Malignant pleural effusion (MPE) is a pleural effusion caused by a malignant tumor originating in the pleura or a malignant tumor metastasizing to the pleura from other sites. At present, there is a lack of epidemiological research data on MPE at home and abroad. According to statistics, the number of patients with MPE in the United States exceeds 150,000 per year.
MPE can occur in almost all malignant tumors; lung cancer is the most common cause, accounting for about 1/3 of MPE, followed by breast cancer, lymphoma is also an important cause of MPE, while ovarian cancer and gastrointestinal tract cancer are not uncommon. 5-10% of MPE cannot be found in the primary tumor lesion.
The presence of MPE indicates tumor dissemination or progression to an advanced stage and significantly shortens the life expectancy of the patient, with a median survival of 3-12 months from the time the diagnosis is established, depending on the type and stage of the primary tumor. It has been shown that patients with MPE due to lung cancer have the shortest survival, those with MPE due to ovarian cancer have the longest survival, and those with MPE where the primary site cannot be found have an intermediate survival.
Diagnosis
First of all, the “gold standard” for the diagnosis of MPE is to find malignant cells in pleural fluid precipitation or to observe pathological changes of malignant tumor in pleural biopsy tissue.
1 Clinical manifestations: Clinical manifestations can be an important clue for the diagnosis of MPE. Most patients with MPE have clinical symptoms, but about 25% of patients can also be asymptomatic and have MPE detected incidentally by physical examination or X-ray chest examination. dyspnea is the most common symptom, reflecting decreased chest wall compliance, restricted ipsilateral diaphragmatic activity, mediastinal shift and reduced lung volume. Chest pain is uncommon, and the presence or absence of chest pain is usually associated with malignancy involving the mural pleura, ribs and other intercostal tissue structures. In addition to respiratory symptoms, it is often accompanied by systemic symptoms such as weight loss, fatigue and loss of appetite, and cachexia may appear in advanced stages.
Other clinical symptoms may be related to the type of tumor. Patients with malignant pleural mesothelioma often have chest pain, mostly confined to the site of the lesion, and generally present with dull pain. hemoptysis in patients with MPE is highly suggestive of tumors of bronchogenic origin.
Past medical history is also important, such as history of smoking, occupational exposure, especially asbestos or other carcinogenic substances, etc. When the amount of MPE reaches a certain level, chest physical examination can reveal corresponding abnormal signs.
2. Imaging examination: Most patients with MPE can observe medium-large amount of pleural fluid on chest X-ray, generally 500-2,000 ml, of which about 10% of patients show large amount of pleural fluid (pleural fluid occupies more than half of one side of the chest cavity), and about 15% of patients have pleural fluid < 500 ml. If the mediastinum is not shifted to the opposite side, it suggests that the mediastinum is fixed, the main trunk of bronchus is blocked by tumor and appears pulmonary atelectasis, or extensive pleural infiltration (commonly seen in malignant pleural mesothelioma).
CT helps to detect small amounts of MPE in patients with malignancy, helps to determine whether MPE is associated with mediastinal lymph node metastases, and allows evaluation of underlying parenchymal lung lesions. pleural spots found on CT suggest a history of asbestos exposure. Ultrasonography helps to understand pleural involvement in patients with MPE and helps to localize thoracentesis in a small number of MPE, thus reducing complications of thoracentesis. MRI has limited diagnostic value in MPE, but MRI may be useful in assessing the extent of tumor invasion of the mediastinum or chest wall. Preliminary studies have shown that fluorodeoxyglucose positron emission CT scan (PET-CT) has good predictive value for MPE, but more evidence-based medical evidence is needed to support this.
3. Diagnostic thoracentesis: There is no absolute contraindication to performing thoracentesis, and relative contraindications include low chest volume (< 1 cm from the chest wall in the unilateral recumbent position), bleeding tendency, and being on anticoagulation therapy and mechanical ventilation. Thoracentesis does not increase the chance of bleeding in patients with mild to moderate coagulation disorders or thrombocytopenia. Major complications of thoracentesis include pleural reaction, pneumothorax, bleeding, infection, and puncture injury to the spleen or liver.
A pleural fluid examination should be performed when considering MPE: routine tests include nucleated cell count and classification, total protein, glucose, lactate dehydrogenase, and tumor cytology.
The vast majority of MPEs are exudate, and the cell classification is predominantly lymphocytic; however, a very small number are leaky. The cause of paraneoplastic pleural effusion is usually mediastinal lymph node involvement, pulmonary insufficiency due to bronchial obstruction, or combined non-malignant disease, etc. Some of these patients have combined congestive heart failure. Routine cytology of leaking fluid is not necessary in cases where the primary cause is clear.
