Advances in the diagnosis and treatment of malignant pleural effusion
Malignant pleural effusion is an important complication of intra- and extra-pulmonary tumors, with a median survival of four months after diagnosis. Its an advanced manifestation of the tumor. The common types of tumors causing malignant pleural effusion are: lung cancer, lymphoma, ovarian cancer, breast cancer and gastrointestinal tract tumors. >75% of malignant pleural effusions are lung cancer, breast cancer, ovarian cancer and lymphoma. Cytology or histology can determine the diagnosis. Even if malignancy is identified, more than 50% are benign diseases. The management of malignant pleural effusions remains palliative and appropriate treatment must be based on the experience of the available literature and the clinical condition of the patient. Xu Dalin, Department of Respiratory Medicine, Lujiang County People’s Hospital
Pathology: Malignant pleural effusion (MPE) is defined as the presence of cancer cells in the pleural cavity. Metastatic MPEs can be caused by direct progression of adjacent cancers (e.g., lung, breast, and chest wall cancers), cancer invasion of the pulmonary vasculature embolizing the dirty pleura, or hematogenous dissemination of distant tumors to the mural pleura. Once the tumor invades the pleural cavity, the tumor will deposit along the mural pleura and obstruct the draining lymphatics, resulting in impaired drainage of pleural fluid. At the same time, pleural tumor deposition leads to the release of cytokines, causing increased vascular and pleural permeability. Even if there are no cancer cells in the pleural cavity, cancer patients suffer from a pleural effusion caused by the indirect effects of cancer. This effusion is called paraneoplastic effusion and can be caused by lymph node tumor invasion, bronchial obstruction, radiotherapy, pulmonary embolism, superior vena cava obstruction, and decreased colloid osmotic pressure.
Pleural effusion develops in 20-30% of patients with lymphoma. Most pleural effusions in Hodgkin patients are caused by tumor invasion of the thoracic duct, and most pleural effusions in non-Hodgkin patients are caused by direct tumor invasion of the pleura. Non-Hodgkin’s lymphoma is the most common cause of celiac pleural effusion.
Lymphomas do not usually present as isolated pleural effusions. An exception is primary effusion lymphoma, where the typical large cell lymphoma involves the pleural cavity exclusively or predominantly, with no lymphoma elsewhere. Body cavity site lymphomas have been reported in patients with AIDS combined with herpes zoster8 infection. These patients may have coexisting Karber’s sarcoma. Primary lymphoma pleural effusions appear to be produced by vascular endothelial growth factor or vascular permeability factor, which appears to alter the permeability of the blood vessels and pleura. Patients with chronic chest infections may develop pustulothorax-associated lymphoma – a distinctive manifestation of non-Hodgkin’s lymphoma.
Diagnosis
The history and physical examination of patients with MPEs is nonspecific and requires cytopathology of the pleural effusion or pleural histology analysis. Most patients with malignant pleural effusions caused by adenocarcinoma do not have chest pain, whereas 60% of patients with mesothelioma have persistent dull pain or localized pleuritic pain. Malignant pleural effusions caused by sarcomas present as pneumothorax. A diagnosis of malignancy in a patient with a pleural effusion does not establish MPE, as 50% of such effusions are nonmalignant.
Some times, determining the etiology of pleural effusion does not provide prognosis or treatment outcome. For example, a person with multiple coexisting disease conditions and no pleural effusion may benefit from observation rather than an invasive workup. Conversely, a person with an underlying malignancy should not assume that a pleural effusion is malignant, as malignant pleural effusions can alter tumor staging and treatment decisions.
Imaging
Although standard chest radiographs can detect as little as 50 ml of fluid from a lateral view, they only provide a constructive diagnosis of MPE: lobar pleural thickening, narrowing of the intercostal space, elevation of the diaphragm or a large amount of longitudinal pleural effusion due to pulmonary atelectasis combined with the moon sign, contralateral displacement of the mediastinum, and diaphragmatic flip suggest a high likelihood of malignant pleural effusion. Radiographic imaging suggests malignant pleural effusion including ipsilateral displacement of the septum.
Ultrasound can detect fluid as small as 5 ml. Ultrasound suggestive of MPE includes solid dense pleura, irregular or lobulated pleural thickening, invasion of pleural masses into adjacent structures, and cellular debris shock. Pleural metastases can be circumscribed, nodular, hemispherical or broad-based lobulated invading the pleural cavity.
Enhanced CT can provide the most valuable information. CT before massive drainage of pleural effusion improves the sensitivity of the diagnosis because it separates the dirty pleura from the mural pleura.
The following CT findings suggest MPE: circumferential pleural thickening, nodular pleural thickening, mural pleural thickening greater than 1 cm, mediastinal pleural thickening, or primary tumor. Findings suggestive of mesothelioma include interlobular fissure involvement and pleural thickening greater than 1 cm. the presence of both pleural spots and diffuse pleural thickening are more suggestive of mesothelioma.
MRI is better for soft tissue imaging than CT and can detect tumor invasion of the chest wall and diaphragm. mri is valuable in distinguishing exudate from leaky fluid and is more likely to detect small amounts of effusion. Although MRI is similar or slightly better for diagnosing MPE, it should be used conservatively because its imaging of the lung parenchyma is not as good as enhanced CT.
