Malignant Pleural Effusion: Diagnosis and management

Corresponding Author: Padraic Ridge, Galway University Hospital, Newcastle, Galway, Ireland Email: P.macaniomaire1@gmail.com

Abstract: Malignant pleural effusion (MPE) is a common clinical entity affecting 40,000 people per year in the UK. Malignant pleural effusion can occur with a primary pleural malignancy, typically mesothelioma or more commonly as a metastatic manifestation of a non pleural primary malignancy. In Ireland mesothelioma is an infrequent diagnosis and therefore the majority of cases of MPE represent advanced Stage IV malignant disease. 1

In this paper we will review the diagnosis and subsequent management of MPE.

Introduction

Malignant pleural effusion (MPE) is defined by malignant cells within the pleural space. The pleural space can be involved by malignancy through direct extension of tumour, haematogenous spread or through primary pleural malignancy (mesothelioma). 2,3 While any cancer can metastasize to the pleural space the most common in descending order are lung, breast, lymphoma, ovarian and gastric cancer. These account for approximately 80% of Malignant pleural effusion. 4,5

The incidence of MPE In the UK is circa 40,000 people/year. Median survival from diagnosis of Malignant pleural effusion ranges from 3-12 months depending on the tumour type. 5 Metastatic involvement of the pleural space by lung cancer is associated with the shortest median survival of 3 months, however novel targeted therapies may improve this prognosis. 4 6

Presentation

Patients may present with dyspnoea, orthopnoea or chest pain. Dyspnoea can be very severe and dramatically affect quality of life. However Individuals can often be relatively asymptomatic and MPE may only be incidentally picked up on routine imaging studies. 4

The size of the effusion does not reliably predict a patients symptom burden as the fluid can accumulate gradually over time allowing the patient to compensate. Symptoms are more strongly correlated with the rate of fluid accumulation. 7

Diagnosis

It is important to note that 50% of pleural effusion in the setting of individuals with cancer are non-malignant. 8 These may be caused by bronchial obstruction from tumour or benign causes such as congestive heart failure or infection. These are termed paramalignant or non-malignant pleural effusions. See Figure 1.

This has important implications for staging and treatment of individuals. 9

Malignant pleural involvement should never be presumed and it is crucial to pathologically stage pleural effusions in the setting of malignancy. Malignant involvement of the pleural space implies stage 4 malignancy thus radical treatment options such as surgery are not an option. For those with para-malignant effusions radical, curative treatments may still be an option. 10-12 Assuming malignant involvement in those with a paramalignant effusion could wrongly deny them potentially curative treatment.

Imaging

Chest radiography (CXR): Is the initial imaging for most. The standard posterior-anterior (PA) CXR will only start to become abnormal in the presence of approximately 200ml of pleural fluid. 13 The initial sign is costophrenic blunting, which may progress to opacification with a meniscus or even a full “white out” with tracheal deviation away from the effusion. 13,14 Lateral films are more sensitive and can detect pleural effusions of 50ml. 13

Ultrasound (US): Ultrasound scanning has become the gold standard in diagnostic imaging for MPE. Ultrasound can differentiate pleural effusion from lung collapse or pleural thickening. 4 USS outperforms CT at identifying pleural features such as: pleural thickness, nodules and adhesions. Features consistent with malignant pleural effusion on USS include: nodules of the pleura or diaphragm, diaphragmatic thickening (>7mm) and pleural thickening (>1cm). These findings on ultrasound have a sensitivity and specificity of differentiating benign from malignant effusions of 79% and 100% respectively. See Figure 2 15

Ultrasound has also developed a key role in pleural procedures. It has the benefit of not exposing the patient to radiation and being able to be performed at the bedside.

Ultrasound should be used to “mark the spot” immediately prior to any form of pleural intervention. As pleural fluid can often be free flowing the patient should be advised to remain as still as possible from the moment of marking the spot until the pleural intervention takes place. The method of marking the spot in the radiology department and then transferring back to the ward for pleural intervention is not recommended. 4 For small effusions, or patients who are liable to move post marking, intervention can be performed under real time ultrasonography. 5

Ultrasound guidance increases the accuracy and reduces the risk of inadvertent damage to surrounding organs and now is a fundamental requirement for any pleural service. 16

Computed Tomography and PET: Standard CT and PET are important modalities to further investigate an effusion and in particular for further assessment for an underlying primary cancer, assessing extent of disease, and identifying alterative cause of the effusion such as bronchial obstruction, infection or pulmonary embolism. 17 If stage 4 disease is confirmed then PET scan is not pursued.

