Ovarian Cancer

Ovarian cancer (human)
Classification and external resources

10 C56
9 183, 220
ICD-O: varied
DiseasesDB 9418
MedlinePlus 000889
eMedicine med/1698
NCI Ovarian cancer
MeSH D010051

Ovarian cancer is when [4]

Ovarian cancer occurs more frequently in women who [3]

Screening is not recommended in women who are at average risk as evidence does not support a reduction in death and there is a high rate of false positive tests leading to unneeded surgery.[5]

In 2012 ovarian cancer occurred in 239,000 women and resulted in 152,000 deaths. This made it the seventh most common cancer and the eighth most common cause of death from cancer in women. It is more common in North America and Europe than Africa and Asia.[5]

Signs and symptoms

Signs and symptoms of ovarian cancer are frequently absent in early stages and when they exist they may be subtle.[11]

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.[12] There may be a build-up of fluid (ascites) in the abdominal cavity.

Ovarian cancer is associated with increased 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).[13]

Cause

In most cases, the exact cause of ovarian cancer remains unknown. The risk of developing ovarian cancer appears to be affected by several factors:[14]

Hormones

[19]

The relationship between use of oral contraceptives and reduced risk of 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).[20]

The ovaries contain eggs and secrete 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.[21]

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.[22] It will remain a complex topic to study as the infertile population differs in parity from the “normal” population.

Genetics

Ovarian and breast cancer patients in a pedigree chart of a family

There is good evidence that in some women genetic factors are important. Carriers of certain [24] 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 any genetic risk.

In the United States, 5 of 100 women with a [27]

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 in people 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.[28]

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

Alcohol consumption does not appear to be related to ovarian cancer.[29]

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.”[31]

Other factors that have been investigated, such as [34]

Risk factors

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. [37]

Pathophysiology

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.”CDK12).

Diagnosis

Instruments and techniques

A very large ovarian cancer as seen on CT

Diagnosis of ovarian cancer starts with a physical examination (including a 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.[40] 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-125 is 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.[41]

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.[42]

A pelvic examination and imaging including CT scan[43] 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 (tumor staging).

Risk scoring

A widely recognized method of estimating the risk of malignant ovarian cancer based on initial workup is the risk of malignancy index (RMI).[44]

It is recommended that women with an RMI score over 200 should be referred to a center with experience in ovarian cancer surgery.[45]

The RMI is calculated as follows:[45]

RMI = ultrasound score x menopausal score x CA-125 level in U/ml.

There are two methods to determine the ultrasound score and menopausal score, with the resultant RMI being called RMI 1 and RMI 2, respectively, depending on what method is used:[45]

Feature RMI 1 RMI 2

Ultrasound abnormalities:

  • multilocular cyst
  • solid areas
  • bilateral lesions
  • ascites
  • intra-abdominal metastases
  • 0 = no abnormality
  • 1 = one abnormality
  • 3 = two or more abnormalities
  • 0 = none
  • 1 = one abnormality
  • 4 = two or more abnormalities
Menopausal score
  • 1 = premenopausal
  • 3 = postmenopausal
  • 1 = premenopausal
  • 4 = postmenopausal
CA-125 Quantity in U/ml Quantity in U/ml

An RMI 2 of over 200 has been estimated to have a [45]

Classification

A pathological specimen of ovarian carcinoma.

A benign tumor of the ovary, discovered during a teratoma

Ovarian cancer is classified according to the prognosis.

Ovarian cancers in women aged 20+, with area representing relative incidence and color representing 5-year relative survival rate.[46]

According to SEER, the types of ovarian cancers in women age 20+ are as follows:[46]