Pleural fluid cytology is the simplest method to diagnose MPE, and its diagnostic efficiency is related to the type of primary tumor and its degree of differentiation, fluctuating from 62% to 90%. Multiple cytologic examinations can increase the positive rate.
Certain tumor markers such as carcinoembryonic antigen, cytokeratin fragment 21-1, and glycoantigens (e.g. CA125, CA15-3, CA19-9, etc.) contribute to the diagnosis of MPE. The sensitivity of these soluble indicators is generally not high, mostly 40%-60%, but the specificity is relatively high, reaching 80%-90%, so they have certain reference value. Combined detection of multiple tumor markers can improve their diagnostic efficiency.
Other methods such as immunohistochemical staining and chromosome analysis by applying monoclonal antibodies to tumor markers can help the differential diagnosis of pleural fluid. Because of their relatively low sensitivity and specificity, the diagnosis cannot be confirmed by these methods alone. Chromosomal analysis may help in the diagnosis of lymphoma and leukemia, especially when the initial cytology is negative, flow cytometry can be applied to detect DNA aneuploidy to assist in the diagnosis.
4. Closed pleural biopsy: The sensitivity of closed pleural biopsy for the diagnosis of MPE is lower than cytology, and its diagnostic rate is 40%-75%. If pleural abnormalities (such as mesothelioma) are detected by CT, percutaneous closed pleural biopsy under ultrasound or CT guidance is recommended. The relatively low diagnostic rate of closed pleural biopsy is related to the following factors: small extent of tumor involvement in the pleura, failure of pleural biopsy to reach the tumor site, and inexperience of the operator. However, studies have shown that 7-12% of MPE patients with negative cytology can still be diagnosed by closed pleural biopsy.
Contraindications to closed pleural biopsy include bleeding tendency, ongoing anticoagulation therapy, chest wall infection, and patient noncompliance. Major complications include pneumothorax, hemothorax, and pleural reactions. Pneumothorax is often caused by air entering the chest cavity through the puncture needle during biopsy, which is not particularly uncomfortable for the patient and usually does not require treatment.
5, endoscopic thoracoscopy: endoscopic thoracoscopy is mainly used for the differential diagnosis of unexplained exudative pleural effusion; MPE can also be treated by endoscopic thoracoscopic spraying of talcum powder for pleural fixation; compared with surgical thoracoscopy, endoscopic thoracoscopy has certain advantages, such as only local anesthesia or sedation is required, and biopsy of lesions in the chest wall, diaphragm, mediastinum, pericardium and lung can be performed. It is less invasive and less expensive than surgical thoracoscopy, etc.
Reasons for false-negative results in medical thoracoscopy include small biopsies or failure to biopsy the lesion, depending on the operator’s experience. In addition, the presence of tissue adhesions in the thoracic cavity that prevent the thoracoscope from reaching the tumor tissue can also limit the use of endoscopic thoracoscopy. Thoracoscopy can determine whether the pleural fluid in lung cancer patients is MPE or paraneoplastic pleural fluid, thus avoiding the need for open-chest exploration due to uncertainty about the stage of the tumor or facilitating more aggressive treatment of the patient once the paraneoplastic fluid is identified.
Because endoscopic thoracoscopy allows access to larger and more representative lesions, it facilitates earlier diagnosis, histologic classification and clinical staging of pleural malignancies than closed pleural biopsy. In addition, pleuroscopy can also detect abnormal changes such as pleural hypertrophy, bead-like lesions and calcifications, at which time benign asbestos pleural fluid can be considered and mesothelioma or other malignant diseases can be excluded.
After medical thoracoscopy, more than 90% of pleural effusions will be diagnosed with a clear etiology. In a very small number of patients, if the diagnosis is still difficult to confirm after thoracoscopy, surgical biopsy including surgical thoracoscopy or open chest biopsy can be considered.
6.Surgical biopsy: surgical biopsy can be performed in two ways: thoracoscopic or open chest. Surgical thoracoscopic biopsy usually requires general anesthesia and double-lumen tracheal intubation. Since the lungs are ventilated unilaterally during surgery, the visualization range of surgical thoracoscopy is wider than that of medical thoracoscopy, and both diagnostic and therapeutic operations can be performed. The patient’s inability to tolerate one-lung ventilation is a contraindication to surgical thoracoscopic biopsy, and open thoracic biopsy should be considered in this case. Thoracoscopy with adhesions in the thoracic cavity carries certain risks and should be performed with extra care. Preoperative chest X-ray or ultrasound examination of the chest cavity reveals obvious pleural adhesions, then open thoracic biopsy should be performed.
