Ovarian cancer is a malignant neoplasm arising from the ovary or fallopian tube, with epithelial ovarian cancer accounting for most adult cases.

Exam domain	One-glance essentials
Definition / diagnosis	*Ovarian cancer comprises malignancies arising from ovary, fallopian tube, or peritoneum; high-grade serous carcinoma is the dominant adult epithelial type* ^[1]^[2] Many high-grade serous cancers originate in distal tubal epithelium ^[1]
Epidemiology / risks	Risk rises with age, BRCA1 or BRCA2, Lynch syndrome, family history, nulliparity, and endometriosis for selected histologies ^[1]^[2] Combined hormonal contraception, pregnancy, and breastfeeding reduce epithelial ovarian-cancer risk ^[1]
Core mechanism	Tumour sheds across peritoneal surfaces → omental and diaphragmatic deposits, ascites, and bowel involvement ^[1] Lymphatic and haematogenous spread produce nodal, pleural, hepatic, or distant disease ^[1]^[2]
Clinical picture	*Persistent bloating, early satiety, pelvic or abdominal pain, urinary frequency, and increasing abdominal size are key symptoms* ^[1]^[2] Ascites, an adnexal mass, nodularity, pleural effusion, weight loss, or leg swelling suggests advanced disease ^[1]
Investigations	Pelvic ultrasound characterises the mass; CA-125 supports risk assessment but is non-specific ^[1]^[2] CT stages suspected disease; definitive diagnosis usually comes from surgery or image-guided tissue within an oncology pathway ^[1]
Management	*Management combines maximal cytoreductive surgery and platinum-based chemotherapy when appropriate* ^[1]^[2] Sequence, maintenance targeted therapy, and fertility-sparing options depend on stage, histology, molecular testing, resectability, and patient goals ^[1]
Complications	Complications include ascites, pleural effusion, bowel or ureteric obstruction, venous thrombosis, malnutrition, and recurrent disease ^[1]^[2] Treatment adds surgical morbidity, neuropathy, marrow suppression, infertility, and premature menopause ^[1]
Prevention / follow-up	Offer genetic counselling and germline testing when indicated; risk-reducing salpingo-oophorectomy is effective for selected high-risk carriers ^[1] There is no effective population screening with CA-125 or ultrasound for average-risk asymptomatic women ^[2]
Exam traps	*A normal CA-125 does not exclude ovarian cancer, and an elevated value is not diagnostic* ^[1]^[2] Avoid rupturing a suspicious mass during unplanned surgery because spill can affect staging and prognosis ^[1]

References

^[1] Lecture slides: GC 118. Pelvic mass ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (pp. 13, 21, 68–69 — ovarian cancer) ^[2] Lecture slides: Block C - Pelvic mass_ ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (ovarian malignancy assessment)

Ovarian Cancer

Faculty pathology distinctions (ovary/tube deck pp. 14–43): HGSC and low-grade serous carcinoma are different diseases; a serous borderline tumour may precede low-grade carcinoma, whereas most HGSC follows a tubal/STIC pathway. Borderline tumours lack destructive stromal invasion. Adult granulosa-cell tumour commonly has a somatic FOXL2 alteration; Sertoli–Leydig tumours warrant consideration of DICER1 counselling/testing. A mucinous ovarian tumour may be a GI metastasis, and pseudomyxoma peritonei should prompt assessment of an appendiceal primary.

Ovarian cancer refers to a malignant neoplasm arising from the ovary (or, in modern understanding, frequently from the fallopian tube fimbria). The term encompasses a heterogeneous group of tumours with distinct histologies, molecular profiles, risk factors, and clinical behaviours. The three broad histogenetic categories are epithelial, germ cell, and sex cord–stromal tumours, with epithelial ovarian cancer (EOC) accounting for ~90% of ovarian malignancies in adults ^[1]^[2].

The word "ovarian" comes from Latin ovarium (egg-bearing), from ovum = egg. "Cancer" derives from Greek karkinos = crab — the ancient description of tumour projections resembling crab legs.

Key Concept

Modern evidence shows that the majority of high-grade serous ovarian cancers (HGSOC) — the most common and lethal subtype — actually originate from the fimbriae of the fallopian tube (serous tubal intraepithelial carcinoma, STIC) rather than the ovarian surface epithelium itself. This paradigm shift underpins the rationale for opportunistic salpingectomy as a risk-reducing strategy.

2. Epidemiology

Ovarian cancer is the 8th most common cancer in women worldwide and the 8th leading cause of cancer death in women globally (GLOBOCAN 2022).
~313,000 new cases and ~207,000 deaths annually worldwide.
The 5-year overall survival remains poor (~30–50%) because the majority present at advanced stage (Stage III/IV).

Ovarian cancer is the 6th most common cancer in Hong Kong females with an age-standardised incidence rate of approximately 8–10 per 100,000 women per year ^[1]^[3].
It ranks among the top 10 causes of cancer death in HK women.
Incidence has been gradually rising over the past two decades, reflecting both true increases (lifestyle westernisation, lower parity) and improved detection.
Mean age at diagnosis: 50–60 years for epithelial ovarian cancer; younger for germ cell tumours (10–30 years).

Subtype	% of Ovarian Cancers	Typical Age	Key Features
Epithelial (overall)	~90%	50–70	Most common, worst prognosis for HGSOC
— High-grade serous (HGSOC)	~70% of EOC	55–65	Most common & most lethal; BRCA-related
— Low-grade serous	~5%	40–55	Indolent, chemoresistant
— Endometrioid	~10%	50–60	A/w endometriosis, Lynch syndrome
— Clear cell	~5–10% (higher in East Asia)	45–55	A/w endometriosis; higher proportion in HK/East Asian populations
— Mucinous	~3%	30–50	Pseudomyxoma if ruptured
Germ cell	~5%	10–30	Excellent prognosis, chemo-sensitive
Sex cord–stromal	~5%	Variable	Hormone-secreting (oestrogen, androgens)

High Yield — Clear Cell Carcinoma in HK

Clear cell carcinoma of the ovary has a notably higher incidence in East Asian populations (including Hong Kong and Japan) compared to Western countries, comprising up to 15–25% of EOC in some East Asian series vs. 5% in Western data. It is strongly associated with endometriosis and is characteristically chemoresistant to standard platinum-taxane regimens.

3. Risk Factors

The fundamental concept underpinning most ovarian cancer risk factors relates to two main theories:

Incessant ovulation hypothesis (Fathalla, 1971): Each ovulation causes micro-trauma and repair of the ovarian surface epithelium (OSE), increasing the chance of DNA replication errors → malignant transformation. Therefore, anything that reduces the total number of lifetime ovulations is protective.
Gonadotropin hypothesis: Persistent high levels of gonadotropins (FSH, LH) stimulate the OSE and inclusion cysts, promoting neoplastic change.
Tubal origin hypothesis (modern): Inflammatory exudate and reactive oxygen species from the fallopian tube reach the ovarian surface, particularly during ovulation when the follicle ruptures and tubal fimbriae are in close contact, causing DNA damage → STIC → HGSOC.

Risk Factor	Mechanism / Explanation
Age	Risk increases with age; peak incidence 55–65 for EOC. Cumulative DNA damage and more ovulatory cycles.
Family history	FHx of breast, ovarian, and colorectal cancer ^[1]. 1st-degree relative with ovarian cancer → ~3.6× risk. Two 1st-degree relatives → ~7× risk.
BRCA1/2 mutation	BRCA1: lifetime risk of ovarian CA ~44% by age 80; BRCA2: ~17% by age 80 ^[4]. BRCA proteins are involved in homologous recombination DNA repair; loss of function → genomic instability → cancer. BRCA1 ovarian cancers tend to be high-grade serous.
Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC)	Lifetime risk of ovarian cancer ~10–12% (up to 24% for some MMR gene mutations) ^[3]^[5]. Due to mismatch repair (MMR) gene defects (MLH1, MSH2, MSH6, PMS2) → microsatellite instability → accumulation of mutations. A/w endometrioid and clear cell subtypes of ovarian cancer rather than serous.
Ethnicity	Ashkenazi Jewish women: BRCA1/2 founder mutations in ~2.5% (vs 0.1–0.2% general population). East Asian: higher proportion of clear cell carcinoma.
Early menarche / late menopause	More ovulatory cycles → more micro-trauma to OSE (incessant ovulation hypothesis).

Risk Factor	Effect	Mechanism
Nulliparity	↑ Risk	More ovulatory cycles (no suppression of ovulation during pregnancy).
No breastfeeding	↑ Risk	Breastfeeding suppresses ovulation (lactational amenorrhoea) → fewer cycles.
Infertility / fertility drug use	↑ Risk (modest)	Anovulatory patients receiving ovulation induction → supraphysiological gonadotropin stimulation. Data is controversial; likely a small effect.
Combined oral contraceptive pill (COCP)	↓ Risk (protective — 30–50% reduction with ≥5 years use)	Suppresses ovulation → fewer ovulatory cycles + suppresses gonadotropin levels. Protection persists for 15–20 years after cessation. One of the most significant modifiable protective factors.
Multiparity	↓ Risk	Each pregnancy suppresses ovulation for ~9 months + post-partum amenorrhoea.
Tubal ligation / salpingectomy	↓ Risk (up to 30% reduction)	Physically prevents passage of carcinogenic agents / inflammatory exudate from the tube to the ovary; may interrupt tubal carcinogenesis pathway.
Obesity	Modest ↑ risk	Peripheral aromatisation of androgens to oestrogens in adipose tissue → chronic oestrogen exposure. More clearly linked to endometrial and breast cancer but also contributes to ovarian cancer risk.
HRT (post-menopausal)	↑ Risk (particularly oestrogen-only HRT)	Prolonged oestrogen exposure to OSE. Current evidence suggests the risk increases with > 5 years of use and applies mainly to serous and endometrioid subtypes.
Endometriosis	↑ Risk for clear cell and endometrioid subtypes	Chronic inflammation → oxidative stress → DNA damage in ectopic endometrial tissue → malignant transformation (endometriosis-associated ovarian cancer).
Smoking	↑ Risk for mucinous subtype specifically	Carcinogens may act on mucinous-type epithelium.
Talcum powder (perineal use)	Controversial/weak association	Hypothesised to cause chronic inflammation if particles ascend through the genital tract. IARC reclassified as "possibly carcinogenic" (Group 2B).

Protective Factor	Mechanism
COCP use	Suppresses ovulation
Multiparity	Fewer ovulatory cycles
Breastfeeding	Lactational anovulation
Tubal ligation / Bilateral salpingectomy	Interrupts tubal carcinogenesis pathway
Hysterectomy	Possibly reduces retrograde flow/transport
Prophylactic BSO in BRCA carriers	Removes at-risk tissue

Protective Effect of COCP — Exam Favourite

The COCP is one of the most effective chemoprevention strategies for ovarian cancer. A meta-analysis showed ~30–50% reduction in risk with ≥ 5 years of COCP use, and the protective effect persists for 15–20 years after cessation. This is important to counsel BRCA carriers who have not yet completed childbearing and are not ready for prophylactic surgery.

4. Anatomy and Function

Understanding the anatomy is essential for understanding spread patterns, clinical features, and surgical management.

Location: Paired organs in the ovarian fossa on the lateral pelvic wall, posterior to the broad ligament.
Size: ~3 × 2 × 1 cm in reproductive age; atrophic post-menopause (~1.5 × 0.5 × 0.5 cm).
Attachments:
- Mesovarium: attaches ovary to the posterior surface of the broad ligament (contains ovarian vessels entering the hilum).
- Suspensory (infundibulopelvic) ligament: connects the ovary to the lateral pelvic wall; contains the ovarian artery (from aorta) and ovarian vein (drains to IVC on the right, left renal vein on the left). This is the key structure that must be identified and ligated during oophorectomy.
- Ovarian ligament (utero-ovarian ligament): connects the ovary to the uterus (medially); contains no major vessels.
- Tubo-ovarian ligament: connects the ovary to the fimbriated end of the fallopian tube.
Blood supply: Ovarian artery (branch of abdominal aorta at L2) + anastomosis with the uterine artery (branch of internal iliac).
Venous drainage: Right ovarian vein → IVC; Left ovarian vein → Left renal vein.
Lymphatic drainage: Para-aortic lymph nodes (follow the ovarian vessels). This is distinct from the cervix/lower uterus which drains to the pelvic (iliac) nodes. This explains why ovarian cancer staging includes para-aortic lymph node assessment.
Nerve supply: Ovarian plexus (sympathetic from T10) — referred pain to the periumbilical region (T10 dermatome).

Layer	Cell Type	Tumours Arising
Surface epithelium (modified peritoneal mesothelium)	Single layer of cuboidal/columnar cells that can undergo metaplasia	Epithelial ovarian cancers (serous, mucinous, endometrioid, clear cell, Brenner)
Stroma / Sex cords	Granulosa cells, theca cells, Sertoli cells, Leydig cells, fibroblasts	Sex cord–stromal tumours (granulosa cell tumour, fibroma, Sertoli-Leydig)
Germ cells	Oocytes	Germ cell tumours (dysgerminoma, teratoma, yolk sac tumour, choriocarcinoma)

The ovary is an intraperitoneal organ. When malignant cells exfoliate from the ovarian surface, they follow the clockwise circulation of peritoneal fluid:

Cells shed from the ovary into the pouch of Douglas (rectouterine pouch — the most dependent part of the peritoneal cavity in the upright position).
Flow along the right paracolic gutter (the main pathway) → up to the right subdiaphragmatic space → omentum (the "policeman of the abdomen" traps tumour cells).
Peritoneal implants form on the omentum (omental cake), diaphragm, bowel serosa, mesentery, and liver surface (Glisson's capsule — not the liver parenchyma).

This explains:

Why ovarian cancer presents with ascites and omental cake (tumour-laden omentum).
Why omentectomy is a key part of surgical staging/debulking.
Why the right hemidiaphragm must be evaluated during staging.

The fimbriated end of the fallopian tube is in intimate contact with the ovarian surface at each ovulation (to pick up the released oocyte). Modern evidence shows:

Serous tubal intraepithelial carcinoma (STIC) lesions, found in the tubal fimbriae, are now considered the precursor of most HGSOC.
The STIC → ovarian cancer pathway: STIC cells exfoliate → implant on ovarian surface → proliferate → form the ovarian tumour mass.
STIC harbours TP53 mutations (found in > 96% of HGSOC).

5. Etiology and Pathophysiology

5.1 Two-Pathway Model of Ovarian Carcinogenesis (Kurman & Shih)

This is the most widely accepted model, dividing epithelial ovarian cancers into two groups:

Arise through a stepwise progression from benign → borderline → invasive cancer.
Generally indolent, present at early stage, but are relatively chemoresistant.
Genetically stable (no TP53 mutations).
Key molecular alterations: KRAS, BRAF, PIK3CA, PTEN, ARID1A, CTNNB1 mutations.

Type I Subtype	Precursor Lesion	Key Mutations
Low-grade serous	Serous cystadenoma → serous borderline tumour	KRAS, BRAF
Endometrioid	Endometriosis / endometriotic cyst	CTNNB1, PIK3CA, PTEN, ARID1A
Clear cell	Endometriosis / endometriotic cyst	ARID1A, PIK3CA, PTEN
Mucinous	Mucinous cystadenoma → borderline	KRAS
Brenner (transitional cell)	Walthard cell nests	—

Arise de novo (no clearly defined precursor within the ovary itself; likely from STIC in the tube).
Aggressive, present at advanced stage, but are chemosensitive (at least initially).
Genetically unstable with TP53 mutations (> 96%) and frequent homologous-recombination deficiency (~50%); this is broader than BRCA1/2 mutation.
Responsible for ~75% of ovarian cancer deaths.

Type II Subtype	Key Features	Key Mutations
High-grade serous (HGSOC)	Most common & lethal	TP53 (> 96%), BRCA1/2 (germline ~15%, somatic ~7%), HRD (~50%)
High-grade endometrioid	Rare	TP53
Undifferentiated carcinoma	Rare	TP53
Carcinosarcoma (MMMT)	Mixed epithelial + mesenchymal	TP53

5.2 Pathophysiology of Non-Epithelial Ovarian Cancers

Arise from primordial germ cells (totipotent or pluripotent).
Can differentiate along various pathways (embryonic → embryonal carcinoma, teratoma; extraembryonic → yolk sac tumour, choriocarcinoma).
Dysgerminoma (the ovarian equivalent of testicular seminoma): most common germ cell tumour. Does NOT produce AFP or hCG (unless mixed with other elements).
Yolk sac tumour: produces AFP (alpha-fetoprotein). Schiller-Duval bodies on histology.
Choriocarcinoma: produces β-hCG. Aggressive.
Immature teratoma: contains immature (embryonic) tissue, usually neuroectodermal. Graded 1–3 based on amount of immature tissue.

Granulosa cell tumour: most common sex cord–stromal tumour. Produces oestrogen → can present with signs of hyperoestrinism (precocious puberty in children, postmenopausal bleeding in elderly, endometrial hyperplasia/cancer). Ovarian granulosa cell tumours are recognised as oestrogen-secreting tumours ^[1]. Histology: Call-Exner bodies (rosette-like arrangement of granulosa cells around eosinophilic fluid). Tumour marker: inhibin B.
Sertoli-Leydig cell tumour: produces androgens → virilisation (hirsutism, deepening voice, clitoromegaly, temporal balding).
Fibroma: benign. A/w Meigs syndrome (ovarian fibroma + ascites + right-sided pleural effusion). The effusion is a transudate caused by peritoneal irritation and lymphatic drainage from the diaphragm.

BRCA1 (chromosome 17q) and BRCA2 (chromosome 13q) are tumour suppressor genes encoding proteins essential for homologous recombination (HR) DNA repair — the high-fidelity repair of double-strand DNA breaks ^[4].

When BRCA is dysfunctional → HR repair fails → cells rely on error-prone repair pathways (e.g., non-homologous end joining, NHEJ) → accumulation of genomic rearrangements → genomic instability → cancer.
This creates a therapeutic vulnerability: PARP inhibitors (e.g., olaparib, niraparib). PARP (poly ADP-ribose polymerase) repairs single-strand DNA breaks. If both PARP and HR are non-functional → "synthetic lethality" — the cancer cell cannot repair any DNA breaks and dies.

BRCA1: lifetime risk by 80y of 72% for CA breast and 44% for CA ovaries ^[4] BRCA2: lifetime risk by 80y of 69% for CA breast and 17% for CA ovaries ^[4] Other associated cancers (BRCA2): male breast cancer, prostate, laryngeal, cholangio, stomach, colon, melanoma, pancreatic ^[4]

Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) is caused by germline mutations in DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, PMS2 ^[3]^[5].

Defective MMR → microsatellite instability (MSI) → accumulation of frameshift mutations → cancer.
Extracolonic tumours in Lynch syndrome include: endometrial (most common), ovaries, stomach, small bowel, hepatobiliary system, renal pelvis/ureter, brain (glioma), sebaceous neoplasms ^[5].
Ovarian cancers in Lynch syndrome are typically endometrioid or clear cell subtype (NOT serous — unlike BRCA).
Lifetime risk of ovarian cancer in Lynch syndrome: ~10–12% (varies by gene; MSH2 and MSH6 carry higher risk for ovarian cancer than MLH1).

