Ovarian cancer is a malignant tumor arising from the ovary, fallopian tube, or peritoneum. In contemporary classification, epithelial ovarian carcinoma is considered together with fallopian tube and primary peritoneal carcinomas as a single disease entity because these tumors share similar molecular features, patterns of spread, and clinical behavior.^[1][2] Epithelial malignancies account for roughly 90% of ovarian cancers, of which 70% to 80% are high-grade serous carcinomas; other major histologic types include endometrioid, clear cell, mucinous, and low-grade serous carcinomas, as well as borderline tumors.^[1][3]

Globally, ovarian cancer is an important cause of cancer morbidity and mortality in women. GLOBOCAN 2022 estimates more than 320,000 new cases and over 200,000 deaths worldwide, corresponding to age-standardized incidence and mortality rates of approximately 6–7 and 4 per 100,000 women-years, respectively.^[4][5] In the United States, ovarian cancer remains a leading cause of gynecologic cancer death, but both incidence and mortality have declined by roughly 3% per year since the mid-2000s, a trend attributed largely to increased use of oral contraceptives and uptake of risk-reducing salpingo-oophorectomy among women with high-risk genetic variants.^[6][1]

The understanding of epithelial ovarian cancer pathogenesis has shifted from the traditional concept of an origin in the ovarian surface epithelium to a model in which many high-grade serous carcinomas arise from serous tubal intraepithelial carcinoma (STIC) in the fimbrial end of the fallopian tube, with subsequent implantation on the ovary and peritoneal surfaces.^[7][2] Endometrioid and clear cell carcinomas are strongly associated with endometriosis, whereas some mucinous tumors may originate in the ovary or represent metastases from gastrointestinal primaries.^[8] Approximately 50% of high-grade serous ovarian cancers are characterized by homologous recombination deficiency (HRD), including germline or somatic variants in BRCA1, BRCA2, and other DNA-repair genes, which has important implications for platinum sensitivity and benefit from poly (ADP-ribose) polymerase (PARP) inhibitors.^[9][10]

Hereditary factors account for roughly one quarter of epithelial ovarian cancers, most commonly germline variants in BRCA1 and BRCA2, although pathogenic variants in other homologous recombination and mismatch repair genes also contribute.^[11][12] Current guidelines recommend that all patients with epithelial ovarian, fallopian tube, or peritoneal carcinoma undergo germline testing (and, when indicated, somatic tumor testing) for hereditary cancer susceptibility genes, as this information influences treatment decisions, surveillance strategies, and cascade testing of relatives.^[13]

Beyond genetic predisposition, risk factors for ovarian cancer include reproductive and hormonal factors such as endometriosis, infertility, and use of postmenopausal estrogen therapy without adequate progestin, as well as lifestyle and environmental exposures.^[8][14] Protective factors include multiparity, breastfeeding, and use of combined oral contraceptives, which are associated with substantial relative risk reductions in both the general population and among BRCA1/2 carriers.^[15][16] Risk-reducing salpingo-oophorectomy significantly decreases ovarian cancer risk and overall mortality in BRCA1/2 mutation carriers and is a cornerstone of preventive strategies in this population.^[17][18][19]

Early detection of ovarian cancer is challenging because there are no effective screening tests for average-risk women. Large randomized trials of screening with CA-125 and transvaginal ultrasonography have not demonstrated a clear mortality benefit and have led to false-positive results and unnecessary surgery; therefore, routine screening is not recommended for asymptomatic women at average risk.^[20][1] Instead, clinical attention is focused on timely evaluation of symptoms and risk assessment in women with hereditary predisposition.^[21]

Most patients lack specific symptoms until disease is advanced, and approximately 70% to 80% of epithelial ovarian cancers are diagnosed at stage III or IV.^[1][22] When present, symptoms are typically nonspecific and may include abdominal bloating or distension, early satiety, pelvic or abdominal pain, urinary urgency or frequency, changes in bowel habits, and unintentional weight loss.^[22][21] Definitive diagnosis and staging require surgical exploration to determine the origin and extent of disease and to obtain tissue for histopathologic and molecular evaluation.^[3][23]

