Imaging Recommendations for Diagnosis, Staging, and Management of Ovarian and Fallopian Tube Cancers

Abstract Ovarian malignancy the third most common gynecological malignancy and is the leading cause of death in women. Non-specific clinical presentation delays the diagnosis, and they often present in the advanced stage of disease. No imaging modality is recommended for screening as there is no significant mortality reduction. Ultrasound (USG) is usually the initial modality in suspected ovarian mass. MRI is recommended for the characterization of indeterminate ovarian or adnexal mass on USG. CT abdomen and pelvis with oral and IV contrast is the recommended imaging modality in staging the disease, predicting the resectability and in selecting the patients who would benefit from neoadjuvant chemotherapy. Early ovarian cancers are staged by post-surgical histology and undergo upfront surgery. Advanced disease benefit by neoadjuvant chemotherapy and less morbidity by interval cytoreduction where image-guided biopsy is performed for histological diagnosis. Follow-up recommendations are based on tumor histology. CT/PET CT is recommended for diagnosing recurrence.

often present in advanced stages. 1 Though ovarian cancers are traditionally staged surgically, up to 40% of patients may be under staged at laparotomy. 2 The role of the imaging is to characterize the ovarian lesion, determine the extent, predict primary resectability or unresectability, to evaluate the response to chemotherapy and localize the recurrence. 3

Risk Factors and Etiopathogenesis
Several theories have been postulated about the origin of ovarian cancers. According to the World Health Organization (WHO), epithelial ovarian cancers are classified into highgrade serous and low-grade serous, mucinous, endometrioid, clear cell carcinomas and malignant Brenner tumor and carcinosarcomas. 4 High-grade serous carcinomas are postulated to arise from the fimbrial end of the fallopian tube through precursor lesions called STIC (serous tubal intraepithelial carcinoma). Low-grade serous tumors may arise from benign or borderline tumors of the ovary.
Risk factors for ovarian cancer include genetic mutations such as BRCA 1 and 2 and Lynch syndrome, nulliparity, endometriosis, obesity, and smoking.
Protective factors include use of oral contraceptive pills, breastfeeding, tubectomy, and tubal ligation. 5

Epidemiology in India and Globally
Ovarian cancer currently ranks as the seventh most common cancer in women, worldwide. Often called a "silent killer," it has high mortality rates due to its insidious onset and lack of specific symptoms. It occurs more commonly in developed countries such as the US and Europe. 6 However, mortality rates are highest in Asian and African countries with the existing disparities in access to healthcare and affordability. In Asia, the highest ovarian cancer-related mortality rate is seen in India. 7 Carcinoma ovary is the third most common cancer in Indian women followed by breast and cervix. The cumulative risk of developing ovarian cancer between 0 and 74 years of age is about 1 in 133. 8

Imaging Referral Guidelines
No imaging is recommended for screening for ovarian carcinoma in the general population as there was no significant reduction in mortality rates due to screening according to ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) trial. 9 Ultrasonogram (USG) with CA-125 levels may be considered for women with hereditary cancer syndromes starting at 30 to 35 years of age if they have not undergone risk-reducing salpingooophorectomy. 10 USG is the initial imaging modality of choice in suspected ovarian lesions. If the lesion is suspected to be malignant on USG, staging CT abdomen and pelvis with oral and IV contrast is indicated to evaluate the extent of disease and identify patients who would benefit from neoadjuvant chemothera-py. 11,12 If the lesion is indeterminate on USG, MRI is recommended for further evaluation. 13 FDG-PET-CT is helpful for patients with primary peritoneal carcinomatosis or elevated tumor markers with inconclusive CT findings. 14 Serum CA-125 levels and CT are the standard tools for assessing the response to chemotherapy. 15 FDG-PET-CT is useful in early prediction of response after neoadjuvant chemotherapy due to its functional imaging. 16 In MR imaging, DWI is useful in early prediction of response by an increase in ADC values. 17 Rising CA-125 levels, symptoms and signs of relapse after treatment prompts imaging evaluation for recurrence. CT chest, abdomen, and pelvis is the imaging modality of choice in clinically suspected/known recurrence of disease in carcinoma ovary. 14 PET-CT has similar or higher accuracy compared to CT in detecting recurrences. 18

