Definition/General

Introduction:
-Ovarian cystadenocarcinomas represent invasive malignant epithelial tumors with predominantly cystic architecture
-They constitute 15-20% of all epithelial ovarian cancers
-These tumors demonstrate destructive stromal invasion and malignant cytological features
-They have intermediate prognosis between borderline tumors and solid carcinomas.
Origin:
-Arise from surface epithelium or inclusion cysts of the ovary
-May develop from pre-existing cystadenomas or borderline tumors
-Show progression through adenoma-borderline-carcinoma sequence
-Acquire capacity for stromal invasion and metastasis
-Demonstrate genetic alterations typical of malignant transformation.
Classification:
-Classified by WHO 2020 guidelines
-Serous cystadenocarcinoma (most common)
-Mucinous cystadenocarcinoma
-Endometrioid cystadenocarcinoma
-Clear cell cystadenocarcinoma
-Mixed types possible
-Further classified as low-grade or high-grade based on nuclear features.
Epidemiology:
-Peak incidence in 5th-6th decades
-Older age than cystadenomas and borderline tumors
-Serous type: Mean age 60 years
-Mucinous type: Mean age 55 years
-Associated with BRCA mutations (serous type)
-Indian population shows similar age distribution with varied outcomes.

Clinical Features

Presentation:
-Pelvic mass with rapid growth
-Abdominal pain and distension
-Ascites (advanced cases)
-Constitutional symptoms (weight loss, fatigue)
-Bowel or bladder symptoms
-Dyspnea (pleural effusion)
-Early satiety
-Family history (BRCA-associated cases).
Symptoms:
-Persistent abdominal or pelvic pain
-Progressive abdominal distension
-Loss of appetite and early satiety
-Nausea and vomiting
-Urinary frequency or urgency
-Constipation
-Unexplained weight loss
-Fatigue and weakness
-Postmenopausal bleeding (rare).
Risk Factors:
-Age >50 years
-BRCA1/2 mutations (especially serous)
-Family history of ovarian/breast cancer
-Nulliparity
-Infertility
-Endometriosis (clear cell, endometrioid)
-Lynch syndrome (endometrioid)
-Hormone replacement therapy.
Screening:
-CA-125 (elevated in 80-85% cases)
-HE4 (human epididymis protein 4)
-ROMA index
-Transvaginal ultrasound with Doppler
-CT/MRI for staging
-PET scan (selected cases)
-Genetic counseling for high-risk patients
-BRCA testing recommended.

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Gross Description

Appearance:
-Large, multilocular cystic masses
-Solid and cystic components
-Papillary excrescences on internal surface
-Necrosis and hemorrhage common
-Surface nodules or involvement
-Ascites fluid may be present
-Bilateral involvement (especially serous)
-Adherent to surrounding structures.
Characteristics:
-Thick-walled cysts with solid areas
-Papillary projections into cyst lumens
-Gray-white solid nodules
-Areas of necrosis and hemorrhage
-Friable consistency
-Surface irregularities
-Capsular breach common
-Variegated cut surface appearance.
Size Location:
-Size typically >10 cm (larger than benign)
-Bilateral involvement: Serous (60-70%), Mucinous (20-30%)
-Surface involvement common
-Capsular rupture frequent
-Adherent to pelvic structures
-Omental involvement (serous type)
-Peritoneal studding may be visible.
Multifocality:
-Bilateral disease common (especially serous)
-Peritoneal implants (carcinomatosis)
-Omental cake formation
-Lymph node metastases
-Diaphragmatic involvement
-Bowel serosa implants
-Liver surface deposits
-Pleural involvement (advanced cases).

Microscopic Description

Histological Features:
-Malignant epithelial cells with destructive stromal invasion
-High-grade nuclear atypia
-Increased mitotic activity
-Necrosis and hemorrhage
-Complex papillary architecture
-Solid growth patterns
-Desmoplastic stromal reaction
-Lymphovascular invasion common.
Cellular Characteristics:
-Epithelial cells show marked pleomorphism
-Enlarged hyperchromatic nuclei
-Prominent nucleoli
-High nuclear:cytoplasmic ratio
-Frequent mitoses including atypical forms
-Loss of cellular polarity
-Bizarre nuclear shapes
-Apoptotic bodies present.
Architectural Patterns:
-Complex papillary patterns with hierarchical branching
-Solid growth areas
-Cribriform architecture
-Micropapillary patterns
-Slit-like spaces
-Invasive glandular patterns
-Single cell infiltration
-Stromal desmoplasia around invasive foci.
Grading Criteria:
-Two-tier grading system: Low-grade and high-grade
-High-grade: Marked nuclear atypia, high mitotic rate (>12/10 HPF), solid growth >50%
-Low-grade: Mild-moderate atypia, low mitotic rate (<12/10 HPF), predominantly glandular
-Grade correlates with prognosis and treatment response.

