What is the role of Pax8 (Paired Box 8) Immunohistochemistry (IHC) in diagnosing gynaecological cancer?

Role of PAX8 Immunohistochemistry in Diagnosing Gynaecological Cancer

PAX8 immunohistochemistry is a critical diagnostic marker for determining the Müllerian origin of gynaecological cancers, with high sensitivity for ovarian and endometrial carcinomas, and serves as an essential component of immunohistochemical panels for distinguishing primary site and tumor type. 1

Diagnostic Value of PAX8 in Different Gynaecological Cancers

Ovarian Carcinomas

• PAX8 is expressed in the vast majority (87.1%) of ovarian carcinomas 2
• Expression varies by histological subtype:
  • High-grade serous carcinomas: 96.4% positive 2
  • Endometrioid carcinomas: 88.9% positive 2
  • Clear cell carcinomas: 100% positive 2
  • Mucinous carcinomas: Only 8.3% positive 2

Endometrial Carcinomas

• PAX8 is highly expressed in endometrial carcinomas:
  • Endometrioid carcinomas: 96% positive 3
  • Serous carcinomas: 95% positive 3
• Intensity and extent of staining is typically higher in serous (mean composite score 8.3) compared to endometrioid (mean composite score 5.3) subtypes 3

Cervical Carcinomas

• PAX8 expression varies significantly by histological subtype:
  • Adenocarcinomas of usual type: 70% positive 4
  • Endometrioid-type cervical adenocarcinomas: 83% positive 4
  • Squamous cell carcinomas: Only 8% positive 4
  • Adenosquamous carcinomas: 29% positive 4

Clinical Applications of PAX8 in Diagnostic Algorithms

Determining Primary Site of Origin

• PAX8 is particularly valuable in distinguishing gynecologic from non-gynecologic malignancies:
  • Ovarian/endometrial vs. breast carcinomas: PAX8 is positive in most gynecologic carcinomas but consistently negative in breast carcinomas 2
  • Gynecologic vs. gastrointestinal origin: PAX8 positivity strongly favors gynecologic primary 5

Differential Diagnosis Within Gynecologic Malignancies

1. Ovarian vs. Uterine Primary:

   • PAX8 alone cannot distinguish between ovarian and endometrial origin as both are typically positive 5
   • Must be used as part of a panel with other markers:
     • WT1: Positive in 80-90% of ovarian serous carcinomas but typically negative in endometrial carcinomas 5
     • p53: Pattern of staining (mutation-type vs. wild-type) helps distinguish high-grade from low-grade serous carcinomas 5

2. Distinguishing Metastatic Disease:

   • First-line panel should include PAX8, WT1, CK7, and CK20 1
   • PAX8+/WT1+/CK7+/CK20- profile strongly suggests high-grade serous ovarian carcinoma 5
   • PAX8+/WT1-/CK7+/CK20- profile suggests endometrioid or clear cell carcinoma 5

Special Clinical Scenarios

1. Neoadjuvant Chemotherapy Candidates:

   • PAX8 is valuable for confirming ovarian origin in ascitic fluid samples before initiating neoadjuvant chemotherapy 6
   • When combined with Calretinin (mesothelial marker), PAX8+/Calretinin- profile identifies Müllerian-derived malignant cells with high accuracy 6

2. Carcinosarcomas (Malignant Mixed Müllerian Tumors):

   • PAX8 is expressed in the carcinomatous component in 97% of cases 7
   • Less frequently expressed in the sarcomatous component (27% positive) 7
   • Helpful for identifying metastatic carcinosarcomas of gynecologic origin 7

Pitfalls and Limitations

• PAX8 cannot reliably distinguish between different types of Müllerian-derived carcinomas (ovarian vs. endometrial) 3
• Mucinous ovarian carcinomas have low PAX8 expression (8.3%), limiting its utility for this subtype 2
• Some benign Müllerian-derived lesions (endosalpingiosis, endometriosis) are PAX8 positive, which can cause diagnostic confusion 6
• Renal cell carcinomas can also express PAX8, requiring correlation with clinical history and other markers 6

Optimal Diagnostic Approach

For determining the primary site of gynecological malignancies, use a systematic approach:

1. First-line panel: PAX8, WT1, CK7, CK20 1
2. Second-line markers based on initial results:
   • p53 pattern assessment for serous carcinomas
   • ER for endometrioid vs. serous
   • BerEP4, calretinin, and CK5/6 for mesothelial vs. serous differentiation 1

When interpreting PAX8 results, always consider the entire immunohistochemical profile and morphologic features rather than relying on a single marker.