Clinical and Diagnostic Work-up Excluding Imaging
Women with ovarian malignancies usually have a wide range of symptoms from vague abdominal discomfort, painless abdominal distension, mass per abdomen and bowel or bladder disturbances. Rarer clinical symptoms include acute abdomen secondary to ovarian torsion, bowel obstruction, gastrointestinal bleeds, vaginal bleeds, lymphadenopathy, and paraneoplastic syndromes.
The serum tumor markers remain the easiest and sensitive screening tool, albeit non-specific. Serum levels of cancer antigen 125 (CA 125) show sensitivity of 78% and specificity of 77% for epithelial tumors. Higher sensitivity and specificity are observed in postmenopausal women, advanced stage, and higher grade. 19,20 The human epididymis protein 4 (HE 4) level may be useful in patients with low/normal CA 125. CEA and CA 19.9 are other markers that can also be elevated.
Specific tumor markers such as inhibin B alfa feto protein (AFP) and beta human chorionic gonadotropin (beta HCG) lactate dehydrogenase (LDH) are used for diagnosis and follow-up of non-epithelial tumors.
Biopsy of ovarian masses is generally not recommended as rupture and peritoneal seeding can upstage the tumor. In patients with ascites, diagnostic cytology yields vary in 30 to 70%. In women who are not eligible for surgical cytoreduction, image-guided biopsies or laparoscopic biopsy may establish diagnosis. [21][22][23] Additional evaluation with upper GI endoscopy and colonoscopy should be considered for all women with clinicradiological suspicion or elevated serum markers suggestive of gastrointestinal primary.
Irrespective of family history, these patients should be offered genetic testing that has an impact on treatment plan and choice and after treatment care. 24 Patients with epithelial carcinoma of the ovary should be offered testing for BRCA1 or BRCA2 mutations and for Lynch syndrome. Patients with mucinous, clear cell, endometrioid cancers are offered testing for DNA mismatch repair deficiency.

Screening for Ovarian Cancer
Ovarian cancer is the most common cause of cancer deaths due to gynecological malignancies. Because it presents with non-specific symptoms, it is diagnosed in the advanced stage in 58% of patients which results in a low 5-year survival rate (30%). When diagnosed early as a localized disease, the 5year survival rate is 93%. 25 This led to the development of screening tools for ovarian cancer.
The common screening tools considered are transvaginal USG and serum CA-125 levels. Both have the disadvantage of high false-positive rates leading to unnecessary interventions. According to the randomised controlled trials on ovarian cancer screening, there was no significant reduction in mortality rates due to ovarian cancer with screening. 9,26, Because of the negative net benefit and risk ratio, it is not recommended to screen asymptomatic high risk women. [27][28][29] For high risk women, risk-reducing salpingo-oophorectomy(RRSO) is recommended at 35 to 40 years of age and upon completion of child bearing. High-risk women who have not elected RRSO, screening with transvaginal sonography and CA-125 levels, although of uncertain benefit, is recommended at the clinician's discretion starting at the age of 30 to 35 years. 8