Understanding why ovarian cancer presents the way it does:

Clinical Manifestation	Pathophysiological Basis
Abdominal distension / bloating	Ascites from peritoneal carcinomatosis (tumour cells on peritoneum → increased vascular permeability + lymphatic obstruction + VEGF secretion)
Omental cake	Tumour cells have tropism for omental milky spots (aggregates of immune cells) → preferential metastasis to omentum
Pelvic / abdominal mass	Direct tumour growth from the ovary; can become massive (especially mucinous tumours, which can reach > 30 cm)
Pleural effusion (usually right-sided)	Ascitic fluid passes through transdiaphragmatic lymphatic channels (more numerous on the right) → pleural effusion. This does NOT necessarily indicate parenchymal lung metastasis — it may still be Stage III if cytology is positive. But if cytology is positive = Stage IV.
Early satiety / nausea	Omental cake and peritoneal implants compress the stomach and bowel
Bowel obstruction	Peritoneal carcinomatosis encasing bowel loops
Urinary frequency / urgency	Direct compression of the bladder by a pelvic mass
Weight loss + cachexia	Tumour metabolic demand + inflammatory cytokines (TNF-α, IL-6)
DVT / PE	Hypercoagulable state (Trousseau syndrome — mucin-secreting tumours activate clotting)
Postmenopausal bleeding	Oestrogen-secreting tumours (granulosa cell tumour) → endometrial hyperplasia/cancer

6. Classification

6.1 Histological Classification (WHO 2020)

Each epithelial subtype can be benign (cystadenoma), borderline (low malignant potential), or malignant (carcinoma):

Subtype	Histological Features	Notes
Serous	Resembles fallopian tube epithelium (ciliated columnar cells). Psammoma bodies (concentric calcifications).	High-grade (HGSOC) = most common. Low-grade serous = separate disease.
Mucinous	Resembles endocervical or GI mucin-secreting epithelium. Mucin-filled cysts.	Often huge. Must exclude metastasis from GI (appendix, colon) primary — always check appendix!
Endometrioid	Resembles endometrial glands.	A/w endometriosis. 15–20% have synchronous endometrial cancer.
Clear cell	Hobnail cells, clear cytoplasm (glycogen-rich).	A/w endometriosis. Higher proportion in East Asian / HK populations. Chemoresistant.
Brenner (transitional)	Resembles urothelial (transitional) epithelium. Walthard cell nests.	Usually benign; malignant Brenner is rare.
Seromucinous	Mixed serous and mucinous.	Rare. A/w endometriosis.
Undifferentiated	No identifiable differentiation.	Aggressive.

Tumour	Features	Marker
Dysgerminoma	Most common malignant germ cell tumour. Equivalent to testicular seminoma. "Fried egg" cells. Lymphocytic infiltrate.	LDH, PLAP
Yolk sac tumour (endodermal sinus tumour)	Schiller-Duval bodies. Most common in children/young women.	AFP
Immature teratoma	Immature (embryonic) tissue, usually neuroectodermal. Graded 1–3.	AFP (if neural tissue)
Mature teratoma (dermoid cyst)	Benign (most common ovarian tumour overall). Contains mature tissue (hair, teeth, fat, skin).	—
Embryonal carcinoma	Rare in pure form.	AFP, β-hCG
Choriocarcinoma (non-gestational)	Very rare. Syncytiotrophoblast + cytotrophoblast.	β-hCG
Mixed germ cell tumour	Combination of above.	Varies

Tumour	Features	Secretory Product	Marker
Granulosa cell tumour	Call-Exner bodies. Oestrogen-secreting → endometrial hyperplasia, postmenopausal bleeding ^[1]	Oestrogen	Inhibin B, AMH
Sertoli-Leydig cell tumour	Virilising	Androgens	Inhibin, testosterone
Fibroma	Benign solid tumour. A/w Meigs syndrome (fibroma + ascites + R pleural effusion)	None	—
Thecoma	Usually benign. Oestrogen-secreting.	Oestrogen	Inhibin
Steroid cell tumour	Virilising or oestrogenic	Steroids	—

Represent ~10–15% of epithelial ovarian neoplasms.
Histology: epithelial proliferation and cytological atypia WITHOUT stromal invasion.
Behaviour: indolent, excellent prognosis (> 95% survival at 10 years for Stage I).
Can have peritoneal implants — classified as non-invasive (good prognosis) or invasive (behaves more like carcinoma).
Key for exam: borderline tumours should be managed conservatively if possible, especially in young women desiring fertility (fertility-sparing surgery = unilateral salpingo-oophorectomy + staging).

Ovarian cancer is surgically staged (unlike cervical cancer, which is clinically staged). This is because peritoneal spread cannot be reliably assessed by imaging alone.

Stage	Description
I	Confined to ovaries/fallopian tubes
IA	One ovary/tube, capsule intact, no surface involvement, negative washings
IB	Both ovaries/tubes, capsule intact, no surface involvement, negative washings
IC	IC1: surgical spill; IC2: capsule ruptured before surgery or tumour on surface; IC3: positive washings/ascites
II	Extension to pelvis (below pelvic brim)
IIA	Extension to uterus, tubes, or ovaries
IIB	Extension to other pelvic intraperitoneal tissues
III	Peritoneal spread beyond pelvis and/or retroperitoneal lymph node metastasis
IIIA1	Retroperitoneal lymph node only (IIIA1(i) ≤10mm; IIIA1(ii) > 10mm)
IIIA2	Microscopic extrapelvic peritoneal involvement ± nodes
IIIB	Macroscopic peritoneal mets ≤2cm beyond pelvis ± nodes
IIIC	Macroscopic peritoneal mets > 2cm beyond pelvis ± nodes (includes liver/splenic capsule)
IV	Distant metastasis (excluding peritoneal mets)
IVA	Pleural effusion with positive cytology
IVB	Parenchymal mets (liver, spleen, extra-abdominal organs — e.g., lung, bone, brain) and/or inguinal/extra-abdominal lymph nodes

Staging Pitfall

A common exam error: liver capsule involvement = Stage III (peritoneal spread), but liver parenchymal metastasis = Stage IVB. Similarly, pleural effusion with positive cytology = Stage IVA, but this does NOT necessarily mean pulmonary parenchymal metastasis.

7. Clinical Features

Ovarian cancer is often called "the silent killer" because it tends to present with vague, non-specific symptoms until advanced stages. However, studies show that most patients DO have symptoms — they are just easily dismissed.

7.1 Symptoms

Symptom	Pathophysiological Basis
Persistent abdominal bloating / increasing abdominal girth	Ascites (peritoneal carcinomatosis → increased vascular permeability via VEGF, lymphatic obstruction, direct peritoneal irritation); also large tumour mass distending the abdomen. This is the most common presenting symptom. ^[2]
Pelvic / abdominal pain	Direct tumour mass effect, stretching of the ovarian capsule, peritoneal irritation by tumour implants, or torsion/haemorrhage of the tumour.
Early satiety / difficulty eating	Omental cake and/or large pelvic mass compressing the stomach → reduced gastric capacity. Peritoneal implants on bowel → reduced motility.
Urinary frequency / urgency	Large pelvic mass directly compressing the bladder (the ovary sits close to the bladder in the pelvis).
Change in bowel habit (constipation or alternating)	Pelvic mass compressing the rectosigmoid. Peritoneal implants on bowel serosa → dysmotility.
Fatigue	Anaemia of chronic disease (inflammatory cytokines), cancer cachexia (TNF-α, IL-6), poor nutritional intake.

The Gilda Radner Symptom Index — Exam Tip

The NICE guidelines recommend that ovarian cancer should be considered if any of the following are present persistently (≥12 times per month), especially in women > 50:

Abdominal bloating
Early satiety / appetite loss
Pelvic or abdominal pain
Urinary urgency/frequency

These four symptoms form the mnemonic "BEAT" — Bloating, Eating difficulty, Abdominal pain, Things urinary.

Symptom	Pathophysiological Basis
Increasing abdominal girth (progressive)	Massive ascites ± tumour bulk. In the exam question scenario: "F/75 complained of increasing abdominal girth. PE found abdominal mass arising from pelvis and ascites." ^[2]^[6]
Shortness of breath	Pleural effusion (usually right-sided — peritoneal fluid ascends through transdiaphragmatic lymphatic channels, which are more numerous on the right). Massive ascites → diaphragmatic splinting → reduced tidal volume.
Nausea / vomiting	Bowel obstruction from peritoneal carcinomatosis (extrinsic compression). Omental cake compressing GI tract.
Weight loss / cachexia	Cancer cachexia — pro-inflammatory cytokines (TNF-α, IL-1, IL-6) → protein catabolism + anorexia. Paradoxically, patients may gain weight initially due to ascites masking muscle wasting ("fat-thin" appearance).
Back pain	Retroperitoneal lymph node metastasis compressing lumbosacral nerve roots, or direct posterior pelvic extension.
DVT / PE	Paraneoplastic hypercoagulability (Trousseau syndrome) — mucin-secreting adenocarcinomas activate tissue factor and promote thrombin generation.
Bone pain	Rare — haematogenous metastasis to bone (late event).

Tumour	Specific Symptom	Mechanism
Granulosa cell tumour	Postmenopausal bleeding, irregular menses, breast tenderness	Oestrogen secretion → endometrial hyperplasia → abnormal uterine bleeding ^[1]
Sertoli-Leydig cell tumour	Hirsutism, acne, deepening voice, amenorrhoea, clitoromegaly	Androgen (testosterone) secretion → virilisation
Yolk sac tumour / immature teratoma	Abdominal mass in young girl/woman	Rapidly growing tumour in a young patient
Choriocarcinoma (non-gestational)	Positive pregnancy test, precocious puberty	β-hCG secretion
Mucinous tumour (if ruptured)	Pseudomyxoma peritonei (gelatinous ascites)	Mucin-secreting cells disseminate in the peritoneum
Fibroma	Meigs syndrome: ascites + right pleural effusion	Peritoneal irritation by fibroma → transudative ascites → transdiaphragmatic lymphatic flow → right pleural effusion

7.2 Signs

Sign	Pathophysiological Basis
Cachexia / wasting	Cancer cachexia (cytokine-mediated). May be masked by ascites.
Pallor	Anaemia of chronic disease.
Left supraclavicular lymphadenopathy (Virchow's node / Troisier's sign)	Metastasis via thoracic duct to the left supraclavicular node — a classical sign of advanced intra-abdominal malignancy.
Peripheral oedema	Hypoalbuminaemia (poor nutrition, chronic disease) and/or compression of iliac veins by pelvic mass.
DVT	Hypercoagulability (Trousseau syndrome).

Sign	Pathophysiological Basis
Pelvic / abdominal mass arising from the pelvis	Ovarian tumour. On palpation, a mass arising from the pelvis cannot get below it (i.e., you cannot feel the lower border). It moves with bimanual examination. ^[2]^[6]
Features suspicious for malignancy: solid, irregular, fixed, bilateral, nodular	Solid and irregular architecture suggests disorganised tumour growth. Fixed = invasion of adjacent structures. Bilateral = metastatic/advanced primary.
Ascites (shifting dullness, fluid thrill)	Peritoneal carcinomatosis → VEGF secretion → increased vascular permeability → fluid exudation into peritoneal cavity. Also lymphatic obstruction by tumour implants preventing reabsorption. ^[2]^[6]
Omental cake (palpable hard mass in upper abdomen)	Omental metastasis — tumour cells have tropism for the omentum (milky spots containing macrophages act as a "trap").
Hepatomegaly (hard, nodular, non-tender)	Liver metastasis (late feature).
Sister Mary Joseph nodule	Metastasis to the umbilicus via peritoneal lymphatics.

Sign	Significance
Adnexal mass (bimanual palpation)	Confirms pelvic origin. Assess size, consistency, mobility, tenderness.
Fixed, hard, irregular mass in the pouch of Douglas (on rectovaginal exam)	Peritoneal implants in the pouch of Douglas (most dependent part of the peritoneum).
Nodularity in pouch of Douglas	"Shelf" of tumour deposits — classical sign of peritoneal carcinomatosis.
Cervical excitation (chandelier sign)	If tumour causes pelvic inflammation or torsion (mimics PID/ectopic pregnancy).
Uterine enlargement	May suggest synchronous endometrial cancer (seen in ~15% of endometrioid ovarian cancer).

Exam Vignette — Classic Presentation

"F/75 complained of increasing abdominal girth. PE found abdominal mass arising from pelvis and ascites. USG abdomen found mixed solid-cystic lesion at pelvis and ascites. Uterus cannot be visualised." ^[6]

This is the classic presentation: elderly postmenopausal woman + pelvic mass + ascites + mixed solid-cystic lesion on USG = ovarian cancer until proven otherwise. The inability to visualise the uterus separately suggests the mass is replacing/engulfing the ovary and is closely related to the adnexal structures.

The ADNEX model (Assessment of Different NEoplasias in the adneXa) is a validated ultrasound-based risk prediction model that distinguishes between benign, borderline, stage I invasive, stage II–IV invasive, and secondary metastatic adnexal tumours ^[7].

Feature	Suggestive of Benign	Suggestive of Malignant
Age	Reproductive age	Postmenopausal
Laterality	Unilateral	Bilateral
Size	Small (<5 cm often)	Large (>10 cm, but mucinous benign can be large too)
Consistency	Cystic (thin-walled, anechoic)	Mixed solid-cystic or predominantly solid
Wall	Thin, smooth	Thick, irregular
Septae	Thin (<3 mm)	Thick (>3 mm), irregular
Papillary projections	Absent	Present (solid projections into cyst cavity)
Vascularity on Doppler	Low flow	High flow, low resistance (RI < 0.4)
Ascites	Absent	Present
CA-125	Normal	Elevated (especially in serous EOC)
Mobility	Mobile	Fixed

8. Special Topics Relevant to Hong Kong Exam

The lecture objective highlights "awareness of the health economics of ovarian cancer screening" ^[2].

No effective population-based screening exists for ovarian cancer in the general population.
The UKCTOCS trial (2021 final results) showed that while multimodal screening (serial CA-125 with ROCA algorithm + TVS) could detect ovarian cancer earlier, it did NOT reduce mortality from ovarian cancer. This was a landmark negative result.
CA-125 alone as a screening tool is limited by:
- Poor sensitivity for early-stage disease (~50% of Stage I ovarian cancers have normal CA-125).
- Poor specificity — elevated in many benign conditions (endometriosis, fibroids, PID, pregnancy, liver disease, peritonitis).
Transvaginal ultrasound (TVS) alone also has insufficient specificity → leads to unnecessary surgeries.
No effective ovarian screening strategy is established for BRCA carriers. NCI BRCA guidance. risk-reducing bilateral salpingo-oophorectomy (rrBSO) remains the gold standard for risk reduction and is recommended after completion of childbearing or by age 35–40 (BRCA1) / 40–45 (BRCA2).

Screening for Ovarian Cancer — Bottom Line

There is NO recommended population-level screening for ovarian cancer. Even in high-risk (BRCA) populations, screening has limitations. Prophylactic BSO remains the most effective risk reduction strategy for BRCA carriers.

Options if gene-positive ^[4]:

Cancer screening: MRI Q1y from 25y, MMG Q1y from 30y, TVUS + CA125 Q6mo from 30y (or 5–10y before earliest dx in family)
Chemoprevention: tamoxifen, AI (limited data, usually not recommended)
Bilateral mastectomy: often skin-sparing ± NAC preservation
Bilateral salpingo-oophorectomy ± HRT: recommended after complete childbearing or before 40y

Key considerations:

Staging of current CA breast: preferred stage I–II (good prognosis → more likely to secure cure)
Age: more beneficial if young
Completion of family: important for breastfeeding or fertility (BSO)

Cancer screening for Lynch syndrome patients ^[5]:

Colorectal: colonoscopy Q1-2y from 20–25y onwards
Endometrial, ovarian: pelvic exam + endometrial Bx Q1y from 30–35y onward (or 3–5y before earliest age of dx in family) with prophylactic TAH+BSO at the end of childbearing or ~40y
Gastric: consider OGD screening from 30–35y onwards
Urinary tract: consider annual urinalysis from 30–35y onwards

High Yield Summary

Definition: Malignant neoplasm of the ovary; most commonly epithelial (90%), with HGSOC being the most common and lethal subtype. Modern evidence: many HGSOC originate from the fallopian tube fimbria (STIC).

Epidemiology: 6th most common female cancer in HK. Peak age 55–65 for EOC; younger for germ cell. Clear cell carcinoma is disproportionately common in East Asian populations.

Risk factors — Think "incessant ovulation" + genetic:

↑ Risk: Age, nulliparity, no breastfeeding, early menarche, late menopause, BRCA1/2, Lynch syndrome, FHx, endometriosis (clear cell/endometrioid), obesity, HRT, fertility drugs.
↓ Risk (protective): COCP (30–50% reduction with ≥5y use), multiparity, breastfeeding, tubal ligation, salpingectomy.

BRCA1: 44% lifetime ovarian cancer risk. BRCA2: 17%. Both → TP53 mutation → HGSOC. Lynch syndrome: ~10–12% lifetime ovarian cancer risk → endometrioid/clear cell.

Two-pathway model: Type I (low-grade, stepwise, KRAS/BRAF/PIK3CA, early stage, chemoresistant) vs. Type II (high-grade, de novo from STIC, TP53/BRCA, late stage, chemosensitive initially).

Clinical features: "BEAT" — Bloating, Eating difficulty, Abdominal pain, Things urinary. Late: ascites, omental cake, cachexia, pleural effusion, bowel obstruction. Granulosa cell tumour → oestrogen → postmenopausal bleeding.

Classic exam vignette: Elderly woman + increasing abdominal girth + pelvic mass + ascites + mixed solid-cystic lesion on USG = ovarian cancer.

Staging: Surgical staging (FIGO 2014). Liver capsule = III; liver parenchyma = IVB. Pleural effusion with positive cytology = IVA.

Screening: No effective ovarian screening method is established, including for BRCA carriers. Discuss gene-specific risk-reducing salpingo-oophorectomy; surveillance is not an equivalent substitute.

Active Recall - Ovarian Cancer (Definition, Epidemiology, Risk Factors, Anatomy, Etiology, Classification, Clinical Features)

^[1] Lecture slides: GC 112. Abnormal vaginal bleeding Gynaecological cancer.pdf (p19, p37–38; Risk factors section including granulosa cell tumours as oestrogen-secreting tumours) ^[2] Lecture slides: Block C - O&G Theme Case 3.pdf (p1; Learning objectives including pelvic pathology, pelvic ultrasound, health economics of ovarian cancer screening) ^[3] Lecture slides: Block C - Abnormal vaginal bleeding_ gynaecological cancer.pdf (p34; Lynch syndrome and risk factors for endometrial cancer) ^[4] Senior notes: Ryan Ho Urogenital.pdf (p205, p213; BRCA1/2 mutation, lifetime risks, prophylactic surgery options, criteria for genetic counselling) ^[5] Senior notes: Ryan Ho GI.pdf (p183; Lynch syndrome, extracolonic tumours, cancer screening recommendations) ^[6] Senior notes: Ryan Ho Radiology.pdf (p39; Exam question M18 Rotation 3 — F/75 with pelvic mass, ascites, mixed solid-cystic lesion = ovarian cancer) ^[7] Lecture slides: GC 118. Pelvic mass ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p60; ADNEX model for risk prediction of malignancy in ovarian tumours)

Differential Diagnosis of Ovarian Cancer

When a patient presents with a pelvic mass, abdominal distension, ascites, or vague lower abdominal/pelvic symptoms, the differential diagnosis is broad. Your job is to systematically think through what structures live in the pelvis and abdomen, what pathologies can arise from each, and how to narrow the list using clinical, biochemical, and radiological clues.

"Uterine fibroid, ovarian mass and cancer are important differential diagnoses of pelvic mass" ^[7]. "History and physical examination usually help to suggest a diagnosis" ^[7].

The key principle: a pelvic mass in a woman can arise from the ovary, uterus, fallopian tube, bowel, bladder, retroperitoneum, or be a non-gynaecological mimic. You need to think anatomically and then match the clinical features.

The most practical approach is to think by organ of origin, then within each organ consider benign vs. malignant pathology. The clinical context — particularly age, menopausal status, laterality, consistency (cystic vs. solid vs. mixed), and associated features (ascites, CA-125, hormonal symptoms) — guides you to the most likely diagnosis.

