Ovarian cancer

Ovarian cancer is a cancerous growth arising from different parts of the ovary.

The most common form of ovarian cancer (?80%) arises from the outer lining (epithelium) of the ovary. However, recent evidence shows cells that line the Fallopian tube (epithelium) also to be prone to develop into the same kind of cancer as seen in the ovaries. Since the ovaries and tubes are closely related to each other, it is hypothesized that these cells can mimic ovarian cancer. Other forms arise from the egg cells (germ cell tumor).

In 2004, in the United States, 25,580 new cases were diagnosed and 16,090 women died of ovarian cancer. The risk increases with age and decreases with pregnancy. Lifetime risk is about 1.6%, but women with affected first-degree relatives have a 5% risk. Women with a mutated BRCA1 or BRCA2 gene carry a risk between 25% and 60% depending on the specific mutation. Ovarian cancer is the fifth leading cause of death from cancer in women and the leading cause of death from gynecological cancer.

In early stages ovarian cancer is associated with abdominal distension.

10-year relative survival ranges from 84.1% in stage IA to 10.4% in stage IIIC.

Ovarian cancer causes non-specific symptoms. Early diagnosis would result in better survival, on the assumption that stage I and II cancers progress to stage III and IV cancers (but this has not been proven). Most women with ovarian cancer report one or more symptoms such as abdominal pain or discomfort, an abdominal mass, bloating, back pain, urinary urgency, constipation, tiredness and a range of other non-specific symptoms, as well as more specific symptoms such as pelvic pain, abnormal vaginal bleeding or involuntary weight loss. There can be a build-up of fluid (ascites) in the abdominal cavity.

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 the abdominal cavity, take biopsies (tissue samples for microscopic analysis) and look for cancer cells in the abdominal fluid. Treatment usually involves chemotherapy and surgery, and sometimes radiotherapy.

In most cases, the cause of ovarian cancer remains unknown. Older women, and in 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, those who have never been pregnant and those who use postmenopausal estrogen replacement therapy are at increased risk. Use of combined oral contraceptive pills is a protective factor. The risk is also lower in women who have had their uterine tubes blocked surgically (tubal ligation).

Classification
 
A benign tumor of the ovary, discovered during a C-section; this is a 4 cm teratomaOvarian cancer 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.
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 (see Teratoma). Germ cell tumor tends to occur in young women and girls. The prognosis depends on the specific histology of germ cell tumor, but overall is favorable.
Mixed tumors, containing elements of more than one of the above classes of tumor histology.
According to SEER, types of ovarian cancers in women age 20+ are as follows:

Percent of ovarian cancers in women age 20+ Histology 5 year
RSR
89.7 Surface epithelial-stromal tumor (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 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 are breast cancer and gastrointestinal cancer (A common mistake is to name all peritoneal metastases from any gastrointestinal cancer as Krukenberg cancer[citation needed], 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.

Staging
Ovarian cancer is 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 (peritomeal) washings for cytopathology. The AJCC stage is the same as the FIGO stage.

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 - involvs 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 - microscopic 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).

Symptoms
Accuracy of symptoms
Two case-control studies, both subject to results being inflated by spectrum bias, have been reported. The first found that women with ovarian cancer had symptoms of increased abdominal size, bloating, urge to pass urine and pelvic pain.[10] The smaller, second study found that women with ovarian cancer had pelvic/abdominal pain, increased abdominal size/bloating, and difficulty eating/feeling full.[14] The latter study created a symptom index that was considered positive if any of the six (6) symptoms "occurred >12 times per month but were present for <1 year".They reported a sensitivity of 57% for early-stage disease and specificity 87% to 90%.

Consensus statement
In 2007, the Gynecologic Cancer Foundation, Society of Gynecologic Oncologists and American Cancer Society originated the following consensus statement regarding the symptoms of ovarian cancer.

Ovarian cancer is called a "silent killer" because symptoms were not thought to develop until the disease had advanced and the chance of cure or remission poor. However, the following symptoms are much more likely to occur in women with ovarian cancer than women in the general population. These symptoms include:

Several other symptoms have been commonly reported by women with ovarian cancer. These symptoms include fatigue, indigestion, back pain, pain with intercourse, constipation and menstrual irregularities. However, these other symptoms are not as useful in identifying ovarian cancer because they are also found in equal frequency in women in the general population who do not have ovarian cancer.[citation needed]

Cause
The exact cause is usually unknown. The risk of developing ovarian cancer appears to be affected by several factors. The more children a woman has, the lower her risk of ovarian cancer. 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. Ovarian cancer is reduced in women after tubal ligation.

