British Journal of Radiology (2005) 78, S94-S102
© 2005 British Institute of Radiology
doi: 10.1259/bjr/29280555
A multidisciplinary approach to ovarian cancer at diagnosis
J A Spencer, MA, MD, FRCP, FRCR
St James's University Hospital, Leeds LS9 7TF, UK
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Clinical background
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Ovarian cancer continues to pose a major challenge to physicians and radiologists. It is the leading cause of mortality from female genital tract malignancy. There are no established population-based screening programmes for the disease and few specific symptoms and signs of ovarian cancer. Consequently the majority of women present with advanced disease with poor prognosis. Survival in all cases at 1 year is 55% and at 5 years is 29%. Median survival is 14 months.
When faced with a woman with an ovarian mass the physician is required to make a judgement about the likelihood of malignancy. Following clinical assessment, ultrasound (US) and serum CA-125 estimation are the next investigations. Based on these three evaluations women can be divided into those with (1) an ovarian mass and evidence of peritoneal spread (the presence of ascites on US almost always indicates this) or (2) an ovarian mass but no clear evidence of metastatic spread. In this review I will first discuss the role of imaging for women in group 1.
For such women believed to have peritoneal spread of cancer (and two thirds of women with ovarian cancer present this way) the next question is whether radical cytoreductive surgery is possible and appropriate. This is a judgement to be made in a multidisciplinary setting. With a working diagnosis of ovarian cancer the main considerations are:
- fitness of the woman for major cytoreductive surgery (performance status);
- imaging assessment of the pattern and extent of disease; and
- the possibility of metastatic tumour to the ovaries from another site, e.g. the gastrointestinal tract or breast.
Such metastases can have an identical presentation to primary ovarian cancer. This consideration becomes even more pertinent when a woman has a prior history of such disease, even many years after the initial presentation.
At the other end of the spectrum are women whose only abnormality is an indeterminate ovarian mass. Some masses will require excision on symptomatic grounds or for concerns about future torsion. The key question is whether simple excision of the mass is all that is required – or full cancer surgery. In some women there are issues regarding future fertility since cytoreductive ovarian cancer surgery removes also the uterus and contralateral ovary. If imaging allowed prediction of which women had benign masses or confined (stage IA or IB) cancers, potentially, surgery could be limited to that required to remove the symptomatic mass, limiting morbidity and where appropriate preserving fertility. I will return to investigation of these women later.
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Current best evidence regarding pre-surgical imaging
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Over the last decade the Radiology Diagnostic Oncology Group (RDOG) conducted a major multicentre diagnostic imaging study of women prior to ovarian cancer surgery and published its findings in three papers [1–3]. These studies compared US, CT and MRI in 280 women suspected to have ovarian cancer who underwent surgery in 5 leading institutions in the USA over a 3 year period, evaluating these modalities for cancer diagnosis and staging. In the study 189 women had unilateral masses and 91 had bilateral masses. Only 114 of the 280 women had ovarian cancer and of these 27 were not primary ovarian cancer but metastates to the ovary from other sites, some of which demand entirely different cancer management.
The RDOG studies reconfirm the difficulty of distinguishing benign complex from malignant lesions and the potential confusion of primary cancers of the ovary and cancers metastatic to the ovary within the malignant spectrum. It is important to note that in the RDOG study women with a history of malignancy were excluded and so the likelihood of confusion between primary ovarian cancer and other cancers metastatic to the ovaries was less than in routine clinical practice. Overall in this study of women with suspected ovarian cancer the majority did not have the condition. Indeed in 58 women their masses were not even neoplastic. Although we are not told whether cytoreductive cancer surgery was carried out in these women or was more limited by findings at surgery, the data re-emphasise the challenge faced by physicians and radiologists in defining appropriate management strategies for women with ovarian masses on a case by case basis.
So what lessons can be learned from these important studies? They have shown that both CT and MRI are superior to US in assessment of the nature of ovarian masses, with the highest accuracy for MRI [1]. In assessment of the stage of disease all had similar accuracy (0.91) since the presence of ascites effectively predicted peritoneal spread of tumour. However, in determination of the sites and extent of this metastatic tumour US was inferior to both CT and MRI [2]. A particular problem for US was in depiction of peritoneal metastases. The ready availability of CT makes it the investigation of choice for planning surgery in women believed to have metastatic spread of ovarian cancer. CT can replace urography and barium studies for assessment of hollow organ involvement and in most cases is the only imaging study required to plan management.