2. Differential Diagnosis by Organ of Origin

These are the most important differentials to distinguish from ovarian cancer because they share the same organ of origin.

Condition	Key Features	How to Distinguish from Ovarian Cancer
Functional ovarian cyst (follicular or corpus luteum)	Common in reproductive-age women. Simple, thin-walled, anechoic on USG. Usually < 5 cm. Resolves spontaneously within 1–3 menstrual cycles.	Age (premenopausal), simple cyst morphology on USG, resolves on repeat imaging in 6–8 weeks. No solid component, no ascites. CA-125 normal. In the exam scenario with a F/75 and ascites, a functional cyst is very unlikely — postmenopausal ovaries should NOT have functional cysts. ^[6]
Dermoid cyst (mature cystic teratoma)	Most common ovarian tumour overall. Contains mature tissue (hair, teeth, fat). Peak 20–40y. On USG: echogenic areas (fat, calcifications), "tip of the iceberg" sign, Rokitansky nodule. On CT/X-ray: fat + calcification (teeth).	Dermoid cyst is in the differential for a pelvic mass in younger women, but USG shows characteristic fat/calcification, not the mixed solid-cystic morphology with ascites seen in ovarian cancer. ^[6] Bilateral in 10%. Risk of torsion. Rarely undergoes malignant transformation (~1–2%, usually squamous cell carcinoma, in older patients).
Endometrioma ("chocolate cyst")	Endometriosis-derived cyst of the ovary. Homogeneous low-level echoes on USG ("ground glass" appearance). Typically in reproductive-age women with dysmenorrhoea, deep dyspareunia, and infertility.	History of endometriosis symptoms, USG ground-glass appearance, no solid papillary projections (unless malignant transformation → clear cell or endometrioid carcinoma). CA-125 can be mildly elevated in endometriosis (a source of false positives for ovarian cancer screening).
Serous/mucinous cystadenoma	Benign epithelial tumour. Serous: thin-walled, unilocular, anechoic (resembles a simple cyst but larger). Mucinous: can be very large (> 20 cm), multilocular with thin septae.	Thin walls, thin septae (< 3 mm), no solid papillary projections, no ascites, normal CA-125. Can be difficult to distinguish from borderline or early malignant tumours — definitive diagnosis is histological.
Fibroma / thecoma	Solid ovarian tumour. Fibroma: benign, a/w Meigs syndrome (ascites + right pleural effusion → mimics ovarian cancer!). Thecoma: oestrogen-producing, endometrial hyperplasia.	Meigs syndrome is an important mimic of advanced ovarian cancer — both cause ascites and pleural effusion. However, Meigs syndrome resolves completely after tumour removal. The mass is solid (not mixed cystic-solid). CA-125 can be elevated in Meigs syndrome (peritoneal irritation), further confusing the picture.

Meigs Syndrome — The Great Mimic

Do NOT automatically diagnose advanced ovarian cancer when you see ovarian mass + ascites + pleural effusion. Meigs syndrome (ovarian fibroma + ascites + right pleural effusion) is BENIGN and completely curable by removing the fibroma. The ascites and effusion are transudative and resolve postoperatively. Always consider this differential, especially if the mass is solid on imaging.

Condition	Key Features	Distinguishing Points
Borderline ovarian tumour	Epithelial proliferation without stromal invasion. Excellent prognosis (> 95% 10y survival for Stage I). Can have peritoneal implants. Mean age 40–50y. USG: papillary projections within a cystic mass, but often less aggressive-appearing than carcinoma.	Younger age than invasive cancer, less ascites, less peritoneal dissemination. Definitive distinction from invasive carcinoma requires histology.
Primary ovarian carcinoma	Mixed solid-cystic lesion, bilateral, ascites, omental cake, elevated CA-125 ^[6]^[7].	This is the index diagnosis. The DDx section focuses on what else could mimic this.
Krukenberg tumour (metastatic to ovary)	Metastasis to the ovary from another primary — classically from gastric cancer (signet ring cell adenocarcinoma), but also from colon, breast, and appendix. Bilateral in > 80%. Histology: mucin-secreting signet ring cells in ovarian stroma.	Crucial DDx: a bilateral ovarian mass in a woman should always prompt consideration of a GI primary. Look for GI symptoms (dyspepsia, weight loss, change in bowel habit). Do upper and lower GI endoscopy. Appendiceal mucinous tumours can also metastasise to ovaries and must be excluded if mucinous histology is found.
Fallopian tube carcinoma	Rare primary. Now considered part of the HGSOC spectrum (STIC origin). Presents similarly to ovarian cancer (pelvic mass, ascites). Classic triad: intermittent profuse watery vaginal discharge (hydrops tubae profluens), pelvic pain, pelvic mass.	Clinically almost indistinguishable from ovarian cancer; often grouped together.
Primary peritoneal carcinomatosis	Serous papillary carcinoma arising from the peritoneum (same Müllerian origin as ovarian surface epithelium). Presents with ascites + peritoneal implants but ovaries may appear normal or only surface-involved.	Can occur even after bilateral oophorectomy. Treated the same way as ovarian cancer. Important in BRCA carriers — prophylactic BSO reduces but does NOT eliminate risk of peritoneal cancer.

Condition	Key Features	How to Distinguish
Uterine fibroid (leiomyoma)	Most common pelvic tumour in women. Benign smooth muscle tumour. Can be very large. On pelvic exam: firm, irregular, non-tender midline mass that moves with the cervix. USG: well-defined hypoechoic solid mass continuous with the myometrium (key sign). Often multiple. Calcifications common. Important DDx of pelvic mass. ^[7]	Fibroids arise from the uterus → mass moves with cervix on bimanual exam. USG clearly shows it arising from the myometrium. No ascites (unless pedunculated subserosal fibroid undergoes torsion/degeneration). CA-125 usually normal (can be slightly raised). In the exam vignette: "Uterus cannot be visualised" — this suggests the mass is separate from or replacing the uterus, making fibroid less likely and ovarian cancer more likely. ^[6]
Endometrial cancer	Postmenopausal bleeding is the hallmark. Mass is intrauterine, not adnexal. USG: thickened endometrium (> 4mm in postmenopausal).	Endometrial cancer presents with vaginal bleeding, not an adnexal mass. However, synchronous ovarian and endometrial cancer occurs in ~15–20% of endometrioid ovarian cancers — always check the endometrium.
Adenomyosis	Diffusely enlarged, boggy, tender uterus. Heavy/painful periods. MRI: ill-defined junctional zone thickening.	Not a discrete mass; diffuse uterine enlargement. Premenopausal.

Condition	Key Features	How to Distinguish
Ectopic pregnancy	Reproductive-age woman with amenorrhoea, vaginal bleeding, pelvic pain. Positive β-hCG. Adnexal mass (can be complex/haemorrhagic). Can have free fluid (haemoperitoneum).	Always do a pregnancy test in any reproductive-age woman with a pelvic mass or acute pelvic pain. β-hCG is the definitive differentiator.
Tubo-ovarian abscess / PID	Fever, bilateral pelvic pain, purulent vaginal discharge, cervical excitation. Complex adnexal mass on USG. Raised WCC, CRP.	Acute presentation with infectious features. History of multiple sexual partners, STI risk. Responds to antibiotics.
Hydrosalpinx	Dilated, fluid-filled fallopian tube. Typically sausage-shaped on USG. Often secondary to previous PID or endometriosis.	Tubular morphology on USG (not round like an ovarian mass). No solid component.

Condition	Key Features	How to Distinguish
Appendiceal pathology (appendicitis, appendiceal mucocele, appendiceal tumour)	Crucial: appendiceal mucinous tumours are one of the most common causes of pseudomyxoma peritonei (gelatinous ascites). Can present as a pelvic mass mimicking ovarian cancer. If mucinous ovarian tumour is found at surgery → always inspect the appendix to exclude appendiceal primary.	Right iliac fossa pain (appendicitis), or may be incidental finding. Appendiceal tumours can metastasise to the ovary → the "ovarian mucinous tumour" may actually be secondary. Immunohistochemistry (CK7/CK20 profile) helps determine origin.
Colorectal cancer	Can present as a pelvic mass (sigmoid or rectal cancer), bowel obstruction symptoms, rectal bleeding, altered bowel habit. Ascites if peritoneal carcinomatosis. Metastatic CRC to ovary (Krukenberg) is important in the DDx ^[5].	PR exam, colonoscopy, CEA, CT imaging shows bowel wall thickening/mass.
Peritoneal metastases from GI primaries	Gastric, pancreatic, colorectal cancers can all cause peritoneal carcinomatosis → ascites + omental cake that can mimic ovarian cancer ^[5]^[8]. "Ascites suggest peritoneal seedling from GI or gynaecological primary" ^[8].	Need CT TAP, OGD, colonoscopy to exclude GI primary. Ascitic fluid cytology and cell block immunohistochemistry can help determine the primary site.
Diverticular abscess	Left iliac fossa pain and mass, fever, raised inflammatory markers. Older patients.	CT shows pericolic abscess with adjacent diverticular disease.
Distended bladder / pelvic kidney	Can be palpated as a suprapubic/pelvic mass.	Catheterisation resolves a distended bladder. USG easily identifies a pelvic kidney.
Retroperitoneal tumours (lymphoma, sarcoma)	Para-aortic or pelvic lymphadenopathy from lymphoma. Retroperitoneal sarcoma can present as a large pelvic/abdominal mass.	CT shows mass arising from retroperitoneum, not from the adnexae. Lymphoma: systemic B-symptoms, diffuse lymphadenopathy.

The Risk of Malignancy Index (RMI) is a widely used tool to differentiate benign from malignant ovarian masses, particularly relevant in the UK and Hong Kong practice ^[7]^[10]:

RMI = U × M × CA-125

Where:

U = Ultrasound score (based on 5 features: multilocular, solid areas, bilateral, ascites, metastases)
- 0 features = U score 0; 1 feature = U score 1; ≥2 features = U score 3
M = Menopausal status: premenopausal = 1; postmenopausal = 3
CA-125 = serum level in U/mL

If RMI ≥ 200 (some studies use ≥ 250): increased risk of malignancy → refer to gynaecological oncology MDT review ^[7]^[10].

Limitation: not all patients with ovarian cancer have an elevated CA-125 ^[10] — particularly mucinous, clear cell, and early-stage tumours.

The ADNEX model is an alternative (and more sophisticated) risk prediction model that can "reliably distinguish between benign, borderline, stage I invasive, stage II–IV invasive, and secondary metastatic adnexal ovarian tumours" ^[11].

Age is one of the most powerful clinical discriminators:

Age Group	Most Likely Ovarian Pathology	Why
Neonates / children	Functional cysts (maternal hormonal stimulation), germ cell tumours (dysgerminoma, yolk sac tumour, immature teratoma)	Germ cells are most active during development. Functional cysts from transplacental gonadotropin stimulation.
Adolescents / young adults (15–30)	Functional cysts, dermoid cysts (mature teratoma), germ cell tumours, sex cord–stromal tumours	Dermoid cysts peak incidence. Germ cell tumours are the commonest malignant ovarian tumour in this age group.
Reproductive age (30–45)	Functional cysts, endometriomas, dermoid cysts, serous/mucinous cystadenomas, borderline tumours	Endometriosis and its complications peak. Borderline tumours often in this age range.
Peri-/postmenopausal (> 50)	Epithelial ovarian cancer (HGSOC), metastatic tumours (Krukenberg), Brenner tumour, fibroma/thecoma	Epithelial ovarian cancers are predominantly a disease of postmenopausal women ^[1]. Any new adnexal mass in a postmenopausal woman must be considered malignant until proven otherwise.

Golden Rule for Postmenopausal Adnexal Mass

In a postmenopausal woman, functional ovarian cysts should NOT occur (no ovulation). Therefore, any new adnexal mass in a postmenopausal woman is suspicious for malignancy and warrants further investigation with CA-125, imaging, and consideration of the RMI/ADNEX model.

CA-125 is the most important tumour marker for ovarian cancer, but it has significant limitations ^[9]^[10]:

Tumour Marker	Elevated In	Clinical Use / Pitfalls
CA-125	Malignant: CA ovary (especially serous), primary peritoneal cancer. Benign: endometriosis, ascites, pleural effusion, menses, PID, fibroids, liver disease, pregnancy, heart failure ^[9]	Sensitivity ~80% for advanced serous EOC but only ~50% for Stage I. Not specific — elevated in many benign conditions. Increase during menses → test done during first half of menstrual cycle ^[9]. Used in RMI calculation.
HE4 (Human Epididymis protein 4)	Ovarian cancer (especially serous and endometrioid). Less likely elevated in endometriosis.	More specific than CA-125 for ovarian cancer; less affected by benign conditions. ROMA algorithm (Risk of Ovarian Malignancy Algorithm) combines HE4 + CA-125 + menopausal status.
AFP	Yolk sac tumour, immature teratoma, HCC, hepatitis, pregnancy ^[9]	Germ cell tumour marker. If AFP elevated in a young woman with an ovarian mass → think yolk sac tumour.
β-hCG	Choriocarcinoma, embryonal carcinoma, pregnancy	Always exclude pregnancy first. Non-gestational ovarian choriocarcinoma is rare but produces very high β-hCG.
LDH	Dysgerminoma, lymphoma	Non-specific but elevated in dysgerminoma.
Inhibin B	Granulosa cell tumour	Useful marker for sex cord–stromal tumours.
CEA	CRC, gastric, pancreatic, breast, lung ^[9]	If CEA is elevated with a mucinous ovarian mass → consider GI primary (appendiceal, colonic) metastasising to the ovary.
CA 19-9	Pancreatic, biliary, CRC, gastric, ovarian (mucinous subtype) ^[9]	Can be elevated in mucinous ovarian tumours but also in many GI primaries.

CA-125 Pitfalls — Exam Favourite

CA-125 is not diagnostic of ovarian cancer. Common exam traps:

Endometriosis can elevate CA-125 → false positive in a premenopausal woman with a pelvic mass.
Early-stage ovarian cancer (especially mucinous and clear cell) often has normal CA-125 → false negative.
Non-gynaecological causes of elevated CA-125: cirrhosis with ascites, peritonitis, heart failure, pleural effusion, pancreatitis.
"Limitation of this rule → not all patients with ovarian cancer have an elevated CA-125" ^[10].

"Pelvic ultrasound is commonly performed" ^[7] as the first-line imaging for a pelvic mass.

USG Feature	Suggests Benign	Suggests Malignant
Walls	Thin, smooth	Thick, irregular
Content	Anechoic (simple fluid)	Mixed solid-cystic
Septae	Thin (< 3 mm), regular	Thick (> 3 mm), irregular
Papillary projections	Absent	Present
Laterality	Unilateral	Bilateral
Ascites	Absent	Present
Doppler flow	Low resistance, low flow	High flow, low resistance index (RI < 0.4)
Size	< 5 cm (functional cyst)	> 5–10 cm (though benign mucinous can be huge)

Specific USG patterns by diagnosis:

Diagnosis	USG Appearance
Simple functional cyst	Thin-walled, anechoic, posterior acoustic enhancement, no septa/solid component
Dermoid cyst	"Tip of the iceberg" sign, echogenic fat, calcification (teeth/bone), Rokitansky nodule
Endometrioma	Homogeneous low-level internal echoes ("ground glass"), no solid components
Haemorrhagic cyst	Complex cystic with reticular (lace-like) internal echoes; resolves on follow-up
Serous cystadenoma	Unilocular, thin-walled, anechoic (looks like a large simple cyst)
Mucinous cystadenoma	Multilocular, thin septae, echogenic mucoid content
Ovarian cancer	Mixed solid-cystic, thick irregular walls/septae, papillary projections, bilateral, ascites ^[6]
Fibroma	Solid, hypoechoic, posterior acoustic shadowing
Uterine fibroid	Arises from myometrium (continuous with uterine wall), well-defined, whorled appearance, may calcify

Krukenberg tumour: Gastric cancer is common in East Asia. Any bilateral ovarian mass, especially with GI symptoms, must prompt exclusion of a gastric or colonic primary. "Peritoneal mets: ascites, Sister Joseph nodule, IO, Krukenberg's tumour" ^[8].
Tuberculosis: TB peritonitis can mimic ovarian cancer with ascites, elevated CA-125, peritoneal thickening, and omental cake-like appearance on CT. In Hong Kong, where TB incidence is non-negligible, this is an important DDx. Ascitic fluid analysis (lymphocyte-predominant exudate, elevated ADA) and peritoneal biopsy (caseating granulomas) differentiate TB from malignancy.
DIC from mucinous tumours: Mucinous tumours (pancreatic, gastric, ovarian) can cause chronic DIC (release of pro-coagulation factors, especially tissue factor, from mucin-secreting cells) ^[12]. This can present with unprovoked VTE as the first manifestation of the underlying malignancy.

Management pathway from lecture slides ^[7]: Postmenopausal ovarian cyst → Measure CA-125 → TVS + TAS → Calculate RMI → If RMI < 200 and meets low-risk criteria (asymptomatic, simple cyst, < 5 cm, unilocular, unilateral) → conservative management with repeat assessment. If RMI ≥ 200 → CT scan + referral for gynaecological oncology MDT review. High likelihood of ovarian malignancy → laparotomy with full staging procedure by a trained gynaecological oncologist. Low likelihood → pelvic clearance (TAH + BSO + omentectomy + peritoneal cytology) by a suitably trained gynaecologist.

High Yield Summary

Differential diagnosis of ovarian cancer — Think anatomically:

Ovarian benign: Functional cyst (resolves in 6–8 weeks; should NOT occur postmenopause), dermoid cyst (fat + calcification on imaging), endometrioma (ground glass on USG), serous/mucinous cystadenoma (thin-walled cystic), fibroma (solid; Meigs syndrome mimics advanced ovarian cancer).
Ovarian borderline: Papillary projections but no stromal invasion. Excellent prognosis. Histological diagnosis.
Ovarian malignant: Primary EOC (HGSOC most common), germ cell tumours (young women, AFP/β-hCG), sex cord–stromal (granulosa cell tumour → oestrogen → PMB).
Metastatic to ovary: Krukenberg tumour (gastric, colon, appendix) — bilateral, signet ring cells. Always exclude GI primary with mucinous ovarian masses.
Uterine: Fibroids (moves with cervix, continuous with myometrium on USG), endometrial cancer (PMB, thickened endometrium).
Tubal: Ectopic pregnancy (always do β-hCG!), TOA/PID, fallopian tube carcinoma.
Non-gynae: TB peritonitis (important in HK), appendiceal tumours/pseudomyxoma peritonei, CRC, retroperitoneal tumours, distended bladder.

Key differentiating tools: Age, menopausal status, USG morphology, CA-125 (+ HE4), RMI/ADNEX, tumour markers (AFP, β-hCG, inhibin, CEA), CT TAP, endoscopy.

RMI = U × M × CA-125. ≥ 200 → refer gynae-oncology MDT.

Meigs syndrome (fibroma + ascites + pleural effusion) is a BENIGN mimic of advanced ovarian cancer.

Postmenopausal adnexal mass = malignant until proven otherwise.

