Drs Marcia Hall (left) and Heather Shaw explain the role of a detailed patient history in confirming a diagnosis of ovarian cancer, as specified in the NICE quality standard
- The incidence of ovarian cancer rises with age, especially over the age of
- Vague bowel complaints, such as a change of bowel habit and abdominal distension, are as important as ascites and pelvic masses in the diagnosis of ovarian cancer
- A new diagnosis of irritable bowel syndrome is very unlikely in women over the age of 50 years—the patient should be asked if she has ever known her bowels to behave like this before
- Healthcare professionals should consider the persistence of a patient's abdominal bloating and whether there is a loss of diurnal variation—does the patient feel as bloated first thing in the morning?
- A family history of breast and ovarian cancer is significant and makes a diagnosis of ovary (or breast) cancer in that patient more likely
- Slower-growing ovarian cancers are more likely to form pelvic masses, with associated pelvic symptoms such as urinary difficulties
- CA125 tests are most helpful in women over the age of 50 years—they are more likely to be raised falsely in pre-menopausal women and such results are likely to cause significant anxiety
- Ultrasound interpretation of pelvic masses is operator dependent particularly as healthy ovaries are dynamic cystic structures.
Ovarian cancer is diagnosed at an advanced stage in about 60% of women;1 however, despite improvements in treatments such as chemotherapy, 5-year survival was only 43% in women diagnosed in England and Wales between 2005 and 2006.2 It is the leading cause of death in women with gynaecological cancer, accounting for 6% of all female death from cancers.2 Although mortality has remained the same, a two-fold increase in 5-year survival rates has been seen over the past three decades.2
When ovarian cancer relapses, it is very unlikely to be cured; at this point it could be considered a chronic disease, with relapses and remissions. More than 80% of women with advanced ovarian cancer will relapse after initial chemotherapy,3 and these individuals will usually die from their disease despite good remissions following further chemotherapy. Patients with relapsed ovarian cancer will often receive three or more lines of chemotherapy but will eventually become resistant to further cytotoxic agents.4
Quality standard for ovarian cancer
The NICE quality standard for ovarian cancer, which was developed by an invited Topic Expert Group, is a set of eight specific statements intended to act as markers of high-quality, cost-effective patient care, with the aim of expediting the diagnosis of ovarian cancer and improving the choice of imaging investigations for such patients (see Table 1).5
Statistics published in 2010 relating to routes of diagnosis for women with ovarian cancer showed that less than half of patients with a possible gynaecological malignancy are referred appropriately to a gynae-oncology service (see 2-week wait and GP referral in Table 2).6 Fifteen percent of women are referred to secondary care but not to gynaecology (these patients are mostly seen in general surgical or gastroenterology clinics) and 29% present through emergency departments.6
This article focuses on factors in a woman that might alert a primary care doctor to a diagnosis of ovarian cancer. An overview of the secondary care quality statements will also be discussed to inform those involved in future commissioning.
|Table 1: NICE quality standard for ovarian cancer5|
|Symptoms and CA125||
|Women aged 50 years or over reporting one or more symptoms occurring persistently or frequently that suggest ovarian cancer are offered a CA125 test.|
|Women with raised CA125 have an ultrasound of their abdomen and pelvis within 2 weeks of receiving the CA125 test results.|
|Women with normal CA125, or raised CA125 but normal ultrasound, with no confirmed diagnosis but continuing symptoms, are reassessed by their GP within 1 month.|
|Women with a risk of malignancy (RMI I) score of 250 or greater are referred to a specialist gynaecological cancer multidisciplinary team.|
|Initial staging CT||
|Women who are offered staging for ovarian cancer, following ultrasound, are offered computed tomography of the abdomen and pelvis as the initial staging investigation.|
|Women who have CT for staging of ovarian cancer, have the results reported by a radiologist who is a core member of the specialist gynaecological cancer multidisciplinary team.|
|Women with an indeterminate adnexal mass on ultrasound are offered magnetic resonance imaging for further characterisation.|
|Optimal surgical staging||
|Women with suspected stage I ovarian cancer have optimal surgical staging.|
National Institute for Health and Care Excellence website. NICE quality standard for ovarian cancer. Available at: www.nice.org.uk/guidance/QS18
Reproduced with kind permission
|Table 2: Routes to diagnosis for ovarian cancer for 5012 patients in England in 20076|
|Cancer type||2-week wait||GP referral||Other outpatient||Inpatient elective||Emergency presentation||Death certificate only||Unknown||Total||Number of patients|
National Cancer Intelligence Network. Routes to diagnosis—NCIN data briefing. NCIN, 2010. Available at: www.ncin.org.uk/publications/data_briefings/routes_to_diagnosis.aspx Reproduced with kind permission.
