Endometrial cancer is the most common gynecological malignancy in high-income
countries. Although the overall prognosis is relatively good, high-grade
endometrial cancers
have a tendency to recur. Recurrence needs to be prevented since the prognosis for
recurrent endometrial cancer is dismal. Treatment tailored to tumor biology is the optimal
strategy to balance treatment efficacy against toxicity. Standard treatment consists of
hysterectomy and bilateral salpingo-oophorectomy.
Lymphadenectomy (with ongoing
studies of sentinel node biopsy) enables identification of lymph node positive patients who
need adjuvant treatment, including radiotherapy and chemotherapy. Adjuvant radiotherapy
is used for Stage I–II patients with high-risk
factors and Stage III lymph node negative
patients. In advanced disease, a combination of surgery to no residual disease and
chemotherapy results in the best outcome. Surgery for recurrent disease is only advocated
in patients with a good performance status with a relatively long disease-free
interval.
K E Y W O R D S
Chemotherapy; Corpus uteri; Endometrial cancer; FIGO Cancer Report; Gynecologic cancer;
Radiotherapy; Surgery
1 | STAGING
1.1 | Anatomy
1.1.1 | Primary site
The upper two-thirds
of the uterus located above the internal orifice
of the uterus is termed the corpus. The fallopian tubes enter at the
upper lateral corners of an inverse pear-shaped
body. The portion of
the muscular organ that is above a line joining the tubouterine orifices
is referred to as the fundus.
Cancer of the corpus uteri is usually referred to as endometrial
cancer, which arises from the epithelial lining of the uterine cavity.
Its first local extension concerns the myometrium. Cancers arising in
the stromal and muscle tissues of the myometrium are called uterine
sarcomas and are not discussed in this overview (readers are
directed to the chapter on uterine sarcomas in this Supplement by
Mbatani et al.1).
1.1.2 | Nodal stations
The lymphatic system of the corpus uteri is formed by three main lymphatic
trunks: utero-ovarian
(infundibulopelvic), parametrial, and presacral.
They collectively drain into the hypogastric (also known as internal
iliac), external iliac, common iliac, presacral, and para-aortic
nodes. Direct
metastases to the para-aortic
lymph nodes are uncommon. This is surprising
given that a direct route of lymphatic spread from the corpus
uteri to the para-aortic
nodes through the infundibulopelvic ligament
has been suggested from anatomical and sentinel lymph node studies.
1.1.3 | Metastatic sites
The vagina, ovaries, and lungs are the most common metastatic sites.
1.2 | Rules for classification
Surgical staging of endometrial cancer replaced clinical staging by the
FIGO Committee on Gynecologic Oncology in 1988 and again revised
1.3 | Histopathology
1.3.1 | Histopathologic types (according to WHO/
International Society of Gynecological Pathology
classification)
All tumors are to be microscopically verified.
The histopathologic types of endometrial carcinomas are2:
1. Endometrioid carcinoma: adenocarcinoma; adenocarcinoma-
variants (with squamous differentiation; secretory variant;
villoglandular variant; and ciliated cell variant).
2. Mucinous adenocarcinoma.
3. Serous adenocarcinoma.
4. Clear cell adenocarcinoma.
5. Undifferentiated carcinoma.
6. Neuroendocrine tumors.
7. Mixed carcinoma (carcinoma composed of more than one
type, with at least 10% of each component).
Apart from the classification of endometrial carcinoma, carcinoma of
the endometrium comprises mixed epithelial and mesenchymal tumors
including:
1. Adenomyoma
2. Atypical polypoid adenomyoma
3. Adenofibroma
4. Adenosarcoma
5. Carcinosarcoma: currently carcinosarcomas, in which both epithelial
and mesenchymal components are malignant and aggressive
tumors, are considered metaplastic carcinomas, and are treated as
aggressive carcinomas.
Endometrial cancers have traditionally been classified in one of the
following two categories:
1. Types 1 (grade 1 and 2 endometrioid carcinoma) are the most
common endometrial cancers. They may arise from complex
atypical hyperplasia and are linked to excess of estrogen stimulation.
As they are usually diagnosed at early stages, they
present a relatively good prognosis.
2. Types 2 are the least common endometrial tumors. They include
grade 3 endometrioid tumors as well as tumors of nonendometrioid
histology, and develop from atrophic endometrium. Type 2
tumors are less hormone sensitive. Since they are diagnosed in later
stages, they are generally more aggressive and have a poorer prognosis
than Type 1 endometrial cancer.
However, the Cancer Genome Atlas studies have identified four
molecular subgroups characterized, respectively, by POLE mutation,
mismatch repair deficiency, TP53 mutation, and a copy number low group
without a specific driver mutation, each with a distinct prognosis.3,4
1.3.2 | Histopathologic grades (G)
1. GX: Grade cannot be assessed.
2. G1: Well differentiated.
3. G2: Moderately differentiated.
4. G3: Poorly or undifferentiated.
Degree of differentiation of the adenocarcinoma is another basis for
classification carcinoma of the corpus, which are grouped as follows:
1. G1: less than 5% of a nonsquamous or nonmorular solid growth
pattern.
