Definition/General
Introduction:
Fallopian tube villoglandular carcinoma is a rare, well-differentiated variant of tubal adenocarcinoma characterized by papillary architecture with glandular differentiation
It represents approximately 2-3% of all fallopian tube carcinomas
The tumor demonstrates complex papillary pattern with well-formed glands resembling endocervical adenocarcinoma villoglandular type
It typically shows better prognosis compared to high-grade serous carcinomas
The architectural pattern is the defining histological feature.
Origin:
Originates from the epithelial cells of the fallopian tube with maintained glandular differentiation capacity
The tumor shows preserved cellular polarity and glandular architecture
May develop from adenofibroma or other benign precursor lesions
The villoglandular pattern suggests retained secretory function
HPV association is not established unlike cervical villoglandular carcinomas.
Classification:
WHO classification recognizes it as a variant of well-differentiated adenocarcinoma
Villoglandular pattern must predominate (>50% of tumor)
Low-grade adenocarcinoma (Grade 1-2) in most cases
May show mixed patterns with conventional adenocarcinoma
Distinguished from serous carcinoma by better differentiation
FIGO staging follows standard tubal carcinoma criteria.
Epidemiology:
Rare entity with limited case reports in literature (<100 cases reported)
Peak incidence in 4th-6th decades (slightly younger than high-grade serous)
No specific racial predilection identified
May be associated with reproductive history (nulliparity)
No established BRCA association
Better prognosis compared to high-grade variants
May be underdiagnosed due to rarity and overlap with other patterns.
Clinical Features
Presentation:
Slowly growing pelvic mass with indolent course
Mild to moderate pelvic pain (less severe than high-grade tumors)
Abnormal vaginal bleeding (irregular or postmenopausal)
Watery vaginal discharge may be present
Abdominal distension (in larger tumors)
Earlier stage at presentation compared to high-grade carcinomas
Less aggressive clinical behavior.
Symptoms:
Pelvic pressure and mild cramping
Irregular menstrual bleeding or postmenopausal bleeding
Mild abdominal fullness
Occasional urinary frequency
Less constitutional symptoms compared to high-grade tumors
Gradual onset of symptoms over months
May be asymptomatic in early stages.
Risk Factors:
Advanced age (>40 years)
Nulliparity and infertility
Family history of gynecological cancers
Personal history of breast cancer
No established BRCA association for this variant
Chronic salpingitis may be a risk factor
Hormone replacement therapy (possible association).
Screening:
No specific screening protocols due to rarity
Standard gynecological examination and imaging
Transvaginal ultrasound for pelvic mass evaluation
CA-125 levels may be normal or mildly elevated
Better detection rate due to earlier symptoms
MRI may show characteristic papillary features.
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Gross Description
Appearance:
Well-circumscribed tumor with papillary surface projections
Tan to pink cut surface with soft consistency
Papillary excrescences visible on gross examination
Minimal necrosis and hemorrhage
Cystic areas may be present
Smooth, lobulated surface
Well-demarcated from surrounding normal tissue.
Characteristics:
Papillary architecture evident grossly
Soft, friable consistency
Pink to tan coloration
Minimal calcifications
Cystic degeneration in some areas
Well-defined margins
Absence of extensive necrosis (unlike high-grade tumors).
Size Location:
Size ranges from 2-8 cm (smaller than high-grade carcinomas)
May involve entire tube or be focal
Ampullary region commonly affected
Fimbrial involvement less common than serous carcinomas
Unilateral in majority of cases
Limited extension beyond tube at diagnosis.
Multifocality:
Usually unifocal within the fallopian tube
Clear transition from normal epithelium
Minimal satellite lesions
Bilateral involvement uncommon
Limited peritoneal seeding
Ovarian surface involvement rare
Confined to tube in early stages.
Microscopic Description
Histological Features:
Complex papillary architecture with fine fibrovascular cores
Well-formed glandular structures within papillae
Cuboidal to columnar epithelium lining papillae and glands
Maintained cellular polarity
Mild to moderate nuclear atypia
Low to moderate mitotic activity (5-15 per 10 HPF)
Minimal necrosis.
Cellular Characteristics:
Cuboidal to low columnar cells with moderate cytoplasm
Eosinophilic to amphophilic cytoplasm
Oval nuclei with mild enlargement
Small to moderate nucleoli
Maintained nuclear polarity
Minimal nuclear pleomorphism
Clear cytoplasmic boundaries.
Architectural Patterns:
Papillary pattern predominates (>50% of tumor)
Glandular pattern within papillary cores
Villoglandular architecture (combination of villous and glandular)
Back-to-back glands in some areas
Minimal solid areas
Cribriform pattern may be focal
Single cell infiltration rare.
Grading Criteria:
Well to moderately differentiated (Grade 1-2)
Architectural grade 1-2 (glandular to papillary pattern)
Nuclear grade 1-2 (mild to moderate atypia)
Mitotic activity low to moderate (<15 per 10 HPF)
Necrosis uncommon
Overall grade typically Grade 1-2.
Immunohistochemistry
Positive Markers:
CK7 (diffusely positive in epithelial cells)
PAX8 (nuclear, positive in 95% confirming müllerian origin)
CA125 (positive in luminal surface and cytoplasm)
WT1 (may be positive, supporting serous-like differentiation)
ER (positive in 60-70% of cases)
PR (positive in 50-60%)
EMA (epithelial membrane antigen, positive).