7.Bronchoscopy: Bronchoscopy should be performed when there is suspicion of intrapulmonary occupancy, hemorrhage, pulmonary insufficiency, bronchial mucosal lesion or large amount of pleural fluid without mediastinal shift. Bronchoscopy can also be used to rule out obstruction of the bronchial lumen in cases of pulmonary insufficiency after pleural fixation.
Treatment
Once the diagnosis of MPE is clear, palliative care should be considered as early as possible. A thorough assessment of the patient’s symptoms, general condition and expected survival time is performed before a treatment plan is developed. The main goal of treatment is to alleviate the symptoms of dyspnea.
The choice of MPE treatment plan depends on a variety of factors, including the patient’s symptoms and physical status, the type of primary tumor and its response to systemic therapy, and the degree of pulmonary reopening after pleural fluid drainage. The treatment methods include clinical observation, therapeutic thoracentesis, intercostal tube drainage and pleural fixation, outpatient long-term indwelling chest drainage tube, thoracoscopy, and other treatments.
1.Clinical observation
Clinical observation means no therapeutic intervention for MPE itself, and is recommended for patients with MPE whose primary tumor has been defined but are asymptomatic. For patients with symptomatic MPE, it is necessary to consult a respiratory specialist to decide whether to take pure observation.
2.Therapeutic thoracentesis
As the disease progresses, most patients with MPE will develop symptoms at some point and require further treatment. There is no evidence that early thoracentesis affects the efficacy of pleural fixation after catheter drainage, but repeated thoracentesis can easily lead to mural and dirty pleural adhesions, which can affect the field of view for medical thoracoscopy.
The recurrence rate of MPE within 1 month after thoracentesis drainage is high, and therefore it is not recommended for patients with a life expectancy of more than 1 month.
Repeated therapeutic thoracentesis may temporarily relieve dyspnea and allow some patients with short survival expectancy and poor physical status to avoid hospitalization, and is indicated for frail and end-stage patients. Small-caliber chest drains are more widely used because of their obvious efficacy and minimal discomfort. The amount of fluid drained by thoracentesis depends on the patient’s symptoms (cough, chest discomfort) and should be limited to 600 ml for the first puncture, with a maximum of 1,000 ml, and with care that the rate of fluid release is not too fast. It is recommended that therapeutic thoracentesis should be performed under ultrasound localization or guidance.
A rapid increase in pleural fluid after puncture suggests the need for other therapeutic measures as soon as possible. If dyspnea is not relieved after thoracentesis, lymphatic vascular spread, pulmonary insufficiency, cardiac insufficiency, pulmonary embolism and tumor compression or invasion of blood vessels should be considered.
3.Intercostal tube placement for drainage and pleural fixation
For patients with very short life expectancy, repeated thoracentesis is generally not recommended. A small caliber drainage tube can be placed between the ribs to drain the pleural fluid to relieve the symptoms of respiratory distress.
The drainage of large amounts of MPE should be increased gradually, and the first drainage should not exceed 1 L. Subsequent drainage can be done every 2 h. The drainage should be stopped if the patient develops chest discomfort, persistent cough or vasovagal symptoms during the drainage process. Resuscitated pulmonary edema is a rare and serious complication, often due to long-term compression of the lung, excessive and rapid drainage of the chest volume for the first time, or rapid resuscitation of the atrophied lung due to early overuse of negative chest pressure suction.
If the lung is not significantly atrophied, pleural fixation should be performed after intercostal tube drainage to prevent recurrence of MPE. The principle of pleural fixation is that the injection of sclerosing agent into the pleural cavity causes diffuse inflammatory reaction in the pleura and activation of local coagulation system with fibrin deposition, which causes adhesion of mural and dirty pleura and eventually leads to the disappearance of pleural cavity for the purpose of treating MPE. Extensive pleural metastasis may increase the fibrinolytic activity of the pleura, resulting in failure of pleural fixation. The recurrence rate of MPE is high in patients with intercostal drainage alone without pleural fixation, so intercostal drainage alone should be avoided.
The most important requirement for successful pleural fixation is satisfactory imaging confirmation of pleural atresia in both the visceral and mural layers. Inadequate lung expansion may be associated with excessive thickening of the dirty pleura (due to pulmonary atrophy), multiple small pleural cavity formation, proximal airway obstruction, or persistent air leak. Complete lack of contact between the dirty and mural pleura can result in failure of pleural fixation, in which case an indwelling chest drain is recommended. When more than half of the mural and dirty pleura are in contact, repleural fixation may be considered. In patients with clinical symptoms and inability to occlude the pleura, an indwelling chest drainage catheter is preferable to repeated thoracentesis.
