Ovarian tumours
Ovarian tumours: epithelial, germ cell and sex cord-stromal tumours and their markers
Ovarian tumours are classified by origin: surface epithelium, germ cells or hormone-making sex cord-stroma, each with its own age group and marker. Age, histological hallmark, tumour marker and hormone effect usually identify the tumour, which is exactly how CPSP asks about them.
Three tissues, three families of tumour
The ovary has a surface coelomic (Müllerian-type) epithelium, germ cells (oocytes) and a hormone-making stroma derived from the sex cords. Each gives its own tumours, and the family predicts the patient's age, the marker and the behaviour.
| Group | Share | Typical age | Key point |
|---|---|---|---|
| Surface epithelial | About 65–70% of tumours, about 90% of cancers | Over 50 (borderline: younger) | CA-125; BRCA, Lynch |
| Germ cell | About 15–20% | Girls and young women | Commonest malignancy under 20; AFP, hCG, LDH |
| Sex cord-stromal | About 5–10% | Any, including children | Make oestrogen or androgen |
| Metastatic | About 5% | Any | Often bilateral and solid (Krukenberg) |
Epithelial tumours: why they arise
- Incessant ovulation: each ovulation ruptures and repairs the surface epithelium (and exposes the fimbria to follicular fluid); every repair cycle is a chance for a replication error. Anything that suppresses ovulation lowers risk: the combined pill (risk falls about 50% after 5 years and the benefit lasts decades), pregnancy and breastfeeding. Tubal ligation and salpingectomy also protect, because many cancers start in the tube.
- Raised risk: nulliparity, early menarche and late menopause, ovulation induction, endometriosis (endometrioid and clear cell types), and inherited syndromes.
- BRCA1/2 (high-grade serous) and Lynch syndrome (mismatch repair genes MLH1, MSH2, MSH6, PMS2). In Lynch syndrome the commonest cancer in women after the colon is endometrial, then ovarian; women are offered hysterectomy with salpingo-oophorectomy once their family is complete.
- A BRCA change found only in tumour tissue is somatic; a germline variant needs a blood test before relatives are counselled.
Epithelial tumours: types and grades
- Graded as benign (cystadenoma), borderline (proliferation and atypia with no destructive stromal invasion, younger women, excellent prognosis) and malignant (stromal invasion with desmoplasia, solid areas, necrosis, capsular breach).
| Type | Features | Marker |
|---|---|---|
| Serous | Commonest benign and commonest malignant ovarian tumour. Ciliated tubal-type cells; psammoma bodies (laminated calcification at papillary tips); often bilateral. High-grade serous carcinoma has TP53 mutation, is BRCA-linked and often begins in the fallopian tube fimbria; low-grade serous (KRAS, BRAF) is a separate, slower disease | CA-125 |
| Mucinous | Very large multilocular cysts with sticky fluid, tall columnar cells with apical mucin, sometimes goblet cells (intestinal type); usually unilateral. Pseudomyxoma peritonei usually comes from an appendiceal mucinous neoplasm, so check the appendix | CEA and CA 19-9; CA-125 often normal |
| Endometrioid | Glands like endometrial carcinoma with squamous morules; endometriosis; may coexist with a uterine primary | CA-125 |
| Clear cell | Clear glycogen-rich cytoplasm, hobnail cells; arises in endometriomas; ARID1A loss; poor response to chemotherapy | CA-125 |
| Brenner | Urothelial-like nests with coffee-bean grooved nuclei in fibrous stroma; usually benign | None |
- Spread: mainly transcoelomic. Cells shed from the surface float in peritoneal fluid, follow its clockwise circulation and implant on the omentum (omental cake), right hemidiaphragm, liver surface and pouch of Douglas; malignant cells in an ascitic tap show this route. Lymph follows the ovarian vessels to para-aortic nodes; blood spread is late. Most cases present at FIGO stage III (peritoneal spread outside the pelvis or retroperitoneal nodes); liver parenchymal or pleural disease is stage IV.
- Malignant ascites is an exudate: tumour blocks the diaphragmatic lymphatic stomata and VEGF raises capillary permeability.
- Paraneoplastic: anti-Yo cerebellar degeneration (serous carcinoma); anti-NMDA receptor encephalitis (teratoma); hypercalcaemia from PTHrP (small cell carcinoma of hypercalcaemic type).
