Cancer, Malignant Mesothelioma


Article Author:
Sumeet Jain


Article Editor:
Jason Wallen


Editors In Chief:
Alexandra Caley
Sameh Boktor


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
3/12/2019 1:03:56 PM

Introduction

Malignant mesothelioma is a rare growth of mesothelial cells strongly associated with asbestos exposure. Mesothelial cells form the lining layers of the viscera. Mesothelioma can occur at any mesothelial layer such as the peritoneum or pericardium. The pleural layer is by far the most commonly affected, giving rise to malignant pleural mesothelioma. [1][2][3][4]The subtypes of asbestos strongly associated with malignant mesothelioma are the amosite and crocidolite asbestos.

Etiology

Malignant pleural mesothelioma is primarily linked to asbestos exposure, with some suggesting that asbestos inhalation causes repeated pleural inflammation, interference with mitosis, activation of proto-oncogenes, and free radical production. Other reports indicate associations with ionizing radiation, such as mantle radiation for Hodgkin lymphoma, or a germline mutation of BRCA 1 Associated Protein (BAP1). [5]Smoking is not linked with malignant pleural mesothelioma, though smoking and asbestos exposure significantly increase the risk of lung cancer.

Professions associated with exposure to asbestos include:

  • Shipbuilding
  • Mining
  • Ceramics
  • Cement manufacturer with asbestos
  • Auto parts manufacturer, especially that of brake lining
  • Paper mill worker
  • Insulation work
  • Railroad repair

There is no evidence that alcohol, tobacco, or dietary intake is involved in malignant pleural mesothelioma.

It is believed that particular genetic makeup or changes may make people more susceptible to this disease. Research shows that the loss of one copy of chromosome 22 is commonly seen in patients with malignant pleural mesothelioma. Other chromosomal anomalies that have been identified include deletions in chromosomal arms 3p, 1p, 6q, and 9p.

Epidemiology

Malignant pleural mesothelioma incidence is approximately 2500 new cases per year in the United States. By comparison, lung cancer incidence is more than 160,000 new cases per year. Most malignant pleural mesothelioma cases in the United States have a history of asbestos exposure.

Median survival is roughly 1 year, with long-term survival being extremely rare. Malignant pleural mesothelioma also predominantly affects males. It usually occurs after the fifth decade of life with an average age at diagnosis of 72 and a history of asbestos exposure of 2 to 4 decades before the diagnosis of disease. Cases have been reported in children, but these are not related to asbestos exposure.

Malignant pleural mesothelioma occurs more frequently in some countries like China where asbestos is still widely used with little oversight. On the other hand, in other places like Hong Kong, asbestos exposure is still high, but malignant pleural mesothelioma rates are low. The reason for these differences remains unknown.

Pathophysiology

The three types of mesothelioma are epithelioid, sarcomatoid, and mixed. The epithelioid type is associated with better outcomes. The tumor is often multifocal, forming multiple nodules starting with the parietal pleura. Spread occurs locally in the visceral pleura before extending to the chest wall, diaphragm, or mediastinum. Regional lymph node spread begins with the bronchopulmonary or hilar lymph nodes before moving to the carinal, internal mammary or peridiaphragmatic nodes.

The pattern of nodal metastases is different from that seen in lung cancer. With malignant pleural mesothelioma, there is a direct local invasion of the lymph nodes. Overall, the involvement of lymph nodes in malignant pleural mesothelioma is not common.

Histopathology

Analysis of excised tissue usually reveals large nodules on the pleural surface. Three histological subtypes that are involved in malignant pleural mesothelioma include sarcomatous, mixed, and epithelial which has the best prognosis.

History and Physical

Malignant pleural mesothelioma usually presents with chest pain and dyspnea. Dyspnea suggests the presence of pleural effusion, the most common initial finding, seen in about 90% of patients. Nonspecific symptoms such as unintentional weight loss, appetite loss, cough, fatigue, and chest wall mass may also occur.

