Mesothelioma is an abnormal cancerous growth in the respiratory, abdominal, heart, or the testicular lining. The name ‘mesothelioma’ stems from the fact that cancer arises in the mesothelium of the body, i.e., a thin, protective lining of several organs in the body.
Cancer lays dormant in the lining, sometimes for decades, without any evident signs or symptoms. It is more like a time-bomb in a person’s body that is waiting to explode. Therefore, the survival time after the diagnosis is usually twelve months, even less in most of the cases1. However, disease progression can be retarded by radiation, chemotherapy, and surgical treatment. Mesothelioma is found to have a deep root connection with long-term asbestos exposure.
How Asbestos Exposure Occurs?
Exposure to asbestos can occur without a person knowing it2. Various possible causes of exposure are found. These can be:
· Occupational Exposure
Many types of asbestos fibers have a carcinogenic effect on the body. Its long-term inhalation results in mesothelioma formation that manifests its symptoms approximately after 20-50 years3. This lethal disease has some additional triggering factors. These factors, along with chronic asbestos exposure, result in mesothelioma. They are:
- Repeated ionizing radiations
- Chronic inflammatory disease
· Para-Occupational Asbestos Exposure
It is defined as an indirect exposure to asbestos that occurs by coming in contact with “directly-exposed” asbestos factory workers. Those who do laundering of these workers’ clothing are almost equally exposed to asbestos. After 20 years, the family members of asbestos workers are often found to have asbestos toxicity as well.
· Residential Exposure to Asbestos
This type of exposure occurs from the non-occupational environment. The probable sources for this exposure are:
- Neighborhood asbestos factory fumes
- Household materials such as amosite roof insulations or gardening equipment
- Living with asbestos workers with fiber residues on their clothing
- Other Potential Substances Causing Mesothelioma
Besides asbestos, there is a chance that several other substances may contribute to mesothelioma formation. The cause of mesothelioma is solely attributed to asbestos exposure. However, not all individuals are exposed to asbestos, and the other unassessed, naturally occurring carcinogenic fibers like erionite can also cause mesothelioma4. These are:
It is a fiber that is identical to asbestos and is found in the area around volcanoes. It has a carcinogenic potential to cause mesothelioma but with lesser incidence than asbestos itself.
- Ionizing Radiations
These are the radiations normally found in a nuclear plant. The nuclear plant workers with long-term exposure to ionizing radiation can develop mesothelioma. However, the incidence of this factor is still lower as compared to asbestos exposure.
- Chronic Inflammatory Diseases
These include the inflammatory diseases of the respiratory tract, abdominal, and heart lining. This is due to the excessive production of cytokines and inflammatory mediators that promote cancer formation. These play a critical role in the tumorigenesis induced by asbestos and other carcinogenic fibers. The deposition of both human mesothelial (HM) cells and macrophages, together with the fibers, allow some of the HM cells to avoid cell death and ultimately go through an oncogenic transformation.
- Carbon Nodules
There are many synthetic fibrous analogs of asbestos. Carbon nanotubes are one example of such fibers. Once these are inhaled, they reach the respiratory pleura and irritate it. This may give rise to mesothelioma in the lungs (called pleural mesothelioma).
Pathogenesis of Mesothelioma
Mesotheliomas can be grouped into benign and malignant types. Although some are called benign, these tumors have high chances for local recurrence after surgery. In rare cases, the benign mesotheliomas undergo malignant transformation. When an asbestos particle is inhaled, it reaches the lining of the lungs and causes irritation. This provokes the body’s defenders called phagocytes. The cell signaling pathway is disturbed, and the release of free radicals and alarmins occurs inside the body. There is an up-regulation of genes that enhance malignant cell growth. The tumor-suppressing pathways are obstructed due to the mutation in tumor-suppressing genes by asbestos particles. In sporadic mesothelioma, a mutation in the BAP1 gene is common. These gene deletions are also made on the mesothelium of the lung, converting it into pleural mesothelioma.
Better to Screen and Diagnose Early
A highly specific test is needed to screen and detect asbestos-exposed cases as early as possible. Therefore, scientists are trying to find out specific biomarkers in the blood to detect high-risk cases for mesothelioma. It is best to detect malignant mesothelioma at an early stage to achieve a good prognosis. Hence, combinations of several biomarkers are being experimented upon the exposed cases to distinguish whether they have dormant mesothelioma or are just an exposed case. Still, if screening turns out asbestos positive, it does not guarantee mesothelioma formation in the future.
Classification of Mesothelioma Based on its Location
There are four types of mesothelioma based on their location in the body. These are:
- Pleural Mesothelioma
It accounts for 75% of the total mesothelioma cases. It is developed in the pleural membrane of the lungs.
