What Is Causing This Man’s Worsening Dyspnea, Back Pain, and Weakness?

A 76-year-old man presented with progressive shortness of breath, back pain, and generalized weakness over the past 6 months. 

His past medical history was significant for prostate cancer, diagnosed 13 years prior, which had been treated with bicalutamide and hormone injections, but not surgery or external radiation therapy. He also had a history of hypertension, osteoporosis, and an unhealed left humerus fracture sustained 2 years ago.

The dyspnea had acutely worsened over the past month, particularly with exertion, and sometimes was accompanied by chest discomfort, which he described as parasternal aching that self-resolves within minutes, with no radiation. He denied paroxysmal nocturnal dyspnea or orthopnea, but he complained of having subjective fevers and chills for the past months. He had lost approximately 9 kg in last 6 months, and he had quit smoking last year, with a 10 pack-year history. He had worked for 30 years as an apartment manager and in the steel industry.

Physical Examination

The patient was alert and oriented. He was thin and appeared somewhat pale. His vital signs were as follows: temperature, 35.6°C; blood pressure, 101/54 mm Hg; heart rate, 107 beats/min; respiratory rate, 30 breaths/min; and oxygen saturation, 93% on room air. Cardiac examination revealed a regular rhythm but tachycardia; a 3/6 systolic murmur was appreciated at the left upper sternal border, with no radiation to the carotids. On auscultation of the lungs, he was tachypneic, with decreased breath sounds to the entire left lung field, along with bibasilar crackles, with the left side worse than the right.

Musculoskeletal examination revealed diffuse thoracolumbar spinal tenderness and a chronic left shoulder deformity with limited range of motion. Examination of the extremities revealed equal 2+ pulses, no pitting edema, and no calf tenderness.

Chest radiographs were obtained (Figure 1) and demonstrated abnormalities, prompting chest computed tomography (CT) with contrast to be performed (Figure 2).

What’s Your Diagnosis?

1. Lung cancer
2. Malignant mesothelioma
3. Empyema
4. Pleural tuberculosis
5. Effusion secondary to pulmonary embolism

Answer: Malignant mesothelioma

The CT scans were negative for pulmonary embolism (PE). However, there was a grossly abnormal, lobulated, thickened contour of the left pleural surface with involvement of the mediastinal pleura, and associated pleural plaques were seen; similar findings were noted involving the right posterior pleural surface to a lesser extent. These findings were highly suggestive of malignant mesothelioma. The patient was admitted to the hospital for further evaluation and workup.

A pulmonologist was consulted and recommended consultation with a thoracic surgeon for video-assisted thorascopic surgery (VATS), but the patient and his family refused further workup or aggressive treatment measures. His code status was changed to do not resuscitate. A palliative care specialist was consulted and helped arrange transfer to a hospice center, where the man died a short time later.

Discussion

Malignant mesothelioma is a rare neoplasm that arises most commonly from the mesothelial surfaces of the pleural cavity, less commonly from the peritoneal surface, and very rarely from the tunica vaginalis or pericardium. Regardless of the therapeutic approach, according to the International Association for the Study of Lung Cancer and the International Mesothelioma Interest Group database, it has an extremely poor prognosis, with a median survival of 11 to 20 months for untreated patients and 12 to 30 months for treated patients.¹

The predominant cause of malignant mesothelioma is asbestos inhalation. The estimated annual US incidence of mesothelioma is approximately 3300 cases,² and this number is declining as a result of control and regulation of asbestos exposure.³

Asbestos is the collective name for a group of hydrated magnesium silicate fibrous minerals. It occurs naturally in soil and rock as long fibers. Asbestos is most useful to industry for its resistance to heat and combustion. It is used in cement, ceiling and pool tiles and insulation, automobile brake linings and friction materials, and in shipbuilding.

