What are Ovaries?
The ovaries are paired, almond-shaped, female-reproductive glands, which sit on either side of the uterus (the hollow, pear-shaped organ that accommodates the growing fetus) and held in position by supporting ligaments.
The main functions of the ovaries include the production of the eggs for reproduction and secretion of the female sex hormones (estrogen and progesterone). The ovaries are made up of mainly 3 types of cells: epithelial cells (that cover the surface of the ovaries), germ cells (that produce the egg/ova), and stromal cells (that provide structural support to the ovary and produce female sex hormones). Each of these cells can develop into one or more types of cancer.
What are the Types of Ovarian Cancer?
Epithelial ovarian cancers
These are the most commonly encountered (about 90% of all cases) ovarian cancers. Epithelial ovarian cancers are further divided into following subtypes based on their histology (appearance under a microscope):
- mucinous, and
- clear cell.
Primary peritoneal cancers and fallopian tube cancers are very much similar to ovarian epithelial cancers and are generally managed via similar treatment approach.
Germ cell ovarian tumors
These constitute about less than 5% of all ovarian cancers.
They are further classified into following subtypes based on the type of cells involved:
- endodermal sinus (yolk sac) tumors,
- choriocarcinomas, and
- embryonal tumors.
They generally occur as a mix of these subtypes.
Ovarian (or sex chord) stromal tumors
These constitute about less than 7% of all ovarian cancers. They are further classified into following subtypes based on the type of cells involved and type of treatment approach usually followed for such tumors: granulosa cell tumor (most common), Sertoli-Leydig cell tumor, thecoma, fibroma, and fibrosarcoma.
Risk Factors for Ovarian Cancer
Early menarche/late menopause
Early starting of menses and delayed menopause increase the number of ovulatory cycles in a female. This repeated injury to ovarian epithelium increases the risk of cancer.
Risk of developing ovarian cancer increases in females with a history of ovarian, breast, and some other cancers in close relatives, especially first degree relatives. Also, the risk increases with more number of family members affected.
Genetic Cancer Predisposition Syndromes
Following are some examples:
- mutations in the genes BRCA1 and BRCA2,
- Cowden disease (caused due to defect in PTEN gene);
- Lynch syndrome (or hereditary nonpolyposis colon cancer [HNPCC] caused due mutation in genes: MLH1, MLH3, MSH2, MSH6, PMS1, PMS2, etc);
- Li-Fraumeni syndrome (caused due mutation in TP53 gene), etc.
Delayed marriage or childbirth
It has been reported that women who got married at a later age and have pregnancy after 35 years of age or who never had a full-term pregnancy are at increased risk of developing ovarian cancer. No child or late birth, after 30 to 35 years of age increases the risk of ovary cancer. Inadequate breastfeeding also increases the risk of ovary cancer.
Hormonal replacement therapy
Women who are using or have used hormone replacement therapy (HRT) after menopause for many years, are generally at higher risk of developing ovarian cancer. Consumption of birth control pills decreases the risk.
Endometriosis is a condition characterized by the appearance of endometrial tissue at places other than the usual place (the uterus), such as on the ovaries, fallopian tubes, etc. This condition can increase the risk of ovarian cancer, especially clear cell and endometrioid type.
An increased body mass index or waist circumference has also been linked to increased risk of ovarian cancer. Increasing obesity is also a risk factor, therefore, the regular physical activity may help in reducing the risk of ovary cancer.
Ovarian cancer generally occurs at higher age and risk increases with age.
Symptoms and Signs of Ovarian Cancer
Local spread may cause:
- Pain, distension, heaviness in abdomen
- Increased urinary frequency or urgency
- Abdominal bloating or constipation
Anyone or combination of these ovary cancer symptoms, when present in a woman is 5th to 7th decade of life, is highly suspicious for ovary cancer.
Distant spread may cause:
- Breathlessness, cough, chest pain
Most common sites of spread of ovarian cancer are liver and lung.
These symptoms can also be experienced due to certain other benign conditions. Other ovarian cancer symptoms include fatigue, backache, menstrual changes, and unexplained weight loss.
Germ cell tumor usually presents as a rapidly enlarging solid mass in the pelvis in women younger than 35 years of age.
Symptoms indicating an excess or abnormal hormonal production (estrogen or androgen) may signal sex cord-stromal tumor.
In early stages, the patient is mostly asymptomatic. When the ovarian mass enlarges in size, it may cause non-specific lower abdominal symptoms like bloating, constipation, urinary complaints, etc due to involvement of adjacent structures like bladder, rectum, etc. Presence of ascitic fluid and/or large peritoneal deposits may cause abdominal distension and/or discomfort.
