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The following module was designed to supplement the clinical experience of medical students. It covers the anatomy, epidemiology, screening, presentation, diagnosis, staging, prognosis, treatment, and follow up care of ovarian cancer.
This module covers the objectives listed below:
The ovaries are intraperitoneal endocrine organs that are found on either side of the uterus. Each ovary is held in place via ligaments that secure the gonadal organ to both the uterus and the pelvic wall. Three ligaments achieve this: the suspensory ligament, the utero-ovarian ligament, and the mesovarium. The suspensory ligament connects the ovary to the pelvic wall, and contains the ovarian nerve plexus, ovarian vein, ovarian artery, and lymphatic vessels that supply the ovary. The utero-ovarian ligament and the mesovarium anchor the ovary to the lateral aspect of the uterus and the broad ligament of the uterus, respectively. The infundibulopelvic ligament contains the ovarian artery and vein.
The organ itself is approximately 3 cm, but this will vary depending on the age of the individual (1). As a woman ages, the ovaries will atrophy following menopause and the dramatic reduction in hormone production (1).
This organ has two primary functions: hormone production (estrogen, progesterone, testosterone, and inhibin) and oocyte storage, maturation, and release.
The outermost layer is the germinal epithelium, composed of simple cuboidal cells. Beneath this, there exists another layer of connective tissue called the tunica albuginea. Moving inwards, the next layer is the ovarian cortex. This is the region where the follicles and oocytes in various stages of development are dispersed within stroma. Throughout the course of the menstrual cycle, the follicles, which each contain an oocyte, will undergo stages of maturation until one result in ovulation with support of Theca and Granulosa cells present in the cortex. Theca cells produce androgen and precursors for estradiol. Granulosa cells provide support for the maturing follicle and will proliferate to create the corpus luteum. At the centre of the ovary is the medulla, which is made of loose connective tissue and contains the ovarian vasculature for nutrient supply.
Ovarian cancer is the third most common gynecologic malignancy, following cervical and uterine cancer and is the 6th most common cause of cancer death in women (1,2). In Canada, 3,100 women are diagnosed with ovarian cancer each year (3). Because in the majority of cases it is diagnosed at an advanced stage, it has an overall poor prognosis, as the 5-year survival rate is 45% (4).
Ovarian cancer is not one type of malignancy. In fact, there are many types of ovarian cancer. The most common is an epithelial ovarian carcinoma, but other types include borderline ovarian tumors (serous and mucinous type), stromal tumors, and germ cell tumors.
Risk of ovarian cancer is correlated with age. Most commonly, epithelial ovarian carcinoma presents after the age of 50, with mean age of diagnosis 63 years of age (5). However, germ cell tumors are most commonly seen in women under 20 years, and borderline tumours predominate in women between the ages of 30 and 50 (6).
There are many additional risk factors that have been identified. If a woman is to have a first degree relative with ovarian cancer, her probability of acquiring the disease will be greater than 5%, particularly in those with genetic mutations (7). Most commonly, pathologic variants of BRCA1 and BRCA2 have been linked with ovarian cancer. Other less common variants have also been identified such as RAD51C, RAD51D, and BRCA1-interacting protein 1 [BRIP1]. There is also an association between ovarian cancer risk and Lynch Syndrome. Up to 10% of ovarian cancer patients have one of these genetic variants/syndromes (8).
In addition to age and family history, ovarian cancer risk appears to increase with late menopause, nulliparity, and patients with pre-existing endometriosis. Conversely, some protective factors include use of oral contraceptives, intrauterine devices, breastfeeding, and previous resection of the fallopian tubes and/or ovaries (8,9).
The decision to screen a patient for ovarian cancer is largely based on whether they are at higher risk of developing the disease than the average person.
It is not recommended to routinely screen for ovarian cancer in patients at average risk (ie those without family history and/or genetic mutations). Both the CA 125 and TVUS have been shown to have high rates of false positive results, which can subject patients to unnecessary surgery, anxiety, and other financial costs (1). Both of these screening tests have also not been able to detect ovarian cancer at an early enough stage to significantly reduce mortality rates (2,3). For these reasons, they are not recommended as screening tools for the average risk patient.
If a woman’s family history is suggestive of a hereditary cancer syndrome, and/or has tested positive for a genetic variant like BRCA1 or BRCA2, then screening can be considered. For ovarian cancer, this includes serum tumor marker cancer antigen 125 and transvaginal ultrasonography. Some patients with genetic mutations will also elect to have a bilateral salpingo-oophorectomy to reduce their risk.
Other screening methods, such as the pelvic exam, can be done to monitor for potential tumors. However, due to the depth at which the ovaries are located in the abdomen, tumors are typically not detected through the pelvic examination until they have grown to extensive sizes or if the cancer has metastasized. At this point, the cancer is usually at an advanced stage and the prognosis is poor, providing little benefit to the patient. As such, studies have found that the pelvic exam has minimal utility in ovarian cancer screening in the average, asymptomatic patient (4).