Diagnosis—quality statements 1, 2, 3
Understanding the pathophysiology regarding the source of the malignant cells in ovarian cancer is helpful, as this enables doctors to recognise the presenting symptoms more easily. Ovarian cancer can present in one of two distinct ways: signs and symptoms of a pelvic mass or rather more vague symptoms relating to the spread of ovarian cancer cells onto the surface of the organs in the peritoneal cavity, particularly the bowels, liver capsule, subdiaphragmatic surfaces, bladder, and rectosigmoid serosa. Type II serous ovarian cancers (or mixed serous), account for 70% of cases, while type I non-serous cancers (endometrioid, mucinous, and clear-cell subtypes) are less common.7-9 Serous ovarian cancers are thought to arise commonly from the inner lining of the fallopian tube, dropping onto the adjacent serosal surface of the ovary and raining down into the peritoneal cavity rather than causing inner enlargement of the ovary itself.10 Patients with this type of ovarian cancer may not necessarily have a large pelvic mass—or any signs at all—and often present with vague bowel and abdominal symptoms, such as change in bowel habit, bloating, distension, and early satiety. However, patients with non-serous ovarian cancers are more likely to present with symptoms and signs of a distinct pelvic/ovarian mass, including urinary urgency and frequency, pelvic pain, and constipation.11
Earlier diagnosis of ovarian cancer will only improve the chance of cure for a patient if the cancer cells are still confined to the ovarian capsule. However, if the origin of the malignant cells is the fallopian tube, their escape onto the surface of the adjacent ovary and into the peritoneal cavity constitutes advanced disease, usually stage IIIc at presentation; there are often no earlier symptoms or signs.12 Nevertheless, pursuing an earlier diagnosis at least allows the patient to recognise that their complaints are real and that treatment can be offered to relieve symptoms. Reducing tumour burden can affect outcome, and this can be undertaken surgically or through chemotherapy. Being alert to a diagnosis of ovarian cancer will also diminish the chance of emergency admissions in 'crisis' and is likely to lengthen survival although not reduce mortality. Non-serous, type I ovarian cancers are more likely to present as pelvic masses than serous type II ovarian cancers, and a higher proportion of these are identified at an earlier stage.11
Primary care teams will need to increase their knowledge and skills to deliver improved detection of early disease and appropriate referral to rapid-access specialist services.
It is important for primary care to elicit the following information from a patient to confirm or refute a suspicion of ovarian cancer:
- age ?50 years
- new diagnosis of irritable bowel syndrome
- the presence of bloating, especially if there is a lack of diurnal variation
- family history of breast or ovarian cancer.
NICE Clinical Guideline 122 (CG122) on the recognition and initial management of ovarian cancer discusses bowel-related symptoms that occur in this condition.13 Patients with widespread serous cancers of the ovary are generally found to have malignant cells coating the serosal surfaces of the bowel and other intraperitoneal organs, which gives rise to nebulous bowel disturbance and abdominal symptoms such as intermittent diarrhoea or increasing constipation, weight loss, bloating, or distension, which often deteriorates slowly over a longer period of time, such as a number of months or perhaps a year or so.14
Intermittent bowel symptoms in patients aged over 50 years cannot be attributed to a new diagnosis of irritable bowel syndrome (IBS), as this condition rarely presents for the first time in this age group.15 Bloating, like IBS, is another exacerbation of a normal phenomenon. It may be useful to ask a patient if they feel bloated first thing in the morning, as this is likely to be more common in patients with intraperitoneal metastases than healthy individuals, in whom it is rare.
