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Malignant pleural effusions
- 1. Malignant Pleural Effusions (MPE) Dr Kamal Bharathi. S
- 2. Malignant Pleural Effusions A malignant pleural effusion is diagnosed by detecting exfoliated malignant cells in pleural fluid or demonstrating these cells in pleural tissue obtained by percutaneous pleural biopsy, thoracoscopy, thoracotomy, or at autopsy. Second leading cause of exudative pleural effusions after parapneumonic effusions. MPE accounts 22% of all pleural effusions (and 42% of exudates)
- 3. Malignant Pleural Effusions Pleural effusion of pleura Malignant Mesothelioma Pleural Effusions Related to Metastatic Malignancies Lung carcinoma Breast carcinoma Lymphoma and leukemia Ovarian carcinoma Sarcoma ( including melanoma ) Uterine and cervical carcinoma Stomach carcinoma Colon carcinoma Pancreatic carcinoma Bladder carcinoma
- 4. Pleural Effusions Related to Metastatic Malignancies Lung Malignancy Pleural effusions occur with all the cell types of lung carcinoma but most frequent with adenocarcinoma. Patients with lung cancer who have anti-p53 antibodies are more likely to have pleural effusions. patients with lung cancer and pleural effusion be classified as M 1a which would make them a stage IV. The presence of a pleural effusion at the time of diagnosis adversely affected prognosis
- 5. Breast Carcinoma The second most leading cause of malignant pleural effusion. Pleural effusions were more common with lymphangitic spread than without lymphangitic spread. Lymphomas: Lymphomas, including Hodgkin's disease, are the third leading cause of malignant pleural effusions. Most patients with Hodgkin's disease and pleural effusion have the nodular sclerosis type. The presence of a pleural effusion at the time of presentation does not adversely affect complete remission or survival rates with non Hodgkin’s lymphoma Leukemia: MCC of pleural effusion in patients with CML and ALL is as a side-effect from the tryrosine-kinase inhibitor dasatinib.
- 6. Mechanisms of Pleural Metastasis MPE have visceral, but not necessarily parietal pleural involvement. It is believed pleural metastases develop when tumors embolize to peripheral lung and invade visceral pleura first then to parietal. Direct invasion from adjacent tumors in the lung, breast or chest wall . Hematogenous and lymphatic spread to pleura. Combination of increased fluid extravasation from hyperpermeable vessels (due to VEGF produced by the tumor) and impaired lymphatic outflow- development of MPE.
- 8. Pathophysiologic Features Direct Result Pleural metastases with increased permeability Pleural metastases with obstruction of pleural lymphatic vessels Mediastinal lymph node involvement with decreased pleural lymphatic drainage Thoracic duct interruption (chylothorax) Bronchial obstruction (decreased pleural pressures) Pericardial involvement. Indirect Result Hyponatremia Postobstructive pneumonitis Pulmonary embolism Postradiation therapy
- 9. Para-Malignant effusions Can develop in cancer patients without tumor involvement of the pleura.
- 10. Clinical Presentation Dyspnea, pain and cough are the most common symptoms . To accommodate the volume of pleural fluid, thoracic cage has to enlarge causing the hemidiaphragm to flatten/evert, the chest wall to expand and the mediastinum to shift contralaterally. Chest pain is usually dull rather than pleuritic. Constitutional symptoms eg: anorexia, weight loss, or tumor fever.