Evaluation

The evaluation includes a thorax CT scan with intravenous contrast, a thoracoscopic pleural biopsy, and thoracentesis of pleural effusion, if present, with cytologic analysis. [6][7][8]Malignant pleural mesothelioma needs to be distinguished from other conditions. These conditions include benign pleural diseases as well as metastasis of other tumors such as lung adenocarcinoma or chest wall sarcoma. A chest CT scan will show focal areas of pleural thickening, with a large invasive mass present in late-stage disease. PET scans may be used to screen for metastatic disease, while MRI and laparoscopy can be used to evaluate diaphragmatic invasion.

Megakaryocyte potentiating factor is used as a serum biomarker for malignant pleural mesothelioma.

The cardiologist must clear all patients deemed candidates for surgery. A stress test should be performed, and lung function should be optimized. 

Treatment / Management

Using National Comprehensive Cancer Network Guidelines, treatment depends upon tumor staging for the feasibility of surgical resection with Stage III-IV malignant pleural mesothelioma being considered unresectable. Ultimately less than a third of patients are candidates for definitive resection. It is recommended that mesothelioma be treated by a multidisciplinary team at a high volume center.[6][9][10][11]

Differential Diagnosis

The differential diagnosis for malignant pleural mesothelioma includes: 

  • Non-small cell lung cancer
  • Small cell lung cancer
  • Drug-induced lung complications
  • Benign pleural mass
  • Lung infection
  • Lung fibrosis

Surgical Oncology

For resectable disease, surgical options include either pleurectomy/decortication (P/D) in early stages, or extrapleural pneumonectomy (EPP; resection of pleura, lung, pericardium, and diaphragm) when attempting curative resection. This choice is controversial as limited evidence is available. EPP is associated with high mortality compared with P/D, though this may be due to the patient population selected to undergo each. High-dose adjuvant radiotherapy is used after EPP to improve local control. There have been some attempts to use prophylactic radiotherapy, but this remains controversial with no clear benefit established. Systemic chemotherapy can be given as neoadjuvant or adjuvant therapy and is usually platinum-based. Neoadjuvant chemotherapy may increase survival if there is a response, but overall efficacy is unproven. Adjuvant chemotherapy is difficult because of the toxicities of the medications after the stress of extensive surgery.

Radiation Oncology

Radiation therapy is used, but the results are extremely poor. The treatment does not affect survival but may provide palliation in patients with chest wall metastases.

Medical Oncology

For unresectable disease, platinum-based chemotherapy agents such as cisplatin are the first treatment option. Malignant pleural mesothelioma is more resistant to chemotherapy, however, and so there is an unclear survival benefit. For example, the combination of gemcitabine and cisplatin has a response rate of between 12% and 48%, but median overall survival still is only 9 to 13 months. Biologic and antiangiogenic therapies are being investigated as well.

Staging

  • Stage I: A totally resected mass confined within the capsule of the parietal pleura. There is no lymphadenopathy.

  • Stage II: Has all the features of a stage I lesion, but the margins are positive after resection. There may be intrapleural lymphadenopathy.

  • Stage III: There is a local invasion of the mass into the mediastinum, pericardium, chest wall or peritoneum. Lymphadenopathy is common.

  • Stage IV: The presence of distant metastatic disease.

Prognosis

Despite advances, the prognosis for most malignant pleural mesothelioma patients is grim; death is inevitable within 4 to 6 months. With treatment, some patients may survive 15 to 18 months. Rarely, 5-year survivals have been reported. The biggest problem is tumor recurrence, especially in patients managed with surgery.

Patients undergoing surgery may have slightly longer survival, but they also develop many complications related to the procedure. These complications include arrhythmias, wound infection, deep vein thrombosis, air leak, respiratory failure, postoperative bleeding, and myocardial infarction. Poor prognostic factors include nonepithelial histology, poor performance status, age over 75, dyspnea and chest pain on presentation, elevated lactate dehydrogenase and low hemoglobin on presentation, and weight loss.

