Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses.
Most (more than 90%) ovarian cancers are classified as "epithelial" and are believed to arise from the surface (epithelium) of the ovary. However, some evidence suggests that the fallopian tube could also be the source of some ovarian cancers.Since the ovaries and tubes are closely related to each other, it is thought that these fallopian cancer cells can mimic ovarian cancer. Other types may arise from the egg cells (germ cell tumor) or supporting cells. Ovarian cancers are included in the category gynecologic cancer.
Signs and symptomsSigns and symptoms of ovarian cancer are frequently absent early on and when they exist they may be subtle. In most cases, the symptoms persist for several months before being recognized and diagnosed. Most typical symptoms include: bloating, abdominal or pelvic pain, difficulty eating, and possibly urinary symptoms.[5] If these symptoms recently started and occur more than 12 times per month the diagnosis should be considered.
Other findings include an abdominal mass, back pain, constipation, tiredness and a range of other non-specific symptoms, as well as more specific symptoms such as abnormal vaginal bleeding or involuntary weight loss. There can be a build-up of fluid (ascites) in the abdominal cavity.
Ovarian cancer is associated with age, family history of ovarian cancer (9.8-fold higher risk), anaemia (2.3-fold higher), abdominal pain (sevenfold higher), abdominal distension (23-fold higher), rectal bleeding (twofold higher), postmenopausal bleeding (6.6-fold higher), appetite loss (5.2-fold higher), and weight loss (twofold higher).
CauseIn most cases, the exact cause of ovarian cancer remains unknown. The risk of developing ovarian cancer appears to be affected by several factors:
Older women who have never given birth, and those who have a first or second degree relative with the disease, have an increased risk.
Hereditary forms of ovarian cancer can be caused by mutations in specific genes (most notably BRCA1 and BRCA2, but also in genes for hereditary nonpolyposis colorectal cancer).
Infertile women and those with a condition called endometriosis, and those who use postmenopausal estrogen replacement therapy are at increased risk.
Hormones
Combined oral contraceptive pills are a protective factor.Early age at first pregnancy, older age of final pregnancy and the use of low dose hormonal contraception have also been shown to have a protective effect.[citation needed] The risk is also lower in women who have had their fallopian tubes blocked surgically (tubal ligation).[11][12] Tentative evidence suggests that breastfeeding lowers the risk of developing ovarian cancer.
The relationship between use of oral contraceptives and ovarian cancer was shown in a summary of results of 45 case-control and prospective studies. Cumulatively these studies show a protective effect for ovarian cancers. Women who used oral contraceptives for 10 years had about a 60% reduction in risk of ovarian cancer. (risk ratio .42 with statistical significant confidence intervals given the large study size, not unexpected). This means that if 250 women took oral contraceptives for 10 years, 1 ovarian cancer would be prevented. This is by far the largest epidemiological study to date on this subject (45 studies, over 20,000 women with ovarian cancer and about 80,000 controls).
The ovaries contain eggs and secrete the hormones that control the reproductive cycle. Removing the ovaries and the fallopian tubes greatly reduces the amount of the hormones estrogen and progesterone circulating in the body. This can halt or slow breast and ovarian cancers that need these hormones to grow.
The link to the use of fertility medication, such as Clomiphene citrate, has been controversial. An analysis in 1991 raised the possibility that use of drugs may increase the risk of ovarian cancer. Several cohort studies and case-control studies have been conducted since then without demonstrating conclusive evidence for such a link.It will remain a complex topic to study as the infertile population differs in parity from the "normal" population.
Genetics
There is good evidence that in some women genetic factors are important. Carriers of certain BRCA mutations are notably at risk. The BRCA1 and BRCA2 genes account for 5%–13% of ovarian cancers[17] and certain populations (e.g. Ashkenazi Jewish women) are at a higher risk of both breast cancer and ovarian cancer, often at an earlier age than the general population.Patients with a personal history of breast cancer or a family history of breast and/or ovarian cancer, especially if diagnosed at a young age, may have an elevated risk, and should be tested for the "cancer gene".
