Ovarian Carcinoma: A Clinical Review
Definition
Ovarian carcinoma represents a complex and diverse group of malignant tumors affecting the female reproductive system. For decades, these cancers were understood to originate exclusively from the cellular components of the ovary itself. However, a significant paradigm shift has reshaped our understanding, particularly regarding the most common and lethal form, High-Grade Serous Carcinoma (HGSC). Compelling evidence now indicates that a majority of these cases do not start in the ovary but actually arise from extra-ovarian tissues, most notably the secretory cells in the fimbrial (finger-like) end of the fallopian tube. These malignant precursor cells, known as Serous Tubal Intraepithelial Carcinoma (STIC), can exfoliate and subsequently implant onto the surface of the adjacent ovary and peritoneum, which then become the secondary, and often more prominent, sites of disease (1, 2). This distinction is fundamental for the modern clinician as it reframes the entire approach to pathogenesis, risk-reducing surgery (e.g., prophylactic salpingectomy), and future screening strategies.
Despite the evolving understanding of its origin, the classification of ovarian neoplasms remains rooted in their histological cell type, which reflects their line of differentiation and dictates their biological behaviour. Ovarian tumours are broadly categorised based on their origin from one of three primary cell types:
Epithelial Tumours: This is the most prevalent category, accounting for a dominant 85-95% of all malignant ovarian tumours and the vast majority of deaths. These cancers arise from the coelomic epithelium lining the ovary or from tubal epithelial cells. This category is further subdivided into distinct histotypes such as serous, mucinous, endometrioid, and clear cell carcinomas, each with unique clinical and molecular features (1).
Germ Cell Tumours: Accounting for about 5% of ovarian malignancies, these tumours arise from the primordial germ cells destined to form ova. They characteristically affect adolescents and young women (typically under 30 years old), are often highly sensitive to chemotherapy, and generally have an excellent prognosis. Examples include dysgerminoma, teratoma, and yolk sac tumour (4).
Sex Cord-Stromal Tumours: Also comprising about 5% of ovarian malignancies, these tumours develop from the connective tissues (stroma) and hormone-producing cells (sex cords) of the ovary. They are often functionally active, secreting oestrogens or androgens, which can lead to distinct clinical syndromes like postmenopausal bleeding or virilization. Granulosa cell tumours and Sertoli-Leydig cell tumours are key examples (4).
Epidemiology
Malaysian Context
Understanding the local epidemiology is paramount for contextualising the disease within the national healthcare system. According to the Malaysia National Cancer Registry (MNCR) Report for 2017-2021, ovarian cancer represents a significant public health burden:
It is the 10th most common cancer among Malaysians overall.
Crucially, it is the fifth most common cancer among women, following breast, colorectal, lung, and corpus uteri cancer (28, 29).
The disease has an age-standardised incidence rate (ASR) of 6.2 per 100,000 population in Malaysia (30).
The most alarming statistic, however, is the critically high rate of late-stage diagnosis, which is the primary driver of poor survival outcomes locally. The MNCR report revealed a worsening trend: 65.1% of ovarian cancer cases were diagnosed at an advanced stage (FIGO Stage III or IV), an increase from 63.7% in the preceding 2012-2016 period (28). This "lethality gap"—the disparity between its incidence rank and its mortality impact—is a direct consequence of this delayed presentation. This trend may reflect a combination of low public awareness of the vague symptoms, diagnostic delays in primary care where symptoms are often mistaken for more common benign conditions, and the lack of a streamlined referral pathway for women with a suspicious adnexal mass.
Global Context
Globally, ovarian cancer is the 18th most frequently diagnosed cancer but the 14th leading cause of cancer-related death in women, a disparity that starkly underscores its high case-fatality rate. The GLOBOCAN 2022 data estimated over 324,000 new cases and nearly 207,000 deaths worldwide (26). Incidence rates are highest in more developed regions, likely reflecting a combination of genetic predispositions and lifestyle factors. However, due to population size, Asia bears the largest burden, accounting for over half of all cases and deaths globally.
Etiology and Risk Factors
The development of ovarian cancer is multifactorial, involving a complex interplay of genetic predisposition, hormonal influences, and environmental factors.
