An Overview of Challenges, Innovations, and Prognostic Grading Mesothelioma

From early detection hurdles to groundbreaking therapies, mesothelioma research continues to evolve in the fight against this aggressive cancer.

Mesothelioma is a rare and aggressive cancer, primarily caused by asbestos exposure, that affects the thin lining of internal organs, most commonly the lungs (pleural mesothelioma). Despite its rarity, with approximately 3,000 cases diagnosed annually in the United States, the disease remains a global threat due to symptom latency, its resistance to treatment, and the poor prognosis that often comes along with diagnosis.

This article explores mesothelioma’s causes, symptoms, and treatment challenges, as well as the latest advancements in grading systems that hold promise for improved patient outcomes.

Comprender el mesotelioma

Mesothelioma typically develops after prolonged exposure to asbestos, a fibrous mineral that was once extensively used in industries such as construction, shipbuilding, automotive parts, and manufacturing due to its durability and heat resistance. When asbestos fibers are inhaled or ingested, they can become lodged in the body’s tissues, particularly in the lining of the lungs, abdomen, or heart, among other organs, triggering a cascade of harmful biological responses. Over time, these fibers cause persistent inflammation and scarring, which can damage healthy cells and lead to the development of malignant tumors.

Mesotelioma most commonly impacts the lungs, although it can also, albeit rarely, appear in the stomach, heart, or testes. The disease is notoriously insidious, with early, nonspecific symptoms that are frequently mistaken for less severe conditions, making early detection and timely treatment exceedingly difficult.

Symptoms and Diagnosis

The symptoms of mesothelioma depend on its location but commonly include chest pain, persistent cough, shortness of breath, unexplained weight loss, and fatigue, regardless of where the cancer originates. Peritoneal mesothelioma, affecting the abdominal lining, may also cause abdominal swelling, nausea, and bowel irregularities. Testicular mesothelioma may cause swelling or a lump in the scrotum, pain, tenderness, or discomfort in this area, fluid buildup or scrotal heaviness. And mesothelioma of the heart, also known as pericardial mesothelioma, can lead to palpitations and fluid buildup in the pericardium, which compresses the heart.

Early diagnosis of the disease is challenging due to the significant latency period that generally exists between exposición al asbesto and symptoms onset. The first signs of mesothelioma are also often misdiagnosed as more benign issues, with the cancer being identified only once it progresses to later stages.

Diagnosis itself can be a complex undertaking, typically requiring imaging studies, tissue biopsies, and biomarker testing. Advanced diagnostic tools, like immunohistochemistry and fluorescence in situ hybridization (FISH), are now used to confirm malignancy and determine its mesothelial origin.

Treatment Resistance and Historical Challenges

Mesothelioma is notoriously resistant to conventional tratamientos, including surgery, chemotherapy, and radiation. Its diffuse growth pattern, late-stage diagnosis, and genomic complexity contribute to poor responses to these more traditional methods for combating cancer.

Because of this, historically, treatment has been largely palliative, aimed at improving quality of life and extending survival times rather than achieving full remission. The median survival time following diagnosis ranges from only 12 to 21 months, depending on factors such as tumor subtype and patient health.

Subtypes and Prognostic Importance

Understanding and accurately classifying mesothelioma into subtypes—epithelioid, biphasic, o sarcomatoid—is essential because these classifications significantly influence how the disease is treated and the patient’s overall outlook. These subtypes refer to the type of cells that make up the tumor, each behaving differently in terms of growth, spread, and response to treatment. Here’s a closer look at each:

  • Epithelioid mesothelioma is the most common subtype, making up more than half of all cases. It is characterized by uniform, cube-shaped cells that tend to clump together, making the disease easier to detect and treat. Patients with this subtype typically have the best prognosis because the cancer cells grow and spread more slowly compared to the other types.
  • Sarcomatoid mesothelioma is a more destructive and less common form. It involves long, spindle-shaped cells that spread quickly and penetrate nearby tissues, making it harder to treat and diagnose early. As a result, this subtype is associated with poor prognoses.
  • Biphasic mesothelioma, as the name suggests, is a mix of both epithelioid and sarcomatoid cells. The ratio of these two cell types within the tumor determines how the disease behaves. If there are more epithelioid cells present, a patient’s prognosis will likely be better; if sarcomatoid cells dominate, the disease tends to be more aggressive, with a poorer outcome.