Active Recall - Differential Diagnosis of Ovarian Cancer

References

^[1] Lecture slides: GC 112. Abnormal vaginal bleeding Gynaecological cancer.pdf (p19, p37–38; risk factors, oestrogen-secreting tumours) ^[5] Senior notes: Ryan Ho GI.pdf (p183; Lynch syndrome extracolonic tumours including ovary, cancer screening) ^[6] Senior notes: Ryan Ho Radiology.pdf (p39; Exam question M18 Rotation 3 — F/75 pelvic mass, ascites, mixed solid-cystic lesion = ovarian cancer; DDx including dermoid cyst, functional cyst, uterine fibroma, endometriosis) ^[7] Lecture slides: GC 118. Pelvic mass ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p68, p71; postmenopausal ovarian cyst algorithm, RMI, management pathway, summary) ^[8] Senior notes: Ryan Ho GI.pdf (p84; Krukenberg tumour, peritoneal metastases, Sister Joseph nodule, ascites from GI primary; p279 liver metastasis ascites from peritoneal seedling) ^[9] Senior notes: Maksim Medicine Notes.pdf (p337; tumour markers — CA-125, AFP, CEA, CA 19-9, HCG) ^[10] Lecture slides: Block C - Pelvic mass_ ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p40; RMI, limitation of CA-125) ^[11] Lecture slides: GC 118. Pelvic mass ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p60; ADNEX model) ^[12] Senior notes: Ryan Ho Haemtology.pdf (p137–138; DIC from mucinous tumours including ovarian, chronic DIC)

Diagnosis of Ovarian Cancer — Criteria, Algorithm, and Investigations

The diagnosis deck p. 8 uses Simple Rules, distinct from the ADNEX probability model. Benign features: unilocular cyst, solid component <7 mm, acoustic shadows, smooth multilocular tumour <100 mm, or absent Doppler flow. Malignant features: irregular solid tumour, ascites, ≥4 papillary projections, irregular multilocular-solid tumour ≥100 mm, or very strong flow. At least one B feature with no M feature suggests benignity; at least one M with no B suggests malignancy. Both or neither is inconclusive, requiring expert assessment rather than automatic reassurance.

Unlike conditions such as rheumatoid arthritis or SLE where you can tick off classification criteria, ovarian cancer does not have a set of "diagnostic criteria" in that sense. Instead, the diagnosis is reached through a systematic pathway that integrates:

Clinical suspicion (symptoms, signs, risk factors)
Biochemical markers (CA-125, HE4, others depending on suspected subtype)
Imaging (ultrasound → CT → MRI/PET-CT)
Risk stratification models (RMI, ROMA, ADNEX)
Histopathological confirmation (the definitive diagnosis — always requires tissue)

"Ovarian cancer is the silent killer — so any symptoms generally suggestive of a late disease" ^[7]^[10]. This means you must have a low threshold for investigation in any woman — especially postmenopausal — with persistent vague abdominal/pelvic symptoms.

Diagnosis normally requires histology from surgery or a core biopsy before neoadjuvant therapy. Cytology is an exceptional alternative when biopsy is not feasible; it is not equivalent to a tissue specimen for subtype and molecular assessment.

1. Risk Stratification Models — Deciding Who Needs Urgent Referral

These models exist because you cannot take every woman with an adnexal mass straight to laparotomy. You need a way to triage: who can be observed, who needs a gynaecologist, and who needs a gynaecological oncologist. This distinction matters because outcomes are significantly better when ovarian cancer surgery is performed by a trained gynae-oncologist.

RMI is more commonly used in the UK and in Hong Kong practice ^[10].

Formula: RMI = U × M × CA-125 ^[7]^[10]

Component	Score	Explanation
U = Ultrasound morphology score	Score 1 point for each: multilocular, solid areas, bilateral, ascites, metastases	0 features = U score 0; 1 feature = U score 1; ≥ 2 features = U score 3
M = Menopausal status	Premenopausal = 1; Postmenopausal = 3	Postmenopausal age scores 3 because any adnexal mass in a postmenopausal woman is inherently more suspicious ^[10]
CA-125	Absolute value in U/mL	Continuous variable, multiplied directly

Interpretation:

RMI < 200: low risk of malignancy ^[7]
RMI ≥ 200 (some studies use ≥ 250): increased risk of malignancy → patient must be referred to gynaecological oncology MDT review ^[7]^[10]

Why these components? Each captures a different dimension of risk:

Ultrasound morphology captures the structural features that distinguish benign from malignant masses (solid components, bilateral involvement, and ascites all correlate with malignancy).
Menopausal status is a powerful prior probability modifier — a functional cyst in a 30-year-old is common and benign; the same-looking cyst in a 65-year-old is abnormal by definition.
CA-125 adds biochemical data. While imperfect alone, when combined with the other two components, it significantly improves discrimination.

Performance: Sensitivity ~78%, Specificity ~87% at the ≥ 200 threshold. This is acceptable for triage but not for definitive diagnosis.

"Limitation of this rule → not all patients with ovarian cancer have an elevated CA-125" ^[10]. This is particularly true for:

Mucinous carcinoma (~50% have normal CA-125)
Clear cell carcinoma (variable CA-125 elevation)
Early-stage disease (~50% of Stage I have normal CA-125)
Germ cell and sex cord–stromal tumours (CA-125 is an epithelial marker)

RMI Worked Example

A 65-year-old postmenopausal woman has a bilateral adnexal mass with solid areas and ascites on USG. Her CA-125 is 350 U/mL.

U score: bilateral (1) + solid areas (1) + ascites (1) = 3 features → U = 3
M score: postmenopausal → M = 3
CA-125 = 350
RMI = 3 × 3 × 350 = 3150 → far exceeds 200 → urgent referral to gynae-oncology MDT

ROMA combines CA-125 + HE4 + menopausal status using a logistic regression formula to calculate a predicted probability of malignancy.

HE4 (Human Epididymis protein 4) is a glycoprotein overexpressed in ovarian cancer (especially serous and endometrioid subtypes). Its advantage over CA-125: it is less frequently elevated in benign conditions (endometriosis, fibroids, PID), so it improves specificity.
ROMA is particularly useful in premenopausal women where CA-125 false positives are more common.
Thresholds differ by menopausal status: premenopausal ≥ 11.4% = high risk; postmenopausal ≥ 29.9% = high risk (values may vary by assay).

The ADNEX model (Assessment of Different NEoplasias in the adneXa) is a risk prediction model that can reliably distinguish between benign, borderline, stage I invasive, stage II–IV invasive, and secondary metastatic adnexal ovarian tumours ^[11].

The ADNEX model uses ultrasound-based parameters (from the IOTA — International Ovarian Tumour Analysis — group):

Patient age
Serum CA-125 level
Maximum lesion diameter
Proportion of solid tissue
Number of papillary projections
More than 10 cyst locules
Acoustic shadows
Ascites
Type of centre (oncology centre or not)

Why is ADNEX superior to RMI? It provides multi-class probabilities (not just benign vs. malignant) — it separately estimates probabilities for benign, borderline, stage I invasive, stage II–IV invasive, and secondary metastatic, allowing more nuanced management decisions.

The pathway below separates uncomplicated cysts from a suspected invasive malignancy.

RCOG's December 2025 update exempts asymptomatic, simple, unilateral, unilocular postmenopausal cysts ≤3 cm from routine follow-up. Do not apply this exception to symptoms, complex morphology or hereditary-risk counselling. Larger low-risk cysts have a separate follow-up pathway; persistence alone at 12 weeks does not mandate cancer surgery. RCOG guideline.

3. Investigation Modalities — Detailed Breakdown

Investigation	Rationale	Key Findings / Interpretation
CBC	Assess for anaemia (chronic disease, nutritional), thrombocytosis (paraneoplastic — common in ovarian cancer, correlates with advanced stage), leukocytosis	Normocytic normochromic anaemia of chronic disease. Thrombocytosis (platelet > 400) is a poor prognostic marker — IL-6 from tumour stimulates hepatic thrombopoietin production.
LFT	Assess for liver metastasis, nutritional status (albumin), biliary obstruction (if omental disease compresses porta hepatis)	↑ALP, ↑GGT suggests liver mets or biliary compression. ↓Albumin reflects poor nutrition / chronic disease (also leaks into ascitic fluid).
RFT / electrolytes	Baseline renal function (hydronephrosis from pelvic mass obstructing ureters; pre-chemotherapy baseline), electrolyte derangement	↑Creatinine may indicate ureteric obstruction. Pre-chemo baseline essential for cisplatin/carboplatin (nephrotoxic).
CaPO4	Hypercalcaemia can occur in ovarian cancer — ectopic PTHrP production, particularly in small cell carcinoma of the ovary ^[13]	"Ectopic PTHrP production, eg. CA lung, HCC, CA breast, small cell CA ovary" ^[13]. Also assess bone metastasis.
Coagulation screen	Baseline (pre-surgery), DIC screening (mucinous tumours are a cause of chronic DIC)	↑PT, ↑aPTT, ↓fibrinogen, ↑D-dimer → DIC. Even without overt DIC, a hypercoagulable state is common → VTE prophylaxis critical.
β-hCG	Exclude pregnancy in reproductive-age women (always first step!). Also a tumour marker for ovarian germ cell tumours (choriocarcinoma, embryonal carcinoma) ^[9]	Positive → pregnancy vs. gestational trophoblastic disease vs. germ cell tumour (non-gestational choriocarcinoma).

This is a critical topic and highly examinable ^[9].

Marker	Primary Use in Ovarian Cancer	Normal Range	Pitfalls / Interpretation
CA-125	Most important marker for epithelial ovarian cancer (especially serous). Used for: (1) aid diagnosis, (2) calculate RMI, (3) monitor treatment response, (4) detect recurrence ^[7]^[9]^[10]	< 35 U/mL	Elevated in benign conditions: endometriosis, ascites, pleural effusion, menses, PID, fibroids, liver disease, pregnancy ^[9]. Increase during menses → test done during first half of menstrual cycle ^[9]. Sensitivity ~80% for advanced serous but only ~50% for Stage I. Normal in ~50% of mucinous/clear cell carcinomas.
HE4	Complementary to CA-125. Better specificity (less affected by endometriosis, fibroids). Used in ROMA algorithm.	Varies by age/menopause	Elevated in ovarian cancer (serous > endometrioid). Less useful for mucinous and germ cell tumours. Combined with CA-125 in ROMA for improved triage.
AFP	Germ cell tumour marker: yolk sac tumour (endodermal sinus tumour), immature teratoma, embryonal carcinoma. Also HCC, hepatitis ^[9]	< 20 mcg/L (Pregnancy: ≤500 mcg/L) ^[9]	If elevated in a young woman with an ovarian mass → strongly suggests germ cell tumour. Must exclude pregnancy.
β-hCG	Germ cell tumours: choriocarcinoma (very high), embryonal carcinoma. Also pregnancy, molar pregnancy ^[9]	Negative in non-pregnant	Non-gestational ovarian choriocarcinoma produces extremely high β-hCG. Dysgerminoma with syncytiotrophoblastic giant cells may produce low levels.
LDH	Dysgerminoma (elevated), also non-specific for tissue turnover	Varies by lab	Non-specific. Useful as part of the germ cell tumour panel (AFP + β-hCG + LDH). AFP, HCG, LDH used for prognostication in germ cell tumours (NSGCT) ^[9].
Inhibin B / AMH	Sex cord–stromal tumours: granulosa cell tumour (inhibin B), also AMH	Varies	Highly specific for granulosa cell tumour. Useful for monitoring recurrence.
CEA	Mucinous tumours (can be elevated). Also CRC, gastric, breast, lung ^[9]	< 3 mcg/L (non-smoker)	If elevated with mucinous ovarian mass → consider GI primary (appendix, colon) metastasising to ovary (Krukenberg). Benign conditions rarely > 10 mcg/L ^[9].
CA 19-9	Mucinous ovarian tumours. Also pancreatic, biliary, CRC, gastric ^[9]	< 37 U/mL	Non-specific. Useful adjunct for mucinous subtype. Not produced by individuals who are Lewis antigen negative (~5–10% of population → false negative).

Tumour Marker Panel — Choose Based on Clinical Scenario

Postmenopausal woman + adnexal mass: CA-125 (± HE4) → think epithelial ovarian cancer
Young woman (< 30) + adnexal mass: AFP + β-hCG + LDH + CA-125 → think germ cell tumour
Any age + virilisation or postmenopausal bleeding with adnexal mass: Inhibin B, oestradiol, testosterone → think sex cord–stromal tumour
Mucinous mass + GI symptoms: CEA + CA 19-9 + CA-125 → exclude GI primary

"Pelvic ultrasound is commonly performed" ^[7] and is "Demonstrate a basic understanding in pelvic ultrasound examination of the common pelvic pathology" — a learning objective ^[2].

Transvaginal ultrasound (TVS) is the gold standard first-line imaging for evaluating adnexal masses because it provides the highest resolution for pelvic structures (the transducer is close to the adnexae). Transabdominal scanning (TAS) is added to assess large masses that extend beyond the TVS field of view, and to survey the upper abdomen for ascites, omental disease, and liver lesions.

Both TVS and TAS should be performed ^[7].

USG Feature	What It Tells You	Interpretation
Morphology (cystic/solid/mixed)	Tissue composition of the mass	Pure cystic = likely benign; mixed solid-cystic = suspicious ^[6]; solid = could be fibroma, thecoma, or malignant
Wall thickness	Regularity of tumour capsule	Thin smooth walls = benign; thick irregular walls = malignant
Septae	Internal architecture of cystic lesions	Thin (< 3mm) regular septae = likely benign cystadenoma; thick (> 3mm) irregular septae = suspicious
Papillary projections	Solid tissue projecting into cyst cavity	Present = suspicious for malignancy (represent areas of proliferating tumour growing into the cyst)
Laterality	Unilateral vs. bilateral	Bilateral = more suspicious for malignancy (or metastatic: Krukenberg)
Ascites	Free fluid in pelvis / abdomen	Ascites with a complex adnexal mass = highly suspicious for ovarian cancer
Colour Doppler	Vascularity and blood flow pattern	Low resistance index (RI < 0.4) with high diastolic flow = neovascularisation of malignancy (tumour vessels lack smooth muscle → low resistance). Benign masses have high-resistance flow.
Pouch of Douglas	Most dependent part of peritoneum	Deposits/nodularity in the pouch of Douglas = peritoneal carcinomatosis ^[7]

Specific USG patterns in common ovarian pathologies:

Diagnosis	Classic USG Appearance
Simple / functional cyst	Thin-walled, anechoic, posterior acoustic enhancement, no internal echoes
Dermoid cyst	Echogenic component (fat/hair), "dermoid plug" (Rokitansky nodule), "tip of the iceberg" sign, ± teeth (strong acoustic shadow)
Endometrioma	Homogeneous low-level internal echoes ("ground glass" appearance), no solid projections
Haemorrhagic cyst	Complex: reticular/fishnet pattern of fibrin strands; resolves on follow-up in 6–8 weeks
Serous cystadenoma	Unilocular, thin-walled, anechoic (large simple cyst)
Mucinous cystadenoma	Multilocular with thin septae, mucoid content (low-level echoes in locules, "stained glass" appearance)
Ovarian cancer	Mixed solid-cystic, thick irregular septae, papillary projections, bilateral, ascites, low-resistance Doppler flow ^[6]
Fibroma	Solid, hypoechoic, may show posterior acoustic shadowing

Exam question recall ^[6]: "F/75 complained of increasing abdominal girth. PE found abdominal mass arising from pelvis and ascites. USG abdomen found mixed solid-cystic lesion at pelvis and ascites. Uterus cannot be visualised. → Most likely diagnosis: Ovarian cancer."

Exam question recall ^[6]: "PV detect Left adnexal mass. The patient has urinary incontinence, which investigation is most appropriate? → Transvaginal US" ^[14]

TVS vs. TAS — When to Use Which

TVS is superior for characterising adnexal masses (higher frequency probe → better resolution for small structures). TAS is needed for large masses that extend beyond the pelvis, and for surveying the upper abdomen (ascites, liver, omentum). In practice, always do BOTH TVS + TAS ^[7].

CT scan is performed when RMI ≥ 200 (or when malignancy is suspected) ^[7] and serves two purposes:

Staging: assess extent of peritoneal disease, lymph node involvement, distant metastases
Surgical planning: determine resectability (can optimal cytoreduction be achieved?)

CT Finding	Significance
Pelvic mass — solid/cystic components, enhancement pattern	Characterises the tumour. Arterial-phase enhancement of solid components supports malignancy.
Ascites	Peritoneal carcinomatosis. Volume and distribution help plan surgery.
Omental cake	Tumour-infiltrated omentum — appears as a thickened, nodular sheet of tissue anterior to the bowel. Hallmark of Stage III disease.
Peritoneal implants	Nodular peritoneal thickening, especially in the pouch of Douglas, paracolic gutters, subdiaphragmatic surfaces, mesentery.
Liver surface deposits	Liver capsule/surface involvement = Stage IIIC (peritoneal spread). Liver parenchymal metastasis = Stage IVB.
Lymphadenopathy	Pelvic (iliac) and para-aortic nodes. Enlarged nodes (> 1cm short axis) suggest metastasis → Stage IIIA1 if retroperitoneal nodes only.
Pleural effusion	Needs cytological confirmation to stage as IVA. Seen on CT as fluid in the pleural space.
Hydronephrosis	Ureteric obstruction by pelvic mass or retroperitoneal nodes.
Bowel involvement	Thickening, obstruction, mesenteric implants — important for surgical planning.

CT also excludes non-ovarian primaries: look for gastric wall thickening (Krukenberg), colonic mass, appendiceal lesion, pancreatic mass, breast mass (if CT includes chest).

MRI is not routinely first-line for all ovarian masses but is used in specific situations:

Indication	Why MRI?
Indeterminate adnexal mass on USG	MRI has the best soft tissue contrast resolution for characterising complex adnexal masses — can differentiate endometrioma from haemorrhagic cyst from malignancy when USG is unclear.
Local staging	Excellent for assessing local invasion (parametrial, bladder, rectum) — analogous to its role in cervical and rectal cancer. "MRI is the best modality for... local spread" ^[15]
Young patient / fertility-sparing considerations	To better characterise the mass and plan surgery when preservation of the contralateral ovary is being considered.
Pregnancy	No ionising radiation → safe alternative to CT for staging in pregnant women with an ovarian mass.

Key MRI features of ovarian cancer: solid enhancing components (T1 post-gadolinium), restricted diffusion on DWI (high cellularity), ascites, peritoneal enhancement.

PET/CT is indicated for diagnosis, staging, restaging and monitoring of treatment in ovarian cancer ^[16].

Role	Explanation
Initial staging	PET/CT has higher sensitivity than CT alone for detecting peritoneal deposits, lymph node metastases, and extra-abdominal disease. Most useful for detecting occult distant disease that changes management.
Restaging / recurrence	When CA-125 rises during follow-up but conventional imaging is negative → PET/CT can detect small-volume recurrence.
Monitoring treatment response	Metabolic response (FDG avidity decrease) may precede anatomical response.
Limitation	Mucinous tumours may have low FDG avidity. Small peritoneal implants (< 1cm) may be below PET resolution.

Radiopharmaceutical: 18F-FDG (most commonly used) ^[16]. FDG is a glucose analogue taken up by metabolically active cells (cancer cells have upregulated GLUT transporters and hexokinase) → trapped intracellularly → detected by PET scanner.

When ascites is present, paracentesis provides both diagnostic and symptomatic benefit:

Test	Purpose	Findings in Ovarian Cancer
Cytology	The most important test on ascitic fluid — can confirm malignancy and sometimes suggest histological subtype	Positive for malignant cells (adenocarcinoma). Cell block can be stained for immunohistochemistry (WT1+, PAX8+ → supports Müllerian/ovarian origin).
Protein / albumin / SAAG	Differentiate exudate vs. transudate; SAAG (Serum-Ascites Albumin Gradient) < 11 g/L = exudate (peritoneal carcinomatosis) vs. > 11 g/L = portal hypertension	Ovarian cancer → exudative ascites (SAAG < 11), high protein, high LDH.
Cell count	Differential: neutrophils (infection) vs. lymphocytes (TB, malignancy)	Malignant ascites: variable, but often mononuclear-predominant.
Glucose, LDH	Supports exudate vs. transudate; very low glucose suggests infection or malignancy	Low glucose, high LDH in malignant ascites.
ADA (adenosine deaminase)	To exclude TB peritonitis — important DDx in Hong Kong	ADA > 39 U/L highly suggestive of TB peritonitis. Normal in ovarian cancer.
Tumour markers in fluid	CA-125, CEA in ascitic fluid	Very high CA-125 in ascites from ovarian cancer. High CEA suggests GI primary.

