Ovarian Cancer (Staging)

• Although surgically defined, preoperative imaging plays an essential role in ovarian cancer staging 6.
• Staging is important to define tumour characteristics, to determine extent of disease (local invasion and metastatic spread), and to predict tumour resectability. This will help to assign patients to optimal treatment and prognostic groups 2, 4.
• The International Federation of Gynaecology and Obstetrics (FIGO) classification system is the most commonly used staging criteria for ovarian cancer. The American Joint Committee on Cancer Tumour Node Metastasis (TNM) classification system is also used at some centres 1, 4, 7.
• Ovarian, fallopian tube and primary peritoneal carcinomas share morphologic and molecular similarities and were all incorporated into the 2013 revision of the FIGO staging system. They are managed in a similar manner 4, 8–11.
• There are many histological types of malignant tumours arising from the ovaries, including 4, 9, 11, 12:
  • Epithelial (90%) – high-grade serous, low-grade serous, endometrioid, clear cell, mucinous
  • Germ cell (3%)
  • Potentially malignant sex cord-stromal tumours (1–2%)
• The tumour stage and the histological type will determine the most appropriate therapy 12, 13.
• Contrast-enhanced CT of the abdomen and pelvis (and chest when indicated) is the initial staging investigation. PET/CT and MRI may be useful when lesions are present on CT but are indeterminate 2.

FIGO staging classification for cancer of the ovary, fallopian tube and peritoneum with corresponding TNM stage 10–12, 14.

• CT abdomen and pelvis with intravenous and oral contrast is the primary staging investigation 2, 4, 15–17.
• Provides information on the size of the primary tumour, local invasion, and metastases to the peritoneum, omentum, mesentery, liver, spleen, lymph nodes and lung parenchyma 2, 4, 17–19.
• Staging accuracy of CT ranges from 53–92% compared to 78–88% for MRI 20.
• Can accurately predict successful surgical cyto-reduction, which is the most important prognostic factor 16, 21. One study found the positive predictive value for CT to determine tumour resectability was 92% 22.
• A significant limitation of CT in staging is its inability to reliably detect bowel surface, mesenteric or peritoneal tumour implants < 5mm, especially in the absence of ascites 2, 16, 23.
• When neoadjuvant chemotherapy is offered, an image-guided biopsy (planned from the staging CT) confirms the diagnosis and provides histological sub-type 16.

Imaging the chest

• Although there is no direct evidence that a plain chest radiograph or chest CT is necessary, the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) guidelines support the use of chest radiography or chest CT if clinically indicated to look for pleural effusions and metastatic disease above the diaphragm 2, 6, 24, 25.
• If a plain chest radiograph shows no abnormalities, the yield of CT chest is low 2, 26.
• When advanced disease is suspected (e.g. subdiaphragmatic carcinomatosis, pleural effusion, or suprarenal lymphadenopathy), CT chest is recommended to detect pleural and pulmonary metastases 2, 26, 27.
• If a PET/CT has also been performed and includes the chest, the added value of a diagnostic quality chest CT is probably even lower 2.

• Although not currently recommended as a routine part of ovarian cancer staging, MRI can be helpful when an adnexal lesion is indeterminate on ultrasound or CT 7, 28–31.
• Some studies have reported better accuracy of MRI over CT for predicting malignancy in ovarian masses, with sensitivity and specificity ranging between 87–97% and 97–98% respectively for MRI compared with 36–100% and 74–93% respectively for CT 32–34.
• MRI has a similar accuracy to CT in detecting disease spread (70–90%) and is also a reliable tool for predicting tumour resectability (accuracy 93–96%) 19, 22, 24, 28, 35.
• Limitations include: more expensive and less widely available than CT, and patient motion can be a significant problem.
• MRI is currently only recommended for staging in patients in whom fertility preservation is being considered (to minimise ionising radiation exposure), or those who have a contraindication for the use of iodinated contrast agents. It can be used as an adjunct to CT when further tumour characterisation is required 2, 7, 20.

