Recognition and initial management of ovarian cancer: summary of NICE guidanceBMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d2073 (Published 21 April 2011) Cite this as: BMJ 2011;342:d2073
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The summary of the NICE guidelines for recognition and initial
management of ovarian cancer stated that magnetic resonance (MR) imaging
should not be used routinely . We are concerned that this sends the
wrong message to commissioners of gynaecology services and may result in
denial of MR imaging for women whose care would be improved by its
The summary quite rightly encourages timely investigation with
ultrasound (US) and referral from primary care on the 'two week' pathway.
Our own experience is that a significant proportion of women on this
pathway are discovered to have US 'indeterminate' adnexal masses i.e. it
is unclear whether the mass represents complex benign disease or
malignancy. In the Yorkshire Cancer Network (YCN), for more than a
decade, MR imaging has been routinely used as a problem solving tool for
such indeterminate masses as written in the YCN guidelines . Indeed in
a recent audit it was the commonest cause of referral for gynaecological
MR imaging within the Cancer Centre.
The benefits of using MR imaging for women on this care pathway are
several: provision of a specific diagnosis; a more timely diagnosis;
prevention of unnecessary referral to a Cancer Centre; and, for some,
avoidance of unnecessary surgery. MR imaging has been shown to be
superior to US in determining the nature of adnexal masses  and a
valuable adjunct to the risk of malignancy index (RMI) specifically
increasing the proportion of women with cancer referred to the Cancer
Centre . The RMI directs referral on the basis of 'risk'; MR imaging
directs individualised care on the basis of a specific diagnosis. MR
imaging has been shown to be cost effective in the care pathway [5, 6].
We see an increasing number of women referred from other
multidisciplinary teams with such indeterminate masses thought likely to
be early ovarian cancers. The non-specific symptoms of ovarian cancer
described in the NICE guidelines are common to gastrointestinal and
urological disease. Computed tomography, now performed as a first line
investigation for such symptoms, may reveal such indeterminate adnexal
masees . Again the use of MR imaging can effectively minimise the need
for further gynaecological intervention and allay patient anxiety.
Whilst we recognise that the main thrust of the NICE guidelines are
the investigation, referral and treatment of women most likely to have
ovarian cancer they do no service to the many women on this pathway who do
not have ovarian cancer. The summary guidelines regarding use of MR
imaging are contrary to the evidence base and at variance with routine
clinical practice in much of the UK. We are concerned that inappropriate
adherence to the headline comments contained within these will promote
minimum standards of care and result in unnecessary diagnostic uncertainty
and inappropriate referral of and intervention for women with suspected
John A Spencer Consultant Radiologist
Richard J Hutson Consultant Gynaecological Oncologist
Timothy J Perren Consultant Medical Oncologist
Michael J Weston Consultant Radiologist
Sarah E Swift Consultant Radiologist
Timothy J Broadhead Consultant Gynaecological Oncologist
St James's Institute of Oncology, Leeds, LS9 7TF, UK
Corresponding author: firstname.lastname@example.org
1. Redman C, Duffy S, Bromham N, Francis K; on behalf of the
Guideline Development Group. Recognition and initial management of
ovarian cancer: summary of NICE guidance. BMJ 2011; 342: d2073. (21
3. Sohaib SA, Mills TD, Sahdev A et al. The role of magnetic resonance
imaging and ultrasound in patients with adnexal masses. Clin Radiol 2005;
4. van Trappen PO, Rufford BD, Mills TD et al. Differential diagnosis of
adnexal masses: risk of malignancy index, ultrasonography, magnetic
resonance imaging, and radioimmunoscintigraphy. Int J Gynecol Cancer 2007;
5. Kinkel K, Lu Y, Mehdizade A, Pelte MF, Hricak H. Indeterminate ovarian
mass at US: incremental value of second imaging test for characterization-
-meta-analysis and Bayesian analysis. Radiology 2005; 236: 85-94.
