**2. Mechanisms of malignant ascites formation**

The word ascites originates from the ancient Greek askos, meaning a sac or bag. Celsus (c.30 BC–c.50 AD) postulated a link between ascites and renal disease, and he coined the term [8]. The peritoneal cavity, located between the parietal and visceral peritoneum, contains approximately 100 mL of serous fluids. Free fluid in the peritoneal cavity acts as a lubricant of the serosal surfaces and originates from the transduction of plasma through capillary membranes of the peritoneal serosa. Healthy women may normally have as much as 20 mL of free peritoneal fluid, depending on the phase of the menstrual cycle [9]. Under physiological conditions, transudation is balanced by efflux of the peritoneal fluid via lymphatic vessels. Tumour growth eventually disrupts the normal regulation of intraperitoneal fluid flow and the maintenance of a steady state in the peritoneal cavity by simultaneously causing a greater fluid inflow and a reduced outflow. Four major factors that contribute to the formation of ascites: two cause increased influx due to tumour-related factors and two cause decreased efflux due to lymphatic obstruction and mechanical obstruction by accumulation of tumour cells at the peritoneal surface (**Figure 1**) [1, 10]. The percentage of cases with a greater ascites volume increased as the stage of ovarian malignancy progressed [1].

#### **2.1. Efflux from the peritoneal cavity into the blood**

The peritoneal lymphatic system collects excess fluid, proteins, other macromolecules (>16 kDa) and cells and returns them to systemic circulation [11]. Decreased efflux from the peritoneal cavity due to lymphatic obstruction by tumour cells was first proposed as a hypothesis for ascites

**Figure 1.** Aetiology of malignant ascites in ovarian cancer.

(17%) observed in the early disease (FIGO stages I and II) and is absent in nearly half of borderline tumours. Unlike in primary OC, recurrent disease is not strongly associated with

Throughout history, ascites has always been regarded as a poor prognostic sign. In the 1700s, Sir Thomas Spencer Wells wrote "surgeons stood and trembled on the brink of ovarian waters" [3]. Studies addressing the prognostic significance of ascites in patients with stage III or IV have shown a significantly poorer survival [4]. Ascites is also associated with pharmacoresistance [4]. Patch et al. showed that matched primary ascites (tumour cells isolated from ascites) share most genomic changes of acquired resistance with primary tumour samples

In newly diagnosed ovarian cancer patients, ascites is treated by using the standard treatment for the underlying disease. However, once the chemoresistant and recurrent features of the disease develop, management of a large volume of ascites can be a major problem. Palliation of symptomatic patients is therefore the foremost goal, and elimination of fluid accumulation in patients with these symptoms will certainly improve their quality of life and may even prolong survival [6, 7]. An understanding of malignant ascites aetiology is of utmost importance

This chapter considers the aetiology and pathophysiology of malignant ascites in OC as well

The word ascites originates from the ancient Greek askos, meaning a sac or bag. Celsus (c.30 BC–c.50 AD) postulated a link between ascites and renal disease, and he coined the term [8]. The peritoneal cavity, located between the parietal and visceral peritoneum, contains approximately 100 mL of serous fluids. Free fluid in the peritoneal cavity acts as a lubricant of the serosal surfaces and originates from the transduction of plasma through capillary membranes of the peritoneal serosa. Healthy women may normally have as much as 20 mL of free peritoneal fluid, depending on the phase of the menstrual cycle [9]. Under physiological conditions, transudation is balanced by efflux of the peritoneal fluid via lymphatic vessels. Tumour growth eventually disrupts the normal regulation of intraperitoneal fluid flow and the maintenance of a steady state in the peritoneal cavity by simultaneously causing a greater fluid inflow and a reduced outflow. Four major factors that contribute to the formation of ascites: two cause increased influx due to tumour-related factors and two cause decreased efflux due to lymphatic obstruction and mechanical obstruction by accumulation of tumour cells at the peritoneal surface (**Figure 1**) [1, 10]. The percentage of cases with a greater ascites volume

The peritoneal lymphatic system collects excess fluid, proteins, other macromolecules (>16 kDa) and cells and returns them to systemic circulation [11]. Decreased efflux from the peritoneal cavity due to lymphatic obstruction by tumour cells was first proposed as a hypothesis for ascites

if more effective treatment strategies for ascites and OC are to emerge in the future.

as current diagnostic modalities and explores the best form of management.

