Draft 1

ENDOMETRIAL CARCINOMA

Index

1. Clinical symptoms and signs

2. Screening
2.1 Family history - Lynch type 2 syndrome

3. Referral pathway
3.1 For GP
3.2 For non-oncological consultants/ firms
3.3 For referral from unit to centre

4. Diagnosis

5. Investigations

6. Gynaecological cancer multidisciplinary team

6.1 Information

7. Pathology
7.1 Endometrial carcinoma classification (adapted from WHO classification)
7.2 Architectural grading of endometrioid adenocarcinoma (FIGO)
7.3 Nuclear grading
7.4 Type 1 and type 2 tumours
7.4.1 Type 1 carcinoma
7.4.2 Type 2 carcinoma
7.4.3 Overall outcome for endometrial carcinoma based on pathology
7.5 Pathological reporting of endometrial carcinoma

8. Staging

9. Histopathology minimum dataset

10. Treatment
10.1 Abdominal, vaginal and laparoscopic hysterectomy
10.2 Pelvic lymphadenectomy
10.3 Indications for adjuvant radiotherapy for stage I disease
10.4 Further indications for radiotherapy
10.5 Management of stage II/III disease
10.6 Chemotherapy / progestogens and HRT
10.7 Uterine sarcomas/ carcinosarcomas

11. Dealing with recurrent disease

11.1 Palliative care

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

Draft 1

12. Survival
12.1 Cancer dataset/ inventory of active trials

13. Follow up
13.1 Identification and management of late effects of treatment

14. Contact names/ numbers

15. Algorithm for postmenopausal bleeding

16. Algorithm

17. Summary

18. References

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

Draft 1

Introduction
Currently about 3900 new cases are diagnosed annually in England and Wales with 770 deaths. This
survival is disappointing considering 75% of patients present with early (stage I) disease, and reflects
the need to develop central referral and the application of All Wales Guidelines (CSCG, 2001).
In Wales, endometrial carcinoma accounts for nearly 4% of all female cancer registrations (1993-
2002) with the highest age-standardised incidence in Anglesey and the lowest in Cardiff. The overall
incidence in Wales is 13.5/100,000 women (WCISU, 1991-1999). The one-year relative survival
increased from 88% for the period 1990-1994 to 92% for the period 1995-1999. A similar
improvement was noted in the five-year relative survival from 75% to 80%.
Endometrial carcinoma is a disease of postmenopausal women with only 25% presenting before the
menopause. Only 2-5% is diagnosed before the age of 40 years. The mean age is 60 years with a peak
incidence between 55 and 70 years.
Risk factors include:
obesity
nulliparity
polycystic ovary syndrome
diabetes
hypertension
family history of endometrial, ovarian or intestinal malignancy
past history of breast, ovarian or intestinal malignancy.

1. Clinical symptoms and signs

Over 90% of endometrial carcinomas present with postmenopausal bleeding. However only 20% of
patients with postmenopausal bleeding will have a malignant origin for their bleeding of which over
50% will be due to endometrial carcinoma. The older the woman the higher the chances are that the
bleeding is due to tumour. A small proportion will present with an offensive vaginal discharge due to a
draining pyometra. About 1 to 5% of tumours are asymptomatic and detected largely by cervical
screening or ultrasonography. It may also be a chance finding at operation for suspected benign
disease.
There is usually little to find on examination. The uterus may be enlarged in advanced disease and
vaginal metastases particularly in the lower third and the suburethral area are the most common sites.

2. Screening
There is no screening programme to detect endometrial carcinoma.

2.1 Family history - Lynch type 2 syndrome

Asymptomatic women are eligible for review with the Cancer Genetics Service in Wales if there are
3 first degree affected relatives with colonic carcinoma or 2 first degree relatives with colonic
carcinoma aged 60 years or less at onset or 1 at 40 years or less at onset with 1 first degree relative
with ovarian cancer. Such women may have a 30% lifetime risk of endometrial carcinoma.
Contact number:
North Wales 01745 534447

3. Referral pathway (see 14. Contact names/ numbers)

3.1 For GP
If endometrial cancer is suspected then referral should be to a general gynaecologist, the lead in the
cancer unit or gynaecological oncologist in the cancer centre.

Standards
Rapid access to the specialist should be available with the patient seen within 2
weeks of date of receipt of the referral letter/ fax.

Definitive treatment should be commenced no later than 62 days after receipt of the
referral letter/ fax.

Definitive treatment should be commenced no later than 31 days after diagnosis for
non urgent suspect cancer referrals.

3.2 For non-oncological consultants/ firms

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

Draft 1

If the diagnosis is suspected or confirmed referral to the local unit lead or gynaecological cancer
centre should be made.

3.3 For referral from unit to centre

This is appropriate for all cancer cases FIGO Ic and type 2/ poorly differentiated FIGO Ib. All
sarcomas and carcinosarcomas should be referred to the centre (see 15. Algorithm for primary
management of patients with endometrial cancer).

4. Diagnosis
Primary assessment in all cases is with transvaginal ultrasound (Karlsson et al, 1995) and pelvic
examination. This strategy also appears to the most cost effective (Clark et al, 2006). All
postmenopausal patients with an endometrial thickness >5mm or persistent bleeding despite a normal
endometrial thickness should have an endometrial biopsy (NHS Executive, 1999; grade B
recommendation). If there is difficulty in obtaining a pelvic scan then an endometrial sample should
be attempted in clinic. If the endometrium is difficult to identify then hysteroscopy should also be
considered. The value of endometrial thickness in perimenopausal bleeding is questionable as the
thickness range is variable. Cervical cytology will detect endometrial carcinoma in only 40% of cases
and is far too unreliable.
Hysteroscopy can be performed in an outpatient setting. It can enable visualisation of the degree of
encroachment of the tumour to the internal os which may then modify the form of treatment offered
(see 15. Algorithm for postmenopausal bleeding ).

