Ovarian Pathology — Cysts and Tumors

FUNCTIONAL (NON-NEOPLASTIC) CYSTS

• Follicular cysts: Result from failure of ovulation or impaired follicular atresia, leading to persistence of the graafian follicle beyond the normal luteal phase. Accumulation of follicular fluid within an unruptured dominant follicle creates a unilocular cyst lined by granulosa cells and theca interna. Estrogen production by granulosa cells may cause unopposed estrogenic stimulation, leading to endometrial hyperplasia or breakthrough bleeding.
• Corpus luteum cysts: Develop from hemorrhage into the corpus luteum or failure of normal involution after ovulation. The cyst wall contains luteinized granulosa and theca cells secreting both progesterone and estrogen. These are typically self-limited, resolving spontaneously within 1–3 menstrual cycles.
• Theca lutein cysts: Occur in settings of elevated β-hCG (pregnancy, molar pregnancy, choriocarcinoma) due to exaggerated luteinization of multiple follicles. The cysts are typically bilateral and regress following resolution of the hCG-secreting condition.

NEOPLASTIC CYSTS AND BENIGN TUMORS

• Epithelial tumors arise from the müllerian-derived coelomic epithelium, the source of serous, mucinous, endometrioid, and clear cell differentiation. The invagination theory proposes that inclusion cysts form from inverted surface epithelium, accumulating in the cortical stroma where repeated ovulation and repair create sites of epithelial inclusion. These inclusion cysts may undergo malignant transformation via activation of KRAS, BRAF, TP53, and PTEN mutations.
• Benign cystadenomas: Display simple cystic architecture with a single layer of epithelial cells producing mucoid (mucinous) or serous fluid. Absence of stromal invasion or cellular atypia defines benignity. The proliferating epithelium maintains normal mitotic rate and lacks the architectural complexity of borderline or malignant counterparts.
• Borderline ovarian tumors (BOT): Demonstrate epithelial proliferation with mild nuclear atypia but lack destructive stromal invasion. Architectural features include micropapillary projections, cribriform nests, and epithelial stratification without invasion into underlying stroma. These occupy an intermediate biologic category between benign cystadenomas and invasive carcinoma.
• Malignant epithelial tumors: Display destructive stromal invasion characterized by irregular nests, trabeculae, and single cells infiltrating stroma. Nuclei exhibit marked atypia, elevated mitotic rate, and abnormal mitotic figures. TP53 mutations predominate in high-grade serous carcinomas, while KRAS and BRAF mutations are common in low-grade tumors and mucinous histotypes. DNA mismatch repair (MMR) deficiency is associated with endometrioid and clear cell carcinomas.

GERM CELL TUMORS

• Dysgerminoma: Arises from primordial germ cells that have undergone malignant transformation without differentiation. The tumor shows mitotic proliferation with central nervous system (CNS)-like architecture and characteristic fibrovascular septa. γ-globulin production occurs in some cases, though α-fetoprotein (AFP) and β-hCG are typically negative, distinguishing dysgerminomas from other germ cell tumors.
• Yolk sac tumor (endodermal sinus tumor): Results from differentiation of germ cells toward extragonadal endoderm. Cells produce α-fetoprotein (AFP) detectable in serum and within the cytoplasm of tumor cells. Characteristic Schiller-Duval bodies—complex papillary structures with a central vessel surrounded by cuboidal cells—represent the hallmark histologic feature.
• Immature teratoma: Composed of tissues from all three germ layers (ectoderm, mesoderm, endoderm) in immature or embryonic form. The presence of immature neuroepithelium (resembling fetal neural tube) determines grade and significantly impacts prognosis. Grading is based on proportion of immature neural tissue: Grade 1 (minimal), Grade 2 (moderate), Grade 3 (extensive).
• Mature teratoma (dermoid cyst): Contains well-differentiated tissue from multiple germ layers, often including skin appendages (hair, sebaceous glands), teeth, bone, and neural tissue. The cyst is lined by stratified squamous epithelium with associated skin appendages, creating the characteristic skin-like adnexal structures. Mature teratomas are benign but carry risk of malignant transformation (squamous cell carcinoma, adenocarcinoma, melanoma) in approximately 1–2% of cases.

