Definition/General
Introduction:
Primary ovarian squamous cell carcinoma is an extremely rare malignant tumor representing less than 1% of ovarian cancers
Most arise from mature cystic teratoma (dermoid cyst) through malignant transformation
Pure squamous cell carcinoma without teratomatous elements is exceptionally rare
Aggressive tumor with variable prognosis.
Origin:
Arises from squamous epithelium in mature cystic teratoma (90% of cases)
Malignant transformation of pre-existing benign squamous epithelium
De novo primary squamous carcinoma extremely rare
Metaplastic transformation of surface epithelium (theoretical)
HPV association rare in ovarian location.
Classification:
WHO 2020 classification: Primary squamous cell carcinoma arising in teratoma
Pure primary squamous carcinoma (extremely rare)
Metastatic squamous carcinoma (cervical, lung, esophageal)
Well-differentiated (Grade 1)
Moderately differentiated (Grade 2)
Poorly differentiated (Grade 3).
Epidemiology:
Peak incidence in 5th-6th decades (mean age 55 years)
Associated with mature teratoma in 90% cases
Unilateral involvement typical (95% cases)
Risk increases with teratoma size (>10 cm)
Better prognosis when arising in teratoma
Indian population - similar incidence patterns.
Clinical Features
Presentation:
Enlarging pelvic mass with change in pre-existing teratoma (80% cases)
Abdominal pain and discomfort (70% cases)
History of known dermoid cyst important
Rapid growth of previously stable mass
Constitutional symptoms in advanced cases
Ca-125 may be elevated (variable).
Symptoms:
Pelvic/abdominal pain (75% cases)
Abdominal distension (60% cases)
Change in bowel habits (mass effect - 30%)
Urinary frequency (pelvic pressure - 25%)
Weight loss and fatigue (40% cases)
Postmenopausal bleeding (rare - 10%)
Acute pain if rupture occurs.
Risk Factors:
Pre-existing mature cystic teratoma (most important)
Large teratoma size (>10 cm)
Age >50 years
Long-standing dermoid cyst
Postmenopausal status
No clear association with HPV or smoking (unlike other sites)
Family history of ovarian cancer.
Screening:
Regular follow-up of known dermoid cysts
Monitoring size changes on imaging
CA 19-9 may be elevated (teratoma marker)
SCC antigen occasionally elevated
MRI helpful for characterizing solid areas
PET-CT shows increased uptake in malignant areas.
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Gross Description
Appearance:
Solid areas within cystic teratoma
Gray-white to tan solid nodules or masses
Firm consistency
Keratinous material and hair from teratoma
Surface ulceration may be present
Necrosis in poorly differentiated tumors
Rupture with peritoneal spillage possible.
Characteristics:
Solid, firm consistency
Gray-white cut surface
Keratin production visible
Associated mature teratoma with hair, teeth, sebaceous material
Well-defined borders in early cases
Infiltrative growth in advanced tumors
Calcifications from teratomatous elements.
Size Location:
Variable size (5-30 cm, average 15 cm including teratoma)
Unilateral involvement in 95% cases
Solid areas within cystic teratoma
May involve ovarian surface
Adherent to surrounding structures in advanced cases
Peritoneal implants possible.
Multifocality:
Usually unifocal within teratoma
Multiple foci of transformation possible
Bilateral teratomas rare (5% cases)
Peritoneal spread if rupture occurs
Lymph node involvement uncommon
Hematogenous spread to lungs possible.
Microscopic Description
Histological Features:
Malignant squamous epithelium with keratinization
Invasive nests and sheets of squamous cells
Loss of basement membrane
Keratin pearl formation (well-differentiated)
Associated mature teratomatous elements
Desmoplastic stromal reaction
Surface ulceration may be present.
Cellular Characteristics:
Pleomorphic squamous cells with enlarged nuclei
Eosinophilic cytoplasm with keratin production
Intercellular bridges (desmosomes)
Nuclear hyperchromasia and pleomorphism
Prominent nucleoli
Mitotic activity variable with grade
Individual cell keratinization.
Architectural Patterns:
Invasive nests and cords
Sheets of malignant cells
Keratin pearl formation (well-differentiated)
Single cell infiltration (poorly differentiated)
Surface ulceration pattern
Pushing or infiltrative borders
Associated teratomatous tissue.
Grading Criteria:
WHO grading system: Grade 1 (well-differentiated) - abundant keratinization, minimal atypia
Grade 2 (moderately differentiated) - moderate keratinization, moderate atypia
Grade 3 (poorly differentiated) - minimal keratinization, marked atypia
Mitotic count correlates with grade
Keratinization extent important.