Early-stage disease (confined to the ovaries or fallopian tubes) is primarily managed with comprehensive surgical staging and, in selected stage I cases, adjuvant platinum-based chemotherapy; 5-year overall survival for appropriately treated early-stage disease is approximately 70% to 95%.^[23][1] Advanced-stage disease typically requires cytoreductive surgery combined with platinum-taxane chemotherapy, delivered either as primary debulking surgery followed by adjuvant chemotherapy or as neoadjuvant chemotherapy followed by interval debulking in patients with high tumor burden or poor performance status.^[3][24] For patients with advanced-stage high-grade serous carcinoma who respond to initial platinum-based chemotherapy, maintenance therapy with PARP inhibitors, with or without the anti-angiogenic agent bevacizumab, improves progression-free survival, particularly in those with BRCA1/2 variants or HRD-positive tumors.^[10][1] Nonetheless, most patients with advanced epithelial ovarian cancer eventually relapse, and 5-year overall survival in this group remains approximately 10% to 40% despite modern systemic therapy.^[3][23]

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Ovarian cancer was first linked to gene mutations by Dr. King who found and named BRCA1 gene on chromosome 17 in 1990 and BRCA2 gene on chromosome 13 in 1994.

• In the 16th and 17th centuries, Dr. Lusitani and Dr. Tulp from Holand, believed that cancers are contagious after they noticed the presence of breast cancers in the same household members.^[1][2][3]
• In 1990, Dr. Mary-Claire King, the professor of genome sciences from Chicago, was the first one to link the single gene on chromosome 17 to many breast and ovarian cancers, after many years of research to find evidence that there is a genetic pattern linked to the incidence of complex diseases.
• In 1991, King named the gene that is linked to many breast and ovarian cancers as BRCA1.^[4]
• In 1994, King also found and named the second gene, BRCA2 on chromosome 13.^[5]
• 1996, King and the Breast Cancer research foundation, conducted a study on women of Ashkenazi Jewish ancestry in NYC and also on Palestinian women, which lead to the definitive confirmation that mutations in BRCA1 and BRCA2 is linked to the incidence of ovarian and breast cancer.

Ovarian cancer is usually diagnosed late resulting in a poor overall outcome for the patient. Pathological findings, therefore, often only occur in advanced symptomatic onset and tend to present more as severe pathologic outcomes.

• Clear cell tumors are part of the surface epithelial-stromal tumor group of ovarian cancers, accounting for 6% of all neoplastic cases. Clear cell tumors are also associated with the pancreas and salivary glands.
• Benign and borderline variants of this neoplasm are rare, and most cases are malignant.
• Typically, they are cystic neoplasms with polypoid masses that protrude into the cyst.

Endometrioid tumors are part of the surface epithelial tumor group of ovarian neoplasms (10-20% of which are the endometrioid type). Benign and borderline variants are rare, as the majority are malignant. There is an association with endometriosis and concurrent primary endometrial carcinoma (endometrial cancer).

Histologic subtypes of epithelial ovarian tumor include:^[1][2][3][4]

• Surface epithelial stromal ovarian tumor (60-70%)

• Ovarian serous tumor

• Ovarian serous cystadenoma: ~60% of serous tumor
• Ovarian borderline serous cystadenoma: ~15% of serous tumor
• Ovarian serous cystadenocarcinoma: ~25% of serous tumor. Commonest malignant ovarian tumor

• Ovarian mucinous tumor: ~20% of all ovarian tumor

• Ovarian mucinous cystadenoma: ~80% of mucinous tumor
• Ovarian bordeline mucinous cystadenoma: 10-15% of mucinous tumor
• Ovarian mucinous cystadenocarcinoma: 5-10% of mucinous tumor

