Table of Contents
Types of Ovarian Cancer
For a better understanding of ovarian tumors, microscopic anatomy of the ovary is mandatory. The ovary is composed of the three main entities that are made up of varying cells which give rise to the various types of tumors.
- The cortex which contains both follicles and stroma. The follicles contain oocytes, which originate from germ cells and are responsible for the formation germ cell tumors. The oocyte is surrounded by two layers of different cells called granulosa cells.
- The mesenchyme from the gonadal stroma which is composed of loose connective tissues filled with blood vessels and nerves. Tumors from these cells are known as stromal tumors.
- The epithelial cubical cell layer from the coelomic epithelium that surrounds the ovary and gives rise to the epithelial ovarian tumors.
Ovarian tumors can originate from different ovarian cell populations that have different pathological characteristics.
These tumors arise from the surface epithelium of the ovary and constitute 60-70% of all ovarian tumors. They can differentiate into serous, mucinous, Brenner, endometrioid, small cell, clear cell and undifferentiated tumors. They can be benign, borderline, or malignant depending on stromal invasion.
These tumors are mostly benign rather than malignant i.e they have a 40% chance of malignancy.
The tumors are bilateral in 40% of cases and represents 40% of all ovarian tumors. They are common in young adults aged 30-40 years.
Serous cystadenocarcinoma are the malignant differentiation of serous tumors and are the most common types of malignant ovarian tumors. Serous tumors are composed mainly of cysts with serous fluid lined with columnar ciliated epithelium that may have a solid area that has papillae.
Malignant differentiation correlates with the solid areas within the tumors as well as the amount of necrosis. Borderline tumors have atypical cells but without invasion of the surrounding stroma. Malignant cystadenocarinoma are characterised by psammoma bodies, which are calcified bodies within the papillae.
Mucinous tumors are usually unilateral and can reach huge sizes. The cyst is lined with a single layer of mucin producing columnar cells without cilia and sometimes septa originates within the cyst.
They can be classified as either benign, borderline or malignant. Malignant mucinous tumors (mucinous cystadenocarcinoma) carry a bad prognosis and can result in pseudomyxoma perotinei where the whole abdomen and pelvis is filled with mucinous cysts like metastases, mucinous ascites and fibrosis.
They are also known as transitional tumors. They represent 1-2% of all ovarian tumors and only 8-10% are bilateral. They are more common among older women aged more than 40 years.
These can be solid or cystic. The tumor is mainly composed of nests or cysts of cells that resemble the transitional epithelium of the urinary tract and spindle stromal cells in-between. The cells are clear and have no mitotic figures, pleomorphism or hyperchormasia.
They are rare tumors representing less than 5% of all ovarian tumors. Endometrioid carcinoma are usually malignant and commonly bilateral. The tumor resembles endometrial carcinoma of the uterus and may be simultaneously present. Microscopically, it consists of glands of atypical cells with large clear nuclei and prominent nucleoli.
Clear cell carcinoma
They are also known as mesonephroid tumors. Malignant clear cell carcinomas carry a bad prognosis. Cells are clear with prominent nucleus and glycogen rich clear cytoplasm and contain abundant glycogen commonly known as hobnail cells. The cells can form tubules or nests that arrange in solid or cystic areas.
Sex cord tumors
Ovarian sex cord tumors arise from stromal/sex cord granulosa cells, thecal cells and fibrocytes. These cells are known for their hormonal function which may lead to virilization or feminization of the opposite sex. CD56 has been proposed to identify sex cord tumors and to follow response to treatment as a marker.
This is almost always benign and unilateral. It is mostly considered to arise from hyperplasia of the cortical stroma and not a true neoplasm. It accounts for only 2% of ovarian tumors. The tumor originates from theca follicular cells and secretes estrogen. The presentation is usually post-menopausal bleeding in elderly women.
Granulosa cell tumor
This is malignant in one in every five patients. The tumor secretes estrogen responsible for abnormal uterine bleeding.
These are firm white grey tumors of fibrocytes which produce concentric layers of collagen. Unlike fibromas they produce no hormones and they are more common among premenopausal women. The tumor is common in middle aged females and is usually benign. It can be associated with ascites and right side pleural effusion to form what is called Meigs’ syndrome.
Meigs’ syndrome is the triad of right pleural effusion, ascites and abdominal mass mostly in ovarian sex cord/stromal tumor. It is most commonly found in fibroma but can also occur in granulosa cell tumors and sometimes even in Brenner’s tumor. The effusion and ascites are reversible after removal of the tumor.
Tumors of testicular origin and can also be present in the ovary e.g. Sertolli-Leydig cell tumor and Sertolli cell tumor.