- Treatment: debulking surgery plus carboplatin and paclitaxel, sometimes given intraperitoneally; PARP inhibitors for BRCA tumours. Altretamine (hexamethylmelamine), used for recurrent disease, is taken orally.
Germ cell tumours
Commonest in girls and young women; most are benign dermoids, and the malignant ones are highly chemosensitive (BEP: bleomycin, etoposide, cisplatin), so fertility-sparing surgery is usual.
| Tumour | Hallmark | Marker |
|---|---|---|
| Mature cystic teratoma (dermoid) | Commonest ovarian tumour in young women; hair, sebum, teeth from all three germ layers; bilateral in about 10%; fat–fluid level on imaging; torsion is the commonest complication; malignant change (1–2%, usually squamous carcinoma) in older women | None |
| Immature teratoma | Graded by the amount of immature neuroepithelium | Sometimes AFP |
| Dysgerminoma | Commonest malignant germ cell tumour; counterpart of seminoma: sheets of large clear polygonal cells with central nuclei, lymphocytes in fibrous septa, granulomas; may be bilateral; linked to gonadal dysgenesis; radiosensitive | LDH (and PLAP); small hCG rise possible |
| Yolk sac (endodermal sinus) tumour | Reticular network, Schiller–Duval bodies (perivascular glomerulus-like structures), PAS-positive hyaline globules; aggressive | AFP |
| Non-gestational choriocarcinoma | Syncytio- and cytotrophoblast, no villi; only the patient's DNA | hCG |
| Struma ovarii, carcinoid | Thyroid tissue (can cause hyperthyroidism); ovarian carcinoid drains systemically, so carcinoid syndrome occurs without liver metastases | Thyroid hormone; 5-HIAA |
- Why a dermoid is 46,XX but homozygous: it arises from a single germ cell after the first meiotic division. Homologous chromosomes have already separated, so the duplicated genome is maternal only and markers near the centromeres are homozygous, unlike the patient's blood. A complete mole is also homozygous 46,XX, but its genome is paternal.
- Gonadoblastoma arises in streak gonads that carry Y material (46,XY gonadal dysgenesis or 45,X/46,XY); it may progress to dysgerminoma, so both gonads are removed.
- A raised AFP in a "dysgerminoma" means a mixed tumour with yolk sac elements.
Sex cord-stromal tumours: think hormones
The stroma normally makes steroids: theca cells make androgen, and granulosa cells aromatise that androgen to oestrogen. Tumours keep this ability.
| Tumour | Features | Hormone and effect |
|---|---|---|
| Granulosa cell tumour | Call–Exner bodies, coffee-bean nuclei; adult type has FOXL2 mutation and recurs late; a juvenile type affects children | Oestrogen: endometrial hyperplasia, postmenopausal bleeding, endometrial cancer; in girls precocious pseudopuberty; marker inhibin |
| Thecoma | Yellow, lipid-laden spindle cells; postmenopausal | Oestrogen |
| Fibroma | Dense collagen, very dark on T2 MRI | None; Meigs syndrome |
| Sertoli–Leydig cell tumour | Tubules and Leydig cells; young women | Androgens: hirsutism, clitoromegaly, deep voice |
- Precocious pseudopuberty from a granulosa cell tumour: a young girl with breast development, vaginal bleeding and rapid growth, but high oestradiol with suppressed LH and FSH that do not rise after GnRH, is making oestrogen independently of the pituitary. A unilateral solid-cystic ovarian mass makes it a (juvenile) granulosa cell tumour. Central (true) precocious puberty would show raised, GnRH-responsive gonadotrophins.
- Meigs syndrome: fibroma, ascites and right pleural effusion that resolve after removal. Fluid crosses diaphragmatic lymphatics, more on the right. CA-125 may rise, so ascites with a mass is not always cancer.
- Pregnancy luteoma: solid hCG-driven nodules that may virilise the mother and regress after delivery.
Metastatic tumours
- Krukenberg tumour: bilateral solid ovaries with signet-ring cells in a cellular stroma, usually from the stomach (also colon, breast, appendix). Bilateral solid masses suggest metastasis.
