Table of Contents
Types of Ovarian Cancer
Ovarian tumors can originate from different ovarian cell populations with different pathological characteristics. Therefore, understanding the ovary’s microscopic anatomy is essential to understanding ovarian tumors. The ovary comprises the three main entities, made up of varying cells, which give rise to the various types of tumors.
- The cortex contains both follicles and stroma. The follicles contain oocytes, which originate from germ cells and are responsible for forming germ cell tumors. The oocyte is surrounded by two layers of different cells called granulosa cells.
- The mesenchyme from the gonadal stroma 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 surrounds the ovary and gives rise to ovarian epithelial tumors.
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 the stromal invasion.
These tumors have a 40% chance of malignancy and are bilateral in 40% of cases. They are most common in younger women aged 30-40 years.
Serous cystadenocarcinoma is the most common type of malignant ovarian tumor. It is composed mainly of cysts with serous fluid lined with a columnar ciliated epithelium that may have a solid area with papillae.
Malignant differentiation correlates with the solid areas within the tumors, as well as the amount of necrosis. Borderline tumors have atypical cells but have not invaded the surrounding stroma. Malignant cystadenocarcinoma is characterized by psammoma bodies, which are calcified bodies within the papillae.
Mucinous tumors are usually unilateral and can become very large. The cyst is lined with a single layer of mucin-producing columnar cells without cilia; sometimes, septa originate within the cyst.
They can be classified as benign, borderline, or malignant. Malignant mucinous tumors (mucinous cystadenocarcinoma) have a poor prognosis and result in pseudomyxoma perotinei, where the entire abdomen and pelvis fill with mucinous cysts like metastases, mucinous ascites, and fibrosis.
Also known as transitional tumors, Brenner tumors represent 1-2% of all ovarian tumors, and only 8-10% are bilateral. They are more common among women over 40.
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 hyperchromasia.
These rare tumors represent less than 5% of all ovarian tumors. Endometrioid carcinoma is usually malignant and commonly bilateral. The tumor resembles endometrial carcinoma of the uterus, which may be simultaneously present. Microscopically, it consists of glands of atypical cells with large clear nuclei and prominent nucleoli.
Clear cell carcinoma
These are also known as mesonephroid tumors. Malignant clear cell carcinomas carry a bad prognosis. Cells are clear with a 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 that may lead to virilization or feminization of the opposite sex. CD56 may identify sex cord tumors and follow response to treatment as a marker.
A thecoma is almost always benign and unilateral. It seems to arise from hyperplasia of the cortical stroma and is 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 tumor is malignant in one of every five patients. The tumor secretes estrogen, which is 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 Meigs’ syndrome.
Meigs’ syndrome is a triad of right pleural effusion, ascites, and an abdominal mass mostly in ovarian sex cord/stromal tumor. It is most commonly found in fibromas but can also occur in granulosa cell tumors and sometimes even in Brenner’s tumors. The effusion and ascites resolve after the tumor excision.
Tumors of testicular origin and can also be present in the ovary e.g., Sertoli-Leydig cell tumor and Sertoli cell tumor.
This is a rare tumor originating from both testicular and ovarian sex cord cells.
Germ cell tumor
Germ cell tumors include tumors that arise from the ovum and its precursor germ cells. Germ cell tumors can arise from the ovary or other body locations 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:
Germinomatous: germinoma/dysgerminoma of the ovary comprises uniform cells with 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 bone tissues. They 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. It is more common in young girls; it 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 cartilage. It is a benign tumor, but close observation is necessary to prevent malignant transformation
- Choriocarcinoma: germ cell tumor where the cells differentiated into placental trophoblasts and secreted beta-hCG without placental villi formation. 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-fetoprotein
- Polyembryoma: a rare malignant tumor associated with Klinefelter syndrome (see picture beside)
- Gonadoblastoma: a rare tumor composed of a mixture of cells, including germ cells, Sertoli 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
Several factors affect the chances of ovarian cancer development. Several theories explain the etiology of ovarian cancer:
- The incessant ovulation theory states that increased activation of the ovary to form mature ova leads to haphazard multiplication and, hence, the cells’ malignant conversion to form malignancy
- The gonadotropin theory postulates that increased gonadotropins lead to uncontrolled activation of the ovary and, thus, malignant conversion of the cells
- The genetic theory states that 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 ovarian cancer
Therefore, most of the risk factors are related to genetic influence, ovulation, or gonadotropin increase—the lower the ovulation and gonadotropin amount, the lower the risk of ovarian cancer.