SEX CORD-STROMAL TUMORS

• Granulosa cell tumor: Arises from granulosa cells of developing follicles, exhibiting characteristic Call-Exner bodies—empty spaces lined by granulosa cells mimicking primitive follicles. These tumors produce inhibin and anti-müllerian hormone (AMH), with inhibin being a valuable serum marker. Activation of FOXL2 mutations (present in ~95% of adult granulosa cell tumors) is pathognomonic.
• Sertoli-Leydig cell tumor (androblastoma): Consists of Sertoli cells and Leydig cells arranged in immature testicular architecture. The tumor secretes androgens (testosterone, androstenedione) from Leydig cells, causing virilization. These are almost always benign with rare malignant behavior.
• Thecoma: Composed of theca cells arranged in short fascicles with abundant lipid-rich cytoplasm, often appearing foamy. These tumors produce estrogen, causing endometrial stimulation and potential hyperplasia or carcinoma. Meige syndrome (ascites with pleural effusion) is a characteristic paraneoplastic syndrome.

MOLECULAR PATHWAYS IN OVARIAN CARCINOGENESIS

• Type I tumors (low-grade serous, mucinous, endometrioid, clear cell): Arise from precursor lesions (borderline tumors or atypical proliferative lesions) via stepwise accumulation of KRAS, BRAF, PTEN, and PIK3CA mutations. These remain morphologically lower-grade and often present at earlier stages.
• Type II tumors (high-grade serous carcinoma): Arise de novo from fallopian tube epithelium or ovarian surface epithelium without identifiable precursor lesion. TP53 mutations are nearly universal (>95%), occurring early in tumorigenesis and driving rapid progression. These tumors are highly aggressive with early metastatic spread.
• BRCA1/BRCA2 associated carcinogenesis: Loss of homologous recombination (HR) DNA repair capacity through BRCA1/2 mutations results in genomic instability and accumulation of additional mutations. These tumors are typically high-grade serous carcinomas with improved platinum sensitivity due to HR deficiency.

NON-NEOPLASTIC CYSTS

• Ovulatory dysfunction from hypothalamic-pituitary axis dysregulation or polycystic ovary syndrome (PCOS)
• Pregnancy and fertility treatments with elevated hCG stimulating multiple follicles
• Hormonally active tumors (e.g., choriocarcinoma, hydatidiform mole) producing excess hCG
• Prolonged estrogen exposure (obesity, late menopause, exogenous estrogen use)

EPITHELIAL OVARIAN CANCER

• Age: Peak incidence 50–70 years; rare before age 30 except borderline and low-grade tumors
• Hereditary cancer syndromes: BRCA1/2 mutations increase lifetime risk to 40–50%; Lynch syndrome (mismatch repair deficiency) increases risk particularly for endometrioid and clear cell carcinomas
• Reproductive history: Nulliparity, infertility, and early menarche increase risk; multiparity and oral contraceptive use decrease risk (protective effect up to 30% risk reduction)
• Ovulatory dysfunction: PCOS, anovulation, and incessant ovulation theory—repeated ovulatory trauma and repair cycles increase epithelial proliferation and mutation risk
• Endometriosis: Clear cell and endometrioid carcinomas arise in up to 0.7% of women with ovarian endometriosis
• Estrogen/progestin exposure: Unopposed estrogen or imbalanced hormone replacement therapy increases risk
• Postmenopausal status: Loss of ovarian hormones with increased baseline FSH and LH stimulation
• Obesity: Increased peripheral estrogen production from adipose tissue aromatization of androgens
• Smoking: Increased risk particularly with mucinous histotype; potential carcinogenic effect of polycyclic aromatic hydrocarbons

GERM CELL TUMORS

• Age: Peak incidence 10–30 years; dysgerminomas typically in adolescents and young women
• Cryptorchidism history: Increased risk in patients with gonadal dysgenesis or intersex disorders
• Gonadal dysgenesis: XO/XY mosaicism increases risk of malignant germ cell transformation