• Ovarian endometrioid tumour: 8-15% of all ovarian tumor
• Clear cell ovarian carcinoma: ~5% of ovarian cancer
• Brenner tumour: ~2.5% of ovarian epithelial neoplasms
• Squamous cell carcinoma of the ovary
• Ovarian cystadenofibroma / ovarian adenofibroma: can be serous, mucinous, endometrioid, clear cell or mixed
• Ovarian cystadenocarcinofibroma: extremely rare
• Undifferentiated carcinoma of the ovary: ~4% of all ovarian tumor

Clear cell tumors can be either clear cell adenocarcinomas or clear cell sarcomas.On microscopic pathological examination, they are composed of cells with clear cytoplasm (that contains glycogen) and hob nail cells (from which the glycogen has been secreted).The pattern may be glandular, papillary or solid.

Shown below is an image of Overian clear cell adenocarcinoma.(H&E stain,very high mag)

Shown below is a video of clear cell adenocarcinoma of the vagina.

{{#ev:youtube|qO2w8VLf690}}

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Ovarian cancer etiology is not completely understood but there are multiple risk factors that can play a role in its occurrence. The theories of the etiology of ovarian cancer suggest that repeated ovulation injures the ovarian epithelium and eventually leads to ovarian cancer development. The other theories discuss the origin of ovarian cancer that can be cortical inclusion cysts that become neoplastic or metaplastic or dysplastic changes of the fallopian tube. Direct effect of persistent Gonadotrophin release from the pituitary gland on the ovary also believed to play a role in ovarian cancer etiology.

• Ovarian cancer etiology is not completely understood but there are multiple risk factors that can play a role in its occurrence such as:
  • Follicle stimulation or fertility drugs as Clomiphene^[1]
• Based on multiple studies, the following are theories of the etiology of ovarian cancer:
  • Theory 1:
    • Repeated ovulations lead to injury of the ovarian epithelium and subsequent exposure to the inflammatory cytokine, transformation of the mesenchymal epithelium, alteration of the genes and hence cancer.
    • With increased age, cortical inclusion cysts develop and its ovarian surface epithelium become metaplastic or neoplastic under the effect of accumulated inflammatory cytokines or stromal factors stimulation ^[2]
  • Theory 2:
    • Ovarian cancer originates from the fallopian tube. This theory evidenced by the presence of dysplastic changes in the fallopian tubes of women who underwent prophylactic removal of their ovaries.
  • Theory 3:
    • Persistent Gonadotrophin release from the pituitary gland has a direct effect on the ovarian epithelium and is considered carcinogenic ^[3]

• Desogestrel and Ethinyl Estradiol
• Estropipate
• Medroxyprogesterone

On the basis of age of onset, vaginal discharge, and constitutional symptoms, ovarian cancer must be differentiated from tubo-ovarian abscess, ectopic pregnancy, hydrosalpinx, salpingitis, fallopian tube carcinoma, uterine leiomyoma, choriocarcinoma, leiomyosarcoma, pregnancy, appendiceal abscess, appendiceal neoplasm, diverticular abscess, colorectal cancer, pelvic kidney, advanced bladder cancer, and retroperitoneal sarcoma.

On the basis of age of onset, vaginal discharge, and constitutional symptoms, ovarian cancer must be differentiated from tubo-ovarian abscess, ectopic pregnancy, hydrosalpinx, salpingitis, fallopian tube carcinoma, uterine leiomyoma, choriocarcinoma, leiomyosarcoma, pregnancy, appendiceal abscess, appendiceal neoplasm, diverticular abscess, colorectal cancer, pelvic kidney, advanced bladder cancer, and retroperitoneal sarcoma.^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81]}