• The routine use of PET imaging in the primary diagnosis, tissue characterisation and pre-treatment staging of ovarian cancer is not currently recommended 2, 36–38.
• Most ovarian cancers demonstrate significant fluorodeoxyglucose (FDG) uptake.
• PET/CT does not provide further information with regard to the primary tumour stage (T stage); however, it is superior to CT alone for detecting metastatic lymph nodes and extra-abdominal metastases (N and M stage) 4, 7, 24, 36, 38–42.
• Tumour stage based on PET/CT has been found to be concordant with the surgical stage in 69–78% of patients compared with 53–55% of patients who underwent CT alone. This is thought to be because PET/CT can detect metastatic involvement of normal-sized lymph nodes 7, 43–45. One study found that PET/CT detected unexpected extra-abdominal lymph node metastases in 16% of cases 46.
• PET/CT is therefore recommended in patients with suspected advanced disease (stage IV) or when there are indeterminate lymph nodes on other imaging modalities 7.
• Overall, however, it is thought that performing a PET/CT does not substantially change treatment and therefore routine use of PET/CT in ovarian cancer staging is not currently recommended 32.
• For monitoring treatment response and for detection of recurrent disease, PET/CT has been validated as an effective tool 7, 47.
• In combination with CA125, the detection rates for recurrence have been found to be as high as 97.8% 20.

• Surgical staging via laparotomy is the gold standard staging system in ovarian cancer.
• Surgical debulking and minimising the volume of residual disease is the most important prognostic factor to increase median survival and enhance response to chemotherapy 6, 8, 48, 49.
• The ideal tumour cytoreductive surgery standard is a maximum postoperative residual tumour diameter of less than 1cm 3.
• Patients whose medical condition permits should generally undergo a primary staging laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy and maximal attempt at optimal cytoreduction (may include bowel resection, and/or partial/complete resection of other organs if involved) 8.
• In younger women when fertility may be an important consideration, conservative surgery with preservation of the uterus and contralateral ovary can be considered in some circumstances 6, 8.
• Whenever possible, surgery should be performed by a surgeon who specialises in gynaecologic oncology.

• An alternative treatment to primary debulking surgery is neoadjuvant chemotherapy combined with interval debulking surgery, although this remains controversial 25.
• In patients with cytologically proven stage IIIC and IV disease whose medical condition is unfavourable for primary debulking surgery or who are assessed by a gynaecologic oncologist and deemed unlikely to be completely cytoreduced (< 1cm residual abdominal-pelvic disease), neoadjuvant chemotherapy (generally 3–4 cycles) prior to interval debulking surgery can be considered 8, 16.
• Two randomised prospective trials (EROTC and CHORUS) demonstrated that interval debulking surgery after neoadjuvant chemotherapy showed equivalent survival with less morbidity compared to primary debulking surgery in these patients 8.
• Recent evidence indicates that neoadjuvant chemotherapy is only effective in certain subtypes of ovarian epithelial tumours (chemotherapy-sensitive tumours such as serous carcinoma) and not in other subtypes (chemotherapy-resistive tumours such as mucinous and clear cell carcinoma). 50, 51 Although imaging can be used to estimate the subtype of ovarian carcinoma, cytological diagnosis is necessary to guide treatment 50.

• For patients who are not suitable for surgery or in patients in whom neoadjuvant chemotherapy is being considered prior to surgery, a precise histological diagnosis is required 52.
• Image-guided percutaneous biopsy of diffuse peritoneal disease or of the adnexal mass can be undertaken using ultrasound or CT guidance 52.
• Image-guided percutaneous biopsy has been found to be safe and effective, resulting in tissue diagnosis in approximately 87–93% of patients 52, 53.
• Studies have found a slightly higher diagnostic yield with ultrasound-guided biopsy over CT-guided biopsy and ultrasound has therefore been recommended as the preferred modality over CT in image-guided biopsies when feasible 53.

• Transabdominal and transvaginal ultrasound is the imaging modality of choice for the initial evaluation of adnexal masses and can help stratify the risk of the malignancy. It is not usually helpful as a staging investigation once a diagnosis of ovarian cancer has been made 6, 26, 28, 54.

