Definition/General
Introduction:
Primary endometrial squamous cell carcinoma is an extremely rare malignant tumor composed entirely of squamous epithelium
It represents less than 1% of all endometrial carcinomas
It must be distinguished from secondary involvement by cervical carcinoma
Strict criteria must be met for diagnosis of primary endometrial origin.
Origin:
Arises from endometrial epithelium through squamous metaplasia and subsequent malignant transformation
May develop from pre-existing squamous metaplasia
Chronic irritation or inflammation may predispose
Squamous differentiation without glandular component distinguishes from adenosquamous carcinoma.
Classification:
WHO classification recognizes primary squamous cell carcinoma as distinct entity
Must meet strict diagnostic criteria
Distinguished from adenosquamous carcinoma (lacks glandular component)
Secondary involvement from cervix must be excluded
Grading follows standard squamous cell carcinoma criteria.
Epidemiology:
Extremely rare with fewer than 100 cases reported in literature
Peak incidence in 6th-7th decades
Mean age 60-70 years
Older than cervical squamous carcinoma
Associated with chronic inflammation
Pyometra and cervical stenosis may predispose.
Clinical Features
Presentation:
Postmenopausal bleeding (most common)
Pyometra (purulent uterine discharge)
Pelvic mass or enlarged uterus
Foul-smelling vaginal discharge
Pelvic pain
Cervical stenosis may be present
Constitutional symptoms in advanced cases.
Symptoms:
Abnormal uterine bleeding (80-90%)
Purulent vaginal discharge
Pelvic pain and pressure
Pyometra with fever
Urinary symptoms
Bowel symptoms (advanced)
Weight loss and fatigue
Abdominal distension.
Risk Factors:
Chronic endometritis
Cervical stenosis
Pyometra
Radiation exposure
Chronic irritation
Immunosuppression
Previous pelvic inflammatory disease
Intrauterine device (long-term use)
HPV infection (uncertain role).
Screening:
No specific screening guidelines
Endometrial sampling for abnormal bleeding
Cervical evaluation essential to exclude cervical primary
Imaging studies (MRI helpful)
Hysteroscopy may show ulcerative lesion
SCC antigen may be elevated.
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Gross Description
Appearance:
Ulcerative, exophytic mass with gray-white to tan coloration
Friable consistency with areas of necrosis
Cut surface shows solid, firm texture
May have keratinizing areas
Size variable but often large at presentation.
Characteristics:
Firm, gray-white mass with ulcerated surface
Areas of necrosis and hemorrhage
Keratinous debris may be present
Friable consistency
Well-demarcated from myometrium in early cases
May show keratin pearl formation grossly.
Size Location:
Usually involves entire endometrial cavity
Size ranges from 3-12 cm
Fundal location helps distinguish from cervical primary
Deep myometrial invasion common
Cervical involvement by direct extension possible.
Multifocality:
Usually unifocal
May have associated squamous metaplasia in adjacent endometrium
Lymphovascular invasion often present
Direct extension to cervix or parametria
Distant metastases possible at presentation.
Microscopic Description
Histological Features:
Pure squamous cell carcinoma without glandular component
Keratinizing or non-keratinizing patterns
Intercellular bridges and keratin pearl formation
Nuclear pleomorphism and hyperchromasia
Absence of glandular differentiation distinguishes from adenosquamous carcinoma.
Cellular Characteristics:
Polygonal squamous cells with eosinophilic cytoplasm
Intercellular bridges visible
Pleomorphic nuclei with prominent nucleoli
Keratin production in well-differentiated areas
Individual cell keratinization
High mitotic activity
Absence of mucin production.
Architectural Patterns:
Solid nests and sheets of squamous cells
Keratin pearl formation in well-differentiated tumors
Invasive pattern with desmoplastic stromal reaction
May show pushing or infiltrative margins
Surface ulceration common
Lymphovascular invasion present.
Grading Criteria:
Grading based on keratinization and nuclear features
Well-differentiated: Abundant keratinization, keratin pearls
Moderately differentiated: Moderate keratinization
Poorly differentiated: Minimal keratinization, high nuclear grade
Most cases are moderately to poorly differentiated.