SEX CORD-STROMAL TUMORS

• Age: Granulosa cell tumors present across broad age range with two peaks (children and perimenopausal women); Sertoli-Leydig tumors typically in second and third decades
• Hormonal stimulation: Chronic estrogenic stimulation may promote granulosa cell proliferation

FUNCTIONAL CYSTS

• Asymptomatic: Most follicular and corpus luteum cysts are discovered incidentally on imaging
• Acute pelvic pain: Rupture of cyst or intracystic hemorrhage causes acute, colicky pain mimicking ovarian torsion
• Irregular vaginal bleeding: Unopposed estrogen from follicular cysts causes endometrial proliferation and breakthrough bleeding
• Amenorrhea or oligomenorrhea: Persistent cysts suppress normal ovulation through negative feedback
• Physical examination: Lower abdominal or adnexal tenderness if cyst is ruptured; usually benign unless hemorrhage is massive
• Imaging: Transvaginal ultrasound reveals simple unilocular cyst, typically <5 cm; follicular cysts resolve within 4–6 weeks

BORDERLINE OVARIAN TUMORS

• Vaginal bleeding or pelvic pressure: Often asymptomatic and discovered incidentally during evaluation for other symptoms
• Abdominal distention and discomfort: Larger tumors may cause mass effect
• Infertility: May be discovered during workup for reproductive dysfunction
• Mucinous BOT: Risk of pseudomyxoma peritonei (gelatinous ascites from epithelial mucin production) if rupture occurs
• Imaging: Multilocular cystic mass with smooth borders; minimal ascites; often early-stage disease (Stage I in 70% of cases)

INVASIVE EPITHELIAL OVARIAN CANCER

• Late presentation: Most patients present with advanced stage disease (Stage III–IV in 70% of cases)
• Abdominal bloating and distention: From ascites accumulation and peritoneal involvement
• Pelvic pain or pressure: From mass effect or peritoneal irritation
• Vaginal bleeding or abnormal menses: Less common; may occur with granulosa cell tumors
• Constitutional symptoms: Unintentional weight loss, fatigue, anorexia from systemic effects of advanced cancer
• Gastrointestinal symptoms: Constipation, diarrhea, early satiety from peritoneal carcinomatosis and bowel involvement
• Abdominal/pelvic mass: Palpable on examination in advanced disease; fixated or nodular mass suggests invasion or metastasis
• Ascites: Dullness to percussion, shifting dullness, fluid wave on examination; indicates peritoneal involvement and advanced stage
• Supraclavicular lymphadenopathy: From distant metastatic disease
• CA-125 elevation: Tumor marker >35 U/mL (positive in ~80% of advanced-stage epithelial cancers, but only 50% of Stage I); useful for monitoring response to therapy

GERM CELL TUMORS

• Age-appropriate presentation: Adolescent or young adult with pelvic mass
• Acute pain: From cyst rupture, torsion, or hemorrhage within tumor
• Abdominal/pelvic mass: Palpable mass in lower abdomen
• Precocious puberty: From hormonal secretion by some germ cell tumors (rare)
• Dysgerminoma: May present with β-hCG elevation in minority of cases if associated with syncytiotrophoblastic cells; positive β-hCG or AFP necessitates chemotherapy
• Yolk sac tumor: Markedly elevated α-fetoprotein (AFP) (often >1000 ng/mL); serum AFP is highly sensitive and specific marker
• Immature teratoma: Elevated α-fetoprotein correlates with grade and degree of immature neural tissue; may have elevated β-hCG if syncytiotrophoblastic elements present
• Imaging: Solid or partially cystic mass with heterogeneous echogenicity; may contain fat, fluid levels, or calcifications

SEX CORD-STROMAL TUMORS

• Granulosa cell tumor: Often endometrial bleeding/hyperplasia from unopposed estrogen; may mimic menopause-related bleeding in older women
• Sertoli-Leydig cell tumor: Virilization with clitoromegaly, deepening of voice, male pattern hair growth, and temporal baldness; elevated serum testosterone and androstenedione
• Thecoma: Vaginal bleeding/postmenopausal bleeding from estrogen-induced endometrial proliferation; ascites and pleural effusion (Meige syndrome) in some cases
• Physical examination: Lower abdominal mass; ascites present in advanced thecomas
• Inhibin elevation: Markedly elevated serum inhibin in granulosa cell tumors (useful tumor marker)

