Ovarian cancer is becoming challenging every year due to the inreasing number of diagnoses. It is considered the 5th leading cause of cancer deaths among women; about 14,000 deaths and more than 20,000 new cases every year.

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an ovarian cancer as seen on CT

Image: “An ovarian cancer as seen on CT.” by James Heilman, MD – Own work. License: CC BY-SA 3.0


Types of Ovarian Cancer

For better understanding of the ovarian tumors, microscopic anatomy of the ovary is mandatory. The ovary is composed of cortex, medulla, and epithelial cubical cell layer surrounding the ovary. Each of these structures has different cells and different origin.

The medulla is composed of loose connective tissue with blood vessels and nerves. The cortex contains both follicles and stroma. The follicles contain oocytes, which originate from germ cells and are responsible for formation of the ova. The oocyte is surrounded by two layers of different cells called granulosa cells. The stroma contains fibroblasts. The follicles exist in various stages of development according to the menstrual cycles.

Ovarian tumors can originate from different ovarian cell populations with different pathological characteristics.

Epithelial tumors

These tumors arise from the surface epithelium of the ovary and constitute the most common ovarian tumors. They can differentiate into serous, mucinous, Brenner, endometrioid, small cell, clear cell and undifferentiated tumors. They can be benign, borderline or malignant according to stromal invasion.

Serous tumors

these tumors are commonly benign rather than malignant. Serous cystadenocarcinoma are the malignant differentiation of serous tumors and are the most common of malignant ovarian tumors. Serous tumors are composed mainly of cysts with serous fluid and lined with columnar ciliated epithelium that may have a solid area with papillae.

Malignant differentiation correlates with the solid areas within the tumors and 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

Mucinous tumors are usually unilateral and can reach a huge size. The cyst is lined with a single layer of mucin producing columnar cells with no cilia and sometimes septa originates within the cyst.

They can be classified also into benign, borderline and malignant. Malignant mucinous tumors (mucinous cystadenocarcinoma) carry a bad prognosis and can result in pseudomyxoma perotinei where the whole abdomen and pelvis are filled with mucinous cysts like metastases, mucinous ascites and fibrosis.

Brenner tumor

These can be solid or cystic. The tumor is mainly formed of nests or cysts of cells that resemble transitional epithelium of the urinary tract and spindle stromal cells in-between. The cells are clear with no mitotic figures, pleomorphism or hyperchormasia.

Endometrioid carcinoma

Endometrioid carcinoma are usually malignant and commonly bilateral. The tumor resembles endometrial carcinoma of the uterus and maybe simultaneously present. Microscopically, it consists of glands of atypical cells with large clear nuclei and prominent nucleoli.

Clear cell carcinoma

Malignant clear cell carcinoma carry bad prognosis. Cells are clear with prominent nucleus and glycogen rich clear cytoplasm. 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.

Thecoma

This is almost always benign and unilateral. 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 of every five patients. The tumor secretes estrogen responsible for abnormal uterine bleeding.

Fibroma

These are firm white grey tumors of fibrocytes which produce concentric layers of collagen. The tumor is common in middle aged females and 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 ovarian sex cord/stromal tumor most commonly fibroma but also granulosa cell tumor and sometimes Brenner’s tumor. The effusion and ascites are reversible after removal of the tumor.

Tumors of testicular origin can also be present in the ovary e.g. Sertolli-Leydig cell tumor and Sertolli cell tumor.

