Definition/General
Introduction:
Cervical medullary carcinoma is an extremely rare variant of cervical carcinoma characterized by solid sheets of malignant cells with prominent lymphocytic infiltration
Accounts for less than 1% of all cervical carcinomas
Shows syncytial growth pattern similar to medullary carcinomas of other organs.
Origin:
Originates from cervical epithelium with unique differentiation pattern
Shows minimal glandular or squamous differentiation
Characterized by high-grade nuclear features and brisk mitotic activity
Associated with tumor-infiltrating lymphocytes suggesting immune response.
Classification:
WHO classification places it under rare cervical carcinoma variants
May show neuroendocrine differentiation in some cases
Pure medullary pattern (70%)
Mixed medullary-squamous (20%)
Medullary with neuroendocrine features (10%).
Epidemiology:
Extremely rare with fewer than 50 cases reported worldwide
Age range 35-65 years with median age 45
No specific geographic distribution
HPV association documented in 60% cases
Better prognosis than conventional poorly differentiated carcinomas.
Clinical Features
Presentation:
Abnormal vaginal bleeding (85%)
Cervical mass on examination (90%)
Pelvic pain (40%)
Vaginal discharge (30%)
Often presents as bulky cervical tumor.
Symptoms:
Postcoital bleeding most common presenting symptom
Intermenstrual bleeding in premenopausal women
Postmenopausal bleeding
Pelvic pressure symptoms from mass effect
Constitutional symptoms rare.
Risk Factors:
HPV infection in subset of cases
Immunosuppression may play role
Prior cervical dysplasia
Multiple sexual partners
Early age at first intercourse.
Screening:
Pap smear shows high-grade malignant cells
Lack of glandular or squamous differentiation on cytology
HPV testing positive in 60%
Colposcopy reveals friable mass
Biopsy essential for diagnosis.
Master Medullary Carcinoma Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Bulky, fleshy tumor mass
Soft to firm consistency
Tan-gray to pink color
Hemorrhagic and necrotic areas common
Well-circumscribed borders in some cases.
Characteristics:
Size typically 3-8 cm at presentation
Exophytic growth pattern predominant
Deeply invasive into cervical stroma
Pushing borders rather than infiltrative
Minimal surface ulceration.
Size Location:
Involves both ectocervix and endocervix
May extend to lower uterine segment
Vaginal extension in 30%
Parametrial involvement less common than conventional carcinoma
Circumferential growth pattern.
Multifocality:
Usually unifocal disease
Satellite nodules rare
Lymph node metastases in 25-30%
Distant metastases uncommon at presentation
Local recurrence if incompletely excised.
Microscopic Description
Histological Features:
Solid sheets and nests of malignant cells
Syncytial growth pattern without distinct cell borders
Prominent lymphocytic infiltrate at tumor-stroma interface
Pushing margins of invasion.
Cellular Characteristics:
Large polygonal cells with abundant cytoplasm
Vesicular nuclei with prominent nucleoli
High nuclear-cytoplasmic ratio
Frequent mitoses (>20/10 HPF)
Apoptotic bodies numerous.
Architectural Patterns:
Solid sheets predominant pattern
Occasional trabecular arrangement
Minimal glandular differentiation
Absence of keratinization
Peritumoral lymphoid aggregates.
Grading Criteria:
Considered high-grade by definition
Nuclear grade 3 features
High mitotic rate
Extensive necrosis common
Lymphocytic response may indicate better prognosis.
Immunohistochemistry
Positive Markers:
Pan-cytokeratin positive (100%)
p63 positive (80%)
p40 positive (75%)
p16 positive in HPV-associated cases (60%)
CK5/6 positive (70%)
EMA positive (85%).
Negative Markers:
Neuroendocrine markers usually negative
Synaptophysin negative (90%)
Chromogranin negative (85%)
CEA negative (80%)
Vimentin negative
S100 negative.