Proper classification, determined through biopsy and microscopic analysis, is key because it guides treatment plans. For example, epithelioid mesothelioma may respond better to surgery and certain long-standing therapies, while sarcomatoid cases may require more aggressive or alternative treatment approaches. Biphasic mesothelioma, due to its mixed nature, often requires an individualized strategy that considers the proportion of each cell type. By identifying the subtype, doctors can provide patients with more accurate information about what to expect with regards to treatment and survival rates.

Prognostic Implications & Advances in Grading Epithelioid Mesothelioma

For decades, the Tumor, Node, Metastasis (TNM) staging system has been the standard for assessing mesothelioma progression. However, many pathologists have stopped at subtype classification, leaving prognostic grading underutilized despite its potential to refine treatment approaches. In 2012, Kadota et al. introduced a three-tiered nuclear grading system specifically for epithelioid mesothelioma based on two independent factors: nuclear atypia and mitotic count.

  • Nuclear atypia evaluates the size, shape, and irregularity of tumor cell nuclei. A score of 1 indicates mild atypia with uniform nuclei, while a score of 3 reflects severe atypia with significant pleomorphism.
  • Mitotic count assesses the number of dividing cells within a defined area. A higher mitotic activity score signifies more aggressive tumor behavior.

These two parameters are combined into a nuclear grade, and patients were separated into three categories based on this:

  1. Grade 1: Low-grade tumors with mild atypia and low mitotic activity.
  2. Grade 2: Intermediate-grade tumors with moderate atypia and mitotic activity.
  3. Grade 3: High-grade tumors exhibiting severe atypia and high mitotic activity.

The differences in prognosis between grades were significant. Grade 1 tumors had a median survival of over two years, while Grade 3 tumors mirrored the dismal outcomes of sarcomatoid mesothelioma, with a survival of approximately five months.

Validation and Refinement

Subsequent studies validated Kadota’s findings. A 2018 multi-institutional study led by Rosen et al. examined over 750 cases, confirming the survival differences across nuclear grades. The study also highlighted the prognostic impact of tumor necrosis, with necrotic tumors showing substantially worse survival outcomes.

The incorporation of necrosis into grading led to the development of a simplified two-tier system:

  • Low-Grade: Includes Grade 1 tumors and Grade 2 tumors without necrosis.
  • High-Grade: Encompasses Grade 3 tumors and Grade 2 tumors with necrosis.

This two-tier system is now endorsed by the World Health Organization (WHO) and recommended in the College of American Pathologists’ synoptic reports.

Broader Morphologic and Genetic Prognostic Factors

The term “morphologic” refers to the structure and appearance of cells and tissues under a microscope. Examining the morphology of mesothelioma tumors can help doctors predict how the disease might progress. Variations in cell structure and tissue composition occur because of the body’s response to asbestos exposure, tumor evolution, and genetic mutations over time. These differences in appearance, noted below, typically correspond with survival outcomes and how aggressive the disease is:

  1. Solid architecture in epithelioid mesothelioma correlates with poorer prognosis.
  2. Myxoid stroma is associated with better outcomes.
  3. Pleomorphic cytologic features point to a more aggressive course.

Pleomorphic epithelioid mesothelioma, in particular, is now considered a distinct prognostic group with a median survival of only 5.4 months.