CT remains inferior to surgical staging in detection of tiny peritoneal, omental and mesenteric nodules even with meticulous technique using multidetector CT technology not available at the time of the RDOG studies [4]. But this is not its role. CT defines and alters patient care at the other end of the spectrum of ovarian cancer. In the presence of bulky peritoneal tumour CT predicts when cytoreductive surgery is likely to be incomplete by defining sites of unresectable tumour. CT indicates when the gynaecologist may require assistance from other surgical colleagues to achieve effective debulking, when, for example, there is involvement of small bowel or colon. The need for colostomy may be highlighted. CT provides the surgeon with the detail required to discuss surgical and other therapeutic options with the patient and her carers.
It is important to understand what is routinely performed in cytoreductive surgery of ovarian cancer (Table 1
) and what sites of disease may limit successful resection (Table 2). Ideally at the end of surgery there should be no residual visible disease. Debulking surgery is deemed unsuccessful if there are residual deposits of tumour in excess of 2 cm.
Bulky disease in the supracolic compartment around the spleen and stomach (Figure 1), within suprarenal lymph nodes (Figure 2), and affecting the subdiaphragmatic recesses and parenchyma of the liver is usually beyond the scope of surgery. A variety of schemes have been devised to judge the tumour extent at key sites but most document site by site involvement rather than address the issue of possible surgical "failure". The scheme of Meyer et al [5] scored the extent of tumour at five key abdominal sites (Table 2
) and in small study of 16 women had a specificity of 100%. The clear aim of pre-operative staging by CT and subsequent multidisciplinary discussion is to prevent inappropriate surgery. Each team will recognise patterns of disease in site and extent which will predict problems for surgical resection (Figures 1 and 2). Ultimately almost any disease can be resected. One needs to consider at what cost, with what benefit and with what alternative option?
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Figure 1. CT of the upper abdomen in a woman with stage IIIC ovarian cancer showing tumour filling the supracolic spaces between the spleen and stomach both of which have extensive serosal disease. Such tumour bulk suggests unsuccessful cytoreductive surgery.
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Figure 2. CT of a patient with stage IIIC ovarian cancer showing bulky high retroperitoneal lymphadenopathy again beyond the scope of cytoreductive surgery.
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The use of debulking surgery in the management of advanced ovarian cancer has long been controversial in the UK and a current MRC funded study (CHORUS) is designed in part to determine its utility (CHORUS – chemotherapy or upfront surgery in ovarian cancer patients, http://www.ctu.mrc.ac.uk/studies/CHORUS.asp). This protocol includes a treatment arm beginning with neoadjuvant chemotherapy followed by debulking surgery.
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Image guided core biopsy at initial diagnosis
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The one virtue of attempting debulking surgery in all women with suspected ovarian cancer was that at least it provided a confident diagnosis even if its primary aim was not achieved, i.e. an "open and shut" laparotomy. What are the alternatives to a surgical diagnosis and what are the therapeutic alternatives? Cytological assessment of ascitic fluid is inadequate to make the distinction of primary versus secondary ovarian cancer [6]. However, peritoneal needle core biopsy using CT (or US) guidance is a valuable and useful alternative to laparoscopy or exploratory surgery and has proven efficacy in the following circumstances [6]:- in women believed to have ovarian cancer with poor performance status or with advanced disease beyond the scope of primary cytoreductive surgery;
- in women with a history of cancer whose metastases may mimic ovarian cancer (e.g. breast, gastrointestinal (GI) tract, melanoma); and
- when there is diagnostic uncertainty, e.g. unusual imaging patterns of disease such as peritoneal carcinomatosis with bilateral solid ovarian masses or non-enlarged ovaries or with an unusual tumour marker profile (Figure 3).
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Figure 3. CT guided biopsy of a woman with a large omental cake, other peritoneal tumour and bilateral solid ovarian masses but no ascites. Histology: non-Hodgkin lymphoma.