Ascitic Cytology — Stage Implications

If ascitic/peritoneal washing cytology is positive for malignant cells, this is at minimum Stage IC3 (if tumour is otherwise confined to ovaries) or higher. Do NOT forget to send peritoneal washings at the time of surgery — it changes staging!

No ovarian cancer treatment should be initiated without histological confirmation (except in rare emergencies).

Method	When Used	Notes
Laparotomy with surgical staging	Gold standard for suspected ovarian malignancy. Performed when RMI ≥ 200 / high clinical suspicion ^[7]	Provides tissue for diagnosis AND simultaneously achieves staging and debulking. The preferred approach.
Image-guided core biopsy (CT or USS-guided)	When primary debulking surgery is not immediately feasible (e.g., too unwell, unresectable disease, need neoadjuvant chemotherapy)	Provides histology and molecular profiling (e.g., BRCA status, HRD status) to guide neoadjuvant treatment. Usually a peritoneal deposit or omental cake is biopsied.
Ascitic fluid cytology (paracentesis)	When ascites is present and patient is not fit for immediate surgery	Can confirm malignancy. Cell block allows immunohistochemistry. Use only exceptionally when biopsy cannot be obtained, with ancillary testing and clinical evidence excluding another primary; a convincing clinical picture alone is insufficient.
Laparoscopic biopsy	Occasionally used for tissue diagnosis and assessment of resectability	Allows visual assessment of peritoneal disease load and targeted biopsy. Risk of port-site metastasis (tumour implanting at trocar sites) is a concern.
Frozen section (intraoperative)	Used during surgery when the nature of the mass is uncertain	Allows the surgeon to decide intraoperatively whether to proceed with full staging (if malignant) or conservative surgery (if benign/borderline). Accuracy ~90%, but false negatives occur, especially with mucinous and borderline tumours → final paraffin section is definitive.

Key histological features that the pathologist reports:

Feature	Clinical Relevance
Histological subtype	Determines prognosis and treatment (e.g., HGSOC vs. clear cell vs. mucinous — very different biology).
Grade	Low-grade vs. high-grade (for serous). Grading system differs by subtype. HGSOC is by definition high-grade.
TP53 immunohistochemistry	Overexpression (diffuse strong) or complete absence (null pattern) = abnormal → supports HGSOC. Wild-type pattern → consider low-grade serous or other subtype.
WT1, PAX8	Müllerian lineage markers — positive in ovarian serous carcinoma, negative in GI primaries → helps distinguish primary ovarian from metastatic.
Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)	Loss of expression → suspect Lynch syndrome → germline testing. Important for endometrioid and clear cell subtypes.
BRCA1/2 status	Germline or somatic testing — determines eligibility for PARP inhibitors and has prognostic value. All HGSOC patients should have BRCA testing.
HRD (Homologous Recombination Deficiency) score	Genomic instability score — predicts response to PARP inhibitors even in BRCA-wild type tumours. Increasingly standard in molecular profiling.

When an ovarian mass is found, especially if bilateral or mucinous, always consider excluding a non-ovarian primary ^[7]^[8]:

Investigation	Target Primary	When to Order
OGD (upper endoscopy)	Gastric cancer (Krukenberg tumour)	Bilateral ovarian mass, signet ring histology, GI symptoms, East Asian population
Colonoscopy	Colorectal cancer	GI symptoms, elevated CEA, mucinous histology, synchronous colon and ovarian masses
Mammogram	Breast cancer (metastatic to ovary)	History of breast symptoms, bilateral ovarian mass
Appendicectomy / appendix inspection	Appendiceal mucinous tumour → pseudomyxoma peritonei	Always inspect the appendix at laparotomy for any mucinous ovarian tumour — it may be the actual primary
CXR	Lung mets, pleural effusion, TB	Baseline for all patients

All patients with epithelial ovarian cancer (especially high-grade serous) should be offered BRCA1/2 germline testing regardless of family history, because:

~15% of HGSOC harbour germline BRCA mutations (many without a significant family history)
BRCA-positive tumours respond to PARP inhibitors (olaparib, niraparib, rucaparib)
Implications for family members (cascade testing) and cancer screening ^[4]

Somatic BRCA testing and HRD scoring on the tumour tissue are increasingly performed to identify patients who may benefit from PARP inhibitors even without germline mutations (~7% have somatic BRCA mutations, ~50% overall have some form of HRD).

Consider Lynch syndrome screening (MMR IHC on tumour) in endometrioid and clear cell ovarian cancers ^[5].

Step	Investigation	Purpose
1. Exclude pregnancy	β-hCG	Mandatory in all reproductive-age women
2. Bloods	CBC, LFT, RFT, CaPO4, coag	Baseline + metastatic workup
3. Tumour markers	CA-125 (all), ± HE4, ± AFP/β-hCG/LDH (young), ± inhibin (suspected stromal), ± CEA/CA19-9 (mucinous)	Aid diagnosis, risk stratification, monitor response
4. First-line imaging	TVS + TAS	Characterise the mass, assess for ascites, provide data for RMI/ADNEX
5. Risk stratification	RMI, ROMA, or ADNEX	Triage: observe vs. operate vs. refer gynae-oncology
6. Staging imaging	CT abdomen + pelvis (if RMI ≥ 200)	Peritoneal disease, nodes, distant mets, surgical planning
7. Additional imaging	MRI (indeterminate mass), PET/CT (staging/recurrence)	Problem-solving, detect occult disease
8. Tissue diagnosis	Surgical histology or image-guided core biopsy before NACT; cytology only an exceptional fallback	Definitive histological diagnosis
9. Molecular profiling	BRCA1/2 (germline + somatic), HRD, MMR IHC	Guide targeted therapy (PARP inhibitors), identify hereditary syndromes
10. Exclude other primary	OGD, colonoscopy, mammogram, appendix inspection	If bilateral, mucinous, or atypical features

High Yield Summary

There are no standalone diagnostic criteria for ovarian cancer — diagnosis is a multi-step pathway culminating in histological confirmation.

Risk stratification: RMI = U × M × CA-125 (≥ 200 = high risk → refer gynae-oncology MDT). Limitation: not all ovarian cancers elevate CA-125. ADNEX model gives multi-class probabilities. ROMA (CA-125 + HE4 + menopausal status) improves specificity in premenopausal women.

First-line imaging: TVS + TAS (always both). Look for mixed solid-cystic morphology, thick irregular septae, papillary projections, bilateral involvement, ascites, low-resistance Doppler flow.

Staging imaging: CT abdomen + pelvis. Look for omental cake, peritoneal implants, lymphadenopathy, pleural effusion, liver deposits.

Tumour markers by scenario:

Postmenopausal + adnexal mass → CA-125 (± HE4)
Young woman + ovarian mass → AFP + β-hCG + LDH + CA-125
Virilisation / PMB with mass → inhibin, oestradiol, testosterone
Mucinous mass → CEA + CA 19-9 (exclude GI primary)

Definitive diagnosis = histology. If neoadjuvant treatment is planned, obtain tissue first, preferably core biopsy. Cytology is an exceptional fallback when biopsy cannot be obtained, with additional evidence excluding another primary. ASCO 2025.

All epithelial ovarian cancers (especially HGSOC) → BRCA testing + consider HRD scoring. Endometrioid/clear cell → MMR IHC (Lynch screening).

Always inspect the appendix if mucinous tumour is found. Always send peritoneal washings for cytology at surgery.

Active Recall - Diagnosis of Ovarian Cancer

References

^[2] Lecture slides: Block C - O&G Theme Case 3.pdf (p1; learning objectives including pelvic ultrasound examination) ^[4] Senior notes: Ryan Ho Urogenital.pdf (p213; BRCA1/2 screening, prophylactic surgery, criteria for genetic counselling) ^[5] Senior notes: Ryan Ho GI.pdf (p183; Lynch syndrome, MSI testing, IHC for MMR proteins, cancer screening) ^[6] Senior notes: Ryan Ho Radiology.pdf (p39–40; exam questions — USG findings in ovarian cancer, adnexal mass investigation, pelvic imaging choice) ^[7] Lecture slides: GC 118. Pelvic mass ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p60, p68; ADNEX model, postmenopausal ovarian cyst algorithm, RMI pathway, management flowchart) ^[8] Senior notes: Ryan Ho GI.pdf (p84, p279; Krukenberg tumour, peritoneal metastases, liver metastasis workup) ^[9] Senior notes: Maksim Medicine Notes.pdf (p337; tumour markers — CA-125, AFP, CEA, CA 19-9, HCG, applications) ^[10] Lecture slides: Block C - Pelvic mass_ ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p16, p40; RMI, limitation of CA-125, ovarian cancer as silent killer) ^[11] Lecture slides: GC 118. Pelvic mass ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p60; ADNEX model) ^[13] Senior notes: Ryan Ho Chemical Path.pdf (p23; ectopic PTHrP production in small cell CA ovary, hypercalcaemia workup) ^[14] Senior notes: Ryan Ho Radiology.pdf (p39; exam question — adnexal mass with urinary incontinence → transvaginal US) ^[15] Lecture slides: Block C - Abnormal vaginal bleeding_ gynaecological cancer.pdf (p21; MRI for local staging, CA-125 for adenocarcinoma) ^[16] Senior notes: Ryan Ho Diagnostic Radiology.pdf (p74; PET/CT clinical indications including ovarian cancer, FDG)

Management of Ovarian Cancer

Faculty surgical checkpoint: Separate staging of apparently early cancer from cytoreduction of advanced disease. The advanced-disease goal is no macroscopic residual tumour. In patients with complete gross resection and clinically normal nodes, routine systematic pelvic/para-aortic lymphadenectomy did not improve survival in LION and increased morbidity; suspicious nodes are a different situation. Obtain histological confirmation (core biopsy preferred) before neoadjuvant chemotherapy. These qualifications refine the broad operation lists in the faculty treatment deck, pp. 4–9. LION trial; ASCO NACT guideline.

Obtain germline/somatic BRCA and tumour HRD results to choose maintenance after a platinum response. Do not copy older all-comer PARP indications: the US niraparib first-line maintenance label is now HRD-positive, and its recurrent-maintenance label requires germline BRCA mutation. Other jurisdictions can differ. Prior PARP exposure also matters when considering maintenance at relapse. (Current niraparib label.)

For platinum-resistant epithelial cancer, test folate receptor alpha (FRα) and relevant PD-L1 expression:

Mirvetuximab soravtansine: FRα-positive platinum-resistant disease after 1–3 previous systemic regimens; requires the approved assay and eye-toxicity precautions. (FDA review.)
Pembrolizumab + paclitaxel ± bevacizumab: FDA-approved February 2026 for CPS ≥1 platinum-resistant disease after one or two systemic regimens. Thus chemo-immunotherapy is no longer universally investigational in ovarian cancer. (FDA indication.)

These recurrence regimens do not replace first-line cytoreduction/platinum treatment for newly diagnosed advanced high-grade epithelial cancer.

Before diving into specifics, you need to understand the fundamental logic of ovarian cancer management. There are three pillars, and their sequencing depends on the stage, resectability, and patient fitness:

Surgery — the cornerstone. Ovarian cancer is unique among solid tumours in that maximal surgical cytoreduction ("debulking") directly improves survival. Every additional centimetre of residual disease left behind worsens the prognosis.
Chemotherapy — platinum-based chemotherapy (carboplatin + paclitaxel) is the backbone for almost all epithelial ovarian cancers.
Targeted therapy — primarily PARP inhibitors (for BRCA/HRD-positive disease) and bevacizumab (anti-VEGF), used as maintenance therapy after initial treatment.

"Management is complicated, depends on many factors. If operable, want to operate first → time-sensitive operation, therapeutic and diagnostic. But if late stage and inoperable, then consider neoadjuvant" ^[17].

This quote captures the central decision point: can we operate first, or do we need chemotherapy first?

2. Surgery — The Cornerstone

Ovarian cancer has a unique relationship with surgery compared to most other cancers:

The volume of residual disease after surgery is the single most important prognostic factor (after stage and grade). Patients with no visible residual disease (R0) after primary surgery have a median survival approximately double that of patients with suboptimal debulking.
Surgery is both diagnostic (provides histological tissue, determines the true stage via systematic exploration) and therapeutic (removes tumour bulk, allowing chemotherapy to work on a smaller residual volume).

The goal is to achieve complete cytoreduction (R0) — no macroscopically visible residual disease. If that is not achievable, the next best is optimal cytoreduction (residual disease ≤ 1 cm).

If operable, want to operate first → time-sensitive operation, therapeutic and diagnostic ^[17].

The standard primary debulking surgery (PDS) for advanced epithelial ovarian cancer includes:

Component	Rationale
Midline laparotomy	Provides full access to the entire abdominal cavity — essential because ovarian cancer spreads diffusely throughout the peritoneum. A transverse or Pfannenstiel incision is inadequate for proper staging/debulking.
Peritoneal cytology / washings	Collect fluid from the pouch of Douglas, paracolic gutters, and subdiaphragmatic areas. Positive cytology upgrades staging (at least IC3).
Total abdominal hysterectomy (TAH)	Removes the uterus, which may harbour synchronous endometrial cancer (15–20% in endometrioid subtype) and eliminates a potential site of metastatic spread.
Bilateral salpingo-oophorectomy (BSO)	Removes both ovaries and tubes. Even if disease appears unilateral, microscopic contralateral involvement is common in advanced disease. TAH + BSO is the standard ^[7].
Omentectomy (infracolic)	The omentum is the most common site of peritoneal metastasis — tumour cells have tropism for omental milky spots. Omentectomy removes the "omental cake" and is essential for staging even if the omentum looks normal (occult deposits). TAH + BSO + omentectomy + peritoneal cytology ^[7].
Peritoneal biopsies	Systematic biopsies from multiple peritoneal sites: pouch of Douglas, paracolic gutters, pelvic side walls, diaphragm, mesentery. Required for accurate staging.
Pelvic and para-aortic lymph node dissection	Ovarian cancer drains to para-aortic nodes (following ovarian vessels) and pelvic (iliac) nodes. Lymph node metastasis without peritoneal spread upgrades to Stage IIIA1. Systematic lymphadenectomy is recommended in apparent early-stage disease for accurate staging. In advanced disease, enlarged nodes are resected for cytoreduction.
Appendicectomy	Mandatory for mucinous tumours (to exclude appendiceal primary). Also routinely done in comprehensive staging.
Any other procedures needed for complete cytoreduction	May include: bowel resection (if tumour involves bowel serosa/mesentery), splenectomy, diaphragm stripping/resection, partial hepatectomy (for surface deposits), peritonectomy. This is why the operation must be performed by a trained gynaecological oncologist ^[7].

From lecture slides ^[7]: "High likelihood of ovarian malignancy → laparotomy, full staging procedure by a trained gynaecological oncologist. Low likelihood of ovarian malignancy → laparotomy, pelvic clearance (TAH + BSO + omentectomy + peritoneal cytology) by a suitably trained gynaecologist."

Why a Gynae-Oncologist?

Multiple studies have shown that patients operated on by gynaecological oncologists have higher rates of complete cytoreduction and better survival compared to those operated on by general gynaecologists or general surgeons. This is because gynae-oncologists are trained in the ultra-radical procedures (bowel resection, diaphragm stripping, etc.) needed to achieve R0. This is why the lecture algorithm specifically differentiates between the two ^[7].

In selected young patients (typically < 40 years) with early-stage disease who desire future fertility, a modified approach can be considered:

Criteria for Fertility-Sparing Surgery	Procedure
Stage IA or IC, Grade 1–2	Unilateral salpingo-oophorectomy (USO) + comprehensive staging (peritoneal biopsies, omentectomy, lymph node sampling, inspection of appendix and contralateral ovary with targeted sampling only if suspicious)
Unilateral disease	Preserve contralateral ovary + uterus
Non-clear cell histology (preferably serous, endometrioid, mucinous, or borderline)	Clear cell has higher recurrence risk → fertility sparing is more controversial
Patient understands the risk	Completion surgery (TAH + contralateral SO) recommended after family completion

For germ cell tumours: fertility-sparing surgery is standard regardless of stage (because germ cell tumours are exquisitely chemosensitive, and survival rates are excellent even with advanced disease treated by USO + chemo).

For borderline tumours in young women: USO + staging is appropriate. Even cystectomy alone may be considered in select cases (but associated with higher recurrence — still borderline, not invasive).

Classification	Definition	Clinical Impact
R0 (complete)	No visible residual disease	Best prognosis. Median survival significantly longer. This is the goal.
Visible residual ≤1 cm (historically “optimal”)	Largest residual deposit ≤ 1 cm	Good prognosis, but inferior to R0.
Visible residual >1 cm (“suboptimal”)	Largest residual deposit > 1 cm	Worst prognosis from surgery. Consider whether NACT + IDS would have been a better strategy.

3. Neoadjuvant Chemotherapy and Interval Debulking Surgery

"If late stage and inoperable, then consider neoadjuvant" ^[17].

Not every patient can — or should — go straight to surgery. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is indicated when:

Indication	Explanation
Unresectable disease	Extensive peritoneal carcinomatosis, heavy disease burden where complete cytoreduction is unlikely (e.g., extensive small bowel mesenteric involvement, porta hepatis involvement, diffuse diaphragmatic deposits)
Patient unfit for major surgery	Severe comorbidities, poor performance status (ECOG ≥ 3), severe malnutrition, massive pleural effusion causing respiratory compromise
Stage IV disease with heavy burden	Parenchymal liver/lung metastases, extensive extra-abdominal disease

How NACT works: Give 3–4 cycles of carboplatin + paclitaxel → reassess with CT and CA-125 → if responding (tumour shrinkage, CA-125 falling), proceed to interval debulking surgery (IDS) → then complete the remaining cycles of chemotherapy (total 6 cycles).

Evidence: The landmark EORTC 55971 and CHORUS trials showed that NACT + IDS has equivalent overall survival to PDS + adjuvant chemo in patients with Stage IIIC–IV disease. However, the trials have been criticised because the PDS arms had suboptimal cytoreduction rates — in centres where high-quality PDS achieving R0 is possible, PDS likely remains superior.

Current consensus: PDS is preferred if R0 cytoreduction is achievable. NACT + IDS is a valid alternative when R0 is unlikely or the patient is unfit.

Before deciding PDS vs. NACT, the surgeon must assess resectability. Tools include:

Method	What It Assesses
CT abdomen + pelvis	Extent of peritoneal disease, omental cake, bowel involvement, lymphadenopathy, liver deposits
Diagnostic laparoscopy	Direct visualisation of disease burden. Scoring systems (e.g., Fagotti score) predict whether R0 is achievable. If Fagotti score > 8 → high risk of suboptimal debulking → NACT preferred.
Serum albumin / nutritional status	Reflects patient fitness. Albumin < 25 g/L is a poor prognostic sign for surgical recovery.
Performance status (ECOG/WHO)	ECOG 0–1: generally fit for PDS. ECOG ≥ 3: consider NACT first to improve fitness.

4. Chemotherapy — Systemic Treatment

The backbone of systemic treatment for epithelial ovarian cancer is:

Carboplatin + Paclitaxel (TC) × 6 cycles, each cycle Q3 weeks

Drug	Class	Mechanism of Action	Key Side Effects
Carboplatin	Platinum agent ("carbo" = carbon, "platin" = platinum)	Cross-links DNA → prevents replication → cell death. Acts on rapidly dividing cells. Dosed by AUC (area under the curve) using the Calvert formula (accounts for renal function — GFR determines carboplatin clearance).	Myelosuppression (especially thrombocytopenia — more than cisplatin), nausea/vomiting, nephrotoxicity (less than cisplatin), neurotoxicity, hypersensitivity reactions (especially after multiple cycles).
Paclitaxel	Taxane ("taxel" from taxus = yew tree, originally derived from Pacific yew bark)	Stabilises microtubules → prevents depolymerisation → arrests cell division in M phase (mitotic spindle cannot disassemble).	Peripheral neuropathy (dose-limiting — cumulative sensory neuropathy), alopecia, myalgia/arthralgia, myelosuppression (neutropenia), hypersensitivity (requires premedication with dexamethasone + antihistamines).

