Malignant Pleural Mesothelioma

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One of many reasons to evaluate all patients for asbestos exposure

Malignant mesothelioma affects 1 in 100,000 U.S. residents, with an estimated 2,000 to 3,000 new cases diagnosed annually.1 It is imperative that primary care providers be aware of the signs and symptoms of mesothelioma, as well as the associated risks and issues.

Case Presentation

TD, a 62-year-old white man, presented to his primary care provider with complaints of pain under his right rib, mild shortness of breath, and fatigue. At a prior visit with another provider, he had been treated for bronchitis and pneumonia with oral antibiotics. His chest x-ray at that time showed a small unilateral pleural effusion with no other abnormalities. TD had recently undergone a colonoscopy and the provider suspected that the pleural effusion was related to bleeding or trauma from the procedure. He was told that the pleural effusion was small and insignificant, and not to worry.

TD was never questioned about his work history or potential exposure to asbestos. He had worked as a mechanic and carpenter. Although he did not correlate his asbestos exposure history with his symptoms, he knew something was wrong and continued to complain. Due to TD’s persistence, his primary care provider agreed to consult a surgeon for analysis of the pleural fluid. A grim diagnosis of malignant pleural mesothelioma (MPM) resulted.

Epidemiology

The American Thoracic Society has described asbestos as “the largest cause of occupational cancer in the United States and a significant cause of disease and disability from nonmalignant disease.”2 Every 2 years, the Agency for Toxic Substances and Disease Registry and the Environmental Protection Agency prepare a list of substances that pose the most significant potential threat to human health due to their known or suspected toxicity.3 The national priority list for 2011 ranked asbestos in the top 100.3

The effects of asbestos exposure are substantial and long-lasting, and mesothelioma is the most devastating diagnosis associated with it. MPM frequently presents with sudden onset of pleural effusion or thickening, dyspnea and chest pain. By the time these symptoms appear, the disease is often rapidly fatal. The average survival time is only 8 to 14 months past diagnosis.2 The 1-year survival rate is less than 30%.2 This disease usually has a long latency period, from 10 to 60 years; 30 to 40 years is typical.2

Pathophysiology

Table 1 provides background on asbestos, and Table 2 outlines other essential information. Prior to 1970, asbestos had been widely used commercially, particularly in the automobile, construction and shipbuilding industries. The most important pathway of exposure to asbestos is via inhalation of contaminated air and dust. Despite the upper respiratory tract’s defenses, deposited asbestos fibers are retained in lung tissue for many years. From the lungs, fragmented fibers can migrate to the pleural and peritoneal spaces, following the patterns of lymphatic drainage.2

A variety of immune responses are activated when asbestos fibers are in the lungs, and these lead to cell injury, fibrosis and potentially, cancer. First, asbestos fibers carry a surface charge enabling them to be absorbed by cellular macromolecules such as protein, DNA or RNA.2 This binding changes the conformation of the molecule, affecting its function and leading to structural changes. Second, the presence of the foreign asbestos fibers in the lungs leads to release of reactive oxygen species (ROS) by alveolar macrophages.2 Excess ROS or oxidative stress can cause distinct effects on cells, including alterations in cell growth and proliferation, apoptosis, inflammation, necrosis and matrix regulation.4 Lastly, the chronic inflammation caused by the presence of asbestos fibers leads to further inflammation and macrophage recruitment, cell damage, proliferation and apoptosis.4

Asbestos is both genotoxic and carcinogenic.2 Four primary respiratory conditions are associated with asbestos exposure: parenchymal asbestosis, asbestos-related pleural abnormalities, lung carcinoma and MPM.

History

Multiple studies have reported delayed diagnosis, fragmented care pathways and poorly coordinated care of MPM.5 Obtaining an accurate history is critical to diagnosis. Remember that asbestos-associated diseases have long latency periods and patients who have had significant exposure may be asymptomatic for decades. Important questions include: What jobs have you had? Did the jobs involve working with asbestos? Did you wear any personal protective equipment such as a respirator?

The possibility of paraoccupational exposure from other family members or from living near vermiculite or asbestos processing plants should be explored as well. For example, the wife of a mechanic may have been exposed because he carried asbestos home on his clothing.

Physical Exam

This case study focuses primarily on MPM, but it is important to remember the other diseases associated with asbestos exposure. Asbestos-associated lung cancer is usually associated with large cumulative exposures 20 to 30 years earlier. Approximately 20% to 25% of heavily exposed asbestos workers develop bronchogenic carcinomas.2 The risk of developing lung cancer depends on the level, frequency and duration of asbestos exposure, the time since first exposure, age of initial exposure, smoking history, and the type and size of asbestos fibers involved.2

Patients often are asymptomatic while MPM tumors are developing. Patients may present with sudden onset of dyspnea, chest pain, pleuritic chest pain or systemic signs of cancer, such as weight loss and fatigue.2 If the patient has a pleural friction rub, it may be audible on auscultation. As the disease progresses, the most common symptoms are shortness of breath and pain (90% of MPM patients).5,6 Other symptoms are tiredness (36%), worry (29%), cough (22%), sweating (22%) and constipation (22%).6

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Diagnostics

If the patient has been exposed to asbestos, proceed with chest radiography and pulmonary function testing.2 Both of these should be periodically obtained by the primary care provider to help identify early signs of disease, regardless of whether symptoms are present.2