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In this third situation peritoneal biopsy should precede an exhaustive (and potentially hazardous and unpleasant) series of investigations of potential primary sites such as upper and lower bowel endoscopy. Needle core biopsy findings can focus the search for the primary tumour when appropriate. In the majority of women undergoing image guided needle core biopsy standard haematoxylin and eosin (H&E) staining is diagnostic – and this can be compared with historical material in women with prior malignancy. In women with poorly differentiated tumours further special immunohistochemical stains may be required which identify specific tumour markers and other cellular proteins such as cytokeratins [6]. CA-125 and cytokeratin 7 stains are positive with mullerian duct epithelium (ovary, Fallopian tube). Carcinoembryonic antigen (CEA) and cytokeratin 20 stains are positive with gastrointestinal tract primary tumours. There are a variety of new site specific marker stains including BRST-2 for breast cancer. In the initial study [6] H&E staining of the core biopsy material alone provided diagnostic information in over 70% of cases and with immunohistochemical techniques this rose to over 90%. For a small group of tumours a site specific diagnosis is elusive, but not for the lack of material, rather from an ambiguous or non-specific immunohistochemical profile.
The use of peritoneal core biopsy should always follow careful review of diagnostic and staging studies in a multidisciplinary setting. The procedure can be performed using CT or US guidance [6] and may be done as a day case procedure (Figures 3–6). Both techniques offer the option of a combined procedure of biopsy and palliative paracentesis when appropriate. Given the ease of the technique US is the preferred method for biopsy of bulky omental tumour. When using CT a limited examination may be performed without the need for intravenous contrast having identified the site for biopsy on the initial study. An 18 G needle is used with the aim of providing the pathologist with the equivalent of two full cores of material. With a bulky omental cake this is usually a simple matter (Figures 3 and 4). Other peritoneal sites may be biopsied including the ovary itself [6]. With the type of wispy omental infiltrate that is present in some cases, e.g. suspected recurrent breast cancer it may be necessary to sample the peritoneum with up to six passes to obtain sufficient material (Figure 6). Peritoneal infiltrates may be predominantly fatty and yield small or fragmented cores which may float on the formalin within the specimen bottle, suggesting an inadequate biopsy. However, with multiple passes and the fragments obtained there is a high diagnostic success. In initial study [6] and in continued audit more than 90% of procedures result in firm histological diagnosis of the site of primary cancer.
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Figure 4. Ultrasound guided biopsy of a large omental cake showing echogenic needle track (courtesy of Dr Michael Weston).
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Figure 6. CT guided biopsy of a wispy omental infiltrate in a woman with prior breast cancer. Histology: infiltrating lobular breast cancer.
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Image guided core biopsy is a recommended alternative to laparoscopy in the CHORUS trial for diagnosis of women in the neoadjuvant (non-surgical arm) at entry. It should occur whenever there is a peritoneal or other mass shown on the staging CT study that is suitable for core biopsy and is to be preferred to cytological assessment [6].
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Primary peritoneal cancer; ovarian metastases
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In the light of the RDOG studies it is time to reconsider our acceptance of and our practical approach to two imaging "rules of thumb":- bilateral solid ovarian masses are the sign of disease metastatic to the ovary
- peritoneal carcinomatosis without an ovarian mass is a sign of a primary tumour at another site
Whilst the results of the third RDOG study [3] challenge the first rule it is wise to raise one's suspicions. Ovarian metastases may be indistinguishable from that of primary ovarian cancer and both may produce the bilateral, solid masses considered typical of Krukenberg tumours. The only factor favouring primary ovarian cancer in the RDOG studies was multilocularity. CT well illustrates the gastrointestinal (GI) tract and the stomach, colon, appendix and pancreas should be inspected as potential primary cancer sites within the abdomen (Figure 7). If there are concerns after multidisciplinary review that disease is not primary ovarian cancer, image guided biopsy should be considered because radical cytoreductive surgery has no place in management of the metastatic GI tract cancer and such surgery may delay initiation of appropriate therapies.
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Figure 7. (a) CT of the pelvis showing a large solid partially necrotic ovarian mass and (b) of the upper abdomen showing a non-obstructive cicatrizing right colon cancer. The mass was resected by a general gynaecologist and histology was that of a Krukenberg tumour. At review of the pre-operative CT in the multidisciplinary meeting the colonic primary was discovered.
