Explain ovarian cancer

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Ovarian Tumors - Classification, Etiology, Pathogenesis, Pathology, Morphology, Clinical Course, Spread & Complications

1. Overview & Epidemiology

Ovarian cancer is the sixth most common malignancy in women, behind breast, lung, colorectal, uterine cancer, and melanoma. Over 90% of cancers arise from the surface epithelium of the ovary (which shares embryological origins with the peritoneum). The peak incidence is at ages 56-70 years. Most cases (about 30% of all ovarian neoplasms) are malignant, but in premenopausal patients only ~7% of ovarian epithelial tumors are malignant. The overall 5-year survival is <50% because approximately two-thirds of women present with advanced disease.

Bailey and Love's Short Practice of Surgery, p. 1613
Berek & Novak's Gynecology, p. 2317

2. Classification of Ovarian Tumors

Ovarian tumors are broadly classified by cell of origin into three main groups, with a fourth category for metastatic tumors:

A. Epithelial Tumors (~90% of malignant ovarian tumors)

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

Histologic Type	Cellular Origin	Key Features
Serous (75-80% of epithelial cancers)	Endosalpingeal (fallopian tube)	Psammoma bodies, papillary pattern
Mucinous (8-10%)	Intestinal / endocervical	Large multilocular cysts, mucin-secreting epithelium
Endometrioid (10%)	Endometrial	Associated with endometriosis (15-20% co-exist with endometrial carcinoma)
Clear Cell (5%)	Mullerian	Hobnail cells, always high-grade; linked to DES exposure & endometriosis
Brenner (Transitional)	Transitional (Walthard rests)	Mostly benign; rare malignant form
Mixed Epithelial	Mixed	-
Undifferentiated	Anaplastic	Worst prognosis

Berek & Novak's Gynecology, Table 39-1, p. 2304

B. Germ Cell Tumors (~20% in young women)

Arise from primordial germ cells. More common in children and young women (<21 years - two-thirds of ovarian malignancies in this group are germ cell tumors). Types include:

Teratoma (mature/dermoid = benign; immature = malignant)
Dysgerminoma (most common malignant germ cell tumor)
Endodermal sinus (yolk sac) tumor - secretes AFP
Choriocarcinoma - secretes hCG
Embryonal carcinoma

C. Sex Cord-Stromal Tumors

Granulosa cell tumor - most common, secretes estrogen (feminizing effects, endometrial hyperplasia/cancer risk)
Theca cell tumor (Thecoma)
Sertoli-Leydig cell tumor - secretes androgens (virilization)
Fibroma - associated with Meigs' syndrome (fibroma + ascites + pleural effusion)

D. Metastatic Tumors (to ovary)

Krukenberg tumor - bilateral metastasis typically from gastric carcinoma (signet ring cells)
Also from breast, colorectal, endometrial primaries

3. Etiology & Risk Factors

Genetic / Hereditary Risk

BRCA1 mutation: 39% lifetime risk of ovarian cancer up to age 70
BRCA2 mutation: 11-17% lifetime risk up to age 70
Lynch syndrome (mismatch repair gene mutations): 9-12% increased lifetime risk (in addition to endometrial cancer risk)
Referral to specialist cancer genetics services is recommended for these high-risk patients

Hormonal / Reproductive Factors

Increased risk: nulliparity, early menarche, late menopause, infertility, hormone replacement therapy
Decreased risk: oral contraceptive use, multiple pregnancies, breastfeeding, tubal ligation - all reduce ovulatory cycles

Environmental

Talc/asbestos exposure (disputed)
High-fat diet, industrialized societies

The "Incessant Ovulation" Hypothesis

Each ovulation causes minor trauma to the ovarian surface epithelium; repeated cycles of trauma and repair increase the chance of oncogenic mutation.

Bailey and Love's Short Practice of Surgery, p. 1615

4. Pathogenesis

A key conceptual shift has occurred in recent decades:

Most serous carcinomas do NOT originate from the ovarian surface epithelium - they originate from the fimbrial end of the fallopian tube. Evidence comes from examination of risk-reducing salpingo-oophorectomy specimens from BRCA patients. Clear cell and endometrioid subtypes are derived from endometriosis.