5. Investigations
After confirming the diagnosis the objectives of further investigations are to
determine the extent of disease
determine suitability for treatment.
Those that penetrate more deeply into the myometrium are more likely to have involved pelvic nodes.
The frequency of pelvic and para-aortic node involvement increases to 25 and 17% respectively for
deep muscle invasion (Creasman et al, 1987).
A chest X-ray is essential. An MR scan will help identify the site and size of the primary tumour, any
evident myometrial invasion (Kim et al, 1995; Yamashita et al, 1993), the presence of lymph node
metastases and the presence of occult cervical involvement but image resolution of the myometrium
can be disturbed by a recently performed uterine curettage. MR scanning should be considered for all
patients with endometrial cancer prior to treatment (grade B recommendation). Ultrasound can be
used as an alternative but is less accurate than MR. CT scanning is less accurate than both ultrasound
and MR for measuring myometrial infiltration but is an alternative method of imaging extra uterine
disease if a patient is unsuitable for MR.

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

Draft 1

6. Gynaecological cancer multidisciplinary team

Core team Named team member Additional member or

Cover (core team only)
Gynae oncologist Mr Leeson / Mr Toon
Gynae lead cancer surgeon Mr Bickerton/ tba
Medical oncologist Prof Stuart Dr Williams
Clinical Oncologist Dr Al-Sammarie tba
Pathologist/ Cytopathologist Dr Lord tba
Palliative care team Dr Williams tba
Radiologist Dr Barwick Dr Wenham
MDT co-ordinator Ms Jones tba
CNS Ms Hall
Extended team
Core/ extended teams to
Ultrasonographer tba
include members from YGC/
Junior doctors
NEWT
Psychologist
Geneticist Ms Grier
Social worker tba
Ward Sister Sr Williams
Research nurse
Colorectal/ urological/ plastics as required

6.1 Information

Standards
All patients must have access to a gynaecological oncology clinical nurse specialist
within 24 hours of the patient being informed of her diagnosis (this should include
a daytime contact telephone number for the clinical nurse specialist). Preferably the
nurse specialist should be at the consultation when the patient is given her
diagnosis.

All referring practitioners and/ or patients GPs should be informed by letter or

secure fax within 24 hours of the patient being informed of her diagnosis.

All patients must be given appropriate literature about the management, treatment
and outcome for cervical cancer such as a Cancerbackup leaflet or equivalent.

All these activities must be documented in the patients case record.

7. Pathology

7.1 Endometrial Carcinoma Classification (adapted from WHO classification).

Endometrioid
Villoglandular
Secretory
Ciliated cell with squamous metaplasia
Endometrioid with squamous differentiation
Serous
Clear cell
Mucinous
Squamous
Mixed types
Undifferentiated

7.2 Architectural grading of endometrioid adenocarcinoma (FIGO)

Grade I 5% or less of the tumour shows a solid pattern
North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)
Draft 1

Grade II Between 6 and 50% of the tumour exhibits solid growth

Grade III More than 50% of the tumour shows a solid growth pattern

It is important to avoid areas with squamous differentiation and evaluate only glandular areas.

7.3 Nuclear grading

Grade 1 Oval/ elongated nuclei, fine chromatin, small nucleoli, few mitoses
Grade 2 Features between 1 and 3
Grade 3 Enlarged/ pleomorphic nuclei, coarse chromatin, prominent nucleoli, many mitoses

If an endometrioid adenocarcinoma is a FIGO morphological grade I or II tumour it should be raised by one

grade if it shows nuclear grade 3 features.
Serous carcinoma, clear cell carcinoma, squamous carcinoma and undifferentiated carcinoma are not graded,
these tumours are basically highly malignant neoplasms. Serous carcinoma, clear cell carcinoma and
undifferentiated carcinoma of large cell type usually exhibit grade 3 nuclear abnormalities.

7.4 Type 1 and type 2 tumours

Over recent years it has become evident that there are two types of endometrial carcinoma. Type 1 is
associated with unopposed oestrogenic stimulation and previous endometrial hyperplasia. This is the
commonest form of endometrial carcinoma and the endometrioid subtype is the prototypic tumour in
this category. Serous carcinoma is the prototypic type 2 carcinoma and these tumours are not related
to oestrogenic hyperstimulation and not usually associated with pre-existing hyperplasia. Mucinous,
endometrioid with squamous differentiation and ciliated cell carcinomas fall into the type 1 group but
clear cell carcinoma is also regarded as a type 2 carcinoma. Recent molecular genetic data support
carcinosarcomas also being epithelial tumours with metaplasia to a stromal component and many
would now put these tumours into the poorly differentiated carcinoma category.
This classification follows the WHO and ISGP histological classification of endometrial carcinomas.

7.4.1 Type 1 carcinoma

Endometrioid carcinoma is the most common tumour in this group and the most common form of
endometrial carcinoma overall, accounting for of all cases. By definition such tumours do not
contain more than 10% squamous, serous, mucinous, or clear cell differentiation, as if they did they
would be regarded as mixed tumours. Most patients with this tumour are peri- or postmenopausal and
those rare cases that occur in women under the age of 30 years appear to have a very good prognosis,
being low grade and often minimally or non-invasive. Endometrioid carcinomas tend to be well
differentiated but the tumours are graded on the basis of a combination of the architecture and nuclear
detail. Zones of squamous epithelium are not included as solid areas and the tumour is graded on the
glandular component only. Marked discordance between the architectural and nuclear grade is
unusual in endometrioid carcinoma and always raises the concern that the tumour may be of type 2.
Discordance in grading between curettage and hysterectomy specimens occurs in up to a cases and
also perhaps 40% of curettage specimens diagnosed as atypical hyperplasia will have carcinoma on
hysterectomy.