Tumour markers and their limits
| Marker | Main ovarian source | Other causes |
|---|---|---|
| CA-125 | Serous and endometrioid carcinoma | Made by any coelomic-derived epithelium (peritoneum, pleura, pericardium): any ascites, cirrhosis, endometriosis, PID, menstruation, pregnancy, heart failure |
| CEA, CA 19-9 | Mucinous tumours | Colorectal, gastric and pancreatic cancer |
| AFP | Yolk sac tumour | Hepatocellular carcinoma (used with ultrasound to survey cirrhotic patients), fetal neural tube defects |
| hCG | Choriocarcinoma | Pregnancy, molar disease |
| LDH | Dysgerminoma | Any cell turnover, haemolysis |
| Inhibin | Granulosa cell tumour | Normal in cycling women |
- CA-125 is not cancer-specific. A man with cirrhosis and tense ascites can have a CA-125 of several hundred because the stretched, irritated peritoneal mesothelium releases it. Its best use is monitoring a known cancer, and combined with ultrasound and menopausal status (risk of malignancy index).
- Pain from a diseased ovary may be felt on the medial thigh via the obturator nerve on the lateral pelvic wall.
Remember Match tumour to marker: yolk sac AFP, dysgerminoma LDH, choriocarcinoma hCG, granulosa inhibin, serous CA-125, mucinous CEA.
Exam trap In girls and young women the commonest ovarian malignancy is a germ cell tumour, not an epithelial one.
Exam trap A normal CA-125 does not exclude a mucinous tumour, and a high CA-125 with ascites can come from the peritoneum itself, even in a man.
How FCPS asks about this
- Commonest malignant ovarian tumour, psammoma bodies, raised CA-125: serous cystadenocarcinoma.
- Young girl, solid mass, clear cells with lymphocytes in septa: dysgerminoma; marker LDH.
- Schiller–Duval bodies, hyaline globules: yolk sac tumour; monitor with AFP.
- Girl with breast development and bleeding, suppressed gonadotrophins, ovarian mass: granulosa cell tumour making oestrogen; marker inhibin.
- Route of spread of ovarian carcinoma: transcoelomic (peritoneal seeding), first to the omentum.
- How the pill protects against ovarian cancer: suppression of ovulation.
- Lynch syndrome woman, commonest cancer after colon: endometrium.
Test yourself on this topic
5 of the 61 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 60-year-old woman has advanced high-grade serous carcinoma with marked atypia and many mitoses; the fimbria shows a small in-situ lesion of the same cells. Mutation of which gene is found in almost every tumour of this type?
Answer: TP53 gene
High-grade serous carcinoma, the commonest and most lethal ovarian cancer, carries TP53 mutations in nearly all cases. Many begin as serous tubal intraepithelial carcinoma in the fimbria, which also shows the TP53 change. KRAS and BRAF mutations mark the separate low-grade serous pathway that arises from borderline tumours. PTEN and ARID1A are typical of endometrioid and clear cell carcinomas.
High-grade serous carcinoma
- Commonest ovarian cancer
- Often starts in fimbria (STIC)
- TP53 mutation almost always
- BRCA linked
Remember High-grade serous: TP53; low-grade serous: KRAS/BRAF.
Exam trap Low-grade and high-grade serous carcinoma are different diseases, not grades of one tumour.
Why the other options are wrong
- KRAS gene Low-grade serous and mucinous pathway.
- BRAF gene Low-grade serous pathway.
- PTEN gene Endometrioid tumours.
- ARID1A gene Clear cell and endometrioid tumours.
A 17-year-old girl has a solid ovarian teratoma containing cartilage, glands and primitive neural tubules and rosettes. The pathologist assigns a grade. Which feature determines the grade of this tumour?
Answer: Amount of immature neuroepithelium
Primitive neural tubules and rosettes mean this is an immature teratoma, a malignant germ cell tumour of young women. It is graded by the quantity of immature neuroepithelium, counted as the number of low-power fields it occupies on any one slide. High-grade tumours behave more aggressively and are given chemotherapy. Size, AFP level and mature elements such as hair do not set the grade.
Immature teratoma
- Contains primitive neuroepithelium
- Grade = amount of immature neural tissue
- Counted in low-power fields
- High grade: worse outcome
Remember Teratoma grade is a count of immature neural tissue.
Exam trap Mitotic counts grade many tumours, but immature teratoma is graded by neuroepithelium.
