Download endometrial carcinoma

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ENDOMETRIAL CARCINOMA
Index
1.
Clinical symptoms and signs
2.
2.1
Screening
Family history - Lynch type 2 syndrome
3.
3.1
3.2
3.3
Referral pathway
For GP
For non-oncological consultants/ firms
For referral from unit to centre
4.
Diagnosis
5.
Investigations
6.
6.1
Gynaecological cancer multidisciplinary team
Information
7.
7.1
7.2
7.3
7.4
7.4.1
7.4.2
7.4.3
7.5
Pathology
Endometrial carcinoma classification (adapted from WHO classification)
Architectural grading of endometrioid adenocarcinoma (FIGO)
Nuclear grading
Type 1 and type 2 tumours
Type 1 carcinoma
Type 2 carcinoma
Overall outcome for endometrial carcinoma based on pathology
Pathological reporting of endometrial carcinoma
8.
Staging
9.
Histopathology minimum dataset
10.
10.1
10.2
10.3
10.4
10.5
10.6
10.7
Treatment
Abdominal, vaginal and laparoscopic hysterectomy
Pelvic lymphadenectomy
Indications for adjuvant radiotherapy for stage I disease
Further indications for radiotherapy
Management of stage II/III disease
Chemotherapy / progestogens and HRT
Uterine sarcomas/ carcinosarcomas
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11.
11.1
Dealing with recurrent disease
Palliative care
12.
12.1
Survival
Cancer dataset/ inventory of active trials
13.
13.1
Follow up
Identification and management of late effects of treatment
14.
Contact names/ numbers
15.
Algorithm for postmenopausal bleeding
16.
Algorithm
17.
Summary
18.
References
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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.
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3.2
For non-oncological consultants/ firms
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.
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6.
Gynaecological cancer multidisciplinary team
Core team
Named team member
Gynae oncologist
Gynae lead cancer surgeon
Medical oncologist
Clinical Oncologist
Pathologist/ Cytopathologist
Palliative care team
Radiologist
MDT co-ordinator
CNS
Extended team
Mr Leeson / Mr Toon
Mr Bickerton/ tba
Prof Stuart
Dr Al-Sammarie
Dr Lord
Dr Williams
Dr Barwick
Ms Jones
Ms Hall
Ultrasonographer
tba
Junior doctors
Psychologist
Geneticist
Ms Grier
Social worker
tba
Ward Sister
Sr Williams
Research nurse
Colorectal/ urological/ plastics as required
6.1
Additional member or
Cover (core team only)
Dr Williams
tba
tba
tba
Dr Wenham
tba
Core/ extended teams to include
members from YGC/ NEWT
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 GP’s 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 patient’s 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
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7.2
Architectural grading of endometrioid adenocarcinoma (FIGO)
Grade I
5% or less of the tumour shows a solid pattern
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 ¾ 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 ¼ 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
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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).
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
Stage 0
Stage I
a
b
c
Stage II
a
b
Stage III
a
b
c
Stage IV a
b
NM categories
primary tumour cannot be assessed
no evidence of primary tumour
carcinoma in situ (preinvasive carcinoma)
TX
T0
Tis
carcinoma confined to the corpus
carcinoma confined to the endometrium
< ½ myometrial invasion
> ½ myometrial invasion
involving cervix but does not extend beyond uterus
glandular involvement only
cervical stromal involvement
local and/ or regional spread as defined in IIIa, b or c
disease involving the adnexae (direct extension or
metastases), serosa or +ve peritoneal cytology
(washings or ascites)
vaginal metastases (direct extension or metastases)
pelvic or para-aortic node metastases
bladder* or rectal mucosal involvement
extrapelvic metastases including
inguinal lymph nodes
T1
T1a
T1b
T1c
T2
T2a
T2b
T3 and/ or N1
T3a
T3b
N1
T4
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
N0 no regional lymph node metastasis
N1 regional lymph node metastasis
MX
M0
M1
distant metastasis cannot be assessed
no distant metastasis
distant metastasis
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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
Yes 
Is there obvious myometrial invasion:
Histology
Type:
No 
Endometrioid  Serous 
Clear cell 
MMMT 
other (please specify) ……………………………………
Grade (FIGO): (only applies to endometrioid carcimona)
I
II
III
N/A
None  <50%  >50% 
Myometrial invasion:
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 
Abnormal:
(please specify) ……………………………………………………
Pelvic Nodes
right
left
left ovary 
right tube 
Common Iliac nodes
left tube 
right
left
……..
……..
……..
……..
(including obturator, internal
and external iliac)
total number of nodes
retrieved
lymph nodes with
tumour deposits
……..
……..
……..
……..
total number of nodes
retrieved
lymph nodes with
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 Müllerian tumour)
T08000 Lymph node
M81406 (Metastatic carcinoma)
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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 salpingooophorectomy 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 paraaortic 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 ½ 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
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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
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 salpingooophorectomy.
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
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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
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.
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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)
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15.
Algorithm for postmenopausal bleeding
Postmenopausal
bleeding
USC (see within 2 weeks of referral)
TV USS
endometrial
thickness
<5mm
Discharge to GP
Biopsy normal
>5mm
Hysteroscopy/
Biopsy*
>5mm
Biopsy inadequate
Endometrial
Biopsy*
Biopsy normal
Endometrial
carcinoma
Other 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.
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16.
Algorithm
Algorithm for management of patients with endometrial cancer
Stage I
Pre-Op
Biopsy
Hysteroscopy
MR scan/ CXR
MDT
Cancer Unit
or Centre
Cancer
Centre only
<50% myo
G I/ II
Low risk or unfit
TAH/BSO/washings/omental biopsy
>50%myo
all G III/ all type 2
High risk and fit
TAH/BSO/washings/omental biopsy
pelvic lymphadenectomy
Consider laparoscopic or vaginal hysterectomy
ERT if
G I/II >50% myo
G III or Type 2 – Ib or greater
ERT if
Node positive
Diagnosed after surgery
or unfit
Diagnosed pre surgery
and fit
Adjuvant vaginal brachytherapy/ pelvic
ERT or
primary brachytherapy/ ERT
Radical hysterectomy/BSO/
washings/omental biopsy
pelvic lymphadenectomy
Stage II
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
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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).
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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.
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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.
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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.
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.
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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 quasiexperimental 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
Philip Toon
Nigel Bickerton
Obstetrician and Gynaecologist (chair)
Obstetrician and Gynaecologist
Obstetrician and Gynaecologist
North Wales Cancer Guidelines, Endometrial Cancer (April, 2008)
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