Genetic Alterations

Genetic mutations were also found to be influential in considering a patient’s prognosis, as follows:

  • Loss of BRCA1-associated protein 1 (BAP1 for short) expression is linked to improved survival. BPA-1 is a gene that produces a protein involved in regulating cell growth and repairing damaged DNA. In healthy cells, BAP1 acts as a tumor suppressor, helping to prevent uncontrolled cell growth that can lead to cancer. However, in mesothelioma and certain other cancers, mutations in the BAP1 gene can cause the loss of BAP1 protein expression, disrupting normal cell repair processes and potentially contributing to tumor development.
  • Deletions of CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A) or loss of MTAP (Methylthioadenosine Phosphorylase) expression are associated with worse outcomes.

Researchers continue to explore connections between gene alterations and tumor grade, hoping to integrate molecular insights into personalized treatment strategies.

Clinical Implications and Patient Experience

Using the above grading systems provides medical teams with a more nuanced understanding of disease aggressiveness, making it easier to develop individualized treatment plans, which are generally more effective. For instance, patients with low-grade tumors may benefit from aggressive surgical interventions, while high-grade cases might prioritize systemic therapies and palliative care.

Grading also supports clinical trial design by identifying patient subgroups most likely to benefit from newer therapies. Immunotherapy, for example, has shown promise in some mesothelioma cases, particularly when combined with targeted treatments. This approach uses the body’s own immune system to recognize and attack cancer cells. When paired with targeted therapies that focus on specific cell alterations, the combination of approaches can enhance treatment effectiveness.

Finally, for patients and their families, grading offers clarity and helps manage expectations. Understanding the specifics of their disease empowers patients to make informed decisions about next steps.

Challenges and Future Directions

Despite its progress, the grading system for mesothelioma faces several significant challenges that limit its ability to provide consistently accurate information. These challenges stem from both subjective and technical limitations, which can affect the reliability and applicability of the grading system in clinical practice. Efforts to address these issues are ongoing, but the following areas remain particularly problematic:

  1. Interobserver Variability: Pathologists may differ in their assessment of key features such as nuclear atypia or mitotic counts, which are vital in determining the grade of mesothelioma. This subjectivity can lead to inconsistent grading across different institutions or clinicians. To overcome this, efforts to standardize grading criteria, as well as enhance training for pathologists, will be essential.
  2. Applicability to Small Biopsies: Grading mesothelioma using small tissue samples, such as those obtained from needle biopsies, is challenging due to the limited amount of tissue and potential sampling errors. However, recent studies have shown that it is possible to grade these small samples with a reasonable degree of accuracy, suggesting that improvements in biopsy techniques and analysis may make this a more viable option soon enough.
  3. Integration with Molecular Data: While histologic grading is based on the appearance of tumor cells under a microscope, integrating this with gene and molecular insights could provide a more comprehensive and accurate assessment of mesothelioma. However, this is still in the early stages and requires further research.

As the field progresses, advancements in imaging technologies, biomarker testing, and the use of artificial intelligence could help refine the accuracy of mesothelioma grading as well. These technologies have the potential to enhance the clinical usability of grading systems, ultimately offering more precise and individualized treatment strategies.

Going Forward

Mesothelioma, though rare, presents immense challenges due to its treatment resistance and poor prognosis. Recent advancements in grading systems, particularly for epithelioid mesothelioma, have transformed projections and opened new avenues for personalized care. The two-tier system using tumor grade and necrosis provides a practical tool for clinicians, empowering better treatment decisions and improving patient outcomes. Continued research, however, is likely to further enhance the medical field’s understanding of this complex disease.

For patients, families, and healthcare providers, continuing to innovate and refine diagnostic tools and prognosis strategies is essential. As grading systems evolve, they offer hope for better outcomes and a clearer path forward. These scientific advancements may one day reduce the number of mesothelioma fatalities, transitioning the disease from highly aggressive to more aligned with less invasive cancers.

If you or a loved one is battling mesothelioma, consider discussing with your physician the possibility of reaching out to specialists who are leading advancements in personalized care and treatment.