Definition/General
Introduction:
Ovarian large cell carcinoma is a rare subtype of poorly differentiated ovarian carcinoma characterized by large pleomorphic tumor cells with abundant cytoplasm
It represents 2-5% of all ovarian carcinomas
Typically shows aggressive behavior with poor prognosis
Often presents at advanced stage (Stage III-IV) due to rapid growth.
Origin:
Arises from ovarian surface epithelium or inclusion cysts
May develop from serous or endometrioid adenocarcinoma through dedifferentiation
Can also arise de novo from pluripotent stem cells
Shows loss of epithelial differentiation markers with retention of malignant characteristics.
Classification:
WHO 2020 classifies as high-grade serous carcinoma variant
Previously categorized under undifferentiated carcinoma
FIGO staging applies (Stage I-IV)
Grading follows universal grading system (typically Grade 3)
Distinguished from giant cell carcinoma by cell size uniformity.
Epidemiology:
Peak incidence in 6th-7th decades (mean age 58-65 years)
BRCA1/2 mutations increase risk by 20-40%
Family history of breast/ovarian cancer
Nulliparity and late menopause
Indian population shows increasing incidence in urban areas
Associated with p53 mutations in 85-90% cases.
Clinical Features
Presentation:
Pelvic mass (85-90% cases) often large and fixed
Abdominal distension due to ascites (70% cases)
Early satiety and bloating
Constitutional symptoms (weight loss, fatigue) in 60% cases
Bowel obstruction (25% advanced cases)
Pleural effusion in metastatic disease.
Symptoms:
Abdominal pain (70-80% cases) - dull, constant
Pelvic pressure and discomfort
Urinary frequency or urgency
Abnormal vaginal bleeding (postmenopausal)
Nausea and vomiting
Dyspnea if pleural involvement
Back pain in retroperitoneal spread.
Risk Factors:
BRCA1/2 mutations (40-fold increased risk)
Lynch syndrome (hereditary nonpolyposis colorectal cancer)
Family history of ovarian/breast cancer
Nulliparity or low parity
Advanced age (>50 years)
Endometriosis history
Hormone replacement therapy (prolonged use).
Screening:
CA-125 levels elevated in 85-90% cases (>35 U/mL)
HE4 (Human Epididymis Protein 4) elevated
ROMA index (Risk of Ovarian Malignancy Algorithm)
Transvaginal ultrasound shows complex solid-cystic mass
CT/MRI for staging and surgical planning
PET-CT for metastatic workup.
Master Large Cell Carcinoma Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Large, solid masses with areas of necrosis and hemorrhage
Gray-white to tan cut surface with friable consistency
Cystic areas may be present (30-40% cases)
Surface shows irregular nodularity with areas of rupture
Ascites often present with tumor implants on peritoneal surfaces.
Characteristics:
Firm to soft consistency with areas of necrosis (60-70% cases)
Hemorrhage common due to rapid growth
Calcifications rare compared to other ovarian carcinomas
Cut surface shows variegated appearance with solid and cystic areas
Capsular invasion evident in most cases.
Size Location:
Mean size 12-15 cm at presentation (range 8-25 cm)
Bilateral involvement in 60-70% cases
Commonly involves both ovaries with peritoneal seeding
Omental involvement (omental cake) in 70-80% cases
May involve fallopian tubes and uterus by direct extension.
Multifocality:
High propensity for peritoneal dissemination at presentation
Synchronous bilateral ovarian involvement common
Omental implants and peritoneal carcinomatosis
Lymph node metastases in 50-60% cases
Hematogenous spread to liver, lung, and bone in advanced stages.
Microscopic Description
Histological Features:
Large pleomorphic cells (diameter >20 μm) with abundant cytoplasm
High nuclear-to-cytoplasmic ratio with marked nuclear pleomorphism
Prominent nucleoli and irregular nuclear contours
Frequent mitotic figures (>20 per 10 HPF)
Extensive necrosis and hemorrhage throughout tumor.
Cellular Characteristics:
Large polygonal to round cells with vesicular nuclei
Abundant eosinophilic cytoplasm often with granular appearance
Bizarre giant cells may be present
Multinucleated cells scattered throughout
Nuclear hyperchromasia with irregular chromatin distribution
Prominent nucleoli (often multiple per nucleus).
Architectural Patterns:
Solid sheets of large pleomorphic cells predominant pattern
Loose cohesion between cells with discohesive pattern
Minimal glandular differentiation (if any)
Absence of papillary architecture
Invasive growth into ovarian stroma and surface
Vascular invasion commonly present.
Grading Criteria:
Universally high-grade (Grade 3) by definition
High mitotic rate (>20 mitoses per 10 HPF)
Marked nuclear pleomorphism (score 3)
Absence of tubule formation (score 3)
Total score 9/9 in modified Bloom-Richardson system
Ki-67 proliferation index typically >70%.
Immunohistochemistry
Positive Markers:
p53 (aberrant expression in 85-90% cases)
WT1 (60-70% positive)
PAX8 (80-85% positive)
CK7 (95% positive)
EMA (85-90% positive)
CA-125 (70-80% positive)
p16 (diffuse positive in 60% cases).