IMAGING EVALUATION

• Transvaginal ultrasound: First-line imaging; superior resolution for characterization of adnexal masses
• Simple cyst (benign functional cyst): Single compartment, thin wall, anechoic fluid, no septations or solid components
• Multilocular cystic mass (borderline or invasive): Multiple locules with thin septations; minimal free fluid
• Complex mass (suggesting malignancy): Solid or predominantly solid component, thick irregular walls, papillary projections, ascites, echogenic material
• Pelvic/abdominal CT or MRI: For staging and evaluation of spread; assesses peritoneal involvement, lymphadenopathy, and distant metastases
• CA-125: Elevated in 80% of advanced epithelial cancers; <35 U/mL considered normal
• CEA and AFP: For specific tumor types (yolk sac tumor, immature teratoma)

Immediate stabilisation

• Suspected ovarian torsion: a surgical emergency. Do not delay for imaging confirmation — ACOG advises prompt diagnostic laparoscopy with detorsion and ovarian conservation (cystectomy rather than oophorectomy) even in a dusky-appearing ovary, since ovarian function frequently recovers.
• Ruptured hemorrhagic cyst with hemoperitoneum: large-bore IV access, crystalloid, type and cross, serial hematocrits. Hemodynamic instability or ongoing bleeding mandates laparoscopy with cystectomy or coagulation of the bleeding bed; reverse anticoagulation if the patient is on warfarin or a DOAC.

Functional cysts — first line

• Expectant management: simple, thin-walled cysts in premenopausal women are observed with repeat transvaginal ultrasound, per ACOG's adnexal mass guidance and the ACR/Society of Radiologists in Ultrasound consensus on ovarian cyst follow-up. Most resolve over one to three cycles.
• Combined hormonal contraceptives (e.g., ethinyl estradiol/levonorgestrel): suppress gonadotropins and prevent new functional cysts; they do not accelerate resolution of an existing cyst and should not be used as "treatment" for one.
• NSAIDs (e.g., ibuprofen) for pain from rupture managed conservatively.

Neoplastic disease — definitive management

• Benign neoplasms (dermoid, cystadenoma): ovarian cystectomy, ideally laparoscopic with avoidance of intraperitoneal spill.
• Suspected epithelial ovarian cancer: NCCN and ACOG/SGO recommend referral to a gynecologic oncologist for comprehensive surgical staging and maximal cytoreduction to no gross residual disease, followed by platinum–taxane chemotherapy (carboplatin plus paclitaxel). Neoadjuvant chemotherapy with interval debulking is the alternative when upfront optimal cytoreduction is not feasible or the patient is a poor operative candidate.
• Escalation/maintenance: PARP inhibitors (e.g., olaparib) for BRCA-mutated or homologous-recombination-deficient disease, and anti-VEGF therapy (bevacizumab) in selected patients (NCCN).
• Malignant germ cell tumors: fertility-sparing unilateral salpingo-oophorectomy plus BEP (bleomycin, etoposide, cisplatin); cure rates are high even with advanced disease.

Contraindicated / avoid

• Routine screening with CA-125 and ultrasound in average-risk asymptomatic women — USPSTF gives this a D recommendation (net harm from false positives and unnecessary surgery).
• Power morcellation or deliberate intraperitoneal rupture of a suspicious mass.
• Prophylactic oophorectomy in a young woman for a benign cyst when cystectomy suffices.