Why carboplatin instead of cisplatin? Carboplatin has equivalent efficacy but a much better toxicity profile: less nephrotoxicity, less ototoxicity, less severe nausea. However, it causes more myelosuppression (especially thrombocytopenia). For ovarian cancer, carboplatin is standard. Cisplatin is reserved for germ cell tumours (BEP regimen).

Because ovarian cancer spreads primarily within the peritoneal cavity, delivering chemotherapy directly into the peritoneal cavity achieves much higher local drug concentrations:

IP carboplatin/cisplatin + IV paclitaxel: shown in GOG 172 trial to improve overall survival by ~16 months compared to IV-only chemo in optimally debulked Stage III disease. HIPEC: OVHIPEC-1 supports improved recurrence-free and overall survival when cisplatin HIPEC is added at interval surgery in selected stage III patients after neoadjuvant chemotherapy. It is not routine for every ovarian cancer operation. (Trial.)
Drawbacks: IP chemo has significant toxicity (abdominal pain, catheter complications, infection). Many patients cannot complete the planned cycles. HIPEC requires specialised facilities and adds to surgical time/morbidity.

Subtype	Chemosensitivity	Standard Regimen	Notes
High-grade serous (HGSOC)	Chemosensitive (responds well to platinum initially)	Carboplatin + paclitaxel × 6	Most respond initially but ~70% relapse within 3 years
Low-grade serous	Chemoresistant	Carboplatin + paclitaxel (low response ~4%)	Hormonal therapy (letrozole, tamoxifen) may be used. MEK inhibitors (trametinib) now approved. Surgery is the most important treatment.
Endometrioid	Moderately chemosensitive	Carboplatin + paclitaxel	Similar to HGSOC
Clear cell	Chemoresistant (particularly in East Asian populations where it is more common)	Carboplatin + paclitaxel (response rate only ~15–30% for advanced disease)	Surgery is critical (even more important to achieve R0). Checkpoint inhibitors under investigation. Consider molecular profiling for actionable mutations.
Mucinous	Chemoresistant to standard regimen	Consider adding oxaliplatin or capecitabine (GI-type regimen, since mucinous tumours resemble GI cancers)	Very poor prognosis if advanced. Surgery is the main treatment for early-stage disease.

Chemoresistance — Why It Matters

Low-grade serous, clear cell, and mucinous ovarian cancers are relatively chemoresistant. This means that:

Surgery is even more critical — achieving R0 may be the only chance for cure.
Standard carboplatin + paclitaxel has low response rates → alternative regimens or targeted therapies should be considered.
In Hong Kong/East Asia, clear cell carcinoma is more common → awareness of its chemoresistance is high yield for local exams.

Germ cell tumours are exquisitely chemosensitive — even advanced-stage disease has cure rates > 90%.

Standard regimen: BEP × 3–4 cycles

Drug	Mechanism	Key Toxicity
Bleomycin	Causes DNA strand breaks via free radical generation	Pulmonary fibrosis (dose-limiting — must monitor with pulmonary function tests; cumulative dose limit ~400 units)
Etoposide	Topoisomerase II inhibitor → DNA double-strand breaks	Myelosuppression, alopecia, secondary leukaemia (rare late effect)
Cisplatin (not carboplatin)	DNA cross-linking	Nephrotoxicity (requires aggressive hydration), ototoxicity, peripheral neuropathy, severe nausea (5-HT3 antagonist + NK1 antagonist + dexamethasone as antiemetic prophylaxis)

Why cisplatin (not carboplatin) for germ cell tumours? Historical evidence from testicular cancer trials established BEP as the gold standard. Cisplatin appears to have slightly superior efficacy in germ cell tumours compared to carboplatin, though this is debated. The cure rates with BEP are so high that there is reluctance to change the regimen.

Granulosa cell tumours are indolent and can recur late (even 10–20 years later).
Surgery is the primary treatment.
For recurrent/advanced disease: hormonal therapy (aromatase inhibitors, GnRH agonists) or chemotherapy (BEP or carboplatin/paclitaxel).

5. Targeted Therapy and Maintenance

This is where the molecular profiling discussed in the diagnosis section pays off.

PARP = Poly ADP-Ribose Polymerase — an enzyme that repairs single-strand DNA breaks.

Mechanism: PARP inhibition and PARP trapping cause replication-associated DNA damage. Cells with BRCA dysfunction / homologous recombination deficiency are less able to repair that damage accurately, producing synthetic lethality. PARP is not their only remaining DNA-repair pathway.

PARP Inhibitor	Key Trial	Indication
Olaparib (Lynparza)	SOLO1, SOLO2, PAOLA-1	1st-line maintenance in BRCA-mutated advanced ovarian cancer after response to platinum-based chemo. Recurrent maintenance eligibility is BRCA- and prior-treatment dependent; do not assume every platinum-sensitive relapse qualifies.
Niraparib (Zejula)	PRIMA/ENGOT-OV26	US first-line maintenance after platinum response requires HRD-positive disease (BRCA mutation and/or genomic instability); the older all-comer indication has been restricted. Recurrent maintenance requires germline BRCA mutation.
Rucaparib (Rubraca)	ARIEL3	Recurrent maintenance in BRCA-mutated disease responding to platinum under the current US indication; consider prior PARP exposure.

Key side effects of PARP inhibitors: Myelosuppression (anaemia, thrombocytopenia, neutropenia — especially niraparib), fatigue, nausea, and a small risk of MDS/AML (~1–2%, from genomic instability in haematopoietic cells).

BRCA carriers with ovarian cancer benefit enormously from PARP inhibitors. In SOLO1, olaparib maintenance reduced the risk of disease progression or death by 70% in BRCA-mutated advanced ovarian cancer.

Bevacizumab (a humanised monoclonal antibody) = a monoclonal antibody against VEGF-A (vascular endothelial growth factor A).

Mechanism: Ovarian cancer is highly angiogenic — tumour cells secrete large amounts of VEGF to stimulate new blood vessel formation (angiogenesis) and increase vascular permeability (contributing to ascites). Bevacizumab binds VEGF-A → blocks it from activating VEGFR on endothelial cells → ↓angiogenesis, ↓vascular permeability, ↓ascites, and ↓tumour growth.

Setting	Evidence	Notes
1st-line treatment (with chemo + maintenance)	GOG 218, ICON7	Bevacizumab added to carboplatin/paclitaxel then continued as maintenance → improved PFS by ~4 months. Most benefit in high-risk subgroups (Stage IV, suboptimally debulked Stage III).
Recurrent disease	OCEANS, AURELIA	Added to chemo in platinum-sensitive and platinum-resistant recurrence → improved PFS.
Maintenance (in combination with PARP inhibitor)	PAOLA-1	Bevacizumab + olaparib maintenance → significant PFS benefit in HRD-positive tumours (median PFS 37.2 vs 17.7 months).

Key side effects: Hypertension (dose-dependent VEGF inhibition → ↓nitric oxide → vasoconstriction), proteinuria (glomerular endothelial damage), GI perforation (2–3% — must be aware in patients with extensive bowel disease), delayed wound healing (must wait ≥ 4–6 weeks after surgery before starting, and stop ≥ 6 weeks before planned surgery), arterial thromboembolism, haemorrhage.

Bevacizumab — Surgical Timing

Bevacizumab impairs wound healing and increases risk of GI perforation. It must NOT be started within 28 days of surgery and must be stopped at least 6 weeks before any planned surgery. This is a common exam point and a critical clinical safety issue.

Currently, the role of immunotherapy in ovarian cancer is more limited than in other cancers (e.g., lung, melanoma), but emerging data exists:

MSI-high / dMMR tumours (a subset of endometrioid and clear cell ovarian cancers, often Lynch-related): respond to pembrolizumab (anti-PD-1). FDA approved pembrolizumab for any MSI-H/dMMR solid tumour regardless of site.
For the majority of HGSOC (which are MSS / pMMR): single-agent checkpoint inhibitors have shown disappointing results. However, pembrolizumab + paclitaxel ± bevacizumab now has a specific CPS ≥1 platinum-resistant indication after 1–2 previous regimens (see above); this does not establish all IO combinations or single-agent IO for unselected HGSOC.

6. Management by Stage

Step	Details
Surgery	Full surgical staging: TAH + BSO + omentectomy + peritoneal biopsies + peritoneal washings + pelvic and para-aortic lymph node dissection + appendicectomy (if mucinous). Accurate staging is critical — up to 30% of apparently Stage I patients are upstaged after comprehensive staging.
Adjuvant chemotherapy	Stage IA/IB, Grade 1–2: observation (no adjuvant chemo). The risk of recurrence is low (~5–10%). Stage IA/IB, Grade 3 or clear cell: adjuvant chemo (carboplatin + paclitaxel × 3–6 cycles). The high grade or clear cell histology confers higher risk. Stage IC or IIA (any grade): adjuvant chemo (carboplatin + paclitaxel × 3–6 cycles).
Fertility-sparing	As described above, for select young patients with low-grade unilateral disease.

Step	Details
Assess resectability	CT + ± diagnostic laparoscopy (Fagotti score). Can R0 be achieved?
If resectable → PDS	Full cytoreductive surgery by gynae-oncologist. Goal: R0. May require ultra-radical procedures.
If not resectable → NACT	3–4 cycles carboplatin + paclitaxel → reassess → IDS ^[17]
Adjuvant chemo	Total of 6 cycles carboplatin + paclitaxel (including any neoadjuvant cycles given).
Maintenance therapy	Based on molecular profiling: BRCA+ → PARP inhibitor (olaparib); HRD+ → PARP inhibitor ± bevacizumab; HR proficient → bevacizumab or observation.

Recurrent ovarian cancer is classified based on the platinum-free interval (PFI) — the time from last platinum dose to relapse:

Category	PFI	Implication	Treatment
Platinum-sensitive	> 6 months (especially > 12 months)	Tumour likely to respond to re-challenge with platinum	Platinum-based combination (e.g., carboplatin + paclitaxel, carboplatin + gemcitabine, carboplatin + PLD) → consider maintenance according to BRCA/HRD, prior PARP exposure and the applicable indication
Partially platinum-sensitive	6–12 months	Intermediate likelihood of response	Platinum-based combination + consider bevacizumab
Platinum-resistant	< 6 months	Poor response to platinum; different mechanism needed	Single-agent non-platinum chemo (PLD = pegylated liposomal doxorubicin, topotecan, gemcitabine, weekly paclitaxel) ± bevacizumab. Consider clinical trials.
Platinum-refractory	Progresses during platinum therapy	Very poor prognosis	Best supportive care or clinical trials. Single-agent non-platinum chemo ± bevacizumab for palliation.

Secondary cytoreductive surgery may be considered in platinum-sensitive relapse with a solitary or oligometastatic recurrence site, especially if the PFI is long (> 12–24 months) and complete resection is feasible (DESKTOP III trial showed survival benefit for secondary CRS in selected patients).

Advanced ovarian cancer has a substantial recurrence risk; durable remissions occur. Palliative and supportive care can accompany active treatment. Palliative and supportive measures are integral:

Symptom / Issue	Management	Mechanism / Rationale
Malignant ascites	Therapeutic paracentesis (symptom relief). Diuretics (spironolactone ± furosemide — limited efficacy in malignant ascites vs. portal hypertensive ascites). Indwelling peritoneal catheter (PleurX/peritoneal drain) for recurrent symptomatic ascites. IP bevacizumab or catumaxomab (in some centres).	Malignant ascites results from peritoneal VEGF secretion and lymphatic obstruction. Paracentesis provides immediate relief. Diuretics work poorly because the pathophysiology is not hydrostatic (unlike cirrhotic ascites).
Malignant bowel obstruction	Conservative (NBG tube decompression, IV fluids, antiemetics, octreotide to reduce GI secretions). Dexamethasone (reduces peri-tumoural oedema). Surgery (bypass or stoma) in selected cases. Venting gastrostomy if surgery not possible.	Peritoneal carcinomatosis encases and compresses bowel loops. Surgery is high risk in this context (friable tissue, multiple levels of obstruction). Octreotide (a somatostatin analogue) reduces intestinal secretions → ↓distension.
Malignant pleural effusion	Therapeutic thoracentesis. Indwelling pleural catheter. Talc pleurodesis if recurrent.	Right-sided pleural effusion common (transdiaphragmatic lymphatic flow).
Pain	WHO analgesic ladder. Neuropathic pain: gabapentin/pregabalin. Bone pain: bisphosphonates/denosumab + RT.	Multi-modal approach needed.
VTE prophylaxis / treatment	LMWH (enoxaparin) or DOAC (rivaroxaban/apixaban). Prophylaxis peri-operatively and during chemotherapy.	Ovarian cancer carries high VTE risk (Trousseau syndrome — mucin-secreting tumours activate tissue factor → thrombin generation).
Nutritional support	Dietitian input. Oral supplements. Parenteral nutrition if bowel obstruction is prolonged.	Cancer cachexia (TNF-α, IL-6 mediated) + mechanical obstruction + poor appetite → malnutrition.
Psychosocial support	Counsel patients and to give bad news in a supportive manner ^[2]. MDT including palliative care team, psychology, social work.	Ovarian cancer diagnosis often presents at advanced stage → patients face significant distress. Breaking bad news with empathy is a key professional skill.

This was covered in detail in earlier sections but is included here as it is a management modality:

Indication	Procedure	Timing
BRCA1/2 carriers	Bilateral salpingo-oophorectomy (BSO) ± HRT ^[4]	Recommended after complete childbearing or before 40y (BRCA1) / 40–45y (BRCA2) ^[4]
Lynch syndrome	TAH + BSO ^[5]	At the end of childbearing or ~40y ^[5]
Opportunistic salpingectomy	Bilateral salpingectomy at the time of other pelvic surgery (e.g., hysterectomy for fibroids, tubal ligation)	Growing practice — removes the fallopian tube fimbria (the origin of most HGSOC) without removing the ovaries, preserving hormonal function

After completion of primary treatment:

Modality	Schedule	Purpose
Clinical examination	Q3–4 months for 2 years, then Q6 months for 3 years, then annually	Detect signs of recurrence
CA-125	At each visit	Rising CA-125 often precedes clinical/radiological relapse by months. However, early treatment of biochemical recurrence (CA-125 rise only) has NOT been shown to improve overall survival (MRC OV05/EORTC 55955 trial). Some centres delay treatment until symptomatic relapse.
Imaging (CT / PET-CT)	Not routinely scheduled — performed if CA-125 rising or new symptoms	To confirm and localise recurrence
BRCA / genetic counselling	If not already done	Implications for family members

The CA-125 Surveillance Dilemma

The MRC OV05 trial showed that treating ovarian cancer relapse based solely on rising CA-125 (before symptoms or imaging evidence) did NOT improve overall survival compared to waiting until clinical relapse. This is counterintuitive but important: early detection of recurrence does not necessarily translate to better outcomes if the available treatments for recurrence are palliative, not curative. Current practice varies — some centres monitor CA-125 and investigate rises, while others inform patients that CA-125 monitoring is optional.

Scenario	Management
Early-stage, low-grade (IA/IB G1–2)	Full surgical staging → observation (no chemo)
Early-stage, high-grade or IC/IIA	Full surgical staging → adjuvant carboplatin + paclitaxel × 3–6 cycles
Advanced, resectable	PDS (aim R0) → adjuvant carboplatin + paclitaxel × 6 cycles → maintenance (PARP ± bevacizumab based on molecular profile)
Advanced, unresectable or unfit	NACT × 3–4 cycles → IDS → complete chemo × 6 total → maintenance
Germ cell tumour	Fertility-sparing surgery (USO) + BEP × 3–4 cycles. Excellent cure rates (> 90%).
Borderline tumour	Surgery (USO + staging for fertility-sparing; TAH + BSO + staging if complete). No adjuvant chemo.
Recurrent, platinum-sensitive	Re-challenge with platinum-based combo ± secondary CRS → PARP inhibitor maintenance
Recurrent, platinum-resistant	Non-platinum single-agent chemo ± bevacizumab. Clinical trials. Palliative care.
BRCA carrier (no cancer yet)	Risk-reducing BSO after childbearing. Screening has not established a mortality benefit; discuss interim options and their limitations with genetics/gynae-oncology.

High Yield Summary

Surgery is the cornerstone: Goal = R0 (no visible residual disease). Standard: TAH + BSO + omentectomy + peritoneal biopsies/washings + appropriate nodal assessment/removal of suspicious nodes ± appendicectomy; systematic lymphadenectomy is not routine after complete gross resection of advanced disease with normal nodes. Must be performed by a trained gynae-oncologist for suspected malignancy.

PDS vs. NACT: If operable → PDS first (time-sensitive, therapeutic and diagnostic). If unresectable/unfit → NACT (3–4 cycles carboplatin + paclitaxel) → IDS → complete 6 cycles total.

Chemotherapy backbone: Carboplatin + paclitaxel × 6 cycles Q3 weeks. Germ cell tumours: BEP (bleomycin, etoposide, cisplatin).

Maintenance therapy (the modern paradigm):

BRCA-mutated → PARP inhibitor (olaparib)
HRD-positive → PARP inhibitor ± bevacizumab
HR proficient → Bevacizumab or observation

PARP inhibitors exploit synthetic lethality (BRCA loss + PARP inhibition = lethal). Bevacizumab targets VEGF → ↓angiogenesis, ↓ascites.

Recurrence: Platinum-free interval guides treatment. > 6 months = platinum-sensitive (re-challenge). < 6 months = platinum-resistant (non-platinum agents ± bevacizumab).

Key chemoresistant subtypes: Low-grade serous, clear cell (common in HK), mucinous. Surgery even more critical.

Fertility-sparing: Possible in Stage IA/IC low-grade (USO + staging). Standard for germ cell tumours.

Risk reduction: BRCA → BSO after childbearing. Lynch → TAH + BSO ~40y. Opportunistic salpingectomy gaining traction.

Active Recall - Management of Ovarian Cancer

References

^[2] Lecture slides: Block C - O&G Theme Case 3.pdf (p1; learning objectives including counselling patients and giving bad news) ^[4] Senior notes: Ryan Ho Urogenital.pdf (p213; BRCA1/2 prophylactic BSO, timing, considerations) ^[5] Senior notes: Ryan Ho GI.pdf (p183; Lynch syndrome cancer screening, prophylactic TAH + BSO) ^[7] Lecture slides: GC 118. Pelvic mass ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p68; management algorithm — high likelihood of malignancy → laparotomy with full staging by gynae-oncologist; low likelihood → TAH + BSO + omentectomy + peritoneal cytology) ^[17] Lecture slides: Block C - Pelvic mass_ ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p57; treatment — if operable operate first, if late stage and inoperable consider neoadjuvant)

Complications of Ovarian Cancer

Complications of ovarian cancer arise from three sources: (1) the disease itself (local tumour effects, metastatic spread, paraneoplastic phenomena), (2) the treatment (surgery, chemotherapy, targeted therapy), and (3) the downstream consequences (psychosocial, fertility, hormonal). A thorough understanding of each mechanism is essential — you need to know why each complication occurs to manage it properly.

1. Complications of the Disease Itself

These complications can occur with both benign and malignant ovarian masses. "Some indications require emergency management — ovarian cyst complications" ^[17]. "Abdominal pain, due to mass effect or complications (sudden / chronic): torsion, haemorrhage, rupture" ^[18].

