Malignant Mesothelioma: Diagnosis, Subtypes, and Challenges

The Complexity of Diagnosing Mesothelioma

For years, mesothelioma has been notoriously difficult to diagnose, often requiring extensive testing, imaging, and biopsy confirmation. Historically, some experts even believed an accurate diagnosis was only possible post-mortem. While this extreme view is no longer widely accepted, there are still many diagnostic pitfalls that make mesothelioma a challenging disease to identify and classify.

Even among experienced pathologists, interobserver disagreement in diagnosing mesothelioma is common—especially when dealing with small biopsy samples like closed needle biopsies. Because mesothelioma can mimic other conditions and has several histological subtypes, getting a precise diagnosis requires a combination of clinical, radiological, and histopathological data.

Mesothelioma Subtypes and Their Challenges

Mesothelioma isn’t just one disease—it’s classified into three main histological subtypes:

1. Epithelioid Mesothelioma – The most common form (around 60% of cases).
2. Biphasic Mesothelioma – A mix of epithelioid and sarcomatoid cells (about 30% of cases).
3. Sarcomatoid Mesothelioma – The least common but most aggressive form (roughly 10% of cases).

Each subtype behaves differently, making proper classification crucial. But here’s the problem: subtyping isn’t always straightforward due to sampling limitations and tumor heterogeneity.

Difficulties in Subclassifying Mesothelioma

Pathologists face several challenges when subclassifying mesothelioma, including:

• Poorly Differentiated Tumors:
  Some epithelioid mesotheliomas can appear poorly differentiated, making them hard to distinguish from sarcomatoid mesotheliomas. This can impact prognosis, as sarcomatoid mesotheliomas tend to be more aggressive.

• Fibroblastic Stroma Mimicking a Biphasic Tumor:
  A purely epithelioid tumor may show extensive fibroblastic (scar-like) tissue, making it appear biphasic. However, this might not represent a true sarcomatoid component, leading to misclassification.

• Sampling Limitations:

  • Small biopsy samples may miss key tumor components, leading to misdiagnosis.
  • Pleural fluid cytology might only detect epithelioid cells in biphasic tumors, missing the sarcomatoid component entirely.

Key Takeaway: A small sample may not be representative of the entire tumor, leading to discrepancies in diagnosis between thin core biopsies, open biopsies, and fluid cytology.

Why Subtyping Matters (Even When Prognosis is Poor)

At first glance, subtyping mesothelioma might seem unnecessary because all forms have a poor prognosis. However, there are important differences in survival rates and treatment responses based on histology:

While all mesotheliomas are aggressive, sarcomatoid tumors tend to be more resistant to treatment, while epithelioid tumors have slightly better outcomes. Most long-term survivors (beyond 2 years) have epithelioid or biphasic tumors.

Sarcomatoid Mesothelioma: The Most Aggressive Form

• Lowest survival rate of all subtypes.
• More resistant to chemotherapy and radiation.
• Frequently misdiagnosed due to its similarity to other spindle-cell tumors.
• Often underrepresented in pleural fluid cytology, making it harder to detect early.

Because of these differences, some oncologists adjust treatment plans based on histology. Sarcomatoid cases may not benefit from standard therapies, while epithelioid tumors might respond better to immunotherapy or multimodal treatment.

Mesothelioma and Emerging Research on Treatment Response

Lately, researchers have been exploring whether different subtypes respond differently to treatment. But diagnostic challenges—like sampling limitations and interobserver variability—complicate these studies.

For example:

• A study on chemotherapy response may underestimate the effectiveness for biphasic tumors if the sarcomatoid component was missed in initial diagnosis.
• Immunotherapy trials may show inconsistent results if tumor heterogeneity isn’t accounted for.

To improve accuracy, many studies now require biopsies to be re-examined by multiple pathologists or confirmed with molecular markers.

Key Takeaway: Research on mesothelioma treatment must consider diagnostic limitations to avoid inaccurate conclusions.

Recognizing Mesothelioma’s Growth Patterns

Because mesothelioma exhibits diverse growth patterns, it is often mistaken for other cancers or benign conditions. Some growth patterns to watch for include:

1. Tubulopapillary Pattern

   • Often confused with lung adenocarcinoma.
   • Requires immunohistochemical staining to differentiate.

2. Desmoplastic Pattern

   • Can mimic benign fibrous pleuritis, leading to misdiagnosis.
   • Requires evidence of invasion for confirmation.

3. Sarcomatoid Pattern

   • Resembles spindle-cell sarcomas or reactive fibroblastic processes.
   • Often misdiagnosed without specialized staining techniques.

These growth patterns overlap with other diseases, making differential diagnosis essential.

How Pathologists Confirm Mesothelioma

Given the challenges in diagnosis, pathologists rely on multiple techniques:

• Immunohistochemistry (IHC) – Key markers include:

  • Calretinin, WT-1, and CK5/6 (positive in mesothelioma).
  • CEA, TTF-1, and Ber-EP4 (negative in mesothelioma but positive in adenocarcinoma).

• Electron Microscopy (EM) – Used in rare cases to look for long microvilli, a hallmark of mesothelioma.

• Molecular Testing – BAP1 loss and CDKN2A deletion can help confirm the diagnosis.

Together, these methods increase diagnostic accuracy and help differentiate mesothelioma from lung cancer or benign pleural conditions.

The Future of Mesothelioma Diagnosis

With new advances in biomarker research, imaging techniques, and AI-assisted pathology, mesothelioma diagnosis and classification may improve significantly in the coming years.

Some exciting developments include:

• Liquid biopsies to detect mesothelioma earlier.
• Artificial intelligence (AI) tools for more consistent pathology interpretations.
• Personalized treatment plans based on genetic profiling.

While mesothelioma remains challenging to diagnose, these advancements offer hope for earlier detection and better treatment options.

Final Thoughts

• Mesothelioma is difficult to diagnose, with interobserver disagreement common.
• There are three main subtypes—epithelioid, biphasic, and sarcomatoid—with different prognoses.
• Small biopsies may not capture the full tumor, leading to misclassification.
• Sarcomatoid mesothelioma is the most aggressive and hardest to diagnose.
• Pathologists use immunohistochemistry, electron microscopy, and molecular testing to confirm diagnoses.
• Future research will improve diagnostic accuracy and personalized treatment options.

Key Takeaway: Mesothelioma remains one of the most challenging cancers to diagnose, but ongoing research and improved diagnostic tools are helping unravel its complexity. The better we understand mesothelioma at the histological level, the better we can tailor treatments for improved outcomes.