ABBREVIATIONS

BTA=Bladder tumor associated antigen, NMP= Nuclear matrix proteins, CEA= Carcinoembryonic antigen, US= Ultrasound, HCG= Human chorionic gonadotropin, LDH= Lactate dehydrogenase, AFP= Alpha fitoprotein, CA125= Cancer antigen 125, H&E= Hematoxylin and eosin, MRI= Magnetic resonance imaging, GI= Gastrointestinal tract, PID= Pelvic inflammatory disease, CA19-9= Carbohydrate antigen 19-9, 5HIAA= 5-hydroxyindoleacetic acid, MEN syndrome= Multiple endocrine neoplasia syndrome, HNPCC= Hereditary nonpolyposis colorectal cancer, UTI= Urinary tract infection, RCC= Renal cell carcinoma

Ovarian cancer is the 7th most common type of cancer in women worldwide and the 8th most common type of cancer in the United States. Ovarian cancer is the second most common gynecologic malignancy and the most common cause of gynecologic cancer death in the United States. Ovarian cancer is the second most common gynecologic malignancy in developed countries, with an incidence of 9.4 per 100,000 women and a mortality rate of 5.1 per 100,000. In developing countries, it is the third most common gynecologic malignancy (cervical cancer is the most common), with an incidence of 5.0 per 100,000 and a mortality rate of 3.1 per 100,000. The age-adjusted prevalence of ovarian cancer in the United States is 71.3 per 100,000 in 2011. The estimated number of new cases of ovarian cancer is approximately 22,000.

• Ovarian cancer 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.^[1][2]
• In the United States, the age-adjusted prevalence of ovarian cancer is 71.3 per 100,000 in 2011.^[3]

• The delay-adjusted incidence of ovarian cancer in 2011 was estimated to be 12.46 per 100,000 persons in the United States.^[3][4]

• In 2011, the age-adjusted incidence of ovarian cancer was 12.09 per 100,000 persons in the United States.^[3]

• Older women are at highest risk. More than half of the deaths from ovarian cancer occur in women between 55 and 74 years of age.

• While the overall age-adjusted incidence of ovarian cancer in the United States between 2007 and 2011 is 12.3 per 100,000, the age-adjusted incidence of ovarian cancer by age category is:^[3]
  • Under 65 years: 7.5 per 100,000
  • 65 and over: 45.2 per 100,000

• Shown below is an image depicting the delay-adjusted incidence and observed incidence of ovarian cancer by age and race in the United States between 1975 and 2011. These graphs are adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.^[3]

• Shown below is a table depicting the age-adjusted prevalence of ovarian cancer by race in 2011 in the United States.^[3]

• Shown below is an image depicting the incidence of ovarian cancer by race in the United States between 1975 and 2011.^[3]

API: Asian/Pacific Islander; AI/AN: American Indian/ Alaska Native

Among patients with histologically confirmed cases of ovarian cancer, the percent distribution of the types of the disease between 2007 and 2011 in the United States are:^[3]

• Carcinoma: 91.7%
  • Epidermoid carcinoma: 0.7%
  • Adenocarcinoma: 84%
    • Adenocarcinoma, not otherwise specified: 12.3%
    • Papillary adenocarcinoma: 1,5%
    • Clear cell adenocarcinoma: 5.2%
    • Endometrioid carcinoma: 9.7%
    • Cystadenocarcinoma, not otherwise specified: 0.4%
    • Serous cystadenocarcinoma: 20.9%
    • Papillary serous cystadenocarcinoma: 23.5%
    • Mucinous cystadenocarcinoma: 1.5%
    • Mucinous adenocarcinoma: 3.5%
    • Mucin-producing adenocarcinoma: 0.2%
    • Other adenocarcinoma: 5.3%
  • Other specific carcinoma: 2.3%
    • Stromal cell tumor: 1.6%
    • Other: 0.7%
  • Unspecified carcinoma, not otherwise specified: 4.6%
• Sarcoma and other soft tissues: 0.4%
• Other specific types: 6.9%
  • Mullerian mixed tumor: 3%
  • Malignant teratoma: 1.5%
  • Other: 2.4%
• Unspecified: 1.1%

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The risk of developing ovarian cancer appears to be affected by several factors; in fact, early age at first pregnancy, older ages of final pregnancy, and the use of low dose hormonal contraception have been associated with a lower incidence of ovarian cancer. There is good evidence that in some women genetic factors are important.