- Peritoneal Mesothelioma
It develops in the abdominal peritoneum. It accounts for less than 20% of the cases. Its best treatment is a combination therapy of chemotherapy and surgery. Its symptoms include abdominal pain, nausea, unexplained weight loss, and abdominal swelling.
- Pericardial Mesothelioma
It is developed around the soft tissues of the heart. It contributes to 1% of the total cases of mesothelioma. Its symptoms include breathing difficulty and chest pain.
- Testicular Mesothelioma
This type of mesothelioma responds efficiently to the surgical treatment method. It contributes to less than 1% of all mesothelioma cases. Its symptoms include swelling or the formation of mass on the testicles.
Histopathological Types of Malignant Mesothelioma
There are many types of mesothelioma discovered to date. All these mesotheliomas are differentiated on the bases of their histological features. These are:
· Diffuse Epithelioid Malignant Mesothelioma
It is rather difficult to diagnose this diffused type of mesothelioma. It needs good quality diagnostic techniques for its accurate identification. The distinguishing features of this type are:
- Sheets of large atypical epithelioid cells
- Giant cells
· Diffuse Sarcomatoid Malignant Mesothelioma
The distinguishing features of this type are:
- Bundles of fibroblasts (a type of connective tissue)
- Long, needle-like cells (called spindle cells) proliferation
· Diffuse Desmoplastic Malignant Mesothelioma
Its distinguishing features are:
- Degeneration of normal structure of the supportive tissue
- Invasion of spindle cells in fat tissue
· Peritoneal Malignant Mesothelioma
Its distinguishing feature is tube-like cancerous cells (tubulopapillary epithelioid)
· Localized Malignant Mesothelioma
Its distinguishing features are:
- A single, localized mass with a clear outer membrane
- Attachment of tumor to the tissue via a stalk (pedunculated or sessile attachment of mass to the serosa)
· Well-Differentiated Papillary Mesothelioma
Its distinguishing features are:
- Multiple thin-walled cysts
- Cysts are lined by a layer of flattened mesothelial cells
- The cystic lining is well-differentiated
Cytology of Malignant Mesothelioma
The most definite symptom of mesothelioma is serosal effusions. The serosa is a membrane made up of smooth tissue that layers the body cavities. These effusions are taken as a sample and investigated for their cytology (cell study). The sensitivity of cytological investigation is usually 30-75%. Since the diagnosis of diffuse mesothelioma is solely dependent upon its cellular architecture, a deep cytological study is needed for accurate determination.
Biomarkers of Mesothelioma
Recently, many innovative immunohistochemical markers have indeed enhanced the veracity of the mesothelioma diagnosis, but still, about 14% to 50% of the diagnoses are false, causing inappropriate treatments and confusion5. The biochemical markers can be divided into:
· Histological Biomarkers
- Glucose Transporter 1 (GLUT 1)
It works as a carrier for the transport of the glucose molecule. It is highly specific to mark pleural mesothelioma, but its sensitivity is less. A positive GLUT-1 assay suggests that malignancy is present.
- Wilm’s Tumor-1 Protein (WT1)
This is a tumor suppressor gene that is over-expressed during organ development and in solid tumors such as in malignant mesothelioma. It is called the negative factor for the prognosis of malignant peritoneal mesothelioma.
- Tumor-protein p53
It is a gene that suppresses the tumor during its developmental stage. Its deposition in the tumor cells indicates a malignant condition. Still, it is not that specific.
It is made up of homo-polymers that bind myofibrils to one another and the plasma membrane. It is said to be a muscle-specific intermediate filament. It is highly specific for marking benign tumors but less specific for malignant mesothelioma.
- Epithelial Membrane Antigen (EMA)
It is a mucin-protein that is bound to the mucous barrier of the epithelial membrane. It contributes to intra-cell signaling and is highly specific for malignancy. Since it is also over-expressed in mesothelial hyperplasia, its use is not that advantageous nowadays.
- Insulin-like Growth Factor II Messenger RNA-binding Protein 3 (IMP-3)
It is an oncofetal protein because of its increased presence in the fetal tissues. It is also over-expressed in several carcinomas with a hundred percent specificity for malignant pleural Mesothelioma.
· Emerging Tissue Biomarkers
- BRCA associated Protein 1 (BAP-1)
It is a protein that targets the transcriptional co-factor of host cell factor-1 and histones. It manages the formation of glucose, cell cycle, and apoptosis.
It inhibits the kinase enzyme via cyclin. It suppresses the tumor and is mutated in the malignant areas.