Signs of malignant pleural effusion on CT include pleural thickening, nodular pleural thickening, mediastinal pleural thickening and circumferential pleural thickening. 18 Figure 3 CT is also useful for helping the USS operator better conceptualize the pleural effusion. 5 However, CT is not as sensitive at detecting pleural thickening or identifying internal septations in a pleural effusion. 19

Sampling

Aspiration:Pleural aspiration is the initial method of obtaining pathological confirmation of MPE. It should always be performed with US guidance. It can be performed at the bedside using a 21G needle and a 50ml syringe or as part of a therapeutic thoracentesis. 4 The procedure should be performed aseptically and local anaesthetic should be administered particularly superficially and at the pleural surface.

The British Thoracic society recommend all pleural samples should be sent to biochemistry for LDH and protein (5ml), microbiology for culture, sensitivity and Acid Fast Bacilli (5ml), and cytology (~40ml). If there is a concern for pleural infection, pleural samples should be inoculated in blood culture bottles as this increases the microbiological yield. 20

We also recommend the pH should be checked within an hour by the person performing the aspiration using a standard arterial blood gas (ABG) needle and ABG machine. In the case of MPE PH is predictive of future chemical pleurodesis rates and may add evidence to the diagnosis of MPE. 4,5,21,22 For Para-malignant effusions, such as pleural infections, pH in combination with USS features may indicate the need for a chest drain and therefore both are important point of care tests. 4

It is important to note pleural aspiration gives a cytological sample. In malignancies such as mesothelioma, where histological samples are recommended, sensitivity of cytological samples can be low as 32%. 23 The overall sensitivity of aspiration for MPE is 60% (range 40-87%). 4 Therefore in the right clinical context a negative aspiration should not out-rule MPE and further tests may be required. One study looked at the benefit of repeating aspiration. This study achieved a yield of 65% from initial aspiration, a further 27% from a second aspiration and 5% from a third aspiration. 24 Each aspiration meant a repeat procedure for the patient with all its associated risks and increased wait time for results. Also repeated interventions may make the pleural space more complex, making it more difficult to perform a definitive procedure in the future. Therefore, if local resources allow, we recommend proceeding to a more definitive procedure as an alternative to repeated aspirations. (See Figure 4 on page 36).

Biopsy

For patients undiagnosed after initial less invasive methods a biopsy is required. This can be achieved by percutaneous or thoracoscopic methods.

Percutaneous pleural biopsy: CT guided biopsy has been the favoured method due to its superior sensitivity of 88%. 25 Prior to this blind percutaneous biopsy was traditionally performed with an Abram’s needle. This method is performed less now due to its low sensitivity of 57% and high complication rate. However, recent studies have shown that biopsies taken with an Abrahm’s needle in combination with USS guidance have comparable sensitivity and safety to CT guided pleural biopsies. 26,27 Thoracoscopy biopsy: Thoracoscopy allows direct visualisation of the pleura and sampling of abnormal pleural patches. A medical thoracoscopy is performed by a respiratory physician. It can be performed in the endoscopy suite under conscious sedation. 28 A Video assisted thoracoscopic surgery is performed by a surgeon and requires a general anaesthetic and single lung intubation. Therefore, a medical thoracoscopy is the preferred method for a frail patient. 4 The sensitivity of medical thoracoscopy and VATS for malignancy is 92.6% and 95% respectively. 4

An advantage of these procedures is that they can be therapeutic as well which we will outline below.

Management

Once a diagnosis has been obtained, Multiple factors should be considered prior to deciding on definitive treatment such as: symptoms, need for future samples for tumour confirmation or molecular markers, rate of fluid accumulation, life expectancy, tumour type and predicted response to treatment. A potential algorithm is outlined in Figure 5. 5 (See figure 5 on page 36).

Management should be delivered by a multidisciplinary team including respiratory physicians, oncology, radiation oncology, Thoracic surgeons, palliative care physicians and other supportive staff. Due to the limited life expectancy of those with MPE care should be delivered in a timely and convenient manner to the patient. We aim to provide pleural management in the outpatient setting as much as possible to achieve this goal. 5

1) Conservative Monitoring

For those who are asymptomatic we do not perform any invasive intervention as there is no benefit to the patient. We educate the patient, provide them with contact details and arrange regular follow up. If they develop symptoms at a future date then we offer a pleural intervention.

2) Systemic Therapy

Response of the MPE depends on the histology of the primary tumour. Lymphoma, small cell lung carcinoma, germ cell tumours, prostate carcinoma and ovarian cancers typically have a favourable response to systemic chemo-radiotherapy. 29

3) Therapeutic Thoracentesis

Breathlessness in malignancy can be multifactorial and even in those with a MPE, it may be due to other causes such as lymphangitis carcinomatosa, bronchial obstruction, pulmonary embolism, chronic lung disease or even ischemic heart disease. 4,30

Before proceeding with definitive pleural management one should always perform a therapeutic thoracentesis to assess for improvement in dyspnoea. The initial procedure can be both therapeutic and diagnostic.