(1) Caliber of intercostal drainage tube: The traditional approach is to use large caliber (24-32 F) drainage tubes for intercostal placement on the grounds that they are less likely to be occluded by fibrin deposits, but to date there is no evidence to support this view. In addition, discomfort is evident with placement of large-bore drains. A recent RCT comparing the efficacy of large-bore and small-bore (10-14 F) drains for the control of MPE found similar results. The success rate of commonly used sclerosing agents injected via small-bore thoracentesis drains was comparable to that of large-bore drains with minimal discomfort. Ultrasound-guided placement of small-bore intercostal drains for pleural drainage and pleural fixation is recommended.
(2) Analgesia and preoperative medication: Intrathoracic injection of sclerosing agent can cause pain, and local anesthetic injection through the drainage tube before pleural fixation can reduce the discomfort. Lidocaine is the most commonly used local anesthetic for thoracic injection, which has a rapid onset of action and should be given immediately before the injection of sclerosing agent. The usual dose of lidocaine is 3 mg/kg, with a maximum dose of 250 mg at a time.
The appropriate level of sedation should reduce anxiety while ensuring that the patient is fully cooperative with the surgeon. The patient should be continuously monitored for pulse oximetry and have CPR equipment available when sedation is administered.
(3) Selection of sclerosing agent: The most common adverse effects after intrathoracic injection of sclerosing agent are pleuritic chest pain and fever. The ideal sclerosing agent must have the following characteristics: large molecular weight, chemical polarity, low local clearance, rapid systemic clearance, steep dose C-response curve, tolerated by the body and no or only minor adverse reactions. The choice of sclerosing agent depends on the success rate, accessibility, safety, ease of administration, number of doses required for complete onset of action, and cost of the sclerosing agent.
Several studies have shown that talcum powder is the most effective sclerosing agent for pleural fixation. Homogeneous talc reduces the risk of hypoxemia due to pleural fixation and should be preferred over non-homogeneous talc. The efficacy of injecting talcum powder homogenate or spraying talcum powder to control MPE is comparable, generally at doses of 2.5-10 g. Unfortunately, medical talcum powder for pleural fixation is not currently produced or sold in China.
Bleomycin is another alternative sclerosing agent with moderate efficacy, typically 45-60 mg per dose. other alternative sclerosing agents are short rods, doxycycline, and tetracycline, with varying efficacy.
Whether the patient turns the position or not after pleural fixation does not affect the distribution of drugs in the thoracic cavity, and the operation is time-consuming and brings inconvenience and discomfort to the patient, so regardless of the sclerosing agent chosen, the patient does not need to turn the position after thoracic injection.
(4) Clamping and removal of intercostal drains: Intercostal drains can be clamped briefly (1 h) after intrathoracic injection of sclerosing agents to prevent rapid drug outflow from the chest cavity. Since there is no study to confirm that prolonged drainage time is better, and considering the discomfort caused by prolonged drainage time, it is recommended to remove the drainage tube within 24-48 h after injection of sclerosing agent, provided that chest X-ray confirms complete lung reopening and MPE drainage flow < 150 ml/d. If the indications for removal are not reached, the drainage time should be extended appropriately.
(5) Failure of pleural fixation: Pulmonary atrophy is the most important cause of failure of pleural fixation. There is no reliable method to predict the failure of pleural fixation, and there is no study to suggest what treatment should be taken next after the failure of pleural fixation. It is recommended to continue drainage of the pleural fluid and to decide whether to repeat pleural fixation or intercostal drainage depending on the status of pulmonary resuscitation.
(6) Metastatic tumor cell implantation at the intercostal drainage channel: Prophylactic radiation therapy should be given at the site of large-bore chest drainage tube placement, at the site of thoracoscopic manipulation, and at the surgical incision in patients with suspected or proven malignant pleural mesothelioma; there is no evidence to support the need for such treatment at the site of thoracentesis or pleural biopsy.
For MPE not caused by pleural mesothelioma, diagnostic or therapeutic thoracentesis, pleural biopsy, intercostal tube drainage and thoracoscopic operations leading to local tumor recurrence or tumor cell implantation are uncommon, and prophylactic radiotherapy is not recommended after various invasive thoracic examinations.