7.4.2 Type 2 carcinoma

Most data on type 2 carcinomas relate to serous carcinoma. There appears to be an in-situ phase of
this tumour, termed endometrial intraepithelial carcinoma but this is usually only seen, when there is
already established serous carcinoma. A papillary pattern typically predominates in serous
carcinomas but a papillary pattern of itself may be seen in low grade as well as high grade carcinoma.
The cytological features of the tumour cells are varied but marked nuclear atypia is always present and
is required for a tumour to qualify as high grade serous carcinoma. A primary feature of this tumour
is the discordance between the architecture, which usually appears well differentiated, and the nuclear
morphology, which is high grade. The aggressive nature of this tumour can be deduced from the fact
that even patients with only endometrial intraepithelial carcinoma, in a completely sampled
endometrium can have metastatic disease in the ovaries, peritoneum or omentum, presumably as a
result of implantation of tumour. Clear cell carcinomas are generally believed to be similar overall in
outcome to serous carcinoma.

7.4.3 Overall outcome for endometrial carcinoma based on pathology

Endometrioid adenocarcinoma spreads by lymphatic and vascular dissemination, direct extension and
transperitoneal seeding. Pelvic lymph nodes tend to be involved before para-aortic. In a GOG study
of 1180 patients with clinical stage I and occult stage II adenocarcinoma, multivariant analysis
showed that advancing age worsens prognosis and cell type, architectural grade, depth of myometrial
invasion, vascular space involvement and peritoneal cytology all appear to be independent risk factors
for recurrence and death (Morrow et al, 1991).
North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)
 Draft 1

Patients with grade I endometrioid carcinoma and with tumour confined to the endometrium and
without vascular invasion, have an approximately 95% or greater 5 years survival disease-free,
whereas patients with grade III tumours and involvement to the middle third of the myometrium,
together with vessel involvement, have a 5 year disease free survival of approximately 65%.
Statistical models to predict survival are the best method of assessing relative risk. In general, as
most endometrioid carcinomas tend to be low stage and low grade, survival is high. The outcome for
type 2 carcinomas is very different. These patients tend to be considerably older than those with
endometrioid carcinoma and are often high stage at the time of presentation. Under-staging clinically
is common. Five and 10 year survival rates for all stages are approximately 36% and less than 20%.
Some studies even for pathological stage I serous carcinomas have revealed 5 year survival of no more
than 40%. With type 2 tumours prognostic factors indicative of shorter survival include increasing
age, vessel invasion and greater than half the myometrial depth involved. Even intraendometrial
carcinomas have a high risk of metastasis, with 13% of carcinomas confined to the endometrium
having para-aortic lymph node metastases and some studies suggest an outcome even for stage Ia
tumours of only 57% survival at 5 years. Endometrial carcinomas containing a component of serous
carcinoma, making up as little as 25% of the tumour, appear to have the same survival as pure serous
carcinomas.

7.5 Pathological reporting of endometrial carcinoma

It is firmly recommended that reporting of endometrial carcinoma of any type should follow the
national minimum dataset for endometrial carcinoma, given below. Either the protocol sheet should
be provided, or the histological report should include all features given in the dataset.

8. Staging

FIGO stages NM categories

primary tumour cannot be assessed TX

no evidence of primary tumour T0
Stage 0 carcinoma in situ (preinvasive carcinoma) Tis

Stage I carcinoma confined to the corpus T1

a carcinoma confined to the endometrium T1a
b < myometrial invasion T1b
c > myometrial invasion T1c
Stage II involving cervix but does not extend beyond uterus T2
a glandular involvement only T2a
b cervical stromal involvement T2b
Stage III local and/ or regional spread as defined in IIIa, b or cT3 and/ or N1
a disease involving the adnexae (direct extension or
metastases), serosa or +ve peritoneal cytology
(washings or ascites) T3a
b vaginal metastases (direct extension or metastases) T3b
c pelvic or para-aortic node metastases N1
Stage IVa bladder* or rectal mucosal involvement T4
b extrapelvic metastases including
inguinal lymph nodes M1

*The presence of bullous oedema is not sufficient evidence to classify a tumour as T4.
FIGO, 2003
Regional lymph nodes (N) Distant Metastasis (M)

NX regional lymph nodes cannot be assessed MX distant metastasis cannot be assessed

N0 no regional lymph node metastasis M0 no distant metastasis
N1 regional lymph node metastasis M1 distant metastasis

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

Draft 1

9. Histopathology minimum dataset

National Minimum Dataset

Endometrial Cancer Histopathology Report

Gross description
Dimensions of uterus: Length ..........mm Transverse .......mm Antero-posterior........mm

Maximum dimensions of tumour: .......mm

Is there obvious myometrial invasion: Yes No

Histology
Type: Endometrioid Serous Clear cell
MMMT other (please specify)

Grade (FIGO): (only applies to endometrioid carcimona) I II III N/A

Myometrial invasion: None <50% >50%

Is there microscopic involvement of;

the cervical stroma Yes No
the appendages Yes No
the serosa Yes No

Is there lymphovascular invasion: Yes No

Is there associated endometrial hyperplasia: No Yes Simple Complex Atypical

Normal: right ovary left ovary right tube left tube

Abnormal: (please specify)
Pelvic Nodes right left Common Iliac nodes right left
(including obturator, internal
and external iliac)
total number of nodes total number of nodes
retrieved .. .. retrieved .. ..
lymph nodes with lymph nodes with
tumour deposits .. .. tumour deposits .. ..