Spread of ovarian cancer to distant organs like lungs, pleura, liver may cause symptoms depending on the site of involvement. For example, pleural effusion or lung parenchyma involvement may cause breathlessness, chest discomfort, etc. Significant liver parenchymal involvement may cause jaundice.
Ovarian Cancer Staging Investigations
CA-125 is the tumor marker for epithelial ovary cancer, which is elevated most commonly. But CA-125 testing has some limitations.
It may be false negative in some cases, that is negative when there is cancer. This could be seen in subtypes other than epithelial ovary cancer. Even in some cases of an early-stage disease, it could be a false negative. Also, in the mucinous subtype of epithelial ovary cancer, it may be negative, and CA 19.9 or CEA may be elevated.
CA-125 may also be false positive, that is elevated in the absence of ovary cancer. Other cancers in which it may be false positive are breast, lung and GI cancer. The non-cancerous conditions in which it may be false positive are PID, endometriosis, pregnancy, cirrhosis, peritonitis, pleuritis and pancreatitis.
Germ Cell Tumor Markers
The tumor markers for germ cell tumor are AFP, beta HCG, and LDH.
Different sub-types of germ cell tumors have different combinations of this tumor marker elevated.
Most commonly elevated in dysgerminoma is LDH, and beta HCG may also be elevated in some cases, but AFP is never elevated in dysgerminoma.
In choriocarcinoma, beta HCG is very high and LDH may also be elevated. In endodermal sinus or yolk sack tumors, AFP is high and LDH may also be elevated.
Inhibin A and inhibin B are the tumor markers for sex cord-stromal tumors, mainly granulosa cell subtype.
Transvaginal Ultrasound (TVUS)
This helps the doctor to examine the ovaries, fallopian tubes, uterus and other nearby structures for any abnormality. It can distinguish between solid tumors (appear as a solid mass) and fluid-filled cysts.
Biopsy sample(s) for ovarian cancer are generally collected during surgery, but can be collected under imaging guidance from the affected area(s) when surgery is not possible due to advanced disease, or poor health condition of the patient.
When subjected to various laboratory tests, these samples provide information about the type of cancer, grade of cancer, presence of specific defective genes or proteins, etc.
One or more of the following are required to stage the disease and assess response after treatment-
- Computed tomography (CT) scan
- Positron emission tomography (PET) scan
- Magnetic resonance imaging (MRI) scan
Stages of Ovarian Cancer
First, we will discuss the normal anatomy of the female reproductive system to understand the staging better.
This pear-shaped structure called the uterus is lined by endometrial lining from inside.
The menstrual cycles in females are due to the regular shedding of this endometrial lining.
It is also called the womb, as it enlarges during pregnancy to accommodate the child.
The fallopian tube is the tubular structure which carries the ovum produced from the ovaries to the uterus.
This figure shows the pelvic anatomy from top. Uterus is connected to both ovaries with fallopian tubes, with urinary bladder present in front and rectum present behind. On both sides are the ureters.
FIGO Stage I
Tumor is localised to one or both the ovaries with/without capsular rupture, but no spread of tumor to adjacent structures.
Stage IA – Tumor is localised to one ovary and has not spread to ovarian surface or elsewhere, ie, capsule of ovary is intact.
Stage IB – Tumor is localised to both ovaries and has not spread to ovarian surface or elsewhere, ie, capsule of ovary is intact.
Stage 1C – There is a capsule rupture either spontaneously or during surgery, with the presence of tumor cells on the surface of ovary or in ascitis fluid, but there is no extension of tumor to the adjacent structures.
FIGO Stage II
To understand the stage 2 better, we will discuss the normal anatomy of the female pelvis. Imagine we are seeing from the top, on both side of the uterus are ovaries which are connected to the uterus with fallopian tube.
In front of the uterus is the urinary bladder, and these tube-like structures joining the bladder on both sides are called as ureters. This tube-like structure present behind the uterus is called as the rectum.
Stage 2A – Cancer spreads to the fallopian tube or uterus. In this figure, it has spread to the fallopian tube.
And here, it extends to the fallopian tube and the uterus.
Stage 2B – Tumor infiltrates into urinary bladder and/or rectum.
This figure shows tumor infiltrating into urinary bladder.
And here it extends posteriorly to involve the rectum.
FIGO Stage III
In stage 3, cancer extends outside the pelvis into the abdominal cavity. Let’s have a look at abdominal structures first.
This is the large intestine. And this is the liver, behind which is the stomach. And these are the lungs, which are present in the thoracic cavity, separated from the abdomen by the diaphragm.
In stage 3 ovarian cancer, there may be involvement of these nodular structures present inside the abdomen, called as retroperitoneal lymph nodes.