In the United States, 10 to 20 percent of women with ovarian cancer have a first- or second-degree relative with either breast or ovarian cancer. Mutations in either of two major susceptibility genes, breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2), confer a lifetime risk of breast cancer of between 60 and 85 percent and a lifetime risk of ovarian cancer of between 15 and 40 percent. However, mutations in these genes account for only 2 to 3 percent of all breast cancers.
A strong family history of uterine cancer, colon cancer, or other gastrointestinal cancers may indicate the presence of a syndrome known as hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome), which confers a higher risk for developing ovarian cancer. Patients with strong genetic risk for ovarian cancer may consider the use of prophylactic, i.e. preventative, oophorectomy the surgical removal of both ovaries, after completion of childbearing years. Prophylactic oophorectomy significantly reduces the chances of developing both breast cancer and ovarian cancer if you're at high risk. Women with BRCA gene mutations usually also have their fallopian tubes removed at the same time (salpingo-oophorectomy), since they also have an increased risk of fallopian tube cancer.
Hereditary breast-ovarian cancer syndromes (HBOC) produce higher than normal levels of breast cancer and ovarian cancer in genetically related families (either one individual suffered from both, or several individuals in the families suffered from one or the other disease). The hereditary factors may be proven or suspected to cause the pattern of breast and ovarian cancer occurrences in the family.
Other[edit]Alcohol consumption does not appear to be related to ovarian cancer.
A Swedish study, which followed more than 61,000 women for 13 years, has found a significant link between milk consumption and ovarian cancer. According to the BBC, "[Researchers] found that milk had the strongest link with ovarian cancer—those women who drank two or more glasses a day were at double the risk of those who did not consume it at all, or only in small amounts."[22] Recent studies have shown that women in sunnier countries have a lower rate of ovarian cancer, which may have some kind of connection with exposure to Vitamin D.
Other factors that have been investigated, such as talc use,asbestos exposure, high dietary fat content, and childhood mumps infection, are controversial[25] and have not been definitively proven; moreover, such risk factors may in some cases be more likely to be correlated with cancer in individuals with specific genetic makeups.
Other[edit]Alcohol consumption does not appear to be related to ovarian cancer.
A Swedish study, which followed more than 61,000 women for 13 years, has found a significant link between milk consumption and ovarian cancer. According to the BBC, "[Researchers] found that milk had the strongest link with ovarian cancer—those women who drank two or more glasses a day were at double the risk of those who did not consume it at all, or only in small amounts."Recent studies have shown that women in sunnier countries have a lower rate of ovarian cancer, which may have some kind of connection with exposure to Vitamin D.
Other factors that have been investigated, such as talc use,asbestos exposure, high dietary fat content, and childhood mumps infection, are controversial[25] and have not been definitively proven; moreover, such risk factors may in some cases be more likely to be correlated with cancer in individuals with specific genetic makeups.
Risk factors[edit]Women who have had children are less likely to develop ovarian cancer than women who have not, and breastfeeding may also reduce the risk of certain types of ovarian cancer. Tubal ligation and hysterectomy reduce the risk and removal of both tubes and ovaries (bilateral salpingo-oophorectomy) dramatically reduces the risk of not only ovarian cancer but breast cancer also.A hysterectomy that does not include the removal of the ovaries has a one-third reduced risk of developing ovarian cancer,[28] it also has no higher risk of developing other types of cancer, heart disease or hip fractures, researchers from the University of California at San Francisco revealed in the journal Archives of Internal Medicine.