Key Risk Factors
Genetic Predisposition (Strongest Risk): Inherited genetic mutations are the single most significant risk factor, accounting for up to 25% of all cases. Identifying these high-risk individuals is a critical clinical task (39).
BRCA1/2 Mutations: Germline mutations in these tumour suppressor genes, which are essential for high-fidelity DNA double-strand break repair, confer the highest risk. Women with a BRCA1 mutation face a staggering lifetime risk of 35-70%, while those with a BRCA2 mutation have a 10-30% lifetime risk (40).
Lynch Syndrome (HNPCC): Caused by inherited mutations in DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2), this syndrome confers a ~10% lifetime risk of ovarian cancer, typically the endometrioid or clear cell subtypes (5).
Advancing Age: Age is the most important non-hereditary risk factor. The risk rises sharply after menopause, with a median age at diagnosis of 63 years (19).
Reproductive History: Factors linked to the "incessant ovulation" theory, which posits that repetitive ovulatory cycles cause micro-trauma and inflammation to the ovarian/tubal epithelium, increasing the chance of malignant transformation. This includes nulliparity (never giving birth), early menarche, and late menopause (1, 6).
Endometriosis: This condition, where endometrial-like tissue grows outside the uterus, creates a chronic inflammatory environment. This is a potent risk factor for the development of endometrioid and clear cell carcinomas (6).
Obesity: A body mass index (BMI) of 30 kg/m² or greater is associated with a higher risk of developing ovarian cancer and poorer survival outcomes (18).
Smoking: While not increasing the overall risk for all types, smoking is specifically and strongly linked to an increased risk of the mucinous subtype of epithelial ovarian cancer (18).
Protective Factors
Oral Contraceptive Pills (OCPs): Use of combined OCPs is a highly effective protective measure, reducing the lifetime risk by 30-50%. This effect is achieved by suppressing ovulation, thereby reducing the inflammatory cycles associated with it. The protection is long-lasting, persisting for decades after discontinuation (18, 40).
Pregnancy and Breastfeeding: Both are protective as they induce long periods of anovulation (6).
Gynaecological Surgery: Procedures like tubal ligation and hysterectomy significantly reduce risk. This finding strongly supports the fallopian tube origin theory, as these surgeries create a mechanical barrier, preventing carcinogenic cells or inflammatory agents from the upper genital tract from reaching the ovary and peritoneum (6).
Pathophysiology
The dualistic model provides an essential framework for understanding the distinct biological pathways of epithelial ovarian cancer (EOC):
Type I Tumours (~25% of EOCs):
This group includes low-grade serous, endometrioid, clear cell, and mucinous carcinomas.
They are defined by a slow, stepwise progression from identifiable benign precursors (e.g., a serous cystadenoma progresses to a borderline tumour, then to a low-grade carcinoma).
Consequently, they are often diagnosed at an early, organ-confined stage and are characterized by relative genetic stability.
Their molecular landscape is defined by the general absence of TP53 mutations but the presence of specific activating mutations in oncogenes like KRAS, BRAF, and PIK3CA, or inactivating mutations in tumour suppressors like ARID1A (1).
Type II Tumours (~75% of EOCs):
This group is overwhelmingly dominated by High-Grade Serous Carcinoma (HGSC), the most common and lethal subtype.
In stark contrast to Type I, these tumours are defined by rapid, aggressive development and profound genetic instability. They appear to arise de novo from precursor lesions like STIC in the fallopian tube, without a recognizable intermediate stage.
They almost invariably present at an advanced stage (III/IV) with widespread peritoneal spread.
The universal molecular hallmark is a mutation of the TP53 tumour suppressor gene (>95%). Loss of this "guardian of the genome" allows cells with damaged DNA to proliferate uncontrollably. Furthermore, ~50% of HGSCs exhibit Homologous Recombination Deficiency (HRD)—a defect in the cell's ability to repair double-strand DNA breaks, most commonly due to BRCA1/2 mutations. This defect, while driving carcinogenesis, also creates a key therapeutic vulnerability known as "synthetic lethality" when treated with PARP inhibitors (1, 13).
The primary mode of spread is transcoelomic dissemination. Cancer cells exfoliate from the primary tumour and are carried throughout the abdomen by the natural flow of peritoneal fluid. These cells then implant on peritoneal surfaces, especially the omentum, a fatty apron of tissue that provides a rich energy source for metastatic tumour cells, fuelling their rapid growth into a confluent mass known as an "omental cake" (13).
