Definition/General
Introduction:
Ovarian micropapillary carcinoma is a rare and aggressive histological variant characterized by distinctive micropapillary architecture without fibrovascular cores
It represents less than 2% of all ovarian carcinomas
The micropapillary pattern shows small papillary tufts floating in clear spaces
This morphology is associated with poor prognosis and aggressive clinical behavior.
Origin:
Arises from ovarian surface epithelium or fallopian tube epithelium through malignant transformation
Most commonly develops as a variant of high-grade serous carcinoma
May also occur in endometrioid or clear cell carcinomas
Molecular pathogenesis involves p53 mutations and chromosomal instability
Associated with STIC (Serous Tubal Intraepithelial Carcinoma) in many cases.
Classification:
WHO 2020 classification recognizes micropapillary pattern as a morphological variant of ovarian carcinoma
Can occur in serous, endometrioid, or clear cell types
FIGO staging system applies with stages I-IV
Binary grading system: low-grade (rare) and high-grade (majority)
Universal grading system for ovarian carcinomas is used.
Epidemiology:
Peak incidence in 6th-7th decades (55-70 years)
Extremely rare in Indian population with estimated incidence 0.1-0.3 per 100,000 women
Associated with BRCA1/2 mutations in 20-25% cases
Risk factors similar to high-grade serous carcinoma
Nulliparity, family history, and genetic predisposition are major risk factors.
Clinical Features
Presentation:
Usually presents at advanced stage (80-90% Stage III-IV)
Rapid clinical deterioration due to aggressive behavior
Massive ascites and carcinomatosis common at presentation
Bilateral ovarian involvement in 70-80% cases
May present with bowel obstruction and pleural effusion
Lymph node metastases frequently present.
Symptoms:
Abdominal distension (90% cases)
Severe abdominal pain (80%)
Early satiety and bloating (70%)
Weight loss and fatigue (60%)
Dyspnea due to pleural effusion (40%)
Nausea and vomiting (50%)
Bowel symptoms due to peritoneal involvement (30%).
Risk Factors:
Age >55 years (95% cases)
BRCA1/2 mutations (20-25% hereditary cases)
Lynch syndrome (rare, <5%)
Family history of ovarian/breast cancer
Nulliparity (3-fold increased risk)
Infertility and endometriosis
Personal history of breast cancer
Hormone replacement therapy.
Screening:
No effective screening available for general population
CA-125 markedly elevated (>500 U/ml) in 90% cases
HE4 also significantly elevated
CT/MRI shows extensive peritoneal disease
PET-CT helpful for staging and monitoring
Genetic counseling essential for BRCA carriers
Prophylactic salpingo-oophorectomy for high-risk patients.
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Gross Description
Appearance:
Predominantly solid mass with irregular surface and nodular appearance
Cut surface shows gray-white to tan tissue with areas of hemorrhage and necrosis
Friable consistency with tendency to fragment
May show cystic areas with papillary excrescences
Surface involvement commonly visible as nodular implants.
Characteristics:
Firm to soft consistency depending on necrotic component
Heterogeneous appearance with solid and cystic areas
Hemorrhagic and necrotic areas prominent
Papillary projections in cystic spaces
Gray-white solid areas alternating with hemorrhagic zones
Adherent to surrounding structures in advanced cases.
Size Location:
Size ranges from 5-30 cm (average 12-18 cm)
Bilateral involvement in 70-80% cases
Replacement of normal ovarian architecture
May involve fallopian tubes and surrounding structures
No site predilection within ovary
Extensive peritoneal implants commonly present at diagnosis.
Multifocality:
Extensive peritoneal carcinomatosis in 85-90% cases
Omental cake formation in 70% cases
Diaphragmatic involvement common
Lymph node metastases to pelvic and para-aortic chains
Liver surface implants and pleural involvement
Multicentric disease from fallopian tube origin
Distant metastases to lung and other organs.
Microscopic Description
Histological Features:
Characteristic micropapillary tufts lacking fibrovascular cores floating in clear spaces or lacunae
Small papillary clusters of 5-20 cells detached from stroma
Hobnail-like appearance of cells in micropapillae
High nuclear-cytoplasmic ratio
Desmoplastic stroma with inflammatory infiltrate
Psammoma bodies in 30-40% cases.
Cellular Characteristics:
High-grade nuclear features with marked pleomorphism
Vesicular nuclei with prominent nucleoli
Increased nuclear-cytoplasmic ratio
High mitotic activity (>20 per 10 HPF)
Atypical mitoses frequently present
Scanty eosinophilic cytoplasm
Loss of cellular polarity and cohesion
Apoptotic bodies commonly seen.
Architectural Patterns:
Micropapillary pattern is the defining feature (>5% of tumor)
Mixed with solid, papillary, and glandular areas
Confluent growth in solid areas
Slit-like spaces between micropapillary tufts
Transition zones between different patterns
Extensive necrosis and hemorrhage
Lymphovascular invasion frequently present.
Grading Criteria:
Majority are high-grade by definition due to micropapillary pattern
Nuclear grade 3 features predominant
High mitotic index (>12 per 10 HPF)
Presence of micropapillary pattern (>5%) automatically classifies as high-grade
Solid areas and necrosis support high-grade designation
Ki-67 proliferation index typically >50%.
Immunohistochemistry
Positive Markers:
CK7 (98-100% cases)
PAX8 (90-95% ovarian origin)
WT1 (85-90% serous type)
p53 (80-90% aberrant expression)
Ki-67 (50-80% proliferation index)
CA-125 (90-95% cases)
p16 (70-80% cases)
Claudin-4 (positive in micropapillary areas).