Diagnostic Utility:
Cytokeratin confirms epithelial nature
p63/p40 suggest squamous differentiation
Absence of neuroendocrine markers excludes small cell carcinoma
CD3/CD20 highlight lymphocytic infiltrate.
Molecular Subtypes:
HPV-positive subset (60%)
HPV-negative subset with different molecular profile
High tumor mutational burden in some cases
Microsatellite instability reported.
Molecular/Genetic
Genetic Mutations:
TP53 mutations in HPV-negative cases (70%)
PIK3CA mutations (30%)
PTEN loss (25%)
NOTCH1 mutations (20%)
FBXW7 mutations (15%).
Molecular Markers:
HPV DNA positive in 60%
High tumor mutational burden (30%)
PDL1 expression (40-50%)
Microsatellite stable in most
HER2 negative (95%).
Prognostic Significance:
Lymphocytic infiltration associated with better prognosis
HPV-positive cases may have better outcome
High TMB predicts immunotherapy response
TP53 mutations indicate aggressive behavior.
Therapeutic Targets:
Immunotherapy promising due to lymphocytic infiltrate
PDL1 inhibitors in clinical trials
Combination chemotherapy standard treatment
Radiation sensitivity similar to conventional carcinoma.
Differential Diagnosis
Similar Entities:
Small cell carcinoma: positive for neuroendocrine markers
Lymphoepithelioma-like carcinoma: EBV association
Poorly differentiated squamous carcinoma: keratinization present
Large cell neuroendocrine carcinoma: synaptophysin positive.
Distinguishing Features:
Medullary pattern: syncytial growth, lymphocytes
Absence of glandular differentiation
Negative neuroendocrine markers
Pushing margins characteristic
Prominent TILs distinguish from conventional carcinoma.
Diagnostic Challenges:
Small biopsy may miss diagnostic areas
Distinction from neuroendocrine tumors crucial
Lymphoma excluded by cytokeratin positivity
Metastatic medullary carcinoma from other sites considered.
Rare Variants:
Medullary carcinoma with neuroendocrine features
Mixed medullary-adenosquamous carcinoma
Medullary carcinoma with rhabdoid features
Dedifferentiated variants reported.
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
Radical hysterectomy with bilateral salpingo-oophorectomy and pelvic lymph node dissection, received [fresh/in formalin]
Diagnosis
Cervical medullary carcinoma with prominent lymphocytic infiltration
Histological Features
Solid sheets of malignant epithelial cells with syncytial pattern, high-grade nuclear features, brisk mitotic activity, and prominent tumor-infiltrating lymphocytes
Tumor Size
Greatest dimension: [X] cm; Additional dimensions: [X] × [X] cm; Gross tumor volume: [X] cm³
Depth of Invasion
Depth of stromal invasion: [X] mm; Cervical wall thickness: [X] mm; Percentage of wall invasion: [X]%
Margins
Ectocervical margin: [Negative/Positive] ([X] mm); Endocervical margin: [Negative/Positive] ([X] mm); Deep stromal margin: [Negative/Positive] ([X] mm)
Lymphovascular Invasion
[Present/Absent]; Pattern: [focal/multifocal]; Vessel type: [lymphatic/blood vessel]
Parametrial Involvement
Right parametrium: [Involved/Not involved]; Left parametrium: [Involved/Not involved]
Lymph Nodes
Total nodes examined: [X]; Positive nodes: [X]; Largest metastatic deposit: [X] mm
Immunohistochemistry
Pan-CK: Positive; p63: [Positive/Negative]; p16: [Positive/Negative]; Synaptophysin: Negative; CD3: Highlights TILs
Molecular Testing
HPV ISH: [Positive/Negative]; PDL1 expression: [Percentage]%; Additional markers: [specify]
Pathological Stage
FIGO Stage (2018): [stage]; TNM Stage (8th edition): pT[X]N[X]M[X]
Additional Findings
Tumor-infiltrating lymphocyte density: [high/moderate/low]; Other findings: [specify]