Decoding Ovarian Cancer

  •   Thu, Sep 26 2024
  •   By Dr Elroy Saldanha

September 26, 2024

Introduction:

As per GLOBOCAN 2022 data, cancer cases are raising with incidence being 14,13,316 cases/ 1,40,66,31,781 population in India. Ovarian Cancer is the third most common cancer in females both in incidence being 47,333 new cases (6.6%) and mortality cases being 32,978 cases (4.6%) after breast and cervical cancer cases. Ovarian Cancer usually got undetected and about 60% of ovarian cancer cases are diagnosed at stage 3. The average 5-year survival rate for stage 3 ovarian cancer drops down to 41%. But then the survival rates can vary depending on several factors, including the cancer spread, general health condition, and their response to the treatment. So, it is important to understand the symptoms of the ovarian cancer, for it to be detected early, reduce the mortality and thereby achieve an early cure. 

Etiology and pathophysiology: 

Ovarian cancers basically comprise of two types epithelial and non-epithelial ovarian malignancies. Epithelial ovarian cancer is the most prevalent type, accounting for more than 95%, while approximately 5% are non-epithelial ovarian cancers. Non-epithelial ovarian cancers like germ cell, sex-cord stromal, and small cell ovarian cancers.  Epithelial ovarian malignancies cancer incidence increase with age and the highest incidence is seen in 55-65 years age group while certain types under germ cell (yolk sac, dysgerminoma) and sex-cord stromal malignancies (adult granulosa cell, sertoli cell tumor) under non-epithelial ovarian cancers can occur early at 20-30 years of age (Figure 1). 


Figure 1: Classification of Carcinoma Ovary Based on the Origin of Malignancy

The risk of developing ovarian cancer is directly proportional to the time a woman spends ovulating and the number of ovulatory cycles. During ovulation, cells are stimulated to divide. If this division is abnormally regulated, tumors may form which can be malignant. Early menarche (first age of menstrual cycle) and late menopause, increase the number of ovulatory cycles a woman undergoes in her lifetime and thereby increases the risk of developing ovarian cancer. Since ovulation is suppressed during pregnancy (a protective factor), not having children also increases the risk of ovarian cancer. Therefore, women who have not borne children are at twice the risk of ovarian cancer than those who have. Both obesity and hormone replacement therapy also raise the risk.  Postmenopausal hormone replacement therapy (HRT) with estrogen and endometriosis likely increases the risk of ovarian cancer. Non-genetic factors such as diabetes mellitus, high body mass index, and tobacco use are also risk factors for ovarian cancer. Certain reports suggests that application of talcum powder to the groin, pesticides, and herbicides increase the risk of ovarian cancer.

Women with hereditary nonpolyposis colon cancer (Lynch syndrome), and those with BRCA-1 and BRCA-2 genetic abnormalities are at increased risk. Several rare genetic disorders are associated with specific subtypes of ovarian cancer. Peutz–Jeghers syndrome, a rare genetic disorder, also predisposes women to sex cord tumour with annular tubules. Ollier disease and Maffucci syndrome are associated with granulosa cell tumors in children and may also be associated with Sertoli-Leydig tumors.

Women who have had fewer menstrual cycles/no menstrual cycles, breast feeding, take oral contraceptives, have multiple pregnancies, and have a pregnancy at an early age are all protective factors against ovarian cancer. The risk of developing ovarian cancer is reduced in women who have had tubal ligation or tubectomy, both ovaries removed, or hysterectomy (an operation in which the uterus is removed). 

Ovaries are located on either side of the uterus and it is situated in between bladder and rectum in the pelvis. The outer layer of the uterus and ovary is lined by the peritoneum. The peritoneum is the inner lining of the abdominal wall which lines abdominal cavity and The peritoneum is made of two layers, the parietal peritoneum and the visceral peritoneum, that are continuous with each other. The parietal peritoneum lines the abdominal and pelvic walls, while the visceral peritoneum wraps around the abdominal organs like liver, stomach and intestines. The peritoneum folds below the stomach in two layers to form omentum.The peritoneum covers most of the intra-abdominal organs. The space between the parietal and visceral peritoneum is called the peritoneal cavity. The peritoneum supports the abdominal organs, insulates them, and helps hold them in place. It also secretes a lubricating fluid to reduce friction between the organs. This anatomical knowledge is essential as the carcinoma of the ovary apart from the lymph nodal spread, has got propensity to spread into the peritoneum layers as it lies in the peritoneal cavity (Figure 2). 


