Etiology of Gynaecological Cancers:

Ovarian:
PRIMARY: Epithelial ovarian carcinoma, germ-cell tumors, sex-cord stromal tumors, and other more rare types. SECONDARY: Metastasis from endometrium, breast, colon, stomach, and cervix. The precise cause is Unknown, but there are several risk factors found to increase the risk of ovarian cancer. Hippisley-Cox and Coupland developed an algorithm to determine risk of breast cancer in women with and without symptoms. In their cohort study, 10% of women with the highest-predicted risk had 63% of all ovarian cancers diagnosed over the next 2 years. Reproductive Factors: 1. Parity Increased risk in nullipara women. 2. Those with early menarche or late menopause. 3. Women who have been pregnant have a 50% decreased risk for developing ovarian cancer compared with nulliparous women. 4. Multiple pregnancies offer an increasingly protective effect. 5. Oral contraceptive use decreases the risk of ovarian cancer. These factors support the idea that risk for ovarian cancer is related to ovulation. Two theories regarding this relationship have been proposed: 1. The incessant ovulation theory - Repeated ovarian epithelial trauma caused by follicular rupture and subsequent epithelial repair results in genetic alterations within the surface epithelium. 2. The gonadotropin theory - Persistent stimulation of the ovaries by gonadotropins, coupled with local effects of endogenous hormones, increases surface epithelial proliferation and subsequent mitotic activity. Thus, the probability of ovarian cancer may be related to the number of ovulatory cycles, and conditions that suppress the ovulatory cycle may play a protective role. Ovulation suppression has been shown to decrease cancer incidence. Although treatment with agents that induce ovulation in women with infertility has been suggested to increase the incidence of epithelial ovarian cancer, this is unproven. Genetic Factors: 1. Family history 5-10% of cases occur in individuals with a family history of the disease. 4-5% when and 1st degree relative is affected, 7% when and 2nd degree relative is affected. 2. The lifetime risk for developing ovarian cancer is 1.6% in the general population.

3. Hereditary epithelial ovarian cancer occurs at a younger age (approximately 10 years younger) than non-hereditary epithelial ovarian cancer, but the prognosis may be somewhat better. Analyses by the Cancer Genome Atlas Research Network have revealed ovarian cancer is characterized by TP53 mutations in almost all tumours. The findings also include the low prevalence but statistically recurrent mutations in 9 further genes, including NF1, BRCA1, BRCA2, RB1, and CDK12.

At least 2 syndromes of hereditary ovarian cancer are clearly identified, involving either: 1. Disorders of the genes associated with breast cancer (BRCA1 and BRCA2) 2. Genes within the Lynch II syndrome complex (rare). Breast/ovarian cancer syndrome is associated with early onset of breast or ovarian cancer. Inheritance follows an autosomal dominant transmission. It can be inherited from either parent. Most cases are related to the BRCA1 gene mutation. BRCA1 is a tumour suppressor gene that inhibits cell growth when functioning properly; the inheritance of mutant alleles of BRCA1 leads to a considerable increase in risk for developing ovarian cancer. Approximately 1 person in 4000 in the general population carries a mutation of BRCA1. Some populations have a much higher rate of BRCA1 and BRCA2 mutations, especially Ashkenazi Jews. In families with 2 first-degree relatives (mother, sister, or daughter) with premenopausal epithelial ovarian cancer, the likelihood of a female relative having an affected BRCA1 or BRCA2 gene is as high as 40%. The probability is much lower when the disease occurs in relatives post-menopausal. Individuals with a BRCA1 gene mutation have a 50-85% lifetime risk of developing breast cancer and a 15-45% risk of developing epithelial ovarian cancer. Those with a BRCA2 gene mutation have a 50-85% lifetime risk of developing breast cancer and a 10-20% risk of developing epithelial ovarian cancer. Families with BRCA2 mutations are at risk for developing cancer of the prostate, larynx, pancreas, and male breast. Germ-line mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers; however, in an investigation of a common genetic variation at the 9p22.2 locus, a decreased risk of ovarian cancer was noted in carriers of a BRCA1 or BRCA2 mutation. Families with Lynch II syndrome or hereditary non-polyposis colorectal cancer are characterized by a high risk for developing colorectal, endometrial, stomach, small bowel, breast, pancreas, and ovarian cancers. This syndrome is caused by mutations in the mismatch repair genes. Mutations have been demonstrated in mismatch repair genes MSH2, MLH1, PMS1, and PMS2.