Common risk factors in the development of ovarian cancer include:^[1]

• Common risk factors in the development of ovarian cancer include:
  • Age:
    • There is a proportional association between age and ovarian cancer, as age increases, ovarian cancer incidence increases.^[14]
  • Hormonal and reproductive factors:
    • Early menarche and late menopause:
      • Both increase the frequency of the ovulation and the ovarian epithelium exposure to persistent injury.^[14][15]
    • Nulliparity
      • Studies have shown that multiparity and full term pregnancies decrease the risk of ovarian cancer and fallopian tubal carcinoma.^[16][17]
    • Infertility:
    • Type of infertility and its causes should be taken in consideration as different causes can increase the risk of ovarian cancer such as:^[18]
      • Primary infertility
      • Secondary infertility as endometriosis
      • The role of medications used for ovulation induction in increasing the risks of ovarian cancer is controversial. The association between the fertility drugs and ovarian cancer could be due to the stimulating effect of these drug, however this association is not a causal relation.^[13]
      • Regardless to the fertility medications use, infertility is an independent risk factor of ovarian cancer.^[13]
    • Endometriosis
      • Ovarian cancers that arise from endometriotic tissue usually affect young women and have better prognosis and survival rates.^[19]
    • Polycystic ovarian syndrome:
      • The association is controversial and complex. Meta-analysis found an association between PCOS and endometrial cancer in general but not with ovarian cancer specifically.^[20]
    • Postmenopausal hormone therapy:
      • A non statistical significant association found between combined estrogen–progesteron therapy and ovarian carcinoma.^[21]
      • Meta-analysis found small significant association between ovarian cancer and estrogen therapy alone.^[22]
    • Intrauterine device:
      • Regardless of the type of the IUD, studies have shown an increased risk of ovarian cancer with IUD use.^[23]
  • Genetic factors
    • BRCA gene mutations: the risk of both ovarian and breast cancers increases in women with BRCA mutations.
    • The risk is more with BRCA1 carriers than BRCA2 carriers.^[3]
    • Ovarian cancer develops at an earlier age in BRCA1-carrier women compared to BRCA2-carrier women. Serous adenocarcinoma is the most common type.^[4]
    • General women and women with BRCA mutations usually present with stage III or IV.^[24]
    • However, the grade is higher in women who are BRCA mutations‘ carries.^[25]
    • The short-term survival rate of ovarian cancer in women with BRCA mutations is higher than non-carriers.^[26]
    • Prophylactic bilateral salpingo-oophorectomy can be done in BRCA mutation carries who are at higher risk of developing fallopian tube cancer and primary peritoneal carcinoma.^[27]
  • Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) :
    • 1 percent of cases with ovarian cancer have Lynch syndrome.^[5]
  • Family history of breast cancer:
    • It is not clear whether the family’s pattern of cancer is due to chance, shared lifestyle factors, a genetic risk passed from parents to children or a combination of these factors.
    • By American cancer society, about 5 to 10% of ovarian cancers are a part of family cancer syndromes resulting from inherited changes (mutations) in certain genes.
    • BRCA mutation carriers with personal or family history of breast cancer have higher risk of developing ovarian cancer that those without BRCA mutation^[28]
  • Other genetic factors:
    • The genes in the Fanconi anemias pathway can undergo different mutations and lead to the development of ovarian and/or breast cancer^[6]. The genes that are associated with ovarian cancer are: BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, PALB2, and BARD1^[7]
  • Environmental factors such as:
    • Cigarette smoking associated with mucinous ovarian cancer^[8]
    • Asbestos,Talc (Its association is controversial)^[9]
  • Other factors such as:
    • Diet:
      • Ddairy food with high animal fat intake is claimed to be associated with ovarian cancer but data are not sufficient to confirm this association.^[10]
    • Exercise:
      • No clear evidence about the association between physical activity and breast cancer.^[11]
    • Obesity:
      • Can increases the risk of ovarian cancer and the risk of its mortality.^[12]
  • Pelvic inflammatory disease can increase the risk of and might be used as tumor marker for ovarian tumor^[29]