Emergencies

• Ovarian torsion: a large or heavy mass (classically a mature cystic teratoma) acts as a fulcrum, twisting the infundibulopelvic ligament. Venous and lymphatic outflow obstruct first, causing edema and eventual arterial compromise and necrosis. Signalled by sudden severe unilateral pain with nausea/vomiting and a tender adnexal mass; ultrasound may show an enlarged edematous ovary with peripherally displaced follicles or the whirlpool sign. Preserved arterial Doppler flow does not exclude torsion because of dual ovarian/uterine artery supply.
• Cyst rupture with hemoperitoneum: most often a corpus luteum cyst, whose vascular luteinized wall bleeds; risk is amplified by anticoagulation. Signalled by acute pain, peritoneal signs, tachycardia/hypotension, and free fluid with echogenic (clotted) blood on ultrasound.
• Bowel obstruction or perforation from peritoneal carcinomatosis, or bevacizumab-associated GI perforation through impaired mucosal healing — sudden pain with free air.

Disease-related

• Chemical peritonitis: spillage of keratin and sebum from a dermoid provokes an intense granulomatous inflammatory response.
• Pseudomyxoma peritonei: mucin-producing epithelium seeds the peritoneum, producing gelatinous ascites; when encountered, search for an appendiceal primary.
• Malignant ascites and pleural effusion: peritoneal seeding and diaphragmatic lymphatic transit; presents with distention, shifting dullness, dyspnea.
• Estrogen-driven endometrial hyperplasia/carcinoma from granulosa cell tumors and thecomas — signalled by postmenopausal bleeding; always sample the endometrium.
• Malignant transformation of a mature teratoma (most often squamous cell carcinoma) — new solid enhancing component in an older woman.
• Paraneoplastic anti-NMDA receptor encephalitis with teratoma: psychiatric change, seizures, dyskinesias; resolves with tumor removal.

Treatment-related

• Bleomycin: dose-dependent pulmonary fibrosis via free-radical injury — declining DLCO, dry cough.
• Cisplatin: nephrotoxicity, ototoxicity, peripheral neuropathy.
• Carboplatin/paclitaxel: myelosuppression, neuropathy, and hypersensitivity reactions (carboplatin typically after repeated cycles).
• PARP inhibitors: cytopenias and rare therapy-related MDS/AML.
• Surgical menopause and VTE after bilateral oophorectomy or major debulking.

• Torsion is the single best next step trap: sudden severe unilateral pelvic pain with vomiting and an adnexal mass → diagnostic laparoscopy, not serial imaging. The classic distractor is "normal Doppler flow, therefore not torsion" — flow may persist because of dual arterial supply.
• Mature cystic teratoma (dermoid) is the most common ovarian neoplasm in women of reproductive age and the mass most likely to torse; imaging shows fat, fluid-fluid levels, and calcification (tooth). Variants examiners love: struma ovarii (thyroid tissue → thyrotoxicosis) and carcinoid (flushing without hepatic metastases, because venous drainage bypasses the portal circulation).
• Histology buzzwords: psammoma bodies → serous tumors; Schiller-Duval bodies + AFP → yolk sac tumor; Call-Exner bodies + inhibin → granulosa cell tumor; sheets of clear cells with lymphocytic septa + LDH/placental ALP → dysgerminoma; signet ring cells → Krukenberg tumor.
• Krukenberg is the association tested most: bilateral ovarian metastases of mucin-filled signet ring cells, classically from diffuse-type gastric adenocarcinoma (colon and breast lobular carcinoma also metastasize to ovary). Bilateral should immediately raise metastasis or high-grade serous carcinoma — most primary epithelial tumors and germ cell tumors are unilateral.
• Meigs syndrome = benign ovarian tumor (classically fibroma) + ascites + right-sided pleural effusion, all of which resolve after resection — not a marker of malignancy.
• High-grade serous carcinoma is a *TP53*-mutant, fallopian tube fimbria–derived (serous tubal intraepithelial carcinoma) tumor; BRCA1/2 carriers should be offered risk-reducing salpingo-oophorectomy after childbearing per NCCN.
• CA-125 is not a screening test — the USPSTF recommends against ovarian cancer screening in average-risk women. False elevations occur with endometriosis, fibroids, pregnancy, PID, and cirrhosis; it is best used for monitoring known disease.
• Virilization (clitoromegaly, voice deepening) with high testosterone → Sertoli-Leydig cell tumor; postmenopausal bleeding with endometrial hyperplasia → estrogen-secreting granulosa cell tumor or thecoma (sample the endometrium).