Definition/General
Introduction:
Paget disease involving the ovary is an extremely rare malignant condition where Paget cells (large cells with abundant pale cytoplasm and large nuclei) are found within the ovarian surface epithelium or as a component of ovarian adenocarcinoma
This represents less than 0.1% of all ovarian malignancies
Most cases are secondary involvement from primary vulvar, cervical, or breast Paget disease.
Origin:
Primary ovarian Paget disease is exceptionally rare with fewer than 20 cases reported worldwide
Most represent secondary spread from extramammary Paget disease of the vulva, cervix, or rectum
The cells arise from primitive pluripotent cells capable of apocrine or eccrine differentiation
Pagetoid spread within existing epithelial structures is the characteristic pattern.
Classification:
WHO 2020 does not list primary ovarian Paget disease as a separate entity
Cases are classified as: Adenocarcinoma with Pagetoid features
Secondary Paget disease (from vulvar/cervical primary)
Metastatic mammary Paget disease
Adenocarcinoma with apocrine differentiation showing Paget-like cells.
Epidemiology:
Extremely rare - fewer than 20 primary cases reported globally
Age range 50-75 years (mean 62 years)
Postmenopausal women predominantly affected
No specific risk factors identified for primary disease
Indian population - no documented cases of primary ovarian Paget disease
Secondary cases associated with vulvar Paget disease (5-10% ovarian involvement).
Clinical Features
Presentation:
Pelvic mass is the most common presentation (80% cases)
Abdominal distension and ascites (50% cases)
Vulvar lesions may be present if secondary spread (60% cases)
Asymptomatic in early cases
Advanced stage at presentation in 70% cases due to late diagnosis
Family history of breast/ovarian cancer should be explored.
Symptoms:
Pelvic/abdominal pain (60% cases)
Vulvar itching or burning (40% secondary cases)
Abnormal vaginal discharge (30% cases)
Postmenopausal bleeding (25% cases)
Urinary symptoms - frequency, urgency (20% cases)
Constitutional symptoms - weight loss, fatigue (advanced disease)
Skin lesions elsewhere if part of systemic disease.
Risk Factors:
Primary ovarian Paget disease - no established risk factors
Secondary disease risk factors: History of vulvar Paget disease
Previous breast cancer with Paget component
Genetic predisposition - BRCA mutations not specifically associated
Age >50 years
Nulliparity (weak association)
Immunosuppression may increase risk.
Screening:
No specific screening for primary ovarian Paget disease
Patients with vulvar Paget disease require pelvic examination and imaging
Annual pelvic examination for high-risk patients
CA-125 may be elevated but non-specific
MRI pelvis for detailed evaluation
Mammography if breast involvement suspected
Dermatological examination for skin lesions.
Master Paget Disease Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Ovarian enlargement with irregular surface nodularity
Gray-white to tan cut surface with areas of necrosis and cystic change
Surface implants may be visible as small nodules
Ascites commonly present
Omental involvement appears as thickened, nodular "cake-like" tissue
Associated vulvar lesions in secondary cases.
Characteristics:
Solid-cystic tumor with predominantly solid component
Firm to soft consistency depending on necrosis extent
Hemorrhagic areas common
Calcifications rare
Mucoid areas may be present
Surface roughening due to surface involvement
Adhesions to surrounding structures common.
Size Location:
Size range 5-20 cm (average 12 cm)
Unilateral in 60% of primary cases
Bilateral involvement suggests secondary disease
Surface involvement prominent feature
Peritoneal implants in advanced cases
Omental involvement in 40-50% cases.
Multifocality:
Multifocal surface involvement characteristic
Pagetoid spread within surface epithelium
Skip lesions may be present
Bilateral ovarian involvement in secondary disease (70%)
Peritoneal carcinomatosis pattern
Vulvar primary with ovarian metastases most common pattern
Synchronous breast involvement rare.
Microscopic Description
Histological Features:
Paget cells - large cells with abundant pale, vacuolated cytoplasm and large, hyperchromatic nuclei
Pagetoid spread within surface epithelium and glandular structures
Mucin-containing cells with signet-ring appearance
Desmoplastic stroma with inflammatory infiltrate
Surface epithelial involvement with loss of polarity.
Cellular Characteristics:
Large Paget cells (2-3 times normal epithelial cell size)
Abundant eosinophilic to pale cytoplasm with mucin vacuoles
Large, pleomorphic nuclei with prominent nucleoli
High nuclear-cytoplasmic ratio
Mitotic activity variable (5-20 per 10 HPF)
Apoptotic bodies frequently present
Intracytoplasmic mucin PAS-positive.
Architectural Patterns:
Pagetoid growth pattern - single cells and small clusters within epithelium
Glandular pattern in invasive areas
Solid sheets of Paget cells
Cribriform architecture occasionally seen
Surface ulceration in advanced cases
Lymphovascular invasion present in 60% cases
Perineural invasion in 30% cases.
Grading Criteria:
No specific grading system for ovarian Paget disease
Assessment based on: Nuclear pleomorphism (usually high-grade)
Mitotic activity
Necrosis extent
Lymphovascular invasion
Surface involvement extent
Depth of invasion
Generally considered high-grade malignancy regardless of pattern.