Type I vs. Type II Serous Carcinoma (molecular classification)

Feature	Type I (Low-grade serous)	Type II (High-grade serous)
Growth	Slow	Rapid, aggressive
Genetics	Stable; KRAS or BRAF mutations; no p53 mutations	Unstable; p53 mutations (almost universal)
Origin	Borderline serous tumors	Fimbrial precursor lesions (STIC)
Stage at diagnosis	Often early	Usually advanced
Behavior	Good prognosis	Poor prognosis

Neoplastic transformation occurs when cells are genetically predisposed and/or exposed to an oncogenic agent.

Berek & Novak's Gynecology, p. 2303-2305

5. Morphology & Histopathology

Serous Tumors (most common)

Psammoma bodies (concentric laminated calcifications) are characteristic. Show papillary structures lined by cuboidal to columnar cells.

Low-grade serous adenocarcinoma - clusters and papillae of malignant cells in contact with fibrous stroma

Low-grade serous adenocarcinoma: clusters and papillae of malignant cells invade fibrous stroma

High-grade serous adenocarcinoma with papillae lined by sheets of cytologically malignant cells and associated necrosis

High-grade serous adenocarcinoma: papillae lined by sheets of cytologically malignant cells, with invasive growth and associated necrosis

Mucinous Tumors

Loculi lined by mucin-secreting epithelium resembling intestinal or endocervical cells. May reach enormous size filling the abdominal cavity. Bilateral in only 8-10%. Can cause pseudomyxoma peritonei (gelatinous mucoid material throughout the peritoneal cavity).

Endometrioid Carcinoma

Complex glandular pattern resembling proliferative endometrium. Co-exists with endometrial carcinoma in 15-20% of cases. This combination may represent synchronous primary tumors (better prognosis: 75-80% 5-year survival) vs. metastatic disease (30-40% 5-year survival).

Clear Cell Carcinoma

Tubulocystic, papillary, reticular, or solid patterns. Cells have clear or vacuolated cytoplasm and hobnail cells (nuclei projecting into apical cytoplasm). Always high-grade - not graded separately.

Borderline (Low Malignant Potential) Tumors

No stromal invasion (key distinguishing feature from invasive carcinoma)
Occur predominantly in premenopausal women (peak age 30-50)
Very good prognosis; extraovarian implants can occur but are usually noninvasive
Berek & Novak's Gynecology, p. 2305-2315

6. Clinical Course & Presentation

Symptoms

Ovarian cancer is the "silent killer" because symptoms are often vague and non-specific:

Abdominal distension and/or pain
Change in appetite, early satiety
Weight gain, increased girth (from ascites)
Urinary symptoms (urgency/obstruction)
Shortness of breath (pleural effusion)
Gastrointestinal disturbance, change in bowel habit

Over half of women initially present to a specialty other than gynaecology with metastatic disease symptoms. A pelvic mass + ascites is the classic combination strongly suggesting ovarian cancer.

Rarely, paraneoplastic syndromes occur: disseminated intravascular coagulation (DIC), polyneuritis, dermatomyositis, hemolytic anemia, cerebellar degeneration.

Physical Signs

Solid, irregular, fixed pelvic mass = highly suspicious for malignancy
Upper abdominal mass with ascites = almost certain ovarian cancer
Bilateral adnexal masses are more likely malignant than unilateral
Berek & Novak's Gynecology, p. 2317-2329

7. Staging (FIGO)

Stage	Description
I	Growth limited to the ovaries
II	Involvement of one or both ovaries with pelvic extension (uterus, bladder, sigmoid, rectum)
III	Peritoneal implants outside pelvis or retroperitoneal/inguinal lymph nodes
IV	Distant metastases (liver parenchyma, pleural effusion cytology positive)

Approximately two-thirds of patients present at Stage III or IV.