6. Chilla B, Hauser N, Singer G, Trippel M, Froehlich JM, Kubik-Huch RA.
Indeterminate adnexal masses at ultrasound: effect of MRI imaging findings
on diagnostic thinking and therapeutic decisions. Eur Radiol 2011; 21:
7. Spencer JA, Gore RM. The adnexal incidentaloma: a practical approach
to management. Cancer Imaging 2011; 11: 48-51.
Competing interests: No competing interests
"Risk Approach" followed by Combination of three modalities (viz. bimanual pelvic examination + ultrasonography + CA-125) of screening would be useful for detection of ovarian cancer
Ovarian cancer the silent killer and the key is early detection. Four
major modes of Ca Ovary screening- screening of risk factors, ultrasound,
CA-125, vaginal/ pelvic examination, are discussed with pros and cons with
Ovarian cancer is fifth most common cause of cancer deaths worldwide.
In India 5-7 cases per 1, 00,000 women per year are reported that means
25-30 thousand new patients every year. Seeing the 13 billion population
of India, 20% of that are adult women makes it 26 million due for
screening (1). With this enormous burden one must start with screening
with at-risk approach viz those who have following risk factors: age
above 50 years, family history of ovarian, breast and colon cancer,
nulliparity, early menarche and late menopause. Using Fertility drugs,
Screening the general population is currently neither cost-effective
nor practical. The pelvic examination does not add additional cost for
women who are already undergoing regular gynecologic evaluation and is
reliable when done by an experienced examiner, but it lacks adequate
sensitivity and specificity as a screening test. 1010 postmenopausal women
were recruited for an ovarian cancer screening programme incorporating
serum CA-125 measurement and vaginal examination as initial tests and real
-time ultrasonography as a secondary procedure in selected cases. The
normal range for serum CA-125 in postmenopausal women was established. The
specificity for ovarian cancer of serum CA-125 measurement and vaginal
examination were 97*0% and 97*3%, respectively. The combinations of serum
CA-125 measurement with ultrasound and vaginal examination with ultrasound
achieved specificities of 99*8% and 99*0%, respectively. 100% specificity
was achieved by serum CA-125 measurement with vaginal examination and by
the combination of all three tests. The findings indicate that no
individual screening test has acceptable specificity for ovarian cancer in
postmenopausal women. However, the combination of CA-125 measurement with
ultrasound did achieve acceptable specificity and offers the most hope of
a specific and sensitive method for early detection2.
CA-125: CA 125 is widely distributed on the surface of both healthy
and malignant cells of mesothelial origin, including pleural, pericardial,
peritoneal and endometrial cells, as well as in normal genital tract and
amniotic membrane. Interestingly the molecule is not present on the
surface of normal ovarian cells, but is present in 80% of malignant
ovarian tissue of non mucinous origin (3).
The radioimmunoassay for CA 125, a tumor-specific antigen, is
elevated in 80% of ovarian carcinomas, but only in 50% of women with
cancer limited to the ovary (stage1a & 1b). It may also be elevated in
women with benign ovarian disease and in otherwise healthy women, which
limits its specificity. Osteosarcoma, Adenocarcinoma breast, colon,
uterus, pancreas, lung, vagina, fallopian tube, Meig's syndrome, as well
as benign conditions like acute peritonitis, pelvic inflammatory disease,
pancreatitis, digestive tract, endometriosis, liver disease, heart
failure, normal menstruation and pregnancy etc are some conditions with
elevated Ca-125 (4).
Sending all the postmenopausal women for CA-125 and ultrasonogpahy
may not be cost effective measure in resource poor or primary care setups
Malkasion et al studied 59 patients with histologically proven benign
ovarian cysts. Out of these patients 17 had elevated concentrations of CA
125 (12 > 35 units/ml, 4 > 65 units/ml and 1 > 2000 units/ml). In
another study by Dixia using 153 patients with benign pelvic masses, 10
patients had CA 125 concentrations >188 units/ml and one patient had a
value of more that 400 units/ml. Nolen et al screened 65 biomarkers in
patients with adnexal masses and more than half of the biomarkers differed
significantly between benign and malignant masses (6&7). Ca-125 may be
useful as prognostic marker(8).
