Definition/General
Introduction:
Ovarian carcinomas with inflammatory features represent a subset of high-grade ovarian carcinomas characterized by prominent inflammatory cell infiltration
These tumors show dense lymphoplasmacytic infiltrate that may obscure the underlying carcinomatous component
They constitute 5-10% of ovarian carcinomas and are associated with aggressive clinical behavior.
Origin:
These carcinomas arise from the ovarian surface epithelium or fallopian tube epithelium (serous type) with secondary ovarian involvement
The inflammatory reaction represents host immune response to tumor antigens
Tumor-infiltrating lymphocytes (TILs) play a crucial role in tumor progression and response to therapy.
Classification:
WHO 2020 classification includes these under high-grade serous carcinoma with inflammatory features
Other types include endometrioid carcinoma with inflammatory infiltrate
Clear cell carcinoma with lymphocytic infiltration
Undifferentiated carcinoma with prominent inflammation
BRCA-associated carcinomas often show inflammatory features.
Epidemiology:
Peak incidence in 6th-7th decades (55-65 years)
More common in BRCA1/2 mutation carriers (15-20% of cases)
Family history of ovarian/breast cancer in 25-30% cases
Nulliparity increases risk by 40%
Indian population shows increasing incidence in urban areas (2.1 per 100,000)
Lynch syndrome associated with endometrioid type with inflammation.
Clinical Features
Presentation:
Pelvic mass (85-90% cases) with rapid enlargement
Abdominal distension due to ascites (70% cases)
Abdominal pain (65-70% cases)
Constitutional symptoms: weight loss, fatigue, anorexia
Intestinal obstruction (15-20% advanced cases)
Pleural effusion (10-15% cases)
Often presents at advanced stage (IIIC-IV) in 75% cases.
Symptoms:
Pelvic/abdominal pain (chronic or acute in 70% cases)
Bloating and early satiety (60-65% cases)
Urinary symptoms: frequency, urgency (40% cases)
Menstrual irregularities in premenopausal women (30% cases)
Postmenopausal bleeding (15% cases)
Cachexia in advanced disease (25% cases)
Fever may be present due to inflammatory component (10-15% cases).
Risk Factors:
Family history of ovarian/breast cancer (25-30% cases)
BRCA1/2 mutations (15-20% hereditary cases)
Lynch syndrome (5% cases - endometrioid type)
Nulliparity (relative risk 1.4)
Infertility and ovulation-inducing drugs
Endometriosis (associated with endometrioid/clear cell types)
Age >50 years (peak 55-65 years)
Hormone replacement therapy (prolonged use).
Screening:
No effective screening for general population
High-risk patients: BRCA carriers, Lynch syndrome
Transvaginal ultrasound and CA-125 for high-risk surveillance
MRI for BRCA carriers (annual screening)
Risk-reducing bilateral salpingo-oophorectomy for BRCA carriers after 35-40 years
Multimodal screening trials ongoing but not yet proven effective.
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Gross Description
Appearance:
Large, irregular mass with soft to firm consistency
Gray-white to tan-yellow cut surface with areas of necrosis and hemorrhage
Cystic areas may be present (30-40% cases)
Surface shows nodular, bosselated appearance
Ascites commonly present (70% cases)
Omental caking in advanced cases (60-70%).
Characteristics:
Solid-cystic appearance with predominant solid component (70-80%)
Friable consistency due to inflammatory infiltrate
Areas of softening and tissue necrosis
Hemorrhagic areas common (50-60% cases)
Calcifications may be present (15-20%)
Papillary excrescences on cyst wall surfaces
Surface adhesions to adjacent organs.
Size Location:
Average size 8-15 cm at presentation (larger than typical ovarian carcinomas)
Range from 5-25 cm
Bilateral involvement in 60-70% cases
Unilateral presentation in early disease
Upper abdominal spread common (omentum, diaphragm)
Peritoneal implants frequently present.