Risk Factors

Efforts to control occupational exposure to asbestos have resulted in a significant decrease in the incidence of mesothelioma; however, there is a prolonged latency period after exposure to asbestos, with almost all cases appearing 15 or more years after exposure. This risk persists for many decades. Workers exposed to higher concentrations of regulated fibers (greater than 0.1 fibers/mL of air) in the United States are mandated to use protective clothing and respirators.⁴ The lifetime risk of developing mesothelioma among asbestos workers is thought to be as high as 10%, with a dose-response relationship between asbestos exposure and mesothelioma (ie, the greater the exposure, the greater the risk of developing mesothelioma).⁵

Other risk factors that increase the potential for developing mesothelioma include environmental nonoccupational exposure to asbestos; exposure to ionizing radiation; exposure to carbon nanotubes; certain viral oncogenes, such as simian virus 40; and genetic factors, such as inactivation of the nuclear deubiquitinase BAP1, which regulates key transcription factors related to the development of tumors.

Presentation

Malignant pleural mesothelioma usually presents with nonspecific pulmonary symptoms such as chest pain, dyspnea, and/or cough related to the presence of extensive intrathoracic disease. Symptoms may be present for months or longer before diagnosis. In patients with advanced disease, systemic symptoms such as fatigue and weight loss also may be present. Common physical findings at the time of diagnosis include decreased air movement on the side of involvement, asymmetric chest wall expansion during inspiration, and unilateral dullness to percussion at the lung base. Palpable chest wall masses and scoliosis toward the side of the malignancy also may be seen in patients with advanced disease.

Diagnostic Tests

Chest imaging generally is done as part of the initial symptom evaluation. Although imaging cannot establish the diagnosis, it may provide substantial evidence suggesting the presence of mesothelioma. Typically, chest radiographs show a unilateral pleural abnormality with a large, unilateral pleural effusion. Other findings include a pleural mass or rind or diffuse pleural thickening in the absence of a pleural effusion, ipsilateral mediastinal shift, and significant unilateral loss of lung volume. Other thoracic imaging approaches such as CT, magnetic resonance imaging, or positron emission tomography–CT are commonly used to further characterize the extent of disease involvement. Several biomarkers, including fibulin-3, mesothelin, and osteopontin are selectively elevated in patients with mesothelioma. However, these biomarkers do not yet have an established role in making the initial diagnosis or monitoring response to therapy.

The diagnosis of malignant pleural mesothelioma always should be based on results of an adequate biopsy. A thoracentesis for cytology and closed pleural biopsy is generally the initial procedure and may be sufficient to establish the diagnosis of mesothelioma; however, negative results do not exclude it.

Surgical intervention with VATS or open thoracotomy is generally the next step to establish a diagnosis.

Malignant mesothelioma typically is classified into 3 broad histologic subtypes: epithelioid, sarcomatoid, and biphasic, with the epithelioid variant being the most common, comprising approximately 60% of all mesotheliomas.⁶

Patients with malignant mesothelioma most often present with locally extensive disease, and prognosis for prolonged survival generally is poor. Surgery with macroscopic complete resection, radiation therapy, and/or systemic chemotherapy may be beneficial.

Disease Course

Local invasion is the primary underlying cause of malignant mesothelioma. Despite treatment with surgery with or without radiation therapy, most patients develop systemic metastases. Patients typically develop dyspnea and chest pain as the tumor gradually overtakes and eliminates the pleural space. As the tumor spreads, deoxygenated blood is shunted, leading to fatigue, dyspnea, and hypoxemia that often is refractory to supplemental oxygen. Local invasion of vital thoracic structures can result in symptoms such as dysphagia, hoarseness, Horner syndrome, spinal cord compression, brachial plexopathy, or superior vena cava syndrome. Extension through the diaphragm into the abdominal cavity also can occur, as can metastases to the opposite lung, brain, and other extrathoracic sites.

The majority of affected patients die from local extension and respiratory failure. Other causes of death include arrhythmias, heart failure, and stroke caused by local invasion of the heart or pericardium; extension below the diaphragm can lead to small bowel obstruction, bowel necrosis, and eventual death.