Why the other options are wrong
- Number of mitoses per ten fields Not the basis of teratoma grading.
- Overall diameter of the tumour Size affects stage, not grade.
- Level of serum alpha-fetoprotein AFP may rise but does not grade.
- Presence of hair and teeth Mature tissue does not raise the grade.
A 19-year-old woman's ovarian dysgerminoma is the counterpart of which testicular tumour, with identical histology, cell of origin and radiosensitivity?
Answer: Classic testicular seminoma
Dysgerminoma is the ovarian counterpart of the classic testicular seminoma. Both arise from primordial germ cells, show sheets of large clear cells with lymphocytic septa, express KIT and OCT3/4, and are very sensitive to radiotherapy and platinum chemotherapy. Embryonal carcinoma and yolk sac tumour are non-seminomatous germ cell tumours. Spermatocytic tumour is a separate tumour of older men and has no ovarian counterpart.
Dysgerminoma = ovarian seminoma
- Same cell: primordial germ cell
- Same look: clear cells + lymphocytes
- Both radiosensitive
- Both KIT and OCT3/4 positive
Remember Dysgerminoma is the seminoma of the ovary.
Exam trap Spermatocytic tumour sounds like seminoma but is a different tumour with no ovarian equivalent.
Why the other options are wrong
- Testicular embryonal carcinoma Non-seminomatous; primitive epithelial cells.
- Testicular yolk sac tumour Non-seminomatous; makes AFP.
- Leydig cell tumour of testis Sex cord-stromal, not germ cell.
- Spermatocytic tumour of testis Tumour of older men with no ovarian twin.
A 52-year-old woman's ovarian tumour shows diffuse sheets of cells with grooved 'coffee-bean' nuclei and small rosettes around eosinophilic fluid (Call–Exner bodies). A somatic point mutation in which gene is found in nearly all tumours of this type?
Answer: FOXL2
Grooved nuclei and Call–Exner bodies identify an adult granulosa cell tumour. Almost all of these tumours carry the same somatic missense mutation in FOXL2 (C134W), a transcription factor that controls granulosa cell development, and testing for it helps confirm the diagnosis. BRCA1 and TP53 are linked to high-grade serous carcinoma, KRAS to mucinous and low-grade serous tumours, and DICER1 to Sertoli–Leydig cell tumours.
Adult granulosa cell tumour
- Coffee-bean nuclei
- Call–Exner bodies
- Mutation: FOXL2
- Marker: inhibin
Remember Adult granulosa cell tumour: FOXL2 mutation.
Exam trap TP53 is the gene of high-grade serous cancer, not of granulosa cell tumours.
Why the other options are wrong
- BRCA1 Linked to high-grade serous carcinoma.
- TP53 Near-universal in high-grade serous carcinoma.
- KRAS Mucinous and low-grade serous tumours.
- DICER1 Linked to Sertoli–Leydig cell tumours.
A 16-year-old with a female phenotype has primary amenorrhoea and no breast development. Karyotype is 46,XY, and laparoscopy shows streak gonads with a normal uterus. Removal of both gonads is advised. Which tumour is she at risk of?
Answer: Gonadoblastoma
This is complete 46,XY gonadal dysgenesis (Swyer syndrome): the gonads never formed testes, so there was no AMH or testosterone, and a uterus developed. Dysgenetic gonads that contain Y chromosome material carry a high risk of gonadoblastoma, a mixed tumour of germ cells and sex cord cells. Gonadoblastoma can progress to dysgerminoma or other malignant germ cell tumours, so the streaks are removed.
Y material in a streak gonad
- 46,XY streak gonads
- Risk of gonadoblastoma
- May progress to dysgerminoma
- Gonadectomy advised
Remember Dysgenetic gonad plus a Y chromosome: remove it.
Exam trap A 45,X/46,XY mosaic also carries this risk, so look for Y material in Turner girls who virilise.
Why the other options are wrong
- Granulosa cell tumour Not the Y-linked risk in streak gonads.
- Serous carcinoma Epithelial tumour of older women.
- Mature cystic teratoma Not linked to Y material in streak gonads.
- Ovarian fibroma Not linked to gonadal dysgenesis.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: Neoplasia of the female genital tract, Ovarian tumours: epithelial, germ cell, sex cord-stromal; tumour markers