Definition/General
Introduction:
Fallopian tube medullary carcinoma is an extremely rare variant of tubal adenocarcinoma characterized by solid growth pattern with prominent lymphocytic infiltrate
It represents less than 1% of all fallopian tube carcinomas
The tumor demonstrates sheets of epithelial cells with pushing borders and dense lymphoplasmacytic infiltrate
It is frequently associated with mismatch repair deficiency (MMR-D) and microsatellite instability
The medullary pattern reflects both architectural and inflammatory features.
Origin:
Originates from the epithelial cells of the fallopian tube with loss of glandular differentiation
The solid growth pattern results from loss of architectural organization
Associated with mismatch repair gene mutations (MLH1, MSH2, MSH6, PMS2)
The lymphocytic infiltrate represents immune response to neoantigens
May arise in setting of Lynch syndrome or sporadic MMR deficiency.
Classification:
WHO classification recognizes it as a rare morphological variant with specific molecular features
Solid growth pattern must predominate (>75% of tumor)
Dense lymphocytic infiltrate required for diagnosis
Associated with microsatellite instability (MSI-H)
High-grade carcinoma despite better prognosis
Distinguished from other solid tumors by inflammatory component.
Epidemiology:
Extremely rare with fewer than 25 cases reported worldwide
Peak incidence in 5th-6th decades (similar to other tubal carcinomas)
May be associated with Lynch syndrome (hereditary nonpolyposis colorectal cancer)
Better prognosis than conventional high-grade carcinomas
Higher response rates to immunotherapy
No racial predilection identified
May be underdiagnosed due to unfamiliarity.
Clinical Features
Presentation:
Pelvic mass with moderate growth rate
Pelvic pain and pressure symptoms
Abnormal vaginal bleeding (irregular or postmenopausal)
Constitutional symptoms less common than high-grade tumors
May present at earlier stage than conventional carcinomas
Family history of Lynch syndrome-associated cancers
Personal history of colorectal or endometrial cancer.
Symptoms:
Pelvic discomfort and cramping pain
Irregular menstrual bleeding or postmenopausal bleeding
Abdominal fullness and bloating
Urinary frequency due to mass effect
Bowel symptoms (mild constipation)
Less constitutional symptoms compared to high-grade tumors
Gradual onset over months.
Risk Factors:
Lynch syndrome (MLH1, MSH2, MSH6, PMS2 mutations)
Personal history of colorectal cancer
Personal history of endometrial cancer
Family history of Lynch syndrome cancers
Advanced age (>50 years)
Nulliparity (possible association)
No established BRCA association.
Screening:
Lynch syndrome screening for all patients with medullary carcinoma
Genetic counseling and testing
Colonoscopy screening for Lynch syndrome patients
Endometrial surveillance in Lynch syndrome
Standard gynecological examination
CA-125 levels (may be normal or mildly elevated).
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Gross Description
Appearance:
Well-circumscribed, solid tumor with pushing borders
Tan to pink cut surface with soft consistency
Homogeneous appearance without significant necrosis
Fish-flesh appearance similar to lymphoma
Well-demarcated margins
Minimal calcifications
Absence of papillary features.
Characteristics:
Solid, fleshy consistency
Pink-tan coloration
Homogeneous cut surface
Well-defined borders
Minimal hemorrhage and necrosis
Soft texture (brain-like consistency)
No cystic areas typically.
Size Location:
Size ranges from 3-8 cm (variable)
May involve entire tube or be focal
Any portion of tube can be affected
Usually unilateral
Limited extension beyond tube at diagnosis
Confined to tube in majority of early cases.
Multifocality:
Usually unifocal within the fallopian tube
Well-demarcated from surrounding tissue
Bilateral involvement rare
Limited peritoneal seeding
Less aggressive spread than high-grade carcinomas
Earlier stage at presentation.
Microscopic Description
Histological Features:
Solid sheets of epithelial cells with syncytial appearance
Pushing borders rather than infiltrative growth
Dense lymphoplasmacytic infiltrate both intra- and peritumoral
High-grade nuclear features with pleomorphism
High mitotic activity (>15 mitoses per 10 HPF)
Minimal necrosis despite high grade
Absence of glandular formation.
Cellular Characteristics:
Large epithelial cells with abundant eosinophilic cytoplasm
Pleomorphic nuclei with irregular contours
Prominent nucleoli
Syncytial growth pattern with indistinct cell borders
Frequent mitotic figures
Minimal keratinization
Vesicular chromatin pattern.
Architectural Patterns:
Solid sheet-like pattern predominates (>75%)
Syncytial arrangement of tumor cells
Pushing borders with minimal stromal invasion
Dense inflammatory infiltrate separating tumor nests
Minimal glandular differentiation
Absence of papillary features
Organoid pattern may be focal.
Grading Criteria:
High-grade carcinoma (Grade 3) despite better prognosis
Nuclear grade 3 (marked pleomorphism)
Architectural grade 3 (solid pattern)
High mitotic count (>15 per 10 HPF)
Paradoxical better prognosis than grade suggests
Inflammatory response influences behavior.