Each full-term pregnancy lowers the risk of ovarian cancers. 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 significantly lowers the risk of ovarian cancer. This can also be due to decreased ovulatory cycles that protect the ovary. Progesterone has some protective function against ovarian cancer.
Breastfeeding after delivery will prevent ovulation for a longer period and also protects against ovarian cancer.
The risk of ovarian cancer is more common in women over the age of 60, especially those who meet the above criteria. It is sporadic in young girls due to less ovarian trauma during ovulation compared to older women.
Clomiphene, which is used to stimulate ovulation for infertility treatment, is associated with higher ovarian cancer rates. Estrogen is associated with a higher risk of ovarian cancer after menopause, while progesterone is associated with a lower risk. Androgens are also associated with increased risk.
Having a first-degree relative – mother, daughter, or sister – with ovarian cancer carries a higher risk for developing ovarian cancer. The risk increases with the number of relatives affected.
Other types of cancers associated with an increased risk of developing ovarian cancer include 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 genetic mutation is associated with a higher risk of colon cancer, ovarian cancer, and endometrial cancer.
Obesity and diet
Low-fat, high-fiber diets are associated with a decreased risk of developing ovarian cancer. Higher BMI is associated with a higher risk of developing ovarian cancer.
Talcum powder is associated with a higher risk of ovarian cancer among women who used it in the genital area. This might be because of 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.
The 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 cannot be assessed
T1: the tumor is limited to the ovaries
- T1A: the tumor is limited to one ovary, and the capsule is intact, with no peritoneal washings or malignant ascites
- T1B: the tumor is limited to both ovaries, but the capsule is intact, with no peritoneal seeding
- T1C: the tumor is limited to one or both ovaries but with a ruptured capsule, peritoneal washings, or malignant ascites
T2: the tumor has extended to the pelvis
- T2A: the tumor has extended to the uterus or tubes but negative malignant ascites or peritoneal washings
- T2B: the tumor has extended to other pelvic tissues with negative malignant ascites or peritoneal washings
- T2C: the tumor has extended to the pelvis with positive malignant cells in ascites or peritoneal washings
T3: the 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 at its 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: no regional lymph nodes can 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 the early detection of ovarian cancer. Transvaginal ultrasound or CA-125 is sometimes used.
This tumor marker is found in the blood of women with ovarian cancer, especially in elderly women. CA-125 is non-specific since it is elevated by many conditions other than ovarian cancer, including menstruation, fibroids, and endometrial cancer. Women with high risk, e.g., BRACA1 & BRACA2 mutations, should be screened.
Tumor markers are generally used to monitor response to treatment and possible recurrence.
Ovarian tumor markers
These non-specific markers can be elevated by other conditions. Clinical correlation and imaging studies are mandatory before treatment with chemotherapy or surgery.
- CA-125: usually elevated in ovarian epithelial 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’s 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 younger women who want to conceive.
Stage IV is treated with chemotherapy only. Some patients may benefit from neoadjuvant chemotherapy to shrink their tumors, so they become operable.
For operable cases, radical hysterectomy involving removing the uterus, fallopian tubes, ovaries, and momentum 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 disease’s extent.
Adjuvant chemotherapy is given after surgery for high-grade tumors, while neo-adjuvant chemotherapy can be given before surgery to improve outcomes and help with tumor resection. Chemotherapy regimens are based on carboplatin and paclitaxel.
Bilateral oophorectomy in young women will require 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, chemotherapy, or after surgery, especially for radiosensitive dysgerminoma.