Ovarian Cancer : The Silent Killer

Of all the gynaccological causes. ovarian malignancies are the most difficult to treat, as different types of cancers originating from one organ. Epithclial ovarian malignancies are most common and are usually asymptomatic until they have metastasized. Patients have advanced disease in more than two-third of the cases.

There is no available statistics for ovarian cancer in Bangladesh. In USA, 24,500 new cases of ovarian cancer causing 14,200 death per alum. It is the d'" most common cancer in women. The annual number of cases has increased by 10 per cent in the past 25 years. It is more common in industrialized countries. A woman's risk of having ovarian cancer sometimes in her life is nearly and of dying due to ovarian cancer is almost 1 per cent. Approximately 90 per cent, of ovarian cancers are derived trout tissues that come from tile coelomic epithelium or mesothelium.

Histological Classification of Ovarian Tumors

There are three main types of ovarian tumors.

  1. Epithelial ovarian tumors are derived frorn the cells oil the surface of the ovary. This is the most common form of ovarian cancer accounting 80 per cent, and occurs primarily in adults. These tumors are further subdivided into three categories- benign. borderline (low-malignant potential or atypical proliferate) and invasive carcinoma. Borderline tumors tend to occur in younger women and can often be treated conservatively. It allows women to preserve their fertility and retain ovarian hormone production which would be lost if both ovaries were removed as occurs with the treatment of invasive carcinoma.
  2. Germ cell ovarian tumors are among the least common ovarian tumors. approximately 10-I5 per cent of ovarian tumors. They are derived from the oocytes. These tumors can also be benign or malignant. The benign tumors arc nearly always mature cystic teratomas or so-called "dermoids" and are successfully treated by the removal of the tumour with preservation of rest of the ovary. No further treatment is nccessary. Malignant germ cell tumors require intensive multiagent chemotherapy, after removal. The treatment is completely different from the chemotherapy administered after surgical treatment of Surface epithelial tumor.
  3. Finally, the least common type of ovarian tumor accounting for approximately 5-10 per cent of ovarian tumors are those derived from the stromal component of the ovary. Since hormone production (female sex hormones such as estradiol and progesterone and male hormones such as testosterone, dehydrocpiandrosterone [DHEA] and androstcndione) occurs in the stroma, tumors derived from this part of the ovary can be associated with abnormal production of sex hormones. This can lead to abnormal vaginal bleeding in reproductive age and postmenopausal women and precocious puberty ill children. Ovarian tumors that produce male sex hormones can cause hirsutism and in extreme cases virilization characterized by an increase in body hair, deepening of the voice, balding, increase in muscle mass, and enlargement of the clitoris.

Aetiology

Any aetiological theory of ovarian epithelial neoplasia has to take into account that though neoplasm is relatively common in the human ovary, it is rare in the testis and infrequent in animals (Marchant 1980, Damjasou 1989). This suggests that the human ovary is exposed to carcinogenic stimuli. Failure of experimental animal research has resulted in epidemiological studies which are to date inconclusive (Fox 19R0).

Reproductive Factors

  1. In any given population nulliparity, small families is the most important risk factor (Beral et al. 1978. Beral 1980. New house et al. 1997). Infertile woman with ovarian malfunction have a tendency to develop neoplastic disease. Nulliparous and infertile woman have an elevated risk which attributes to deprivation of some direct benefit associated with pregnancy (Whittemore et al. 1992 b). The more pregnancies a woman has the less is the chance of developing ovarian adenocarcinoma. The first pregnancy decreases the chance of ovarian neoplasm by 40 per cent and each additional pregnancy by 14 per cent, (Newhouse et al. 1977; Beral et al. 1978; Kuale et al. 1988; Mori et al. 1985; Gwinn et al. 1990; Vegri et al. 1991; Parazzini et al. 1991; Whittemore et al. 1992 b).

    However the first pregnancy above the age of 35 years dose not exert any protective affect (Berth et al. 1989).