Complications

Complications can arise because of malignant pleural mesothelioma itself, chemotherapy, and surgery. The surgery is associated with extremely high morbidity and mortality. Some of these complications include:

  • Myocardial infarction
  • Dependency on the ventilator
  • Bronchial air leak
  • Postpneumonectomy stump failure
  • Multiorgan failure
  • Wound infection
  • Renal failure from cisplatinum
  • Pancytopenia from chemotherapy

Postoperative and Rehabilitation Care

Patients are encouraged to enter a rehab program to recover functionality after treatment. A good diet should be encouraged as most patients are frail and emaciated. Home oxygen is often required.

Pearls and Other Issues

  • Malignant pleural mesothelioma is a life-threatening malignancy. Even with treatment, it has a very poor outcome.
  • The epithelial histology has a better prognosis than other histologies.
  • Patients often present with dyspnea and weight loss.
  • A pleural effusion is often present on the initial chest X-ray.
  • Diagnosis can be difficult. Thorough immunostaining techniques must be employed.
  • The ideal treatment is surgery for a localized disease, but most patients are not candidates for the procedure. The surgery is also associated with severe complications.
  • Cisplatinum-based chemotherapy is used for advanced cases.
  • Radiation has not been shown to affect survival but may play a role in palliation.

Enhancing Healthcare Team Outcomes

Malignant mesothelioma is a system disorder that requires a multidisciplinary team of doctors including an oncologist, thoracic surgeon, pulmonary specialist, radiation oncologist, and pain specialist. The cancer is difficult to diagnose and all the currently available treatments have not had any major impact on life expectancy. Using National Comprehensive Cancer Network Guidelines, treatment depends upon tumor staging for the feasibility of surgical resection with Stage III-IV malignant pleural mesothelioma being considered unresectable. Ultimately less than a third of patients are candidates for definitive resection. It is recommended that mesothelioma be treated by a multidisciplinary team at a high volume center. These patients may benefit from palliative or hospice care as most are frail and have only months to live at the time of diagnosis. Even though surgery is done, it is associated with severe life-threatening complications. Most patients with this cancer are dead within 12 months. [12][13]


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Cancer, Malignant Mesothelioma - Questions

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Which of the following is not a feature of benign mesothelioma?



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Which of the following is not done when extrapleural pneumonectomy is performed for a mesothelioma?



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In which of the following diseases is a lung biopsy not helpful?



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What is the most common presentation of mesothelioma on chest radiographs?



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What is the average clinical latency period between asbestos exposure and development of mesothelioma?



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What is the most common finding on physical exam in a patient with mesothelioma?



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Exposure to which of the following is most likely to cause peritoneal mesotheliomas?



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Which of the following is a correct statement about the treatment for malignant mesothelioma?



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Which of the following is linked to mesothelioma?



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Which substance is thought to be a causative factor in mesothelioma?



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Which of the following mineral dust particles is related to the development of malignant mesothelioma of the pleura?



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Which of the following geometric forms of asbestos results in the production of mesothelioma?



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A male who worked briefly at a shipyard 30 years ago has developed progressive pulmonary symptoms. For which of the following is he at high risk?



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A 75-year-old man who worked in a shipyard presents with dyspnea and right sided chest pain. CT of the chest shows thickening of the pleural surface near the diaphragm, a large right sided effusion, and right sided perihilar lymphadenopathy bilaterally. A chest tube is placed and pleural fluid analysis shows an exudative effusion though cytologic analysis is nondiagnostic. A thoracoscopic pleural biopsy is performed which shows malignant pleural mesothelioma with a sarcomatoid histologic pattern. Which of the following is the most appropriate treatment for this patient?



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Malignant mesothelioma is known to have a strong association with asbestos exposure. Which of the following exposures is also associated with the development of malignant mesothelioma?



