Mesotheliomas are neoplasms arising from the lining of the pleural, pericardial, and peritoneal cavities. Malignant peritoneal mesothelioma (MPM) is a rare neoplasm arising from serosal cells lining the abdominal and pelvic peritoneum. The appropriate management of MPM remains a difficult therapeutic challenge. This underscores the importance of increased awareness of MPM, prompt diagnosis, and judicious surgical management. Previously, these tumors were regarded as a preterminal condition, where the majority of surgeries did not prolong survival and were performed mainly with palliative intent. More recently, aggressive surgical approaches, including cytoreductive radical tumor debulking combined with intraperitoneal hyperthermic chemoperfusion (IPHC), are associated with prolonged survival in selected patients with MPM.

Little is known about the natural history of MPM. The median age at diagnosis is 60 years, and there is a male-to-female ratio of 3:1. The age range in which the tumor has been reported is 2 to 92 years, however, the greater majority occur between 45 and 64 years of age (1). The geographic distribution of mesothelioma around the world does not appear to be uniform, and incidence rates in some countries continue to rise. The proportion of peritoneal mesotheliomas seen in the United States appears to be increasing. Peritoneal mesotheliomas now account for up to one-third of all malignant mesotheliomas (1,2,3). The incidence of MPM among all malignant mesotheliomas is approximately 15% but varies greatly among different studies. The annual rate of mesothelioma in Australia is reported as 15.8 to 28.9 per 1 million population age 20 years and older and appears to be on the rise (4). This is in contrast to the rate in the United States, which is about 2.2 cases per 1 million population and appears to be declining (5). This may be in part due to varying timing of asbestos exposure and the long latency period (20–40 years) between maximal asbestos exposure and disease presentation.

The most common presenting symptoms of MPM are increasing abdominal girth from ascites, pain, and weight loss. Patients generally present clinically as either the “pain-predominant” type or the “ascites-predominant” clinical type, and some patients present with concomitant pain and abdominal distension (6). The presence of symptoms as compared to patients with MPM diagnosed incidentally has been reported as a negative prognostic indicator. There are no uniformly accepted staging systems for MPM. This disease is generally confined to the abdominal cavity and will eventually spread to one or both pleural cavities late in the disease course. However, most patients die without evidence of distant metastases. The most important prognostic indicator in patients with MPM may be the biological phenotype of the tumor. Progressive tumor growth eventually leads to incapacitating ascites, abdominal organ and intestinal encasement, and repeated bowel obstructions. When left untreated, the median survival is a dismal 5 to 12 months (7).

Epidemiologic studies have linked chronic peritoneal irritation (mainly from asbestos fibers) as the primary cause of MPM. Many other risk factors have also been implicated in the eventual development of MPM and include: radiotherapy for conditions such as Hodgkin disease (8,9), thorotrast exposure (10), recurrent peritonitis (11), familial Mediterranean fever (12), Simian virus 40 (SV40) (11,12,13), and endometriosis. It is interesting to note the long latency of MPM from time of environmental exposure to the onset of disease, which can often exceed 20 years. This finding would suggest that multiple somatic genetic mutational events need to occur prior to the eventual development of the malignant phenotype (7). No specific chromosomal alteration is known to occur in MPM. However, recent studies have begun to elucidate the molecular events that eventually lead to the malignant phenotype. For example, loss of a copy of chromosome 22 is the single most consistent numerical change seen in malignant mesothelioma (7).

Chronic asbestos exposure is believed to be a major risk factor for development of MPM (14). Although not uniformly accepted, up to 70% of MPM cases are believed to be associated with chronic exposure to asbestos (15,16,17). Occupational exposure to asbestos fibers in industrial and building trades is a common factor associated with most cases of MPM. In some series, it appears that the incidence and epidemiology of MPM may differ between men and women. The incidence rates of various countries parallels exposure to asbestos, and the peak incidences appear to follow the expected long latency period of MPM. For example, maximal exposure rates in Australia and Britain, which occurred during the 1960s and 1970s, would predict that peak incidence rates can be anticipated from 2010 to 2020 (15,16,17). How fiber inhalation leads to peritoneal seeding is unclear, but there are reports where inhaled asbestos fibers reach the peritoneal cavity (17). The precise mechanism by which asbestos exposure leads to the development of MPM remains to be fully elucidated (18).