Para-aortic nodes: not sampled positive negative

Peritoneal washings: not sampled positive negative

Comments

SNOMED Codes
T82000 Uterus (endometrium) M81403 (Adenocarcinoma) M84413(Serous adenocarcinoma)
M83103 (Clear cell carcinoma) M89503 (Mixed Mllerian tumour)
T08000 Lymph node M81406 (Metastatic carcinoma)

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

Draft 1

10. Treatment (see 16. Algorithm and 17. Summary)

Factors such as tumour stage, medical fitness and wishes of the patient will all influence management.

10.1 Abdominal, vaginal and laparoscopic hysterectomy

Stage I disease is treated with surgery. Total abdominal hysterectomy and bilateral salpingo-
oophorectomy is routine and appropriate for stage Ia/b well and moderately differentiated tumours
(Mariani et al, 2000; grade B recommendation). Peritoneal washings are part of standard surgical
assessment but may be misleading in modern practice following hysteroscopy (Leveque et al, 1998).
Disease free survival was found to be reduced in a retrospective study of 369 patients with stage I
endometrioid adenocarcinoma where 13 patients had positive peritoneal cytology and appeared to be
an independent prognostic indicator for disease free status (Obermair et al, 2001). Peritoneal
washings should be used in the routine assessment at laparotomy (grade B recommendation) but
would not determine adjuvant therapy in early stage disease. Omental biopsy should be considered
(Neito et al, 2002; grade C recommendation).
Vaginal hysterectomy with or without adnexectomy may be considered in a grossly obese patient with
a degree of uterine prolapse and an adequate vaginal capacity. A large episiotomy can be helpful.
Laparoscopic assisted hysterectomy with or without laparoscopic lymphadenectomy is a useful
technique to reduce morbidity of major surgery in the elderly with equivalent 3 year survival and
recurrence rates to abdominal hysterectomy (Magrina et al, 1999). At present laparoscopic assisted
vaginal hysterectomy accounts for only a small minority of cases (preliminary ASTEC data).
Patients are to be referred to the Liverpool Womens Hospital if for laparoscopic node
dissection.

10.2 Pelvic lymphadenectomy

Approximately 10% of patients have occult pelvic lymph node involvement (Creasman et al, 1976).
Selective sampling of the para-aortic, common iliac, internal and external iliac and the obturator
nodes may indicate which high risk patients are more likely to be upstaged and require adjuvant
therapy. Lymph node sampling is unlikely to be therapeutic and its value is questionable as it provides
limited assessment of the pelvic nodal status.
Bilateral pelvic lymphadenectomy provides a more logical surgical approach for provisionally staged
Ic tumours and /or poorly differentiated tumours and other adverse histological sub types (high risk)
for patients fit enough to withstand a more prolonged procedure (Podratz et al, 1998; grade C
recommendation). This may obviate the need for external beam radiotherapy for node negative high
risk patients (Nelson et al, 1999; grade B recommendation). Preliminary data from ASTEC (a
prospective RCT of 1408 women assessing the role of lymphadenectomy and radiotherapy for
endometrial carcinoma) suggests that there is no survival benefit from bilateral pelvic
lymphadenectomy for any group of stage I patients. However until this data has been published and
subject to critique, Ic tumours at MR imaging, poorly differentiated or type 2 tumours and sarcomas
should be considered for bilateral pelvic lymphadenectomy if a patient is fit enough to have the
extensive surgery. A retrospective review of 12,333 patients from the SEER database found an
improved survival for stage Ib poorly differentiated and all stage Ic women after multivariate analysis
adjusted for confounders including adjuvant radiotherapy (Chan et al, 2006). The management of
node positive patients is less clear (see 10.4 and 10.6). A case control study showed improved survival
in lymphadenectomised women, but these results could have been influenced by case mix and non
surgical treatment (Kilgore et al, 1995). The COSA /NZ /UK Endometrial Cancer Study Groups, 1996
examined the role of pelvic lymphadenectomy in 238 high risk patients as part of a randomised trial
of adjuvant hormone therapy. Although this study had a 45% (14/31) recurrence rate in node positive
patients as opposed to 14% (29/207) in the node negative group, all but 5% of the node positive
recurrences were extrapelvic. Clearly residual disease appears likely in node positive patients and this
residual disease may be locoregional at the time of surgery. The role of para-aortic sampling and para-
aortic lymphadenectomy is unclear.

10.3 Indications for adjuvant radiotherapy for stage I disease

Although the efficacy of adjuvant locoregional radiotherapy appears unproven such treatment appears
appropriate for node positive patients until further information becomes available. The role of
adjuvant vaginal brachytherapy is unclear (Irwin et al, 1998). It is associated with additional pelvic
morbidity and is not incorporated into all treatment protocols (grade B recommendation).
For patients having TAH/BSO without pelvic lymphadenectomy, adjuvant radiotherapy is appropriate
for patients with myometrial invasion to more than of its thickness, if there is unsuspected cervical
involvement, if sampled nodes are involved or if the tumour is infiltrating myometrium and poorly
differentiated. Stage Ib adenosquamous, clear cell and serous-papillary tumours should have post
operative radiation (grade C recommendation). Two RCTs have found that adjuvant radiotherapy
reduced the rate of local recurrences, but there was no evidence of a survival advantage (Aalders et al,
1980; Creutzberg et al, 2000). However a recent retrospective non-randomised analysis of over 21,000
North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)
Draft 1

women from 1988-2001 has shown that adjuvant radiotherapy after hysterectomy improved overall
and relative survival in stage Ic well and poorly differentiated tumours (Lee et al, 2006). The lack of a
survival advantage for moderately differentiated tumours may have been due to insufficient size of this
cohort of patients.
All cases must be discussed at the gynae cancer MDT to decide further treatment.