Stage 3 may also present as surface deposits inside the abdomen, called peritoneal deposits.
Based on this, ovarisn cancer stage 3 may be explained as follows-
Stage IIIA1 – Tumor limited to ovary/fallopian tube with involvement of only retroperitoneal lymph nodes
Stage IIIA2 – Tumor limited to ovary/fallopian tube with microscopic peritoneal deposits with/without involvement of retroperitoneal lymph nodes
Stage IIIB – Tumor limited to ovary/fallopian tube with macroscopic peritoneal deposits (</=2 cm) with/without involvement of retroperitoneal lymph nodes.
Stage IIIC – Tumor limited to ovary/fallopian tube with macroscopic peritoneal deposits (>2 cm) with/without involvement of retroperitoneal lymph nodes. There may be spread to capsule of liver and/or spleen, without parenchymal involvement.
FIGO Stage IV
Now we come to the stage 4 ovarian cancer.
Stage IVA – Spread of the tumor to pleural cavity to cause pleural effusion.
Stage IVB – Spread of the tumor to parenchyma of liver and/or spleen and/or organs outside the abdomen (like lungs, bones, etc) and/or nodes other than the retroperitoneal lymph nodes.
It may also present as the involvement of inguinal lymph nodes.
Where does Ovarian Cancer spread first? How is It’s Staging different from other Cancers?
Apart from local infiltration into adjacent structures, the first and most common site of spread of ovarian cancer is peritoneum. This is so because ovary and peritoneum are almost attached to each other. Moreover, they have a common origin and are considered to be the same organ. That is why, staging and treatment of primary peritoneal cancers is almost same as ovarian cancer.
That is why, peritoneal involvement in ovarian cancer is considered to be stage III, unlike other malignancies where it is considered to be stage 4.
What is the Importance of Staging ? How does the It determine the Treatment?
Staging of ovarian cancer helps to plan the treatment for a patient, keeping other factors into consideration. The decision to move ahead with surgery or chemotherapy as the primary treatment is taken based on the staging.
If the ovarian cancer is at an early stage and can be removed adequately and the patient’s performance status is good, then primary cytoreductive surgery is the preferred treatment. Then depending upon the surgical staging, decision for the type of chemotherapy and number of cycles is taken.
Whereas, if there is an advanced disease, or the performance status of the patient is not good for surgery, then chemotherapy is started first (neoadjuvant chemotherapy) and then decision for surgery (interval debulking surgery) is taken depending upon response to treatment.
Treatment of Ovarian Cancer
There are mainly 2 aims of surgery in ovarian cancer: first is to stage the disease and second is to remove maximum possible cancerous tissue (this is also called as debulking). This help in establishing accurate stage and thus selecting an appropriate adjuvant treatment for the disease.
In most cases, the surgery which we do for ovary tumors is known as cytoreductive surgery. It may be called as primary cytoreductive surgery or interval debulking surgery, depending upon whether we are giving chemotherapy before or after surgery.
Primary Cytoreductive Surgery
When surgery is done first before chemotherapy, it is called as primary cytoreductive surgery. If the disease appears upfront resectable on the scans, and the performance status of the patient is good as assessed by the oncologist, we can proceed directly with primary cytoreductive surgery. Then, depending on the subtype, stage and grade of the tumor after surgery, chemotherapy may be added. Intraperitoneal chemotherapy is also an option for certain subsets of patients.
Interval Debulking Surgery
Sometimes, the disease may not be upfront resectable, or the performance status of the patient may be poor. In either of these conditions, the surgery might not be possible upfront. In these cases, interval debulking surgery is preferred in which chemotherapy is given first, and then the decision for surgery is depending upon the response to chemotherapy.
Secondary Cytoreductive Surgery
If the surgery is done when there is a relapse of the disease after the patient has completed treatment previously, it is known as secondary cytoreductive surgery.
Fertility Preservation Surgery
For most patients, surgery for ovarian cancer involves removal of the uterus (hysterectomy), along with both ovaries and fallopian tubes (salpingo-oophorectomy or BSO). Depending upon the extent of disease, omentum (the fatty tissue layer covering abdominal organs) may also be removed (omentectomy) along with the affected lymph nodes and/or other structures with high suspicion of involvement by the disease. Any fluid present in the pelvis or abdominal cavity along with peritoneal washings are also collected for analysis. Blind biopsies may also be taken from certain places in case no gross disease is visible in abdomen.
In some cases, upfront surgery may not be possible, and chemotherapy is the preferred treatment option in such cases. And if the disease becomes resectable after some cycles of chemotherapy, interval debulking surgery may be done.