Gynanderoblastoma

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 location of the body due to germ cell migration. Germ clee tumors include:

  • Gerninomatous: germinoma/dysgerminoma of the ovary is composed of uniform cells with clear cytoplasm and lymphocytes infiltration. The tumor is malignant with hCG used as a marker if a small percentage.

    klinefelter's syndrome

    Image: “Signs of Klinefelter’s syndrome.” No machine-readable author provided. The cat~commonswiki assumed (based on copyright claims). – No machine-readable source provided. Own work assumed (based on copyright claims). License: CC BY-SA 3.0

  • Non-germinonatous: including
    • Teratoma: tumor cells differentiate into derivatives of embryonic germ layers – ectoderm, mesoderm and endoderm. The tumors usually contain hair, teeth, eyes, limbs or bones. It can be cystic or solid, benign or malignant. Mature cystic teratoma with high grade of differentiation into mesodermal or ectodermal origin is known as dermoid cyst which is usually benign.
    • Immature teratoma: malignant germ cell tumor. The cells are poorly differentiated to any of the germ cell layers derivatives. Usually, it is common in young girls but has a good prognosis and good response to therapy.
    • Dermoid cyst: cystic teratoma that arise from embryonic totipotent germ cells and contain different developmental tissue origins and usually include skin, teeth, hair, nails, thyroid tissue, eyes and bone or cartilage. It is a benign tumor but close observation is required to avoid malignant transformation.
    • Choriocarcinoma: germ cell tumor while 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 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. Most of them are related to ovulation. The less ovulation means the less risk of ovarian cancer.

Pregnancy

Full term pregnancy lowers the risk of ovarian cancers with lower risk with each full term pregnancy. The risk is higher in women who had late pregnancy or have never been pregnant. Pregnancy hormones prevent ovulation and lower the risk of ovarian cancer.

Contraception

Birth control with OCPs or injectable hormones lower the risk of ovarian cancer for a long period. This can be also due to decreased ovulatory cycles and thus protecting the ovary. Progesterone has some protective function against ovarian cancer.

Breast feeding

Breast feeding after delivery will prevent ovulation for a longer period and protect against ovarian cancer.

Age

Ovarian cancer risk is more with old women over 60 years of age, e specially with the above criteria. It is less common in young girls due to less ovarian trauma during ovulation compared to elder women.

Medications

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.

Genetic mutation

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.

Other types of cancers known to have association with ovarian cancer increasing the risk are e.g. colorectal cancer and breast cancer. Mutations of PTEN, BRACA1 and BRACA2 genes are associated with high risk of ovarian, breast, thyroid and pancreatic cancer.

Hereditary nonpolyposis 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 diet is associated with decreased risk of ovarian cancer. Higher risk of developing ovarian cancer is associated with higher BMI.
Talcum powder in women who used it over the genital area has been associated with ovarian cancer. This could be explained by contamination with asbestos.

Clinical Picture of Ovarian Cancer

General symptoms of malignancy may exist according to the cancer stage.

  • Fever
  • Loss of appetite
  • Weight loss
  • Bloating
  • Mass effect on the bladder including frequent micturition and urgency
  • Pelvic pain or dyspareunia.

Some patients will present with metastases. Symptoms will vary according to 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 cancer secrete hormones leading to a variety of symptoms:

  • Amenorrhea
  • Hirsutism
  • 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 and 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

      diagram showing stage 3a to 3c ovarian cancer

      Image: “Diagram showing stage 3A to 3C ovarian cancer.” by Cancer Research UK – Original email from CRUK. License: CC BY-SA 4.0

  • T3: tumor has extended outside the pelvis
    • T3A: microscopic extension outside pelvis with no macroscopic extension
    • T3B: macroscopic extension outside pelvis less than 2 cm in greatest dimensions
    • T3C: macroscopic metastases outside 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 and specific screening method for early detection of ovarian cancer. Transvaginal ultrasound or CA-125 are sometimes used.

CA-125

This is a tumor marker found in blood of women with ovarian cancer, especially in elderly women. CA-125 is non-specific as it is elevated in 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 with 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 with 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. Surgery will provide biopsy for diagnosis, better staging and debulking or excision of the tumor.

Surgery also can extend to lymphadenectomy, splenectomy, appendectomy, diaphragmatic resection, intestinal resection and pelvic exenteration according to extent of the disease.

Chemotherapy

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 with 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.

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