- 11. Radiographic features Plain radiograph Insensitive at distinguishing it from a benign effusion. In cases where multiple nodular regions or pleural thickening are present the diagnosis may be evident
- 12. CT number of features are recognised, including: a) circumferential pleural thickening b) nodular pleural thickening c) parietal pleural thickening greater than 1 cm d) mediastinal pleural involvement e) pleural calcification generally suggests a benign process In many cases the primary malignancy will be visible (e.g. breast cancer, bronchogenic cancer) and/or evidence of pulmonary or bony metastases will be visible. Left-sided effusion and multiple pleural nodules. Pleural biopsy showed adenocarcinoma
- 13. showing pleural calcification (left, black arrow) and a nodule (black arrow) in the right lower lobe with a minimal right-sided effusion. Fine needle aspiration and immunohistochemistry from the nodule confirmed adenocarcinoma
- 14. (left) showing right moderate pleural effusion (black arrow) and mediastinal lymphadenopathy (white arrow). Thoracocentesis suggested a chylothorax (triglyceride 150 mg/dl and cholesterol of 45 mg/dl, right) and mediastinoscopic biopsy confirmed lymphoma.
- 15. • showing right moderate pleural effusion (black arrow) and a large right lower lobe mass (red arrow).
- 16. FDG-PET: More sensitive than conventional imaging in diagnosing malignant pleural disease and distinguishing them from benign processes PET/CT image demonstrating metastatic lung cancer, evident as bright areas (in yellow) at the left base and the right hilum.
- 17. Medical Approaches for Diagnosis and Management
- 18. Pleural fluid analysis The first diagnostic step in determining pleural effusion characteristics. Routinely analyzed for total and differential cell counts, proteins, lactate dehydrogenase (LDH), glucose, and pH, as well as subjected to microbiological and cytological examinations. Always categorized as exudates, a few are transudates. There are no absolute contraindications to performing thoracentesis. Relative contraindications include a minimal effusion ( <1 cm in lateral decubitus view), bleeding diathesis, anticoagulation, and mechanical ventilation. Serum creatinine levels of > 6.0 mg/dl are at a considerable risk of bleeding
- 19. patient with massive left-sided pleural effusion (left). Subsequent to intercostal tube drainage, the patient developed re-expansion pulmonary edema (right). The patient was managed with diuretics and oxygen and recovered at 48 hours.
- 21. Closed pleural biopsy • Abrams or Cope needle • lower sensitivity due to the lower early stage and distribution of tumor
- 22. Tumor markers in pleural fluid Possibility of diagnosing MPE when increased levels of tumor markers are found in the pleural fluid. First, measurement of pleural CEA is a diagnostic tool for confirming MPE and is useful for the differential diagnosis between malignant pleural mesothelioma and metastatic lung cancer. A high level of pleural CEA seems to rule out malignant mesothelioma. Second, CA 15-3, CA 19-9, and CYFRA 21-1 are highly specific but insufficiently sensitive to diagnose MPE, and the combination of two or more tumor markers appears to increase the diagnostic sensitivity. Vascular endothelial growth factor (VEGF) as a diagnostic biomarker of MPE Mesothelin and fibulin-3 – to detect pleural mesothelioma at an earlier stage.
- 23. Medical thoracoscopy & VATS Medical Thoracoscopy (pleuroscopy) - advantage that it can be performed under local anaesthesia or conscious sedation. MT into VATS has allowed for an even greater range of therapeutic solutions MT is primarily a diagnostic procedure. Indication: a) the evaluation of exudative effusions of unknown. b) to rule out cause, staging of malignant mesothelioma or lung cancer, & treatment of malignant or other recurrent effusions. c) talc pleurodesis. d) Another purpose may be biopsy of the diaphragm, lung, mediastinum, or pericardium. e) Thoracic surgery backup should be available.
- 24. Mortality rate related to MT alone is approximately 0.34% Major complications: a) empyema, b) hemorrhage, c) port site tumor growth (mesothelioma), d) bronchopleural fistula, e) postoperative pneumothorax or air leak f) pneumonia were reported in 1.8% of cases VATS and MT is an invaluable diagnostic tool for the diagnosis of pleural mesothelioma- pleural fluid cytology alone. Port side radiation post procedure in patients with mesothelioma to decrease the risk of tract tumor seeding with malignant cells.
