Definition/General

Introduction:
-Ovarian villoglandular carcinoma is an extremely rare variant of ovarian adenocarcinoma characterized by villous papillary architecture combined with well-formed glands
-Represents less than 1% of all ovarian carcinomas
-Originally described in cervical location but exceptionally rare in ovary
-Shows intermediate biological behavior between well-differentiated and poorly differentiated adenocarcinomas.
Origin:
-Arises from ovarian surface epithelium or inclusion cysts with müllerian differentiation
-May develop from endometrioid or serous adenocarcinoma with acquisition of villoglandular features
-Shows combination of papillary (villous) and glandular differentiation
-HPV association not established in ovarian location (unlike cervical villoglandular adenocarcinoma).
Classification:
-WHO 2020 classifies under rare variants of surface epithelial tumors
-May be considered as mixed müllerian tumor subtype
-FIGO staging system applies (Stage I-IV)
-Grading typically intermediate to high-grade (Grade 2-3)
-Distinguished from pure papillary or pure glandular patterns by mixed architecture.
Epidemiology:
-Extremely rare with fewer than 30 cases reported worldwide
-Peak incidence in 5th-6th decades (mean age 50-60 years)
-No clear association with BRCA mutations
-Indian population data extremely limited
-Associated with endometriosis in some cases
-May be associated with Lynch syndrome (requires investigation).

Clinical Features

Presentation:
-Pelvic mass (90-95% cases) often moderately sized and mobile
-Abdominal bloating and discomfort (70-80% cases)
-Pelvic pain (60-70% cases) - mild to moderate
-Abnormal vaginal bleeding (40-50% cases)
-Early satiety and digestive symptoms
-Less aggressive presentation compared to high-grade serous carcinoma.
Symptoms:
-Pelvic pressure and fullness (70-80% cases)
-Urinary frequency or urgency (50-60% cases)
-Abdominal pain (60-70% cases) - often intermittent
-Menstrual irregularities (40-50% cases)
-Constipation or bowel changes
-Fatigue and general malaise
-Weight loss in advanced cases (rare).
Risk Factors:
-Endometriosis history (30-40% cases)
-Nulliparity or low parity
-Lynch syndrome (possible association)
-Advanced age (>45 years)
-Family history of gynecologic cancers
-Infertility treatment history
-Unopposed estrogen exposure.
Screening:
-CA-125 levels mildly elevated in 60-70% cases (often <100 U/mL)
-CA 19-9 may be elevated (glandular component)
-CEA occasionally elevated
-Transvaginal ultrasound shows complex cystic mass with solid components
-MRI demonstrates mixed signal intensity
-CT shows heterogeneous enhancement.

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Gross Description

Appearance:
-Mixed cystic and solid masses with papillary projections into cystic spaces
-Gray-white to tan cut surface with areas of hemorrhage
-Villous, cauliflower-like excrescences from cyst walls
-Soft to firm consistency with focal firm areas
-Minimal necrosis compared to high-grade carcinomas.
Characteristics:
-Complex cystic architecture with intracystic papillary growth
-Smooth external surface in early cases
-Focal solid areas representing glandular components
-Clear to hemorrhagic cystic fluid
-Calcifications uncommon
-Mucin production variable (glandular areas).
Size Location:
-Mean size 8-12 cm at presentation (range 5-15 cm)
-Unilateral involvement in 80-85% cases
-Surface involvement less common than high-grade serous
-Capsular integrity often maintained
-Bilateral involvement uncommon (15-20% cases).
Multifocality:
-Usually unifocal within affected ovary
-Bilateral synchronous occurrence rare (15-20%)
-Peritoneal seeding less common than high-grade serous
-Nodal involvement in 30-40% cases
-Distant metastases uncommon at presentation.

Microscopic Description

Histological Features:
-Complex papillary architecture with thin fibrovascular cores
-Well-formed glands within papillary fronds
-Cuboidal to columnar epithelium lining papillae and glands
-Moderate nuclear atypia with vesicular nuclei
-Mitotic activity variable (5-15 per 10 HPF)
-Minimal necrosis and stromal invasion.
Cellular Characteristics:
-Cuboidal to tall columnar cells with moderate pleomorphism
-Eosinophilic to amphophilic cytoplasm with distinct cell borders
-Vesicular nuclei with small to prominent nucleoli
-Nuclear stratification present but not marked
-Mitotic figures present but not numerous
-Apical snouts may be present (glandular areas).
Architectural Patterns:
-Mixed papillary and glandular patterns (defining feature)
-Complex branching papillae with fibrovascular cores
-Well-formed glands within papillary structures
-Cribriform pattern may be present focally
-Minimal solid areas
-Stromal invasion present but limited.
Grading Criteria:
-Intermediate grade (Grade 2) in most cases
-Moderate mitotic rate (5-15 mitoses per 10 HPF)
-Moderate nuclear pleomorphism (score 2)
-Glandular differentiation present (score 1-2)
-Overall grade typically 2/3 (6-7 points)
-Ki-67 proliferation index 30-60%.

