Malignant pleural mesothelioma (MPM) is a rare disease of pleural mesothelial cell origin, predominantly locally invasive and highly malignant.
1. etiology and epidemiology [1]
The most common etiology of MPM is exposure to asbestos; in addition, infection with tuberculosis, Rhesus virus40, exposure to nitrosamines, glass fibers, radiation, oxytocic thorium, zeolites, beryllium, and hydrocyanic acid, and lipid aspiration pneumonia may act as causative factors, causing mutations or deletions in human genes that lead to MPM; other studies suggest that MPM may be an autosomal dominant familial disorder. Australia has the highest incidence of MPM in the world, with 3,54 per 100,000 people over the age of 20. The prevalence of MPM varies greatly across China, ranging from 0.1/100,000 to 0.6/100,000, with an overall increasing trend. Among them, Dayao County in Yunnan Province has the highest prevalence, with an incidence rate of 8,5/100,000 (1977~1983) and 17,75/100,000 (1987~1995) per year. The ratio of men to women is 2:1 to 3:1 in China, while it is 6:1 in Australia.
It usually takes 20 to 65 years from the first exposure to asbestos to the onset of MPM. In the 1990s, the production and use of asbestos was banned in developed countries in Europe and the United States, whose peak MPM incidence is expected to be around 2020. Industrial development and labor protection in China are lagging behind, and asbestos is still being used today, so the incidence of MPM will continue to grow for a long time.
2. Diagnosis In most areas of China, the incidence of MPM is low, while the disease has a high misdiagnosis rate, up to 83,3%, due to the lack of specific symptoms and signs [2]. It takes about two to three months from the onset of symptoms to confirm the diagnosis of MPM, and 25% of patients are diagnosed definitively six months after the onset of symptoms [3]. Therefore, clinicians should have a better understanding of the disease.
Early stage patients may be asymptomatic or present only with shortness of breath after exercise, and may develop cough, shortness of breath, and persistent chest pain as the lesion progresses. In late stages, patients may present with dyspnea, thoracic deformities, arrhythmias, pericardial tamponade, or even abdominal masses and ascites, or with intestinal obstruction; 60% to 95% of patients have pleural effusion, which can be seen in any stage, especially the epithelial type; pleural fluid is mostly bloody, and a few are straw-yellow exudate, which can be viscous due to the richness of hyaluronic acid, and regenerates more quickly after aspiration [1, 4].
A characteristic feature of MPM is local invasion, which can metastasize along fine needle puncture, thoracoscopy or surgical incision sites, with an incidence of 2-51%. Autopsy reveals 54%-82% of extrathoracic metastases, but they are often clinically asymptomatic and are rarely the cause of death. The most common abdominal metastases are to the liver, adrenal glands, and kidneys, and 3% present with intracranial metastases and are mostly sarcomatous.
The non-specific manifestations of X-ray and CT examination include pleural effusion, rib destruction, blunted rib-diaphragm angle, widened mediastinum, and enlarged heart shadow. The specific manifestations are: (1) nodular thickening of the pleura, usually 5-15 mm in thickness, sometimes up to 25 mm, or obscured by pleural fluid; (2) thickening of the lung fissure pleura; (3) limited mass; and (4) decreased pleural volume on the affected side, which can be offset if pleural fluid is present [1, 4]. In addition, there are also presentations of isolated intrapulmonary lesions [5] or spherical masses of variable size disseminated within the lung.
CT is the most valuable screening method for pleural lesions. Notably, 20% of patients with mesothelioma present with calcified pleural plaques, which are easily misdiagnosed as benign disease [1].
Ultrasound has advantages over CT in identifying fluid and non-fluid lesions, microfluids and pleural thickening, and allows dynamic observation of lesions with respiratory motion. Due to the high resolution of soft tissue, especially sensitive to subpleural fat, MRI can identify pleural-based soft tissue nodules or confined effusions, and has high application value in the diagnosis, staging and efficacy evaluation of MPM.
PET/CT can be used for: (i) differentiation of benign and malignant pleural mesothelioma, especially in patients with a history of asbestos exposure and diffuse pleural thickening; (ii) staging of MPM; (iii) cases with pleural effusion but no abnormalities on CT and MRI examination; (iv) evaluation of tumor treatment response, etc.
The diagnostic rate of pleural fluid cytology examination is very low; fine needle aspiration of tissue under localization can improve the diagnostic rate.