4.Long-term outpatient chest drainage tube
The placement of a chest drain is an effective way to control recurrent MPE, especially for patients with pulmonary atrophy or those who wish to shorten their hospital stay. Although a disposable vacuum drainage bottle attached to the drainage tube adds to the cost, this treatment shortens the length of stay, reduces the number of hospitalizations, and may reduce the cost of treatment.
Connecting the catheter to the vacuum drainage bottle for drainage at intervals may promote pulmonary resuscitation and thoracic atresia, and most drains can be removed after a short stay.
5.Intra-thoracic injection of fibrinolytic agent
Intrathoracic injection of fibrinolytic agent is to reduce the viscosity of pleural effusion by degrading the fibrin in the pleural cavity, so as to remove pleural adhesions and compartmentalization and avoid or reduce the formation of multihomogeneous encapsulated pleural effusion. Unlike systemic drugs, intrapleural injection of fibrinolytic agents rarely results in complications such as immune-mediated adverse reactions or bleeding tendencies. For patients with multiatrial MPE and poor drainage effect alone, intrathoracic injection of fibrinolytic agents such as urokinase and streptokinase is recommended to reduce pleural adhesions and improve MPE drainage to relieve dyspnea symptoms.
6.Transthoracoscopic treatment
Thoracoscopy is a safe operation with low complication rate, and it has been widely used in the treatment of MPE under sedation or general anesthesia. It is recommended for the diagnosis of suspected MPE in patients in good physical condition, and for the drainage of pleural fluid and pleural fixation in patients with confirmed MPE. The invasive nature of thoracoscopy and talc spraying needs to be considered when patients choose to undergo it. The distinct advantage of thoracoscopy is that diagnosis, drainage of pleural fluid, and pleural fixation can be performed simultaneously in a single operation.
In patients with a definite diagnosis of MPE and chest imaging suggestive of pulmonary atrophy, the benefit of performing thoracoscopy is relatively small. However, thoracoscopy under general anesthesia allows direct visualization of lung re-expansion, clarifies the presence of pulmonary atrophy, and guides the next step in treatment, including talc spraying or placement of a chest drain. Thoracoscopy facilitates the management of small cavities, removal of blood clots from bloody pleural fluid, and release of pleural adhesions, thus facilitating lung re-expansion and pleural fixation after talc spraying.
The perioperative morbidity and mortality rate of thoracoscopy is low (< 0.5%). The most common complications are abscess chest and acute respiratory failure secondary to infection or diplopia pulmonary edema; fractionated slow drainage of pleural fluid can prevent diplopia pulmonary edema.
7.Other treatment
(1) Systemic treatment: MPE due to pleural metastasis of certain tumors such as small cell lung cancer may have a better response to chemotherapy; if there is no contraindication, systemic treatment can be considered, along with combined thoracentesis or pleural fixation. Chemotherapy is also effective for MPE combined with breast cancer and lymphoma, and may be effective for MPE related to prostate cancer, ovarian cancer, thyroid cancer, and blastocytoma. In addition, targeted therapy can be tried in selected suitable patients.
(2) Surgical treatment: Pleurectomy is a treatment for MPE. Open pleurodesis is an invasive operation, and its complications include septic chest, hemorrhage, cardiac insufficiency, and respiratory failure; some data show that the intraoperative morbidity and mortality rate is 10%-19%. A few studies have reported surgical thoracoscopic pleurectomy for the treatment of pleural mesothelioma. Due to insufficient evidence-based medical evidence, pleurodesis is not recommended as an alternative to pleural fixation or indwelling chest tube for recurrent pleural fluid or pulmonary atrophy at this time.
Larger surgical procedures such as mural pleurodesis, pleurodesis or total pleuropneumonectomy are more invasive and have a higher morbidity and mortality rate than pleural fixation alone, and are rarely used at this time. However, combined surgical procedures with talc pleural fixation and/or thoraco-peritoneal shunts can alleviate symptoms and can be performed through surgical thoracoscopic small incision open chest.
(3) Intrathoracic treatment: When malignant tumors are confined to the thoracic cavity, intrathoracic injection of antitumor drugs can treat the tumor itself in addition to reducing pleural fluid exudation. In order to achieve maximum antitumor activity with minimal systemic side effects, intrathoracic injection of chemotherapeutic drugs with high concentration of local distribution and low concentration of systemic distribution is required. However, there is insufficient evidence to support such therapy.
Cytokines can be directly injected into the thoracic cavity for the treatment of MPE, and IL-2, IFN-β and IFN-γ have been injected directly into the thoracic cavity for the treatment of MPE and mesothelioma. The efficacy of all these methods varies and has not been confirmed by multicenter RCT studies with large samples, so rigorous clinical studies are necessary to collect reliable evidence.