Malignant pleural mesothelioma is an aggressive tumor originating in the pleura. Patients have a short life expectancy after diagnosis also due to limited treatment options. Exposure to asbestos fibers is considered the main risk factor for developing pleural mesothelioma. Since the disease progresses insidiously over decades, it is often discovered very late.
Malignant pleural mesothelioma is an aggressive tumor originating in the pleura. Patients have a short life expectancy after diagnosis also due to limited treatment options. Exposure to asbestos fibers is considered the main risk factor for developing pleural mesothelioma. Since the disease progresses insidiously over decades, it is often discovered very late.
Malignant pleural mesothelioma is an aggressive tumor originating in the pleura. Patients have a short life expectancy after diagnosis also due to limited treatment options. Exposure to asbestos fibers is considered the main risk factor for developing pleural mesothelioma. Since the disease progresses insidiously over decades, it is often discovered very late. Therefore, patients are often diagnosed with inoperable pleural mesothelioma, which is already in an advanced stage. This limits the therapeutic measures and is also reflected in a low life expectancy of about 12 months after diagnosis.
Origin of pleural mesothelioma
The most common cause of pleural mesothelioma development is exposure to asbestos fibers, usually occurring decades before the first symptoms appear. Inhalation of the fibers leads to chronic inflammation of the pleura, which contributes to malignant transformation of mesothelial cells. The fibers can directly cause DNA damage in mesothelial cells, leading to cell death and release of inflammatory mediators such as HMGB1 and CCL2. Inflammatory mediators, particularly CCL2, recruit macrophages and act directly on mesothelial cells by binding to RAGE receptors on mesothelial cells and inducing their cell division and migration. Recruited macrophages also contribute to local inflammation and proliferation of mesothelial cells. Uptake of asbestos fibers by macrophages stimulates the immune sensor inflammasome, leading to secretion of IL-1β. In addition to IL-1β, macrophages also secrete TNF-α, and both cytokines contribute to mesothelial cell survival and further malignant transformation (Fig. 1) [1].
Gene signatures
Approximately 80% of tumors have asbestos exposure decades earlier at their root. A familial genetic predisposition due to germline mutations in the BAP1 genemay increase the likelihood of developing pleural mesothelioma. In contrast to other tumor diseases, in which activating mutations in oncogenes are frequently present, pleural mesothelioma is characterized primarily by alteration and loss of whole chromosome parts and by mutations in tumor suppressor genes. For a long time, little attention was paid to genetic alterations in pleural mesothelioma, due to the low mutation rate of this cancer and a few cases where targeted therapy would be possible. The most frequent mutations and deletions affect the genes BAP1, CDKN2A and NF2. BAP1 is a tumor suppressor gene involved in DNA damage repair and cell cycle control. BAP1 is altered in approximately 45% of all pleural mesotheliomas, although this number may differ between histologies.
CDKN2A is also a tumor suppressor gene that is frequently deleted in pleural mesothelioma. Alterations in this gene are found in approximately 47% of all tumors. CDKN2A has an important role in the regulation of the cell cycle, it encodes the inhibitor of cyclin-dependent kinase 4 and 6. Loss of this gene therefore leads to pro-mitotic signaling and cell survival.
NF2 is also involved in cell cycle regulation and is altered in approximately 32% of pleural mesotheliomas. NF2 regulates the Hippo signaling pathway via the YAP and TAZ proteins. Inactivation of NF2 leads to hyperactivated YAP and uncontrolled cell division.
Few pleural mesotheliomas have mutations in genes that can be targeted by small-molecule inhibitors. We demonstrated in a study that in about 5% of all pleural mesotheliomas the genes ALK, KRAS EGFR, PDGFRA/B, ERBB2 or FGFR3 are mutated, which could be treated with targeted therapies [2]. Further studies have yet to demonstrate the efficacy of this treatment in pleural mesothelioma.
Tumor environment
The interaction of different cell types such as immune cells, stromal cells, tumor cells and endothelial cells of the blood vessels in the tumor is very complex and not yet fully understood in pleural mesothelioma. Depending on tumor type and patient, the heterogeneity of cell types and functions is large. Because of this, therapies that act directly on the tumor environment are difficult to develop. In addition, immune cells often have inhibitory and regulatory phenotypes, mainly represented by regulatory T cells, type 2 macrophages, and myeloid suppressor cells.
