OVARIAN CANCER: A DETAILED REVIEW
Ovarian cancer is a heterogeneous disease that can develop from different cell types in the ovaries and adjacent tissues, including the fallopian tubes and peritoneum.
Pathogenesis involves genetic mutations, chronic inflammation, hormonal influences, and environmental factors that promote uncontrolled cell proliferation and malignant transformation.
It is most often diagnosed in the later stages due to the lack of pronounced symptoms in the early stages.
It is one of the most deadly types of gynecological cancer due to its late detection and rapid progression.
1. ETIOLOGY
Ovarian cancer has a multifactorial nature, including genetic predisposition, chronic inflammation and infections, hormonal and environmental factors.
Main risk factors:
Genetic mutations (BRCA1/BRCA2)
Family history of ovarian, breast, or colorectal cancer
Hormonal factors (early menstruation, late menopause, hormone replacement therapy)
Endometriosis
Chronic inflammation of the pelvic organs
Obesity and high fat diets
Absence of births (nullparity)
Use of talc (controversial but researched factor)
2. GENETICS OF OVARIAN CANCER
Ovarian cancer has a strong genetic component, with inherited mutations associated with approximately 10-15% of cases. Key genetic factors include:
A. BRCA1 and BRCA2 mutations
BRCA1: increases the risk of ovarian cancer by 39-46%.
BRCA2: increases risk by 12-20%.
These genes are involved in DNA repair through the mechanism of homologous recombination.
Their mutations cause genomic instability, promoting carcinogenesis.
B. TP53 mutations
They are detected in 95% of high-grade serous carcinomas.
Loss of TP53 function results in uncontrolled cell proliferation.
C. Mutations in DNA mismatch repair genes (Lynch syndrome)
Mutations in MLH1, MSH2, MSH6, PMS2 increase the risk of colorectal and ovarian cancer.
D. Mutations in PTEN, KRAS, BRAF (found in low-grade ovarian cancer).
PTEN: a tumor suppressor whose dysfunction leads to tumor growth.
KRAS/BRAF: common in mucinous ovarian cancer.
E. Changes in the number of gene copies
Frequent amplifications of MYC, CCNE1, and PIK3CA promote tumor growth.
3. PATHOGENESIS OF OVARIAN CANCER
Ovarian cancer has a multifactorial nature, including genetic predisposition, chronic inflammation and infections, hormonal and environmental factors.
EPITHELIAL OVARIAN CANCER (EOC) – ~90% OF CASES
It arises from the superficial epithelium of the ovaries or the epithelium of the fallopian tubes.
Includes serous, mucinous, endometrioid and clear cell carcinomas.
4. OVARIAN CANCER SUBTYPES
A. High-grade serous carcinoma (HGSOC)
The most common (~70%) and aggressive.
It arises from the epithelium of the fallopian tubes.
TP53 is mutated in almost all cases.
B. Low-grade serous carcinoma
Rare, slow growing.
Often associated with KRAS and BRAF mutations.
C. Endometrioid and clear cell carcinoma
Associated with endometriosis.
ARID1A, PTEN – common mutations.
D. Mucinous carcinoma
Rare, can be confused with metastases from the gastrointestinal tract.
KRAS is the main mutated gene.
5. STAGES OF DEVELOPMENT OF EPITHELIAL OVARIAN CANCER
Initially: Genetic and epigenetic changes including primary genetic mutations, genomic instability and impairment of DNA repair mechanisms.
Hormonal factors and microenvironmental factors can be promoters of oncogenesis.
Tumor progression and metastasis occur through local invasion (the tumor spreads within the ovary).
Next comes peritoneal dissemination, that is, the cancer metastasizes through direct shedding of cells into the abdominal cavity.
In addition, tumor cells can be implanted on the peritoneum, omentum, and intestines.
Further spread occurs through the lymphogenous and hematogenous routes, which leads to the appearance of metastases in the lymph nodes, liver, lungs, brain, etc.
However, recent studies show that many high-grade serous carcinomas (HGSOC) arise from the epithelium of the fallopian tubes rather than from the surface of the ovaries.
6. OTHER OVARIAN TUMORS
A. GERM CELL TUMORS (~5-10%)
- Develop from germ cells.
- Includes dysgerminomas, yolk sac tumors and teratomas.
- More common in young women.
B. SEX CORD STROMAL TUMORS (~5%)
- They originate from hormone-producing cells of the ovaries.
- Includes granulosa cell tumors and Sertoli-Leydig tumors.
7. TWO TYPES OF OVARIAN CANCER DEVELOPMENT
Type I (slow growth, gradual progression):
- Includes serous low-grade, mucinous, endometrioid and clear cell carcinomas.
- Associated with mutations of KRAS, BRAF, PTEN, ARID1A.
- Develops from borderline tumors or endometriosis.
Type II (aggressive, high mutation load):
- Includes high grade serous carcinoma
(HGSOC).
- TP53, BRCA1/2 mutations.