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There are many causes of peritoneal carcinomatosis (Table 3) but the key consideration in a woman with peritoneal tumour but no ovarian enlargement should not be metastatic disease from another occult site but rather primary peritoneal carcinoma (PPC). PPC arises from the peritoneal surfaces as a papillary serous tumour of Mullerian duct origin. This entity is managed in an identical manner to primary ovarian cancer with cytoreductive surgery and platinum based chemotherapy, yet has some differences in imaging findings. The typical CT features of PPC are of ascites, omental and peritoneal masses, which may be calcified, but with normal sized ovaries (Figure 8) [7, 8]. PPC was initially recognised as a subset of women with peritoneal carcinomatosis whose prognosis was more favourable [9–11]. Median survival was 23 months with PPC compared with 3 to 4 months for peritoneal carcinomatosis related to non-gynaecological malignancy. So in a woman with suggestive CT findings rather than an exhaustive search for an occult primary tumour, it is histological diagnosis that should be sought.
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Figure 8. (a) CT of the upper abdomen showing bulky supracolic peritoneal tumour invading the hilum of the spleen, (b) CT of the right lower quadrant showing a large calcified infracolic omental cake and (c) CT of the pelvis showing a 4.5 cm right adnexal mass, partially calcified. Note tumour encasing the sigmoid colon. Histology of CT guided core biopsy: papillary serous adenocarcinoma consistent with primary peritoneal carcinoma.
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The diagnosis of PPC in those series was made at laparotomy but it is a diagnosis which can be suggested on the basis of imaging and confirmed using image guided needle core biopsy [6]. Both ovarian cancer and PPC may occur in women with the BRCA1 and BRCA2 gene mutations for breast cancer [12]. The treatment options and prognosis differ markedly between ovarian cancer/PPC and abdominal recurrence of breast cancer. In a woman with prior breast cancer with peritoneal carcinomatosis needle core biopsy allows this distinction to be made with confidence allowing comparison with tissue from the breast at initial diagnosis [6].
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Use of MRI in initial diagnosis of ovarian cancer
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In the introduction to this review a convenient (and not entirely reliable) division was made on the basis of US and clinical assessment between women with (1) an ovarian mass and evidence of peritoneal spread and those (2) with an ovarian mass but no clear evidence of metastatic spread. MR has an important role in investigation of women in group 2. The RDOG studies concluded that MRI was not only the best staging study but also superior to CT and US in characterization of adnexal masses.
In the RDOG study only "routine" MR sequences were used. Low and colleagues have shown that use of a dynamic gadolinium enhanced fat-suppressed technique allows depiction of tiny peritoneal deposits [13]. The technique was applied in the context of treated women with potential residual or recurrent disease but one would anticipate similar efficacy at initial diagnosis. The issues in diagnosis of recurrent disease are different from those at diagnosis where demonstration of small tumour deposits do not usually impact upon surgical planning. By contrast with the RDOG studies the dynamic gadolinium enhanced MR technique has been validated only in small groups of women against surgical findings and was not compared with what would have been regarded as current "state of the art" CT. This is a recurring problem in evaluation of imaging tests when one state of the art modality is either not compared with the previous gold standard modality or is only compared with that modality employing outdated technology or suboptimal technique. There is greater rationale for using MRI for diagnostic rather than staging purposes.
The first RDOG study [1] indicated that MRI was the best single modality for assessment of the nature of an adnexal mass and this is a much more promising role at initial diagnosis. When US cannot confidently characterize an adnexal mass MRI is a valuable problem solving tool, notably in the following circumstances:
- with echogenic masses for confident distinction of fat within dermoid lesions from blood;
- with solid masses for distinction of fibroma and thecoma from malignant masses (Figure 9);
- with masses where adnexal or uterine origin is unclear;
- when the option of interval re-examination with US is not available.
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Figure 9. (a) Axial T2 weighted MR of the pelvis showing one large and one small solid adnexal mass and a fibroid uterus in the left posterior aspect and T1 weighted MR images (b) before and (c) after injection of gadolinium showing bland masses which show marked enhancement. Histology: Krukenberg tumours. Note the areas of necrosis and the lobulated surface.