Macrophages are the most abundant immune cells in pleural mesothelioma and are recruited from the blood by CCL2 secreted by mesothelial cells in the form of monocytes. Tumor-associated macrophages express an immunosuppressive type 2 phenotype and support malignant mesothelial cell proliferation and tumor growth, also correlating with poor prognosis. The second most abundant immune cells in pleural mesothelioma are T lymphocytes, with all subtypes present such as CD4+ helper T cells, CD8+ cytotoxic T cells, and FoxP3+ regulatory T cells. Cytotoxic T cells frequently express markers such as Lag-3, Tim-3, PD-1, which define a non-reactive phenotype. These T cells are no longer able to perform effector functions, giving tumor cells a survival advantage. The presence of T cells in the tumor is positively associated with survival in pleural mesothelioma, depending on the study, but this may vary depending on histology and the specific phenotype of T cells. Thus, regulatory T cells in tumors are associated with shorter survival. Other suppressive immune cells in the tumor include myeloid suppressor cells, which can account for up to 10% of all infiltrating immune cells. They have a negative effect on T cells and can inhibit their cell division.
Pathology
Pleural mesothelioma is divided into three histologic subtypes, epithelioid (approximately 80% of disease), biphasic, and sarcomatoid pleural mesothelioma. The biphasic subtype is characterized by a combination of epithelioid and sarcomatoid structures.
The histologic subtypes differ primarily in life expectancy. Patients with epithelioid pleural mesothelioma have a longer life expectancy compared with patients with biphasic or sarcomatoid pleural mesothelioma. In addition, patients with an epithelioid subtype usually benefit from resection, whereas the other subtypes do not benefit from surgery. Sometimes the diagnosis of pleural mesothelioma is difficult due to the cellular morphology, because, on the one hand, the pleura is often altered by inflammatory changes or metastases of another malignant disease are present. Therefore, further analysis of a pleural biopsy by immunohistochemistry (IHC) of two mesothelioma markers such as calretinin, podoplanin, Wilms’ tumor-1 (WT-1), or cytokeratin 5/6 is necessary. In addition, other carcinomas can be excluded by staining with CEA, Ber-EP4, pancytokeratin, or claudin-4. Pleural mesothelioma with squamous cell-like change can be differentiated from squamous cell carcinoma by staining for markers p40 and p63. Furthermore, genetic alterations in the BAP1 and CDKN2A genes frequently occur, resulting in loss of expression of these proteins in the tumor. Based on this, immunohistochemical analysis of BAP1 and MTAP expression (MTAP is analyzed as a proxy for CDKN2A, as these genes are located directly adjacent to each other on chromosomal segment 9p21 and co-deletion is often present) may also be helpful in making a definitive diagnosis.
Symptoms, diagnosis and staging
Patients often present with vague symptoms of dyspnea, chest pain, and weight loss. Patients often present with unilateral pleural effusion. Diagnosis of pleural mesothelioma is made by several examinations: i) Radiological examinations including CT of the thorax, ii) Pleural biopsy by thoracoscopy for further verification of the diagnosis of pleural mesothelioma and determination of histology. A pleural biopsy should therefore always extend into the subpleural fat and be performed from three or more different sites. To prevent the risk of implantation of tumor cells into the chest wall, only 1-2 thoracoscopic entry sites should be used [3]. Preferably, these are placed in the same intercostal space of the macroscopically complete resection planned in the further course.
Staging is performed by positron emission tomography (PET-CT) and is supplemented by mediastinoscopy or endobronchial ultrasound (EBUS) if mediastinal lymph node involvement is suspected, contralateral thoracoscopy if contralateral pleural involvement is suspected, or laparoscopy if peritoneal involvement is suspected. Magnetic resonance imaging (MRI) of the thorax can also provide valuable information for staging purposes regarding infiltration into the diaphragm, chest wall, pericardium, or mediastinum.
Surgical interventions
Treatment should be discussed in an interdisciplinary tubmorboard with specialists from thoracic surgery, oncology, radiation oncology, pathology, and radiology. If the patient’s tumor stage and general condition qualify for a multimodality treatment approach, neoadjuvant chemotherapy with platinum-containing cytostatics and folic acid antagonists is followed by re-staging by PET-CT to reassess operability. Due to the anatomical situation with proximity to mediastinal structures, adequate safety distances cannot be maintained during MPM resection. Therefore, radical resection in this case means a macroscopically complete resection with the goal of maximal cytoreduction, but with the risk of residual microscopic tumor [4]. Macroscopically complete resection can be achieved by extrapleural pneumonectomy (EPP) or lung parenchyma-preserving extended pleurectomy and decortication (EPD) [4]. While EPP involves an en bloc resection of the affected lung with visceral and parietal pleura, as well as diaphragm and pericardium, in EPD only the parietal and visceral pleura are detached and removed together with the affected diaphragm and pericardium, leaving the lung intact [4]. In the absence of evidence of pericardial or diaphragmatic involvement, isolated pleurectomy and decortication (PD) may be elected. Systematic mediastinal lymphadenectomy should also be performed for all surgical resections. In recent years, there has been an increasing shift from EPP to EPD because the lung parenchyma and functional reserves are preserved, allowing the patient to have a better quality of life. Furthermore, EPP is additionally associated with increased perioperative morbidity and mortality. EPP should be considered exclusively in selected cases with extensive infiltration of the lung parenchyma and sufficient cardiopulmonary reserves and should be performed only at experienced centers.