Pathophysiology[edit]A long-standing hypothesis that has considerable support via animal model studies is the incessant ovulation hypothesis. According to this, "repeated cycles of ovulation-induced trauma and repair of the OSE [ovarian surface epithelium] at the site of ovulation, without pregnancy-induced rest periods, contributes to ovarian cancer development."[30] Analysis of 316 high-grade serous ovarian adenocarcinomas found that the TP53 gene was mutated in 96% of cases.[31] Other genes commonly mutated were NF1, BRCA1, BRCA2, RB1 and cyclin-dependent kinase 12 (CDK12).
Diagnosis
Diagnosis of ovarian cancer starts with a physical examination (including a pelvic examination), a blood test (for CA-125 and sometimes other markers), and transvaginal ultrasound. The diagnosis must be confirmed with surgery to inspect theabdominal cavity, take biopsies (tissue samples for microscopic analysis) and look for cancer cells in the abdominal fluid.
Ovarian cancer at its early stages (I/II) is difficult to diagnose until it spreads and advances to later stages (III/IV). This is because most symptoms are non-specific and thus of little use in diagnosis.The serum BHCG level should be measured in any female in whom pregnancy is a possibility. In addition, serum alpha-fetoprotein (AFP) and lactate dehydrogenase (LDH) should be measured in young girls and adolescents with suspected ovarian tumors because the younger the patient, the greater the likelihood of a malignant germ cell tumor.
When an ovarian malignancy is included in the list of diagnostic possibilities, a limited number of laboratory tests are indicated. A complete blood count (CBC) and serum electrolyte test should be obtained in all patients. A blood test called CA-125is useful in differential diagnosis and in follow up of the disease, but it by itself has not been shown to be an effective method to screen for early-stage ovarian cancer due to its unacceptable low sensitivity and specificity. Another tests used is OVA1.
Current research is looking at ways to combine tumor markers proteomics along with other indicators of disease (i.e. radiology and/or symptoms) to improve accuracy. The challenge in such an approach is that the disparate prevalence of ovarian cancer means that even testing with very high sensitivity and specificity will still lead to a number of false positive results (i.e. performing surgical procedures in which cancer is not found intra-operatively). However, the contributions of proteomics are still in the early stages and require further refining. Current studies on proteomics mark the beginning of a paradigm shift towards individually tailored therapy.
A pelvic examination and imaging including CT scan[35] and trans-vaginal ultrasound are essential. Physical examination may reveal increased abdominal girth and/or ascites (fluid within the abdominal cavity). Pelvic examination may reveal an ovarian or abdominal mass. The pelvic examination can include a Rectovaginal component for better palpation of the ovaries. For very young patients, magnetic resonance imaging may be preferred to rectal and vaginal examination.
To definitively diagnose ovarian cancer, a surgical procedure to take a look into the abdomen is required. This can be an open procedure (laparotomy, incision through the abdominal wall) or keyhole surgery (laparoscopy). During this procedure, suspicious areas will be removed and sent for microscopic analysis. Fluid from the abdominal cavity can also be analysed for cancerous cells. If there is cancer, this procedure can also determine its spread (which is a form of tumor staging).
Classification
Ovarian cancer is classified according to the histology of the tumor, obtained in a pathology report. Histology dictates many aspects of clinical treatment, management, and prognosis.
Surface epithelial-stromal tumour, also known as ovarian epithelial carcinoma, is the most common type of ovarian cancer. It includes serous tumour, endometrioid tumor, and mucinous cystadenocarcinoma. Less common tumors are malignantBrenner tumor and transitional cell carcinoma of the ovary.
Sex cord-stromal tumor, including estrogen-producing granulosa cell tumor and virilizing Sertoli-Leydig cell tumor or arrhenoblastoma, accounts for 8% of ovarian cancers.
Germ cell tumor accounts for approximately 30% of ovarian tumors but only 5% of ovarian cancers, because most germ cell tumors are teratomas and most teratomas are benign. Germ cell tumors tend to occur in young women (20's-30's) and girls. Whilst overall the prognosis of germ cell tumors tend to be favourable, it can vary substantially with specific histology: for instance, the prognosis of the most common germ cell tumor (dysgerminomas) tends to be good, whilst the second most common (endodermal sinus tumor) tends to have a poor prognosis. In addition, the cancer markers used vary with tumor type: choriocarcinomas are monitored with beta-HCG; dysgerminomas with LDH; and endodermal sinus tumors withalpha-fetoprotein.