Women with a history of breast cancer have an increased risk of epithelial ovarian cancer. In a study by Rafner et al, whole-genome sequencing identified a rare mutation in BRIP1, which behaves like a classical tumour suppressor gene in ovarian cancer. This allele was also associated with breast cancer. Previous Hormone Therapy: A nationwide prospective cohort study over 10 years that included all Danish women aged 50-79 years concluded that risk for ovarian cancer is increased with hormone therapy, regardless of duration of use, formulation, oestrogen dose, regimen, progestin type, and administration route. Nearly 1 million women without hormone-sensitive cancer or bilateral oophorectomy were followed. In an average of 8 years of followup, 3068 ovarian cancers were detected, of which 2681 were epithelial cancers. Current users of hormones had incidence rate ratios for all ovarian cancers of 1.38 compared with women who never took hormone therapy. Risk declined as years since last hormone use increased. Incidence rates in current and never users of hormones were 0.52 and 0.40 per 1000 years, respectively. This translates to approximately 1 extra ovarian cancer for approximately 8300 women taking hormone therapy each year. Other Factors: 1. Lactose consumption 2. Talcum powder on the vulva and perineum

Fallopian Tube:
Primary fallopian tube cancer is the rarest (only about 1%) of all gynecologic cancers. The most common type of fallopian tube cancer (>95%) is papillary serous adenocarcinoma, the rest are sarcomas (leiomyosarcomas) or transitional cell carcinomas. The causes and risk factors for developing primary fallopian tube cancer are not clearly defined, due to its rarity. There has been some association of the cancer with chronic infection and/or inflammation of the fallopian tubes (due to untreated sexually transmitted diseases), although a cause-effect relationship has not been definitively established. There are several genetic mutations that have been reported in women with primary fallopian tube cancer. The mutations involve the hereditary breast and ovarian cancer genes, and particularly BRCA1. Given the relative rarity of fallopian cancer, any woman diagnosed with this disease should undergo thorough family history assessment, and be offered genetic counselling. Conversely, if a woman knows that she carries a BRCA mutation, rigorous screening for fallopian cancer should be considered in order to increase chances for early detection.

Uterine : Endometrial 1. Obesity: Women who are more than 50 pounds over ideal weight have a 10times greater risk of developing endometrial cancer than women of ideal weight. Body fat produces oestrogen, and women with excess fat have a higher level of oestrogen than women without excess fat. The higher level of oestrogen is believed to increase the risk of cancer. 2. Nullipara: Women who have never been pregnant have a 2-3 times higher risk than women who have been pregnant. 3. Early puberty: Women who begin their periods before 12 years of age are at an increased risk due to the increased number of years that the endometrium is exposed to oestrogen. 4. Late menopause: Women who go through menopause after 52 years of age are at a higher risk of developing endometrial cancer than women who go through menopause earlier in life. Like early puberty, late menopause increases the number of years that the endometrium is exposed to oestrogen. 5. Treatment with unopposed oestrogen: The risk of developing endometrial cancer is increased by several times in women who take Oestrogen Replacement Therapy without added progesterone. 6. High level of oestrogen: Women who have a high level of unopposed oestrogen in the body are also at an increased risk. Several different conditions, such as polycystic ovarian disease, can cause a woman to have high, unopposed oestrogen level. 7. Treatment with Tamoxifen: Women who have been treated with Tamoxifen, a drug used to prevent and treat breast cancer, may have a slightly increased risk of developing endometrial cancer. 8. Other cancers: Cancers of the breast, ovary and colon are linked with an increased risk of endometrial cancer. 9. Family History: Women who have a close relative with endometrial cancer have an increased risk of the disease. The use of combination oral contraceptives decreases the risk of developing endometrial cancer.

Women who use oral contraceptives at some time have half the risk of developing endometrial cancer as women who have never used oral contraceptives. This protection occurs in women who have used oral contraceptives for at least 12 months. The protection continues for at least 10 years after oral contraceptive use. The protection is most notable for women who have never been pregnant.

Myometrial (Adenomyosis) The cause is unknown, although it has been associated with trauma to the uterus, such as: 1. 2. 3. 4. Caesarean Section Tubal Ligation Pregnancy Termination Pregnancy

It is also linked with endometriosis. Myometrial cancer is common in women between the ages of 35 and 50 is because it is between these ages that women have an excess of oestrogen (Oestrogen Dominance). Near the age of 35, women typically cease to create as much natural progesterone, which counters the effects of oestrogen. After the age of 50, due to menopause, women do not create as much oestrogen. Adenomyosis correlates with abnormal amounts of:

Endometrial IL-18 receptor mRNA and the ratio of IL-18 binding protein to IL-18 are significantly increased in adenomyosis patients in comparison to normal people. Leukemia Inhibitory Factor is dysregulated in the endometrium and uterine flushing fluid of women with adenomyosis during the implantation window.

Placental:
Choriocarcinoma of the placenta during pregnancy is preceded by: 1. 2. 3. 4. Hydatidiform mole (50% of cases) Spontaneous abortion (20% of cases) Ectopic pregnancy (2% of cases) Normal term pregnancy (20-30% of cases)

Cervical: Vaginal: Vulvar:

The cause of cancer vulva is unclear; however, some conditions such as condyloma or squamous dysplasias may have preceded the cancer. Human papillomavirus (HPV) is suspected to be a possible risk factor in the cause of vulvar cancer. Patients infected with HIV tend to be more susceptible to vulvar malignancy. Also, smokers tend to be at higher risk.

References: 1. http://emedicine.medscape.com/article/255771-overview#a0101 2. http://www.oncolink.org/types/article.cfm?c=6&s=49&ss=801&id=9502 &CFID=42987116&CFTOKEN=14615116 3. http://www.emedicinehealth.com/endometrial_cancer/page2_em.htm 4.