Immunohistochemistry
Positive Markers:
CK7 - strongly positive in 95% cases
CEA - positive in 80-90% cases
GCDFP-15 - positive in 70% cases (apocrine differentiation)
CK20 - focal positive in 40% cases
Mucin stains (PAS, mucicarmine) - positive
PAX8 - may be positive in ovarian primary
GATA3 - positive in mammary-type Paget.
Negative Markers:
ER/PR - typically negative (unlike breast ductal carcinoma)
HER2 - negative in most ovarian cases
TTF-1 - negative (excludes lung primary)
CDX2 - negative (excludes GI primary)
Melanoma markers (S100, Melan-A) - negative
p63 - negative
CK5/6 - negative.
Diagnostic Utility:
Paget cell identification: CK7+, CEA+ pattern characteristic
Site of origin determination: GCDFP-15+ suggests apocrine origin
Mammary vs extramammary: GATA3+ favors mammary origin
Primary vs metastatic: PAX8+ suggests ovarian primary
Mucin stains highlight intracytoplasmic mucin
HER2 testing important for targeted therapy decisions.
Molecular Subtypes:
Apocrine-type Paget (70%): GCDFP-15+, androgen receptor+
Eccrine-type Paget (20%): CEA+, CK7+
Mammary-type Paget (rare in ovary): GATA3+, may be HER2+
Intestinal-type (very rare): CDX2+, CK20+
Undifferentiated type (10%): Limited marker expression.
Molecular/Genetic
Genetic Mutations:
Limited data due to rarity - fewer than 20 cases studied molecularly
TP53 mutations reported in 60% of studied cases
PIK3CA mutations in 30% cases
ERBB2 amplification rare in ovarian cases (unlike mammary Paget)
KRAS mutations in 20% cases
No BRCA1/2 mutations reported in primary ovarian cases.
Molecular Markers:
p53 protein overexpression in 60% cases
Ki-67 proliferation index typically high (>50%)
HER2 amplification rare (5% cases)
Mucin expression (MUC1, MUC2) variable
E-cadherin loss in invasive areas
β-catenin membranous pattern preserved
Cyclins D1 and E overexpressed.
Prognostic Significance:
Generally poor prognosis due to late presentation and aggressive behavior
5-year survival <30% for advanced disease
Stage at presentation most important prognostic factor
TP53 mutations associated with worse outcome
Lymphovascular invasion predicts poor prognosis
Response to chemotherapy generally poor
Local recurrence common (40-50% cases).
Therapeutic Targets:
Limited targeted options due to rarity and molecular profile
HER2-targeted therapy (trastuzumab) if HER2+ (rare)
Standard chemotherapy: platinum-based regimens
Immunotherapy under investigation for Paget diseases
Anti-EGFR therapy potential option
Mucin-targeting approaches experimental
Surgical resection remains primary treatment when feasible.
Differential Diagnosis
Similar Entities:
Metastatic signet-ring cell carcinoma - gastric or colorectal primary
Primary ovarian mucinous adenocarcinoma with signet-ring features
Metastatic lobular breast carcinoma - single file pattern
Clear cell carcinoma with clear cytoplasm
Metastatic adenocarcinoma from other sites
Lymphoma with signet-ring morphology.
Distinguishing Features:
Metastatic signet-ring carcinoma: CDX2+, CK20+, CEA variable, lacks Paget morphology
Mucinous adenocarcinoma: Intestinal-type mucin, CDX2+, lacks pagetoid spread
Lobular breast carcinoma: ER/PR+, single file pattern, E-cadherin negative
Clear cell carcinoma: Clear cytoplasm, glycogen-rich, Napsin A+
Primary ovarian serous carcinoma: WT1+, p53 aberrant, papillary architecture.
Diagnostic Challenges:
Determining primary site - comprehensive IHC panel essential
Distinguishing from reactive changes - atypia and architectural distortion help
Limited tissue samples - may not show characteristic features
Pagetoid spread vs invasion - basement membrane integrity assessment
Mixed histological patterns - thorough sampling required
Secondary vs primary disease - clinical correlation essential.
Rare Variants:
Pagetoid variant of serous carcinoma - WT1+, p53 aberrant pattern
Signet-ring variant of endometrioid carcinoma - ER/PR+, squamous differentiation
Adenocarcinoma with apocrine features - GCDFP-15+, androgen receptor+
Collision tumor - two distinct histological patterns
Paget disease with neuroendocrine differentiation - chromogranin/synaptophysin+.
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
Ovarian mass, [side], [X] cm in greatest dimension, with/without fallopian tube
Diagnosis
Adenocarcinoma with Paget cell features
Microscopic Features
Large cells with abundant pale cytoplasm and pleomorphic nuclei (Paget cells) involving surface epithelium and glandular structures
Immunohistochemistry
CK7: [Positive], CEA: [Positive], GCDFP-15: [Positive/Negative], PAX8: [Result], CK20: [Result], ER/PR: [Usually Negative]
Staging Features
Surface involvement: [Present/Absent], Lymphovascular invasion: [Present/Absent], Peritoneal implants: [Present/Absent]
Comments
Given the extreme rarity of primary ovarian Paget disease, clinical correlation recommended to exclude secondary involvement from vulvar/cervical primary
Final Diagnosis
[Ovary location]: Adenocarcinoma with Paget cell features, FIGO Stage [X] (pending clinical correlation for primary vs secondary disease)