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This last indication bears particular consideration in the situation of a complex adnexal mass discovered by US at a gestational dating scan or as part of a "symptomatic" US scan performed in pregnancy (Figure 10). CT is not an option for further evaluation and laparoscopy difficult and hazardous. CA-125 estimation can be unreliable in pregnancy. There is a need to know quickly and accurately whether the mass is a threat to the mother or likely to compromise the delivery and MRI is appropriately used in the second and third trimesters [14, 15].
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Figure 10. (a) Axial T2 weighted MR of the pelvis in a pregnant woman found to have a complex pelvic mass at her booking scan. The mass behind the gestation sac in the right posterior pelvis shows complex papillary elements on the right lateral wall and coronal T1 weighted MR images (b) without and (c) with fat suppression showing small bright fatty elements superiorly. Histology: mature cystic teratoma with skin appendage elements accounting for the wall complexity. The fatty element was not recognized by ultrasound and the complex mural elements raised concerns for malignancy.
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In addition to the RDOG studies there are other large studies attesting to the value of MRI in diagnosis of adnexal masses [16, 17]. These studies emphasise the use of gadolinium enhancement to show papillary elements (vegetations) attached to the wall of cystic lesions or along internal septa [16, 17] as well as necrosis within solid elements [16]. Interestingly in multivariate analysis vegetations and the presence of ascites were the most important features [17] re-emphasising the importance of this latter finding in the pathway of imaging (Figure 11).
MRI should be regarded as the most accurate pre-surgical test for assessment of adnexal masses. Its limited availability means that in most hospitals it will be used as a problem solving tool after multidisciplinary discussion for investigation of indeterminate masses when the findings of imaging will alter management.
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Risk of malignancy index (RMI)
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US remains the mainstay of investigation in a woman with suspected ovarian cancer and provides both a guide to likelihood of cancer and for further investigation. The aim of initial investigation is to rapidly direct those women thought likely to have ovarian cancer to a multidisciplinary team specializing in its management. For adnexal masses without evidence of peritoneal disease there can be problems in distinction of benign complex masses from malignancy and the search for a better method of ultrasound assessment has resulted in many false hopes of technical advance and a wide variety of scoring systems [18]. Of these the RMI described by Jacobs and colleagues but widely tested by other teams [19, 20] has proved most durable. Here the combination of US findings with serum CA-125 level and a further factor reflecting menopausal status result in the RMI score. The method has significant limitations in assessment of some non-epithelial lesions and complex non-malignant lesions [20] which may be diagnosed with MRI.
RMI=serum CA-125 level x ultrasound score x menopausal score
Ultrasound score=up to 3; Post-menopausal=3; Pre-menopausal=1.
Some elements within the ultrasound score (e.g. ascites, intra-abdominal metastases) direct investigation down differing pathways (Figure 11) to others (solid elements, multilocularity, bilaterality). A score of over 200 is considered significant and it is appropriate to use this a threshold for referral for specialist multidisciplinary care at which time the individual ultrasound findings can be carefully reviewed to indicate how best to proceed with further imaging on case by case basis (Figure 11).
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Conclusions
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The results of the RDOG studies have guided the use of imaging for women with suspected ovarian cancer at initial diagnosis and supplemented by data from other recent studies provide a partial evidence based pathway for imaging in this disease (Figure 11). US is the workhorse of initial investigation and combined with clinical factors as part of the RMI is used to direct women to the specialist multidisciplinary team. CT is the mainstay of imaging of women believed to have ovarian cancer based on a combination of its efficacy and availability and the familiarity of radiologists and physicians with its strengths and weaknesses. It allows planning of primary cytoreductive surgery and directs the need for and feasibility of image guided needle biopsy when primary surgery is not appropriate. MRI is the problem solving investigation of choice for the indeterminate adnexal mass.
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Acknowledgments
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I would like to thank Dr Nafisa Wilkinson, Consultant Pathologist, and Dr Michael Weston and Dr Sarah Swift, Consultant Radiologists for help in developing the image guided peritoneal core biopsy technique and clinical colleagues within the Leeds multidisciplinary meeting for its acceptance and dissemination.
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References
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Clinical background
Current best evidence regarding...
