation
receptors in a manner similar to that of estradiol and induces
the binding of the tamoxifen/receptor complex to the nuclear
DNA, resulting in a decrease of available unbound receptors. It is
still considered as an important adjuvant therapeutic agent for this
cancer, based on its antiestrogenic effect on the breast tissue. The
effect of tamoxifen therapy on the endometrium is more complicated. A majority of patients do not develop abnormal changes and
endometrial biopsies of about 60% of patients from a large cohort
displayed normal cyclic and atrophic changes. However, endometrial
polyps were found in a larger proportion (about 24%) and endometrial carcinoma, mostly seen in the polyps, was diagnosed in 4.7% of
the cases. Interestingly, the endometrial cancers (33 out of 700 patients
treated with Tamoxifen) were non-endometrioid (Figs. 9 and 10) in
about two thirds of the cases. They were mostly associated with
atrophic glands, therefore are not characteristic for a hyperestrogenic
milieu.
6
The estrogenic agonist/antagonist effect of Tamoxifen on
Early Diagnosis of Endometrial Cancer 161
Fig. 9 Endometrial polyp in a 57 years old patient treated with Tamoxifen for
breast carcinoma. Cystic atrophic glands and non-endometrioid clear cell adenocarcinoma (right lower quadrant). Hematoxylin/eosin, orginal magnification 100×.
the uterus by eliciting both myometrial (leiomyomas, adenomyosis)
and endometrial (polyps) abnormal proliferation and even cancer has
resulted in the recent recommendation to replace this drug with
other antiestrogenic agents. An early diagnosis of endometrial neoplasms, including EIN, EIC, and overt carcinoma is possible by
screening the patients treated with Tamoxifen with sonograms and
endometrial biopsies.
Early endometrial cancer is considered to be an endometrial neoplasm confined to the uterus, Stage I, with or without invasion of
the adjacent myometrium. Endometrial carcinoma confined to the
endometrial layer represents Stage Ia; invading the inner half of the
myometrium is Stage Ib; and invading the myometrium beyond
the inner half is Stage Ic. Invasion of the cervix uteri represents a
more advanced stage (Stage II); extension to the pelvis and vagina
represents Stage III; and to the bladder and rectum, Stage IV (FIGO
classification).
Endometrioid adenocarcinomas represents the majority of
endometrial carcinomas in the developed countries, where they are also
162 L Deligdisch
Fig. 10 Same patient as in Fig. 9. Clear cell adenocarcinoma with marked nuclear
atypia. Hematoxylin/eosin, orginal magnification 400×.
diagnosed in Stage I (confined to the uterine corpus) in about 75% of
cases. Histologically, they are composed of glandular structures
resembling the normal endometrial tissue from which they originate.
Non-endometrioid histologic variants may coexist in up to 10% of the
tumor volume.
While most patients are peri and postmenopausal, endometrioid
adenocarcinomas can be diagnosed in younger women. They are usually but not always associated with polycystic ovarian disease and with
other conditions leading to anovulation. Most often in younger
women, EC is well differentiated and non-invasive.
The majority of endometrial carcinomas are manifested by vaginal
bleeding and can be diagnosed in the early stages as opposed to nonendometrioid carcinomas which may be diagnosed only in later stages
when they are spread beyond the uterus and even beyond the pelvicabdominal cavity.
An early diagnosis of endometrial cancer is possible and more likely
in the endometrioid variant, due to the frequent association with
endometrial hyperplasia of all degrees which is symptomatic, the patients
presenting with vaginal bleeding. Hyperplasia and carcinoma often coexist and represent indications for hysterectomy even if the proportion of
overt carcinoma admixed with hyperplasia is low in the examined
endometrial tissue. Hysterectomy is also indicated in atypical endometrial hyperplasia or EIN, especially in postmenopausal women.
PATHOLOGY OF ENDOMETRIAL CARCINOMA
Gross examination reveals a shaggy often polypoid surface with hemorrhagic and necrotic areas in the more advanced cases. The tumor
expansion is more often exoplytic than infiltrative but can be both.
The uterus is usually enlarged but sometime small uteri may harbor
diffuse and infiltrative tumors. The neoplasm may be diffuse or localized to one or more areas, mostly protruding into the endometrial
cavity and often with myometrial invasion. Many endometrial carcinomas are confined to the endometrial lining. Extension into the
lower uterine segment is common but the endocervical canal is
involved only in 20% of the cases.
Early Diagnosis of Endometrial Cancer 163
Histopathologic examination should define the grade of differentiation of the tumor based on architectural and cytological criteria.
The histologic architecture of endometrial carcinoma derives
from the glandular structures lining the uterine cavity. The more similar the tumor is to the normal glands, the better the differentiation.
The glands are closely packed, with little or no intervening stroma
and lined by atypical epithelial cell often piled up in multiple layers
(Fig. 11). In Grade 1 EC 95% or more of the tumor has a glandular
pattern; in grade 2, 6%–50% is composed of solid masses of tumor
cells; and in grade 3, more than 50% of the tumor is composed of
solid masses. The solid masses of tumor cells should not be represented by squamoid cells which represent squamous metaplasia and
are often seen in better differentiated tumors.