Immunohistochemistry
Positive Markers:
Squamous cell markers: CK5/6 (diffusely positive)
p63 (nuclear staining)
p40 (more specific than p63)
High molecular weight cytokeratins (34βE12)
EMA (variable)
SCC antigen (variable)
CK7 (may be positive).
Negative Markers:
Glandular markers: CK20 (usually negative)
CEA (negative or focal)
TTF-1 (negative)
Napsin A (negative)
Thyroglobulin (negative)
CDX2 (negative)
Hormone receptors (ER, PR) usually negative.
Diagnostic Utility:
p63 and CK5/6 confirm squamous differentiation
p40 more specific than p63
Absence of glandular markers distinguishes from adenocarcinoma
CK7 positivity supports müllerian origin
HPV testing may be negative (unlike cervical).
Molecular Subtypes:
HPV-independent pathway (most primary endometrial cases)
p53 mutations possible
p16 staining usually negative (unlike cervical)
Microsatellite status variable
Most cases show chromosomal instability.
Molecular/Genetic
Genetic Mutations:
p53 mutations (variable frequency)
KRAS mutations possible
PIK3CA mutations
PTEN mutations reported
p16 inactivation
HPV integration rare (unlike cervical)
Chromosomal instability pattern common.
Molecular Markers:
p53 expression (wild-type or mutant pattern)
p16 staining usually negative or patchy
High Ki-67 proliferation index
HPV DNA usually negative
Loss of p16/CDKN2A
Chromosomal alterations common.
Prognostic Significance:
Stage most important prognostic factor
Grade correlates with prognosis
HPV status less relevant than in cervical carcinoma
p53 mutations may predict aggressive behavior
Early stage has better prognosis than advanced disease.
Therapeutic Targets:
Standard chemotherapy for advanced disease
Radiation therapy for local control
Immunotherapy under investigation
Targeted therapy based on molecular profiling
PI3K/AKT inhibitors for pathway mutations.
Differential Diagnosis
Similar Entities:
Secondary involvement by cervical squamous carcinoma
Adenosquamous carcinoma (has glandular component)
Squamous metaplasia
Metastatic squamous carcinoma (lung, head and neck)
Carcinosarcoma with squamous differentiation
Primary vaginal squamous carcinoma.
Distinguishing Features:
Primary endometrial: No cervical primary tumor
Primary endometrial: Fundal location
Primary endometrial: Adjacent squamous metaplasia
Secondary cervical: Cervical mass present
Secondary cervical: HPV positive
Adenosquamous: Glandular component present
Metastatic: Primary tumor elsewhere
Metastatic: Clinical history.
Diagnostic Challenges:
Most important: Excluding cervical primary
Distinguishing from adenosquamous carcinoma
Separating from squamous metaplasia
Confirming invasive nature
Identifying site of origin
Excluding metastatic disease.
Rare Variants:
Verrucous carcinoma (well-differentiated variant)
Papillary squamous carcinoma
Basaloid squamous carcinoma
Adenoid squamous carcinoma
Spindle cell squamous carcinoma
Clear cell variant of squamous 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
Hysterectomy specimen measuring [X x Y x Z] cm, weighing [X] grams
Diagnosis
Primary endometrial squamous cell carcinoma
Classification
WHO Classification: Primary squamous cell carcinoma, Grade: [well/moderately/poorly differentiated]
Histological Features
Pure squamous cell carcinoma without glandular differentiation
Cervical Primary Exclusion
No evidence of cervical primary tumor, tumor located in fundus/corpus
Differentiation
[Well/Moderately/Poorly] differentiated with [degree] of keratinization
Size and Extent
Tumor size: [X] cm, myometrial invasion: [depth/total thickness], [percent]%
Margins
Margins: [involved/uninvolved], closest margin: [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Cervical Involvement
Cervical involvement: [present by direct extension/absent]
Special Studies
IHC: p63: [positive], CK5/6: [positive], p40: [positive]
HPV testing: [negative/not performed]
Molecular studies: [if performed]
FIGO Staging
FIGO Stage: [stage] ([staging criteria])
Prognostic Factors
Grade: [X], Stage: [X], primary endometrial origin confirmed
Final Diagnosis
Primary endometrial squamous cell carcinoma, [grade], FIGO Stage [X]