Multifocality:
Bilateral ovarian involvement in 60-70% cases
Peritoneal carcinomatosis in 80% of advanced cases
Omental deposits ("omental cake") in 70% cases
Lymph node metastases: pelvic (40%), para-aortic (35%)
Distant metastases: pleura (15%), liver surface (20%)
Synchronous fallopian tube involvement in serous type (40-50%).
Microscopic Description
Histological Features:
Dense inflammatory infiltrate composed of lymphocytes, plasma cells, and macrophages
Carcinomatous component may be obscured by inflammation
High-grade nuclear features with prominent nucleoli
Increased mitotic activity (>20 mitoses/10 HPF)
Necrosis present in 60-70% cases
Desmoplastic stroma with inflammatory cell infiltration.
Cellular Characteristics:
Pleomorphic epithelial cells with enlarged, irregular nuclei
Prominent nucleoli and coarse chromatin
Increased nuclear-cytoplasmic ratio
Eosinophilic to amphophilic cytoplasm
Multinucleated giant cells occasionally present
Tumor-infiltrating lymphocytes within and around tumor nests
Apoptotic bodies frequently seen.
Architectural Patterns:
Solid growth pattern predominates (60-70% cases)
Papillary architecture with inflammatory infiltrate
Cribriform pattern may be present
Sheet-like growth of carcinoma cells
Pseudoglandular spaces due to central necrosis
Infiltrative margins with inflammatory reaction
Surface involvement of ovary common.
Grading Criteria:
Universal grading system applies but may be difficult due to inflammation
High-grade features predominate: solid growth (3 points), marked nuclear pleomorphism (3 points), high mitotic count (3 points)
Total score 8-9 points = Grade 3
Inflammatory component does not affect grading
Necrosis assessment important for staging.
Immunohistochemistry
Positive Markers:
Cytokeratin 7 (CK7) - positive in 90-95% serous type
PAX8 - positive in 85-90% Müllerian origin tumors
WT1 - positive in 80-85% serous carcinomas
p53 - aberrant pattern (overexpression or null pattern) in 90% high-grade serous
Ki-67 - high proliferation index (>50%)
CA-125 - positive in 80-85% cases
p16 - diffuse positive in high-grade serous.
Negative Markers:
CK20 - negative (helps exclude GI primary)
CDX2 - negative (excludes colorectal primary)
TTF-1 - negative (excludes lung primary)
Napsin A - negative (excludes lung adenocarcinoma)
ER/PR - may be negative in high-grade tumors
Hepatocyte antigen - negative (excludes hepatocellular carcinoma)
RCC marker - negative.
Diagnostic Utility:
Primary ovarian vs metastatic: PAX8+, WT1+ favors ovarian primary
Serous vs endometrioid: WT1+ favors serous
ER/PR+ favors endometrioid
Primary site determination crucial for staging and treatment
p53 pattern helps distinguish high-grade from low-grade serous
Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) for Lynch syndrome screening.
Molecular Subtypes:
High-grade serous carcinoma (70% of inflammatory type): p53 aberrant, WT1+, PAX8+
Endometrioid carcinoma (20%): ER/PR+, MMR proteins variable
Clear cell carcinoma (5%): Napsin A+, HNF-1β+
Undifferentiated carcinoma (5%): Negative for specific lineage markers
BRCA-associated tumors show specific IHC patterns.
Molecular/Genetic
Genetic Mutations:
TP53 mutations - present in 95% high-grade serous type
BRCA1/2 mutations - germline (15-20%) or somatic (5-7%)
Homologous recombination deficiency (HRD) - 50% of high-grade serous
PTEN mutations - 20% endometrioid type
PIK3CA mutations - 15-20% endometrioid/clear cell
CTNNB1 mutations - 15% endometrioid
POLE mutations - 10% endometrioid (ultramutated).