Diagnosis
The initial imaging modality of choice is ultrasonography in a suspected adnexal or ovarian mass (USG). 10 The International Ovarian Tumour Analysis (IOTA) and Ovarian-Adnexal Reporting and Data System (O-RADS) may be used for the characterization and risk stratification of adnexal masses. 30 If the lesion is benign, it can be followed up or no further evaluation is recommended.
If the USG findings are indicative of a lesion with high risk of malignancy, evaluation by a gyneco-oncologist along with CT of the abdomen and pelvis or CT thorax, abdomen and pelvis is recommended for staging of the disease and treatment planning. 11 In patients with indeterminate features, MRI of the abdomen and pelvis is recommended for further characterization. 11 In the evaluation of indeterminate adnexal lesions, MRI is a superior modality than USG/CT. MRI has increased specificity compared with the USG, decreasing the number of false-positive diagnoses for malignancy and thereby avoiding unnecessary or over-extensive surgery. 31 The Ovarian-Adnexal Reporting and Data System (O-RADS) is released by American College of Radiology for USG and MRI. 30,31 It assigns a probability of malignancy based on the imaging features of an adnexal lesion and provides information to facilitate optimal patient management and a uniform reporting system with standardized lexicons. The primary goal of the O-RADS risk stratification system is to improve communication between radiologists and referring physicians in a reproducible fashion, so that women with benign lesions or borderline tumors can avoid unnecessary or over-extensive surgery, respectively, and women with potential malignancy are promptly referred for gynecologic oncologic surgical evaluation.
The classical benign adnexal lesions on ultrasound include unilocular cyst < 10 cm with smooth inner walls and also typical dermoid cysts, typical hemorrhagic and endometriosis cysts, hydrosalpinx and paraovarian/peritoneal inclusion cysts. On MRI, typical benign feature is cysts with T2 dark/DWI dark solid components. 30,31 High-risk features that indicates malignancy in adnexal masses on ultrasound include unilocular cyst with > 4 papillary projections, multilocular cyst with solid component with color score of 3 to 4, solid lesion with smooth outer contour with color score of 4, solid lesion with irregular outer contour and when the lesion is associated with ascites and/or peritoneal nodules. Solid tissue with high-risk time intensity curve in dynamic post contrast MRI is a high-risk feature. 30,31 Indeterminate features of adnexal masses on ultrasound include unilocular cyst > 10 cm in size or with irregular inner walls, multilocular cyst, multilocular cyst with solid component with a color score of 1 to 2. Unilocular cyst with 1 to 3 papillary projections or solid components and solid lesion with smooth outer contour with color score of 1 to 3. Highrisk features on MRI include solid components showing lowrisk or intermediate-risk time intensity curve on dynamic post contrast images. 30,31

Image-Guided Intervention for Diagnosis
In ovarian cancer patients amenable to primary cytoreductive surgery, definitive diagnosis is by surgical histopathology.
Image-guided biopsy is recommended only in patients who are not amenable for primary cytoreductive surgery. Trans-abdominal or trans-vaginal ultrasound-guided biopsy of omental, peritoneal, or adnexal mass can be done to confirm diagnosis and histopathological type of ovarian cancer before starting optimal neoadjuvant chemotherapy. If biopsy is not feasible, ascitic or pleural fluid aspiration, cystoscopy, and CA-125:CEA ratio of > 25 can be used for diagnosis. 3 In patients with pleural effusion, nature of effusion must be confirmed with pleural fluid aspiration and cytology.

Staging
Contrast-enhanced CT (CECT) of the abdomen and pelvis or CECT thorax, abdomen and pelvis is the recommended imaging for staging of ovarian cancer. CT plays an important role in the assessment of operability and for identifying lesions in regions that are difficult to resect CT characterizes the tubo-ovarian lesion and detects the involvement of the adjacent pelvic organs such as infiltration into the uterus, rectum, and sigmoid colon, involvement of the ureter. It also detects the extension of the disease outside the pelvis with involvement of the peritoneum, omentum, mesentery, visceral organs, and lymph nodes (►Fig.1). The reported accuracy of CT in staging of ovarian cancer is up to 94%. 14 Further CT detects the involvement of certain sites such as the mesenteric root, gastrosplenic ligament, lesser sac, porta hepatis, hepatic intersegmental fissures, subdiaphragmatic regions, infiltrating liver, and splenic deposits and also helps in detecting lymphadenopathy at or above the celiac axis, extraperitoneal disease, and pelvic sidewall invasion and thereby predicts non resectability (►Fig. 2). 14 The limitation of the CT is to detect deposits that are less than 5 mm within the peritoneum, bowel surface especially when there is no ascites. 32 For deposits that are < 5 mm, the sensitivity of CT is only 11%. 33 Positive oral and rectal contrast improves detection of visceral peritoneal deposits. CT chest can be used in cases of suspected pleural or pulmonary metastasis.
Alternatively, MRI and FDG-PET-CT may be appropriate for staging. MRI has equivalent accuracy to CT in staging of ovarian cancer with sensitivity of 0.88, specificity of 0.74, and accuracy of 0.84. 34 However, the limitations are that MRI is more sensitive to motion and has long duration of study compared to CT. FDG PET has a specificity as low as 54% and sensitivity of 86% in diagnosis and treatment of ovarian cancers. PET CT can be false positive in certain benign tumors such as fibroma and dermoid and in non-neoplastic conditions such as hydrosalpinx and endometriosis. However, various studies demonstrate that when combined with CT, it has a higher accuracy than FDG-PET or CT alone. 35,36 Others imaging modalities such as non-contrast CT, ultrasound of abdomen and pelvis are not recommended for staging. 14 CT is also recommended to assess response in patients who are undergoing neoadjuvant chemotherapy before interval debulking (►Fig. 3). 14 The 2014 revised FIGO staging classification is used for staging of ovarian, fallopian tube, and peritoneal malignancies. 37 In the recent FIGO 2021 staging report, there are no changes in the staging system. FIGO classification along with equivalent stages in the Union of International Cancer Control (UICC) TNM staging is given in ►Table 1.

