| disease | Metastatic Pleural Tumor |
Metastatic pleural tumors often cause exudative malignant pleural effusion, indicating that the patient already has systemic metastatic disease with an extremely poor prognosis.
bubble_chart Etiology
There are three types of tumors that metastasize to the pleura, causing malignant pleural effusion, accounting for approximately 75% of all malignant pleural effusion cases: lung cancer (30%), breast cancer (25%), and lymphoma (20%). Metastatic ovarian cancer accounts for 6%. Solid tumors, particularly melanoma, make up 3%. In 6% of patients with malignant pleural effusion, the primary cancer is never identified.
Metastatic pleural tumors can cause malignant pleural effusions through various mechanisms (Table 1). According to Light's view, tumor metastasis to the pleura increases pleural surface permeability, allowing more proteins to leak into the pleural cavity. However, the pleural protein content in patients with malignant pleural effusions is similar, so increased pleural permeability is not the primary cause of effusion.
In most patients with metastatic pleural tumor diseases, the main mechanism of pleural effusion may be the reduced ability to clear proteins from the pleural cavity. The amount of lymphatic fluid drained from the pleural cavity of malignant pleural effusion patients is less than that of patients with subcutaneous node disease, pulmonary embolism, or congestive heart failure. This is due to tumor metastasis to the parietal pleura, obstructing its lymphatic vessels, or tumor involvement of mediastinal lymph nodes, reducing lymphatic flow to the parietal pleura.
If a lobe or main bronchus is obstructed by a tumor, the lung tissue distal to the obstruction collapses, while the remaining lung tissue becomes hyperinflated or the ipsilateral chest wall invades inward, leading to increased negative pleural pressure. If partial bronchial obstruction causes distal pneumonia, parapneumonic pleural effusion may form.
Table 1 Mechanisms of pleural effusion caused by malignant tumors| Increased pleural permeability after pleural metastasis |
| Pleural metastasis obstructing pleural lymphatic vessels |
| Involvement of mediastinal lymph nodes, reducing pleural lymphatic drainage |
| Bronchial obstruction, decreased pleural cavity pressure |
| Post-obstructive pneumonia |
| Rupture of the thoracic duct (chylothorax) |
| Pericardial involvement |
| Hypoproteinemia |
| Pulmonary embolism |
| Post-radiotherapy |
Obstruction of the thoracic duct by tumors can also cause chylothorax. Most non-traumatic chylothorax cases are secondary to tumor invasion of the thoracic duct, with lymphoma being particularly prone to causing chylothorax. If the tumor involves the pericardium, increasing venous pressure in the systemic and pulmonary circulation, it may lead to pleural transudate. Pleural effusion in patients with metastatic pleural tumor diseases may also result from hypoproteinemia, pulmonary embolism, or post-radiotherapy.
In patients with bronchial lung cancer, pleural metastasis occurs when tumor emboli from the pulmonary circulation flow into the ipsilateral visceral pleura, while parietal pleural metastasis is an extension of visceral pleural metastasis. Bilateral pleural metastasis indicates that the patient's liver is already involved, with tumor emboli metastasizing from liver metastases.
bubble_chart Clinical Manifestations
Approximately 50% of patients with pleural metastasis have malignant pleural effusion, with the most common symptom being shortness of breath. Only 25% of patients with malignant pleural effusion experience chest pain, typically dull in nature. Some symptoms are related to the tumor itself, such as weight loss, general malaise, and anorexia. About 20% of patients are asymptomatic when pleural effusion occurs. The volume of pleural effusion ranges from a few milliliters to several liters, completely opacifying the patient's thoracic cavity and shifting the mediastinum to the contralateral side. If one side of the thoracic cavity becomes opaque without mediastinal shift, the patient may have bronchial lung cancer combined with main bronchial obstruction or tumor involvement fixing the mediastinum, or malignant pleural mesothelioma. If the mediastinum shifts toward the side with pleural effusion, it indicates higher negative pressure in the affected thoracic cavity compared to the healthy side, making pleurodesis less effective.
Approximately 50% of patients with breast carcinoma metastasizing to the pleura develop pleural effusion, most often on the same side as the primary tumor. The average time from the discovery of primary breast carcinoma to the appearance of pleural effusion is 2 years, with rare cases extending up to 20 years.
Pleural effusion in lymphoma or leukemia patients may result from mediastinal lymph node involvement, which can only be detected by mediastinal CT.
