Definition/General

Introduction:
-Ovarian cribriform carcinoma is a rare histological variant characterized by a distinctive cribriform growth pattern with sieve-like architecture
-It represents less than 1% of all ovarian epithelial carcinomas
-It shows rounded spaces or punched-out holes within nests of carcinoma cells
-It is most commonly associated with serous or endometrioid ovarian carcinomas.
Origin:
-Arises from the ovarian surface epithelium or fallopian tube epithelium through the process of malignant transformation
-May develop through progressive genetic alterations in normal epithelial cells
-Associated with tubal intraepithelial carcinoma (TIC) in high-grade cases
-Molecular pathways involve p53 mutations and chromosomal instability.
Classification:
-WHO 2020 classification recognizes cribriform pattern as a morphological variant
-Can occur in both low-grade and high-grade serous carcinomas
-Also seen in endometrioid adenocarcinoma
-FIGO staging applies with stages I-IV
-Grading follows universal grading system for ovarian carcinomas.
Epidemiology:
-Peak incidence in 6th-7th decades (55-65 years)
-Rare in Indian population with estimated incidence 0.5-1 per 100,000 women
-Associated with BRCA1/2 mutations in 15-20% cases
-Risk factors include nulliparity, family history, and late menopause
-Higher frequency in Ashkenazi Jewish population.

Clinical Features

Presentation:
-Often asymptomatic in early stages (60-70% cases)
-Abdominal distension and pelvic mass in advanced stages
-Ascites present in 40-50% at diagnosis
-May present with bowel obstruction due to peritoneal implants
-Pleural effusion in cases with diaphragmatic involvement.
Symptoms:
-Abdominal pain (75% cases)
-Bloating and early satiety (60%)
-Urinary frequency (40%)
-Weight loss in advanced disease (30%)
-Vaginal bleeding (20% post-menopausal women)
-Fatigue and weakness
-Dyspnea if pleural effusion present.
Risk Factors:
-Age >50 years (90% cases)
-Nulliparity (2-fold increased risk)
-Family history of ovarian/breast cancer
-BRCA1/2 mutations (15-20% hereditary cases)
-Lynch syndrome (3-5% cases)
-Personal history of breast cancer
-Infertility and endometriosis.
Screening:
-No effective screening for general population
-CA-125 elevated in 80% advanced cases
-HE4 (human epididymis protein 4) complementary marker
-Transvaginal ultrasound for high-risk patients
-MRI for complex adnexal masses
-Genetic counseling for BRCA carriers.

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Gross Description

Appearance:
-Solid and cystic mass with irregular external surface
-Cut surface shows gray-white to tan solid areas
-Friable and hemorrhagic areas commonly present
-May show papillary excrescences in cystic areas
-Necrosis present in 30-40% cases
-Calcifications occasionally visible.
Characteristics:
-Firm to soft consistency depending on cystic component
-Multilocular cystic areas with thick septa
-Solid nodular areas with gray-white appearance
-Surface papillary projections in some cases
-Hemorrhagic fluid in cystic spaces
-Adherent to surrounding structures in advanced cases.
Size Location:
-Size ranges from 3-25 cm (average 8-12 cm)
-Unilateral in 70-80% cases
-Bilateral involvement in 20-30% cases
-Right ovary slightly more common
-May involve both ovaries synchronously
-Fallopian tube involvement in high-grade cases.
Multifocality:
-Peritoneal implants in 60-70% advanced cases
-Omental involvement ("omental cake") in 50% cases
-Ascites with malignant cells
-Lymph node metastases to pelvic and para-aortic nodes
-Distant metastases to liver, lung, and pleura
-Multicentric origin from fallopian tube fimbriae.

Microscopic Description

Histological Features:
-Characteristic cribriform architecture with rounded spaces within tumor nests
-Sieve-like pattern with punched-out holes
-Spaces are empty or contain eosinophilic material
-Back-to-back glands in some areas
-Stromal desmoplasia and inflammatory infiltrate
-Psammoma bodies in 20-30% cases.
Cellular Characteristics:
-Pleomorphic nuclei with irregular contours
-Prominent nucleoli in high-grade cases
-Increased nuclear-cytoplasmic ratio
-Mitotic activity variable (5-50 per 10 HPF)
-Atypical mitoses present
-Eosinophilic cytoplasm with occasional clear cells
-Loss of polarity and stratification.
Architectural Patterns:
-Cribriform pattern is the defining feature
-Mixed with solid and papillary areas
-Glandular differentiation in low-grade tumors
-Sheet-like growth in high-grade cases
-Transitional-like areas occasionally present
-Necrosis and hemorrhage in viable tumor areas.
Grading Criteria:
-Follows binary grading system: Low-grade and High-grade
-Low-grade: uniform nuclei, rare mitoses (<5 per 10 HPF)
-High-grade: pleomorphic nuclei, frequent mitoses (>12 per 10 HPF)
-Nuclear atypia and architectural complexity determine grade
-Presence of solid areas favors high-grade designation.