On chest radiograph, the appearance of asbestos-associated lung cancer is often the same as that of lung cancer of other etiologies (Table 3). MPM typically produces pleural effusions, a pleural mass or a diffuse pleural thickening. Computed tomography of the chest is useful in detecting and assessing early parenchymal changes and subtle pleural disease (plaques and rounded atelectasis). It can also help differentiate among asbestos-associated pleural plaques, soft tissue densities and mesothelioma.2

Diagnosis

None of the clinical signs of MPM are specific or sensitive enough to warrant diagnosis; the diagnosis of MPM should always be based on immunohistochemical evaluation. Pleural biopsy specimens are considered the best approach for diagnosis, better than cytologic examination of pleural effusions.7 This technique requires staining of biopsy specimens for comparison of validated markers for MPM or other carcinomas.

Reliable diagnosis may require multiple specimens, which may be difficult for many patients to handle. Recent research has identified type III collagen, CCL2 and galectin 3 as clinical indicators of MPM using fluid collected from pleural effusions.7 Further research is needed before changes in practice occur.

Treatment and Follow-up

Primary care management for MPM focuses on aggressive treatment of secondary respiratory infections; influenza and pneumococcal vaccination as recommended; and prevention of further exposure to asbestos and other irritants. Any patient who still works near or is exposed to asbestos should be advised to wear proper personal protective equipment.2

Primary care providers also provide support and coordinate care for patients with MPM.8 A patient education handout on asbestos toxicity can assist in equipping patients with thorough knowledge (http://www.atsdr.cdc.gov/csem/asbestos/docs/asbestos_patient-education.pdf).2 For the rare patient who is diagnosed with MPM, prompt referral to a pulmonologist and oncologist is imperative.

When formulating treatment plans for patients with MPM, it is important to know whether the patient wants palliative treatment or radical treatment. Palliative care is aimed at symptom control with the goal of decreasing pain and shortness of breath. Debulking pleurectomy, palliative radiation and palliative chemotherapy are the primary interventions in this approach.6

For radical treatment, the first intervention is surgery. Patients with stage I, II or III MPM may be candidates for surgical intervention.5 Extrapleural pneumonectomy (EPP) involves removal of the pleura, lung and mediastinal lymph nodes.6 In a study involving 636 patients who underwent EPP, 117 (18%) survived 3 or more years following surgery.9 Another review of 83 patients who underwent EPP reported a 15% 5-year survival rate.5

Radiotherapy, chemotherapy and multimodal treatments are used as part of radical treatment plans. Pemetrexed (Alimta) was the first agent to receive FDA approval for use in combination with cisplatin (Platinol) for the treatment of malignant mesothelioma.5 Since then, A large trial of 456 patients reported median survival with pemetrexed and cisplatin combination therapy at 12.1 months, compared to 9.3 months with cisplatin alone.6

Case Outcome

TD put up a valiant fight in his struggle against MPM. His grim prognosis of 6 months to live was not acceptable for him or his family. He elected for radical multimodal therapy and underwent surgical extrapleural pneumonectomy, radiation, chemotherapy and alternative holistic treatments. TD’s early diagnosis, aggressive treatment plan, use of renowned specialists and strong will to live extended his life for 4 years after his initial diagnosis.

References

1. Howlader N, et al. SEERS Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). National Cancer Institute. http://seer.cancer.gov/csr/1975_2009_pops09/results_merged/sect_17_mesothelioma.pdf

2. Kapil V. Transcript for Agency for Toxic Substances and Disease Registry’s

Environmental Medicine Grand Rounds: Asbestos Toxicity.http://www.atsdr.cdc.gov/csem/asbestos/grand_rounds/asbestos_grand_rounds_transcript.pdf

3. Priority list of hazardous substances That Will Be the Subject of Toxicology Profiles. Agency for Toxic Substances & Disease Registry. http://www.atsdr.cdc.gov/spl/

4. Brashers VL. Alterations of pulmonary function. In: McCance KL et al, eds. Pathophysiology: the Biological Basis for Disease in Adults and Children. 6th ed. Maryland Heights, MO: Mosby Elsevier; 2010: 1266-1309

5. Chen SE, Pace MB. Malignant pleural mesothelioma. Am J Health Syst Pharm. 2012;69(5):377-385.

6. Thiel EV, et al. European guidelines for the management of malignant pleural mesothelioma. J Adv Res.2011;2(4):281-288.

7. Gueugnon F, et al. Identification of novel markers for the diagnosis of malignant pleural mesothelioma. Am J Pathol. 2011;178(3):1033-1042.

8. Moores S, et al. Living with mesothelioma: A literature review. Eur J Cancer Care. 2010;19(4):458-469.

9. Sugarbaker DJ, et al. Clinical and pathological features of three-year survivors of malignant pleural mesothelioma following extrapleural pneumonectomy. Eur J Cardiothorac Surg. 2011;40(2):298-303.

10. Tucker P. Asbestos toxicity. Agency for Toxic Substances and Disease Registry. http://www.atsdr.cdc.gov/csem/asbestos/docs/asbestos.pdf

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About Author

Ellen Nicole Desimone

Ellen is a student in the nurse practitioner program at the University of North Florida in Jacksonville.

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