· Soluble Biomarkers
It is a glycoprotein in nature. It anchors the surface of the cell via glycosyl-phosphatidyl-inositol. Its level increases in mesothelioma.
- Soluble Mesothelin Related Peptides (SMRP)
It is an FDA-approved biomarker for the prognosis and diagnosis of tumors. It increases the level of interleukin-6 and mesothelin. MESOMARK assay is a monitoring device for Mesothelioma.
It is a biomarker for the presence of malignant mesothelioma.
It is a cell-adhesion glycoprotein and an excellent biomarker of malignant mesothelioma. Its presence is elevated in patients with high asbestos exposure.
· Tissue Biomarkers
- Calretinin (CR)
It is a protein that binds calcium to the EF-hand family. It is the best biomarker to differentiate malignant mesothelioma from the adenocarcinoma of the lungs. It can easily diagnose epithelioid malignant mesothelioma type.
- Cytokeratin 5 (CK 5)
These are the intermediate filaments found in the epithelial and mesothelial cells. Their presence is detectable in malignant mesothelioma as well as in the squamous cell carcinoma. Hence, it is not as specific as calretinin.
- Podoplanin (PDP)
It is sialoglycoprotein that is expressed in the podocytes of mesothelial and epithelial cells. It helps to differentiate between pleural mesothelioma and adenocarcinoma.
Staging of Mesothelioma
The stages of mesothelioma are based on the size of the tumorous mass and its location in the body. There are a total of four stages of mesothelioma. These are:
· Stage 1
The tumor is localized at this stage. It is the best stage for surgical removal of the tumor. The prognosis and life expectancy are about 22 months. Hence, the chances for survival are greatest in stage 1.
- Stage 2
At this stage, the tumor detaches from its local position and spreads into the nearby tissues. The option for surgery in this stage is still open. The longevity at this stage is about 20 months.
- Stage 3
In this stage, cancer spreads to the nearby lymph nodes. In selected circumstances, surgery can be performed. The longevity is about 17 months here.
- Stage 4
This is an advanced stage tumor depicting that cancer has reached distant organs. Symptomatic relief can be provided by chemotherapy and radiation.
Diagnostic Radiology of Mesothelioma
Diagnostic radiology uses computer software for quantitative data analysis of the provided image data. Several modalities for the analysis of mesothelioma are discussed below:
· Chest Radiography
It is a good start for the evaluation of malignant conditions such as mesothelioma. Being two-dimensional, it is neither a specific nor sensitive test. Limitations are there in this testing modality. Many anatomical structures are overlapping with one another. This limits the visibility of the involvement of critical areas by the malignant mesothelioma. Due to this, secondary signs are used to detect malignancy. These signs include:
- One-sided pleural effusion
- A shift of mediastinum towards the affected area
- Diffused lobulated thickening of pleura
- Asymmetric loss of lung volume
§ Computed Tomography
CT scan gives a series of trans-axial images of the involved structure. It is far superior to a chest x-ray. An iodinated contrast agent is injected intravenously to the patient. This enhances the heavily vascularized soft tissue to differentiate from the surrounding structures. Likewise, a dynamic contrast-enhanced CT (DCE-CT) allows the capturing of physiological data about the flow of blood.
· Magnetic Resonance Imaging (MRI)
MRI is used to analyze biological mechanisms. It uses a pulsed sequence method to capture images on the cellular level. It detects those soft tissues that are beyond CT to scan. Hence, this analytical technique is best for the clinical analysis of mesothelioma. An MRI can also be utilized in detecting secondary findings that are linked with the invasion of the tumor, hence, excluding the benign lesion involvement.
· Positron Emission Tomography (PET) Scan
In the PET Scan, the metabolic activity is detected in the form of functional images. These images are provided by a radiotracer called as Fluorine-18 labeled 2-deoxyglucose (FDG). It also specifies the stage of the tumor. The basic role of PET scan in mesothelioma investigation is to provide the extent of involvement of the tumor into the surrounding structures.
The World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) introduced a tumor measurement method. These include:
- Choosing 3 CT scan sections in which the cancerous mass is most visible
- Encircling two specific areas within these three sections
- Measuring the thickness in these selected areas which further includes:
- Selection of the outer margin of the tumor to initiate measurement within these sections
- Finding out the direction that gives the most accurate dimension of the mass
- Selection of the inner margin of the tumor
- Measuring out the distance between the outer and the inner margin
Nutrition Management during Radiation Therapy
Maintenance of nutritional balance is of vital importance for radiation treatment therapy. The patients undergoing radiation therapy often feel pain and nausea. During radiation, the oncology team will help the patient to consume calories if they have a hard time eating. They encourage the patient to consume a healthy, nutritious diet. A nutritious protein-rich diet is beneficial for wound healing. The team will also make sure that the patient does not have any stress, especially during the treatment procedure.
