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Malignancy-Related Effusions
Summary of Key Points
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Malignancy-Related Ascites
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Malignancy-related ascites is a common complication of advanced cancer.
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Malignancy-related ascites accounts for 10% of all cases of ascites, with a majority of these cases related to carcinomatosis.
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Malignancy-related ascites most commonly occurs in patients with ovarian cancer, gastrointestinal malignancies, and carcinoma of unknown primary location.
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Malignancy-related ascites is rarely life threatening, but its occurrence signals advanced cancer and may portend a poor prognosis.
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Evaluation
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A history and physical examination are important in evaluation.
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Diagnostic paracentesis with cytology is the gold standard for diagnosis.
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Treatment
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Small-volume or asymptomatic ascites may be monitored.
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Treatment approach depends on the patient's performance status and likelihood of response to systemic therapy.
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Treatment may include diuretics, drainage or diversion of fluid, or intracavitary therapies.
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Malignant Pericardial Effusion
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The appearance of malignant pericardial effusion portends a poor prognosis.
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Malignant pericardial effusion is most commonly associated with lung and breast carcinomas.
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Evaluation
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The differential diagnosis of pericardial effusion in patients with cancer also includes treatment-related adverse effects.
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Clinical assessment should include evaluation for clinical signs of cardiac tamponade.
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Diagnostic evaluation includes fluid sampling for cytology and two-dimensional echocardiography, which provides information regarding the location, size, and effect of the effusion on the heart's function.
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Treatment
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Small or asymptomatic effusions may be monitored.
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The presence of cardiac tamponade requires urgent pericardiocentesis to drain the fluid.
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Treatment depends on symptoms of effusion and performance status of the patient.
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Treatment options include subxiphoid pericardiostomy, instillation of sclerosants in the pericardial space, and pericardial window.
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Malignancy-Related Pleural Effusion
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Malignancy-related pleural effusion is a common complication of cancer.
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Malignancy-related pleural effusion is a frequent occurrence in carcinomas of the lung and breast and in persons with lymphoma.
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Evaluation
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Fluid sampling with evaluation of cytology is required for definitive diagnosis of a malignant pleural effusion.
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Exudative effusions are more common; chylous effusions are more common in persons with lymphoma.
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Thoracentesis under ultrasound guidance improves diagnostic yield.
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Treatment
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Small-volume- or asymptomatic effusions can be monitored.
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For symptomatic patients, effective options include systemic therapy for patients with very responsive disease (e.g., hematologic malignancies, germ cell tumors, breast cancer, and small cell lung cancer) or repeated thoracentesis.
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For patients with rapidly recurring effusions, options include pleurodesis with talc, long-term intrapleural drainage catheters, or video-assisted thoracoscopic surgery with mechanical abrasion.
Malignancy-Related Ascites
Ascites is a pathologic accumulation of fluid within the peritoneal cavity. The word ascites is derived from the Greek askites and askos, meaning bladder, bag, or belly. In adults, the most common cause of ascites is parenchymal liver disease with cirrhosis, which accounts for 85% of cases. The next most common cause of ascites is malignancy, which accounts for 10% of cases. Malignancy-related ascites comprises ascites that occurs as a result of peritoneal carcinomatosis or due to other tumor-related factors in the absence of known tumor implants in the peritoneal cavity. Malignancy-related ascites occurs as a result of various primary abdominal and extraabdominal neoplasms, the most common of which are gastric, uterine, ovarian, breast, lung, lymphoma, and pancreatic. Malignancy-related ascites is more common in women because of its incidence in patients with ovarian cancer, and it develops in up to 15% of patients with gastrointestinal (GI) cancers at some stage in their disease. Additionally, it is estimated that up to 20% of cases occur without an identifiable primary tumor. Regardless of its cause, with the exception of ovarian cancer, in which median survival is longer than in GI tract malignancies, the appearance of malignancy-related ascites usually heralds the onset of advanced disease and portends a poor prognosis. Management focuses on palliation of symptoms.