Negative Markers:
CK20 (typically negative)
CDX2 (negative - excludes GI primary)
TTF-1 (negative - excludes lung primary)
ER/PR (usually negative)
HER2 (negative in most cases)
Inhibin (negative - excludes sex cord-stromal tumors).
Diagnostic Utility:
PAX8/WT1/CK7 panel confirms ovarian origin
p53 staining pattern (mutation-type vs
wild-type)
Ki-67 index >70% confirms high-grade nature
CK20/CDX2 negative excludes metastatic adenocarcinoma
TTF-1 negative excludes lung primary.
Molecular Subtypes:
p53-mutated subtype (85-90% cases) with aberrant staining
Homologous recombination deficiency (HRD) in 50-60% cases
BRCA1/2 deficient subset (30-40%)
Microsatellite stable (>95% cases)
High-grade serous pattern molecular signature.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (85-90% cases) - most common alteration
BRCA1/2 mutations (30-40% cases) - germline or somatic
RB1 pathway alterations (40-50% cases)
PI3K/AKT pathway mutations (25-30%)
NOTCH pathway alterations (20% cases)
Homologous recombination deficiency genes (PALB2, RAD51C, RAD51D).
Molecular Markers:
CA-125 elevated (>35 U/mL) in 85-90% cases
HE4 (Human Epididymis Protein 4) elevated
p53 protein overexpression or complete loss
Ki-67 proliferation index >70%
Homologous recombination deficiency score (HRD) >42
VEGF overexpression in 60-70% cases.
Prognostic Significance:
BRCA1/2 mutations indicate better response to platinum and PARP inhibitors
HRD-positive tumors have better initial platinum sensitivity
p53 wild-type (rare) may have better prognosis
High HRD score predicts PARP inhibitor sensitivity
Low CA-125 levels post-surgery indicate better prognosis.
Therapeutic Targets:
PARP inhibitors (olaparib, niraparib, rucaparib) for BRCA-mutated cases
Anti-angiogenic agents (bevacizumab) for VEGF-positive tumors
Platinum-based chemotherapy (carboplatin/paclitaxel) first-line
Immunotherapy (pembrolizumab) for microsatellite instability
CDK4/6 inhibitors under investigation.
Differential Diagnosis
Similar Entities:
Metastatic adenocarcinoma (GI, lung, breast primaries)
Undifferentiated carcinoma (lacks large cell morphology)
Giant cell carcinoma (larger cells, >50 μm)
Embryonal carcinoma (younger patients, AFP positive)
Dysgerminoma (clear cytoplasm, lymphocytic infiltrate)
High-grade serous carcinoma (conventional type).
Distinguishing Features:
Large cell carcinoma: uniform large cells (20-50 μm)
Large cell carcinoma: PAX8/WT1 positive
Metastatic GI: CK20/CDX2 positive
Metastatic lung: TTF-1 positive
Giant cell carcinoma: cells >50 μm
Dysgerminoma: PLAP/OCT4 positive
Embryonal carcinoma: AFP/CD30 positive.
Diagnostic Challenges:
Distinguishing from metastatic carcinoma requires comprehensive IHC panel
Primary site determination crucial for treatment
Frozen section diagnosis challenging due to poor differentiation
Small biopsy specimens may not show classic morphology
Extensive necrosis may obscure diagnostic features.
Rare Variants:
Large cell neuroendocrine carcinoma (synaptophysin/chromogranin positive)
Large cell carcinoma with rhabdoid features
Pleomorphic carcinoma with large cell component
Large cell variant of clear cell carcinoma
Anaplastic large cell carcinoma (ALK-positive subset).
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 specimen, right ovary measuring [X x Y x Z] cm, left ovary measuring [X x Y x Z] cm, with attached fallopian tubes
Gross Description
Large, solid, lobulated mass with gray-white cut surface, areas of necrosis and hemorrhage, capsular surface involvement, [bilateral/unilateral] involvement
Diagnosis
High-grade serous carcinoma, large cell variant
Histological Features
Large pleomorphic cells (>20 μm) with abundant cytoplasm, high nuclear-to-cytoplasmic ratio, prominent nucleoli, high mitotic rate (>20/10 HPF), extensive necrosis
Immunohistochemistry
PAX8: Positive, WT1: Positive, p53: [Aberrant pattern], CK7: Positive, CK20: Negative, TTF-1: Negative, CDX2: Negative, Ki-67: >70%
Staging (FIGO 2014)
Stage [I/II/III/IV] - [detailed staging criteria based on extent of disease]
Prognostic Factors
High-grade morphology, large cell variant, bilateral involvement, [peritoneal implants], [lymph node status], [residual disease]
Molecular Testing Recommendations
BRCA1/2 germline testing recommended, HRD testing for PARP inhibitor sensitivity, consider tumor genetics counseling
Final Diagnosis
Bilateral ovarian high-grade serous carcinoma, large cell variant, FIGO Stage [X], Grade 3