Antony S. Moore,     Wauchope, Australia

Pathophysiology

The traditional view of the physiology of malignant effusions is that invasion of lymphatic vessels by tumor cells leads to lymphatic obstruction, which in turn is exacerbated by increases in vascular and lymphatic permeability. The end result is increased fluid production with decreased fluid removal leading to accumulation. This view is supported by lymphoscintigraphy that demonstrates decreased lymphatic flow in such patients. Additionally, metastases to lymph nodes (e.g., hilar lymph nodes) may obstruct lymphatic flow, and direct implantation of tumor cells on the mesothelial surfaces results in inflammation as well as obstruction of drainage.

In addition to decreased removal of fluid by lymphatics, there is an increase in fluid production that is mediated by angiogenesis. In the early 1980s it was demonstrated that cell-free malignant ascitic fluid led to increased capillary permeability and increases in omental edema. The factor responsible (originally called vascular permeability factor, now known as vascular endothelial growth factor [VEGF]) is produced by tumor cells, mesothelial cells, macrophages, monocytes, and tumor-infiltrating T lymphocytes. Not only does VEGF induce the proliferation of new vasculature, which is more permeable than normal vessels, it also increases the permeability of existing vasculature. Therefore VEGF is responsible for both initiating and maintaining production of ascitic or pleural fluid in a wide range of cancers. When this is coupled with decreases in lymphatic drainage, it is easy to see how malignant effusions are able to arise and re-form so rapidly. It has been shown that the total volume of ascitic fluid correlates directly with the concentration of VEGF in that fluid. In addition, the concentration of VEGF in the effusion also is correlated with both response to therapy and survival in human studies (Rudlowski et al, 2006). In dogs with pleural, pericardial, and abdominal effusions, VEGF concentrations have been shown to be elevated in the effusions. Concentrations are similar in both malignant and nonmalignant effusions, so VEGF concentration is not helpful in distinguishing the cause of an effusion; however, the elevation in VEGF concentration substantiates the potential role of inhibitors of VEGF signaling in the palliation of malignant effusions (Clifford et al, 2002).

Diagnosis

In many patients the malignant effusion arises after the primary tumor has been diagnosed and possibly after surgery, radiation therapy, or chemotherapy. In such patients in which a histologic diagnosis already is confirmed, palliative measures to relieve symptoms associated with the effusion should be implemented, and then further treatment options appropriate to the primary tumor should be evaluated and discussed with the owner.

In patients in which the presentation with effusion precedes a definitive diagnosis, the primary objective should be to stabilize the patient’s condition because many dogs and cats with pleural effusion are in a delicate state and may not tolerate manipulations even for imaging studies. This is less true of pets with abdominal effusion than of those with pericardial or thoracic effusion, although complete assessment of the circulatory and respiratory systems is important. Fluid removal by needle centesis may be needed before more specific investigations are undertaken; however, samples collected at the time should be put aside for analysis. Investigations should focus on obtaining a cytologic or histologic diagnosis, which can help in selecting therapeutic options, as well as palliation of the effusion itself. If there is diffuse involvement with implanted cancer cells on the parietal and visceral surfaces, the resulting effusion is more likely to contain malignant cells. Therefore cancer cells are more likely to be found in ascitic or pleural fluid of patients with carcinomatosis (97%) than in the fluid of patients with lymphoma and those with deep visceral (e.g., pulmonary or liver) metastases.

Once the patient with suspected malignant effusion is in stable condition, fluid can be submitted for evaluation by a veterinary cytopathologist. Chylous effusions may be present in lymphoma. Routine cytologic examination may not provide a definitive diagnosis, but immunocytochemical testing using markers such as CD3 and CD79a (or other B-lymphocyte markers), as well as stains for intermediate filaments (e.g., cytokeratins, which are markers for epithelium-derived cells), may allow at least a narrowing of the diagnosis to lymphoma or carcinoma. Reactive mesothelial cells are found in most malignant effusions, regardless of cause, and may be difficult to distinguish from malignant mesothelial cells (mesothelioma). Additional investigations include polymerase chain reaction testing for antigen receptor rearrangements or flow cytometry in patients with suspected lymphoma.

When fluid is present, particularly when there is a large volume, radiography may not be helpful in identifying a primary site, but ultrasonography can assist in guiding fluid sample collection, safe removal of a volume of fluid for palliation, and potentially identification of an underlying neoplasm. In the latter case, ultrasonographically guided needle aspiration or biopsy may allow a histologic diagnosis.

Thoracoscopy and laparoscopy may be minimally invasive methods of obtaining a specimen for tissue diagnosis when there are no obvious masses on ultrasonography and a parietal or visceral surface tumor is suspected. The advantage is minimal morbidity, although invasion of mesothelioma cells along a thoracoscopy tract has been reported in people and in one dog (Brisson et al, 2006). To put this in context, surgical exploration to obtain a biopsy specimen also would carry a risk of tumor cell seeding, and even centesis poses some risk of seeding of mesothelioma. Minimally invasive techniques also may allow concurrent therapeutic and palliative procedures (e.g., pericardectomy) to be performed.