Mesothelioma is a highly symptomatic disease. Five symptoms are common among most of the patients. These symptoms are:
The treatment of these symptoms is included in the overall treatment plan. Therefore, the symptomatic management of mesothelioma in the patients is given below:
· Uncontrollable Cough
The patients usually experience an uncontrollable cough, which can further irritate the respiratory tract lining. This cough can also be linked with dyspnea, pain, and nausea. It is seen in many patients that the progression of mesothelioma results in the damage of the surrounding nerves, bronchioles, and pleura, which induces cough. It is important to order a detailed workup that covers the drugs for cough management as well. The effusion from the pleura is also the reason for this recurrent cough. If the cough remains persistent, surgical intervention can be opted to clear the pleural effusion. The drugs indicated for cough management are:
To soothe the sensitized nerves, a centrally acting drug with the antitussive effect is prescribed by the doctors.
- The most suitable one is gabapentin.
- Drugs like amitriptyline, paroxetine, and benzodiazepines also have antitussive effects.
- Benzonatate is a peripherally acting antitussive drug that anesthetizes stretch receptors in the lungs. This causes relief to the patients.
- The anticholinergic drug, such as scopolamine, is also an effective antitussive.
- Opioid drugs include morphine, codeine, and dextromethorphan. These are strong antitussives with a strong anesthetic effect.
· Shortness of Breath
It is commonly observed in progressive mesothelioma that the patient experiences shortness of breath or dyspnea due to restrictive lungs and pleural effusion. These patients are unable to take deep breaths. This symptom of malignant mesothelioma is treated just like all any other malignant disease condition. A supplementary source of oxygen is provided to the patient for the treatment of hypoxia. Some patients with even normal oxygen concentrations do complain about shortness of breath. For such patients, the overall ventilation of the room is improved either by opening up the window or turning on the fan.
One of the greatest handicapping symptoms of mesothelioma is cancer-related fatigue (CRF). It is the most under-assessed symptom of malignancy. Various etiologies of fatigue can be found in patients. These are:
- Shortness of breath
- Simultaneous psychological disease
- Abnormal eating pattern
- Abnormal sleeping pattern
- Uncontrollable pain
- Systemic chemo-radiation-therapy
Medications for CRF are:
- Opioid drugs for pain management
- Open ventilation system for dyspnea patients
- Anxiolytics for depression and anxiety management
- Anti-psychotics for psychiatric condition management
- Psycho-stimulatory drugs such as methylphenidate and modafinil
- Corticosteroids for inflammatory conditions
- Anti-emetics for nausea reduction
Also, frequent motivational counseling sessions are the obligatory needs of all cancer patients.
Treatment of Mesothelioma
Different types of surgeries are performed depending upon the type of mesothelioma. Patients with pleural mesothelioma undergo extrapleural pneumonectomy (EPP). In this surgery, the lining of the lungs and the surrounding nearby areas are removed. This has proven to be very effective in pleural and peritoneal mesothelioma. However, it is to be noted that not every mesothelioma patient qualifies for the surgery. There are certain criteria and protocols for that such as:
- The health, in general, is great
- The spread of mesothelioma is not too far
- The lungs and heart are working properly
- The mesothelioma type is not a sarcomatoid cell type
This therapy treats mesothelioma in two ways. These are:
- Inhibiting the tumor growth
- Symptoms reduction
The chemotherapy is not a cure, but it can relieve the symptoms and ease the life a bit. The major drugs used in the treatment are:
· Radiation Therapy
It is the type of non- invasive therapy in which high energy particles are thrown onto the body of the patients. Care is taken by the radiation therapist to direct the rays onto the affected area without exposing it to healthy areas. Advantages of radiation therapy are as under:
- It prevents seeding by irradiating the cancerous area along with the site of the surgical incision.
- It relieves pain by shrinking the tumor and thus releasing the pressure inside the lungs
- It improves the prognosis by combining the surgical technique, chemotherapy and radiation therapy
Types of Radiation Therapies are:
- External Beam Radiation Therapy
Targeted Therapies in Malignant Pleural Mesothelioma
Malignant pleural mesothelioma (MPM) is considered one of the most lethal tumors with the poorest prognosis. It is due to its chemo-resistant nature. The asbestos belongs to either the serpentine or amphibole group, so the risk to develop MPM appears highest when exposed to amphiboles (Emilye, Raymond & Andy, 2019). For such types of tumors, molecular targets are set under clinical trials for MPM.