10.4 Further indications for radiotherapy

Standards
Radiotherapy should start 14 days after referral for radical treatment (good
practice) although 28 days is acceptable (minimum standard).
Radiotherapy should start 28 days after referral for adjuvant treatment (minimum
standard).
JCCO/RCR guidance

External beam / brachytherapy should be given to all stage II patients unsuspected at laparotomy.
Bilateral pelvic lymphadenectomy and radiotherapy may improve local control for node positive
women but additional morbidity (particularly small bowel and ureteric obstruction) must be
considered (Mariani et al, 2006; grade B recommendation). Radiotherapy should be considered for
stage II patients treated with radical hysterectomy if nodes are subsequently found to be involved (re-
staged IIIc).
Patients with stage III and IV disease should be treated with brachytherapy and external beam therapy.
This should be used for stage I and II patients where surgery is contraindicated. Patients with uterine
serosal disease (stage IIIa) and positive peritoneal washings may indicate risk of peritoneal
carcinomatosis and adjuvant chemotherapy could be considered with or without pelvic radiotherapy.
To refer for radical radiotherapy at YGC. Brachytherapy provided by the Christie Hospital in
Manchester.
All cases must be discussed at the gynae cancer MDT to decide further treatment.

10.5 Management of stage II/III disease

Patients with disease clinically involving the cervix should have a radical hysterectomy with bilateral
pelvic lymphadenectomy and removal of a vaginal cuff with dissection of the ureters (Lawton, 1997;
Mariani et al, 2001; grade B recommendation). For patients unsuitable for such radical surgery,
radiotherapy is appropriate (external beam and additional brachytherapy to the vaginal vault) as
primary treatment or preferably as adjuvant following total abdominal hysterectomy and bilateral
salpingo-oophorectomy.
Stage III disease needs to be considered on an individualised basis but cytoreductive surgery with
omentectomy may be an option. A retrospective report of patients with stage IIIc disease found benefit
in surgical cytoreduction prior to adjuvant radiotherapy, 45% of patients had palpable nodes (Mariani
et al, 2006; grade B recommendation).
All cases must be discussed at the gynae cancer MDT to decide further treatment.

10.6 Chemotherapy / progestogens and HRT

Combination chemotherapy including a platinum based agent has been shown to have a substantial
response rate (up to 60%; Lovecchio et al, 1984) in advanced disease but rarely provides a suitable
option as drug combinations are toxic despite a progression free survival of around 15 months as
overall survival is not obviously improved (Humber et al, 2007; grade A recommendation).
Chemotherapy may have a role for papillary serous tumours and carboplatin and taxol appearing the
most active. Anthracyclines such as doxorubicin or epirubicin may be considered as alternatives to
taxanes and could precede pelvic radiotherapy or pelvic radiotherapy with para-aortic extension in
node positive cases.
Progesterone receptors may inhibit the stimulatory effect of oestrogens as mitogens in endometrial
carcinoma. Hormonal therapy has a place in the management of recurrent disease particularly where
vaginal bleeding is distressing. Kelley and Baker (1961) first described a beneficial effect of
progestogens in metastatic endometrial carcinoma. Although popular, further trials have not shown
endocrine therapy to be effective as adjuvant treatment for primary disease (MacDonald et al, 1988;
grade A recommendation).
HRT does not appear to alter disease free survival and continuous combined therapy may be
theoretically most appropriate for post operative patients with persistent climacteric symptoms using a

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

Draft 1

low dose progestin (grade C recommendation). Cases should be managed on an individual basis and
patients deserve a comprehensive explanation balancing any potential risks with benefits.
To refer for radical radiotherapy at YGC. Brachytherapy provided by the Christie Hospital in
Manchester. Chemotherapy provided at all 3 North Wales Trusts.
All cases must be discussed at the gynae cancer MDT to decide further treatment.

10.7 Uterine sarcomas/ carcinosarcomas

Uterine sarcomas and carcinosarcomas (leiomyosarcomas, mixed Mullerian tumours and stromal
sarcomas) are not discussed in detail. These are aggressive tumours which frequently metastasise and
commonly present at an advanced stage. Low grade sarcomas are occasionally encountered but these
generally have a propensity to recur locally. If disease is confined to the uterus then total abdominal
hysterectomy and bilateral salpingo-oophorectomy is standard, usually combined with adjuvant pelvic
radiotherapy. The role of bilateral pelvic lymphadenectomy is unclear for this group but may be
offered to patients able to tolerate the longer surgical procedure. The outlook for these tumours as a
whole is poor with an overall 5 year survival of 42% for endometrial stromal sarcomas, 34% for
leiomyosarcomas and 33% for carcinosarcomas (Olah et al, 1992).
All cases must be discussed at the gynae cancer MDT to decide further treatment. Case
discussion with the Royal Liverpool Hospital MDT should be considered.