Immunohistochemistry

Positive Markers:
-CK7 (95-100% positive)
-PAX8 (85-90% positive)
-WT1 (60-70% positive)
-EMA (90-95% positive)
-CA-125 (70-80% positive)
-p53 (wild-type pattern in 60-70%)
-ER/PR (variable, 40-60% positive).
Negative Markers:
-CK20 (typically negative)
-CDX2 (negative - excludes GI primary)
-TTF-1 (negative - excludes lung primary)
-p16 (patchy positive, not diffuse)
-Inhibin (negative - excludes sex cord-stromal)
-Calretinin (negative)
-Napsin A (negative).
Diagnostic Utility:
-CK7/PAX8/WT1 panel confirms ovarian müllerian origin
-p53 wild-type pattern distinguishes from high-grade serous
-CK20/CDX2 negativity excludes metastatic colorectal
-TTF-1 negativity excludes lung primary
-ER/PR variability helps distinguish from endometrioid
-Ki-67 30-60% confirms intermediate grade.
Molecular Subtypes:
-p53 wild-type subtype (60-70% cases)
-Microsatellite stable in most cases
-No specific molecular signature identified
-BRCA1/2 typically wild-type
-Homologous recombination proficient
-Intermediate proliferation profile.

Molecular/Genetic

Genetic Mutations:
-KRAS mutations (40-50% cases) - most common alteration
-PIK3CA mutations (30-40% cases)
-ARID1A mutations (25-35% cases)
-PTEN loss (20-30% cases)
-TP53 mutations less common (30-40% vs
-95% in HGSC)
-MSH2/MLH1 alterations (Lynch syndrome association).
Molecular Markers:
-CA-125 mildly elevated (mean 60-80 U/mL)
-CA 19-9 may be elevated (30-40% cases)
-p53 protein wild-type expression pattern
-Ki-67 proliferation index 30-60% (intermediate)
-Beta-catenin normal membranous pattern
-ARID1A protein loss in 25-35%.
Prognostic Significance:
-Intermediate prognosis between low-grade and high-grade carcinomas
-5-year survival 60-70% (better than HGSC)
-KRAS mutations may predict platinum resistance
-ARID1A loss may predict better response to PI3K inhibitors
-Stage at presentation most important prognostic factor.
Therapeutic Targets:
-Platinum-based chemotherapy (carboplatin/paclitaxel) standard first-line
-PI3K/AKT inhibitors for ARID1A-deficient tumors
-MEK inhibitors for KRAS-mutated cases (investigational)
-PARP inhibitors limited efficacy (HRD-negative)
-Bevacizumab may be considered for recurrent disease.

Differential Diagnosis

Similar Entities:
-Serous borderline tumor (with micropapillary features)
-Low-grade serous carcinoma (papillary architecture)
-Endometrioid carcinoma (glandular component)
-Clear cell carcinoma (papillary variant)
-Metastatic adenocarcinoma (GI, lung, endometrial)
-Mixed müllerian tumor (heterologous elements).
Distinguishing Features:
-Villoglandular: mixed papillary-glandular pattern
-Villoglandular: intermediate-grade nuclei
-Borderline tumor: absence of stromal invasion
-Low-grade serous: uniform small nuclei
-Endometrioid: pure glandular pattern
-Clear cell: clear cytoplasm, hobnail cells
-Metastatic GI: CK20/CDX2 positive.
Diagnostic Challenges:
-Distinguishing from serous borderline tumor requires demonstration of stromal invasion
-Mixed architecture may be confused with collision tumor
-Frozen section diagnosis challenging due to architectural complexity
-Small biopsy specimens may not show full architectural spectrum
-Rare entity unfamiliar to many pathologists.
Rare Variants:
-Villoglandular carcinoma with clear cell features
-Villoglandular pattern in mixed müllerian tumor
-Villoglandular adenocarcinoma with squamous differentiation
-Villoglandular carcinoma with neuroendocrine features
-Micropapillary variant of villoglandular 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

[Unilateral/Bilateral] salpingo-oophorectomy specimen, [right/left] ovary measuring [X x Y x Z] cm, with attached fallopian tube

Gross Description

Complex cystic and solid ovarian mass with papillary projections into cystic spaces, gray-white cut surface, [intact/ruptured] capsule

Diagnosis

Ovarian villoglandular adenocarcinoma

Histological Features

Mixed papillary and glandular architecture, complex branching papillae with fibrovascular cores, well-formed glands within papillary structures, moderate nuclear atypia

Histological Grading

Grade 2 (intermediate grade): moderate nuclear pleomorphism, intermediate mitotic rate ([X] mitoses/10 HPF), glandular differentiation present

Invasion and Extent

Stromal invasion present, [depth] mm, lymphovascular invasion: [present/absent], capsular involvement: [present/absent]

Immunohistochemistry

CK7: Positive, PAX8: Positive, WT1: [Positive/Negative], p53: Wild-type pattern, CK20: Negative, CDX2: Negative, Ki-67: [X]%

Staging (FIGO 2014)

Stage [I/II/III/IV] - [detailed staging criteria based on extent of disease]

Prognostic Factors

Intermediate-grade morphology, villoglandular pattern, [unilateral/bilateral] involvement, stage [X], [lymph node status]

Molecular Testing Recommendations

Consider Lynch syndrome screening if family history present, KRAS/PIK3CA mutation testing for targeted therapy selection may be considered

Comments

Rare variant of ovarian adenocarcinoma with mixed papillary-glandular architecture. Intermediate biological behavior. Multidisciplinary team discussion recommended.

Final Diagnosis

[Unilateral/Bilateral] ovarian villoglandular adenocarcinoma, FIGO Stage [X], Grade 2