Clinical Presentation
The classic description of ovarian cancer as a "silent killer" is a dangerous misnomer. While it lacks specific early signs, over 90% of women are symptomatic in the months leading up to their diagnosis (45). The clinical challenge is that these symptoms are vague, non-specific, and easily misattributed to more common benign conditions. The key is to recognise a symptom complex defined by its persistence, frequency (>12 times per month), and recent onset (43).
Common Symptoms
Bloating or Increased Abdominal Girth: One of the most common symptoms, reported by ~75% of women. This is not simple gas but a persistent feeling of fullness or visible swelling caused by the physical bulk of the tumour, the accumulation of malignant fluid (ascites), or the development of an omental cake (14).
Pelvic or Abdominal Pain: Often described as a dull, constant ache or persistent pressure rather than a sharp pain. It results from the tumour mass compressing adjacent organs or stretching the ovarian capsule (14).
Early Satiety or Difficulty Eating: This symptom arises from the tumour or ascites compressing the stomach, reducing its capacity and leading to a feeling of fullness after eating only a small amount of food (43).
Urinary Symptoms: Increased urinary frequency or urgency is common and results from direct pressure of the pelvic mass on the bladder (19).
⚠️ Red Flag Signs & Symptoms
The presence of the above symptom complex—especially when occurring together in a postmenopausal woman or persisting for several weeks in a premenopausal woman—is a major red flag. It is critical to understand that the onset of these classic symptoms often signifies advanced disease (Stage III/IV). Therefore, the goal of acting on them is not necessarily to find a rare Stage I cancer, but to diagnose the existing advanced-stage cancer as expeditiously as possible to initiate treatment (44).
Physical Examination Findings
Abdominal Exam: Should be inspected for distension and palpated for any masses, tenderness, or a hard, fixed "omental cake." Percussion may reveal shifting dullness, a sign of ascites.
Pelvic Exam: A comprehensive bimanual pelvic examination is mandatory. An adnexal mass that is solid, irregular, fixed (non-mobile), and bilateral is highly suspicious of malignancy. A rectovaginal examination is essential to assess for nodularity in the pouch of Douglas (cul-de-sac), a classic sign of metastatic peritoneal deposits (23).
Investigations
First-Line Investigations
Serum CA-125: This is a crucial initial blood test but must be interpreted with caution. It is not a standalone diagnostic tool, as it can be elevated in many benign conditions (endometriosis, fibroids, pelvic inflammatory disease) and, importantly, it may be within the normal range in up to 50% of early-stage ovarian cancers and is often not elevated in mucinous or germ cell tumours (23).
Pelvic Ultrasound: This is the primary imaging modality for evaluating the adnexa. A transvaginal scan (TVS) is preferred for its superior resolution. The sonographer assesses the ovaries for features suggestive of malignancy, including a complex mass with both solid and cystic components, thick septations (>3 mm), papillary projections, the presence of ascites, and increased vascularity on Doppler flow studies (36).
Risk Stratification and Referral
Risk of Malignancy Index (RMI): This scoring system is superior to CA-125 alone for risk assessment. It incorporates the ultrasound score, menopausal status, and the CA-125 level to generate a risk score. A high RMI (typically >200-250) indicates a high probability of malignancy and mandates an urgent referral to a gynaecologic oncology centre. Management by a specialist from the outset is proven to improve outcomes through more accurate staging and higher rates of optimal cytoreduction (23).
Definitive Diagnostic and Staging Workup
CT Scan (Chest, Abdomen, Pelvis): This is the standard imaging modality for staging. It provides a roadmap for the surgeon, detailing the size of the pelvic mass, the extent of peritoneal and omental disease, the status of retroperitoneal lymph nodes, and the presence of distant metastases, which is critical for surgical planning (6).
Histopathological Confirmation: The definitive diagnosis of cancer can only be made by examining tissue. This is obtained via:
Surgical Staging (Laparotomy): This is the gold standard for presumed resectable disease. It is both a diagnostic and therapeutic procedure, involving a systematic exploration including peritoneal fluid cytology, inspection and biopsy of all peritoneal surfaces, a total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO), an omentectomy, and sampling of pelvic and para-aortic lymph nodes. This is the only way to accurately determine the cancer's stage (53).