Ultrasonography: is more sensitive than pelvic examination in
detecting ovarian abnormalities but lacks specificity in distinguishing
benign from malignant ovarian lesions. Combined with serum CA 125 levels,
ultrasonography may provide an effective screening tool, although cost-
effectiveness has not been demonstrated.
Review of literature from 1990 to 2006 which included 143 studies
showed that Ultrasound findings were similar to CT and MRI in
differentiation of benign from malignant ovarian masses (9).
Clinical Pelvic Examination: Bimanual examination involves insertion
of one or two examiner fingers into the vaginal vault with simultaneous
palpation of the lower abdomen to characterize the size and shape of the
uterus and adnexa; a recto-vaginal examination may also be included.
Following a single elevated CA 125 measurement with abdominal ultrasound
yielded a sensitivity of 58%-79%. Even a test with 99% specificity and
100% sensitivity would yield only 1 in 21 women with a positive screen
actually having the disease (10 &11).
Emphasis is therefore on using powerful tool of clinical pelvic
examination (CPE), which is comparable in detecting ovarian mass early.
Among the abnormal adnexal mass of 19 women with recurrent borderline
tumor, one patient had diagnosis due to persistent free fluid. Gynecologic
examination was suspicious (palpable mass) in 7 cases and obviously
abnormal (large mass or nodules) in another 7. CA 125 serum levels were
elevated in 8 cases (7).
Limitations of the pelvic examination for evaluation of the female
pelvis: Review of the literature indicates that the use of routine pelvic
examination as screening for ovarian malignancy (with or without serum CA-
125 and ultrasound) cannot be justified due to the low prevalence of the
disease. However whenever physician medical and paramedical workers get
chance or in high risk women, can explore pelvis by manual examination and
would prove most economical and effective measure for early detection of
Ca Ovary (12).
Further research is needed by calculating the combined sensitivity
and specificity by putting the above modalities applying tests in series
and parallel: starting from risk approach, bimanual pelvic examination, CA
-125 and ultrasound. This will help to prepare the guidelines for
screening in countries like India where number matters.
1.. Madhutandra Sarkar, Hiralal Konar and D. K. Raut. Knowledge and Health
Care-Seeking Behavior in Relation to Gynecological Malignancies in India:
A Study of the Patients with Gynecological Malignancies in a Tertiary Care
Hospital of Kolkata. Obstet Gynecol. 1991 May;77(5):787-92.
2. Ian Jacobs, Jane Bridges, Colin Reynolds. Multimodal Approach To
Screening For Ovarian Cancer. The Lancet, Volume 331, Issue 8580, Pages
268 - 271, 6 February 1988
3. Gerardo Zanetta, Sonia Rota, Andrea Lissoni. Ultrasound, Physical
Examination, and CA 125 Measurement for the Detection of Recurrence after
Conservative Surgery for Early Borderline Ovarian TumorsGynecologic
Oncology. Volume 81, Issue 1, April 2001, Pages 63-66
4. S. Grover, M.A. Quinn, P. Weideman, H. Koh. et al. Screening for
ovarian cancer using serum CA125 and vaginal examination: report on 2550
females. International Journal of Gynecological Cancer. Volume 5, Issue 4,
pages 291-295, July/August 1995
5. Sparks JM, Varner RE. Ovarian cancer screening. Obstet Gynecol.
6. Danijela Jelovac, MD1; Deborah K. Armstrong Recent Progress in the
Diagnosis and Treatment of Ovarian Cancer CA CANCER J CLIN 2011;61:183-
7. Asher V, Hammond R, Duncan TJ. Pelvic mass associated with raised
CA 125 for benign condition: a case report. World J Surg Oncol. 2010 Apr
8. Ian Jacobs and Robert C. Bast Jr The CA 125 tumour-associated
antigen: a review of the literature Human Reproduction,Volume4, Issue1.Pp.