Mixed tumors, containing elements of more than one of the above classes of tumor histology.
According to SEER, the types of ovarian cancers in women age 20+ are as follows:
Ovarian cancer can also be a secondary cancer, the result of metastasis from a primary cancer elsewhere in the body. 7% of ovarian cancers are due to metastases while the rest are primary cancers. Common primary cancers arebreast cancer and gastrointestinal cancer. (A common mistake is to name all peritoneal metastases from any gastrointestinal cancer as a Krukenberg tumor,but this is only the case if it originates from primary gastric cancer). Surface epithelial-stromal tumor can originate in the peritoneum (the lining of the abdominal cavity), in which case the ovarian cancer is secondary to primary peritoneal cancer, but treatment is basically the same as for primary surface epithelial-stromal tumor involving the peritoneum.
Ovarian cancer is bilateral in 25% of cases.
Ovarian cancer staging is by the FIGO staging system and uses information obtained after surgery, which can include a total abdominal hysterectomy, removal of (usually) both ovaries and fallopian tubes, (usually) the omentum, and pelvic (peritoneal) washings for cytopathology. The AJCC stage is the same as the FIGO stage. The AJCC staging system describes the extent of the primary Tumor (T), the absence or presence of metastasis to nearby lymph Nodes (N), and the absence or presence of distant Metastasis (M).
Stage I — limited to one or both ovaries
IA — involves one ovary; capsule intact; no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings
IB — involves both ovaries; capsule intact; no tumor on ovarian surface; negative washings
IC — tumor limited to ovaries with any of the following: capsule ruptured, tumor on ovarian surface, positive washings
Stage II — pelvic extension or implants
IIA — extension or implants onto uterus or fallopian tube; negative washings
IIB — extension or implants onto other pelvic structures; negative washings
IIC — pelvic extension or implants with positive peritoneal washings
Stage III — peritoneal implants outside of the pelvis; or limited to the pelvis with extension to the small bowel or omentum
IIIA — microscopic peritoneal metastases beyond pelvis
IIIB — macroscopic peritoneal metastases beyond pelvis less than 2 cm in size
IIIC — peritoneal metastases beyond pelvis > 2 cm or lymph node metastases
Stage IV — distant metastases to the liver or outside the peritoneal cavity
Para-aortic lymph node metastases are considered regional lymph nodes (Stage IIIC). As there is only one para-aortic lymph node intervening before the thoracic duct on the right side of the body, the ovarian cancer can rapidly spread to distant sites such as the lung.
The AJCC/TNM staging system includes three categories for ovarian cancer, T, N and M. The T category contains three other subcategories, T1, T2 and T3, each of them being classified according to the place where the tumor has developed (in one or both ovaries, inside or outside the ovary). The T1 category of ovarian cancer describes ovarian tumors that are confined to the ovaries, and which may affect one or both of them. The sub-subcategory T1a is used to stage cancer that is found in only one ovary, which has left the capsule intact and which cannot be found in the fluid taken from the pelvis. Cancer that has not affected the capsule, is confined to the inside of the ovaries and cannot be found in the fluid taken from the pelvis but has affected both ovaries is staged as T1b. T1c category describes a type of tumor that can affect one or both ovaries, and which has grown through the capsule of an ovary or it is present in the fluid taken from the pelvis. T2 is a more advanced stage of cancer. In this case, the tumor has grown in one or both ovaries and is spread to the uterus, fallopian tubes or other pelvic tissues. Stage T2a is used to describe a cancerous tumor that has spread to the uterus or the fallopian tubes (or both) but which is not present in the fluid taken from the pelvis. Stages T2b and T2c indicate cancer that metastasized to other pelvic tissues than the uterus and fallopian tubes and which cannot be seen in the fluid taken from the pelvis, respectively tumors that spread to any of the pelvic tissues (including uterus and fallopian tubes) but which can also be found in the fluid taken from the pelvis. T3 is the stage used to describe cancer that has spread to the peritoneum. This stage provides information on the size of the metastatic tumors (tumors that are located in other areas of the body, but are caused by ovarian cancer). These tumors can be very small, visible only under the microscope (T3a), visible but not larger than 2 centimeters (T3b) and bigger than 2 centimeters (T3c).