Image-Guided Biopsy: In patients with extensive disease deemed unresectable or those who are medically unfit for major surgery, a CT- or ultrasound-guided core biopsy of an accessible metastatic deposit (e.g., omentum) is used to confirm the diagnosis before starting neoadjuvant chemotherapy (23).
Molecular Testing: As per modern guidelines, this is mandatory for all patients with high-grade, non-mucinous ovarian cancer at diagnosis. This includes testing for both germline and somatic BRCA1/2 mutations and for Homologous Recombination Deficiency (HRD). These results are not just prognostic; they are predictive and essential for determining eligibility for first-line maintenance therapy with PARP inhibitors (8).
Management
Management is complex, requiring a multidisciplinary team (MDT), and is guided by FIGO stage, histology, performance status, and molecular profile.
Early-Stage Disease (Stage I-IIA)
Surgery: Comprehensive surgical staging is the cornerstone of treatment. The goal is to accurately stage the disease and resect the tumour (55). For highly selected young patients with Stage IA or IC, Grade 1 tumours who wish to preserve fertility, a fertility-sparing surgery (unilateral salpingo-oophorectomy with full staging) may be considered (54).
Adjuvant Chemotherapy: Recommended for all except fully staged Stage IA/IB Grade 1 tumours to eliminate microscopic residual disease. The standard regimen is intravenous (IV) Carboplatin and Paclitaxel for 3 to 6 cycles (8).
Advanced-Stage Disease (Stage IIB-IV)
The paramount goal is optimal cytoreduction, defined as removing all visible tumour to achieve no residual disease (R0 resection). This is the most powerful surgeon-controlled prognostic factor.
Primary Debulking Surgery (PDS): This is the preferred approach for patients who are medically fit and whose disease appears resectable. This often requires aggressive procedures like bowel resection or diaphragm stripping. Surgery is followed by 6 cycles of Carboplatin and Paclitaxel (54).
Neoadjuvant Chemotherapy (NACT): This approach is reserved for patients with very high-volume disease where R0 resection is deemed unlikely, or for those with poor performance status. Patients receive 3-4 cycles of NACT, and if they respond, they undergo interval debulking surgery (IDS), followed by more chemotherapy. This approach has been shown to have non-inferior survival with lower surgical morbidity in appropriately selected patients (54).
First-Line Maintenance Therapy
This represents a new standard of care, administered to patients in remission after primary chemotherapy to delay or prevent recurrence.
PARP Inhibitors (e.g., Olaparib, Niraparib): These drugs induce synthetic lethality in cancer cells with HRD. Their use is guided by biomarker status:
BRCA-mutated patients: Maintenance with a PARP inhibitor offers a profound and durable improvement in progression-free survival and is the standard of care (8).
HRD-positive patients: Also derive substantial benefit and should be offered a PARP inhibitor (8).
Bevacizumab (Anti-VEGF): This anti-angiogenic agent can be added to chemotherapy and continued as maintenance for up to 15 months. It provides a modest but significant survival benefit and is an option for patients with high-risk disease (8).
Management of Recurrent Disease
Most women with advanced disease will eventually recur. Management is guided by the platinum-free interval (PFI)—the time from completion of platinum therapy to recurrence.
Platinum-Sensitive (PFI > 6 months): The tumour is considered still sensitive to platinum. Treatment is re-treatment with a platinum-based doublet. Maintenance with a PARP inhibitor after achieving a response is a powerful strategy to prolong this remission, especially for BRCA-mutated patients (15).
Platinum-Resistant (PFI < 6 months): The tumour has a poor prognosis and is unlikely to respond to platinum again. The goal of treatment is palliative. Therapy consists of sequential single-agent, non-platinum chemotherapy (e.g., pegylated liposomal doxorubicin, weekly Paclitaxel) with or without bevacizumab to control symptoms and maintain quality of life (54).
Palliative Care
Palliative care is an essential component of management, focused on improving quality of life by preventing and relieving suffering. It should be integrated early for any patient with symptomatic advanced disease.
Malignant Ascites: This can cause severe bloating, pain, and shortness of breath. Management includes repeated therapeutic paracentesis for rapid relief or the placement of indwelling peritoneal catheters (e.g., PleurX™) to allow for regular, intermittent drainage at home, which significantly improves quality of life (62).
