## Overview: Malignant Mesothelioma of Pleura (C45.0) Malignant Mesothelioma of Pleura (MMP) is an aggressive and rare cancer that originates from the mesothelial cells lining the pleura, the protective membrane covering the lungs and inner chest wall. It is overwhelmingly associated with inhalation of asbestos fibers, with a long latency period typically ranging from 20 to 50 years after initial exposure. Due to its aggressive nature and late presentation, MMP often carries a poor prognosis. ### Pathophysiology The primary etiological agent for malignant mesothelioma is asbestos. Inhaled asbestos fibers, particularly long, thin amphibole fibers like crocidolite and amosite, can reach the pleura. Once embedded in the pleura, these fibers induce chronic inflammation, oxidative stress, and direct cellular damage, leading to genetic mutations and aberrant cell proliferation in mesothelial cells. This prolonged inflammatory response and genetic instability eventually culminate in malignant transformation. Mesothelioma typically grows by spreading diffusely along the pleural surfaces, often encasing the lung, rather than forming a distinct, localized mass. Histologically, MMP is classified into three main subtypes: epithelioid (the most common, accounting for 50-70% of cases, generally associated with a better prognosis), sarcomatoid (10-20%, poorer prognosis, often resembling sarcoma), and biphasic (20-30%, a mixture of epithelioid and sarcomatoid features). ### Clinical Presentation Symptoms of malignant pleural mesothelioma are often vague and non-specific in its early stages, leading to delayed diagnosis. The most common presenting symptoms include dyspnea (shortness of breath), often progressive, due to the accumulation of pleural fluid (effusion) or the encasement of the lung by tumor. Persistent, dull, non-pleuritic chest pain is also frequently reported, resulting from tumor invasion into the chest wall. Other common symptoms include unexplained weight loss, chronic cough (which can be dry or productive), and profound fatigue. In advanced stages, patients may experience symptoms related to local invasion, such as hoarseness (due to recurrent laryngeal nerve involvement), dysphagia (difficulty swallowing), or swelling of the face and arms if the superior vena cava is compressed. Physical examination findings may include diminished breath sounds, dullness to percussion over areas of pleural effusion, and in some cases, clubbing of the fingers, although this is less common than in other chronic lung diseases. ### Diagnostic Criteria Diagnosis of MMP is challenging and requires a high index of suspicion, especially in individuals with a history of asbestos exposure. #### Imaging Initial evaluation typically involves a chest X-ray, which may reveal pleural effusion or diffuse pleural thickening. A contrast-enhanced computed tomography (CT) scan of the chest is crucial, showing characteristic features such as nodular pleural thickening, mediastinal pleural involvement, thickening of interlobar fissures, and often ipsilateral hemithorax volume loss. Positron emission tomography (PET-CT) is useful for assessing metabolic activity, detecting distant metastases, and guiding biopsy. Magnetic resonance imaging (MRI) can be helpful in evaluating chest wall invasion. #### Biopsy A definitive diagnosis necessitates histological confirmation from tissue biopsy. Pleural fluid cytology obtained via thoracentesis is often non-diagnostic due to the reactive nature of mesothelial cells mimicking malignancy. Therefore, larger tissue samples are preferred, obtained via CT-guided core needle biopsy, video-assisted thoracoscopic surgery (VATS), or open surgical biopsy. #### Histopathology and Immunohistochemistry Microscopic examination of the tissue biopsy is critical, complemented by immunohistochemical staining. This helps differentiate mesothelioma from other malignancies, particularly adenocarcinoma, which can metastasize to the pleura. Immunohistochemical markers such as calretinin, WT1, CK5/6, and D2-40 are typically positive in mesothelioma, while markers like TTF-1, CEA, and Ber-EP4 are usually negative, helping confirm the mesothelial origin. ### Standard of Care The management of malignant pleural mesothelioma is complex and typically involves a multidisciplinary team. Treatment goals range from attempting a cure (rare) to prolonging life and palliating symptoms, depending on the stage of the disease, histological subtype, and patient's overall health status. #### Surgery For selected early-stage patients with epithelioid histology and good performance status, surgery may be considered. Two main surgical approaches are extrapleural pneumonectomy (EPP), a radical procedure involving removal of the affected lung, pleura, pericardium, and diaphragm, associated with high morbidity and mortality; and pleurectomy/decortication (P/D), a lung-sparing procedure that removes the pleura and all macroscopic tumor, generally favored for its lower mortality and better quality of life outcomes. #### Chemotherapy Systemic chemotherapy is the cornerstone of treatment for most patients. The standard first-line regimen is a combination of pemetrexed (an antifolate agent) with either cisplatin or carboplatin. For patients who progress on first-line therapy, second-line options may include gemcitabine or vinorelbine. #### Radiation Therapy Radiation therapy can be used in the adjuvant setting following surgery, particularly EPP, to target residual microscopic disease. It also plays a significant role in palliative care to manage localized pain, chest wall recurrence, or other sites of symptomatic disease. #### Immunotherapy Recent advancements include the use of immune checkpoint inhibitors. The combination of nivolumab and ipilimumab has been approved for unresectable malignant pleural mesothelioma, showing improved overall survival compared to chemotherapy in some patients. Pembrolizumab is another option in specific circumstances. #### Palliative Care Given the often aggressive nature of the disease and its challenging prognosis, early integration of palliative care is essential to manage symptoms, improve quality of life, and support patients and their families throughout the disease trajectory.