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Introduction
Ovarian cancer is a type of cancer that begins in the ovaries.
Epidemiology
Approximately 1.1% of
women will be diagnosed with ovarian cancer at some point. In 2022, ovarian
cancer accounted for 324,603 new cases, claiming 206,956 lives. The risk of ovarian cancer is noted to be highest in
high-income countries but is also noted to be rising disproportionately in
low-income countries. It is the second most
common gynecologic malignancy in high-income countries and the third most
common malignancy in low- to middle-income countries (cervical cancer being the
most common). It is important to note that
ovarian cancer is the most lethal female cancer, with a 5-year survival rate of
roughly 49%. Although survival is longer for
select patients with early disease and certain histological subtypes. It is the leading cause of death from gynecologic
cancer-related deaths. The median age at the time of diagnosis is 63 years and
>70% present with advanced disease.
Among the different continents, Asia has the highest incidence of
ovarian cancer, having as many as 178,223 new cases in 2022. The continent also
saw the highest mortality rate, with 109,547 deaths. In the Philippines, there
were 6,453 new cases in 2022, with 4,073 deaths.
Pathophysiology
Ovarian endometroid carcinomas have been suggested to be derived from endometriosis. The mutation of the beta-catenin gene is one of the most common molecular abnormalities observed in ovarian endometroid carcinomas. These tumors also exhibit high levels of microsatellite instability. Another subtype that is associated with endometriosis is ovarian clear cell carcinoma. Just like ovarian endometroid carcinoma, ovarian clear cell carcinoma has also shown significant microsatellite instability. Ovarian mucinous tumors may be endocervical-like or intestinal-like. It is noteworthy that KRAS mutations are common in these tumors as well as several mucin genes (eg MUC2, MUC3, MUC17), characteristic of mucinous carcinomas regardless of their origin.
In the case of ovarian sex-cord stromal cancers, they arise from cells that typically would become specialized gonadal stroma that surrounds the oocytes, including granulosa cells, theca cells, Sertoli cells, Leydig cells, and fibroblasts. Lastly, ovarian germ cell tumors are histologically diverse but have a common origin in the primitive germ cell.
Etiology
The etiology of
ovarian cancer remains poorly understood; however, the source of epithelial
ovarian cancer has become a matter of controversy. All ovarian cancer was
initially thought to arise from ovarian surface epithelium. The theory of
incessant ovulation presupposes that repetitive involvement of the ovarian
surface in the process of ovulation is a risk factor for ovarian cancer. As a
female ages, ovulation occurs repeatedly, leading to repetitive trauma or
injury to the epithelium, ultimately causing cellular DNA damage, and upon
exposure to ovarian hormones, these cells with DNA damage are transformed into
cancer cells. However, evidence has accumulated that shows that many epithelial
ovarian cancers originate from the distal fallopian tube. Indeed, epithelial
dysplasia resembling HGSCs was found in high incidence in those fallopian tubes
of women with BRCA1/2 mutations undergoing prophylactic
salpingo-oophorectomy and those with a strong family history of ovarian cancer.
This epithelial dysplasia, called tubal intraepithelial carcinoma (TIC),
demonstrated high levels of TP53 mutations. Later, similar lesions were
also found in as much as 60% of cases of sporadic ovarian carcinomas. Yet these
precursor lesions are not found in nonserous ovarian cancers, implying a
different mechanism, such as endometriosis. Though the exact mechanism is yet
to be explained, endometriosis has been associated with ovarian cancer
particularly the endometroid and clear cell types.
Ovarian cancer can be part of an inherited site-specific familial ovarian
cancer condition (2 or more first-degree relatives having ovarian cancer), a
breast-ovarian cancer syndrome (clusters of breast and ovarian cancer among
first- and second-degree relatives), or Lynch syndrome.
Risk Factors
Increased
Risk
A family history of cancer is associated with early-onset
disease. Patients having ≥2 first-degree relatives with ovarian cancer increase
the risk for ovarian cancer. A family history of male breast cancer, bilateral
or early-onset (<50 years old) breast cancer, and a personal or family
history of colon, ovarian, or endometrial cancer also increases the risk.
