Latest Treatment of Diffuse Pleural Mesothelioma
Mesothelioma is still a challenging diagnosis, but advances in knowledge and treatment have improved outcomes and life quality.
Mesothelioma is a rare but aggressive cancer that affects the thin layers of tissue lining different parts of the body – most often, the lungs, but it can also originate in the abdomen, heart, or testicles. Mesothelioma development is linked to breathing in asbestos fibers—a toxic mineral once commonly sought after in various industries due to its strength, durability, and heat resistance. Microscopic asbestos fibers can get stuck in the body, causing damage over many years that eventually leads to malignancy. Despite progress in understanding this disease, it’s still very difficult to diagnose early, treat effectively, or predict how it will develop in different people.
This article will take a closer look at how asbestos exposure leads to mesothelioma, along with other possible, yet less common, causes. It also explores what happens inside the body at a cellular level, how doctors study and classify the disease, and what treatments are currently available, as well as those still emerging. For mesothelioma patients and their families, it’s important to stay well-informed about all aspects of the disease in order to remain diligent in the fight against its progression.
Globally, mesothelioma accounts for approximately 30,000 new cases annually, with the majority involving pleural mesothelioma (that which originates in the lungs). Historically, the industrial boom of the 19th and 20th centuries drove widespread asbestos use in construction, automotive manufacturing, textiles, shipbuilding, and other sectors. Asbestos fibers, prized for their incredible tinsel strength, ability to withstand high temperatures, and relative inexpensiveness (asbestos can be found abundantly in the natural world), became pervasive in all sorts of infrastructure, military artillery, and household products during that time. Tragically, however, health risks resulting from exposure were ignored for a number of years, leading to significant damage.
Understanding exactly what asbestos is
Asbestos fibers are categorized into two groups: amphibole (e.g., amosite and crocidolite) and serpentine (e.g., chrysotile). Crocidolite, the most carcinogenic type, poses a particularly grave risk due to its long, thin fibers that readily embed in lung tissue. Chrysotile, though less carcinogenic, remains the most widely used globally, and thus, has led to a large number of asbestos disease cases.
For decades, workers in high-risk industries came into direct contact with the substance, as did their loved ones who lived with residential asbestos as well as came into contact with fibers carried home. It is now known that secondary (or secondhand) asbestos exposure is just as deadly as direct, firsthand contact, causing health complications like cancer, asbestosis, and severe respiratory illnesses.
Mesothelioma disproportionately affects men, largely due to occupational exposure in male-dominated industries. However, the number of mesothelioma cases in women has gradually increased over the years—as have ovarian and lung cancer cases—which researchers attribute to secondhand and domestic exposure.
The Pathophysiology of Mesothelioma
Mesothelioma’s long latency period, typically spanning 20–40 years, reflects the chronic processes underlying its development. Upon inhalation or ingestion, asbestos fibers become lodged in mesothelial tissues (where the disease gets its name), both inflicting mechanical damage and inducing oxidative stress. This triggers inflammation, characterized by macrophages attempting to phagocytize the fibers. The process releases tumor necrosis factor-alpha (TNF-α), which binds to mesothelial cells and activates the nuclear factor κB (NF-κB) pathway, promoting cell survival while causing tumorigenic DNA damage.
Latency: Asbestos Diseases usually take a long time to appear.
Over time, asbestos-induced cellular damage disrupts normal DNA repair, leading to mutations in key tumor suppressor genes such as CDKN2A, NF2, and BAP1. These genetic alterations then led to unregulated cell growth, enabling mesothelial cells to evade apoptosis, or programmed cell death activated internally to protect the body against malignancies. This then results in an increase in inflammation, resulting in the rapid progression from localized tissue damage to aggressive, invasive tumors.
Beyond Asbestos: Other Factors that Can Influence Mesothelioma Development
While asbestos remains the primary culprit for the onset of mesothelioma, other environmental and occupational exposures have also been implicated in its development, including:
Erionite: A naturally occurring zeolite mineral, erionite has been linked to cancerous clusters, particularly in the Cappadocia region of Turkey. Its fibers are actually more carcinogenic than those of asbestos.
Fluoro-edenite: This volcanic mineral has been associated with mesothelioma outbreaks in parts of Italy.
Radiation: Therapeutic or occupational exposure to ionizing radiation has been implicated in mesothelioma cases, particularly in individuals with predisposing genetic factors that undergo this treatment.
Chronic Inflammation: Chronic inflammation of the thin, smooth membrane that covers and protects internal organs, known as the “serosal,” may lead to tumor development. This is generally a result of long-standing infections, autoimmune conditions, or foreign bodies that make their way inside the body.
Simian Virus 40 (SV40): Once suspected of contributing to mesothelioma due to contaminated polio vaccines, SV40’s role remains controversial, with no conclusive evidence from genomic studies, but researchers have suspected that it could also be a contributor.
