Impaired lymphatic drainage of the pleural space is an important mechanism responsible for accumulation of large volumes of pleural fluid in malignancy. The lymphatic system can be blocked at any point from the stoma of the parietal pleura to the mediastinal and parasternal (internal mammary) lymph nodes. The autopsy studies by Meyer⁴² and Chernow and Sahn⁶ have demonstrated the association of mediastinal lymph node involvement and the presence of substantial pleural fluid. Conversely, these studies showed evidence of pleural involvement with tumor in the absence of pleural effusions, lending support to this mechanism. Furthermore, as Meyer⁴² noted, pleural effusions usually do not occur when the pleura is involved by sarcoma because of the absence of lymphatic metastasis. Weick and associates⁶⁷ noted that Hodgkin’s disease tends to cause pleural effusions by lymphatic obstruction, and Jenkins and colleagues²⁷ and Xaubet and associates⁷¹ noted that non-Hodgkin’s lymphoma tends to produce effusions by both lymphatic obstruction and direct pleural invasion.

The inflammatory response to pleural tumor invasion results in increased microvascular permeability and produces variable volumes of pleural effusion. Chretien and Jaubert⁷ suggested that oxygen radicals, arachidonic acid metabolites, proteases, lymphocytes, and immune complexes are probably causative.

Vascular endothelial growth factor (VEGF) has been shown to play an important role in the formation of pleural effusions.¹⁷ The cytokine VEGF has been documented to induce vascular leakage in the formation of both pleural effusion and ascites. Tumor cells implanted in the pleura of experimental animals secrete VEGF, leading to microvascular permeability. Blocking the VEGF receptor has inhibited pleural fluid formation in an in vivo model of adenocarcinoma of the lung. Mesothelial cells appear to be an important source of VEGF, and transforming growth factor beta has been shown to increase VEGF production both in vivo and in vitro.³²

Pleural effusion is an early manifestation of a malignant mesothelioma and probably results from a combination of increased capillary permeability from direct pleural invasion and impaired lymphatic drainage of the pleural space. As the tumor progresses and the visceral and parietal pleura fuse, the fluid diminishes or disappears.

Autopsy series have shown that in patients with carcinoma of the lung, pleural metastasis is virtually always found on both the visceral and parietal pleural surfaces. Meyer⁴² noted that rarely is only the visceral pleural surface involved, and isolated parietal pleural metastases were never identified. Visceral pleural metastasis in lung cancer appears to result from contiguous spread or pulmonary arterial invasion and embolization. Once seeded with tumor, these malignant cells migrate from the visceral to parietal pleural surface along either preformed or tumor-induced pleural adhesions. Alternatively, free tumor cells exfoliated from the visceral pleural surface can adhere to the parietal pleura and multiply. Chernow and Sahn⁶ reported that adenocarcinoma of the lung is the most common cell type to involve the pleura, presumably owing to its peripheral location and propensity for vascular invasion. When bilateral pleural metastases develop in lung cancer, hepatic spread and parenchymal invasion in the contralateral lung usually are causative. Once contralateral lung metastasis occurs, pulmonary artery invasion and embolization follow, as in the initial ipsilateral lesion. The data concerning the laterality of the pleural effusion in relation to the primary lesion support this mechanism.

Chernow and Sahn⁶ pointed out that in lung cancer, pleural effusions occur either ipsilaterally or bilaterally and virtually never occur solely in the contralateral pleural space. With other cancers, pleural involvement is usually from tertiary spread from established liver metastases with no predilection for side. Fentiman and associates¹⁶ summarized the conflicting data in breast carcinoma, with some studies showing a high incidence of ipsilateral pleural effusion and others no predilection for side. Probably two mechanisms are operative: chest wall lymphatic invasion resulting in ipsilateral effusion, and hepatic spread with bilateral, unilateral, or contralateral hematogenous metastasis.

Malignant pleural effusions may be serous, serosanguineous, or grossly bloody. A grossly bloody effusion suggests direct pleural involvement, whereas a serous effusion results from either lymphatic obstruction or an endobronchial lesion with atelectasis. Light and coworkers³³ suggested that when the red blood cell count in the pleural fluid is greater than 100,000/μL in the absence of trauma, malignancy is the most likely diagnosis. Most of the nucleated cells (2,500 to 4,000/μL) in pleural fluid, as Yam⁷² noted, are lymphocytes, macrophages, and mesothelial cells; more than 50% of the cellular population are lymphocytes in approximately half the cases. Lymphomatous pleural effusions typically have lymphocyte counts >80%. The percentage of neutrophils usually is <25% of the cell population, but on rare occasions, when there is intense pleural inflammation, neutrophils may predominate. In a prospective study, Rubins and Rubins⁵⁰ reported that pleural fluid eosinophilia occurred in 7.8% (10 of 128) of patients with malignant effusions and that malignancy is as prevalent among eosinophilic as among noneosinophilic effusions.

Carcinomatous pleural effusions typically are exudative; however, the protein concentration is variable. Chernow and Sahn⁶
and Light and associates³⁴ reported protein concentrations ranging from 1.5 to 8.0 g/dL. Up to 5% of malignant pleural effusions are transudates. These transudative malignant effusions are caused by early stages of lymphatic obstruction, atelectasis from bronchial obstruction, or most often by a concomitant disease, such as congestive heart failure. With a discordant exudate by lactate dehydrogenase (LDH) criterion only, Light and associates³⁴ emphasized that malignancy should be suspected. Sahn and Good⁵⁵ found that approximately one-third of patients with malignant pleural effusions have a low pleural fluid pH (<7.30, range of 6.95–7.29) and a low glucose concentration (<60 mg/dL or ratio of pleural fluid to serum of <0.5) at presentation. These effusions usually have been present for a few months and are associated with a large tumor burden and possibly fibrosis of the pleural surface. Good and colleagues²⁰ suggested that the abnormal pleural membrane reduces glucose entry into the pleural space and impairs glucose end-product (CO₂ and lactic acid) efflux, resulting in a local acidosis. Furthermore, Sahn and Good⁵⁵ noted that low pH–low glucose malignant effusions are associated with shorter survival, higher diagnostic yield on initial cytologic examination, and a poorer response to chemical pleurodesis compared with normal pH and glucose malignant effusions.

Pleural effusions caused by lymphoma have characteristics similar to those of carcinoma of the pleura. These effusions, however, tend to be less hemorrhagic and less likely to result in pleural fluid acidosis and low glucose concentrations. Both Sahn⁵¹ and Gottehrer and colleagues²¹ have pointed out that a pleural effusion in malignant mesothelioma is more likely to have a low pH and low glucose content and greater protein and LDH concentrations than effusions from carcinoma of the pleura. Because of an overlap of values, however, these data are not helpful in separating carcinoma from mesothelioma in an individual patient.