- 25. a) Candle wax metastatic nodules on the pericardium of a 70-year-old patient with a pleural effusion from breast adenocarcinoma. Note the diffuse invasion of the parietal pleura b) Invasion of the parietal pleura from Hodgkin’s lymphoma as discovered during thoracoscopy in a 39- year-old patient with a pleural effusion. In addition to the nodule, there is diffuse invasion of the parietal pleura as well as a mass within the mediastinum
- 26. a) A peripheral lung adenocarcinoma in a 46-yearold male, nonsmoker, presenting as an “undiagnosed” pleural effusion. Note the satellite nodule on the visceral pleura and the invasion of the parietal pleura b) tumor nodules and whitish areas with pleural thickening on the parietal pleura- diffuse malignant mesothelioma
- 27. (A) showing right-sided hydropneumothorax following thoracocentesis and lung entrapment due to a thick visceral pleural peel. The computed tomography image. (B) shows a large intra-bronchial mass, loculated effusion and ipsilateral mediastinum
- 28. Bronchoscopy The diagnostic yield of bronchoscopy is low in patients with undiagnosed pleural effusions. Indicated when, Endobronchial lesions are suspected because of hemoptysis, atelectasis, or large effusions without contralateral mediastinal shift. Left complete lung collapse Left main bronchus endobronchial hamartoma.
- 29. Management of malignant effusion MPE whether primary or metastatic- advanced incurable disease with poor prognosis. Median survival of 4-6 months. Among lung cancers have shortest and longest (9-12 months) if due to other causes. Management should include measures to control the symptoms arising from the pleural disease as well as underlying malignancy. Therapeutic thoracocentesis may be adequate to allow time to assess respond to systemic therapy. Lung cancers with EGFR mutations, Lymphoma, Small Cell Carcinoma of lung respond well to chemotherapy.
- 30. Management of malignant effusion Ideal therapy for MPE: Complete fluid control, Improved symptoms, Quality of life, Minimally invasive, Reduced hospital stay. The 2 primary modes of treatment to control the accumulation of pleural fluid are insertion of an indwelling pleural catheter or creation of a pleurodesis.
- 31. Therapeutic thoracentesis The first step in the management of newly diagnosed MPE. Only the patients who are dyspeic and whose dypnea improves after thoracocentesis are candidates for fluid removal If the patient remains symptomatic despite large-volume thoracentesis, causes such as lymphangitic spread, pulmonary embolism, or malignant airway obstruction should be suspected and investigated appropriately. To prevent reexpansion pulmonary edema, the amount of fluid removed by thoracentesis should be assessed by patient symptoms (cough, chest discomfort) and limited to 1.5 L on a single occasion.
- 32. Systemic Chemotherapy The presence of a malignant pleural effusion usually indicates disseminated tumor therefore the only hope is prolonged palliation with systemic chemotherapy. Points to remember: Anti-VEGF antibody (bevacizumab) + standard first-line chemotherapy, provides survival advantage in NSCLC. It is important not to attempt pleurodesis in these patients because angiogenesis is necessary for pleurodesis and angiogenesis will be inhibited by anti-VEGF drugs. Pleural effusions should be aspirated before chemotherapy is given because the antineoplastic drugs may accumulate in the pleural space and lead to increased systemic toxicity. But not in the case of pemetrexed.
- 33. lntrapleural Chemotherapy Results are mostly disappointing.
- 34. Staphylococcus aureus superantigen, a powerful T-cell stimulant. Rituximab Interferon-gamma, tumor necrosis factor, interleukin-2, cisplatin have all been tried in small numbers of patients with results that are not particularly impressive.
- 35. Indwelling pleural catheter The PleurX catheter is a 15.5 F silicone rubber catheter, 66 cm in length, with fenestrations along the proximal 24 cm Inserted using the Seldinger technique under local anesthesia. The catheter is maintained in place with a chest wall tunnel 5 to 8 cm in length. The valve prevents fluid or air from passing in either direction through the catheter unless the catheter is accessed with the matched drainage line.