2. G2: 6%–50% of a nonsquamous or nonmorular solid growth pattern.
3. G3: greater than 50% of a nonsquamous or nonmorular solid
growth pattern.
1.3.3 | Pathologic grading notes
Notable nuclear atypia (pleomorphism and prominent nucleoli), inappropriate
for the architectural grade, raises the grade of a grade 1 or
grade 2 tumor by 1. However, this should not be done too easily as
grade 2 will then lose its discriminative power.5
Most authors consider serous and clear cell carcinomas high grade
by definition.
Grading of adenocarcinomas with squamous differentiation is allocated
according to the nuclear grade of the glandular component.
1.4 | FIGO staging classification
Table 1 shows the current FIGO staging classification for cancer of
the corpus uteri. Comparison of the stage groupings with the TNM
classification is represented in Table 2.
1.4.1 | Regional lymph nodes (N)
1. NX: Regional lymph nodes cannot be assessed.
2. N0: No regional lymph node metastasis.
3. N1: Regional lymph node metastasis to pelvic lymph nodes.
4. N2: Regional lymph node metastasis to para-aortic lymph nodes,
with or without positive pelvic lymph nodes.
1.4.2 | Distant metastasis (M)
1. MX: Distant metastasis cannot be assessed.
2. M0: No distant metastasis.
3. M1: Distant metastasis (includes metastasis to inguinal lymph
nodes or intraperitoneal disease
FIGO Stage
Ia Tumor confined to the corpus uteri
IAa No or less than half myometrial invasion
IBa Invasion equal to or more than half of the
myometrium
IIa Tumor invades cervical stroma, but does not extend
beyond the uterusb
IIIa Local and/or regional spread of the tumor
IIIAa Tumor invades the serosa of the corpus uteri and/or
adnexaec
IIIBa Vaginal involvement and/or parametrial involvementc
IIICa Metastases to pelvic and/or para-aortic
lymph nodesc
IIIC1a Positive pelvic nodes
IIIC2a Positive para-aortic
nodes with or without positive
pelvic lymph nodes
IVa Tumor invades bladder and/or bowel mucosa, and/or
distant metastases
IVAa Tumor invasion of bladder and/or bowel mucosa
IVBa Distant metastasis, including intra-abdominal
metastases and/or inguinal nodes
Diagnosis
The utility of population screening for endometrial cancer remains to
be fully substantiated.17 Transvaginal ultrasound (TVS) is a possible
screening test, as it is reasonably sensitive and specific. Screening is
only recommended for high-risk
groups, such as those with Lynch
type 2 syndrome with a wish for fertility preservation, before the decision
for prophylactic hysterectomy is made at a later age.18 In these
cases, endometrial surveillance is performed by aspiration biopsy
and transvaginal ultrasonography starting from the age of 35 years
(annually until hysterectomy). Prophylactic surgery (hysterectomy and
bilateral salpingo-oophorectomy),
preferably using a minimally invasive
approach, should be discussed at the age of 40 as an option for
Lynch type 2 syndrome mutation carriers to prevent endometrial and
ovarian cancer.19
After physical examination, endometrial cancer is usually suspected
with ultrasound—an effective first test with a high negative
predictive value when the endometrial thickness is less than 5 mm.20
Specifically, combination of transvaginal ultrasound with endometrial
biopsies obtained by curettage has been shown to have a negative predictive
value of 96%.20 When a biopsy is required, this can be obtained
usually as an office procedure using a number of disposable instruments
developed for this purpose. In patients with diagnostic uncertainty,
hysteroscopy may be performed, and with flexible instruments
can also be done without recourse to general anesthesia. However,
the prognostic role of cells that are transtubally flushed during hysteroscopy
remains uncertain. Anesthesia might be necessary in cases
of cervical stenosis or if patient tolerance does not permit an office
procedure. Individuals whose pelvic examination is unsatisfactory may
also be evaluated with transvaginal or abdominal ultrasound to rule
out concomitant adnexal pathology.
After a histopathologic diagnosis of endometrial adenocarcinoma,
other factors need to be assessed. These include the local extent of
the tumor, evidence of metastatic disease, as well as perioperative risk.
The pathology report from endometrial sampling should indicate
at least the tumor type and grade of the lesion. Overall there is only
moderate agreement on tumor grade between preoperative endometrial
sampling and final diagnosis, with the lowest agreement for grade
2 carcinomas. Agreement between hysteroscopic biopsy and final
diagnosis is higher than for dilatation and curettage; however, it is not
significantly higher than for office endometrial biopsy.21
Full biochemistry (renal and liver function tests), and blood count
also represent routine tests in the diagnosis of corpus uterine cancers.
A chest X-ray
is often performed as it is a universally available, low-cost
examination and the consequences of detecting lung metastases,
although rare in early stage disease, are significant. Serum CA125 may
be of value in advanced disease for follow-up.