  2. Breast feeding also decreases the risk of ovarian carcinoma. Breast feeding for the first 6 months after delivery exerts the maximum risk reduction than for the later period of lactation (Whittemore et al. 1992 b).
  3. Ovulatory agents may increase the risk of ovarian carcinogenesis (Whittemore et al. 1992b).
  4. Short term (one year or less) use of oral contraceptives have no protective effect on the ovary (Gross et al. 1992). Protective effect of oral contraceptives is most marked on older women. The early high potency oral contraceptives were more protective than those in current use.
  5. Hormone replacement therapy (HRT) with unopposed estrogen appears to have little. or no effect in the risk of developing ovarian carcinoma (Whittemore et al. 1992b).
  6. Hysterectomy and tubal ligation reduces the risk of ovarian carcinoma. This operation before the age of 40 confirm greater protection (Whittemore et al. 1992 b). It is argued that the above named operations alter the blood supply to the ovaries and thus induce a tendency for anovulatory cycles to occur (Neil et al. 1975; Radwanska et al. 1982; Ellisworth et al. 1983: Cattanach 1985: De Stcfi1's et al. 1985).

Genetic Factors

There are tow types of familial ovarian adenocarcinoma: site specific ovarian cancer, the common variety and the breast/ ovarian cancer syndrome (Piver et al. 1991; Watson and lynch 1992).

In both syndromes the average age at which the cancer develops is lower than the non familial cases and is always a serous adenocarcinoma. Cytogenetic studies have shown that structural abnormalities particularly of chromosomes 3,6,11 and 17 are common in sporadic ovarian cancer (Atkin and Baker 1987; Tauaka et al. 1989, Foulkes et al. 1992).

Ascending Exogenous Carcinogen

May be involved in ovarian neoplasia and the finger of guilt has been pointed at talcom powder (longo & Young 1979) partly because talcom powder crystals can be found in ovarian carcinoma (Henduson et al. 1971; Cramec et al. 1982; Whittemore et al. 1988).

Ovarian Cancer : Incidence by Age

The peak incidence of invasive ovarian epithelial cancer is at 50-70 years of age. The age specific incidence of ovarian epithelial cancers rises presumably from 20-80 years of age and subsequently declines fewer than 2 per cent of epithelial ovarian neoplasm after the age of 80 years. Two third of these malignancies are being germ cell tumors. About 30 per cent, of' ovarian tumors in post menopausal women are malignant, whereas 7 per cent of ovarian tumors in pre-menopausal women are frankly malignant (Sully RE, Young RH, Clement PB, Atlas of Tumor pathology 1998). The average age of patients with borderline tumors is approximately 46 years (Seidman JD, Kurman RJ, Am J. Sung Pathol 1996-20, 1331, 1335). 80-90 per cent of ovarian cancers including borderline forms occur after the age of 40 years, whereas 30 per cent-40 per cent of malignancies occur alter the age of 65 years.

Clinical Features and Presentation

The most unfortunate of ovarian cancer is, until the disease has spread (it remains asymptomatic). In some cases often there is a vague abdominal discomfort. dyspepsia, irregular vaginal bleeding. What is of prime importance is the reproductive history from faulty treatment of infertility, and age of the patient.

Unfortunately since the composition of the ovary is very multiple, the nature of the malignancies also varies. In early stage of disease patient may experience irregular mass, if she is pre-menopausal. If a pelvic mass causing compression she may complaint of increased frequency of micturation or constipation.

In advanced stage of disease the symptoms are related to the presence of ascities, omental meta or bowel meta. The symptoms Often include abdominal distension, bloating, constipation, nausea, anorexia, or early satiety. Pre-menopausal women may complaint of irregular or heavy, menstruation. whereas vaginal bleeding may occur in post-menopausal women.

Screening

Physical Examination (Pervaginal)

  1. To be examined by a gynaecologist to detect/exclude mass or lump in the lower abdomen. A per rectal examination is also adviced at this point.
  2. A per abdominal or transvaginal ultrasonography may he carried out to detect and evaluate the type of ovarian mass palpated.

Blood Examination

In addition to routine blood examination there are some special test called tumor markers.

In case of ovarian cancers these are CA-1?5, alpha-feto Protein, human chorionic gonadotrophin and inhibin. The type of marker is often specific for the tumor type and unfortunately some tumors have no known marker todate.

Biopsy

Only tissue examined Under a microscope can confirm ovarian cancer.

Stages of Ovarian Cancer

Only by surgery an ovarian cancer patient can be staged. The prognosis of the patient depends on the stage, histopathology and treatment available.