- 36. Indwelling pleural catheter If the patient is dyspneic and if the dyspnea is relieved by a therapeutic thoracentesis,outpatients who receive home health care or who have strong family support are ideal candidates for IPC. Long-term IPCs may lead to spontaneous pleurodesis in 40−58% of patients with IPC. Therefore, sclerosants can be instilled through the catheter if spontaneous pleurodesis does not occur after several weeks of drainage. Complications include infections, clogging of the catheter, or other rare events, such as empyema or tumor spread along the catheter track.
- 39. Cumulative evidence proposes potential advantages of IPCs over talc pleurodesis First, pleurodesis is only useful in patients with fully expanded lungs after fluid evacuation. non-expandable (or ‘trapped’) lungs- not suitable. Second, Pleurodesis failure progressively increased with prolonged survival. By 6 months, talc pleurodesis had failed in approximately 50% of patients. 32% of all patients required further pleural intervention. Third, talc pleurodesis requires hospitalisation, often for 4–5 days. Fourth, pleurodesis is known to provoke intense pleural and systemic inflammation, with a median rise in C reactive protein of 360% from baseline. The resultant pain and fever can be severe. Talc pleurodesis can cause hypoxaemia and, in severe cases, acute respiratory failure.
- 40. Complications of indwelling pleural catheter IPC-related pleural infection: Cutaneous flora, including Staphylococcus spp (especially S. aureus), followed by Pseudomonas aeruginosa and Enterobacteriaceae. typically occurs at least 6–8 weeks after insertion. Patient-related factors IPC-related factors Clinician-related factors Underlying tumour Ongoing chemotherapy Immune status Comorbidities Skin diseases Ability to adhere to aseptic techniques Drainage regimen Drainage volume Patients and carers education Manufacturers Duration of IPC in situ Insertion procedure Expertise in after-care Surveillance and audit Dressing techniques Infection control bundles
- 41. Complications of indwelling pleural catheter a) Catheter tract metastasis: Treated effectively with simple analgaesics and external beam radiotherapy without the need to remove the IPC. Prophylactic radiotherapy in reducing postprocedural tract metastases in mesothelioma remains controversial. CT images of a patient with mesothelioma who developed catheter tract metastasis around his indwelling pleural catheter (IPC), which was in place for 5 months
- 42. Complications of indwelling pleural catheter b)Symptomatic loculations: facilitate pleural symphysis or ‘spontaneous pleurodesis’ in approximately 40% of patients. Effusion that fails to evacuate through a patent IPC. Intrapleural fibrinolysis provides a feasible alternative.
- 43. Complications of indwelling pleural catheter c) Fracture of catheters on removal: Spontaneous pleurodesis can develop, which permits catheter removal. IPC may be removed due to cessation of drainage or development of empyema or severe pain. Removal of the catheter requires freeing the cuff from the often tight fibrinous adhesions. the part distal to the cuff adhered tightly to underlying tissue after freeing the cuff.
- 44. d) Catheter blockage: The formation of dense fibrinous tissue around and within the IPC can occasionally lead to blockage of some lumen. Saline flush and manipulation along the catheter may dislodge occluding materials. e) Cost of IPC f) Nutrition and cell loss g) Chest pain
- 45. Pleurodesis Pleurodesis is the obliteration of the pleural space by fusion of the visceral and parietal pleurae with fibrous tissue. Sclerotic agents Talc (Poudrage or Slurry) Antibiotics (Tetracyclines, Minocycline, Doxycycline), Antimalarials (Quinacrine, Mepacrine), Antineoplastic Drugs (Bleomycin, 5-fluorouracil, Mitomicin, Thiotepa, Nitrogen Mustard), 50% Glucose And Water, Immunomodulating Agents [Interferon alpha], Iodopovidone, Radioactive Colloidal Gold, Autologous Blood, Fibrin Glue, Biological Agents (Corynebacterium Parvum, Or BCG), Nitrates.