11. Dealing with recurrent disease

Up to 35% of patients with endometrial cancer will develop recurrent disease within 2 years. Fifty per
cent of recurrent disease is local and usually at the vaginal vault. A central isolated post radiation
recurrence can be dealt with exenterative surgery. Most of the remaining metastases occur in lung,
liver or bone. Radiotherapy for isolated vault recurrence can be considered for patients who had not
previously received radiotherapy with a 5 year survival of around 65% (Creutzberg et al, 2003; grade
A recommendation). Extrapelvic recurrence must be excluded by CT scan prior to treatment.
Medroxyprogesterone or megestrol should be considered although a modest response rate of 11-33%
is more marked in well differentiated tumours and those with a prolonged time from treatment to
recurrence (grade C recommendation). Goserelin may be an alternative particularly for those patients
at risk of the cardiac side effects of high dose progestins. Tamoxifen does not appear to offer
improvement in survival or overall quality of life (Quinn and Campbell, 1989).
Localised symptomatic distant recurrences in bone or supraclavicular glands should be offered
radiotherapy.
Chemotherapy may be considered for other sites of recurrent disease in younger patients who are fit to
tolerate treatment (grade A recommendation). Remissions are partial and improve survival by about 6
months. Platinum based combination chemotherapy gives a higher response rate than single agents
but is more toxic (Aapro et al, 1994; Thigpen et al, 1993).
All cases must be discussed at the gynae cancer MDT to decide further treatment.

11.1 Palliative care (see palliative care file)

The provision of palliative and supportive care for patients with gynaecological malignancies should
be an integral part of service. The NICE guidance Improving Supportive and Palliative Care for
Adults with Cancer was published in March 2004 and provides detailed recommendations which
complement and inform this guidance (NICE, 2004).
There is little robust evidence from the palliative care literature that is specific to patients with
advanced gynaecological malignancies, therefore this guidance is based on evidence from studies
looking at patients with a broad range of advanced malignancies.

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

Draft 1

12. Survival
Patients over 59 years of age at diagnosis may have poorer survival than younger patients (Frick et al.,
1973) and may partly be explained by the increase of poorly differentiated adenocarcinomas,
adenosquamous and clear cell adenocarcinomas in this age group.

Five year survival:

Stage I 77%
Stage II 48%
Stage III 34%
Stage IV 7%

Frick et al, (1973); Morrow et al, (1973); Berman et al, (1980); Kauppila et al, (1982); Connelly et
al, (1982).
Seventy four percent of patients present with stage I disease. Overall 5 year survival varies from
66 - 77%.

12.1 Cancer dataset/ inventory of active trials

CaNISC data items to be developed.
Active trials Wales Cancer Bank

13. Follow up
The value of clinical follow up is debatable. There is no evidence that an earlier detection of
recurrence leads to an improved survival. However careful inspection and palpation of the vaginal
vault and palpation for any pelvic masses should be performed 3 monthly for 2 years, 6 monthly for 1
year and then annually.
Hospital follow up should be for 5 years. Vaginal vault cytology is not helpful.
All patients must be encouraged to report any symptoms suggestive of recurrent disease immediately
by contacting their CNS rather than wait until their next outpatient appointment.

13.1 Identification and management of late effects of treatment

Pyschosexual, emotional, bowel, genitourinary, neuropraxia other problems may need detailed
discussion with the clinical nurse specialist and psychological, lymphoedema, pain, spiritual and other
support services.

14. Contact names/ numbers

Simon Leeson Obstetrician and Gynaecologist YG (t 01248 384954); CNS Sr Liz Hall (t 01248
385003)
Philip Toon Obstetrician and Gynaecologist NEWT (t 01978 725834)
Nigel Bickerton Obstetrician and Gynaecologist YGC (t 01745 534655)

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

 Draft 1

15. Algorithm for postmenopausal bleeding

Postmenopausal
bleeding
USC (see within 2 weeks of referral)

TV USS
endometrial
thickness

<5mm >5mm >5mm

Biopsy normal Biopsy inadequate

Discharge to GP Hysteroscopy/ Endometrial
Biopsy* Biopsy*

Biopsy normal

Endometrial Other carcinoma

carcinoma

Endometrial
carcinoma
algorithm (see 16) MDT

*other pathology excluded from this algorithm (such as atypical hyperplasia and endometrial polyps).
In the presence of recurrent bleeding hysteroscopy and biopsy is appropriate.

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

 Draft 1

16. Algorithm
Algorithm for management of patients with endometrial cancer

Stage I Pre-Op
Biopsy
Cancer Unit Hysteroscopy Cancer
or Centre MR scan/ CXR Centre only
MDT
<50% myo >50%myo
G I/ II all G III/ all type 2

Low risk or unfit High risk and fit

TAH/BSO/washings/omental biopsy TAH/BSO/washings/omental biopsy
pelvic lymphadenectomy

Consider laparoscopic or vaginal hysterectomy

ERT if ERT if
G I/II >50% myo Node positive
G III or Type 2 Ib or greater

Stage II
Diagnosed after surgery Diagnosed pre surgery
or unfit and fit

Adjuvant vaginal brachytherapy/ pelvic Radical hysterectomy/BSO/

ERT or washings/omental biopsy
primary brachytherapy/ ERT pelvic lymphadenectomy

ERT if node positive

Stage III/IV
ERT/ Surgical debulking and chemotherapy decided on case by case basis

ERT = external beam radiotherapy

Myo = myometrial infiltration

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

Draft 1

17. Summary

Pre-op assessment
TVS - if postmenopausal for endometrial thickness/ assess adnexae
Biopsy +/- hysteroscopy - if ET >5mm/ repeat referral
Hb, U+E, liver function tests, consider 2 unit cross match
chest X-ray
MR scan abdomen/ pelvis

Surgery
Low risk endometrial cancer (stage I; well/ moderately differentiated
adenocarcinoma, <1/2 thickness myometrial invasion and no lymph
node metastases on MR scanning) - TAH/BSO/washings/omental
biopsy.
High risk endometrial cancer (stage I; poorly differentiated,
adenosquamous, clear cell or serous papillary carcinoma, or well/
moderately differentiated >1/2 thickness myometrial invasion) -
TAH/BSO/washings/omental biopsy/pelvic lymphadenectomy if patient
suitable for prolonged surgery.
Consider laparoscopic or vaginal hysterectomy.
Stage II disease - radical (Wertheim) hysterectomy/pelvic
lymphadenctomy.
Post radiation isolated central pelvic recurrence - anterior/ posterior
exenteration.
Isolated vaginal recurrence consider surgical excision/radiotherapy.

