Getting the Right Diagnosis: Pathology and Biomarkers

Getting an accurate diagnosis for Malignant Peritoneal Mesothelioma (MPM) is a complex process. Because it is so rare, it is frequently misdiagnosed as other abdominal cancers, most commonly peritoneal carcinomatosis (cancer that has spread to the abdomen from the colon, stomach, or ovaries) ^[1]. To ensure you have the correct diagnosis, your pathology report must show a specific pattern of markers and follow the most recent international standards.

The Immunohistochemical (IHC) Panel

Pathologists use a technique called immunohistochemistry (IHC) to “stain” your biopsy samples. This helps them identify specific proteins (markers) on the surface or inside the cells. A “complete” diagnosis usually requires at least two positive markers for mesothelioma and two negative markers (which would be positive in other cancers) ^[1].

• Standard Positive Markers (The “Yes” List): These markers are usually present in MPM cells.
  • Calretinin: The most sensitive marker for mesothelioma.
  • WT1 (Wilms Tumor 1): Often found in mesothelioma.
  • CK5/6 (Cytokeratin 5/6): Frequently positive in the epithelioid subtype.
• Standard Negative Markers (The “No” List): If these are positive, the cancer is likely not mesothelioma but something else (like colon or lung cancer).
  • MOC-31 and CEA (Carcinoembryonic Antigen).
  • Claudin-4: A very strong marker for distinguishing other cancers from mesothelioma ^[1].

The Role of BAP1, CDKN2A, and Genetic Testing

Two critical genetic markers often appear on a pathology report: BAP1 and CDKN2A (p16).

1. Diagnostic Role of BAP1: When a pathologist sees a loss of BAP1 nuclear expression on your IHC report, it is a very strong indicator for a malignant diagnosis rather than a benign (non-cancerous) reaction ^[1].
2. Somatic vs. Germline: It is incredibly important not to panic if you see a “BAP1 loss.” In about 50% of cases, this mutation is somatic—meaning it only exists inside the tumor cells and was acquired over time ^[1]. However, about 7% of MPM patients have a germline BAP1 mutation, meaning the mutation was inherited and is present in every cell of their body ^[1]. A genetic counselor can help arrange a blood or saliva test to determine which type you have.
3. CDKN2A (p16): This is another gene often evaluated. If the pathology report shows a deletion or loss of CDKN2A (often measured by a protein called p16), it confirms malignancy and generally indicates a more aggressive tumor behavior ^[1]. Around 23% of cases have alterations in this gene ^[1].

Important 2021 WHO Updates

In 2021, the World Health Organization (WHO) updated how these tumors are named to help doctors choose better treatments.

• Well-Differentiated Papillary Mesothelial Tumor (WDPMT): Formerly called “mesothelioma,” this was renamed to “tumor” because it is usually slow-growing (indolent) and does not typically spread like malignant mesothelioma ^[1].
• Mesothelioma in situ (MIS): This is a newly recognized “pre-cancerous” state where the cancer is only on the very surface of the peritoneum. It is rare and requires careful monitoring ^[1].

Your Diagnosis Checklist

Before starting treatment, ensure your pathology report or doctor has addressed the following:

• [ ] Was a full IHC panel performed (including at least 2 positive and 2 negative markers)?
• [ ] Did the report specifically mention BAP1 or CDKN2A (p16) status? ^[1]
• [ ] Does the report use the 2021 WHO terminology to clearly state if the tumor is malignant?
• [ ] Have you been offered a referral for genetic counseling to clarify your BAP1 status? ^[1]