Some chemotherapy agents that are a part of ovarian cancer treatment regimens are-
- Paclitaxel, Docetaxel
- Carboplatin, Cisplatin
- Liposomal Doxorubicin
Stagewise Treatment for Epithelial Ovarian Cancer
In case of Stage I epithelial ovarian cancer, primary cytoreductive surgery is generally preferred. Chemotherapy may be added after surgery depending upon stage (IA/IB/IC), grade, and other factors.
In case of Stage II epithelial ovarian cancer, cytoreductive surgery followed by chemotherapy may be done in most cases.
In case of Stage III epithelial ovarian cancer, chemotherapy may be given before or after surgery. If the performance status of patient is poor or the disease is not upfront resectable, chemotherapy may be given before surgery, otherwise after surgery.
In case of Stage IV epithelial ovarian cancer, chemotherapy is considered as the first-line treatment. Surgery may also be employed after chemotherapy depending on response. Other palliative treatment may be used to relieve the symptoms of advanced disease.
Targeted Therapy for Ovarian Cancer
Various targeted agents have been approved for the treatment of advanced-stage ovarian cancer. Following are the targeted drugs approved for the treatment of ovarian cancer:
It is an angiogenesis inhibitor that inhibits vascular endothelial growth factor (VEGF)-receptor (VEGFR), a factor that promotes angiogenesis (formation of new blood vessels). Bevacizumab is reported to be more efficacious when combined with chemotherapy for both shrinking the existing tumors and preventing recurrence of already treated ovarian cancers.
Side effects of bevacizumab include high blood pressure, fatigue, bruising or bleeding, mouth sores, loss of appetite, and diarrhea. Other rare but possibly serious side effects include severe bleeding, blood clots, gastrointestinal perforations, and slow wound healing.
A multifunctional tyrosine kinase inhibitor that inhibits many factors responsible for growth and proliferation of ovarian cancer cells including VEGFR, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and c-kit. It also inhibits other factors like colony stimulating factor 1, lymphocyte-specific tyrosine kinase, and interleukin (IL)-2-inducible T-cell kinase.
It is a Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. PARPs are enzymes that are normally involved in the repair of damaged DNA by homologous recombination inside the cells. Inhibition of PARP leads to an accumulation of single-strand DNA breaks, which causes cells to die if not corrected. Such defects can be repaired by BRCA proteins via homologous recombination, a highly efficient process. However, the cells with a mutation of defective BRCA genes cannot repair such defects and die. Thus, tumors with BRCA1/2 mutation (about 10% to 20% of all cases), are particularly sensitive to PARP inhibition.
Single-agent olaparib is generally recommended for the treatment of patients with advanced, BRCA mutation positive, recurrent ovarian cancer (both platinum sensitive or resistant) who have received >/=3 lines of chemotherapy.
It can also be used as maintenance therapy for BRCA positive patients after first line platinum based therapy, and irrespective of BRCA after platinum based therapy in a platinum sensitive relapse.
Rucaparib and Niraparib are other PARP inhibitors that may be used in ovarian cancer. PARP Inhibitors may be associated with side effects like nausea, vomiting, fatigue, anemia, loss of appetite, diarrhea, taste changes, and pain in stomach, muscle, and joints.
Pembrolizumab, an immune check-point inhibitor, is approved immunotherapeutic agent for the treatment of ovarian cancer . It has been approved for the treatment of advanced stage ovarian cancer as the second-line or subsequent line therapy for the treatment of unresectable/metastatic, Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) ovarian cancer that has progressed on prior treatment and for which no satisfactory alternative treatment option is available.
MSI-H ovarian cancers are observed in approximately 2% of all the cases, which indicate the limited application of immunotherapy in the treatment of ovarian cancer.
Hormonal cancer therapy includes treatment with drugs that modulate the activity of certain hormones that promote the growth of cancer cells. Hormonal drugs commonly used for ovarian cancer treatment include tamoxifen, aromatase inhibitors (anastrozole and letrozole), leuprolide acetate, or megestrol acetate among others.
Best Ovarian Cancer Specialist in Delhi
Dr Sunny Garg is a renowned Medical Oncologist in New Delhi with an experience of around 10 years of treating ovarian cancer patients. He has treated ovarian cancer patients with Chemotherapy, Targeted Therapy and Personalized Cancer Treatment. He is currently practicing at Manipal Hospital, Dwarka.
Diagnostic modalities available at our hospital include Ultrasound and CT guided biopsy, CA-125, AFP, beta HCG, LDH, Inhibin, Transvaginal Ultrasound, Whole Body PET CT, etc. Other treatment facilities for Ovary Cancer available are Primary Cytoreducative Surgery, Interval Debulking Surgery, Secondary Cytoreductive Surgery, Radiation Therapy, etc.
Call +91 9686813020 for appointment.