Finally, enquiries about any family history of cancer may reveal a wide history of breast cancers (and some ovarian cancers), which will raise suspicion of genetically inherited defects in DNA repair mechanisms, such as breast cancer susceptibility protein type 1 (BRCA1) and type 2 (BRCA2),16,17 and autosomal dominantly inherited genetic defects that permit the accumulation of other mutations that give rise to predominantly breast and ovary malignancies.
Quality statements 1 and 2 need to be read in context with the information in section 2 of the full guideline version of CG122.18 The quality standard guides primary care doctors who suspect ovarian cancer through the first tests. The importance of examination, including pelvic examination, cannot be overemphasised. Although examination is sometimes taxing due to the need to arrange chaperones and wait for patients to undress/dress, the information gained can be invaluable, confirming an enlarged fibroid uterus or feeling a more sinister fixed pelvic mass, both of which will require very different management and discussion.5
It is important to note that the first quality statement specifies that women older than 50 years have a CA125 test.5 This is because the CA125 level is very unreliable in pre-menopausal women, often being increased in benign conditions such as endometriosis and even during menstruation, which leads to considerable and unnecessary worry for all. In younger women who are less likely to have ovarian cancer anyway, it is therefore preferable to prioritise ultrasound imaging, perhaps alongside the CA125 test. Sadly, ultrasound imaging is operator dependent and is likely to place an unsustainable burden on diagnostic resources if recommended first for all patients. Even in women older than 50 years, an increased CA125 level alone does not confirm a diagnosis of ovarian cancer, as it can be increased in many other malignancies, such as pancreatic cancer, and some non-malignant conditions, such as heart failure.19
Quality statement 3 relates to patients with vaguer symptoms, fewer (if any) signs, and a negative result for CA125.5 Reassessment of patients whose symptoms persist is vital, as symptoms of this disease regularly predate the diagnosis, sometimes by many months, and CA125 is not increased in about 10% of patients with ovarian cancer.20 Review by the same GP is obviously likely to help most.
Imaging choice—quality statements 5, 6, and 7
Quality statements 5, 6, and 7 should be considered in tandem with the existing guidance from the Royal College of Radiologists (RCR).5,21
Women with suspected ovarian cancer who are referred to secondary care benefit most from a staging computed tomography (CT) scan to evaluate further the extent of any possible ovarian cancer.5 This is required in order to discuss effectively the management of such patients, who are usually offered a combination of surgery and chemotherapy. The initial intervention can be either of these, but unless surgical intervention can confidently remove all visible macroscopic disease, it is often preferable to initiate chemotherapy first and consider surgery later. This is especially important for those patients who are unwell as a consequence of bowel dysfunction, as these patients are often quite malnourished and hypoalbuminaemic.
Radiological signs of ovarian cancer can be very subtle and include peritoneal nodularity/thickening and omental stranding. The uterus and ovaries are often impossible to see clearly. Quality statement 6 therefore clearly mandates reporting of CT images from patients with possible ovarian cancer by trained radiologists and core members of a specialist gynaecological cancer multidisciplinary team (MDT), as defined by cancer peer review.5 Similarly, images of localised adnexal masses of indeterminate cause should also be examined and reported by gynae-oncology radiologists. However, statement 7 recommends magnetic resonance imaging (MRI) rather than CT for the evaluation of indeterminate adnexal masses, which are often not malignant and are generally found as incidental findings or in younger women without other indications of possible cancer.5
Malignancy indices—quality statement 4
Women with suspected ovarian cancer are often discussed first in the multidisciplinary team (MDT) meeting at the local district general hospital. The risk of malignancy index (RMI I) is the best scoring system and is designed to highlight patients who need further assessment with CT imaging and a decision about further intervention or management at the specialist gynaecological cancer MDT meeting.22 The scoring system includes points allocated for imaging, age (pre- or post-menopausal) and CA125 level. If the final score is >250, the patient requires referral to the specialist gynaecological cancer MDT for review, as the likelihood of cancer is greatest in this group.5 It is not expected that GPs should calculate the RMI I for patients, as it requires discussion with gynaecological radiologists (usually in the local gynaecology MDT) to confirm the ultrasound findings, which often closely impact on the final score.