This is a rare tumor originating from both testicular and ovarian sex cord cells.
Germ cell tumor
Germ cell tumors include tumors which arise from the ovum and its precursor germ cells. Germ cell tumors can arise from the ovary or from other locations of the body due to germ cell migration. They represent 40-50% of all benign ovarian neoplasms. They are asymptomatic until complications such as torsion or rupture arise. Germ cell tumors include:
Gerninomatous: germinoma/dysgerminoma of the ovary is composed of uniform cells that have clear cytoplasms and lymphocyte infiltration. The tumor is malignant and hCG is used as a marker in a small percentage of cases.
- Teratoma: tumor cells differentiate into derivatives of embryonic germ layers – ectoderm, mesoderm and endoderm. The tumors usually contain hair, teeth, eyes, limbs or bones tissues. It can be cystic or solid, benign or malignant. A mature cystic teratoma with a high grade of differentiation into mesodermal or ectodermal origin is known as a dermoid cyst and is usually benign.
- Immature teratoma: malignant germ cell tumor. The cells are poorly differentiated from any of the germ cell layer derivatives. Usually, it is common in young girls and has a good prognosis and responds well to therapy.
- Dermoid cyst: cystic teratoma that arises from embryonic totipotent germ cells and contains different developmental tissue origins and usually includes skin, teeth, hair, nails, thyroid tissue, eyes and bones or cartilage. It is a benign tumor but close observation is required to avoid malignant transformation.
- Choriocarcinoma: germ cell tumor where the cells differentiate into placental trophoblasts and secreted beta-hCG without formation of placental villi. The tumor is malignant with early hematogenous spread to the lung.
- Embryonal carcinoma: malignant tumor formed of sheets of poorly differentiated cells that secrete hCG and alpha-fetoprotein.
- Yolk sac tumor/endometrial sinus tumor: malignant tumor which secretes alpha-phetoprotein.
- Polyembryoma: rare malignant tumor that has been associated with Klinefelter syndrome (see picture beside).
- Gonadoblastoma: rare tumor composed of a mixture of cells including germ cells, Sertolli cells, stromal cells and granulosa cells. It is commonly associated with genetic disorders e.g. y chromosome and androgen insensitivity syndrome.
Risk Factors for Ovarian Cancer
There are several factors affecting the chances of ovarian cancer development. Several theories explain etiology of ovarian cancer:
- Incessant ovulation theory where increased activation of the ovary to form mature ova leads to haphazard multiplication and hence malignant conversion of the cells to form malignancy.
- The gonadotropin theory postulates that increase in the amount of gonadotropins lead to uncontrolled activation of the ovary and thus malignant conversion of the cells.
- Genetic theory where patients with a family history of associated conditions such as hereditary non-polyposis coli and BRCA-1/2 mutations are at an increased risk of developing ovarian cancer.
Therefore, most of the risk factors are related to genetic influence, ovulation, or gonadotropin increase. The lesser the ovulation and gonadotropin amount, the lower the risk of ovarian cancer occurring.
Full term pregnancies lower the risk of ovarian cancers with lower risk with each full term pregnancy. The risk is higher in women who had late pregnancy or those who have never been pregnant. Pregnancy hormones prevent ovulation and lower the risk of ovarian cancer.
Birth control with OCPs or injectable hormones lower the risk of ovarian cancer significantly. This can also be due to decreased ovulatory cycles and thus protecting the ovary. Progesterone has some protective function against ovarian cancer.
Breast feeding after delivery will prevent ovulation for a longer period and also protects against ovarian cancer.
The risk of ovarian cancer is more common in older women over the age of 60, especially those who fit the above criteria. It is less common in young girls due to less ovarian trauma during ovulation compared to elder women.
Clomiphene, which is used to stimulate ovulation for infertility treatment is associated with higher rates of ovarian cancer. Estrogen is associated with more risk of ovarian cancer after menopause, while progesterone is associated with less risk. Androgens are also associated with increased risk.
Having a first degree relative – mother, daughter or sister – with ovarian cancer carries higher risk for developing ovarian cancer with the risk increasing with the number of relatives affected.
Other types of cancers known to be associated with increased risk of developing ovarian cancer includes colorectal cancer and breast cancer. Mutations of PTEN, BRACA1 and BRACA2 genes are associated with a high risk of developing ovarian, breast, thyroid and pancreatic cancer.
Hereditary non-polyposis colon cancer (Lynch syndrome)
This is a genetic mutation associated with higher risk of colon cancer, ovarian cancer and endometrial cancer.
Obesity and diet
Low fat and high fiber diets are associated with decreased risk of developing ovarian cancer. Higher BMI is associated with a higher risk of developing ovarian cancer.