Hormones
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 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 mutations of the BRCA1 or the BRCA2 gene are notably at risk. The BRCA1 and BRCA2 genes account for 5%-13% of ovarian cancers 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.

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 II 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 after completion of childbearing.[citation needed] Australia being member of International Cancer Genome Consortium is leading efforts to map ovarian cancer's complete genome.

Alcohol
A pooled analysis of ten (10) prospective cohort studies conducted in a number of countries and including 529,638 women found that neither total alcohol consumption nor alcohol from drinking beer, wine or spirits was associated with ovarian cancer risk." The results of a case-control study in the region of Milan, Italy, "suggests that relatively elevated alcohol intake (of the order of 40 g per day or more) may cause a modest increase of epithelial ovarian cancer risk". "Associations were also found between alcohol consumption and cancers of the ovary and prostate, but only for 50 g and 100 g a day." "Statistically significant increases in risk also existed for cancers of the stomach, colon, rectum, liver, female breast, and ovaries."

Other
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 and have not been definitively proven.

Diagnosis
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 of the common symptoms are non-specific.

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.

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.

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. However, this is the only widely-used marker currently available.

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 very low population 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[citation needed] 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).

Prevention
There are a number of ways to reduce or eliminate the risk of ovaran cancer. Pregnancy before the age of 25 as well as breastfeeding provides some reduction in risk. Tubal ligation and hysterectomy reduce the risk and removal of both ovaries (bilateral oophorectomy) nearly eliminates the risk. The use of oral contraceptives (birth control pills) for five years or more decreases the risk of ovarian cancer in later life by 50%.

Screening
Routine screening of the general population is not recommended by any professional society. This includes the U.S. Preventitive Services Task Force, the American Cancer Society, the American College of Obstetricians and Gynecologists, and the National Comprehensive Cancer Network.

No trial has shown improved survival for women undergoing screening.

Screening tests include the CA-125 marker, transvaginal ultrasound, and combinations of markers such as OvaSure (LabCorp). A definitive diagnosis requires surgical excision of the ovaries and fallopian tubes, so a positive screening test must be followed up by surgery.

The purpose of screening is to discover ovarian cancer in early stages, when it is more curable, on the hypothesis that early-stage cancer develops into later-stage cancer. However, it is not known whether early stage ovarian cancer evolves to later stage cancer, or whether stage III (peritoneal cavity involvement) arises as a diffuse process.

The goal of ovarian cancer screening is to detect ovarian cancer at stage I. Several large studies are ongoing, but none have recommended screening. In 2009, however, Menon et al. reported from the UKCTOCS that utilizing mutimodal screening, in essence first performing annual CA 125 testing, followed by ultrasound imaging on the secondary level, the positive predictive value was 35.1% for primary invasive epithelial ovarian and tubal carcinoma, making such screening feasible. However, it remains to be seen if such screening is effective to reduce mortality.

Management
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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.[citation needed] 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 malignancy, where complete resection is not feasible, as much tumor as possible is removed (debulking surgery). In cases where this type of surgery is successful (i.e. < 1 cm in diameter of tumor is left behind ["optimal debulking"]), the prognosis is improved compared to patients where large tumor masses (> 1 cm in diameter) are left behind. Minimally invasive surgical techniques may facilitate the safe removal of very large (greater than 10 cm) tumors with fewer complications of surgery.

Chemotherapy has been a general standard of care for ovarian cancer for decades, although with highly variable protocols. 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.

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.  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 standard of care for the first-line treatment of ovarian cancer, the basis for this recommendation has been challenged.

Radiation therapy is not effective for advanced stages because when vital organs are in the radiation field, a high dose cannot be safely delivered.

Prognosis
Ovarian cancer usually has a 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. More than 60% of patients presenting with this cancer already 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 implant on other abdominal (peritoneal) structures, included the uterus, urinary bladder, bowel and the lining of the bowel wall (omentum [disambiguation needed]). These cells can begin forming new tumor growths before cancer is even suspected.

The five-year survival rate for all stages of ovarian cancer is 45.5%. For cases where a diagnosis is made early in the disease, when the cancer is still confined to the primary site, the five-year survival rate is 92.7%.

Germ cell tumors of the ovary have a much better prognosis than other ovarian cancers, in part because they tend to grow rapidly to a very large size, hence they are detected sooner.

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
 
The exact cause is usually unknown. The disease is more common in industrialized nations, with the exception of Japan. In the United States, females have a 1.4% to 2.5% (1 out of 40-60 women) lifetime chance of developing ovarian cancer. Older women are at highest risk.[citation needed] 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.