**2. Mechanisms of malignant ascites formation**

increased as the stage of ovarian malignancy progressed [1].

**2.1. Efflux from the peritoneal cavity into the blood**

ascites, which was found in 38% of patients with recurrent OC [2].

across the whole genome [5].

198 Ovarian Cancer - From Pathogenesis to Treatment

formation by Holm-Nielsen more than 60 years ago [12]. Published data using lymphoscintigraphy showed that patients with malignant ascites had no activity above the diaphragm after intraperitoneal injection of the isotope, in contrast to control patients with no ascites or cirrhotic ascites. Bronskill et al. [13] showed that OC patients with persistent, intractable ascites, who were approaching their terminal illness, had low peritoneal drainage rates (below 50 ml/h). This result generally indicates obstruction of the diaphragmatic plexus [13]. Initial events that lead to fluid accumulation were studied by Nagy et al. [14] who showed that in mice efflux the peritoneal cavity of <sup>125</sup>I-labelled human serum albumin and <sup>51</sup>Cr-labelled red blood cells is markedly reduced (fivefold) within 1 day of *i.p.* ovarian tumour cell line injection. A significant reduction preceding a detectable increase in tumour cell number was not attributable to the blockage of peritoneal lymphatics by tumour cells and by itself did not provoke peritoneal fluid accumulation. These results suggest a prominent role for nonobstructive mechanisms, including contraction of lymph vessels induced by secretion of tumour cell product(s). At later periods, the absorption of fluid from the peritoneal cavity might also be affected due to carcinomatosis [14].

#### **2.2. Influx into the peritoneal cavity**

Nagy et al. studied the influx of fluid into the peritoneal cavity of mice [14]. They found that after *i.p.* ovarian tumour cell line injection, influx of 125I-labelled human serum albumin rose between days 5 and 7 to values 13- to 25-fold higher than control values, when the tumour cell number had increased >500-fold. By day 10, influx had increased sufficiently to exceed efflux, resulting in net accumulation of fluid [14]. An increase in influx is a result of various factors: (1) increased capillary permeability, (2) angiogenesis, (3) increased area for filtration and (4) decreased oncotic pressure difference. In malignant ascites, various factors secreted by tumour cells are present, which increase vascular permeability and induce angiogenesis. An early step leading to angiogenesis is partial proteolysis of vascular basal lamina, resulting in hyperpermeability. Vascular endothelial growth factor (VEGF) is the most potent and specific angiogenic factor, secreted by a large variety of tumours, peritoneal mesothelial cells, monocyte/ macrophages in malignant ascites and even tumour-infiltrating T cells [7]. Additionally, VEGF increases the permeability of vessels to plasma proteins, including albumin and fibrinogen, with a potency 10,000 times higher than histamine [15, 16]. Other factors that may also induce angiogenesis have been identified in malignant ascites and include basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor alpha and beta (TGF-alpha, TGF-beta), interleukin-8, placental growth factor (PIGF) and platelet-derived endothelial cell growth factor (PD-EGF) [11]. Influx into the peritoneal cavity after *i.p.* ovarian tumour cell line injection rose significantly when the surface area for filtration also increased; the size and number of vessels lining the peritoneal cavity increased as much as 15-fold [16]. The protein content of malignant ascites is greater than in peritoneal fluid of healthy women [11]. The oncotic pressure difference between plasma and ascites therefore decreases, and as a consequence, reabsorption decreases and interstitial fluid accumulation results [11]. Liver metastasis causing hepatic vein obstruction may be an important aetiology factor in some cases of malignant ascites [1].