Immunohistochemistry
Positive Markers:
Cytokeratins (AE1/AE3) (100% positive)
CK5/6 (95% positive - squamous marker)
p63 (90% positive - basal cell marker)
CK14 (85% positive)
p40 (90% positive - specific for squamous)
34βE12 (high molecular weight cytokeratin)
p16 (variable - not related to HPV in ovary).
Negative Markers:
PAX8 (negative - excludes Müllerian origin)
WT1 (negative)
TTF1 (negative - excludes lung primary)
CDX2 (negative - excludes GI primary)
CK7 (usually negative)
CK20 (usually negative)
ER/PR (negative).
Diagnostic Utility:
p63 and p40 confirm squamous differentiation
CK5/6 supports squamous phenotype
Negative PAX8 important to exclude Müllerian primary
p16 staining usually patchy (unlike cervical SCC)
Ki-67 correlates with grade
Panel essential to exclude metastatic disease.
Molecular Subtypes:
HPV-negative type (majority of ovarian cases)
HPV-positive extremely rare in ovary
TP53-mutated type (common)
PIK3CA-mutated type
Different molecular profile from cervical squamous carcinoma.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (60% of cases)
PIK3CA mutations (30-40%)
KRAS mutations (20%)
CDKN2A loss (p16 locus - 25%)
PTEN mutations (15%)
HPV integration rare (unlike cervical)
NOTCH1 mutations (10%).
Molecular Markers:
p53 overexpression (mutant pattern)
Ki-67 proliferation index (varies with grade - 20-80%)
p16 expression (usually patchy, not block-positive)
EGFR overexpression (60% cases)
Cyclin D1 amplification
β-catenin (membranous pattern).
Prognostic Significance:
Grade most important prognostic factor
Size of squamous component correlates with outcome
Stage at diagnosis critical
Association with teratoma better prognosis than pure SCC
p53 mutations associated with poor prognosis
Age >60 years adverse factor.
Therapeutic Targets:
EGFR inhibitors: cetuximab, panitumumab (EGFR overexpressing tumors)
PI3K/mTOR inhibitors: for PIK3CA-mutated tumors
Immunotherapy: PD-1/PD-L1 inhibitors under investigation
Conventional chemotherapy: cisplatin-based regimens
Radiation therapy for local control.
Differential Diagnosis
Similar Entities:
Metastatic squamous carcinoma (cervical, lung, esophageal)
Endometrioid carcinoma with squamous differentiation
Transitional cell carcinoma
Poorly differentiated carcinoma
Squamous metaplasia in benign teratoma
Malignant transformation of other teratomatous elements.
Distinguishing Features:
Primary ovarian: associated teratoma, unilateral, PAX8-negative
Metastatic cervical: HPV+, p16 block-positive, bilateral
Metastatic lung: TTF1+, clinical history
Endometrioid: glandular areas, ER/PR+, PAX8+
Transitional: uroplakin+, thrombomodulin+
Benign squamous: no invasion, no atypia.
Diagnostic Challenges:
Distinguishing primary from metastatic squamous carcinoma
Extensive sampling needed to find teratomatous elements
Small biopsy specimens may be inadequate
HPV testing helpful (negative in primary ovarian)
Clinical correlation essential
Bilateral involvement suggests metastatic disease.
Rare Variants:
Verrucous carcinoma (extremely rare variant)
Basaloid squamous carcinoma
Adenosquamous carcinoma (mixed glandular and squamous)
Spindle cell squamous carcinoma
Lymphoepithelioma-like carcinoma
Keratoacanthoma-like 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
[Laterality] salpingo-oophorectomy, measuring [size] cm
Diagnosis
Squamous cell carcinoma arising in mature cystic teratoma
Classification and Grade
Squamous cell carcinoma, Grade [1/2/3] ([well/moderately/poorly] differentiated)
Histological Features
Shows invasive squamous carcinoma with [keratinization status], arising from mature teratoma with [hair, sebaceous glands, other elements]
Size and Extent
Tumor size: [X] cm, teratoma size: [X] cm, [confined to ovary/extraovarian extension]
Surgical Margins
Surgical margins: [clear/involved]
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Lymph Node Status
Lymph nodes: [X] examined, [X] positive
Special Studies
IHC: p63 (+), p40 (+), CK5/6 (+), PAX8 (-), WT1 (-), Ki-67 [X]%
HPV testing: negative (if performed)
Clinical correlation required to exclude metastatic squamous carcinoma
Prognostic Factors
Grade: [1/2/3]; Size: [X] cm; Associated teratoma: present; Stage: [if known]
Final Diagnosis
Squamous cell carcinoma (Grade [grade]) arising in mature cystic teratoma of [laterality] ovary