Malignant Bowel Obstruction (MBO): A common and distressing late-stage complication. For non-surgical candidates, medical management with antisecretory agents (e.g., octreotide), steroids, and antiemetics is key. A venting gastrostomy tube can relieve nausea and vomiting. In select patients, surgical bypass or endoscopic stenting may be considered (62).
References
Ovarian cancer - Wikipedia. (n.d.).
Kurman, R. J., & Shih, I. M. (2010). The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. The American journal of surgical pathology, 34(3), 433–443.
Poliklinika Harni. (n.d.). The Origin and Pathogenesis of Epithelial Ovarian Cancer: A Proposed Unifying Theory.
GynecolOncol. (n.d.). Ovarian Cancer: Types and Histology.
Lisio, A., et al. (2024). Ovarian Cancer—Epidemiology, Classification, Pathogenesis, Treatment, and Estrogen Receptors' Molecular Backgrounds. International Journal of Molecular Sciences, 26(10), 4611.
Pantai Hospitals. (n.d.). Ovarian Cancer: Types, Symptoms, Diagnosis, Treatment.
Momenimovahed, Z., et al. (2022). The Evolution of Ovarian Carcinoma Subclassification. Cancers, 14(3), 565.
Okamoto, A., et al. (2024). Pan-Asia adapted ESMO Clinical Practice Guideline for the management of patients with newly diagnosed and relapsed epithelial ovarian cancer. Annals of Oncology.
Johns Hopkins Pathology. (n.d.). Types of Ovarian Tumors.
Le, N. D., et al. (2014). Biomarker-based ovarian carcinoma typing: a histological investigation in the Ovarian Tumor Tissue Analysis consortium. Cancer Epidemiology, Biomarkers & Prevention, 23(5), 794-804.
Reid, B. M., et al. (2017). Epidemiology of ovarian cancer: a review. Cancer Biology & Medicine, 14(1), 9–32.
Libre Pathology. (n.d.). Ovarian tumours.
Tan, D. S., et al. (2017). The Unique Molecular and Cellular Microenvironment of Ovarian Cancer. Frontiers in Oncology, 7, 24.
Di Lorenzo, G., et al. (2024). Early Diagnosis of Ovarian Cancer: A Comprehensive Review of the Advances, Challenges, and Future Directions. Diagnostics, 15(4), 406.
National Cancer Institute. (n.d.). Ovarian Epithelial, Fallopian, & Peritoneal Cancer Treatment (PDQ®)–Health Professional Version.
Cancer Research UK. (n.d.). Risks and causes of ovarian cancer.
Cleveland Clinic. (n.d.). Ovarian Cancer: Symptoms, Diagnosis & Treatment.
Cancer Research UK. (n.d.). Tests for ovarian cancer.
World Cancer Research Fund. (n.d.). Ovarian cancer statistics.
CodeBlue. (2024). Late-Stage Cancer Detection Rises To 65%: Malaysia's New Cancer Registry.
The Malaysian Insight. (2024). Rising cancer cases cause for concern, says group.
Scribd. (2024). Summary of Malaysia National Cancer Registry Report 2017-2021.
Ministry of Health Malaysia. (n.d.). Risk of Ovarian Cancer Algorithm (ROCA) Using Serial CA 125.
American Cancer Society. (n.d.). Ovarian Cancer Risk Factors.
National Ovarian Cancer Coalition. (n.d.). Risk Factors.
American Cancer Society. (n.d.). Signs and Symptoms of Ovarian Cancer.
Jones, B. P., et al. (2020). Ovarian cancer symptoms, routes to diagnosis and survival – Population cohort study in the 'no screen' arm of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). British Journal of Cancer, 123(6), 1037-1045.
Relias Media. (n.d.). Frequency of Symptoms of Ovarian Cancer in Women Presenting to Primary Care Clinics.
NHS. (n.d.). Tests and next steps: Ovarian cancer.
MIMS Malaysia. (n.d.). Ovarian Cancer: Management.
OCRAhope. (n.d.). Treatment for Ovarian Cancer: Options and Advances.
Cancer Research UK. (n.d.). Treating the symptoms of advanced ovarian cancer.