Mesothelioma Classification Systems
Modern mesothelioma classification systems integrate histologic, architectural, and molecular findings in order to pinpoint and refine diagnosis as well as predict the disease’s progression. This allows medical teams to offer patients a more accurate prognosis. These updates rely on the disease’s diverse presentation, introducing nuanced categories to guide treatment strategies. Two common classification types are:
Diffuse Pleural Mesothelioma (DPM): The most common type, DPM is characterized by diffuse tumor growth across the pleural surface.
Localized Pleural Mesothelioma: A rarer form, confined to discrete pleural regions.
DPM is further broken down into three subtypes:
Epithelioid Mesothelioma: The most common and subtype that also carries the best prognosis, exhibiting patterns such as tubulopapillary and trabecular.
Sarcomatoid Mesothelioma: The most aggressive subtype that includes a spindled structure and high cell division activity.
Biphasic Mesothelioma: A mix of epithelioid and sarcomatoid components, with outcomes influenced by the proportions of each.
Recent advances in molecular profiling have identified the genetic underpinnings of these subtypes, revealing distinct pathways that shape their clinical behavior. Thus, understanding the exact makeup of each disease case can help doctors determine what a patient can expect moving forward.
The Role of Gene Activity in Cancer Development
The inactivation of tumor suppressor genes is a key component of mesothelioma, driving detection avoidance and unchecked proliferation throughout the body. Key genes include:
CDKN2A: CDKN2A encodes two critical proteins: p16INK4a, which inhibits CDK4/6 to enforce cell cycle arrest, and p14ARF, which stabilizes p53 to promote apoptosis. Loss of CDKN2A disrupts these pathways, leading to aggressive tumors. Homozygous deletions of CDKN2A occur in 70% of DPM cases, particularly in sarcomatoid subtypes.
NF2 (Merlin): NF2 mutations occur in approximately 40% of mesothelioma cases, especially in non-epithelioid subtypes. Loss of NF2 disrupts Hippo pathway signaling, which regulates cell growth, organ size, and tissue development, enabling the oncogenic transcriptional coactivators YAP/TAZ to drive tumor progression.
SETD2: SETD2 mutations, though less common, impair histone methylation and genomic stability. This contributes to tumor heterogeneity and resistance to DNA-damaging therapies.
In addition to genetic mutations, epigenetic changes such as DNA methylation and histone changes further dysregulate gene expression in mesothelioma.
Tailored Treatment Options
Mesothelioma is notoriously hard to diagnose because of its characteristics at the tissue and molecular levels. This means doctors need special tools and tests, like advanced imaging (scans) and molecular markers, to figure out the exact type and stage of the cancer. These tests help doctors understand how far the cancer has spread and which specific type of mesothelioma it is. As we’ve seen, the outlook for someone with mesothelioma can also be very different depending on the type of cancer. Understanding these differences is important for doctors to give the best treatment plan and help with predicting the patient’s future health.
Some traditional treatment approaches include:
Surgery: Extra pleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) can attempt to remove tumors, though success is limited to only earlier stages of the disease.
Chemotherapy: Platinum-based treatments, usually combined with another drug called pemetrexed, are the main approaches used for treating mesothelioma from a medicinal standpoint.
Immunotherapy: Checkpoint inhibitors targeting PD-1/PD-L1 have shown promise, particularly in cases where the cancer does not respond to more common treatments.
Targeted Therapy: Emerging treatments focus on using molecular vulnerabilities, such as CDKN2A loss or YAP/TAZ activation, to treat the disease.
The Broader Impact of Mesothelioma: Public Health and Advocacy
The ongoing burden of the aftereffects of asbestos exposure and mesothelioma development calls for continued asbestos regulation and exposure prevention. While many countries have banned its use in industry, the legacy of asbestos unfortunately persists in aging infrastructure and environmental contamination and isn’t an issue that’s likely to go away anytime soon. Public health initiatives must prioritize:
Asbestos Abatement: Safely removing asbestos from homes, schools, and workplaces. This means letting only professional, certified abatement contractors test for asbestos and perform removal, rather than attempting to do so without proper equipment and support.
Global Bans: Pushing for comprehensive asbestos bans in all countries around the world.
Survivor Support: Expanding resources for mesothelioma patients and their families.
Efforts to improve public awareness of the dangers of asbestos, especially in regions where regulation and enforcement remain inadequate, will be key to both identifying asbestos-related diseases at an earlier, more treatable, stage as well as preventing the development of these diseases moving forward. Strengthening research into the early detection and effective treatment of mesothelioma csan also improve patient outcomes, while supporting better preventive measures for future generations.
One thing remains painfully clear: The fight against mesothelioma extends well beyond the clinic, calling for policymakers, industry leaders, and communities to prioritize health and safety while investing in prevention, research, and advocacy. By addressing both the legacy of past exposure and preventing future risks, we can move closer to minimizing the impact of asbestos on public health, and ultimately reduce the number of mesothelioma cases globally.