Radiotherapy/ hormone therapy/ chemotherapy

ERT - if had TAH/BSO: adjunct to well/mod differentiated if post
operative specimen reveals >1/2 myometrial invasion, all Ib tumours
with poor differentiation, adenosquamous, clear cell or serous papillary
histology. Adjunct to all high risk lymph node positive patients.
Additional brachytherapy considered on a case by case basis. Adjunct
with brachytherapy for post operative stage II for patients not having
radical hysterectomy and lymphadenectomy. Adjunct to all radical
hysterectomy lymph node positive patients.
Primary treatment for surgically unfit patients and stage III-IV disease.
Progestogen therapy - for recurrent disease (megace 160mg. od or
provera 150mg. bd).
Chemotherapy consider for stage III/ recurrent disease (consider
carboplatin + taxol/ epirubicin).

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

Draft 1

18. References

Aalders J, Abler V, Kolstad P et al. (1980) Postoperative external irradiation and prognostic
parameters in stage I endometrial carcinoma: clinical and histopathological study of 540 patients.
Obstet Gynecol, 56, 419-27.

Aapro M, Bolis G et al. (1994) An EORTC-GCCG randomised phase II trial of doxorubicin

(DOX) versus dox-cisplatin (CDDP) in endometrial carcinoma (abstract). Proc Am Soc Clin
Oncol, 13, 275.

Berman ML, Barlow SC, Lagasse LD et al. (1980) Prognosis and treatment of endometrial
cancer. Am J Obstet Gynecol, 136, 679.

Chan JK, Cheung MK, Huh WK et al. (2006) Therapeutic role of lymph node resection in
endometrioid corpus cancer. Cancer, 107, 1823-30.

Clark TJ, Barton PM, Coomarasamy A et al. (2006) Investigating postmenopausal bleeding for
endometrial cancer: cost-effectiveness of initial diagnostic strategies. Br J Obstet Gynaecol, 113,
502-10.

Connelly PJ, Alberhashy RC, Christopherson WM (1982) Carcinoma of the endometrium III.
Analysis of 865 cases of adenocarcinoma and adeno-acanthoma. Obstet Gynecol, 59, 569.

COSA-NZ-UK Endometrial cancer study groups. (1996) Pelvic lymphadenectomy in high risk
endometrial cancer. Int J Gynecol Cancer, 6, 102-7.

Creasman WT, Boronow RC, Morrow CP et al. (1976) Adenocarcinoma of the endometrium: Its
metastatic lymph node potential. Gynecol Oncol, 4, 239

Creasman W, Morrow C, Bundy B et al. (1987) Surgical pathologic spread patterns of

endometrial cancer. A Gynecologic Oncology Group study. Cancer, 60, 2035-41.

Creutzberg CL, van Putten WL, Koper PC et al. (2000) Surgery and postoperative radiotherapy
versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised
trial. PORTEC Study Group. Lancet; 35, 1404-11.

Creutzberg CL, van Putten WLJ, Koper PC et al. (2003) Survival after relapse in patients with
endometrial cancer: results from a randomised trial. Gynecol Oncol; 89, 201-9.

FIGO (2003) FIGO gynaestaging-booklet.pdf.

Frick HC II, Munnell EW, Richart RM et al. (1973) Carcinoma of the endometrium. Am J Obstet
Gynecol, 115, 663.

Humber CE, Tierney JF, Symonds RP et al. (2007) Chemotherapy for advanced, recurrent or
metastatic endometrial cancer: a systematic review of Cochrane collaboration. Ann Oncol. 18,
409-20.

Irwin C, Levin W, Fyles A et al. (1998) The role of adjuvant radiotherapy in carcinoma of the
endometrium - results in 550 patients with pathologic stage I disease. Gynecol Oncol, 70, 247-
54.

Karlsson B, Granberg S, Wikland M et al. (1995) Transvaginal ultrasonography of the

endometrium in women with postmenopausal bleeding a Nordic multicentre study. Am J Obstet
Gynecol, 172, 1488-94.

Kauppila A, Gronroos M, Niemineu U. (1982) Clinical outcome of endometrial cancer. Obstet

Gynecol, 60, 473.

Kelley RM, Baker WH (1961) Progestational agents in the treatment of carcinoma of the
endometrium. N Eng J Med, 264, 216.

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

Draft 1

Kilgore C, Partridge EE, Alvarez RD et al. (1995) Adenocarcinoma of the endometrium:survival

comparisons of patients with and without pelvic node sampling. Gynecol Oncol, 56, 29-33.

Kim SH, Kim HD, Song YS et al. (1995) Detection of deep myometrial invasion in endometrial
carcinoma: comparison of transvaginal ultrasound, CT, and MRI. J Comput Assist Tomogr, 19,
766-72.

Lawton F. (1997) The management of endometrial cancer. Br J Obstet Gynaecol, 104, 127-34.