Complication	Pathophysiology	Clinical Presentation	Management
Ovarian torsion	The ovarian pedicle (infundibulopelvic ligament + utero-ovarian ligament + mesovarium) twists on itself → vascular compromise → venous outflow obstruction first (veins are low pressure, easily compressed) → venous congestion → further swelling → arterial inflow obstruction → ischaemia → infarction → necrosis. Risk increases with mass size 5–10 cm (large enough to create a lever arm, but not so large as to be immobilised). Dermoid cysts are the classic risk factor (because they are heavy, mobile, and have a long pedicle).	Sudden onset severe unilateral pelvic/lower abdominal pain, often with nausea/vomiting. Pain may be colicky (intermittent torsion-detorsion). Tender adnexal mass on examination. Low-grade fever. USG: enlarged ovary with "whirlpool sign" (twisted pedicle on Doppler), absent/reduced venous then arterial flow.	Emergency surgery — laparoscopic detorsion (untwist) if viable ± cystectomy/oophorectomy. If necrotic → oophorectomy. Time-critical: viability decreases with duration of torsion.
Haemorrhage (into the cyst)	Rupture of blood vessels within the cyst wall or tumour → intracystic bleeding → sudden expansion → pain. In malignant tumours, neovasculature is fragile and prone to bleeding. Haemorrhagic corpus luteum cyst is the benign equivalent.	Sudden worsening of pain, tender enlarging mass. If cyst ruptures with haemorrhage → haemoperitoneum → hypotension, tachycardia, peritoneal signs.	Haemodynamic resuscitation + analgesia. If haemodynamically unstable → emergency laparoscopy/laparotomy for haemostasis. If stable → conservative management with observation.
Rupture	Capsule of the cyst or tumour gives way → contents spill into the peritoneal cavity. In malignant tumours: rupture causes peritoneal dissemination of tumour cells → upstages the disease (from IA to at least IC2). In mucinous tumours → pseudomyxoma peritonei (gelatinous mucin fills the abdomen). In dermoid cysts → chemical peritonitis (sebaceous material irritates the peritoneum).	Acute abdominal pain, peritoneal signs (rebound tenderness, guarding). Free fluid on USG. Depending on contents: chemical peritonitis (dermoid), tumour dissemination (malignant), or bland fluid (serous).	Emergency laparotomy if haemodynamically unstable or peritonitis. Surgical washout. For malignant rupture → comprehensive staging + adjuvant chemotherapy (the rupture itself changes management).
Infection / abscess	Secondary infection of a cyst or tumour, especially post-procedure or if communication with the bowel exists.	Fever, tender mass, raised WCC/CRP, USG shows complex mass with debris.	Antibiotics ± drainage ± surgery.

Torsion vs. Rupture — Why the Distinction Matters

Both present with acute pelvic pain, but:

Torsion: pain is intermittent/colicky (torsion-detorsion), USG shows viable/swollen ovary, Doppler may show absent flow. Treatment = detorsion (save the ovary if possible).
Rupture: pain is sudden onset then constant, free fluid on USG, may have haemodynamic instability. For malignant rupture, this is an iatrogenic disaster if it occurs during surgery (IC1 = surgical spill) or a prognostic worsening if pre-operative (IC2) — always handle ovarian tumours gently during laparotomy to avoid rupture.

The hallmark of advanced ovarian cancer is peritoneal carcinomatosis — tumour cells exfoliate from the ovarian surface and implant throughout the peritoneal cavity.

Complication	Pathophysiology	Clinical Features	Management
Malignant ascites	Tumour implants on the peritoneum → (1) VEGF secretion → ↑vascular permeability → protein-rich fluid exudation; (2) tumour cells block peritoneal lymphatic stomata → ↓fluid reabsorption; (3) direct tumour secretion of fluid. Unlike cirrhotic ascites (portal hypertensive, transudate), malignant ascites is an exudate (SAAG < 11 g/L).	Abdominal distension ^[7]^[18], shifting dullness, fluid thrill, dyspnoea (diaphragmatic splinting). Paradoxical weight gain despite cachexia ("big belly, thin limbs").	Therapeutic paracentesis (symptomatic relief). Indwelling peritoneal catheter (PleurX) for recurrent drainage. Diuretics (limited efficacy). Definitive: treat the underlying cancer (chemo, surgery). IP bevacizumab in refractory cases.
Malignant bowel obstruction (MBO)	Peritoneal carcinomatosis encases bowel loops → extrinsic compression. Direct tumour infiltration of the bowel wall → intramural narrowing. Tumour-related peritoneal adhesions → kinking. Often at multiple levels simultaneously (unlike benign adhesive obstruction, which is usually single-level).	Colicky abdominal pain, vomiting (faeculent if distal), abdominal distension, absolute constipation (complete) or overflow diarrhoea (partial). AXR: dilated loops, multiple air-fluid levels. CT: transition point(s), peritoneal thickening, omental cake.	Conservative: NGT decompression, IV fluids, antiemetics (cyclizine, haloperidol), octreotide (↓GI secretions → ↓distension), dexamethasone (↓peri-tumoural oedema). Surgical: bypass or stoma if single-level, patient fit, reasonable prognosis. If inoperable: venting gastrostomy (PEG for decompression, not feeding). Palliative care input essential.
Malignant pleural effusion	Peritoneal fluid ascends through transdiaphragmatic lymphatic channels (more numerous on the right → hence right-sided predominance). Positive cytology = Stage IVA. Also direct diaphragmatic invasion, haematogenous pleural metastasis, or mediastinal lymphatic obstruction.	Pleural effusion ^[7], progressive dyspnoea, reduced breath sounds, stony dullness to percussion on affected side. CXR: meniscus sign.	Therapeutic thoracentesis (send cytology). Talc pleurodesis if recurrent. Indwelling pleural catheter (IPC) for symptom control. Treat underlying cancer.
Ureteric obstruction / hydronephrosis	Large pelvic mass or peritoneal deposits compress one or both ureters → obstructive uropathy → hydronephrosis → renal impairment if bilateral.	Rising creatinine, flank pain, anuria (bilateral complete obstruction). USG: dilated renal pelvis/ureter.	Ureteric stent (JJ stent) or percutaneous nephrostomy. Treat underlying cancer to relieve obstruction.
Fistula formation	Advanced tumour eroding into adjacent hollow viscera (bladder → vesicovaginal fistula; rectum → rectovaginal fistula).	Continuous passage of urine or faeces through the vagina, recurrent UTIs, pneumaturia.	Surgical repair if feasible. Diversion (colostomy for rectovaginal fistula, ureteric diversion for vesicovaginal). Often palliative.

"Symptoms related to metastasis" and "Signs of metastasis, e.g. lymphadenopathy, DVT, pleural effusion, organomegaly, deposits in Pouch of Douglas" ^[7]^[18].

Site	Mechanism of Spread	Clinical Features	Management
Omentum (most common metastatic site)	Transcoelomic — tumour cells have tropism for omental milky spots	Palpable "omental cake" (hard epigastric mass), early satiety (compresses stomach)	Omentectomy at surgery
Liver	Surface: peritoneal spread (Stage III). Parenchyma: haematogenous (Stage IVB).	Organomegaly ^[7], RUQ pain, jaundice (if biliary compression), deranged LFT	Systemic chemo for parenchymal mets. Surface deposits managed with peritonectomy at debulking.
Lymph nodes	Lymphatic spread to pelvic (iliac) and para-aortic nodes (following ovarian vessels). Distant: lymphadenopathy (supraclavicular = Virchow's node, inguinal = Stage IVB) ^[7]	Palpable lymphadenopathy, lower limb lymphoedema (pelvic node compression)	Lymph node dissection at staging surgery. Systemic chemo for widespread nodal disease.
Lung	Haematogenous metastasis (parenchymal = Stage IVB). Also lymphangitis carcinomatosis. "Common primaries for secondary lung tumours: breast, kidneys, uterus, ovary, testes, thyroid" ^[19].	Cough, haemoptysis, dyspnoea. CXR: multiple bilateral nodules or pleural effusion. Lymphangitis carcinomatosis: severe rapidly progressive SOB, marked hypoxaemia, CXR shows diffuse reticulonodular shadowing, CT shows thickened interlobular septa ^[19].	Systemic chemo. Palliative: pleurodesis, supportive care. Lymphangitis carcinomatosis has very poor prognosis (≤3–12 months) ^[19].
Bone (rare in ovarian cancer)	Haematogenous	Bone pain, pathological fracture, hypercalcaemia, cord compression. "4 complications of bony metastasis: bone pain, pathological fracture, malignant hypercalcaemia, neurological symptoms e.g. cord compression" ^[20].	Analgesics, osteoclast inhibitors (bisphosphonates, denosumab), EBRT, surgery if impending fracture or cord compression ^[20].
Brain (rare)	Haematogenous. More common in HGSOC with BRCA mutations. "Most common primary sites for brain mets: lung, breast, RCC, melanoma" ^[20] — ovarian is less common but occurs.	Headache, seizures, focal neurological deficits, personality change.	Dexamethasone (for vasogenic oedema). Single met: surgery ± SRS. Multiple: WBRT ^[20].

"Systemic symptoms, e.g., loss of weight and appetite, unexplained fever, lower limb swelling, lymph node, etc" ^[7]^[18].

Paraneoplastic Syndrome	Mechanism	Tumour Subtype	Clinical Features
Venous thromboembolism (DVT/PE) — Trousseau syndrome	Mucin-secreting adenocarcinomas release tissue factor and mucin glycoproteins that activate the clotting cascade → hypercoagulable state. Immobility, pelvic venous compression by tumour, and surgery further compound risk. "DVT" listed as a metastatic sign ^[7].	All epithelial (especially mucinous)	DVT (leg swelling, pain, Homan's sign), PE (dyspnoea, pleuritic chest pain, haemodynamic collapse), migratory thrombophlebitis.
Hypercalcaemia	"Ectopic PTHrP production, e.g. small cell CA ovary" ^[13]. Also from bone metastasis (rare in ovarian cancer).	Small cell carcinoma of the ovary (hypercalcaemic type — a rare, aggressive tumour in young women)	Polyuria, polydipsia, confusion, constipation, nausea, shortened QTc, renal stones. Severe: coma, cardiac arrest.
Lower limb swelling / lymphoedema	"Lower limb swelling is an interesting constitutional symptom for the gynae cancers → due to lymphatic invasion impeding lymphatic return" ^[10]. Pelvic lymph node metastases compress iliac lymphatics → impaired drainage from the lower limbs. Also IVC/iliac vein compression by pelvic mass → venous congestion.	Advanced pelvic disease	Bilateral or unilateral lower limb swelling. Non-pitting if lymphoedema; pitting if venous. Must distinguish from DVT (requires Doppler USG).
Dermatomyositis / polymyositis	Paraneoplastic autoimmune inflammatory myopathy. "Adult form associated with malignancy: 5× risk in dermatomyositis, 2× risk in polymyositis. Types: adenocarcinoma of cervix, lung, ovaries, pancreas, bladder, stomach, NPC" ^[21].	Adenocarcinoma (any epithelial subtype)	Proximal symmetrical weakness, heliotrope rash (periorbital violaceous discolouration), Gottron's papules (scaly erythematous lesions over knuckles), elevated CK.
Cancer cachexia	Pro-inflammatory cytokines (TNF-α, IL-1, IL-6) from tumour and host immune response → skeletal muscle proteolysis + adipose tissue lipolysis + central anorexia via hypothalamic signalling. "Loss of weight and appetite" ^[7]^[18].	All subtypes (advanced disease)	Progressive weight loss despite adequate caloric intake (often masked by ascites), muscle wasting, fatigue, poor functional status.
Chronic DIC	Mucinous tumours release tissue factor and mucin glycoproteins → chronic activation of coagulation cascade → ongoing thrombosis with compensated clotting factor production.	Mucinous ovarian carcinoma	Unprovoked arteriovenous thromboembolism. Lab: elevated D-dimer, normal or mildly prolonged PT/aPTT, normal or elevated fibrinogen (compensated).
Subacute cerebellar degeneration	Anti-Yo antibodies (anti-Purkinje cell antibodies) — cross-react with tumour antigens expressed on cerebellar Purkinje cells → immune-mediated Purkinje cell destruction → cerebellar ataxia. Classic paraneoplastic syndrome of ovarian and breast cancer.	HGSOC, breast	Progressive cerebellar ataxia (gait unsteadiness, limb incoordination, dysarthria, nystagmus) developing over weeks to months. MRI: cerebellar atrophy (late). Anti-Yo antibody positive. Often irreversible even if tumour is treated.
Hormonal effects (sex cord–stromal tumours)	Granulosa cell tumour → excess oestrogen → endometrial hyperplasia → endometrial cancer (in 5–10%). Sertoli-Leydig → excess androgens → virilisation.	Granulosa cell tumour, Sertoli-Leydig cell tumour	Postmenopausal bleeding, endometrial thickening (granulosa). Hirsutism, acne, amenorrhoea, deepening voice (Sertoli-Leydig).

Granulosa Cell Tumour → Endometrial Cancer

An important and examinable complication: granulosa cell tumours secrete oestrogen → chronic unopposed oestrogen stimulation of the endometrium → endometrial hyperplasia → endometrial cancer (in ~5–10% of cases). This is why endometrial sampling should be performed at the time of surgery for any granulosa cell tumour, and the uterus should be inspected carefully.

2. Complications of Treatment

Complication	Mechanism	Prevention / Management
Intraoperative tumour rupture (surgical spill)	Handling the tumour during surgery causes capsule breach → tumour cells spill into the peritoneal cavity → upgrades staging from IA to IC1. Worsens prognosis and mandates adjuvant chemotherapy even if previously not indicated.	Handle masses with extreme care. Use endo-bags for retrieval during laparoscopy. Avoid morcellation of suspected malignant masses. Thorough peritoneal washout if spill occurs.
Haemorrhage	Extensive debulking surgery involves highly vascular tissue (omental vessels, retroperitoneal vessels, pelvic sidewall). Adhesions from tumour increase bleeding risk.	Meticulous surgical technique. Interventional radiology (embolisation) if needed. Blood products on standby.
Bowel injury / anastomotic leak	Bowel resection is commonly required for complete cytoreduction (tumour implants on bowel serosa/mesentery). Risk of leak from the anastomosis → peritonitis.	Experienced gynae-oncologist. Consider defunctioning stoma for low rectal anastomoses.
Ureteric injury	The ureter runs close to the infundibulopelvic ligament (where ovarian vessels are ligated) and along the pelvic sidewall (where tumour often infiltrates).	Identify ureters before clamping. Consider ureteric stenting pre-operatively in complex cases.
Venous thromboembolism	Major pelvic surgery + malignancy + immobility = very high VTE risk.	Mechanical (TED stockings, pneumatic calf compression) + pharmacological (LMWH) prophylaxis. Early mobilisation. Extended VTE prophylaxis (28 days post-op for major cancer surgery).
Wound infection / dehiscence	Large midline laparotomy incision, malnutrition, ascites (continuous fluid leak from wound), immunocompromised state.	Optimise nutrition pre-operatively. Wound care. Antibiotics if indicated.
Lymphocyst / lymphoedema	Pelvic and para-aortic lymph node dissection disrupts lymphatic channels → fluid collects as a lymphocyst (retroperitoneal fluid collection) or chronic lower limb lymphoedema.	Lymphocyst: usually self-resolving. Drainage if symptomatic/infected. Lymphoedema: compression garments, physiotherapy, skin care.
Premature menopause / ovarian failure	BSO in premenopausal women → immediate surgical menopause (sudden loss of oestrogen and progesterone).	HRT consideration (if not contraindicated by tumour biology — generally avoided in oestrogen-sensitive tumours but may be considered in serous/non-hormonal subtypes). Counsel about vasomotor symptoms, vaginal dryness, osteoporosis risk, cardiovascular risk.
Infertility	TAH + BSO = permanent loss of fertility. Even USO reduces ovarian reserve.	Fertility-sparing surgery in select early-stage cases. Pre-treatment oocyte/embryo cryopreservation in young women (limited time before chemo starts).

Complication	Drug(s)	Mechanism	Management
Myelosuppression (neutropenia, thrombocytopenia, anaemia)	Carboplatin (especially thrombocytopenia), paclitaxel (especially neutropenia)	Cytotoxic drugs kill rapidly dividing haematopoietic precursors in bone marrow	Neutropenic fever protocol (broad-spectrum antibiotics if febrile neutropenia). G-CSF (filgrastim) for secondary prophylaxis. Platelet/RBC transfusion. Dose reduction if severe.
Peripheral neuropathy	Paclitaxel (dose-limiting), carboplatin (cumulative)	Paclitaxel stabilises microtubules → disrupts axonal transport in peripheral nerves → sensory neuropathy (stocking-glove distribution). Platinum compounds cause direct neuronal toxicity.	Dose reduction or switch to weekly paclitaxel (lower neuropathy rate). Gabapentin/pregabalin for neuropathic pain. Often partially irreversible.
Nausea / vomiting	Carboplatin (moderate emetogenicity), cisplatin (highly emetogenic — in BEP regimen)	Chemotherapy → serotonin release from enterochromaffin cells in GI mucosa → stimulates vagal afferents → vomiting centre in medulla. Also direct CTZ stimulation.	Antiemetic prophylaxis: 5-HT3 antagonist (ondansetron) + NK1 antagonist (aprepitant) + dexamethasone.
Alopecia	Paclitaxel (very common), cyclophosphamide	Destruction of rapidly dividing hair follicle cells	Scalp cooling caps (may reduce severity). Reassure: hair regrows after chemo completion (may change texture/colour initially).
Nephrotoxicity	Cisplatin (dose-limiting — in BEP), carboplatin (less)	Cisplatin accumulates in renal tubular cells → direct tubular cell toxicity → acute tubular necrosis.	Aggressive IV hydration before and after cisplatin. Monitor RFT. Carboplatin dosed by GFR (Calvert formula) to avoid overdosing in renal impairment.
Hypersensitivity reactions	Carboplatin (especially after multiple cycles — risk increases from cycle 6+), paclitaxel (Cremophor EL vehicle)	Carboplatin: IgE-mediated type I hypersensitivity (develops after repeated exposures). Paclitaxel: Cremophor EL solvent can trigger anaphylactoid reactions.	Paclitaxel: premedication with dexamethasone + diphenhydramine + ranitidine. Carboplatin hypersensitivity: desensitisation protocol or switch to cisplatin/oxaliplatin.
Pulmonary fibrosis	Bleomycin (in BEP for germ cell tumours)	Bleomycin generates free radicals → oxidative damage to pulmonary epithelium → fibrosis. Lungs are susceptible because they lack bleomycin hydrolase (the enzyme that inactivates bleomycin). Cumulative dose-dependent (limit ~400 units total).	Monitor with pulmonary function tests (DLCO). Stop if DLCO drops > 25% from baseline. Avoid high FiO2 in patients with bleomycin exposure (worsens oxidative damage — important for anaesthetists to know).
Secondary malignancy	Alkylating agents, platinum compounds, PARP inhibitors	DNA damage to normal cells → mutagenesis → secondary MDS/AML. PARP inhibitors: ~1–2% risk of MDS/AML.	Long-term surveillance. Monitor CBC.

Drug	Key Complications	Mechanism
PARP inhibitors (olaparib, niraparib, rucaparib)	Myelosuppression (especially anaemia with olaparib, thrombocytopenia with niraparib), fatigue, nausea, MDS/AML (~1–2%)	PARP is needed for DNA repair in all rapidly dividing cells (including normal bone marrow). MDS/AML from mutagenesis in haematopoietic stem cells.
Bevacizumab (anti-VEGF)	Hypertension (VEGF maintains endothelial NO → vasodilation; blocking VEGF → ↓NO → vasoconstriction). GI perforation (2–3% — impaired bowel wall healing in tumour-involved bowel). Proteinuria (VEGF maintains glomerular endothelial fenestrations; blockade → loss of filtration barrier). Delayed wound healing. Arterial thromboembolism. Haemorrhage.	VEGF is essential for normal endothelial function, wound healing, and vascular integrity. Blocking it causes widespread vascular side effects.
Immune checkpoint inhibitors (pembrolizumab — for MSI-H/dMMR tumours)	Immune-related adverse events (irAEs): colitis, hepatitis, pneumonitis, thyroiditis, hypophysitis, dermatitis, myocarditis	Checkpoint inhibition removes immune "brakes" → uncontrolled T-cell activation → autoimmune attack on normal tissues.