Percent of
ovarian cancers
in women
age 20+
Histology 5 year
RSR
89.7 Adenocarcinoma) 54.4
 26.4 Papillary serous cystadenocarcinoma 21.0
 15.9 “Borderline” adenocarcinoma
(underestimated b/c short data collection interval)
98.2
 12.6 Adenocarcinoma, not otherwise specified 18.3
 9.8 Endometrioid tumor 70.9
 5.8 Serous cystadenocarcinoma 44.2
 5.5 Papillary 21.0
 4.2 Mucinous cystadenocarcinoma 77.7
 4.0 Clear-cell ovarian tumor 61.5
 3.4 Mucinous adenocarcinoma 49.1
 1.3 Cystadenocarcinoma 50.7
5.5 Carcinoma
 4.1 Carcinoma not otherwise specified 26.8
 1.1 Sex cord-stromal tumour 87.8
 0.3 Other carcinomas, specified 37.3
1.7 Mullerian tumor 29.8
1.5 Germ cell tumor 91.0
 0.8 Teratoma 89.1
 0.5 Dysgerminoma 96.8
 0.3 Other, specified 85.1
0.6 Not otherwise specified 23.0
0.5 Epidermoid (Squamous cell carcinoma) 51.3
0.2 Brenner tumor 67.9
0.2 Other, specified 71.7

Ovarian cancer can also be a secondary cancer, the result of [48]

Ovarian cancer is bilateral in 25% of cases.[49]

Staging

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).[50]

  • 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

Ovarian adenocarcinoma deposit in the mesentery of the small bowel

  • 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 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 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

In addition to being staged, like all cancers ovarian cancer is also graded. The histologic grade of a tumor measures how abnormal or malignant its cells look under the microscope.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

[53]

Screening

Screening is not recommended using either [56] 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. 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.

Ovarian cancer has low prevalence and screening of women with average risk is more likely to give ambiguous results than detect a problem which requires treatment.[56] 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.

Management

Treatment usually involves chemotherapy and surgery, and sometimes radiotherapy.[57]

Surgery

Surgical treatment may be sufficient for malignant tumors that are well-differentiated and confined to the ovary. Addition of chemotherapy may be required for more aggressive tumors that are confined to the ovary. For patients with advanced disease a combination of surgical reduction with a combination chemotherapy regimen is standard. Borderline tumors, even following spread outside of the ovary, are managed well with surgery, and chemotherapy is not seen as useful.

Surgery is the preferred treatment and is frequently necessary to obtain a tissue specimen for differential diagnosis via its histology. Surgery performed by a specialist in gynecologic oncology usually results in an improved result.[58] Improved survival is attributed to more accurate staging of the disease and a higher rate of aggressive surgical excision of tumor in the abdomen by gynecologic oncologists as opposed to general gynecologists and general surgeons.

The type of surgery depends upon how widespread the cancer is when diagnosed (the cancer stage), as well as the presumed type and grade of cancer. The surgeon may remove one (unilateral oophorectomy) or both ovaries (bilateral oophorectomy), the fallopian tubes (salpingectomy), and the uterus (hysterectomy). For some very early tumors (stage 1, low grade or low-risk disease), only the involved ovary and fallopian tube will be removed (called a “unilateral salpingo-oophorectomy,” USO), especially in young females who wish to preserve their fertility.

In advanced [59]

Chemotherapy

Chemotherapy has been a general standard of care for ovarian cancer for decades, although with highly variable protocols.[60] Chemotherapy is used after surgery to treat any residual disease, if appropriate. This depends on the histology of the tumor; some kinds of tumor (particularly teratoma) are not sensitive to chemotherapy. In some cases, there may be reason to perform chemotherapy first, followed by surgery.

Intraperitoneal chemotherapy

For patients with stage IIIC epithelial ovarian adenocarcinomas who have undergone successful optimal debulking, a recent clinical trial demonstrated that median survival time is significantly longer for patient receiving intraperitoneal (IP) chemotherapy.[61] Patients in this clinical trial reported less compliance with IP chemotherapy and fewer than half of the patients received all six cycles of IP chemotherapy. Despite this high “drop-out” rate, the group as a whole (including the patients that didn’t complete IP chemotherapy treatment) survived longer on average than patients who received intravenous chemotherapy alone.

Some specialists believe the toxicities and other complications of IP chemotherapy will be unnecessary with improved IV chemotherapy drugs currently being developed.