Malignant pleural effusion is exudative, primarily identified by elevated lactate dehydrogenase levels rather than protein levels. Grossly, the effusion may appear bloody, but 50% of malignant pleural effusions have red blood cell counts <10×109/L (10,000/mm3). The cell differential mainly consists of small lymphocytes, with other cells like polymorphonuclear or neutrophils being less common, and eosinophils rarely seen. About 15% of malignant pleural effusions have glucose levels below 3.3 mmol/L (60 mg/dL), with low pH and high lactate dehydrogenase levels. These patients often have a large tumor in the thoracic cavity, poor prognosis, and an average survival time of 1 month. Amylase levels are elevated in 10% of malignant pleural effusions, but the primary tumor in these cases is usually not pancreatic.
The diagnosis of malignant pleural effusion primarily relies on cytological examination of the pleural fluid and pleural biopsy. Chest CT is also helpful for diagnosis (Figure 1).
**Figure 1** CT scan of metastatic carcinoma in the right upper chest wall two years after resection of squamous cell carcinoma in the right upper lobe.
Cytological examination of pleural fluid can detect tumor cells and classify them pathologically. Experience shows that if it is adenocarcinoma, the location of the primary tumor is generally difficult to identify, and it is not easy to distinguish from malignant pleural mesothelioma.
2. **Pleural Biopsy** It is generally believed that pleural fluid cytology is more effective than pleural biopsy for definitive diagnosis. However, in some cases, pleural fluid cytology is negative while pleural biopsy is positive. Needle biopsy of the pleura confirms malignant pleural involvement in about 40–75% of cases. In clinical practice, for patients suspected of malignant pleural involvement, diagnostic thoracentesis is performed first. If the fluid is exudative, cytological examination should be done first. If the result is negative, a pleural biopsy should be performed, and another pleural fluid specimen should be sent for cytology.
3. **Other Diagnostic Tests** In recent years, measuring various tumor markers in pleural fluid has been suggested for diagnosing malignant pleural effusion, including carcinoembryonic antigen (CEA), immunosuppressive acidic protein, carbohydrate antigen IgG, tissue polypeptide antigen, alpha-fetoprotein, alpha-acid glycoprotein, and β2-microglobulin. Generally, the average levels of these tumor markers are higher in malignant pleural effusions than in benign effusions. However, due to frequent overlap between the two groups, an elevated level of any single marker cannot be used as a definitive diagnostic criterion for malignant pleural effusion. Recently, immunochemical staining of pleural fluid cells using a panel of monoclonal antibodies has shown promise for diagnosing malignant pleural effusion, but this method requires further development.
Analysis of chromosomes in pleural fluid cells can sometimes be effective. Malignant cells often exhibit more chromosomes and marker chromosomes, i.e., structurally abnormal chromosomes. Chromosomal analysis may be more useful than routine cytology in diagnosing pleural leukemia, lymphoma, or cases where pleural biopsy is negative but malignant pleural effusion is highly suspected.
4. **Pleural Biopsy** Many patients with exudative pleural effusion show no diagnostic results from pleural fluid cytology, thoracentesis, or other tests, yet some may still have malignant pleural effusion. If the effusion is asymptomatic, subcutaneous node tests are negative, and the effusion gradually resolves, observation for 3 months may be advised. However, if the patient experiences dyspnea, worsening symptoms, weight loss, and a significant history of cancer, thoracotomy for pleural biopsy should be considered. During surgery, extensive gauze abrasion of the pleural surface can effectively achieve pleurodesis.
bubble_chart Treatment Measures
For patients with malignant pleural effusion, the first step is to determine the nature of the primary tumor. The presence of malignant pleural fluid indicates systemic dissemination, and the only viable treatment option is systemic chemotherapy. In patients with carcinoma of the breast metastasizing to the pleura, pleural effusion disappears in 40% of cases after systemic chemotherapy. For small-cell lung cancer treated with systemic chemotherapy, pleural effusion is controlled in less than 35% of patients.
In 75% of patients with malignant pleural effusion, the primary tumor originates from the lung, breast, or lymphoma, while most other primary tumors arise from the abdominal cavity. For patients with malignant pleural effusion of unknown origin, chest and abdominal CT scans, mammography, and pelvic examinations should be performed. If these tests fail to identify the primary tumor, further investigations are unnecessary. The survival time of patients with malignant pleural effusion is limited, and prolonged hospitalization or extensive testing to locate the primary tumor is not warranted. Approximately 6% of patients never have their primary tumor identified.