There are no recommendations for screening ovarian cancer in asymptomatic women although better outcome is associated with early diagnosis. Biomarkers from peritoneal fluid can be used as a mean of early detection of ovarian cancer but this is still an emerging proof. Examples of screening and diagnostic methods for ovarian cancer include pelvic examination, cancer antigen 125 (CA125) tumor marker, transvaginal ultrasound (TVU), multimarker panels, and bioinformatic analysis of proteomic patterns.

• There are no recommendations for screening ovarian cancer in asymptomatic women although better outcome is associated with early diagnosis.^[1][2]
• Ovarian cancer is the fifth most common cause of cancer-related mortality in women
• 75% of women with ovarian cancer are diagnosed in an advanced stage
• Ovarian cancer is the most lethal gynecological cancer
• The reason of increased mortality and late detection of ovarian cancer in its advanced stage is because the screening systems that are being used have poor or limited sensitivity and specificity.
• Biomarkers from peritoneal fluid can be used as a mean of ealy detection of ovarian cancer but this is still an emerging proof.
• Examples of screening and diagnostic methods for ovarian cancer include:^[3]
  • Pelvic examination
  • Cancer antigen 125 (CA 125) tumor marker
  • Transvaginal ultrasound (TVU)
  • Multimarker panels and bioinformatic analysis of proteomic patterns
• The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)is evaluating a multimodal screening strategy (MMS) efficacy which consists of:
  • Annual CA125 screening, risk of ovarian cancer algorithm (ROCA), TVU
• Patients with family history of ovarian cancer or breast cancer can have ovarian cancer hereditary syndrome as breast-ovarian cancer syndrome which is associated with
  • BRCA1 and BRCA2 gene mutations
  • Lynch II syndrome
• Should undergo the following screening:
  • Annual rectovaginal pelvic examinations
  • CA125
  • TVU until completing childbearing or until age 35 years at least, where at this point prophylactic bilateral oophorectomy is recommended

Ovarian cancer is often diagnosed late resulting in a poor overall outcome for the patient. Ovarian cancer complications can be spread of cancer to other organs, progressive function loss of various organs, ascites (fluid in the abdomen), intestinal obstruction. Ovarian cancer has a poor prognosis. 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 cancer is often diagnosed late resulting in a poor overall outcome for the patient.

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

• Ovarian cancer has a poor prognosis. It is disproportionately deadly because symptoms are vague and non-specific, hence diagnosis is late. 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 that are malignant 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, lining of the bowel wall (omentum) and can even spread to the lungs. These cells can begin forming new tumor growths before cancer is even suspected.
• More than 50% of women with ovarian cancer are diagnosed in the advanced stages of the disease because no cost-effective screening test for ovarian cancer exists.
• The five year survival rate for all stages is only 35% to 38%. If, however, diagnosis is made early in the disease, five-year survival rates can reach 90% to 98%.
• 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.

• Between 2004 and 2010, the 5-year relative survival of patients with ovarian cancer was 44.6%.^[1]

• When stratified by age, the 5-year relative survival of patients with ovarian cancer was 57.5% and 27.3% for patients <65 and ≥ 65 years of age respectively.^[1]

• The survival of patients with ovarian cancer varies with the stage of the disease. Shown below is a table depicting the 5-year relative survival by the stage of ovarian cancer:^[1]

• Shown below is an image depicting the 5-year conditional relative survival (probability of surviving in the next 5-years given the cohort has already survived 0, 1, 3 years) between 1998 and 2010 of ovarian cancer by stage at diagnosis according to SEER.
• These graphs are adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.^[1]

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