This staging system also uses N categories to describe cancers that have or not spread to nearby lymph nodes. There are only two N categories, N0 which indicates that the cancerous tumors have not affected the lymph nodes, and N1 which indicates the involvement of lymph nodes close to the tumor.
The M categories in the AJCC/TNM staging system provide information on whether the ovarian cancer has metastasized to distant organs such as liver or lungs. M0 indicates that the cancer did not spread to distant organs and M1 category is used for cancer that has spread to other organs of the body.
The AJCC/TNM staging system also contains a Tx and a Nx sub-category which indicates that the extent of the tumor cannot be described because of insufficient data, respectively the involvement of the lymph nodes cannot be described because of the same reason.
The ovarian cancer stages are made up by combining the TNM categories in the following manner:
Stage I: T1+N0+M0
IA: T1a+N0+M0
IB: T1b+N0+M0
IC: T1c+N0+M0
Stage II: T2+N0+M0
IIa: T2a+N0+M0
IIB: T2b+N0+M0
IIC: T2c+N0+M0
Stage III: T3+ N0+M0
IIIA: T3a+ N0+M0
IIIB: T3b+ N0+M0
IIIC: T3c+ N0+M0 or Any T+N1+M0
Stage IV: Any T+ Any N+M1
Ovarian cancer, as well as any other type of cancer, is also graded, apart from staged. The histologic grade of a tumor measures how abnormal or malignant its cells look under the microscope.There are four grades indicating the likelihood of the cancer to spread and the higher the grade, the more likely for this to occur. Grade 0 is used to describe non-invasive tumors. Grade 0 cancers are also referred to as borderline tumors.Grade 1 tumors have cells that are well differentiated (look very similar to the normal tissue) and are the ones with the best prognosis. Grade 2 tumors are also called moderately well differentiated and they are made up by cells that resemble the normal tissue. Grade 3 tumors have the worst prognosis and their cells are abnormal, referred to as poorly differentiated.
Prevention[edit]Tubal ligation appears to reduce the risk of ovarian cancer in women who carry the BRCA1 (but not BRCA2) gene.[42] The use of oral contraceptives (birth control pills) for five years decreases the risk of ovarian cancer in later life by half.
Screening[edit]Routine screening of women for ovarian cancer is not recommended by any professional society — this includes the U.S. Preventive Services Task Force, the American Cancer Society, the American College of Obstetricians and Gynecologists, and the National Comprehensive Cancer Network.[44][45] This is because no trial has shown improved survival for women undergoing screening.[44] Screening for any type of cancer must be accurate and reliable — it needs to accurately detect the disease and it must not give false positive results in people who do not have cancer. As yet there is no technique for ovarian screening that has been shown to fulfil these criteria. However, in some countries such as the UK, women who are likely to have an increased risk of ovarian cancer (for example if they have a family history of the disease) can be offered individual screening through their doctors, although this will not necessarily detect the disease at an early stage.
The purpose of screening is to diagnose ovarian cancer at an early stage, when it is more likely to be treated successfully. However, the development of the disease is not fully understood, and it has been argued that early-stage cancers may not always develop into late-stage disease.With any screening technique there are risks and benefits that need to be carefully considered, and health authorities need to assess these before introducing any ovarian cancer screening programmes.