Differential DIAGNOSIS

The term lung cancer is used for tumors arising from the respiratory epithelium (bronchi, bronchioles, and alveoli) and is divided into several histologic subtypes. The 2015 World Health Organization classification for primary lung cancer is the foundation for this classification.⁷ 

Until recent years, the simple pathologic separation of non-small cell lung cancer (NSCLC) from small cell lung cancer (SCLC), along with the cancer stage, was adequate to make treatment decisions for a new diagnosis of lung cancer. However, with advances in treatment, further differentiation has proven beneficial.⁷ Treatment decisions are based on whether a tumor is classified as an SCLC or as one of the NSCLC types (squamous, adenocarcinoma, large cell, bronchioloalveolar, or a mixed version of these).

Approximately 90% of patients with lung cancer, regardless of histologic subtype, are current or former cigarette smokers.⁸ Lung cancer gives rise to signs and symptoms caused by local tumor growth, invasion or obstruction of adjacent structures, growth in regional nodes through lymphatic spread, growth in distant metastatic sites after hematogenous spread, and paraneoplastic syndromes. The appearance of lung cancer on chest radiographs and/or CT scans is quite variable and depends on the type and the extent of the disease at the time of imaging. Lung cancer is 1 of the 3 tumors (along with breast and lymphoma) responsible for approximately 75% of all malignant pleural effusions.⁹ Although imaging findings may be suggestive of a diagnosis of lung cancer, a definitive diagnosis cannot be made without a biopsy/tissue diagnosis.

Parapneumonic effusions are associated with bacterial pneumonia, lung abscess, or bronchiectasis. Empyema refers to a grossly purulent effusion. Patients with aerobic bacterial pneumonia and pleural effusion present with an acute febrile illness, chest pain, sputum production, and leukocytosis. Patients with anaerobic infections present with a subacute illness and a predisposition to aspirate. The presence of free pleural fluid can be demonstrated with a lateral decubitus chest radiograph, CT of the chest, or ultrasonography. If the free fluid separates the lung from the chest wall by greater than 10 mm, a diagnostic/therapeutic thoracentesis should be done. Factors indicating the need for a more invasive procedure, such as placement of a chest tube, include loculated pleural fluid, pleural fluid with a pH less than 7.2, a pleural fluid glucose level less than 60 mg/dL, positive Gram stain or culture of the fluid, or the presence of gross pus. Failure to drain most or all of the fluid indicates the need for additional treatment such as decortication or a thoracotomy.

Tuberculosis (TB) is classified as pulmonary, extrapulmonary, or both. Involvement of the pleura accounts for approximately 20% of extrapulmonary cases in the United States.¹⁰ It is common in primary TB and may result from either contiguous spread of parenchymal inflammation or actual penetration by tubercle bacilli into the pleural space. Symptoms include fever, weight loss, dyspnea, and pleuritic chest pain. Examination findings include the absence of breath sounds and dullness to percussion. A chest radiograph exposes the effusion and in up to a third of cases also shows a parenchymal lesion. Thoracentesis is required to differentiate the effusion from manifestations of other etiologies. The diagnosis can be established by demonstrating high levels of TB markers in the pleural fluid (adenosine deaminase greater than 40 IU/L, interferon-γ greater than 140 pg/mL, or positive polymerase chain reaction test results for tuberculous DNA). Otherwise, the diagnosis can be established by culture of the pleural fluid, needle biopsy of the pleura, or thoracoscopy. The recommended treatment of pleural and pulmonary TB is the same. A less common complication is tuberculous empyema. Surgical drainage usually is required as an adjunct to chemotherapy.

PE is frequently overlooked in the differential diagnosis of a patient with a pleural effusion. The most common symptom is dyspnea. The pleural fluid almost always is an exudate. The diagnosis is established with CT scan with a PE protocol or pulmonary arteriography. Treatment is the same as for any patient with PE. If the pleural effusion increases in size after anticoagulation, the patient likely has recurrent emboli or another complication such as a hemothorax or infection.

Emily Dodge, MD, is assistant professor of emergency medicine at Case Western Reserve University School of Medicine and an attending physician in the Department of Emergency Medicine at MetroHealth Medical Center in Cleveland, Ohio.

David Effron, MD, is assistant professor of emergency medicine at Case Western Reserve University and an attending physician in the Department of Emergency Medicine at MetroHealth Medical Center in Cleveland, Ohio.

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