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A 66-year-old shipyard worker presents with a long history of dyspnea and chest pain. Over the past few months, he has lost 15 pounds, has a fever, is sweating, and has no exercise endurance. He spent the last 40 years working in the shipyard industry but had to retire a few years early because of worsening of his medical condition. He denies smoking. On a chest x-ray, there is a moderate size left pleural effusion with thickening of the pleura. Aspiration of the pleural fluid reveals a few white and red blood cells. The fluid tests positive for megakaryocyte precipitating factor. What is not true about this condition?



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A middle-aged shipyard worker presents to the clinic with vague chest pain and dyspnea for the past 6 months. Over the past few weeks, he has been experiencing night sweats, fever, and fatigue. He worked in the shipyard industry for over 30 years but 2 years ago he had to quit work because of fatigue and dyspnea. He is on a bronchodilator and aspirin. His chest x-ray prompted a CT scan of the chest, which is shown below. To work up the diagnosis, which test is not recommended?

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  • Image 6247 Not availableImage 6247 Not available
    Image courtesy S Bhimji MD
Attributed To: Image courtesy S Bhimji MD



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Cancer, Malignant Mesothelioma - References

References

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Mlika M,Lamzirbi O,Limam M,Mejri N,Ben Saad S,Chaouch N,Ben Miled K,Marghli A,Mezni F, [Clinical and pathological profile of the pleural malignant mesothelioma: A retrospective study about 30 cases]. Revue de pneumologie clinique. 2018 Dec;     [PubMed]
Ettinger DS,Wood DE,Akerley W,Bazhenova LA,Borghaei H,Camidge DR,Cheney RT,Chirieac LR,D'Amico TA,Dilling T,Dobelbower M,Govindan R,Hennon M,Horn L,Jahan TM,Komaki R,Lackner RP,Lanuti M,Lilenbaum R,Lin J,Loo BW Jr,Martins R,Otterson GA,Patel JD,Pisters KM,Reckamp K,Riely GJ,Schild SE,Shapiro TA,Sharma N,Swanson SJ,Stevenson J,Tauer K,Yang SC,Gregory K,Hughes M, NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016. Journal of the National Comprehensive Cancer Network : JNCCN. 2016 Jul;     [PubMed]
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Odisio EG,Marom EM,Shroff GS,Wu CC,Benveniste APA,Truong MT,Benveniste MF, Malignant Pleural Mesothelioma: Diagnosis, Staging, Pitfalls and Follow-up. Seminars in ultrasound, CT, and MR. 2017 Dec;     [PubMed]
Butnor KJ,Brownlee NA,Mahar A,Pavlisko EN,Sporn TA,Roggli VL, Diffuse malignant mesothelioma and synchronous lung cancer: A clinicopathological study of 18 cases. Lung cancer (Amsterdam, Netherlands). 2016 May;     [PubMed]
Churg A,Attanoos R,Borczuk AC,Chirieac LR,Galateau-Sallé F,Gibbs A,Henderson D,Roggli V,Rusch V,Judge MJ,Srigley JR, Dataset for Reporting of Malignant Mesothelioma of the Pleura or Peritoneum: Recommendations From the International Collaboration on Cancer Reporting (ICCR). Archives of pathology     [PubMed]
Chen R,Lou J,Zhang X, [Guidelines for pathologic diagnosis of malignant mesothelioma--2012 update of the consensus statement from the International Mesothelioma Interest Group]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases. 2015 Nov;     [PubMed]
Fournel L,Janet-Vendroux A,Canny-Hamelin E,Mansuet-Lupo A,Guinet C,Bobbio A,Damotte D,Alifano M, [Malignant pleural mesothelioma: The role of surgery]. Revue de pneumologie clinique. 2018 Oct;     [PubMed]
Bibby AC,Maskell NA, Current treatments and trials in malignant pleural mesothelioma. The clinical respiratory journal. 2018 Jul;     [PubMed]

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