Surgery for ovarian cancer—quality statement 8
Quality statement 8 was considered in the context of the improving outcomes guidance for gynaecological cancers, which was published in 1999.23
The role of surgery in ovarian cancer is three-fold. If possible, it is therapeutic—that is, every last cancer cell is removed and the patient cured. In most patients, however, the surgery stages the patient and thus allows the best determination of prognosis. When the tumour appears to be confined to one or both ovaries, it is important to check the rest of the pelvis and peritoneal cavity to ensure that there are no nodules of malignant cells elsewhere, particularly beneath the diaphragm and in the paracolic gutters. Suspicious areas should be biopsied if they are not amenable to full resection, and random biopsies should be taken from the pelvis and abdominal peritoneum.24
An omentectomy is always performed, as this is a favoured site of spread and metastatic disease is not always visible macroscopically. As about 22% of women considered to have stage I ovarian cancer will, in fact, have occult retroperitoneal lymph node metastases,25 assessment of the para-aortic lymph nodes with representative biopsy is required, with removal of any that seem enlarged or involved.24
There is no current rationale for systematic retroperitoneal lymphadenectomy for therapeutic benefit in women with early-stage ovarian cancer outside of a clinical trial.
A new key priority for primary care is the availability of single longer duration appointments for gynaecological and pelvic examinations. These should be provided in each surgery; a chaperone should also be made available. This service should be advertised in the surgery so that women can specify when they feel this might be needed.
The new quality standard for ovarian cancer is a welcome tool that will help drive improvements in the diagnosis, care, and initial treatment of this less common but symptomatic and often incurable cancer. If GPs have this quality standard in the back of their minds when seeing older women with vague abdominal complaints, the diagnosis of ovarian cancer will be more timely and in line with Improving outcomes: a strategy for cancer, which was published in January 2011.26
- The number of CA125 tests in primary care over a specified period of time:
- percentage in post-menopausal women and pre-menopausal women
- percentage that helped with diagnosis (not necessarily of ovarian cancer)
- Number of ultrasound investigations for possible ovarian cancer ordered from primary care:
- percentage that identified problems
- time to obtain reports
- Quality of ultrasound reports from secondary care:
- gynaeradiologist or ultrasonographer used to imaging ovaries
- clear reporting of features such as complex or simple cyst, septations, solid, cystic areas
- recommendations for future management—for example, further imaging or repeat ultrasound for reassurance
- Reporting of abdominal pelvic computed tomography and pelvic magnetic resonance imaging for indeterminate adnexal masses to ensure that these are done by gynaeradiologists from multidisciplinary teams
- Number of cases of ovarian cancer diagnosed via non-gynaecological service routes, particularly emergency departments and emergency care.
- Commissioners should ensure that:
- there are sufficient ultrasonographers/gynae-radiologists to cover requests for CT-staging scans, pelvic ultrasound scans, and subsequent imaging of indeterminate masses
- radiologists have time to undertake some gynae-ovary ultrasound themselves and to attend gynae (local and/or specialist) multidisciplinary team meetings
- there is access to timely imaging—for both the initial ultrasound and subsequent staging CT or MRI
- requisite numbers of gynaecology oncology consultants are available locally in order to facilitate rapid-access assessment of possible ovarian cancers; additionally, sufficient surgical theatre time and surgical workforce are needed to undertake the ovarian cancer staging surgery
- local follow-up surgical cancer clinics are available to allow patients with gynaecological cancers to attend locally rather than going to the surgical centre repeatedly after their surgery
- provision of chemotherapy unit care and palliative care arrangements are local as much possible
- there is sufficient local clinical nurse specialist time, with adequate holiday cover, to support women with possible ovarian (gynaecological) cancers. Similarly, central nervous system support is needed at surgical and oncological centres to support women through treatment for ovarian cancer.
CT=computed tomography; MRI=magnetic resonance imaging
- Eastern Cancer Registry and Information Centre (ECRIC). Personal communication.
- Cancer Research UK website. Ovarian cancer survival statistics. info.cancerresearchuk.org/cancerstats/types/ovary/survival/ (accessed 20 August 2012).
- National Cancer Institute website. Ovarian epithelial cancer treatment. www.cancer.gov/cancertopics/pdq/treatment/ovarianepithelial/HealthProfessional/page6
- Gillet J, Calcagno A, Varma S et al. Multidrug resistance-linked gene signature predicts overall survival of patients with primary ovarian serous carcinoma. Clin Cancer Res 2012; 18 (11): 3197–3206.