Genetic syndromes are also associated with
early-onset disease. BRCA1 and BRCA2 mutations have an absolute
lifetime risk of 39-58% and 13-29% of developing ovarian cancer,
respectively. PALB2 mutations have an absolute risk of 3-5% of
developing ovarian cancer. BRIP1, RAD51C,
and RAD51D mutations have an absolute risk of >10% of developing
ovarian cancer. MLH1 and MSH2 mutations have an absolute risk
of >10% of developing epithelial ovarian cancer. Lynch syndrome (hereditary
nonpolyposis colorectal cancer) has a lifetime risk of 10%. Cowden’s disease
has an increased risk of ovarian cancer due to mutations in the PTEN gene. Peutz-Jeghers
syndrome secondary to mutations in the STK11 gene and MUTYH-associated
polyposis secondary to mutations in gene MUTYH are both associated with
increased risk for ovarian cancer.
The risk of developing ovarian cancer gets higher with
age and is most prevalent in the eighth decade of life. Reproductive history such
as nulliparity or age >35 years at first childbirth, early menarche, and late
menopause likewise increases the risk of ovarian cancer. A personal history of
breast cancer or epithelial ovarian cancer also increases the risk of ovarian
cancer. The risk of ovarian cancer after breast cancer is highest in women with
a family history of breast cancer. Obese
women with a body mass index of at least 30 kg/m2 have a higher risk
of developing ovarian cancer. Pelvic inflammatory disease (PID) may also
increase the risk for ovarian cancer. Smoking is associated with an increased
risk for mucinous carcinomas.
Some studies show that using the fertility drug
Clomiphene citrate for >1 year increased the risk of developing low
malignant-potential ovarian tumors. The risk was shown to be highest in women
who did not get pregnant while receiving the drug. Studies have shown that
postmenopausal women using Estrogen monotherapy for at least 5-10 years have
a higher risk of developing ovarian cancer. The risk of borderline ovarian
cancer may be increased after ovarian stimulation for in vitro fertilization
(IVF). A study had shown that women who took androgens were found to have a
higher risk of ovarian cancer. Some studies suggest a very slight increase in the
risk of ovarian cancer in women who used talc on their genital area.
Decreased Risk
A history of being at a younger age at pregnancy and
at first childbirth (≤25 years old) has a 30-60% lower risk of developing
ovarian cancer. Oral contraceptive use
for >5 years significantly lowers the risk of ovarian cancer. Breastfeeding
has a 30-60% lower risk. A study has shown that a low-fat diet for at least 4
years had a lower risk for ovarian cancer. Gynecologic surgery (eg
hysterectomy, prophylactic oophorectomy, tubal ligation) also decreases the
risk of ovarian cancer. Tubal ligation may reduce the chance of developing
ovarian cancer by up to 67%. Smoking is associated with decreased risk for
clear cell carcinoma.
Classification
Ovarian cancer has 3 histologic types which are as follows:
- Epithelial ovarian cancer which is primarily seen in women >50 years of age and is seen in >90% of patients with ovarian neoplasms
- Germ cell ovarian cancer which is more commonly seen in women <20 years of age
- Sex cord-stromal ovarian cancer which is rare and produces steroid hormones
Less common ovarian histopathologies (LCOH) include the following:
- Carcinosarcomas - malignant mixed Müllerian tumors of the ovary
- Clear cell carcinomas
- Mucinous carcinomas
- Low grade or grade 1 serous carcinomas or endometrioid epithelial carcinomas
- Borderline epithelial tumors which are also known as low malignant-potential tumors
Integrating histological, clinical, genetic,
and molecular findings, several groups have established 2 distinct types of
ovarian epithelial carcinoma, type I and type II.
Type I ovarian cancer consists of LGSCs,
mucinous, endometroid, clear cell, and transitional histology types. These
tumors are often in the early stage, low-grade (except for clear cell types
which are considered high-grade), have a relatively indolent course, are
usually diagnosed early, and carry a good prognosis. These tumors are
characterized by KRAS, BRAF, ERBB2, CTNNB1, PTEN, PIK3CA, ARID1A, PPP2R1A, and
BCL2 mutations.
On the other hand, type II ovarian
tumors include HGSCs, carcinosarcoma, and undifferentiated carcinoma. These
tumors are high-grade tumors, have high proliferative activity with rapid and
aggressive progression, and are almost always advanced in stage. Type II
ovarian cancers have high genetic instability with a high rate of TP53
mutations in a lot of cases.