Endometrial cancer is the fifth leading cause of cancer in women
worldwide, with approximately 150,000 cases diagnosed each year, and
is the most common malignancy of the female genital tract in the
United States. Dr. Chen and colleagues provide an excellent review of
current clinical investigations focusing on the evaluation and
treatment of this carcinoma.
Hereditary Endometrial Cancers
Most cases of endometrial carcinoma are thought to be sporadic.
However, some clearly have a hereditary origin. Daughters and sisters
of women with endometrial carcinoma have a 2.7 relative risk of
developing endometrial carcinoma when compared to women without such
a family history.
The vast majority of endometrial carcinomas recognized as inherited
occur in women affected with the hereditary nonpolyposis colorectal
cancer (HNPCC) syndrome. This autosomal-dominant inherited disease is
associated with an increased risk of developing a number of different
types of cancer, especially colorectal cancer, with endometrial
carcinoma being the most common extracolonic cancer. Women who are
HNPCC carriers have a 10-fold increased risk of developing
endometrial carcinoma, compared to the general population. However,
the percentage of endometrial cancers due to HNPCC is not well defined.
A small body of literature suggests the possibility of a
site-specific form of inherited endometrial carcinoma. However, at
present, there are insufficient data to conclusively prove its
existence as a clinical genetic entity.
Evolution of Treatment
Many patients with endometrial cancer present with early-stage
disease, which has a high rate of cure. However, a significant number
of patients present with more advanced disease or unfavorable
histologies, which result in significant morbidity and death.
The evolution of therapy for patients with adenocarcinoma of the
endometrium has been based on the elucidation of the pattern of
spread of the disease, resulting in treatment regimens (adjuvant
radiation and/or chemotherapy) tailored to surgicopathologic
findings. Such regimens are associated with improved survival and
decreased recurrence rates in patients whose disease is confined to
the pelvis even in the face of known adverse factors.
It remains unanswered whether patients with intermediate risk factors
for recurrence should receive adjuvant therapy. Nevertheless,
patients who demonstrate extrauterine disease, especially to the
para-aortic lymph nodes, continue to face a dismal prognosis.
Clinical Behavior and Histology
There appear to be two types of endometrial cancer (referred to as
type I and type II). The two types differ in epidemiology,
presentation, and behavior.
The majority of patients with endometrial carcinomaabout
two-thirds of the totalhave a history of exposure to estrogen,
and their the mean age (59 years) is slightly lower than the overall
mean age for patients with the disease. These tumors usually behave
in a relatively indolent manner. This group of tumors have been
designated type I endometrial carcinoma and are often
referred to as estrogen related. They are generally low
grade and low stage, and have a good prognosis.
Both epidemiologic and light microscopic studies have suggested that
this type of carcinoma develops from normal epithelium, under the
influence of estrogen stimulation, through a continuum of
histopathologically recognizable lesions known as hyperplasias.
Histologically, the majority of type I tumors tend to have
architectural features that resemble the appearance of normal
endometrial glands; these tumors are called endometrioid
carcinomas to denote this resemblance. The overall survival
rate for patients with type I endometrial cancer exceeds 80%.
Type II carcinomas, in contrast, are unrelated to estrogenic
stimulation, occur in older women (mean age, 68 years), and have an
aggressive behavior. Such lesions are characterized by deep
myometrial invasion, frequent nodal and extrauterine metastasis, and
poor outcome (up to 50% of patients develop recurrences).
Many type II carcinomas are composed of cuboidal cells showing marked
cytologic atypia and nuclear pleomorphism that grow in either a
glandular or papillary architecture. These features are strikingly
similar to those of the serous carcinoma of the ovary, giving rise to
the name uterine serous carcinoma to distinguish these
endometrial tumors from primary serous ovarian tumors.
By definition, serous carcinomas of the endometrium are all high
grade, frequently have extrauterine spread by the time of diagnosis,
carry a poor prognosis, and behave much like ovarian serous
carcinomas. Serous tumors of the endometrium generally arise in
the setting of an atrophic, not a hyperplastic, endometrium.
A putative precursor of uterine serous carcinoma has been described
and is termed endometrial intraepithelial carcinoma.
Endometrial intraepithelial carcinoma, even in the absence of
definitive invasion in the uterus, can be associated with
intraabdominal carcinoma, illustrating the aggressive nature of this
There are several other minor histologic variants of endometrial
carcinoma (eg, mucinous, villoglandular, and clear cell). The
appropriate category in which these histologic variants belong is not
well established. These histologic variants are rare and poorly understood.
Adjuvant Therapy for Endometrial Cancer
Patients at high risk for developing recurrent endometrial cancer are
candidates for adjuvant treatment following primary surgery.
Definitions for intermediate-risk patients vary among studies, but
generally include stage IA, grade 3 tumors and stages IB or IC
cancers of any grade. The benefit of adjuvant treatment following
surgery in this group of patients remains unsettled.
The only prospective, randomized trial in endometrial cancer patients
with intermediate-risk factors after surgical staging is the
Gynecologic Oncology Group study (GOG 99), which randomized
intermediate-risk patients to surgery only or surgery plus adjuvant
pelvic radiation. Total abdominal hysterectomy, bilateral
salpingo-oophorectomy, and pelvic and para-aortic node sampling were
required in all patients. Patients with stage Ib, Ic, IIa, and IIb
adenocarcinoma, but not papillary serous or clear cell carcinoma,
were eligible. Of 448 women entered into this study, 390 met all of
the eligibility requirements. The investigators of this study are
currently analyzing the results. Median follow-up is 56 months, with
only 9% of patients followed for less than 2 years. To date, there
have been 39 recurrences and 52 deaths among these women; 56% of
these deaths were the result of the disease or its treatment. The
estimated 2-year progression-free survival rate is 88% in patients
treated with surgery onlyand 96% in those given pelvic radiation (P = .004).
Thus far, this study shows that use of adjunctive radiation therapy
in patients with intermediate-risk endometrial cancer decreases the
risk of recurrences but has an unappreciable effect on overall
survival. The overall recurrence rate in this study was lower than
expected based on prior staging and prognosis studies. One
possibility is that this was the result of a trend to perform more
complete (therapeutic) rather than incomplete (sampling)
Treatment of Advanced Disease
Although localized endometrial cancer can be effectively treated with
surgery and radiation therapy, treatment of advanced endometrial
cancer remains controversial. Adjuvant therapy for stage IIIC tumors,
particularly pelvic node-positive disease, has primarily consisted of
pelvic radiation. Systemic failures occur frequently, suggesting that
systemic adjuvant treatment may have a role in patients with stage
IIIC or IV disease.
The optimal adjuvant therapy after surgical staging and maximum
cytoreduction is unknown. The ongoing protocol GOG 122, which is
randomizing patients with advanced endometrial carcinoma to
whole-abdominal radiotherapy vs combined doxorubicin-cisplatin
(Platinol) chemotherapy, may answer the question of which adjuvant
regimen is most effective and least toxic in patients with metastatic
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