Previous radiation exposure to the peritoneal cavity has been postulated as a causative factor for MPM. The presence of ascites or pleural effusion in a previously normal radiated abdomen should alert the physician to the possible development of MPM (8). It is unlikely that SV40 acts alone in MPM oncogenesis. More likely is the concept that MPM develops as a result of multiple factors cooperating to affect MPM oncogenesis. In this sense, many cocarcinogens (e.g., asbestos, SV40)
can come together and lead to MPM (19). In some areas of Turkey, MPM appears to be inherited with an autosomal pattern of genetic inheritance (20). Whether genetic factors acting alone or in combination with environmental exposures result in MPM is unknown.

Most patients presenting with MPM have had numerous nonspecific symptoms that often result in a delay in diagnosis. Among other complaints, patients can present with abdominal pain, increasing abdominal distension, anorexia, malaise, and increasing abdominal girth from ascites (4). Rarely, patients may present with weight loss, a palpable mass, dysphagia, incomplete bowel obstruction, new onset inguinal hernia, deep vein thrombosis, or even a fever of unknown origin (4,6,8,21,22,23). Ascites is a nonspecific sign that occurs in roughly 90% of patients with MPM. It is not uncommon for many patients with MPM to be explored without a preoperative diagnosis. The symptoms of patients with MPM are often nonspecific and can overlap with a spectrum of diseases.

There are a variety of rare and unusual presentations of MPM that have been reported in the literature. They have been described in hernia sacs and hydroceles, and they may sometimes mimic gynecologic malignancies. These tumors can also present as isolated umbilical, small bowel, or retroperitoneal tumors. Some unusual presentations have been reported where MPM has an ectopic hormone-producing function. There are reports of patients with excess secretion of antidiuretic hormone (24), growth hormone (25,26), corticotrophin (27), and insulinlike substances (25).

The diagnosis of MPM is often elusive because it is an uncommon disease and the symptoms and clinical presentation are varied and nonspecific. A high index of suspicion, coupled with the presence of nonspecific findings and a significant history of asbestos exposure or findings of ascites, will suggest the diagnosis in the majority of cases. Diagnostic paracentesis of ascitic fluid is rarely helpful in providing the physician with an accurate diagnosis. Often, the aspirate will yield cells that are indeterminate in nature or that contains cells that resemble “mesothelial hyperplasia” (28). Paracentesis will infrequently yield a definitive diagnosis. Most patients will undergo an imaging study for nonspecific complaints such as an abdominal ultrasound (US) or an abdominal CT scan. Findings on US are nonspecific and may demonstrate an intra-abdominal mass, omental caking, or presence of ascites. The endoscopic appearance of MPM may be indistinguishable from other primary peritoneal neoplasms or metastases from other primaries. In addition to these findings, CT scan may display a wide spectrum of findings. Thickening of the mesentery and peritoneum and the presence of ascites should alert the physician to the possibility of MPM. Although some CT scan findings can predict surgical outcomes, CT scan rarely establishes a preoperative diagnosis but in some cases may help guide the physician for a CT-guided biopsy (1).