Etiology and Pathogenesis
The peritoneal membrane is a single-layer mesothelial tissue comprising a surface area of approximately 7500 cm 2 and totaling about 90 µm in thickness (five layers of connective tissue of a basal membrane). It covers the abdominal and pelvic spaces and is composed of capillaries that filter the plasma by exchanging substances and cells with the abdominal cavity through a large number of channels called “foramina” distributed along the peritoneal squamous epithelium. Peritoneal fluid is drained by the open ends of lymphatic channels, which are called stomata , found on the serosal layer. Under normal conditions, approximately 100 mL of free fluid lubricates the serosal surfaces. Factors influencing fluid balance include the portal pressure, the oncotic pressure, the sodium-water equilibrium, and the permeability of vascular channels for cells and macromolecules. Two-thirds of peritoneal fluid is reabsorbed by lymphatic system and ultimately drains into the right subclavian vein.
Several mechanisms for the development of malignancy-related ascites have been described and include increased permeability of tumor vessels, increased production and release of peritoneal fluid, decreased resorption of fluid, obstruction or compression of portal veins or lymphatics, and liver failure. Upregulation of vascular endothelial growth factor (VEGF) has been implicated in the increase in permeability of small blood vessels, as well as the uncontrolled angiogenesis of tumor mass. Carcinomatosis has been implicated in a majority of cases, wherein ascites occurs through marked neovascularization of the peritoneum and increased production of glycoproteins, which also increase the vascular permeability of small vessels. Other methods of increased vascular permeability include peritumoral inflammation and the production of matrix metalloproteinases, which are thought to disrupt tissue matrices during cancer spread. Interleukin-2, tumor necrosis factor (TNF), and interferon-αhave also been implicated. The formation of malignancy-related ascites through activation of the renin–angiotensin–aldosterone system (RAAS) with resultant sodium retention occurring as a result of decreased circulating blood volume has also been described.
The aforementioned hypotheses mainly explain increased production of malignant ascites; however, decreased resorption of peritoneal fluid also plays a significant role. Tumor growth in the abdominal cavity leads to obstruction of micro- and macroinvasion of lymphatic channels, leading to impaired fluid drainage.
Diagnosis and Evaluation
A thorough physical examination, radiographic imaging studies, and invasive diagnostic procedures such as paracentesis are important in the evaluation of the presence, quantity, and etiology of ascites.
History and Physical Examination
Patients with malignancy-related ascites often report increased abdominal girth, abdominal pain, nausea, fatigue, and early satiety. When a large volume of fluid is present that increases pressure on the diaphragm and reduces lung expansion, a patient may report dyspnea. In the presence of large volumes of ascites, patients may have bulging flanks, a fluid wave, and a protuberant abdomen. Signs such as jaundice, spider angiomata, collateral abdominal veins, and palmar erythema are more common in ascites caused by primary liver disease but may also be present if there is significant tumor burden in the liver or if the patient also has underlying cirrhosis. However, the physical examination is variable in its sensitivity and specificity with regard to reliably diagnosing ascites (50% to 94% sensitivity and 29% to 82% specificity).
Imaging Studies
Ascites fluid often layers in the dependent regions of the abdomen such as in the hepatorenal recess or Morison pouch and in the pelvic cul-de-sac and can be detected using ultrasonography. Although this imaging modality is limited in patients who are obese or have complex, loculated ascites, it is a sensitive test in most patients and is the gold standard for diagnosing malignancy-related ascites. The use of ultrasonography during fluid drainage also helps to decrease the risk of injury to viscera.
Malignancy-related ascites can also be detected by plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI). These studies are not usually used in the initial evaluation of ascites because it is often found incidentally when patients are undergoing imaging for other reasons. Nevertheless, imaging studies are very useful in situations in which the presence of ascites precedes a diagnosis of malignancy and when a primary site of tumor in the liver or peritoneal metastasis may be present. When a gynecologic cancer is suspected, ultrasonography may be useful in helping to make the diagnosis and should be performed in all women who present with ascites without any evident primary tumor.