- Probably arises from the epithelium of the fallopian tubes.
8. THE ROLE OF INFECTIONS AND INFLAMMATION IN THE PATHOGENESIS OF OVARIAN CANCER
Chronic infections and inflammation may promote carcinogenesis.
Inflammatory and infectious diseases of the pelvic organs:
- Chronic inflammation and infection (Chlamydia trachomatis, Mycoplasma
genitalium) increases the level of cytokines and oxidative stress.
- Chlamydia trachomatis: causes chronic inflammation and damage
DNA.
- Helicobacter pylori: may have an indirect effect through
systemic inflammation.
- Long-term inflammation can lead to DNA damage and
malignant transformation.
Endometriosis-associated ovarian cancer (endometriosis increases the risk
clear cell and endometrioid cancer):
Mechanism of development and progression:
- Chronic inflammation → increased oxidative stress.
- Hormonal imbalance → excess estrogen stimulates
proliferation.
- Immune evasion → endometriotic lesions escape the immune system
elimination.
Viral infections:
- HPV and Epstein-Barr virus (EBV) were detected in tumor tissues
ovaries.
- Human endogenous retroviruses (HERVs) have been detected in tumor tissues
ovaries and may participate in tumor progression.
9. ARTICLES SHOWING THE CONNECTION BETWEEN INFECTIONS, INFLAMMATION AND
OVARIAN CANCER
1. Xie X, Yang M, Ding Y, Chen J. Microbial infection, inflammation and epithelial
ovarian cancer. Oncol Lett. 2017 Aug;14(2):1911-1919. doi:
10.3892/ol.2017.6388. Epub 2017 Jun 15. PMID: 28789426; PMCID:
PMC5529868.
2. Pathak S, Wilczyński JR, Paradowska E. Factors in Oncogenesis: Viral Infections
in Ovarian Cancer. Cancers (Basel). 2020 Feb 29;12(3):561. doi:
10.3390/cancers12030561. PMID: 32121320; PMCID: PMC7139377.
3. Jonsson, Sarah et al. Pelvic inflammatory disease and risk of epithelial ovarian
cancer: a national population-based case-control study in Sweden. American
Journal of Obstetrics & Gynecology, 2024. Volume 230, Issue 1, 75.e1 - 75.e15
4. Fortner, RT, Terry, KL, Bender, N. et al. Sexually transmitted infections and risk
of epithelial ovarian cancer: results from the Nurses' Health Studies. Br J Cancer
120, 855–860 (2019). https://doi.org/10.1038/s41416-019-0422-9
5. Pathak S, Wilczyński JR, Paradowska E. Factors in Oncogenesis: Viral Infections
in Ovarian Cancer. Cancers (Basel). 2020 Feb 29;12(3):561. doi:
10.3390/cancers12030561. PMID: 32121320; PMCID: PMC7139377.
10. SYMPTOMS OF OVARIAN CANCER
A. GERM CELL TUMORS (~5-10%)
- Develop from germ cells.
- Includes dysgerminomas, yolk sac tumors and teratomas.
- More common in young women.
B. SEX CORD STROMAL TUMORS (~5%)
- They originate from hormone-producing cells of the ovaries.
- Includes granulosa cell tumors and Sertoli-Leydig tumors.
10. SYMPTOMS OF OVARIAN CANCER
Ovarian cancer is known as the "silent killer" because it has no obvious symptoms:
It is necessary to pay constant attention to:
- Bloating
- Pain in the pelvic area
- Frequent urination
- Unexplained weight loss
- Fatigue
- Menstrual cycle disorders
11. FORECAST
Five-year survival rate:
Stage I: ~90%
Stage II: ~70%
Stage III: ~39%
Stage IV: <20%
12. FACTORS INFLUENCING THE PROGNOSIS
- Stage at the time of diagnosis
- Histological subtype
- BRCA1/2 mutations (BRCA tumors respond better to PARP inhibitor therapy)
- Sensitivity to chemotherapy
13. TREATMENT
Surgery
- Debulking – removal of the uterus, ovaries, omentum, lymph nodes.
Chemotherapy
- Carboplatin + Paclitaxel is a standard regimen.
- PARP inhibitors (Olaparib, Niraparib) – for BRCA mutations.
- Bevacizumab (anti-VEGF therapy) – for advanced stages.
Immunotherapy
- Checkpoint inhibitors (Pembolizumab) – for MSI-H tumors.
Adjuvant therapy
- Some studies show that anti-inflammatory
drugs such as aspirin may reduce the risk of ovarian cancer, and
some treatments, such as chemotherapy, may help
cope with symptoms associated with inflammation.
Supportive therapy
- Treating cancer while reducing the risk of infection
prophylactic antibiotics and longer follow-up after
treatment.
14. PREVENTION
- Reduce repeated ovulation cycles with high quality
contraceptives.
- Prophylactic oophorectomy – for BRCA1/2 carriers.
- Tubal ligation – reduces the risk.
- Reduction of chronic inflammation