The majority of tumors involving the surface of the peritoneal cavity are due to primary or metastatic serous epithelial tumors (14). This may make the distinction between an MPM and a primary serous epithelial malignancy particularly challenging based on morphologic characteristics alone. The diagnosis is often aided with immunohistochemistry staining for mesothelial markers that increase the accuracy of a diagnosis preoperatively. Based on histologic features and combined with immunophenotyping, the correct diagnosis of MPM can be made in many of the patients prior to surgical exploration. This may represent an opportunity to select those patients who will be the best candidates for surgical exploration from those patients who have highly aggressive phenotype who may not benefit from primary surgical debulking up front. Furthermore, there may be some variants of MPM that behave less aggressively than other variants and carry a significantly better prognosis. One such variant arising in younger women has been reported and may have a better prognosis than other MPM patients (21,22). These may be the optimal candidates for an aggressive approach with cytoreductive tumor debulking and IPHC. In some instances, obtaining a definitive diagnosis may require a multimodality approach, including clinicians, radiologists, and pathologists with special immunohistochemical stains and sometimes the aid of electron microscopy to secure an appropriate diagnosis (6).

The optimal technique of diagnosis should be some form of surgical biopsy. This approach avoids delay and potential misdiagnosis, and can be performed using various techniques. One technique that may be used is laparoscopic-guided biopsy, which is often required and can provide the surgeon with an assessment of the tumor burden prior to exploratory laparotomy (29). The laparoscopic appearance of MPM may be indistinguishable from other primary peritoneal neoplasms or metastases from other primaries. Knowledge of the absence of solid organ involvement including the liver may alert the surgeon that the tumor may represent an MPM, and careful examination of the entire abdomen and pelvis, including the mesentery and adnexa, should be made. Multiple laparoscopic-guided biopsies combined with peritoneal cytology might reveal lesions that are potentially mesothelial neoplasms and can be confirmed as MPM by immunocytochemistry. However, there is a measurable concern for port site tumor seeding, which may facilitate tumor dissemination (30,31,32). Laparoscopic intraperitoneal chemoperfusion is a newer treatment modality that may also provide a means of relief of debilitating ascites in patients who are not candidates for more radical surgical approaches. In a recent study of 14 patients with varying tumor histologies, all patients were relieved of their disabling ascites with acceptable morbidity (33).

Multiple different pathological subtypes of mesothelioma have been identified and are broadly divided into multicystic, epithelioid, epithelial, biphasic, sarcomatous, and deciduoid (7). Patients with deciduoid, sarcomatous, or biphasic morphology tend to have a worse prognosis among the group. A broad spectrum of heterogeneous pathological subtypes has been reported with varying degrees of malignant potential (Fig. 53.1). This makes the interpretation of which therapeutic approaches are optimal for each different subtype difficult. Furthermore, the natural history of pleural mesothelioma is distinct from that of MPM and makes the extrapolation of phenotype characterization and selection for treatment strategies inappropriate.

There are a few benign tumors of the peritoneal cavity that may mimic MPM at presentation and are worth mentioning. Multicystic mesothelioma, also known as multilocular peritoneal inclusion cyst, is a benign inclusion cyst formed by multiple cysts arranged in grapelike clusters (7). Adenomatoid mesotheliomas are benign epithelial lesions of the genital system that may present with an abdominal or pelvic mass. Well-differentiated papillary mesothelioma is another benign proliferation that is commonly found in young women. There have been reports of malignant degeneration after prolonged observation of the lesions (7). These tumors histologically appear to be formed by papillary structures covered by cytologically benign mesothelial cells. In some instances, the differentiation between ovarian cancer and mesothelioma cannot be made until after removal of the surgical specimen along with the ovaries.

It is unclear what the exact histologic subtype has been for many of the patients reported in the recent literature. This
will become increasingly important in identifying which patients will be best candidates for the aggressive surgical approaches to the treatment of MPM. Better understanding of the histologic features that separate the benign from frankly malignant tumors may help stratify patients for the appropriate surgical intervention. The presence of deep invasion in examined specimens may have stronger prognostic significance than histologic subtype (34). Histomorphologic parameters have been found to carry prognostic significance in predicting survival in patients with MPM (34a). Some patients with benign-appearing neoplasms may require only surgical excision and observation, whereas others with highly aggressive tumors may be spared the morbidity of aggressive surgery and IPHC.