Post thoracentesis, patients should be assessed for radiological expansion of the underlying lung and symptomatic benefit. When a lung does not fully expand to oppose the parietal pleura this is termed a trapped lung.

Only those who show an improvement in symptoms post thoracentesis should have a definitive pleural procedure performed. Those who do not show an improvement should be investigated for an alternative cause of their symptoms. 4

The minimal amount of fluid to remove to assess for clinical response is 500ml. 30 Thoracentesis is associated with a risk of re-expansion pulmonary oedema (RPO). Standard practice is to remove 1.2L in one session.

However no maximal volume has ever been identified. Methods of minimising the risk of RPO include pleural manometry and monitoring for chest tightness, cough or dyspnoea during thoracentesis and stopping if they begin to develop. 5,31

As mentioned above, therapeutic thoracentesis allows the identification of individuals who have a trapped lung. This is important as those with a trapped lung do not derive benefit from chemical pleurodesis as there is no pleural opposition to allow this process to occur. Therefore an indwelling pleural catheter is the best option for these patients.

4) Chest Drain Insertion and Complete Drainage

Chest drain insertion and full drainage of the pleural effusion can be considered for those who accumulate fluid very slowly, have a short life expectancy or choose to not have a definitive procedure. In particular it is a viable option in those who have a chemo-sensitive tumour that is expected to respond to systemic therapy.

5) Chemical Pleurodesis

Chemical pleurodesis can be performed using talc, tetracycline or bleomycin. It induces pleural inflammation resulting in adhesion of the visceral pleura to the parietal

pleura. Talc is the most effective and most used agent in Ireland. 32 For chemical pleurodesis to be effective the effusion needs to be drained and the lung expanded to allow the apposition of visceral and parietal pleura. 4

Talc can be administered at the bedside via a chest drain (talc slurry). (See Figure 6 on page 37). It can also be administered at the time of thoracoscopy (talc poudrage). The thoracoscopy method is more invasive but allows one to examine and sample the pleura, lyse any adhesions and spread the talc more evenly on the pleura which may lead to better control. (See Figure 7 on page 37). However, neither method has been shown to be superior. 33-35

Talc administration can be associated with pain therefore lidocaine is always administered to the pleura beforehand and generous analgesia should be prescribed. 36 A study has shown that non-steroidal anti-inflammatories do not effect pleurodesis rates. 37 It is not unusual for patients to have a temperature post administration due to a systemic inflammatory response. 4

6) Indwelling Pleural Catheter

An IPC involves tunnelling a catheter through the skin into the pleural space. This catheter can then remain in place for a prolonged period allowing a family member to intermittently drain the effusion at home using a vacuum bottle (usually every 2 nd day). (See Figure 8 on page 37). The drain can be inserted in an outpatient setting and thus does not require admission. It can also be inserted at the time of diagnostic thoracoscopy with or without concomitant talc which is termed an accelerated pleurodesis. 38-40

7) IPC vs Chemical Pleurodesis

An IPC is the only effective option in those with non-expandable or trapped lung where chemical pleurodesis has been shown to be ineffective. 4 In those with expandable lung the two methods are comparable in terms of symptom control and safety. Generally we discuss the benefits and drawbacks of each method of managing the pleural fluid with the patient and in turn allow them to make an informed decision based on evidence and personal preference.

The advantages of chemical pleurodesis are that it is a one-off procedure, if successful and there is no ongoing management of an indwelling drain for the patient. However it requires chest drain insertion, hospital admission for a few days, can be painful and pleural infection has been reported. 5

IPCs are associated with less repeated procedures and fewer days in hospital as it can be inserted as a day case. 41 However, IPC insertion’s can be complicated by local skin infections, pleural infection and catheter blockage or fracture. Some patients do not like the burden of managing the drain long term. 42

Ultimately the choice between chemical pleurodesis andvs IPC is usually made based on the patients preference for avoiding a hospital admission versuss the burden of the ongoing management of the IPC drain. 41,42

8) Palliative

Occasionally patients may be too unwell for an invasive procedure and optimal control of symptoms is best achieved through systemic opioid and benzodiazepine therapy guided by the palliative care services. 5

Conclusion

MPE are common, indicate advanced stage and are associated with a high morbidity and mortality. Diagnosis should always be prompt and confirmed pathologically.

MPE results in a major burden on the health service and account for significant inpatient days. It’s for this reason that we have developed a pleural service in Galway University Hospital which has been in constant development since 2010. Our service has been pivotal in reducing inpatient days and reducing symptom burden in those suffering from MPE through the provision of the treatment strategies outlined in this review.

We believe management of patients with MPE should focus on symptom control, be delivered on an outpatient basis (when possible) and should always be led by patient preference.

References available on request

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