FIGO staging for ovarian cancer is as follows:

Stage I - Growth limited to the ovaries

Stage Ia - Growth limited to one ovary, no ascites, no tumor on external surface, capsule intact

Stage Ib - Growth limited to both ovaries, no ascites, no tumor on external surface, capsule intact

Stage Ic - Tumor either stage la or In but with tumor on surface of one or both ovaries, ruptured capsule, ascites with malignant cells or positive peritoneal washings.

Stage II - Growth involving one or both ovaries, with pelvic extension

Stage IIa - Extension and/or metastases to the uterus or tubes

Stage IIb - Extension to other pelvic tissues

Stage IIc - Stage IIa or IIb but with tumor on surface of one or both ovaries, ruptured capsule, ascites with malignant cells or positive peritoneal washings.

Stage III - Tumor involving one or both ovaries, with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes; superficial liver metastases equal stage III

Stage IIIa - Tumor grossly limited to pelvis, negative lymph nodes but histological proof of microscopic disease on abdominal peritoneal surfaces

Stage IIIb - Confirmed implants outside of pelvis in the abdominal peritoneal surface; no implant exceeds 2 cm in diameter and lymph nodes are negative

Stage IIIc - Abdominal implants larger than 2 cm in diameter and/or positive lymph nodes.

Stage IV - Distant metastases; Pleural effusion must have a positive cytology to be classified as stage IV; parenchymal liver metastases equals stage IV.

Spread of Ovarian Cancer

Ovarian epithelial cancer spreads primarily by exfoliation of cells into the peritoneal cavity, by lymphatic dissemination and haematogenous spread.

Treatment

The primary treatment of ovarian epithelial cancer of all varieties is surgery. Debulking or decreasing the tumor load as much as Possible is the optimal treatment. This is followed by chemotherapy and occasional radiation therapy.

For advanced ovarian cancer docetaxel (Taxotere)/ carboplatin combination is more effective and beneficial to the patient population. The biggest problem with chemotherapy is the quality of life. The regimen of docetaxcl (Taxotere)/carboplatin injected every 3 weeks provides the patient less neurotoxicity, less nausea, and therefore better quality of life.

Prognosis of Ovarian Cancer

Ovarian cancer has a poor prognosis mainly due to the fact that 70 per cent of the patients are diagnosed at advanced stages. In addition, the recurrence rate after initial treatment is as high as 60 per cent (Ozols 1999). In Norway, the age-adjusted 5-year survival was increased from 39 per cent to 43 per cent and the median survival from 29 months to 39 months from 1975-1979 to 1990-1994. This was probably due to the introduction of cisplatinum-based chemotherapy and more aggressive surgery. However, no major improvement in long-term survival was seen (Bjorge et al. 1998). The introduction of docetaxel has improved the initial complete response (51 per cent vs. 31 per cent), progression free survival (18 months vs. 13 months) and overall survival (38 months vs. 24 months) (McGuire et al. 1996). However, there is a wide spectrum of clinical behaviours front an excellent prognosis and high likelihood of cure to those with rapid progression and poor prognosis irrespective of clinical stage of the disease, most probably reflecting different biological properties of the tumour.

Survival Rates in Women with Advanced Ovarian Cancer

Women age of 45 or younger with advanced ovarian cancer (stages III and IV) have significantly higher survival rates compared to women older than 45 years with the same stage of cancer. The overall five-year survival rate in women with advanced ovarian cancer is 23 per cent. However, one study found that the five year survival rate and median survival period in women up to age 45 was 48 per cent and 54 months respectively, compared to 22 per cent and 34 months in women who were older than 45 years. Because advanced-staged invasive ovarian cancer is particularly uncommon in young women before age 45, few reports have evaluated the outcome in younger women with stages III and IV ovarian cancer.

It is not clear why the overall outcome is better for younger women. Researchers found that differences in tumor biology and immunological response between the younger and older women, as well as a higher prevalence of gene mutations in older women, may explain the improved outcomes in the younger group.

Submitted By
Dr. Naseem Rahman, MBBS, MS (OBS & GYMAE), FAGGH, PHD. The author is a Specialist Gynae Oncology.

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