Immunohistochemistry

Positive Markers:
-CK7 (cytokeratin 7)
-PAX8 (müllerian marker)
-WT1 (serous type, strong nuclear)
-p53 (mutant pattern in high-grade serous)
-CA-125
-ER/PR (variable)
-p16 (high-grade serous)
-BRCA1 (loss in BRCA1-mutated cases).
Negative Markers:
-CK20 (negative in serous, may be positive in mucinous)
-CDX2 (negative in serous)
-TTF-1
-Napsin A
-Inhibin (sex cord-stromal)
-Calretinin (mesothelial)
-CD45 (lymphoma)
-Melanoma markers.
Diagnostic Utility:
-PAX8 and WT1 confirm ovarian origin
-p53 pattern distinguishes high-grade from low-grade
-CK7/CK20 profile aids subtyping
-p16 overexpression in high-grade serous
-BRCA1 loss suggests BRCA1 pathway defect
-Helps exclude metastases and other primaries.
Molecular Subtypes:
-High-grade serous: p53 mutant, high Ki-67, p16+
-Low-grade serous: p53 wild-type, low Ki-67
-Mucinous: CK20+, CDX2+
-Endometrioid: ER+, PR+
-Clear cell: Napsin A+, HNF-1β+
-Molecular classification guides therapy.

Molecular/Genetic

Genetic Mutations:
-TP53 mutations (high-grade serous, >95%)
-BRCA1/2 mutations (20-25% of high-grade serous)
-KRAS mutations (low-grade serous, mucinous)
-PIK3CA mutations (endometrioid, clear cell)
-ARID1A mutations (clear cell, endometrioid)
-PTEN mutations (endometrioid)
-CTNNB1 mutations (endometrioid).
Molecular Markers:
-p53 overexpression (mutant pattern)
-High Ki-67 (proliferation index >40%)
-PARP expression (BRCA-deficient tumors)
-PD-L1 expression (subset of cases)
-Microsatellite instability (Lynch syndrome)
-HRD score (homologous recombination deficiency).
Prognostic Significance:
-Stage most important prognostic factor
-Grade influences survival
-BRCA mutations associated with better response to platinum
-HRD predicts PARP inhibitor sensitivity
-p53 mutations associated with aggressive behavior
-Age and debulking status important factors.
Therapeutic Targets:
-Platinum-based chemotherapy (carboplatin/paclitaxel)
-PARP inhibitors (BRCA-mutated, HRD)
-Bevacizumab (anti-angiogenic)
-PD-1/PD-L1 inhibitors (immunotherapy)
-Folate receptor α (mirvetuximab soravtansine)
-HER2 (selected cases)
-CDK4/6 inhibitors (under investigation).

Differential Diagnosis

Similar Entities:
-Borderline tumor with microinvasion
-Metastatic adenocarcinoma (GI, breast, lung)
-Primary peritoneal carcinoma
-Fallopian tube carcinoma
-Endometrial carcinoma with ovarian extension
-Clear cell carcinoma
-Sex cord-stromal tumor.
Distinguishing Features:
-Cystadenocarcinoma: Destructive stromal invasion
-Cystadenocarcinoma: High-grade nuclear atypia
-Borderline: No destructive invasion
-Metastases: Clinical history, bilateral small nodules
-Primary peritoneal: Normal-sized ovaries
-Endometrial: Uterine involvement, ER/PR positive.
Diagnostic Challenges:
-Distinguishing primary vs metastatic disease
-Grading accuracy (sampling issues)
-Subtype classification in poorly differentiated tumors
-Synchronous primaries (ovary vs endometrium)
-Peritoneal vs ovarian origin
-Mixed histological patterns.
Rare Variants:
-Micropapillary variant (aggressive behavior)
-Transitional cell variant
-Squamous differentiation
-Adenosquamous carcinoma
-Carcinosarcoma (malignant mixed müllerian tumor)
-Undifferentiated carcinoma
-Small cell carcinoma.

Sample Pathology Report

Template Format

Sample Pathology Report

Complete Report: This is an example of how the final pathology report should be structured for this condition.

Specimen Information

Bilateral salpingo-oophorectomy with omentum, [additional specimens]

Diagnosis

Ovarian cystadenocarcinoma, [subtype], [grade]

Classification

WHO 2020: [subtype] cystadenocarcinoma, [low/high] grade

Histological Features

Invasive adenocarcinoma with [architectural pattern] and [nuclear grade]

Size and Extent

Size: [X] cm, bilateral: [yes/no], surface involvement: [present/absent]

Invasion

Stromal invasion: present, lymphovascular invasion: [present/absent]

Special Studies

IHC: PAX8+, WT1+/-, p53 [pattern], Ki-67 [%]

Molecular: [BRCA/HRD status if tested]

Staging

FIGO Stage: [stage], peritoneal involvement: [present/absent]

Prognostic Factors

Stage: [stage], Grade: [grade], Debulking: [optimal/suboptimal]

Final Diagnosis

High-grade serous cystadenocarcinoma, FIGO Stage [stage]