"Counsel patients and to give bad news in a supportive manner" ^[2]. "Late stage, advanced age, histological subtype — but all poor prognostic factors" ^[22].

Complication	Explanation	Management
Psychological distress (anxiety, depression)	Diagnosis of advanced cancer with poor prognosis causes significant emotional trauma. Fear of recurrence. Loss of femininity/fertility after surgery. Body image changes (alopecia, surgical scars, stoma).	MDT psycho-oncology support. Psychiatric referral if needed. Patient support groups. Describe the professional roles and responsibilities of doctors ^[2] — holistic care is a professional obligation.
Premature menopause symptoms	Surgical BSO in premenopausal women → sudden oestrogen withdrawal → vasomotor symptoms (hot flushes, night sweats), vaginal dryness/atrophy, mood changes, reduced libido, accelerated bone loss (osteoporosis), cardiovascular risk.	HRT (may be appropriate in non-hormone-sensitive tumours — discuss with oncologist). Non-hormonal: gabapentin/venlafaxine for vasomotor symptoms. Vaginal moisturisers/oestrogen (local). Bone density monitoring ± bisphosphonates.
Infertility	Permanent after TAH + BSO. Even unilateral surgery reduces ovarian reserve. Chemotherapy (especially alkylating agents) causes premature ovarian failure.	Pre-treatment fertility counselling. Oocyte/embryo cryopreservation. Ovarian tissue cryopreservation (experimental). Discuss surrogacy/adoption if appropriate.
Chronic lymphoedema	Post lymphadenectomy disruption of lymphatic channels → permanent lower limb swelling → skin changes (fibrosis, hyperkeratosis) → increased infection risk (cellulitis).	Compression garments, manual lymphatic drainage, physiotherapy, skin care, prompt antibiotic treatment for cellulitis.
Financial and social burden	Prolonged treatment, multiple hospital visits, inability to work, cost of medications (especially targeted therapy). Resource limitation — refer to medical social worker, try to arrange transfer to elderly care home / CSSA ^[22].	Medical social worker referral. Community services. Financial assistance schemes. Palliative care and hospice services for end-stage disease.
Recurrence	~70% of advanced-stage ovarian cancer recurs within 3 years despite initial treatment response. Each recurrence is typically harder to treat (chemo-resistance develops).	Surveillance (CA-125 ± imaging). Platinum-based re-challenge if platinum-sensitive. Non-platinum regimens if resistant. Clinical trials. Palliative care integration early.

"Late stage, advanced age, histological subtype — all poor prognostic factors" ^[22].

Stage	5-Year Survival	Comment
Stage I	~85–90%	Excellent if properly staged and managed
Stage II	~70–75%	Good if completely resected
Stage III	~30–40%	Most common stage at diagnosis. Outcome depends heavily on completeness of cytoreduction.
Stage IV	~15–20%	Poor prognosis. Stage III/IV is not fully palliative — can trial neoadjuvant chemo to see if downstaging is possible ^[22].

Prognostic factors:

Factor	Better Prognosis	Worse Prognosis
Stage	Early (I–II)	Advanced (III–IV)
Residual disease after surgery	R0 (no visible residual)	R2 (suboptimal, > 1cm)
Grade	Low-grade	High-grade
Histological subtype	Low-grade serous, borderline	Clear cell, mucinous (chemoresistant)
BRCA status	BRCA-mutated (better platinum response, eligible for PARP inhibitors)	BRCA wild-type with HR proficiency
Age	Younger	Older (fewer treatment options, more comorbidities)
Performance status	ECOG 0–1	ECOG ≥ 3

Ovarian Cancer Stage III/IV Is Not Automatically Palliative

"Ovarian cancer is interesting → stage III/IV is not full palliative, can trial neoadjuvant chemo to see if downstaging is possible" ^[22]. Unlike many other solid organ cancers where Stage IV means purely palliative care, advanced ovarian cancer can still be treated with curative or near-curative intent through aggressive debulking surgery + chemo + maintenance therapy. This is a unique feature of ovarian cancer biology.

High Yield Summary

Complications of ovarian cancer — Think in three categories:

1. Disease complications:

Acute emergencies: torsion (twisted pedicle → ischaemia), haemorrhage, rupture (upgrades staging if malignant → IC2). All need emergency surgery consideration.
Peritoneal carcinomatosis → malignant ascites (exudate, VEGF-mediated), malignant bowel obstruction (multi-level, manage with NGT + octreotide + dexamethasone ± surgery/venting gastrostomy), pleural effusion (right-sided, transdiaphragmatic lymphatics).
Metastatic: omental cake, liver, nodes, lung (lymphangitis carcinomatosis → very poor prognosis), bone (rare), brain (rare).
Paraneoplastic: VTE/Trousseau syndrome (mucin-secreting tumours), hypercalcaemia (small cell CA ovary → PTHrP), lower limb lymphoedema (lymphatic invasion), dermatomyositis, cerebellar degeneration (anti-Yo), cancer cachexia, chronic DIC.
Granulosa cell tumour → oestrogen → endometrial hyperplasia/cancer (5–10%).

2. Treatment complications:

Surgery: tumour rupture/spill (→ IC1), haemorrhage, bowel/ureteric injury, VTE, wound infection, premature menopause, infertility.
Chemo: myelosuppression, peripheral neuropathy (paclitaxel), nephrotoxicity (cisplatin), alopecia, hypersensitivity (carboplatin after multiple cycles), pulmonary fibrosis (bleomycin in BEP), secondary MDS/AML.
Targeted therapy: PARP inhibitor → MDS/AML (1–2%). Bevacizumab → hypertension, GI perforation, proteinuria, delayed healing.

3. Long-term / psychosocial:

Premature menopause symptoms, infertility, chronic lymphoedema, psychological distress, financial burden, ~70% recurrence rate.
Stage III/IV ovarian cancer is NOT automatically palliative — unique biology allows aggressive treatment even in advanced disease.

Active Recall - Complications of Ovarian Cancer

References

^[2] Lecture slides: Block C - O&G Theme Case 3.pdf (p1; learning objectives — counsel patients, give bad news, professional responsibilities) ^[7] Lecture slides: GC 118. Pelvic mass ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p13, p21, p68, p69; specific symptoms and signs of ovarian cancer — ascites, metastasis signs, lymphadenopathy, DVT, pleural effusion, organomegaly, deposits in Pouch of Douglas; management algorithm) ^[10] Lecture slides: Block C - Pelvic mass_ ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p10; ovarian cancer as silent killer, lower limb swelling due to lymphatic invasion) ^[13] Senior notes: Ryan Ho Chemical Path.pdf (p23; ectopic PTHrP production in small cell CA ovary, hypercalcaemia of malignancy) ^[17] Lecture slides: Block C - Pelvic mass_ ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p18, p57; emergency management of ovarian cyst complications, treatment — if operable operate first, if late stage consider neoadjuvant) ^[18] Lecture slides: GC 118. Pelvic mass ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p12, p13; specific symptoms of ovarian cyst and cancer — torsion, haemorrhage, rupture, systemic symptoms, loss of weight, fever, lower limb swelling) ^[19] Senior notes: Ryan Ho Respiratory.pdf (p151; secondary lung tumours from ovary, lymphangitis carcinomatosis — common primaries, clinical features, prognosis) ^[20] Senior notes: Maksim Medicine Notes.pdf (p55; bone metastasis — 4 complications, diagnostic tools, management including bisphosphonates, denosumab, EBRT, surgery; brain metastasis — dexamethasone, surgery + SRS, WBRT) ^[21] Senior notes: Ryan Ho Neurology.pdf (p194; inflammatory myopathies — dermatomyositis/polymyositis associated with malignancy including ovarian cancer, 5x risk in dermatomyositis) ^[22] Lecture slides: Block C - O&G Theme Case 3.pdf (p6; prognosis — late stage, advanced age, histological subtype all poor prognostic factors; Stage III/IV not fully palliative, can trial neoadjuvant chemo; resource limitation and social worker referral)

High Yield Summary

September 2026 update: maintenance is BRCA/HRD- and prior-treatment dependent; the US first-line niraparib label now requires HRD-positive disease. For platinum-resistant recurrence, consider FRα-selected mirvetuximab after 1–3 regimens, or CPS ≥1 pembrolizumab–paclitaxel ± bevacizumab after 1–2 regimens. The management tab gives the current label sources and eligibility details.

Epidemiology: 6th most common female cancer in HK. Peak age 55–65 for EOC; younger for germ cell. Clear cell carcinoma is disproportionately common in East Asian populations.

Risk factors — Think "incessant ovulation" + genetic:

↑ Risk: Age, nulliparity, no breastfeeding, early menarche, late menopause, BRCA1/2, Lynch syndrome, FHx, endometriosis (clear cell/endometrioid), obesity, HRT, fertility drugs.
↓ Risk (protective): COCP (30–50% reduction with ≥5y use), multiparity, breastfeeding, tubal ligation, salpingectomy.

BRCA1: 44% lifetime ovarian cancer risk. BRCA2: 17%. Both → TP53 mutation → HGSOC. Lynch syndrome: ~10–12% lifetime ovarian cancer risk → endometrioid/clear cell.

Two-pathway model: Type I (low-grade, stepwise, KRAS/BRAF/PIK3CA, early stage, chemoresistant) vs. Type II (high-grade, de novo from STIC, TP53/BRCA, late stage, chemosensitive initially).

Classic exam vignette: Elderly woman + increasing abdominal girth + pelvic mass + ascites + mixed solid-cystic lesion on USG = ovarian cancer.

Staging: Surgical staging (FIGO 2014). Liver capsule = III; liver parenchyma = IVB. Pleural effusion with positive cytology = IVA.

High Yield Summary — Differential Diagnosis

Differential diagnosis of ovarian cancer — Think anatomically:

Ovarian benign: Functional cyst (resolves in 6–8 weeks; should NOT occur postmenopause), dermoid cyst (fat + calcification on imaging), endometrioma (ground glass on USG), serous/mucinous cystadenoma (thin-walled cystic), fibroma (solid; Meigs syndrome mimics advanced ovarian cancer).
Ovarian borderline: Papillary projections but no stromal invasion. Excellent prognosis. Histological diagnosis.
Ovarian malignant: Primary EOC (HGSOC most common), germ cell tumours (young women, AFP/β-hCG), sex cord–stromal (granulosa cell tumour → oestrogen → PMB).
Metastatic to ovary: Krukenberg tumour (gastric, colon, appendix) — bilateral, signet ring cells. Always exclude GI primary with mucinous ovarian masses.
Uterine: Fibroids (moves with cervix, continuous with myometrium on USG), endometrial cancer (PMB, thickened endometrium).
Tubal: Ectopic pregnancy (always do β-hCG!), TOA/PID, fallopian tube carcinoma.
Non-gynae: TB peritonitis (important in HK), appendiceal tumours/pseudomyxoma peritonei, CRC, retroperitoneal tumours, distended bladder.

Key differentiating tools: Age, menopausal status, USG morphology, CA-125 (+ HE4), RMI/ADNEX, tumour markers (AFP, β-hCG, inhibin, CEA), CT TAP, endoscopy.

RMI = U × M × CA-125. ≥ 200 → refer gynae-oncology MDT.

Meigs syndrome (fibroma + ascites + pleural effusion) is a BENIGN mimic of advanced ovarian cancer.

Postmenopausal adnexal mass = malignant until proven otherwise.

High Yield Summary — Diagnosis

There are no standalone diagnostic criteria for ovarian cancer — diagnosis is a multi-step pathway culminating in histological confirmation.

First-line imaging: TVS + TAS (always both). Look for mixed solid-cystic morphology, thick irregular septae, papillary projections, bilateral involvement, ascites, low-resistance Doppler flow.

Staging imaging: CT abdomen + pelvis. Look for omental cake, peritoneal implants, lymphadenopathy, pleural effusion, liver deposits.

Tumour markers by scenario:

Postmenopausal + adnexal mass → CA-125 (± HE4)
Young woman + ovarian mass → AFP + β-hCG + LDH + CA-125
Virilisation / PMB with mass → inhibin, oestradiol, testosterone
Mucinous mass → CEA + CA 19-9 (exclude GI primary)

All epithelial ovarian cancers (especially HGSOC) → BRCA testing + consider HRD scoring. Endometrioid/clear cell → MMR IHC (Lynch screening).

Always inspect the appendix if mucinous tumour is found. Always send peritoneal washings for cytology at surgery.

High Yield Summary — Management

Surgery is the cornerstone: Goal = R0 (no visible residual disease). Standard: TAH + BSO + omentectomy + peritoneal biopsies/washings + lymph node dissection ± appendicectomy. Must be performed by a trained gynae-oncologist for suspected malignancy.

PDS vs. NACT: If operable → PDS first (time-sensitive, therapeutic and diagnostic). If unresectable/unfit → NACT (3–4 cycles carboplatin + paclitaxel) → IDS → complete 6 cycles total.

Chemotherapy backbone: Carboplatin + paclitaxel × 6 cycles Q3 weeks. Germ cell tumours: BEP (bleomycin, etoposide, cisplatin).

Maintenance therapy (the modern paradigm):

BRCA-mutated → PARP inhibitor (olaparib)
HRD-positive → PARP inhibitor ± bevacizumab
HR proficient → Bevacizumab or observation

PARP inhibitors exploit synthetic lethality (BRCA loss + PARP inhibition = lethal). Bevacizumab targets VEGF → ↓angiogenesis, ↓ascites.

Recurrence: Platinum-free interval guides treatment. > 6 months = platinum-sensitive (re-challenge). < 6 months = platinum-resistant (non-platinum agents ± bevacizumab).

Key chemoresistant subtypes: Low-grade serous, clear cell (common in HK), mucinous. Surgery even more critical.

Fertility-sparing: Possible in Stage IA/IC low-grade (USO + staging). Standard for germ cell tumours.

Risk reduction: BRCA → BSO after childbearing. Lynch → TAH + BSO ~40y. Opportunistic salpingectomy gaining traction.

High Yield Summary — Complications

Complications of ovarian cancer — Think in three categories:

1. Disease complications:

Acute emergencies: torsion (twisted pedicle → ischaemia), haemorrhage, rupture (upgrades staging if malignant → IC2). All need emergency surgery consideration.
Peritoneal carcinomatosis → malignant ascites (exudate, VEGF-mediated), malignant bowel obstruction (multi-level, manage with NGT + octreotide + dexamethasone ± surgery/venting gastrostomy), pleural effusion (right-sided, transdiaphragmatic lymphatics).
Metastatic: omental cake, liver, nodes, lung (lymphangitis carcinomatosis → very poor prognosis), bone (rare), brain (rare).
Paraneoplastic: VTE/Trousseau syndrome (mucin-secreting tumours), hypercalcaemia (small cell CA ovary → PTHrP), lower limb lymphoedema (lymphatic invasion), dermatomyositis, cerebellar degeneration (anti-Yo), cancer cachexia, chronic DIC.
Granulosa cell tumour → oestrogen → endometrial hyperplasia/cancer (5–10%).

2. Treatment complications:

Surgery: tumour rupture/spill (→ IC1), haemorrhage, bowel/ureteric injury, VTE, wound infection, premature menopause, infertility.
Chemo: myelosuppression, peripheral neuropathy (paclitaxel), nephrotoxicity (cisplatin), alopecia, hypersensitivity (carboplatin after multiple cycles), pulmonary fibrosis (bleomycin in BEP), secondary MDS/AML.
Targeted therapy: PARP inhibitor → MDS/AML (1–2%). Bevacizumab → hypertension, GI perforation, proteinuria, delayed healing.

3. Long-term / psychosocial:

Premature menopause symptoms, infertility, chronic lymphoedema, psychological distress, financial burden, ~70% recurrence rate.
Stage III/IV ovarian cancer is NOT automatically palliative — unique biology allows aggressive treatment even in advanced disease.

Ovarian Cancer

1. Definition

2. Epidemiology

2.1 Global Burden

2.2 Hong Kong Epidemiology

2.3 Demographics by Histological Subtype

3. Risk Factors

3.1 Non-Modifiable Risk Factors

3.2 Modifiable / Reproductive Risk Factors

3.3 Protective Factors (Summary)

4. Anatomy and Function

4.1 The Ovary

4.2 Histological Layers

4.3 The Peritoneal Cavity — Routes of Spread

4.4 The Fallopian Tube and STIC

5. Etiology and Pathophysiology

5.1 Two-Pathway Model of Ovarian Carcinogenesis (Kurman & Shih)

Type I Tumours — "Low-grade pathway"

Type II Tumours — "High-grade pathway"

5.2 Pathophysiology of Non-Epithelial Ovarian Cancers

Germ Cell Tumours

Sex Cord–Stromal Tumours

5.3 BRCA Pathway — Molecular Detail

5.4 Lynch Syndrome and Ovarian Cancer

5.5 Pathophysiology of Key Clinical Manifestations

6. Classification

6.1 Histological Classification (WHO 2020)

A. Epithelial Tumours (~90%)

B. Germ Cell Tumours (~5%)

C. Sex Cord–Stromal Tumours (~5%)

6.2 Borderline Ovarian Tumours (Low Malignant Potential)

6.3 Staging — FIGO 2014 (Revised)

7. Clinical Features

7.1 Symptoms

A. Early / Non-specific Symptoms (often present for months before diagnosis)

B. Symptoms of Advanced Disease

C. Symptoms Specific to Tumour Type

7.2 Signs

A. General Examination

B. Abdominal Examination

C. Pelvic / Vaginal Examination

7.3 Features of Specific Ovarian Masses — Benign vs. Malignant

8. Special Topics Relevant to Hong Kong Exam

8.1 Ovarian Cancer Screening — Health Economics Perspective

8.2 Prophylactic Surgery for BRCA Carriers

8.3 Lynch Syndrome and Ovarian Cancer

Active Recall - Ovarian Cancer (Definition, Epidemiology, Risk Factors, Anatomy, Etiology, Classification, Clinical Features)

References

1. Framework for Differential Diagnosis

2. Differential Diagnosis by Organ of Origin

2.1 Ovarian — Benign Conditions

2.2 Ovarian — Borderline and Malignant Conditions

2.3 Uterine Conditions

2.4 Tubal and Inflammatory Conditions

2.5 Non-Gynaecological Conditions

3. Key Differentiating Features — Algorithmic Approach

4. Differentiating Ovarian Masses by Age

5. Differentiating by Tumour Markers

6. Differentiating by Imaging Characteristics

7. Special DDx Considerations in the Hong Kong Context

8. Summary Algorithm — Approaching a Pelvic Mass DDx

Active Recall - Differential Diagnosis of Ovarian Cancer

Faculty ultrasound checkpoint: IOTA Simple Rules

The Core Principle: There Is No Single "Diagnostic Criterion" — Diagnosis Is a Multi-Step Process

1. Risk Stratification Models — Deciding Who Needs Urgent Referral

1.1 Risk of Malignancy Index (RMI)

1.2 ROMA Algorithm (Risk of Ovarian Malignancy Algorithm)

1.3 IOTA / ADNEX Model

2. The Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3.1 Baseline Blood Tests

3.2 Tumour Markers

3.3 Imaging — First Line: Pelvic Ultrasound

3.4 Imaging — Staging: CT Scan of Abdomen and Pelvis

3.5 Imaging — MRI Pelvis

3.6 Imaging — PET/CT

3.7 Ascitic Fluid Analysis

3.8 Histopathological Diagnosis — The Gold Standard

3.9 Additional Investigations to Exclude Other Primaries

3.10 Genetic Testing