Lastly, other tumor markers including human epididymis protein 4 [HE4], carcinoembryonic antigen [CEA], and cancer antigen 19-9 [CA 19-9], have been shown in some studies to identify patients at high risk for ovarian cancer (5). Particularly, HE4 has had high sensitivity and detection rates in combination with CA125 (5), however it is not used in routine clinical practice. Further research in this area will need to be completed to determine if and how these markers will be used to screen for ovarian cancers in the future, without creating more harm.
Ovarian cancer often does not have any signs or symptoms until advanced stage disease, as symptoms typically become noticeable with excessive growth or spread throughout the body. This is why the majority of patients present with stage 3 or 4 disease. However, some signs and symptoms to watch out for include (1):
*Higher positive likelihood ratio associated with ovarian cancer
For patients that have suspected ovarian cancer, the following basic investigations should be completed:
When there are several of the following features on ultrasound, this may be suggestive of malignancy, prompting referral to gynecologic oncology (1):
Staging should be surgical to determine histologic diagnosis, stage, and prognosis. Full surgical staging may include bilateral salpingo-oophorectomy, hysterectomy, omentectomy, directed peritoneal biopsies, peritoneal washings, and pelvic and/or para-aortic lymphadenectomy.
FIGO’s Committee for Gynecologic Oncology revised the staging of ovarian cancer in 2014 to include ovarian, fallopian tube, and peritoneal cancer collectively (1). A detailed overview of ovarian cancer staging is outlined in Table 1. In brief, the stages of ovarian cancer are:
Epithelial ovarian carcinoma, also known as epithelial tubo-ovarian carcinoma, accounts for more than 90% of ovarian cancers (1). The 2020 edition of the WHO Classification of Female Genital Tumours lists five principal histotypes: high-grade serous carcinoma, low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, and clear cell carcinoma. Each histotype has a different cell of origin and molecular alterations, leading to different clinical behaviour and management. Histotypes can be further stratified into molecular subtypes, for which predictive biomarker tests are still evolving. An overview of the five principal histotypes is provided below (2,3).
Non-epithelial ovarian tumours are less common than epithelial tumours and account for approximately 10% of all ovarian cancers (4). Note that there are various types of non-epithelial ovarian tumours and not all are covered in this module (2,3).
Ovarian tumors may also be due to metastases from other cancer, including GI cancers and lymphoma.
The management of ovarian carcinoma is often multimodal and depends largely on the tumour type and extent of disease. All patients with suspected ovarian carcinoma or a suspicious adnexal mass should be referred to a gynecologic oncologist, as this is associated with improved outcomes and survival (1).
Complete surgical staging: surgery that intends to treat as well as stage ovarian cancer. This usually includes abdominal hysterectomy and bilateral salpingo-oophorectomy. It also usually includes omentectomy, systematic pelvic and para-aortic lymph node dissection, peritoneal biopsies, and/or cytological analysis for staging purposes (2).
Primary cytoreductive surgery: initial surgical procedure for advanced-stage ovarian cancer to remove as much tumour burden as possible. This is usually done before adjuvant chemotherapy. Also known as primary debulking surgery. Depending on the extent of the disease, other procedures may be considered including bowel resection, appendectomy (removal of the appendix), splenectomy (removal of the spleen), diaphragm stripping or resection, and/or partial hepatectomy (removal of part of the liver).
Complete/optimal cytoreduction: leaving no visible residual disease or reducing visible disease to less than 1 cm in maximum diameter. This is the goal in cytoreductive surgeries. Also known as complete debulking.
Interval cytoreductive surgery: surgical procedure in advanced-stage ovarian cancer to remove as much tumour burden as possible after neoadjuvant chemotherapy. Also known as interval debulking surgery The goal is again to resect all visible disease to less than 1cm.
Secondary cytoreductive surgery: surgical procedure to remove recurrent disease after initial treatment (usually cytoreductive surgery and chemotherapy).
Palliative surgery: surgery intended to alleviate symptoms and improve quality of life rather than cure disease. This is performed for example in patients with GI malignancies with a large metastasis to the ovary.
Fertility-sparing surgery: unilateral salpingo-oophorectomy (removal of one ovary and fallopian tube) with surgical staging, avoiding tumour rupture. This treatment may be considered in patients with lower-risk tumour types when fertility preservation is a goal.
When epithelial ovarian carcinoma is detected in stage I or II, the primary treatment is surgery, usually followed by adjuvant chemotherapy.
The first step in treatment is typically complete surgical resection with surgical staging. The goal of surgery is to achieve complete cytoreduction of all pelvic, abdominal, and retroperitoneal disease (if any) and evaluate for occult metastases through staging procedures (2,3).