Talcum powder in women who have used it over their genital area has been associated with ovarian cancer. This can be explained by fact that there may be contamination with asbestos.
Clinical Picture of Ovarian Cancer
General symptoms of malignancy may exist according to the cancer stage.
- Loss of appetite
- Weight loss
- Mass effect on the bladder including frequent micturition and urgency
- Pelvic pain or dyspareunia.
Some patients will present with metastases. Symptoms will vary depending on the location, including ascites, pleural effusion or pelvic mass.
Sister Mary Joseph sign is a nodule found in the umbilicus due to metastasis. Some ovarian cancers secrete hormones leading to a variety of symptoms:
- Precautious puberty
- Postmenopausal bleeding
- Irregular uterine bleeding.
Emergent complications due to ovarian cysts include rupture and torsion. Intestinal obstruction is the most common cause of death.
Staging of Ovarian Cancer
FIGO classification of ovarian cancer is widely used for cancer staging as follows:
T: primary tumor stages
- TX: where the tumor can’t be assessed
T1: tumor is limited to the ovaries
- T1A: tumor limited to one ovary and the capsule is intact with no peritoneal washings or malignant ascites
- T1B: tumor limited to both ovaries but the capsule is intact with no peritoneal seeding
- T1C: tumor limited to one or both ovaries but with capsule ruptured, peritoneal washings or malignant ascites
T2: tumor has extended to the pelvis
- T2A: tumor extended to the uterus or tubes but negative malignant ascites or peritoneal washings
- T2B: tumor extended to other pelvic tissues with negative malignant ascites or peritoneal washings
- T2C: tumor extended to the pelvis with positive malignant cells in ascites or peritoneal washings
T3: tumor has extended outside the pelvis
- T3A: microscopic extension outside the pelvis with no macroscopic extension
- T3B: macroscopic extension outside the pelvis is less than 2 cm in greatest dimensions
- T3C: macroscopic metastases outside the pelvis more than 2 cm in greatest dimensions and/or positive regional lymph nodes
- N: regional lymph nodes
- NX: regional lymph nodes cannot be assessed
- N0: no regional lymph node metastases
- N1: positive regional lymph node metastases
- M: distant metastases
- M0: no distant metastases
- M1: distant metastasis.
Diagnosis of Ovarian Cancer
There is no sensitive or specific screening method for early detection of ovarian cancer. Transvaginal ultrasound or CA-125 are sometimes used.
This is a tumor marker found in the blood of women with ovarian cancer, especially in elderly women. CA-125 is non-specific as it is elevated by many conditions other than ovarian cancer including menstruation, fibroids and endometrial cancer. It is considered for screening in women with high risk e.g. BRACA1 & BRACA2 mutations.
Tumor markers are generally used to monitor response to treatment and possible recurrence.
Ovarian tumor markers
They are non-specific markers and can be elevated by other conditions. Clinical correlation and imaging studies are mandatory before treatment with chemotherapy or surgery.
- CA-125: usually elevated in epithelial ovarian tumors
- Alpha-fetoprotein, hCG: both usually elevated in germ cell tumors
- LDH lactate dehydrogenase: elevated with dysgerminoma
- Hormonal markers e.g. estrogen, testosterone and inhibin: elevated in stromal tumors.
Trans-vaginal and trans-abdominal ultrasound
These can be used with CA-125 for screening or sometimes help with staging.
CT scan & MRI
Both are used for better staging of the disease’ extent in the pelvis.
Treatment of Ovarian Cancer
Stage 1A, where the cancer is limited to one ovary, is treated by unilateral oophorectomy, especially in young women who want to conceive.
Stage IV is treated with chemotherapy only. Some cases will benefit from neo-adjuvant chemotherapy to become operable.
For operable cases, radical hysterectomy involving removal of the uterus, fallopian tubes, ovaries and omentum is carried out. Surgery will provide a biopsy for diagnosis, better staging and debulking or excision of the tumor.
Surgery can also extend to lymphadenectomy, splenectomy, appendectomy, diaphragmatic resection, intestinal resection and pelvic exenteration depending on the extent of the disease.
Adjuvant chemotherapy is given after surgery for high grade tumors while neo-adjuvant chemotherapy can be given prior to surgery to improve outcome and help with tumor resection. Chemotherapy regimens are based on carboplatin and paclitaxel.
Bilateral oophorectomy in young women necessitates hormonal therapy with estrogen to avoid early menopausal symptoms including hot flashes, cardiovascular disorders and osteoporosis.
Radiation therapy can be used in advanced cases for palliation with chemotherapy or after surgery, especially for radiosensitive dysgerminoma.