- 46. It has been supposed that the ideal pleural sclerosing agent should be easily administered, safe, inexpensive, and widely available. Pleurodesis should be considered in patients with MPE who are not candidates for the tunneled catheter or systemic chemotherapy and who do not have a chylothorax.
- 48. Pleuritic chest pain and fever are the most common side effects of sclerosant administration. Lidocaine (3 mg/kg; maximum 250 mg) should be administered intrapleurally just prior to sclerosant administration. Premedication should be considered to alleviate anxiety and pain associated with pleurodesis. Patient rotation is not necessary after intrapleural instillation of sclerosant. The intercostal tube should be clamped for 1 h after sclerosant administration. In the absence of excessive fluid drainage (>250 ml/ day) the intercostal tube should be removed within 24-48 hr of sclerosant administration.
- 49. Failure of Pleurodesis Pleural fluid glucose (< 60 mg/dl), Karnofsky performance status (< 70), Size of the effusion in chest radiographs (massive effusion), Pleural fluid pH (< 7.20), Presence of concomitant alterations in chest radiographs, and pleural lactic acid dehydrogenase levels (> 600 U/l) showed a significant association with the probability of failure. The most likely cause of pleurodesis failure is the presence of trapped lung. Before pleurodesis, the position of mediastinum should be evaluated.
- 50. Definitions of Success or Failure of Pleurodesis (as per ATS guidelines) Successful pleurodesis Complete success: Long-term relief of symptoms related to the effusion, with absence of fluid reaccumulation on chest radiographs until death Partial success: Diminution of dyspnea related to the effusion, with only partial reaccumulation of fluid (less than 50% of the initial radiographic evidence of fluid), with no further therapeutic thoracenteses required for the remainder of the patient’s life. Failed pleurodesis: Lack of success as defined above
- 51. Therapeutic options after failed pleurodesis Talc pleurodesis fails in 30-50% of patients in which repeat pleurodesis can be performed. But success rate will be lower than the first attempt. Repeated aspiration is appropriate for patients with short expected survival. In terminally ill patients, narcotics and oxygen are more appropriate. The use of IPC is increasingly the preferred option. Surgical options such as decortication or pleurectomy are aggressive and only used rarely in selected patients.
- 53. Pleurectomy Parietal pleurectomy consists of stripping all of the parietal pleura from the rib cage and the mediastinum. Attempted in two different situations: The patient who undergoes a diagnostic thoracotomy for an undiagnosed pleural effusion. If malignant disease is found, an immediate parietal pleurectomy is useful to prevent recurrence of the effusion. The symptomatic patient with a persistent pleural effusion and trapping of the ipsilateral lung so that the sclerosing agents is contraindicated.
- 54. Pleuroperitoneal Shunt Pleuroperitoneal stunt connects pleural and peritoneal cavities by a one way valve pump chamber. It can be used as a alternative in patients with trapped lung or following failed pleurodesis. The need for PPs decreased with advent of IPC, the pleuroperitoneal shunt is recommended because the nutritional status of the patient is preserved with this method.
- 55. Gene therapy One approach is the intrapleural administration of replication-deficient recombinant adenovirus (rAd)that has been genetically engineered to contain the herpes simplex virus thymidine kinase gene (HSV tk). It is hoped that delivery of rAd HSV tk directly into the pleural cavity of patients with mesothelioma will transduce the tumour cells, enabling them to express viral thymidine kinase and conveying sensitivity to the normally nontoxic antiviral drug ganciclovir. A phase I dose escalation clinical trial ofadenovirus-mediated intrapleural HSV tk-glanciclovirgene therapy demonstrated that the HSV tk gene iswell tolerated and results in detectable gene transferwhen delivered at high doses. Further development oftherapeutic trials for the treatment of localizedmalignancy is warranted
- 56. Thank You…!!!