Lee CM, Szabo A, Shrieve DC et al. (2006) Frequency and effect of adjuvant radiation therapy
among women with stage I endometrial adenocarcinoma. JAMA, 295, 389-97.

Leveque J, Goyat F, Dugast J et al. (1998) Value of peritoneal cytology after hysteroscopy in
surgical stage I adenocarcinoma of the endometrium. Oncol Rep, 5, 713-5.

Lovecchio JL, Averette HE, Lichtinger M et al. (1984) Treatment of advanced or recurrent
endometrial adenocarcinoma with cyclophosphamide, doxorubicin, cis-Platinum and megestrol
acetate. Obstet Gynecol, 63, 557.

MacDonald RR, Thorogoog J, Mason MK. (1988) A randomised trial of progestogens in the
primary treatment of endometrial carcinoma. Br J Obstet Gynaecol, 95, 160-74.

Magrina JF, Mutone NF, Weaver AL et al. (1999) Laparoscopic lymphadenectomy and vaginal or
laparoscopic hysterectomy with bilateral salpingo-oophorectomy for endometrial cancer:
morbidity and survival. Am J Obstet Gynecol, 181, 376-81.

Mariani A, Webb MJ, Keeney GL et al. (2000) Low-risk corpus cancer: Is lymphadenectomy or
radiotherapy necessary? Am J Obstet Gynecol, 182, 1506-19.

Mariani A, Webb MJ, Keeney GL et al. (2001) Role of wide/ radical hysterectomy and pelvic
node dissection in endometrial cancer with cervical involvement. Gynecol Oncol, 83, 72-80.

Mariani A, Dowdy SC, Cliby WA et al. (2006) Efficacy of systematic lymphadenectomy and
adjuvant radiotherapy in node-positive endometrial cancer patients. Gynecol Oncol, 101, 200-8.

Morrow CP, DiSaia PJ, Townsend DE. (1973) Current management of endometrial carcinoma.
Obstet Gynecol, 42, 339.

Morrow CP, Bundy BN, Kurman RJ et al. (1991) Relationship between surgical-pathological risk
factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic
Oncology Group study. Gynecol Oncol, 40, 55-65.

Nelson G, Randall M, Sutton G et al. (1999) FIGO stage IIIc endometrial carcinoma with
metastases confined to pelvic lymph nodes: analysis of treatment outcomes, prognostic variables,
and failure patterns following adjuvant radiation therapy. Gynecol Oncol, 75, 211-4.

NHS Executive. (1999) Guidance on commissioning cancer services. Improving outcomes in

gynaecological cancers. The manual. Department of Health.

NICE. (2004) Improving Supportive and Palliative Care for Adults with Cancer.

Nieto JJ, Gornall R, Toms E et al. (2002) Influence of omental biopsy on adjuvant treatment field
in clinical stage I endometrial carcinoma. Br J Obstet Gynaecol, 109, 576-8.

Obermair A, Geramou M, Tripcony L et al. (2001) Peritoneal cytology: impact on disease-free

survival in clinical stage I endometrial adenocarcinoma of the uterus. Cancer Lett, 10, 105-10.

Olah KS, Dunn JA, Gee H. (1992) Leiomyosarcomas have a poorer prognosis than mixed
mesodermal tumours when adjusting for known prognostic factors: the result of a retrospective
study of 423 cases of uterine sarcoma. Br J Obstet Gynaecol, 99, 590-4.

Podratz KC, Mariani A, Webb MJ. (1998) Staging and therapeutic value of lymphadenectomy in
endometrial cancer. Gynecol Oncol, 70, 163-4.

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

Draft 1

Quinn MS, Campbell JJ. (1989) Tamoxifen therapy in advanced/ recurrent endometrial
carcinoma. Gynecol Oncol, 32, 1-3.

Thigpen, T, Blessing J et al. (1993) Phase III trial of doxorubicin +/- cisplatin in advanced or
recurrent endometrial carcinoma: a Gynecologic Oncology Group (GOG) study (abstract). Proc
Am Soc Clin Oncol, 12, 261.

Yamashita Y, Mizutani H, Torashima M et al. (1993) Assessment of myometrial invasion by

endometrial carcinoma: transvaginal sonography vs contrast enhanced MR imaging. Am J
Roentgenol, 161, 595-9.

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)

 Draft 1

Classification of evidence levels

Ia Evidence obtained from meta-analysis of randomised controlled trials

Ib Evidence obtained from at least one randomised controlled trial

IIa Evidence obtained from at least one well designed controlled study
without randomisation

IIb Evidence obtained from at least one other type of well designed quasi-
experimental study

III Evidence obtained from well designed non-experimental descriptive

studies, such as comparative studies, correlation studies and case
studies

IV Evidence obtained from expert committee reports or opinions and/or

clinical experience of respected authorities

Lower limit of acceptable evidence base is level IIa.

Grades of recommendation

A Requires at least 1 randomised controlled trial as part of a body of

literature of overall good quality and consistency addressing the specific
recommendation

B Requires the availability of well controlled clinical studies but no

randomised clinical trials on the topic of recommendation

C Requires evidence obtained from expert committee reports or opinions

and/or clinical experiences of respected authorities. Indicates an
absence of directly applicable clinical studies of good quality

Lower limit of acceptable grade of recommendation is B.

This guideline has been developed by the North Wales Cancer Centre Guideline Group

Simon Leeson Obstetrician and Gynaecologist (chair)

Philip Toon Obstetrician and Gynaecologist
Nigel Bickerton Obstetrician and Gynaecologist

North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)