It is a gene that suppresses the tumor but is mutated in MPM. Large scale studies were performed with MPM specimens to confirm alteration in the NF2 gene. This gene encodes a protein called merlin. It is observed that the sarcomatoid sub-type carries higher NF2 mutation as compared to the epithelioid subtypes of mesothelioma. NF2 blocks several signal transduction mechanisms such as metabolism and cell proliferation pathway. Merlin is regulated with post-translational modifications that define its activity. Then merlin is inactivated via phosphorylation mechanism in the presence of a cAMP-dependent kinase. The protein is again activated by myosin phosphate. Hence, merlin level decreases in the absence of NF2 gene mutation. The wildtype NF2 were present in high quantity in the samples containing MPM. This shows that merlin is completely inactivated.
· Tyrosine Kinase Receptors
These are vital receptors of the transmembrane protein. When growth factors bind with these receptors, they transduce growth factor signals. Binding activates transduction pathways such as phospholipases and protein kinases. These help in cell proliferation, survival, migration, angiogenesis, and invasion. Hence, these receptors are overexpressed in MPM.
· Apoptosis Dysregulation
In MPM, the apoptotic pathway is dysregulated. It also shows an increase in antiapoptotic proteins such as BC-2, BCL-XL, and Mcl-1. Hence, the proapoptotic proteins such as Bad, Bax, and Bid are lowered. The percentage of BCL-X upregulation and Bad & Bid downregulation is significantly higher in sarcomatoid MPM than the epithelioid MPM samples. The two caspase inhibitors X-linked Inhibitors of Apoptosis (XIAP) & Survivin are also increased in MPM.
Prevention of Mesothelioma
Mesothelioma formation can be prevented by taking these precautionary steps below:
- Reducing Exposure
Reducing the exposure to the asbestos will decrease the chance of getting mesothelioma.
Search the living place for any sort of asbestos exposure. Maintain a distance with the asbestos miners, plumbers, electricians, pipefitters, insulators, brake mechanics, demolition workers, and shipyard workers.
· Follow the Safety Regulations set by the Employers
Every corporate has its set rule and regulations for the safety of its employees. Wearing protective equipment can also help reduce the chance of exposure to toxic asbestos fibers. Showering and changing work clothes before going home is also a great precautionary step for those who work in the exposed areas.
· Avoid Breaking Asbestos in Old buildings
Many older houses have asbestos in them, which is very troublesome. It should be made sure that it does not break during its removal, or it will release toxic asbestos fibers that will become airborne. These particles can be easily inhaled by anyone in that area. There are specially trained experts to detect asbestos in any particular area. They test the air for airborne asbestos and can tell whether your area is toxic or not.
Support System & Coping with Mesothelioma
A diagnosis of malignant mesothelioma can be mortifying to the family of the patient and as well as to the investigators. It is better to understand the disease for the sake of one’s positively diagnosed family member. Write down the possible questions to ask the doctor about the mesothelioma prognosis. A support network is the one filled with family members and close friends. They should be the ones that a diagnosed person can rely on for their everyday tasks without any hesitation. Being honest with oneself and asking for help when in need is the biggest favor that one can do to themselves. In many places, there are support services that provide patients with identical advantages as that of your family support.
Immunotherapy & Care for patients
Immunotherapy is a systematized treatment with a distinctive approach as compared to chemotherapy. The U.S. Federal Drug Administration (FDA) has not approved immunotherapy for mesothelioma as of yet. Still, many clinical trials are going on that are using various types of immunotherapy. The immunotherapy provokes the body’s inner immunity through a special checkpoint system. This causes the immune system to attack these cancer-producing cells. The types of immunotherapy for mesothelioma under trial are PD-1, PDL-1, & CTLA4 inhibitor. PD1/PD-L1 pathway has a central role in tumor immune evasion that makes it a predictive and prognostic marker6. To conduct such trial, special mesothelioma teams are required to administer immunotherapy doses at a required fixed interval.
Mesothelioma is a rare time-bomb that sets out after several years of exposure. Although everyone knows that asbestos is the main cause of mesothelioma, still many of the products in the market contain asbestos fibers in them, such as talcum and baby powders. Recently, many countries are joining hands to ban asbestos. Still, several industries are saying that asbestos can be used safely with controlled measures. Despite all the protocols and regulations, the safe utilization of asbestos is thought to be impossible until now.
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Cedrés S, Ponce-Aix S, Felip E. Analysis of Expression of Programmed Cell Death 1 Ligand 1 (PD-L1) in Malignant Pleural Mesothelioma (MPM). PLoS One. 2015;10(3):e0121071.