Negative Markers:
CK20 (negative, excludes GI origin)
CDX2 (negative, excludes colorectal primary)
TTF1 (negative, excludes lung primary)
Napsin A (negative, excludes lung)
ER/PR (usually negative or focal)
Inhibin (negative, excludes sex cord-stromal)
AFP (negative, excludes germ cell).
Diagnostic Utility:
Ovarian origin confirmation: PAX8 + CK7 + WT1 panel
High-grade serous identification: p53 aberrant pattern (>60% or null)
Micropapillary pattern recognition: Claudin-4 highlighting
Proliferation assessment: Ki-67 >50% supports aggressive behavior
Site of origin: CK7+/CK20-/PAX8+ favors gynecologic primary.
Molecular Subtypes:
High-grade serous subtype: p53 aberrant (90%), WT1+ (85%), PAX8+
BRCA-deficient phenotype: Homologous recombination deficiency markers
Chromosomal instability signature present
p53 signature in associated STIC
Microsatellite stable (MSS) in majority (>95%).
Molecular/Genetic
Genetic Mutations:
TP53 mutations (95-98% cases)
BRCA1/2 mutations (20-25% hereditary cases)
CCNE1 amplification (15-20% cases)
PIK3CA mutations (8-12% cases)
NF1 mutations (10-15% cases)
CDK12 mutations (5-8% cases)
RB1 mutations (rare, <5%).
Molecular Markers:
Extensive chromosomal instability characteristic
Homologous recombination deficiency (HRD score >42)
High genomic scarring signature
Copy number alterations extensive
Tumor mutational burden moderate to high
PD-L1 expression (15-20% cases)
Aneuploidy common feature.
Prognostic Significance:
Micropapillary pattern independently predicts poor prognosis
Worse survival compared to conventional serous carcinoma
Higher propensity for peritoneal spread
BRCA mutations may confer better response to platinum
HRD-positive tumors respond to PARP inhibitors
Stage and residual disease remain most important prognostic factors.
Therapeutic Targets:
PARP inhibitors (olaparib, niraparib) for BRCA/HRD-positive
Anti-angiogenic therapy: bevacizumab maintenance
Platinum-based chemotherapy remains backbone
Immunotherapy limited efficacy
Folate receptor alpha targeted therapy (mirvetuximab soravtansine)
WEE1 inhibitors for p53-mutated tumors
CDK4/6 inhibitors under investigation.
Differential Diagnosis
Similar Entities:
Conventional high-grade serous carcinoma
Metastatic breast carcinoma with micropapillary pattern
Metastatic lung adenocarcinoma
Papillary serous carcinoma
Endometrioid carcinoma with micropapillary areas
Clear cell carcinoma
Yolk sac tumor in younger patients.
Distinguishing Features:
Conventional serous: lacks extensive micropapillary pattern (<5%)
Metastatic breast: GCDFP-15+, mammaglobin+, PAX8-
Metastatic lung: TTF1+, Napsin A+, PAX8-
Papillary serous: true papillae with fibrovascular cores
Endometrioid: ER/PR+, squamous differentiation
Clear cell: clear cytoplasm, hobnail pattern
Yolk sac: AFP+, young age.
Diagnostic Challenges:
Quantifying micropapillary pattern: >5% threshold required
Distinguishing from artifactual retraction
Metastatic vs primary: requires comprehensive IHC panel
Sampling adequacy: micropapillary areas may be focal
Frozen section diagnosis: pattern may be subtle
Mixed patterns complicating classification.
Rare Variants:
Pure micropapillary carcinoma (>90% micropapillary)
Micropapillary with signet ring cells
Micropapillary endometrioid variant
Mixed micropapillary-clear cell
Micropapillary with neuroendocrine differentiation
Cystic micropapillary pattern
Micropapillary with mucinous features.
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 ovarian masses with [associated structures], [left ovary X x Y x Z cm], [right ovary X x Y x Z cm]
Gross Description
Ovarian surface: [smooth/nodular/involved]. Cut surface: predominantly [solid/cystic] with [color] areas. [Necrosis/hemorrhage] [present/absent]. Peritoneal implants: [present/absent].
Microscopic Findings
High-grade serous carcinoma with micropapillary pattern comprising [X]% of tumor. Micropapillary tufts lack fibrovascular cores. Nuclear grade: 3. Mitotic activity: [count] per 10 HPF.
Immunohistochemistry
CK7: positive. PAX8: positive. WT1: positive. p53: [aberrant pattern/overexpression/null]. Ki-67: [percentage]%. CA-125: positive.
Molecular Studies
p53 mutation: [detected/not detected]. BRCA1/2 status: [wild-type/mutated/pending]. HRD score: [value/pending].
Diagnosis
High-grade Serous Carcinoma with Micropapillary Pattern ([X]% micropapillary)
Staging
FIGO Stage: [III/IV]. TNM: T[X]N[X]M[X]. Peritoneal involvement: [present/absent]. Lymph nodes: [X] positive of [X] examined.
Prognostic Factors
High-grade morphology. Micropapillary pattern (poor prognostic factor). Advanced stage. Residual disease: [yes/no]. BRCA status: [mutated/wild-type].
Final Diagnosis
High-grade Serous Carcinoma with Micropapillary Pattern, Bilateral, FIGO Stage [III/IV]