In patients in whom maximal cytoreduction by macroscopic complete resection is not an option, recurrence of symptomatic pleural effusion can be prevented in a palliative approach. If the lung is extensive, this is done by thoracoscopic talc pleurodesis; if the lung is chronically trapped, it is done by a subcutaneously tunneled catheter system, through which regular effusion drainage can also be performed in the home environment.
Palliative VATS-PP is recommended to control recurrent pleural effusions in patients who are fit enough for surgical treatment and cannot benefit from chemical pleurodesis (or after unsuccessful pleurodesis) or indwelling catheterization [5].
System therapy
Since 2004, patients have been treated with systemic combination therapy consisting of pemetrexed and platinum-based chemotherapy. The introduction of bevacizumab, an angiogenesis inhibitor, in combination with cisplatin/pemetrexed increased life expectancy by approximately 2.5 months. Based on the success of immune checkpoint inhibitors in various solid tumors, combination therapy of ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) was tested. This therapy showed significant improvement in survival in sarcomatoid pleural mesothelioma and epithelioid with PD-L1>1% [6]. Thus, this treatment was approved by the FDA and EMA as a first-line therapy in 2020. However, in later lines of treatment, pleural mesothelioma still remains a disease without standardized treatments and patients are often enrolled in clinical trials.
Currently, many clinical trials with different therapeutic approaches and new combination therapies are ongoing worldwide. This includes some trials using combination therapies of immune checkpoint inhibitors and various chemotherapy. In addition, based on mutation analyses of the tumor, specific drugs are tested which act directly on these changes. In tumors with a defect in repair genes for homologous recombination, PARP inhibitors will be tested in combination with anti-PD-1 antibodies; in tumors with a loss in the NF2/LATS1/LATS2 genes or with functional AYP/TAZ fusions, specific inhibitors with an unpublished mechanism of action will be tested. In addition, studies are ongoing in which tumors are genetically analyzed and treated based on the specific mutation, such as BRCA1/BAP1 negative are treated with PARP inhibitors or CDKN2A negative with CDK4/6 inhibitors, other groups are treated with immune checkpoint inhibitors or anti-VEGF antibodies, depending on PD-L1 expression.
Some studies are analyzing immunomodulators that have an activating effect on the immune system, with advanced forms of polyI:C (Hiltonol) currently being tested as adjuvants via direct injection into the pleura. Other studies are sampling dendritic cells, which are loaded with tumor antigens and can elicit a direct immune response against the tumor in the patient. Furthermore, new and modified versions of IL-2 are tested in combination with immune checkpoint inhibitors (THOR-707) and CAR-T cells recognizing the antigen mesothelin.
Take-Home Messages
- In selected patients with early-stage MPM and adequate cardiopulmonary reserves, maximal surgical cytoreduction by macroscopic complete resection is recommended.
- Macroscopically complete resection should always be performed as part of a multimodality therapy concept in combination with chemotherapy.
- Treatment recommendations and decisions should always be made at an interdisciplinary thoracic oncology tumor board in the presence of oncologists, radiation oncologists, pulmonologists, and thoracic surgeons.
- First-line therapy in non-operable patients is based on nivolumab and ipilimumab for patients with epitelioid pleural mesothelioma with PD-L1 expression >1% and for all other histologic subtypes. Otherwise, therapy with platinum-pemetrexed and bevacizumab is the other option.
Literature:
- Hiltbrunner S, Mannarino L, Kirschner MB, et al: Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma, Frontiers in oncology 11 (2021) 660039.
- Hiltbrunner S, Fleischmann Z, Sokol E, Curioni-Fontecedro A: 1734P Genomic landscape of pleural and peritoneal mesothelioma tumors, Annals of Oncology 32 (2021) S1200.
- Kindler HL, Ismaila N, Armato SG, et al: Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline, J Clin Oncol 36(13) (2018): 1343-1373.
- Rice D, Rusch V, Pass H, et al: Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the international association for the study of lung cancer international staging committee and the international mesothelioma interest group, J Thorac Oncol 6(8) (2011): 1304-1312.
- Opitz I, Scherpereel A, Berghmans T, et al: ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma, Eur J Cardiothorac Surg 58(1) (2020): 1-24.
- Baas P, Scherpereel A, Nowak AK, et al: First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial, Lancet 397(10272) (2021) 375-386.
InFo ONCOLOGY & HEMATOLOGY 2022; 10(3): 6-9.
