Definition/General
Introduction:
Endometrial medullary carcinoma is a rare variant of endometrial adenocarcinoma
It is characterized by solid growth pattern and prominent lymphocytic infiltrate
It is strongly associated with microsatellite instability (MSI)
It has a better prognosis than conventional high-grade carcinomas.
Origin:
Arises from endometrial glandular epithelium
Associated with mismatch repair deficiency
Often occurs in the setting of Lynch syndrome
May develop from atypical hyperplasia
Microsatellite instability drives tumorigenesis.
Classification:
Classified as special variant of endometrial adenocarcinoma by WHO
High-grade morphology but better prognosis
MSI-high molecular subtype
Part of Lynch syndrome spectrum
Mismatch repair deficient tumors.
Epidemiology:
Rare variant of endometrial carcinoma
Peak incidence in 5th-6th decades
Younger age than conventional high-grade carcinomas
Strong association with Lynch syndrome
Family history of colorectal/endometrial cancer common.
Clinical Features
Presentation:
Abnormal uterine bleeding (most common)
Postmenopausal bleeding
Family history of Lynch syndrome cancers
Personal history of colorectal cancer
Synchronous ovarian cancer possible.
Symptoms:
Heavy menstrual bleeding
Intermenstrual bleeding
Pelvic pain
Constitutional symptoms rare
Early stage at presentation common
Better clinical behavior than grade suggests.
Risk Factors:
Lynch syndrome (strongest association)
Family history of colorectal/endometrial cancer
Mismatch repair gene mutations (MLH1, MSH2, MSH6, PMS2)
Young age
Personal history of Lynch-associated cancers.
Screening:
Genetic counseling for Lynch syndrome
Family history assessment important
Immunohistochemistry for mismatch repair proteins
Microsatellite instability testing
Germline genetic testing.
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Gross Description
Appearance:
Soft, fleshy mass with pushing borders
Tan-gray cut surface
Well-circumscribed appearance
Homogeneous consistency
Minimal necrosis typically.
Characteristics:
Size ranges from 2-8 cm
Pushing margins rather than infiltrative
Cut surface shows uniform appearance
Soft consistency
Minimal hemorrhage or necrosis.
Size Location:
Variable size at presentation
Involves endometrial cavity
Superficial myometrial invasion common
Deep invasion less common
Early stage presentation typical.
Multifocality:
Usually unifocal presentation
Limited local invasion
Lymphovascular invasion uncommon
Lymph node metastases rare
Synchronous ovarian cancer in Lynch syndrome.
Microscopic Description
Histological Features:
Solid sheets of epithelial cells
Pushing margins with surrounding tissue
Prominent lymphocytic infiltrate
Large, pleomorphic nuclei
High mitotic activity
Minimal glandular formation.
Cellular Characteristics:
Large epithelial cells with abundant cytoplasm
Vesicular nuclei with prominent nucleoli
High nuclear grade
Syncytial growth pattern
Mitotic figures abundant
Apoptotic bodies common.
Architectural Patterns:
Solid, syncytial pattern
Pushing borders
Dense lymphocytic infiltrate at periphery
Minimal stromal desmoplasia
Geographic necrosis may be present
Peritumoral lymphoid reaction.
Grading Criteria:
Morphologically high-grade (FIGO Grade 3)
Solid growth pattern >95%
High nuclear grade
High mitotic rate
Despite high grade, better prognosis than conventional carcinomas.
Immunohistochemistry
Positive Markers:
Cytokeratins (CK7 positive, CK20 negative)
EMA
p53 (wild-type pattern)
High Ki-67 (>50%)
PD-L1 (often positive)
CD8 (tumor-infiltrating lymphocytes).
Negative Markers:
Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2 - one or more lost)
ER and PR (usually negative)
p16 (usually negative)
WT1 (negative).
Diagnostic Utility:
Loss of mismatch repair proteins diagnostic
MLH1 loss most common
PMS2 loss accompanies MLH1 loss
MSH2/MSH6 loss in hereditary cases
Wild-type p53 pattern
High PD-L1 expression.
Molecular Subtypes:
MSI-high molecular subtype
Hypermutated phenotype
POLE mutations rare in medullary type
Copy number low
Mismatch repair deficient.
Molecular/Genetic
Genetic Mutations:
Mismatch repair gene mutations (MLH1, MSH2, MSH6, PMS2)
High tumor mutational burden
Microsatellite instability
PTEN mutations
PIK3CA mutations
ARID1A mutations.
Molecular Markers:
Microsatellite instability-high (MSI-H)
Loss of mismatch repair protein expression
High tumor mutational burden
Hypermutated phenotype
MLH1 promoter hypermethylation (sporadic cases).
Prognostic Significance:
MSI-high status indicates better prognosis
Immunogenic tumor with good response to immunotherapy
Despite high grade, favorable outcome
Early stage at presentation common
Lynch syndrome patients have better survival.
Therapeutic Targets:
Immunotherapy (pembrolizumab, dostarlimab)
PD-1/PD-L1 inhibitors
PARP inhibitors (investigational)
PI3K/mTOR inhibitors
Chemotherapy (standard regimens)
Hormonal therapy limited efficacy.
Differential Diagnosis
Similar Entities:
Conventional high-grade endometrial carcinoma
Undifferentiated carcinoma
Dedifferentiated carcinoma
Lymphoepithelioma-like carcinoma
Squamous cell carcinoma.
Distinguishing Features:
Conventional carcinoma: Infiltrative borders
Conventional: Mismatch repair intact
Medullary: Pushing borders
Medullary: Prominent lymphocytes
Medullary: MSI-high
Undifferentiated: Lacks cohesive pattern.
Diagnostic Challenges:
Recognizing pushing vs infiltrative borders
Identifying lymphocytic infiltrate
Confirming mismatch repair deficiency
Distinguishing from other high-grade carcinomas
MSI testing essential.
Rare Variants:
Pure medullary carcinoma
Mixed with conventional adenocarcinoma
Medullary-like features in other histotypes
Lynch syndrome-associated vs sporadic.
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
[specimen type], measuring [size] cm, soft consistency
Diagnosis
Endometrial adenocarcinoma, medullary type
WHO Classification
Endometrial adenocarcinoma, special variant (medullary type)
Histological Features
Solid growth pattern with pushing borders and prominent lymphocytic infiltrate
Grade
FIGO Grade: 3 (morphologically high-grade)
Tumor Borders
Tumor borders: Pushing margins with peritumoral lymphocytes
Mismatch Repair Proteins
MLH1: [retained/lost], MSH2: [retained/lost], MSH6: [retained/lost], PMS2: [retained/lost]
p53: [wild-type/overexpressed], Ki-67: [percentage]%
PD-L1: [positive/negative]
Molecular Studies
Microsatellite instability: [MSI-high/MSS/pending]
Lynch Syndrome Screening
Mismatch repair deficiency identified, recommend genetic counseling
Final Diagnosis
Endometrial adenocarcinoma, medullary type, mismatch repair deficient