Adjuvant chemotherapy may not be required in stage I low-risk disease but is recommended for some stage I and all stage II disease. The regimen of choice for chemotherapy is most often platinum-based, most commonly with six cycles of carboplatin and paclitaxel (2,3).
Epithelial ovarian carcinoma detected in stage III and IV is usually treated with a combination of cytoreductive surgery and adjuvant chemotherapy. This can be followed by maintenance oral chemotherapy, based on BRCA status (2,3).
Primary cytoreductive surgery is the standard treatment if complete resection of all disease > 1cm seems feasible. If the patient is not considered suitable for primary surgery, due to sites of disease and/or performance status, then the recommended treatment approach is neoadjuvant chemotherapy (chemotherapy done before surgery) followed by interval cytoreductive surgery. In this case, the intent of neoadjuvant chemotherapy is to reduce disease burden to increase the likelihood of optimal cytoreduction with surgery. Interval cytoreductive surgery is usually planned after 3-4 cycles of chemotherapy (2,3).
Indications for neoadjuvant chemotherapy followed by interval cytoreductive surgery:
Adjuvant chemotherapy is recommended for all stage III and IV epithelial ovarian cancer, even when neoadjuvant chemotherapy is done. As for early-stage disease, the regimen of choice is typically six cycles of carboplatin and paclitaxel in total (2,3).
Maintenance chemotherapy is done after completing adjuvant chemotherapy. The choice of agent is based on the molecular and clinical characteristics of the tumour. Most often, the agent of choice is either a PARP inhibitor (Olaparib or niraparib) or bevacizumab (2,3). PARP inhibitors are more commonly recommended in those with BRCA mutations or HRD tumors. Bevacizumab is more often recommended in those with stage 4 disease and/or un-resectable disease or incomplete resection.
Recurrence rates are 25% in patients with early-stage ovarian cancer and over 80% in patients with advanced-stage disease (4). Recurrent ovarian cancer is rarely curable, but there are multiple strategies for controlling progression and managing symptoms. It is important to consider the patient’s functional status, symptoms, and preferences when choosing treatments (5).
The approach to management of recurrent ovarian epithelial carcinoma depends on multiple factors including the time to recurrence and if the tumour is deemed platinum-sensitive (recurrence after 6 months from the last adjuvant cycle) or platinum-resistant (recurrence within 6 months). In some cases, secondary cytoreductive surgery may be recommended. Chemotherapy may also be recommended, either with or without preceding surgery (5).
Palliative surgical procedures may be considered for rapidly progressing disease with limited systemic options. Such procedures are broad and may include paracentesis or insertion of an indwelling peritoneal catheter for drainage of ascites, thoracentesis or insertion of a pleural catheter for draining of pleural effusions, and nephrostomy or gastrostomy in the setting of obstructions (3). Malignant bowel obstruction is a frequent complication of recurrent ovarian cancer and may be managed surgically (less commonly) or medically with steroids and/or octreotide (5).
While radiation therapy is not routinely used as an adjuvant treatment modality for ovarian cancer, it is beneficial in the palliative setting where it is mainly used for symptom control, especially for pain from large tumors for example at the skin. Radiation may also be considered for localized relapse, nodal disease, or distant metastases, but this is very uncommon (6).
The management of non-epithelial ovarian carcinoma is unique, as these tumours often have better prognosis and affect younger patients. Thus, fertility-sparing surgery is often performed instead of complete surgical resection. Adjuvant systemic therapy may be considered. The agents of choice in non-epithelial ovarian carcinoma may differ from those in epithelial ovarian carcinoma. Commonly used agents include bleomycin/etoposide/cisplatin (BEP) and etoposide/cisplatin (EP), although in some cases carboplatin/paclitaxel may be used (7).
While the exact prognosis of ovarian cancer depends on many factors including tumour histology, stage at diagnosis, and patient factors such as BRCA status, the average 5-year survival across all types is approximately 46% (4).
The most common distant metastatic sites in ovarian cancer are the liver, distant lymph nodes, lungs, bone, and brain. The presence of distant metastases significantly decreases overall survival in ovarian cancer (8).
After the completion of treatment, follow-up appointments are typically scheduled every 3-4 months for the first two years, then every 6 months for the following three years. The focus of follow-up appointments is to detect recurrence and manage any ongoing symptoms the patient may have. Symptoms and quality of life should be assessed as early as possible and at each appointment. Resources patients can be connected with include psycho-oncology, social care, physiotherapy, and patient support groups (1).
For the detection of recurrence, it is imperative that patients are asked about any new or developing symptoms. Physical examination, including bimanual pelvic and rectovaginal examination, is also important but will only aid in detecting local recurrence. There is insufficient data to support routine radiographic surveillance in asymptomatic patients (2). Routine monitoring of CA-125 after completion of chemotherapy is an option that should be discussed with the patient but is somewhat controversial (1).
Menopausal symptoms should be addressed after BSO in patients who were premenopausal upon diagnosis.
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