- National Institute for Health and Care Excellence. NICE quality standard for ovarian cancer. publications.nice.org.uk/quality-standard-for-ovarian-cancer-qs18 (accessed 20 August 2012).
- National Cancer Intelligence Network. Routes to diagnosis—NCIN data briefing. NCIN, 2010. Available at: www.ncin.org.uk/publications/data_briefings/routes_to_diagnosis.aspx
- Crum C, Drapkin R, Miron A et al. The distal fallopian tube: a new model for pelvic serous carcinogenesis. Curr Opinion Obstet Gyneacol 2007; 19: 3–9.
- Kurman R, Shih M. Pathogenesis of ovarian cancer. Lessons from morphology and molecular biology and their clinical implications. Int J Gyn Onc 2008; 27 (2): 151–160.
- Crum C, Drapkin R, Kindelberger D et al. Lessons from BRCA: the tubal fimbria emerges as an origin for pelvic serous cancer. Clin Med Res 2007; 5 (1); 35–44.
- Kindelberger D, Lee Y, Miron A et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship. Am J Surg Pathol 2007; 31 (2): 161–169.
- Lurie G, Wilkens L, Thompson P et al. Symptom presentation in invasive ovarian carcinoma by tumour histological subtype and grade in a multiethnic population: a case analysis. Gynecol Oncol 2010; 119 (2): 278–284.
- Olsen C, Cnossen J, Green A, Webb P. Comparison of symptoms and presentation of women with benign, low malignant potential and invasive ovarian tumors. Eur J Gynaecol Oncol 2007; 28 (5): 376–380.
- National Institute for Health and Care Excellence. Ovarian cancer: the recognition and initial management of ovarian cancer. Clinical Guideline 122. London: NICE, 2011. Available at: www.nice.org.uk/guidance/CG122
- Lataifeh I, Marsden D, Robertson G et al. Presenting symptoms of epithelial ovarian cancer. Aust N Z J Obstet Gynaecol 2005; 45 (3): 211–214.
- Mayer E. Clinical practice. Irritable bowel syndrome. N Engl J Med 2008; 358: 1692–1699.
- Gras E, Cortes J, Diez O. Loss of heterozygosity on chromosome 13q12-q14, BRCA2 mutations and lack of BRCA-2 promoter hypermethylation in sporadic epithelial ovarian tumours. Cancer 2001; 92 (4): 787–795.
- Garcia A, Bussaglia E, Machin P et al. Loss of heterozygosity on chromosome 17q in epithelial ovarian tumours: Association with carcinomas with serous differentiation. Int J Gynecol Pathol 2000; 19: 152–157.
- National Collaborating Centre for Cancer. Ovarian cancer: the recognition and initial management of ovarian cancer. Cardiff: NCCC, 2011. Available at: www.nice.org.uk/nicemedia/live/13464/54266/54266.pdf
- Dorigo O, Berek J. Personalising CA125 levels for screening. Cancer Prev Res (Phila) 2011; 4 (9): 1356–1359
- Bast R, Badgwell D, Lu Z et al. New tumor markers: CA125 and beyond. Int J Gynecol Cancer 2005; 15 (Suppl 3): 274–281.
- The Royal College of Radiologists website. RCR referral guidelines. www.rcr.ac.uk/content.aspx?PageID=995
- Geomini P, Kruitwagen R, Bremer G. The accuracy of risk scores in predicting ovarian malignancy: a systematic review. Obstet Gynecol 2009; 113 (2 Pt 1): 384–394.
- Department of Health. Guidance on Commissioning cancer services improving outcomes in gynaecological cancers: the manual. London: DH, 1999. Available at: www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4005385
- Winter-Roach B, Kitchener H, Dickinson H. Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database Sys Rev 2009; Issue 3. Art. No: CD004706. DOI: 10.1002/14651858.
- Maggioni A, Grassi R, Mangioni C et al. Randomised study of systematic lymphadenectomy in patients with epithelial
ovarian cancer macroscopically confined to the pelvis. Br J Cancer 2006; 95: 699–704.
- Department of Health. Improving outcomes: a strategy for cancer. London: DH, 2011. Available at: www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_123371 G