The sensitivity of PET-CT for MPE is 93%-100%, negative predictive value is 94-100%, specificity is 67-89%, and positive predictive value is 63-94%. False positives include: uremic pleurisy, parapneumonic effusion and other inflammatory states of the pleura.PET-CT can guide puncture.
Analysis of pleural effusions
Despite the availability of new chest imaging methods, for determining the diagnosis must rely on cytology and pathology. 3-10% of malignant pleural effusions are leaky, which is related to diagnostic criteria, coexisting diseases such as hypoproteinemia, cirrhosis, and heart failure.
Criteria for determining exudative pleural effusion
1.Cell count
Lymphocytes: greater than 50% of MPEs have lymphocytes occupying 50-70% of the nucleus; lymphocytes greater than 85% suggest tuberculous, lymphoma, chronic rheumatoid pleural effusion, yellow nail syndrome, or cholesterol chest.
Erythrocytes: MPEs are common, but also seen in benign asbestos pleurisy, trauma, and pulmonary infarction.
Eosinophils: Greater than 10% eosinophils are called eosinophilic pleural effusion, and 12-24% of eosinophilic pleural effusions are malignant.
2. Biochemical tests.
Protein and LDH: Most are exudate, but 3-10% are leaky; LDH > 1000 IU/L narrows the differential diagnosis: MPE, pustular pleural, rheumatoid pleurisy and pulmonary schistosomiasis.
Amylase: unless pancreatic disease or esophageal rupture is suspected, elevated amylase in MPEs suggests short survival.
Sugar: <60 mg/dL suggests MPE, rheumatoid pleural effusion, complicated parapneumonic effusion, tuberculous pleurisy, lupus pleural effusion, and esophageal rupture.
Treatment of MPEs
The management of pleural effusions in MPEs is palliative and does not improve survival, and most physicians wait for the onset of symptoms associated with pleural effusions that affect respiratory function before intervening. However, some experts recommend interventions to avoid pleural lobulation at the outset of the diagnosis of MPEs, complicating treatment. Interventions include aspiration of the pleural fluid, pleural fixation when appropriate, or long-term drainage to prevent fluid accumulation.
Therapeutic thoracentesis
Treatment of symptomatic MPEs should be initiated with therapeutic thoracentesis and evaluation of dyspnea in response to fluid aspiration. When the patient’s dyspnea does not resolve with massive fluid aspiration, other causes of dyspnea should be considered, including: microscopic tumor thrombosis, lymphoma, or radiotherapy toxicity. Large volumes of fluid may lead to post-relaxation pulmonary edema.
Although the patient’s symptoms can improve after thoracentesis, most patients have fluid recolonization within 30 days. Repeated aspiration should be performed when 1) fluid accumulates slowly after each aspiration, 2) the pleural fluid resolves on its own with tumor treatment, 3) survival is less than 1-3 months, and 4) other interventions such as pleural cavity fixation cannot be performed. Otherwise, long-term chest drainage or pleural fixation should be performed.
Issues of concern for pleural fixation
1. How do the underlying tumor and the tumor causing the malignant pleural effusion respond to treatment? (e.g. small cell lung cancer)
2. Are the patient’s symptoms caused by the effusion?
Have symptoms improved after therapeutic thoracentesis?
Are there other causes of dyspnea that do not improve and do not respond to pleural cavity fixation?
3.Is the patient’s life expectancy greater than 2-3 months?
4. Can pleural fixation eliminate effusion and improve the patient’s symptoms sufficiently?
Can the lung be reopened after pleural aspiration?
Is imaging suggestive of multilobar pleural effusion or thickening of the dirty pleura suggestive of atrophic lung?
5.Does the intrathoracic tumor hinder the effect of pleural fixation?
Are large tumor masses found on the pleural surface?
Successful pleural fixation requires docking of the dirty pleura and mural pleura. Intratracheal tumors causing airway obstruction, extensive intrapleural tumor masses, and multiple pleural masses causing atrophic lung make such docking impossible. When a review of the chest radiograph after thoracentesis suggests a pneumothorax, it often suggests an atrophic lung. The cause of this pneumothorax is often the inability of the atrophic lung to reopen and the formation of a very large negative intrathoracic pressure after aspiration, with air entering the pleural cavity through the aspiration needle hole.
Most experts recommend the use of 9F-14F tubes rather than 20-32F tubes. Sclerosing agents may be injected into the pleural cavity at a drainage rate of less than 150 ml per day, and the drainage tube may be removed at a rate of less than 150 ml per day after injection.
Closed chest drains can be placed to drain pleural fluid 2-3 times a week at 1000 ml each time, but close attention should be paid to complications: catheter infection, cellulitis, catheter obstruction, abscess chest and tumor dissemination along the tube.
Some studies have found spontaneous pleural fixation in 40-58% of patients with 2-6 weeks of cannula drainage. Because of the high rate of spontaneous pleural fixation in those with long-term drainage, some experts suggest that MPE should be treated primarily with long-term drainage.
Conclusion
The diagnosis of MPEs can be confirmed by cytology, imaging-guided pleural biopsy, etc. Although MPEs can be treated by pleural fixation or long-term drainage, all approaches are palliative. All of these methods must be based on evidence-based medicine, combined with our own experience, to establish a set of diagnosis and treatment methods suitable for the actual situation of the department, and constantly summarize and improve in practice.