Bailey and Love's Short Practice of Surgery, Table 87.15, p. 1615

8. Routes of Spread

Direct extension - to adjacent pelvic structures (uterus, fallopian tube, bladder, rectum)
Peritoneal seeding (most common) - exfoliated cells implant throughout the peritoneal cavity; preferentially to the omentum (omental caking), paracolic gutters, diaphragm
Lymphatic spread - pelvic and para-aortic lymph nodes
Hematogenous spread - liver parenchyma, lung (late/rare)
Transdiaphragmatic spread - to pleural cavity causing pleural effusion

9. Investigations & Tumor Markers

CA-125

A glycoprotein expressed on coelomic and Mullerian-derived epithelia
Normal cut-off: 35 U/mL
Elevated in 50% of stage I and >90% of advanced disease
Primarily detects epithelial ovarian cancers
Non-specific: also elevated in endometriosis, PID, pregnancy, other cancers
Very high CA-125 (>200 U/mL) in postmenopausal women with adnexal mass = 96% positive predictive value for malignancy

Imaging

Transvaginal ultrasound - preferred; malignant features: irregular borders, multiple echogenic patterns, dense irregular septae, bilateral, >8 cm, ascites
CT scan - staging, assessing peritoneal disease and lymph nodes
Screening with CA-125 + TVU has not been proven to reduce mortality in average-risk women (USPSTF recommends against routine screening)

Other Markers

AFP - Yolk sac tumor
hCG - Choriocarcinoma, dysgerminoma
LDH - Dysgerminoma
Inhibin - Granulosa cell tumor

10. Treatment

Surgery (Primary Cytoreduction)

Total abdominal hysterectomy + bilateral salpingo-oophorectomy (TAH + BSO)
Infracolic omentectomy
Pelvic and para-aortic lymph node sampling
Peritoneal washings (diaphragm, right and left abdomen, pelvis)
Appendicectomy for mucinous tumors
Biopsies of all suspicious peritoneal surfaces

Goal: reduce residual tumor to <1 cm (optimal cytoreduction)

Fertility-sparing surgery (unilateral oophorectomy) is an option only for young women with stage IA/IB disease or borderline tumors.

Chemotherapy

First-line: Carboplatin + Paclitaxel (IV or intraperitoneal)
BRCA-mutated: PARP inhibitors (olaparib, niraparib) as maintenance therapy
Bevacizumab (anti-VEGF) as add-on for advanced disease

Prophylactic Risk Reduction

Prophylactic bilateral salpingo-oophorectomy (PBSO) recommended for BRCA carriers after childbearing is complete; reduces but does not eliminate risk (2-3% residual peritoneal carcinoma risk remains)

11. Complications

Complication	Notes
Ascites	From peritoneal seeding and lymphatic obstruction
Intestinal obstruction	From peritoneal implants and adhesions (leading cause of death)
Pleural effusion	Transdiaphragmatic spread or lymphatic obstruction
Ureteric obstruction	From pelvic mass
Paraneoplastic syndromes	DIC, cerebellar degeneration, dermatomyositis
Malnutrition/cachexia	Advanced disease
Deep vein thrombosis/PE	Hypercoagulable state associated with malignancy
Pseudomyxoma peritonei	From mucinous tumors; gelatinous mucoid material fills peritoneal cavity

Summary Points for Exam

90% of malignant ovarian tumors are epithelial (most: serous type)
Most high-grade serous carcinomas originate from the fallopian tube fimbria, NOT the ovary
Type I (low-grade, KRAS/BRAF mutations) vs. Type II (high-grade, p53 mutations) is the key molecular distinction
BRCA1 = 39% lifetime risk; BRCA2 = 11-17% lifetime risk
Classic spread = peritoneal seeding (omentum, diaphragm, paracolic gutters)
CA-125 >35 U/mL is the main marker; elevated in 50% Stage I, >90% advanced disease
No effective screening in average-risk women
Treatment: cytoreductive surgery + carboplatin/paclitaxel chemotherapy
Borderline tumors = no stromal invasion, good prognosis, occur in younger women (30-50 yrs)

Sources: Berek & Novak's Gynecology, pp. 2303-2340; Bailey and Love's Short Practice of Surgery, 28th Ed., pp. 1613-1616

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