Figure 2: Anatomy and Peritoneal Spread

Symptoms and Investigations:

Early signs and symptoms of ovarian cancer is usually subtle. Therefore in most cases, symptoms exist for several months before being recognized and diagnosed. Symptoms can often be misdiagnosed as gastritis since the early stages of ovarian cancer tend to be painless which makes it difficult to detect it early on. The most typical symptoms of ovarian cancer include 

  • Bloating, abdominal or pelvic pain or discomfort, back pain.
  • Irregular menstruation or postmenopausal vaginal bleeding, pain or bleeding after or during intercourse.
  • Fatigue, diarrhoea, constipation, nausea, loss of appetite and frequent urination.
  • Later symptoms of ovarian cancer are due to the growing mass causing pain by pressing on other abdominopelvic organs or from metastases. Most of the occasions, there might be peritoneal deposits (peritoneum is the inner lining of the abdominal wall) leading to abdominal distension (increase in the size of the abdomen). In India, this is the most common presentation since the early signs and symptoms are usually ignored by general population. Sometimes, the growing mass may cause pain if ovarian torsion develops.

Patients having any of these symptoms might get evaluated after routine ultrasound of the abdomen to have an ovarian mass. Later would require to undergo routine laboratory workups with complete blood count (CBC), iron panel, renal function tests, liver function and coagulation tests. Pre-operative Serum CA- 125 is usually raised in all epithelial ovarian cancer. CA-125 is useful tumour marker, if elevated in pre-operative condition, can be used as a marker follow-up and to detect early recurrence. In non-epithelial ovarian cancer, based on the subtypes other blood serum markers like serum alpha-fetoprotein, neuron-specific enolase, and lactate dehydrogenase in young girls and adolescents with suspected ovarian tumors as younger women with malignant germ cell tumors. Serum inhibin A and inhibin B can indicate a granulosa cell tumor. In women in whom pregnancy is a possibility and choriocarcinoma is suspected, BHCG level can be measured during the diagnosis process.

Baseline CT of the chest, abdomen, and pelvis with intravenous (IV) and oral contrast or PET-CT Scan is the preferred staging imaging study to assess local, regional and distant spread. Contrast MRI abdomen or pelvis alternatively can be done to assess the ovarian cancer status and its spread to the pelvic, para-aortic lymph nodes, peritoneum (peritoneal thickening/nodules), ascites, deposits in the diaphragm, liver surface and omentum (omental nodules). Based on the imaging, if the disease is involving uterus, ovary and confined to the pelvis, it would be considered upto FIGO Stage 2. If the disease involves para-aortic nodes, peritoneum, omentum and possibility of ascites (fluid accumulation in the abdomen), it would be considered FIGO Stage 3 and above (Figure 3 and 4). Above FIGO Stage 3, patient would require to undergo Neo-Adjuvant Chemotherapy/NACT (chemotherapy given prior to surgery) to reduce the disease status and surgical induced morbidity. For this, ultrasound guided ascitic fluid tapping or biopsy from the omental/peritoneal deposits is taken for the confirmation of the malignancy. Gene panel analysis for suspected genetic cause of BRCA and lynch syndrome. Immune-histochemistry analysis for PDL1 receptors.