Molecular Markers:
p53 protein expression - aberrant in 90% high-grade serous
BRCA1/2 protein loss by IHC
Microsatellite instability (MSI) - 10-15% endometrioid type
Tumor mutational burden (TMB) - variable, higher in POLE-mutated
Homologous recombination score for PARP inhibitor sensitivity
VEGF expression for antiangiogenic therapy.
Prognostic Significance:
BRCA mutations - better response to platinum and PARP inhibitors
HRD status - improved outcome with PARP inhibitor maintenance
MSI status - better prognosis and immunotherapy response
p53 mutations - associated with chemoresistance
POLE mutations - excellent prognosis
Tumor-infiltrating lymphocytes - better prognosis in 40% cases.
Therapeutic Targets:
PARP inhibitors (olaparib, niraparib) for BRCA/HRD tumors
Anti-VEGF therapy (bevacizumab) for angiogenesis inhibition
Immunotherapy (pembrolizumab) for MSI-high tumors
CDK4/6 inhibitors under investigation
PI3K/AKT inhibitors for PIK3CA-mutated tumors
WEE1 inhibitors for p53-mutated tumors
Folate receptor alpha - target for mirvetuximab soravtansine.
Differential Diagnosis
Similar Entities:
Primary ovarian lymphoma - predominantly lymphoid cells, B-cell markers positive
Metastatic carcinoma with inflammatory reaction - IHC helps determine primary site
Inflammatory pseudotumor - benign reactive process, no epithelial atypia
Granulomatous inflammation - infectious etiology, epithelioid cells present
Ovarian sarcoma with inflammation - mesenchymal markers positive.
Distinguishing Features:
Primary ovarian lymphoma: CD20/CD3 positive, cytokeratin negative, monotonous lymphoid population
Metastatic carcinoma: Site-specific markers (CK20/CDX2 for GI, TTF-1 for lung)
Inflammatory pseudotumor: Polyclonal inflammation, no epithelial atypia, ALK may be positive
Infectious causes: Special stains for organisms, clinical correlation
Ovarian sarcoma: Vimentin positive, specific sarcoma markers.
Diagnostic Challenges:
Extensive inflammation obscuring carcinoma - multiple sections and IHC needed
Determining primary site - comprehensive IHC panel required
Distinguishing from lymphoma - mixed population vs monoclonal
Frozen section diagnosis - inflammation may mask malignancy
Small biopsy samples - limited tissue for diagnosis
Necrotic areas - may prevent accurate assessment.
Rare Variants:
Carcinoma with eosinophilia - prominent eosinophilic infiltrate, better prognosis
Lymphoepithelioma-like carcinoma - undifferentiated carcinoma with dense lymphoid infiltrate
Medullary-type carcinoma - syncytial growth with lymphoid stroma
Carcinoma with plasma cell infiltrate - prominent plasma cell component
Giant cell variant - multinucleated giant cells with inflammation.
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
Right/Left ovarian mass, [X] cm, with/without fallopian tube and omentum
Diagnosis
High-grade serous carcinoma with prominent inflammatory infiltrate
Classification
WHO 2020: [Specific type] with inflammatory features, Grade [X]
Size and Extent
Tumor size: [X] cm, Surface involvement: Present/Absent, Capsular rupture: Present/Absent
Microscopic Features
High-grade carcinoma with [architectural pattern], prominent inflammatory infiltrate composed of lymphocytes and plasma cells
Immunohistochemistry
PAX8: Positive, WT1: Positive/Negative, p53: [pattern], Ki-67: [%], CK7: Positive, CK20: Negative
Molecular Studies
BRCA1/2: [status], MSI: [status], HRD score: [if available]
FIGO Staging
FIGO Stage [I/II/III/IV][A/B/C] based on [extent of disease]
Final Diagnosis
[Ovary location]: High-grade serous carcinoma with inflammatory features, FIGO Grade 3, Stage [X]