Evaluation for metastasis
is useful particularly in patients with abnormal liver function tests,
and clinical findings such as parametrial or vaginal tumor extension. In
high-risk
patients, CT-based
imaging of the chest, abdomen, and pelvis
or PET-CT
may help determine the surgical approach. Cystoscopy and/
or proctoscopy may be helpful if direct extension to the bladder or
rectum is suspected.
3 | PROGNOSTIC TUMOR
CHARACTERISTICS FOR HIGH-RISK
DISEASE
Its early presentation following postmenopausal bleeding results in
a generally good prognosis, but it should be treated using evidence-based
protocols, and where appropriate, by expert multidisciplinary
teams. Four main histopathologic criteria are recommended to determine
high-risk
disease:
1. Tumor grade 3 (poorly differentiated).
2. Lymphovascular space invasion.
3. Nonendometrioid histology (serous, clear cell, undifferentiated,
small cell, anaplastic, etc.).
4. Cervical stromal involvement.
MRI scanning and intraoperative frozen section represent the most
accurate means of assessing both the depth of myometrial invasion and
cervical involvement.22–24 Although CT and MRI are equivalent in terms
of evaluating nodal metastases, neither is suitable to replace surgical
lymph node assessment, which provides histological confirmation.25,26
PET-CT
is the best imaging method to evaluate lymph node and distant
metastases, and could be considered in high-risk
or advanced stage disease.
The role of PET-MRI
is currently being investigated.
Nonsurgical staging for endometrial cancer, where extrauterine
disease exists, is inherently inaccurate. This is particularly the case for
the detection of small nodal involvement, intraperitoneal implants,
and adnexal metastasis.
4 | SURGICAL ST AGING PR OCEDURE F OR
ENDOMETRIAL CANCER
Staging of endometrial cancer was changed from clinical to surgical
in 1988, by the FIGO Gynecologic Oncology Committee. This recommendation
has led to considerable debate and effort to define surgical
staging procedures that can be implemented internationally. A generally
recommended protocol includes opening of the abdomen with a vertical midline incision and peritoneal washings taken immediately
from the pelvis and abdomen, followed by careful exploration of the
intra-abdominal
contents. The omentum, liver, peritoneal cul-de-
sac,
and adnexal surfaces should be examined and palpated for any possible
metastases. These procedures should be followed by careful palpation
for suspicious or enlarged nodes in the aortic and pelvic areas.
However, laparoscopic procedures have increasingly been introduced
as standard, especially for early stage disease, as these have been
proven safe and reduce acute treatment-related
complications.27,28
The recommended standard surgical procedure is an extra-fascial
total hysterectomy with bilateral salpingo-oophorectomy.
Adnexal
removal is recommended even if the tubes and ovaries appear normal,
as they may contain micrometastases. In premenopausal women with
low-grade
early stage disease, ovarian preservation could be considered.
29,30 Vaginal cuff removal is not advised, nor is there any benefit
from excising parametrial tissue in the usual case. Where obvious cervical
stromal involvement is demonstrated preoperatively, a modified
radical hysterectomy has been historically performed. However, there
is consensus (ESMO-ESGO-
ESTRO)
that simple hysterectomy with
free margins together with pelvic and para-aortic
lymphadenectomy
may be sufficient.31
The safety of endoscopic surgery for the treatment of endometrial
cancer has also been the subject of considerable debate. Recent
studies have demonstrated that laparoscopic removal of the uterus
and adnexae appears to be safe. For instance, not many differences
have been reported in terms of major complications between abdominal
hysterectomy and laparoscopically assisted vaginal hysterectomy
(LAVH) or total laparoscopic hysterectomy (TLH). Additionally, laparoscopic
interventions are associated with significant decreased risk
of major surgical adverse events, shorter hospital stays, less pain,
and faster recoveries.32–34 Owing to the demonstrated oncological
safety of the laparoscopic approach,28,35 hysterectomy and bilateral
salpingo-oophorectomy
by this route is recommended in those
patients with no contraindications to laparoscopy (e.g. large-volume
uterus). The endoscopic route also appears safe in high-risk
endometrial
cancer.36 This approach can be accompanied by a laparoscopic
lymphadenectomy, if surgical staging is to be undertaken. Robotic
surgery for morbidly obese patients represents a valuable option for
experienced surgeons. In these instances, surgical management using
robotics is safe and presents fewer perioperative complications compared
with open surgery.37 Furthermore, retrospective studies have
suggested equivalent oncologic outcomes compared with traditional
laparoscopic surgery.38,39
The utility of lymphadenectomy of the pelvic and para-aortic
areas is disputed, albeit it is currently mandated through the staging
system. Currently, it is advised that complete lymphadenectomy
is reserved for cases with high-risk
features. In contrast, selective
node sampling has been deemed dubious as a routine approach.
Since many individuals with endometrial cancer are obese or elderly,
with concomitant medical problems, clinical judgment is required
to determine if additional surgery is warranted. Any deeply invasive
tumor or radiological suggestion of positive nodes is an indication
for retroperitoneal lymph node evaluation, which might be followed