Although IP chemotherapy has been recommended as a [63]

Radiation therapy

Radiation therapy is not effective for advanced stages because when vital organs are in the radiation field, a high dose cannot be safely delivered. Radiation therapy is then commonly avoided in such stages as the vital organs may not be able to withstand the problems associated with these ovarian cancer treatments.[64]

Immunotherapy

Immune-cell therapies have been reported which have been administered with chemo and/or radiotherapy with efficacy in several patients.[66]

Follow-up

Specific [68]

Recommendations for the use of the CA-125 antigen in monitoring extent of cancer after treatment include:[69]

  • people with increased pretreatment CA-125 concentrations, which later normalise, need to show evidence of a
    • CA-125 concentration greater than, or equal to, two-times the upper normal limit on two occasions at least 1 week apart;
  • pwoplw with increased pretreatment CA-125 concentrations, which never normalise, need to show evidence of
    • CA-125 concentrations greater than, or equal to, two-times the nadir value on two occasions at least 1 week apart; or
  • peoplw with CA-125 concentrations in the normal range pretreatment need to show evidence of
    • CA-125 concentrations greater than, or equal to, two-times the upper normal limit on two occasions at least 1 week apart.

For women with [68]

Women with ovarian cancer should not have routine surveillance imaging to monitor the cancer unless new symptoms appear or [70]

Prognosis

Relative 5-year survival of invasive epithelial ovarian cancer by stage.[71]

Ovarian cancer usually has a relatively poor prognosis. It is disproportionately deadly because it lacks any clear early detection or screening test, meaning that most cases are not diagnosed until they have reached advanced stages. Women with advanced ovarian cancer or a relapse should get palliative care immediately and if appropriate a referral to a palliative care physician.[72]

More than 60% of women presenting with this cancer have stage III or stage IV cancer, when it has already spread beyond the ovaries. Ovarian cancers shed cells into the naturally occurring fluid within the abdominal cavity. These cells can then implant on other abdominal (peritoneal) structures, included the omentum forming new tumor growths before cancer is even suspected.

The [74]

Ovarian cancer is the second most common [73]

Complications

  • Spread of the cancer to other organs
  • Progressive function loss of various organs
  • Ascites (fluid in the abdomen)
  • Intestinal obstructions

These cells can implant on other abdominal (peritoneal) structures, including the uterus, urinary bladder, bowel, lining of the bowel wall (omentum) and, less frequently, to the lungs.

Epidemiology

[75]

  no data
  less than 0.6
  0.6-1.2
  1.2-1.8
  1.8-2.4
  2.4-3
  3-3.6
  3.6-4.2
  4.2-4.8
  4.8-5.4
  5.4-6
  6-7
  more than 7

Globally, as of 2010, approximately 160,000 people died from ovarian cancer, up from 113,000 in 1990.[77] More than half of the deaths from ovarian cancer occur in women between 55 and 74 years of age and approximately one quarter of ovarian cancer deaths occur in women between 35 and 54 years of age.

In 2010, in the United States, it is estimated that 21,880 new cases were diagnosed and 13,850 women died of ovarian cancer. The risk increases with age and decreases with numbers of pregnancy. Lifetime risk is about 1.6%, but women with affected first-degree relatives have a 5% risk. Women with a mutated [63]

From 2004–2008, the median age at diagnosis for cancer of the ovary was 63 years of age. Approximately 1.2% were diagnosed under age 20; 3.5% between 20 and 34; 7.3% between 35 and 44; 19.1% between 45 and 54; 23.1% between 55 and 64; 19.7% between 65 and 74; 18.2% between 75 and 84; and 8.0% 85+ years of age. 10-year relative survival ranges from 84.1% in stage IA to 10.4% in stage IIIC.[74]

The age-adjusted incidence rate was 12.8 per 100,000 women per year. These rates are based on cases diagnosed in 2004–2008 from 17 SEER geographic areas.[46]

Society and culture

Other animals

Ovarian tumors have been reported in [86]

Research

Researchers are assessing different ways to screen for ovarian cancer. Screening tests that could potentially be used alone or in combination for routine screening include the [88] However, it’s not yet clear if this approach could actually help to save lives—the full results of the trial will be published in 2015.

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Further reading

External links



This article uses material from the Wikipedia article Ovarian Cancer, which is released under the Creative Commons Attribution-Share-Alike License 3.0.

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