Immunohistochemistry
Positive Markers:
CK7 (positive in epithelial cells)
PAX8 (nuclear, confirming müllerian origin)
p53 (wild-type pattern typically)
MSH2, MSH6, MLH1, PMS2 (loss of expression in MMR-deficient cases)
CD3, CD20 (highlighting lymphocytic infiltrate)
PD-L1 (often positive, tumor and immune cells)
EMA (epithelial membrane antigen).
Negative Markers:
CK20 (negative, excludes gastrointestinal origin)
CDX2 (negative, excludes intestinal differentiation)
TTF-1 (negative, excludes lung origin)
ER/PR (typically negative or weakly positive)
WT1 (usually negative, unlike serous carcinomas)
p63 (negative in tumor cells)
Synaptophysin, Chromogranin (negative).
Diagnostic Utility:
PAX8 positivity confirms müllerian origin
MMR protein loss (MLH1, MSH2, MSH6, PMS2) indicates mismatch repair deficiency
p53 wild-type pattern distinguishes from high-grade serous
PD-L1 positivity predicts immunotherapy response
Lymphocytic markers confirm dense inflammatory infiltrate
CK7+/CK20- supports gynecological primary.
Molecular Subtypes:
MMR-deficient subtype (MLH1, MSH2, MSH6, or PMS2 loss)
MSI-H subtype (microsatellite instability-high)
High tumor mutational burden subtype
Immune-inflamed subtype (high PD-L1, dense TILs)
p53 wild-type subtype
Lynch syndrome-associated subtype.
Molecular/Genetic
Genetic Mutations:
Mismatch repair gene mutations (MLH1, MSH2, MSH6, PMS2)
High tumor mutational burden (>10 mutations/Mb)
Microsatellite instability (MSI-H)
POLE mutations (may be present)
TP53 mutations (less common than in HGSC)
PIK3CA mutations (may be present)
ARID1A mutations (chromatin remodeling).
Molecular Markers:
Microsatellite instability (MSI-H in majority)
High tumor mutational burden (TMB-H)
PD-L1 expression (often positive)
Tumor-infiltrating lymphocytes (high density)
p53 wild-type pattern (normal expression)
Ki-67 proliferation index (high despite better prognosis)
Neoantigen load (elevated).
Prognostic Significance:
Better prognosis than conventional high-grade carcinomas
Higher response rates to immunotherapy
Stage-for-stage better survival
Lower recurrence rate
MSI-H status predicts treatment response
Dense TILs associated with better outcome
5-year survival significantly higher than HGSC.
Therapeutic Targets:
PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab for MSI-H tumors)
CTLA-4 inhibitors (ipilimumab)
Standard chemotherapy (platinum-based)
PARP inhibitors (limited role)
Immunotherapy combinations
Clinical trials for immune checkpoint inhibitors
Adoptive cell therapy (investigational).
Differential Diagnosis
Similar Entities:
Poorly differentiated adenocarcinoma (lacks prominent lymphocytic infiltrate)
Lymphoepithelioma-like carcinoma
Primary tubal lymphoma
Undifferentiated carcinoma
Metastatic medullary carcinoma from colorectum
Inflammatory carcinoma
Squamous cell carcinoma with lymphocytic infiltrate.
Distinguishing Features:
Medullary vs poorly differentiated: Dense lymphocytic infiltrate, pushing borders, MMR deficiency
Carcinoma vs lymphoma: Epithelial markers (CK7, PAX8) vs lymphoid markers
Primary vs metastatic: Clinical history, immunohistochemistry, site of origin
Medullary vs lymphoepithelioma-like: EBV negativity, different morphology.
Diagnostic Challenges:
Recognizing medullary pattern in limited tissue
Distinguishing from lymphoma
Identifying MMR deficiency
Determining primary site
Crush artifact may obscure morphology
Mixed histological patterns.
Rare Variants:
Mixed medullary and conventional adenocarcinoma
Medullary with focal glandular differentiation
Medullary with squamous features
Pleomorphic medullary variant
Medullary with neuroendocrine features
Cystic medullary pattern.
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 solid tumor
Diagnosis
Medullary carcinoma of fallopian tube
Classification
High-grade adenocarcinoma with medullary features (Grade 3)
Histological Features
Shows solid sheets of epithelial cells with pushing borders and dense lymphoplasmacytic infiltrate
Medullary Pattern
Solid growth pattern >75%, pushing borders, dense inflammatory infiltrate, syncytial appearance
Inflammatory Infiltrate
Dense lymphoplasmacytic infiltrate present both intratumorally and peritumorally
Extent of Disease
Size: [X] cm, Growth pattern: [solid/pushing borders], Necrosis: [minimal/absent]
Special Studies
CK7: positive, PAX8: positive (confirming müllerian origin)
MLH1: [intact/lost], MSH2: [intact/lost], MSH6: [intact/lost], PMS2: [intact/lost]
PD-L1: [positive/negative], CD3/CD20: highlighting dense lymphocytic infiltrate
Molecular Testing
MSI status: [MSI-H/MSS], TMB: [high/low], Consider Lynch syndrome genetic testing
FIGO Staging
FIGO Stage: [IA/IB/IC/II] - [typically early stage at presentation]
Prognostic Factors
Medullary carcinoma (better prognosis than grade suggests), MMR deficiency: [present/absent], MSI-H status
Final Diagnosis
Primary fallopian tube medullary carcinoma with mismatch repair deficiency, FIGO Stage [IA/IB/IC/II]