9. Liu J, Xu Y, Wang J. Ultrasonography, computed tomography and
magnetic resonance imaging for diagnosis of ovarian carcinoma. Eur J
10. Jacobs IJ, Skates S, Davies AP, Woolas RP, Jeyerajah A, Weidemann
P, Sibley K, Oram DH. Risk of diagnosis of ovarian cancer after raised
serum CA 125 concentration: a prospective cohort study. BMJ.
11. Guilherme H.C Cantuaria, Roberto Angioli, Leslie Frost.
Comparison of Bimanual Examination With Ultrasound Examination Before
Hysterectomy for Uterine Leiomyoma. Obstetrics & Gynecology
Volume 92, Issue 1, July 1998, Pages 109-112
12. L.A. Padilla, D.M. Radosevich, M.P. Milad et al. Screening
asymptomatic women for ovarian cancer: American College of Preventive
Medicine, Practice Policy Statement. International Journal of Gynecology
Volume 88, Issue 1 , Pages 84-88, January 2005
Competing interests: No competing interests
These new guidelines suffer from a lack of GP involvement in their
making. They currently are incomplete and this makes them insecure.
There are a number of glaring omissions, some of which I have detailed
Firstly. What timescale is it reasonable for a woman with a raised
CA125 to wait for her ultrasound?
Should it be done within 2 weeks ("I might have cancer then
urgently ("so its only a small risk but we want to pick it up
routine ("so the CA125 test is pretty poor and there is hardly any
risk at all?").
Routine scans in my area can be 12 weeks and I know it will be very
difficult to explain to worried patients with an abnormal cancer test that
their is not a great risk.
Secondly the guidelines offer no help with patients with abnormal
CA125 who have a normal ultrasound.
What should we do next?
Should we repeat it later (if so when?), should we refer to secondary
care? Should we repeat the scan, or should we just say "come back if
symptoms persist, tho' I've no idea what to do when you do?"
The lack of thought over the pathway for the normal patient (which
will make up the bulk of the patients we see in general practice) makes
these guidelines unworkable and full of traps that will lead to more
worry, needless investigations, referrals and probably very little
improvement in the early diagnosis of ovarian cancer.
NICE, you must include GPs in your guidance, and you must think
through the normal, not just let your highly specialised secondary care
members remain blinkered on the diseased.
Competing interests: No competing interests
If the purpose of the NICE guidelines (1) on ovarian cancer is to
improve outcome by, among other strategies, allowing earlier diagnosis,
then they are unlikely to succeed.
The recommendations for detection in primary care are flawed. While
the indications for suspecting ovarian cancer are valid, the sequence of
diagnostic tests is illogical. Measuring Ca125 as an initial test will
fail to detect at least 23% of women with non-mucinous stage 1 epithelial
ovarian cancer (2). The rarer epithelial ovarian cancers such as the clear
cell and mucinous sub-types which carry a worse prognosis are not
associated with an elevated serum C125.
An ultrasound scan is recommended only if the Ca125 is abnormal. This
appears to be based on the assumption that women with obvious pelvic
masses would have been detected and referred under the two-week rule. This
does not take into account the fact that General Practitioners and indeed
junior doctors have lost the skill of clinical pelvic assessment and that
an ultrasound in now used as the first test to detect pelvic masses.
In my opinion women with suspicious symptoms should have immediate
access to a high quality ultrasound scan and if this shows a complex
adnexal mass, should be referred to secondary care without delay,
irrespective of serum Ca125 level. This, along with a high index of
suspicion and a low threshold for investigation, is the only way that we
will make a significant impact on early detection and outcome of this
1. National Institute for Health and Clinical Excellence. Recognition and
Initial Management of Ovarian Cancer (Clinical Guideline 122) 2011
2. Woolas RP, Xu FJ, Jacobs IJ, Yu YH, Daly L, Berchuck A, Soper JT,
Clarke-Pearson DL, Oram DH, Bast RC Jr. Elevation of multiple serum
markers in patients with stage I ovarian cancer. J Natl Cancer Inst. 1993
Competing interests: No competing interests