Figure 3: Stage 1 and 2 Spread


Figure 4: Stage 3 and 4 Spread 

Treatment:

Surgery forms the mainstay in the treatment of the ovarian cancer. Upto Stage 2 (the disease is restricted in the pelvis), patient can undergo staging laparotomy, Peritoneal Carcinomatosis Index (PCI) scoring and cytoreductive surgery/CRS (removal of uterus, both the ovaries, appendix, pelvic and para-aortic lymph nodes). But if it is stage 3 and beyond, 3 cycles NACT is given and then the patient is taken up for staging laparotomy, Peritoneal Carcinomatosis Index (PCI) scoring and cytoreductive surgery. This time apart from removal of uterus, both the ovaries, appendix, pelvic, para-aortic lymph nodes; total peritonectomy along with the resection of any visceral organs (colon, rectum etc.) is done. Combined with CRS if HIPEC (Hyperthermic intra-peritoneal chemo-therapy) is added, then the 5 year survival rate increases to 57%. HIPEC (Hyperthermic intra-peritoneal chemo-therapy) refers to continuous circulation of chemotherapy agent at higher temperatures of 43-450 for 60-90mins after performing optimal CRS, so that the microscopic tumour cells are destroyed. This is an advanced facility which is performed in limited centers which requires trained medical and surgical oncologist, ICU care (Figure 5). Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique delivering normothermic chemotherapy into the abdominal cavity as an aerosol under pressure, based on trials, there is a positive outcome by enhancing drug depth penetration with elevated tumoral interstitial fluid pressure (Figure 6). PIPAC is currently used for palliative setting in selected patients. Currently HIPEC and PIPAC facilities are available in few centres in Mangaluru.


Figure 5: Hyperthermic Intra-Peritoneal Chemo-Therapy (HIPEC) 


Figure 6: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

Chemotherapy is offered to all the patients post-operatively except for FIGO Stage 1 and as NACT for the FIGO Stage 3 patients. Current chemotherapy protocols are safe and has got minimal side effects. Immunotherapy has evolved in management of ovarian cancer especially with BRCA 1, IHC positive for Lynch syndrome, PDL1 receptors. Pembrolizumab, Dostarlimab, Bevacizumab and Poly ADP-ribose polymerase (PARP) inhibitors are few of immunotherapy, mono-clonal antibodies and targeted therapy agents respectively. These agents can prolong the disease progression time. Radiotherapy has very limited role in treatment of ovarian cancer.

Precautions to avoid ovarian cancer:

  • Anything that stops ovulation for a time, like birth control pills, pregnancy or breastfeeding, can lower the average woman's ovarian cancer risk. Taking oral contraceptives (birth control pill) for at least five years may lower the risk of ovarian cancer. Pregnancy and breastfeeding avoids ovulation for at least a year may lower the risk of ovarian cancer. But all these should be followed based on the guidance of the gynaecologist or a oncologist.
  • Tubal ligation: Having a tubal ligation, which is a surgery to close both fallopian tubes, may lower the risk of ovarian cancer. Having both ovaries removed, both fallopian tubes removed, or a hysterectomy may lower the risk of ovarian cancer. 
  • Weight: Maintaining a healthy weight, following good diet habits and regular exercise may lower the risk of ovarian cancer. 
  • Quitting smoking may lower the risk of ovarian cancer. 
  • Genetic testing: Women with a family history of ovarian or breast cancer may want to consider genetic testing. Patients with BRCA positive genes have 90% risk to develop breast and ovarian cancer. After completion of the family, undergoing bilateral subcutaneous mastectomy (both the breasts) and bilateral salphingo-oopherectomy (both ovaries) can reduce the risk to 5%.
  • Annual health check-up after age of 45 years in terms of getting ultrasound abdomen and blood investigations to detect and undergo screening
  • Ovarian cancer survivors to be on regular follow-up with ultrasound/PET-CT scan and blood investigations.

I have covered the ovarian cancer topic briefly and I hope this basic information is sufficient to guide you on ovarian cancer, you can approach me if there are any further queries. 

Thank you for patiently going through the article!

 

 

 

 

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By Dr Elroy Saldanha
Dr Elroy Saldanha is the Consultant Surgical Oncologist, Father Muller Medical College Hospital, Mangaluru. He is the first trained Robotic Surgical Oncologist in the Coastal Karnataka under Vattikuti Foundation, Southfield, Michigan, USA in Manipal & Aster Hospitals, Bengaluru. He has received training in colorectal unit, Cleveland Clinic, Ohio and Thoracic Oncology training in New York Langone Hospital and a Certified Tobacco Cessation Specialist, Gujarat University. He is an avid researcher, with several presentations, research papers, review articles and textbook chapters published in National and International print to his credit.
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