Follow-up
Except for a few tumors with low malignant potential, patients are seen every 2 to 4 months in the first 2 years, then every 3 to 6 months in the next 3 years, and annually after 5 years. Follow-up is mainly with clinical examination and tumor markers for epithelial tumors. The role of imaging for routine surveillance is unclear due to poor sensitivity of imaging in picking up small volume recurrence and due to no proven positive effect on survival. Thus, imaging is indicated     only in patients with biochemical recurrence. Imaging is also of benefit also in patients with high clinical suspicion of recurrence but show no elevation of tumor markers.
As of now, use of other imaging modalities for follow-up is unsupported. Refer to ►Table 2 for follow-up recommendations for tumors with various histological types.

Recurrence
CECT of the thorax, abdomen, and pelvis is the recommended imaging modality of identifying recurrence. The tumor usually recurs as peritoneal implants within the peritoneal cavity and along the surface of the visceral organs. The sensitivity and specificity of CECT ranges from 58% to 84% and 59% to 100%, respectively. 39 MRI was comparable to CT for detecting recurrence > 2 cm. However, for overall detection of recurrence, MRI had significantly lower accuracy than CT/FDG PET/PET CT. 40 The reported diagnostic accuracy of FDG-PET/CT is similar or more than the CECT in detecting recurrent ovarian tumors (►Fig. 4). 18,41 The sensitivity and specificity of FDG-PET/CT ranges from 95% to 97% and 80% to 100%, respectively. 18 However, these figures are predominantly from high-grade

Principles of Management
Depending on the stage and extent of disease, ovarian cancer patients are managed with primary cytoreduction (removal of uterus, tubes and ovaries, omentum, peritoneal biopsy and lymph-node dissection), secondary cyto-reduction following neo-adjuvant chemotherapy, palliative intent chemotherapy, and best supportive care. Chemotherapy may be omitted in low-grade, stage IA or IB cancers. All other stages are given four to six cycles of adjuvant chemotherapy. Fertility-sparing surgery may be an option in ovary-confined disease, if the woman wishes to consider future child-bearing options.
The principle of management in advanced stages is "optimal debulking (removal of all macroscopic disease)" followed by adjuvant chemotherapy. 43,44 The preferred chemotherapy regimen is six cycles of paclitaxel and carboplatin. Neoadjuvant chemotherapy with interval cytoreductive surgery has become a preferred option, especially in high-volume disease. [44][45][46] Targeted therapies such as bevacizumab and PARP inhibitors, have shown to improve overall or progression survival, especially in women with genetic mutations such as BRCA 1 and 2. 47,48 Hyper-thermic intraperitoneal chemotherapy (HIPEC) is also given in optimally debulked advanced stage III/IV ovarian cancers. ►Table 3 summarizes the principles of management.

Follow-up Management and Treatment of Relapse
Clinical examination is routinely performed posttreatment and at 3 to 4 monthly intervals. Serum markers, if elevated at diagnosis, is the simplest methodology to follow-up. 49,50 The role of serial imaging posttreatment is debatable and is left to the institutional protocol.
The roles of surgical management including secondary cytoreduction, HIPEC in patients with relapsed epithelial cancers remains controversial. The management of relapsed cancers remains systemic chemotherapy and appropriate choice of PARP inhibitor and/or VEGF inhibition.
The flowchart below summarizes the imaging and management guidelines for ovarian cancer (►Fig. 5).  chest is a useful addition in those with pleural effusion. 4. CT abdomen and pelvis with oral and IV contrast is also used to assess the response to neoadjuvant chemotherapy before interval debulking surgery. 5. In case of suspected recurrence, contrast-enhanced CT thorax, abdomen, and pelvis with oral contrast is the imaging modality of choice. FDG PET CT may be considered when CT findings are inconclusive and there is high clinical suspicion of recurrence.

Summary of Recommendations
Funding None.