Immunohistochemistry

Positive Markers:
-CK7 (95-100% cases)
-PAX8 (90-95% ovarian origin)
-WT1 (80-90% serous cases)
-p53 (70-80% high-grade)
-Ki-67 (20-60% proliferation index)
-CA-125 (85-90% cases)
-p16 (60-70% cases)
-Calretinin (variable in serous).
Negative Markers:
-CK20 (negative, excludes GI origin)
-CDX2 (negative, excludes GI primary)
-TTF1 (negative, excludes lung primary)
-Napsin A (negative, excludes lung)
-ER/PR (variable, may be positive or negative)
-Inhibin (negative, excludes sex cord-stromal)
-Calretinin (negative in endometrioid type).
Diagnostic Utility:
-Ovarian origin confirmation: PAX8 + CK7 panel
-Serous vs endometrioid: WT1 and p53 patterns
-High-grade identification: p53 aberrant expression (overexpression or null)
-Proliferation assessment: Ki-67 >30% indicates high-grade
-Site of origin: CK7+/CK20- pattern favors gynecologic primary.
Molecular Subtypes:
-High-grade serous: p53 aberrant (90%), WT1+ (85%)
-Low-grade serous: p53 wild-type, WT1+ variable
-Endometrioid type: ER/PR positive (70%), beta-catenin aberrant (20%)
-BRCA-deficient: Homologous recombination deficiency markers
-Microsatellite instability rare (<5% cases).

Molecular/Genetic

Genetic Mutations:
-TP53 mutations (85-95% high-grade cases)
-BRCA1/2 mutations (15-20% hereditary cases)
-KRAS mutations (10-15% low-grade)
-PIK3CA mutations (8-12% cases)
-PTEN mutations (5-10% endometrioid type)
-CTNNB1 mutations (20% endometrioid)
-ARID1A mutations (15% cases).
Molecular Markers:
-Chromosomal instability (high-grade serous)
-Homologous recombination deficiency (HRD score >42)
-Microsatellite stability (MSS) in majority
-PD-L1 expression (10-15% cases)
-HER2 amplification rare (<5%)
-Tumor mutational burden generally low
-Copy number alterations extensive in high-grade.
Prognostic Significance:
-BRCA1/2 mutations associated with better survival
-HRD-positive tumors respond better to platinum therapy
-p53 mutations indicate aggressive behavior
-High Ki-67 (>30%) predicts poor outcome
-Stage remains most important prognostic factor
-Residual disease after surgery affects survival
-Platinum sensitivity determines treatment response.
Therapeutic Targets:
-PARP inhibitors for BRCA-mutated and HRD-positive cases
-Anti-angiogenic agents: bevacizumab maintenance
-Immunotherapy: pembrolizumab for MSI-high (rare)
-Platinum-based chemotherapy remains standard
-CDK4/6 inhibitors under investigation
-Folate receptor alpha targeted therapy (mirvetuximab)
-WEE1 inhibitors for p53-mutated tumors.

Differential Diagnosis

Similar Entities:
-Transitional cell carcinoma of ovary
-Brenner tumor (benign and malignant)
-Metastatic urothelial carcinoma
-Adenoid cystic carcinoma
-Solid pseudopapillary tumor
-Yolk sac tumor with cribriform pattern
-Metastatic breast carcinoma with cribriform features.
Distinguishing Features:
-Transitional cell carcinoma: uroplakin III positive, PAX8 negative
-Brenner tumor: benign epithelium, WT1 negative
-Metastatic urothelial: CK20+, GATA3+, PAX8 negative
-Adenoid cystic: MYB-NFIB fusion, p63 positive
-Yolk sac tumor: AFP positive, young age
-Metastatic breast: GCDFP-15+, mammaglobin+.
Diagnostic Challenges:
-Distinguishing from Brenner tumor: malignant nuclear features required
-Metastatic vs primary: comprehensive IHC panel needed
-Grade assessment: solid areas may be missed
-STIC identification: requires careful fallopian tube examination
-Frozen section diagnosis: cribriform pattern may be subtle.
Rare Variants:
-Mixed cribriform-endometrioid pattern
-Cribriform with clear cell features
-Micropapillary cribriform variant
-Solid cribriform areas predominant
-Psammomatous cribriform type
-Transitional-like cribriform morphology
-Neuroendocrine cribriform differentiation.

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

Ovarian mass, [side], measuring [X x Y x Z] cm, with [associated structures]

Gross Description

External surface: [smooth/irregular]. Cut surface: [solid/cystic] with [color] areas. [Necrosis/hemorrhage] present/absent.

Microscopic Findings

Tumor shows characteristic cribriform architecture with [description]. Nuclear grade: [low/high]. Mitotic activity: [count] per 10 HPF.

Immunohistochemistry

CK7: [positive/negative]. PAX8: [positive/negative]. WT1: [positive/negative]. p53: [pattern]. Ki-67: [percentage]%.

Diagnosis

Ovarian [High-grade/Low-grade] Serous Carcinoma with Cribriform Pattern

Staging

FIGO Stage: [I/II/III/IV]. TNM: T[X]N[X]M[X]. [Lymph node status]. [Peritoneal involvement].

Prognostic Factors

Grade: [low/high]. Stage: [early/advanced]. Residual disease: [yes/no]. BRCA status: [wild-type/mutated/unknown].

Final Diagnosis

Ovarian [High-grade/Low-grade] Serous Carcinoma with Cribriform Pattern, FIGO Stage [X]