Ultrasound in the Initial Assessment of an Adnexal Mass

• When an ovarian/adnexal mass is identified, it is important to estimate the risk of malignancy to determine which patients need further investigation and treatment.
•  The Risk of Malignancy Index (RMI) has been the most widely used model to help distinguish between benign and malignant adnexal masses.
• Although there have been a number of iterations to the RMI, a systematic review of diagnostic studies found that the RMI I was the most effective for women with suspected ovarian malignancy. 55 The British Royal College of Obstetricians and Gynaecologists (RCOG) and National Institute for Health and Care Excellence (NICE) guidelines recommend calculating the RMI I score in all patients with an adnexal mass on US 55–57.
• The RMI is calculated based on CA125 level, menopausal status (M), and ultrasound (U) characteristics of the mass. Reported and validated sensitivities and specificities for differentiating benign from malignant masses based on the RMI range from 78–85% and 77–97% respectively 20.
• RMI = U × M × CA125 55, 56.
• U = 0 if there are none, U = 1 if there is one, and U = 3 if there are two or more of the following ultrasound characteristics: 56
  • Multilocular cysts
  • Solid areas
  • Metastases
  • Ascites
  • Bilateral lesions
• The menopausal status (M) is scored as 1 = pre-menopausal and 3 = post-menopausal. A woman is classified as post-menopausal when she has had no period for more than 1 year or is over 50 and has had a hysterectomy 56.
• Serum CA125 is measured in U/mL and can vary between 0 and hundreds or even thousands of units 56.
• NICE guidelines recommend that all women with an RMI I score ≥ 250 be referred to a specialist multidisciplinary team for further workup 56.
• RCOG guidelines for management of ovarian cysts in post-menopausal women recommend CT of the abdomen and pelvis, and onward referral to a gynaecological oncology multidisciplinary team for women with an RMI I score ≥ 200 57.
• Studies investigating risk of malignancy indices have not specifically looked at premenopausal women, however, and therefore reported results may not be applicable to these women 55.
• The American College of Obstetricians and Gynaecologists and the Society for Obstetricians and Gynaecologists of Canada have guidelines for the management of premenopausal women with a pelvic mass. They consider any of the following suspicious for ovarian malignancy, warranting referral to a gynaecological oncologist: 55
  • CA125 > 200U/mL.
  • Ascites.
  • Evidence of abdominal or distant metastasis.
  • A first degree relative with breast or ovarian cancer.
• The International Ovarian Tumour Analysis (IOTA) group have also defined an algorithm based on ultrasound findings to help distinguish adnexal masses with benign features from those which demonstrate malignant features and require further investigation. The IOTA ultrasound rules have demonstrated superior sensitivity and specificity over the RMI model 20.

• IOTA Group ultrasound ‘rules’ to classify masses as benign (B-rules) or malignant (M-rules).
• It is recommended that any patient who has one or more M-rule ultrasound finding should be referred to a gynaecological oncological service 55.
• Due to a lack of standardised ultrasound descriptors in adnexal imaging reporting and subsequent inconsistencies in patient management, the American College of Radiology formed the Ovarian-Adnexal Reporting and Data System (O-RADS) committee in 2015. Using descriptors similar to the IOTA rules, the aim was to create a standardised lexicon for describing imaging characteristics of ovarian and adnexal masses. Ultimately they hope to apply the lexicon to a risk stratification and management algorithm to ensure more standardised image interpretation and patient management 58.
• See the Adnexal Masses (Incidental) Pathway for guidance on the imaging investigation of incidental ovarian and other adnexal masses.

Ultrasound in the Screening and Staging of Ovarian Cancer

• The role of US in ovarian cancer screening remains under investigation and currently has been limited to variable screening of high-risk patients 1.
• Although not routinely used for staging, one study found that transvaginal US correctly identified peritoneal carcinomatosis with a sensitivity and specificity of 84% and 96% respectively. The authors of this study postulated the potential future use of transvaginal US as an imaging method in the staging of local spread of ovarian cancer in the pelvis 59.