Diagnostic Paracentesis
Diagnostic paracentesis is an expedient, inexpensive, and relatively safe procedure that can provide a lot of information about the etiology of ascites. In most cases, malignancy-related ascites follows a diagnosis of malignancy. However, in up to 20% of cases, the primary tumor cannot be identified, and as such, analysis of the ascites fluid is critical in the evaluation of patients. The appearance of the fluid may provide some clues as to the etiology of the ascites. Clear fluid is usually associated with cirrhosis. Infected fluid is cloudy. Milky fluid can indicate chylous ascites and should be sent for triglyceride evaluation. Such fluid often has triglyceride levels greater than 200 mg/dL and often as high as 1000 mg/dL. Some studies have demonstrated that the most common cause for chylous ascites in adults is malignancy.
Fluid obtained during paracentesis is submitted for chemical, microscopic, and cytologic evaluation, including cell count and differential, albumin concentration, lactate dehydrogenase (LDH), and cultures; the latter should involve immediate inoculation of the culture bottles at the bedside to maximize culture growth. Fibronectin may also be used as a marker of tumor-related ascites, although its use is controversial. In approximately 50% of cases, the presence of ascites in patients with known neoplasms heralds the presence of peritoneal carcinomatosis. In these patients, malignant cells can be detected in the fluid up to 97% of the time, making this test very sensitive and the gold standard for diagnosing peritoneal carcinomatosis. However, given that malignancy-related ascites can occur in the absence of peritoneal carcinomatosis, positive cytology findings are variable in the presence of hepatic metastases, lymphoma, or hepatocellular carcinoma. Performing immunohistochemical analysis for S100, carcinoembryonic antigen (CEA), human melanoma black 45, leukocyte common antigen, cytokeratin, vimentin, and other tumor markers can also be a useful adjunct to the workup.
Surgical Approaches
Despite all the efforts previously described, on occasion, the diagnostic workup may confirm the presence of cancer but may not reveal a primary tumor even in the setting of positive cytology, as is sometimes the case for patients with small tumors of gynecologic or peritoneal origin. In these cases, laparoscopy or laparotomy may help make the diagnosis and may facilitate placement of catheters for future therapy in the peritoneum. To minimize risk of procedure-related tumor spread and infection, these procedures should be performed by experienced practitioners.
Management
It is important to determine whether it is appropriate to treat malignancy-related ascites. Small amounts of ascites are very well tolerated and often do not require any treatment. However, after the ascites has become symptomatic (e.g., causing severe pain, respiratory compromise), the benefits and risks of treatment must be assessed to improve quality of life. Fig. 59.1 outlines the approach to managing malignancy-related ascites. Management strategies include both medical and surgical treatments.
Diuretics
The first-line approach to managing malignancy-related ascites usually involves the use of diuretics that reduce ascites via their effect on the RAAS, which is not prominent in the development of malignancy-related ascites. No randomized controlled trials that assess the efficacy of diuretics in managing malignancy-related ascites have been published. Retrospective analyses indicate that diuretic therapy is effective in controlling ascites and its symptoms in approximately 40% of patients with ascites who have peritoneal carcinomatosis. Nevertheless, diuretic therapy is one of the most commonly used interventions to manage malignancy-related ascites, second only to large-volume paracentesis. Aldosterone antagonists such as spironolactone and loop diuretics such as furosemide or bumetanide are used with varying doses and duration. The use of diuretics is associated with complications such as systemic blood volume depletion, hypotension, electrolyte imbalances, and renal dysfunction. The incidence and severity diuretics-related adverse effects are not known, especially given that these adverse effects may also occur as a result of cancer itself or its treatment. Despite their frequent use, diuretics are generally not very effective in managing most cases of malignancy-related ascites, and other approaches often need to be implemented.
Large-Volume Paracentesis
Large-volume paracentesis is the most frequently used and most effective means of managing malignancy-related ascites. A clear benefit in achieving symptom control has been shown in patients (e.g., prompt relief of dyspnea in about 90% of patients). The benefits are often short-lived, with many patients experiencing recurrence of symptoms within days of fluid evacuation. Repeat procedures may be necessary but may lead to complications similar to those observed with diuretic use. The use of colloidal volume expansion products such as albumin has been shown to reduce the risk of hemodynamic and renal compromise, although no survival benefit has been demonstrated. The mortality rate of paracentesis is low (0.16%–0.39%) but repeated procedures increase the risk of bleeding, pain, bowel perforation, and secondary peritonitis. The use of ultrasound guidance and sterile technique can mitigate these risks.
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