Chemical pleurodesis: For patients unsuitable for or unresponsive to systemic chemotherapy, chemical pleurodesis should be considered. The goal is to obliterate the pleural space to prevent fluid reaccumulation, not to reduce tumor size. Therefore, this procedure is only suitable for symptomatic patients. If the patient is asymptomatic, there is no need to subject them to unnecessary interventions. Patients in the terminal stages due to tumor spread also do not require pleural drainage. For symptomatic patients, if symptoms improve after thoracentesis, pleurodesis should be considered. Before performing pleurodesis, mediastinal shift must be assessed. If the mediastinum shifts toward the side of the effusion, it indicates that the ipsilateral lung cannot expand normally, and the increased negative pressure in the pleural space prevents pleural apposition, making pleurodesis unsuitable.
Chemical pleurodesis involves injecting an agent into the pleural cavity to induce a strong inflammatory reaction, causing the parietal and visceral pleurae to adhere and close the pleural space, preventing further fluid accumulation. Before the procedure, a chest tube should be placed to drain the fluid, ensuring the pleural surfaces are apposed for effective adhesion after sclerosing agent injection.
Choice of sclerosing agents: Several agents are available, including anticancer drugs like nitrogen mustard and bleomycin, radioactive isotopes, quinacrine, talc powder, tetracycline, and Corynebacterium parvum. Animal studies show tetracycline is the most effective sclerosing agent, while quinacrine has poor long-term efficacy. Intrapleural talc can cause severe pneumonitis, and anticancer drugs may lead to systemic chest pain, fever, and poor outcomes.
Technique: Before chemical pleurodesis, a closed chest drainage system should be established to drain as much fluid as possible. If the lung fails to re-expand after 24 hours of water-seal drainage, negative-pressure suction can be applied for rapid drainage. However, chronic effusions may risk re-expansion pulmonary edema. If chest tube drainage fails to re-expand the lung, pleurodesis is contraindicated, as it may further thicken the visceral pleura and impair underlying lung function.
Once the lung is fully re-expanded, pleurodesis should be performed promptly without delaying until drainage cessation. Given the severe pain caused by sclerosing agents, local or systemic analgesics should be administered before tetracycline injection. For local anesthesia, 150 mg lidocaine diluted in 50 ml solution can be instilled into the pleural cavity, with the patient changing positions frequently over 10–15 minutes to ensure full pleural coverage. Tetracycline (20 mg/kg) is diluted in 50 ml solution and injected via the chest tube, followed by 15 ml saline to flush residual tetracycline.
After injecting tetracycline, immediately clamp the chest tube for 2 hours and have the patient change positions: supine, prone, left and right lateral decubitus, and sitting, to ensure tetracycline contacts all surfaces of the pleural membrane. Then open the chest tube and connect it to negative pressure of -1.47 to -1.96 kPa (-15 to -20 cmH2O), maintaining continuous suction for at least 48 hours until pleural drainage is less than 150 ml/day. Tetracycline works by inducing a strong inflammatory reaction, causing the visceral and parietal pleural membranes to adhere to each other, thereby obliterating the pleural cavity.
Chemical pleurodesis achieves an 80-90% success rate in appropriately selected cases. Failed pleurodesis cases are those with mediastinal shift toward the effusion side and lungs that fail to re-expand after chest tube drainage.
Thoracentesis: A series of intermittent therapeutic thoracentesis provides limited efficacy for malignant pleural effusion patients, as pleural fluid typically reaccumulates within 1-3 days after drainage. Additionally, repeated thoracentesis leads to protein depletion—it is estimated that draining 2000ml of pleural fluid (400g/L) results in a loss of 80g of protein. Repeated thoracentesis can also cause loculated effusions, complicating subsequent pleurodesis. Therefore, therapeutic thoracentesis is more suitable for advanced-stage cases where the goal is merely symptom relief from fluid compression. It may also be considered for patients whose lungs fail to re-expand and are thus unsuitable for pleurodesis.
Pleurectomy: The following scenarios warrant consideration of pleurectomy: ① Patients with a high suspicion of malignant effusion but unclear diagnosis may undergo parietal pleurectomy during diagnostic thoracotomy. ② Patients with confirmed malignant disease may require parietal pleurectomy to prevent recurrent malignant effusion. ③ Patients with persistent symptomatic pleural effusion and ipsilateral lung collapse should undergo decortication of the visceral pleura (to re-expand the lung) and parietal pleurectomy. Pleurectomy effectively controls effusion in 90% of cases, though surgical mortality is around 10%. The procedure is suitable for patients in relatively good general condition, with slow-progressing or controlled primary tumors, and symptomatic effusions.
The prognosis for patients with malignant pleural effusion is very poor. Chernow reported that among 96 patients, the average survival time after diagnosis was only 3.1 months, with 54% dying within one month and a mortality rate of 84% at six months. The average survival time for 30 lung cancer patients was 7.3 months. Currently, there are no effective measures to prolong the lives of these patients.