Surgical diagnostic methods include diagnostic thoracoscopy, surgical thoracoscopy, dissecting thoracic biopsy, mediastinoscopy, etc., which have high sensitivity and specificity, among which, surgical thoracoscopy can also administer treatment, such as controlling pleural fluid and performing pleurodesis, etc.
Broadly speaking, MPM is divided into limited and diffuse types; the histological classification includes epithelioid, sarcomatoid and biphasic [1]. Under light microscopy, epithelial-type pleural mesothelioma and hypodifferentiated adenocarcinoma are difficult to distinguish, sometimes with the help of immunohistochemistry. cEA and CD15 are often expressed in adenocarcinoma, but not in MPM in general, and epithelial membrane antigen is expressed in MPM cell membranes, but in adenocarcinoma cell plasma. In addition, CK5, CK6 and calreticulin are also more specific for MPM. When immunohistochemical results are ambiguous, the diagnosis can be made using electron microscopy, the gold standard, with MPM having long and branched microvilli, more bridging granules and tensegrity filaments [9].
Recently, we treated a patient with epithelial MPM. The tissue sections were consulted by several pathologists, some of whom diagnosed hypofractionated adenocarcinoma, followed by immunohistochemical staining for calreticulin (+), waveform protein (+), CEA (-), thyroid transcription factor-1 (-), and CD68 (+), which supported the diagnosis of MPM. Interestingly, two of the three pre-surgical serum CEA examinations were highly expressed in this patient, while there was no expression in the tumor tissue. This reflects the biological diversity of MPM.
At present, at least five MPM staging systems have been born, and now most of them refer to the TNM staging system developed by the International Mesothelioma Group in 1995, but compared with lung cancer staging, they cannot yet fully reflect the true face of the pathology and biology related to survival, and at the same time, affect the selection of treatment methods and the evaluation of efficacy.
3, Treatment of MPM Without treatment, the median survival time (MST) of MPM patients is only a few months, and most patients die from local tumor invasion. Therapeutically, achieving good local control is the key to obtain long-term survival. Surgical procedures are the only possible means to achieve a radical outcome. However, very few patients are suitable for surgery at the time of definitive diagnosis. Treatment of MPM revolves around both surgical and non-surgical approaches.
(1) Surgical multidisciplinary treatment commonly used surgical modalities are extrapleural pneumonectomy (EPP) and pleurodesis, which involves the removal of half of the pleura, diaphragm, pericardium and lung as a whole, with 2-year and 5-year survival rates of 30%-40% and 5%-15%, respectively; and significantly prolongs tumor-free survival. Today, the mortality rate of EPP has been reduced from 30% to 3 or 4%-8%, but there is still a risk of more than 50% postoperative complication rate, and skilled surgeons can make EPP safer.
For limited MPM, pleurodesis can also yield better results, as well as lower operative mortality and complication rates than EPP [11]. Television-assisted thoracoscopic pleurodesis has also shown better outcomes in some early stage patients [17]. Compared to pleurodesis, hemithorax-enhanced radiotherapy is more appropriate after EPP and seems to be more effective in controlling tumor recurrence.
A retrospective study including 945 patients showed that surgery improved survival, with a median survival of 20, 1 months in patients treated with surgical multidisciplinary therapy. The addition of hemithoracic conformal radiotherapy after EPP did not increase surgery-related complications while increasing the efficacy.
A multicenter study showed that EPP after phase III chemotherapy with gemcitabine and cisplatin, followed by thoracic radiotherapy, resulted in an MST of 23 months. In another eight patients with stage III or IV MPM, gemcitabine and cisplatin IV chemotherapy followed by EPP and then half-sided thoracic radiotherapy (54 cGy) resulted in an MST of 33, 5 months [20]. Similar results were obtained in patients with stage I to III MPM treated with neoadjuvant chemotherapy with gemcitabine and carboplatin, followed by EPP and hemithoracic radiotherapy. It is suggested that this treatment modality may become the standard of care for MPM.
After surgery, MPM patients with N2 lymph node metastases recur more rapidly and seem to be inappropriate for surgical treatment. The choice of surgical modality needs to take into account the extent of disease, concomitant disease, and multidisciplinary treatment modality to reap better local control.
2) Non-surgical multidisciplinary treatment of patients who have lost the opportunity for surgery can be treated with chemotherapy, radiotherapy, and also biological therapies such as cytokines.
Overall, chemotherapy for MPM is not as effective as it could be, with an MST of 13 to 17 months for patients treated with single or multi-drug combinations.