The nuclei generally correlate with the architectural pattern being
less atypical in the well differentiated tumors. However, in the presence of grade 3 nuclei (markedly enlarged, with irregular coarse chromatin, pleomorphic in shape and with multiple prominent nucleoli), the
164 L Deligdisch
Fig. 11 Well differentiated (Grade 1) adenocarcinoma, endometrioid type. Backto-back glands lined by a stratified epithelium. Hematoxylin/eosin, orginal magnification 400×.
better differentiated adenocarcinoma (grade 1 or 2) should be
upgraded to grade 3.
The same tumor often displays various degrees of differentiation
in different areas. Discordance between the grade of differentiation
of an endometrial carcinoma from endometrial curettage to that
seen in the hysterectomy specimen is not very unusual due to
sampling.
Early endometrial carcinoma is often associated with endometrial
hyperplasia of all degrees of severity, and especially with atypical complex hyperplasia (or EIN).
Endometrioid EC are the most common early endometrial carcinomas, with a polypoid or diffuse exophytic expansion and no or just
local myometrial invasion. Also often seen in early endometrial adenocarcinoma is an associated adenomyosis with areas of endometrial
glandular hyperplasia and even neoplastic changes confined to the
adenomyotic area, with diminished or absent stroma. Because these
changes are early neoplastic rather than invasive infiltrating, they represent a challenging dilemma for the patients’ management. Most of
such cases, however, are treated as infiltrating carcinomas to the
myometrium, despite their origin in adenomyotic foci to which they
are confined.
HISTOLOGIC PATTERNS OF ENDOMETRIAL
CARCINOMAS (TABLE 2)
Endometrioid Adenocarcinomas Histologic Variants
Endometrioid adenocarcinomas composed of glandular structures
somewhat analogous to normal endometrial glands can present
villous infoldings lined by epithelial cells similar to those lining
the glands, with rather bland nuclei. This represents the villoglan-
dular endometrial carcinoma which is a variant of a low grade
endometrioid adenocarcinoma. It should not be confused with
papillary carcinoma which represents a non-endometrioid uterine
carcinoma. Secretory carcinomas may be seen along with low grade
endometrioid adenocarcinomas. The glandular structures display
Early Diagnosis of Endometrial Cancer 165
an epithelial lining with vacuolated cytoplasm representing secretory changes, often due to progesterone therapy, with glycogen
vacuoles in a subnuclear location reminiscent of normal post
ovulatory changes (Fig. 12).
These features should not be interpreted as clear cell carcinoma,
which is a non-endometrioid carcinoma characterized by atypical,
often hobnail-shaped cells.
Squamous differentiation in endometrioid carcinoma occurs very
frequent, and the grading of these tumors is that of the glandular
166 L Deligdisch
Fig. 12 Endometrial adenocarcinoma, endometrioid type, treated with progesterone (megace) for six months. Subnuclear vacuoles similar to secretory changes in
a crowded glandular pattern. No mitotic activity is noted. Nuclei are relatively small
and quiescent. Hematoxylin/eosin, orginal magnification 100×.
Table 2. Pathologic Classification of Endometrial Adenocarcinoma
Endometrioid adenocar
cinoma Non-endometrioid carcinoma
Villo-glandular adenocarcinoma Serous carcinoma
Secretory adenocarcinoma Clear cell carcinoma
Ciliated (with tubal metaplasia) carcinoma Papillary carcinoma
Squamous differentiation in adenocarcinoma Mixed types and MMMT
Mucinous adenocarcinoma Undifferentiated
component rather than of the squamous elements. Squamous metaplasia of the endometrium is associated with estrogen effect and
consists of “morules” similar to those seen in endometrial hyperplasia, or diffuse sheets with keratinized areas replacing the glandular
structures.
Mucinous and ciliated endometrial carcinoma are less common,
are usually well differentiated (Grade 1) and diagnosed in Stage I as
most endometrioid carcinomas. Their origin in the endometrium on
biopsy has to be confirmed because mucinous adenocarcinomas usually originate in the endocervix.
Non-Endometrioid EC
These tumors are less commonly seen than endometrioid EC. The
histologic variants are serous, papillary and clear cell carcinomas.
Serous carcinomas were described also as papillary carcinomas
because of their similarity to ovarian serous papillary carcinomas. They
are a group of highly aggressive tumors. Most patients in this group are
elderly.
7
Clinically, they do not have the classical endogenous risk factors
(obesity, hyperestrogenism nulliparity etc.), neither were they likely to
have been treated with estrogens. Cervical cytology may detect abnormalities more often in this group than in endometrioid EC. The uteri
tend to be smaller and atrophic, sometimes with polypous growths that
are partially benign, containing EIC and/or early serous carcinomas.
Histologically, these tumors have glandular, papillary, and solid
patterns. The cells are often hobnail-shaped with clear cytoplasm
and atypical nuclei. The papillary fronds resemble those of ovarian
serous carcinomas (Fig. 13). Multinucleated and bizarre-shaped nuclei
are also present. Mitotic activity is high and abnormal. Psammoma
bodies are also encountered. The adjacent endometrium is often
atrophic and endometrial hyperplasia is unusual. EIC and minimal
serous carcinoma represent the early stages of these tumors which
can, however, metastasize to early to the ovary and peritoneum by
exfoliation and implantation (Fig. 7).
Clear cell carcinomas are infrequent EC, also seen more often in
older women. The tumor cells are mostly large containing glycogen-rich
Early Diagnosis of Endometrial Cancer 167