Negative Markers:
CK20 (negative, excludes gastrointestinal origin)
CDX2 (negative, excludes intestinal differentiation)
TTF-1 (negative, excludes lung origin)
p16 (negative to weak, unlike cervical villoglandular type)
HPV DNA (negative, no viral association)
p63 (negative in tumor cells)
Calretinin (negative).
Diagnostic Utility:
PAX8 positivity confirms müllerian origin
CK7+/CK20- pattern supports gynecological primary
ER/PR positivity indicates hormone receptor status
p16 negativity helps exclude cervical origin
WT1 positivity may suggest serous-like features
HPV negativity distinguishes from cervical counterpart.
Molecular Subtypes:
Hormone receptor positive subtype (ER+/PR+)
Low proliferation subtype (low Ki-67 index)
p53 wild-type subtype (normal p53 pattern)
Microsatellite stable subtype (MSS)
Low-grade molecular features
BRCA wild-type subtype (no BRCA association).
Molecular/Genetic
Genetic Mutations:
TP53 mutations (less common, 20-30% vs 95% in HGSC)
PIK3CA mutations (present in 15-25%)
CTNNB1 mutations (Wnt pathway, 10-15%)
KRAS mutations (uncommon, <10%)
PTEN alterations (may be present)
BRCA1/2 mutations (no established association)
Microsatellite instability (rare).
Molecular Markers:
p53 wild-type pattern (normal nuclear staining)
β-catenin expression (may show nuclear accumulation)
Ki-67 proliferation index (low, 10-30%)
Cyclin D1 expression (may be positive)
EGFR expression (variable)
PD-L1 expression (typically low)
Homologous recombination proficiency.
Prognostic Significance:
Better prognosis than high-grade serous carcinomas
Earlier stage at diagnosis (majority Stage I-II)
Lower metastatic potential
Better response to treatment
Longer overall survival (5-year survival >80%)
Lower recurrence rate
Hormone receptor positivity predicts endocrine therapy response.
Therapeutic Targets:
Hormone therapy (for ER/PR positive cases)
Platinum-based chemotherapy (standard for advanced cases)
PI3K/mTOR inhibitors (for PIK3CA-mutated cases)
Wnt pathway inhibitors (for CTNNB1-mutated cases)
Anti-angiogenic agents (bevacizumab in advanced cases)
Immunotherapy (limited role due to low TMB)
CDK4/6 inhibitors (hormone receptor positive cases).
Differential Diagnosis
Similar Entities:
Serous carcinoma with papillary features
Endometrioid carcinoma of fallopian tube
Cervical adenocarcinoma, villoglandular type (metastatic)
Serous borderline tumor
Papillary adenofibroma with malignant transformation
Clear cell carcinoma with papillary pattern
Metastatic adenocarcinoma from other sites.
Distinguishing Features:
Villoglandular vs serous: Better differentiation, lower grade, ER/PR positivity
Primary tubal vs cervical metastasis: PAX8 positivity, p16 negativity, clinical history
Carcinoma vs borderline: Stromal invasion, higher grade, mitotic activity
Villoglandular vs endometrioid: Papillary architecture predominance, different morphology.
Diagnostic Challenges:
Distinguishing from metastatic cervical adenocarcinoma
Differentiating from serous carcinoma with good differentiation
Determining primary site when multiple organs involved
Limited tissue samples may not show characteristic features
Overlap with endometrioid features
Mixed histological patterns.
Rare Variants:
Mixed villoglandular and serous pattern
Villoglandular with endometrioid features
Micropapillary villoglandular variant
Solid villoglandular pattern
Villoglandular with squamous differentiation
Cystic villoglandular variant
Villoglandular with clear cell areas.
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, fallopian tube measuring [size] cm with papillary tumor
Diagnosis
Villoglandular carcinoma of fallopian tube
Classification
Well to moderately differentiated adenocarcinoma, villoglandular type (Grade 1-2)
Histological Features
Shows complex papillary architecture with well-formed glandular structures and maintained cellular polarity
Villoglandular Pattern
Papillary architecture with glandular differentiation present in >50% of tumor, low mitotic activity
Histological Grading
Grade: [1/2], Architecture: [glandular to papillary], Nuclear atypia: [mild to moderate], Mitoses: [<15/10 HPF]
Extent of Disease
Size: [X] cm, Growth pattern: [papillary/infiltrative], Necrosis: [minimal/absent]
Special Studies
CK7: positive, PAX8: positive (confirming müllerian origin)
ER: [positive/negative], PR: [positive/negative]
p16: negative/weak (excluding cervical origin), CK20: negative
Molecular Features
p53: [wild-type pattern], Ki-67: [low proliferation index, <30%]
FIGO Staging
FIGO Stage: [IA/IB/IC/II/III/IV] - [staging details]
Prognostic Factors
Villoglandular carcinoma (better prognosis), Low-grade (Grade 1-2), Hormone receptor status: [ER/PR status]
Final Diagnosis
Primary fallopian tube villoglandular carcinoma, FIGO Stage [IA/IB/IC/II/III/IV]