UpToDate Mesothelioma Module

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Alexander HR Malignant peritoneal mesothelioma In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2009

Author
H Richard Alexander, Jr, MD

Section Editor
Kenneth K Tanabe, MD

Deputy Editor
Diane MF Savarese, MD

Last literature review version 17.1: January 2009 | This topic last updated: January 8, 2009

INTRODUCTION — Malignant mesothelioma is a highly lethal malignancy of the serosal membranes of the pleura, peritoneum, pericardium, or tunica vaginalis testes. Approximately 3300 cases are diagnosed in the United States every year, of which 10 to 15 percent are peritoneal [1-4]. The peritoneum is the second most frequent site of origin of mesothelioma, following the pleura. The pathogenesis of all forms of mesothelioma is strongly associated with industrial pollutants, of which asbestos is the principal carcinogen associated with the disease.

Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm that arises from the lining mesothelial cells of the peritoneum and rapidly spreads within the confines of the abdominal cavity. Morbidity and mortality are almost entirely due to disease progression within the peritoneum and not distant metastatic spread.

MPM is an understudied disease, largely because most molecular and clinical studies have been conducted predominantly in patients with the more common pleural variant. However, it is not clear that the two diseases are similar. While they share the same predominant risk factor (asbestos exposure), gene expression profiles of pleural and peritoneal mesotheliomas are distinct, suggesting differences in molecular pathogenesis between the two [5,6].

This topic review will cover the epidemiology, histology, clinical features, diagnosis and treatment of malignant peritoneal mesothelioma. The epidemiology, pathology, clinical presentation, diagnosis, staging, and treatment of pleural, pericardial, and testicular mesothelioma are presented elsewhere.

EPIDEMIOLOGY AND RISK FACTORS — In the US, MPM accounts for about 10 to 15 percent of all cases of mesothelioma, and there are about 400 new cases diagnosed annually [1,2]. The rising worldwide incidence of mesothelioma is expected to peak between 2015 and 2025, and is largely a reflection of occupational asbestos exposure [1,4,7,8]. However, pleural mesothelioma accounts for most of the rising number of cases. At least in the US, incidence rates of MPM have remained stable over the last 30 years [4].

In contrast to pleural mesothelioma, which has a male predominance (male to female ratio of between four and five to one), men comprise a smaller proportion of cases of MPM [1,2,4,9]. As an example, in a study of the 10,589 cases of mesothelioma reported to the SEER database between 1973 and 2005, 44 percent of the 1112 peritoneal cases arose in women as compared to 19 percent of the 9211 pleural primaries [4].

The higher proportion of females who develop MPM is generally interpreted to reflect a higher background rate of mesothelioma which is unrelated to asbestos exposure [1,10].

The median age at presentation is 63, younger than that of the average patient with pleural mesothelioma [4,11]. Although MPM is typically a disease of adults, childhood cases have been reported [12-15].

Risk factors

Asbestos — There is a strong relationship between asbestos exposure and the development of mesothelioma at any location. The lifetime risk of developing mesothelioma among asbestos workers is thought to be as high as 10 percent, and the latency period between exposure and the development of mesothelioma is approximately 30 years.

The link between exposure to asbestos and peritoneal mesothelioma is less strong than it is for pleural mesothelioma, particularly among women [10,16-18]. In a population-based study that was based upon telephone interviews of mesothelioma cases and controls, the attributable risk for exposure to asbestos was 58 percent for peritoneal and 88 percent for pleural mesothelioma among men, and 23 percent for both types among women [10].

Nevertheless, asbestos is the best defined risk factor for peritoneal mesothelioma, as reflected by the following observations:

In cohorts of workers exposed to asbestos, MPM was responsible for 0.1 to 1 percent of all deaths overall [3].

The role of occupational asbestos exposure in causing MPM was confirmed in two community-based studies [10,19]. In one, the odds ratio of a peritoneal cancer was 180 for insulation workers and 7.6 for manufacturers of nonmetallic mineral products, including asbestos.

Two studies provide evidence for an increased risk of MPM following nonoccupational (ie, household or residential) exposure [20,21].

The main fiber type implicated in the US is amosite (an amphibole); chrysotile has not been convincingly shown to cause peritoneal mesothelioma [3]. The pathogenesis of the disease is largely unknown [22].

Peritoneal mesothelioma induced by asbestos is generally related to a higher cumulative dose than its pleural counterpart. The risk of MPM is proportional to the square of cumulative exposure, while the risk of pleural mesothelioma rises less than linearly with the cumulative asbestos dose [23]. Thus, the risk of pleural mesothelioma appears to rise more steeply at low levels of exposure, while at higher levels of exposure, peritoneal tumors predominate.

This concept can be illustrated by a study examining the relative risk (RR) of developing pleural or peritoneal mesothelioma based upon the type of occupation [24]. Relative risks (RRs) ranged from 2.6 in construction workers to 46.1 in insulation workers [24]. Occupations with the highest overall RR had a higher proportion of peritoneal primaries. In fact, 44 percent of the mesotheliomas that arose in these groups were peritoneal. The biologic basis underlying this observation is not understood.

Radiation therapy — Although asbestos exposure is the predominant defined risk factor, there are also case reports of MPM arising in irradiated fields, although the number is small overall, and the magnitude of the risk is undefined [25-27]. Due to the low number of reported cases, full-scale epidemiologic studies on the relationship between prior irradiation and peritoneal mesothelioma have not been possible.

Other factors — Exposure to other mineral fibers (eg, erionite, a silicate fiber of the zeolite family) is reported to be a risk factor for peritoneal as well as pleural mesothelioma [28].

Peritoneal mesothelioma has been reported in three separate cohorts of patients who received thorotrast for radiological examinations [29-31]. The cumulative incidence of MPM in these series is 0.2 to 0.6 percent, higher than that seen in many cohorts of asbestos-exposed workers.

A large number of pleural mesotheliomas contain sequences of the papovavirus, simian virus 40 (SV40), and this has been seen in peritoneal mesothelioma as well. In one study, 7 of 11 German cases of MPM were positive for SV40 sequences [32]. However, the causal nature of this association has been questioned, and laboratory contamination may explain some of the findings. Cases have also been reported in the setting of chronic peritonitis [33,34].

CLINICAL PRESENTATION AND IMAGING FEATURES — There are no signs or symptoms that are specific for MPM. Although most cases are symptomatic, a few are diagnosed incidentally, after inquiry into an unrelated process, such as infertility, or recognized during a routine physical examination [35-37].

The majority of cases of MPM present with diffuse peritoneal involvement and are variably referred to as diffuse peritoneal mesothelioma, malignant peritoneal mesothelioma or just peritoneal mesothelioma. However, a minority of cases have localized disease, and they have a different presentation and natural history [38].

Classifying MPM into diffuse and localized subtypes may be of prognostic significance. Diffuse MPM is highly aggressive, with a few exceptions (such as the well-differentiated papillary mesotheliomas that occur in women. In contrast, patients with a localized MPM usually have a good prognosis following complete surgical excision.

Diffuse peritoneal mesothelioma — Clinical manifestations of diffuse MPM are related to ascites or tumor progression within the abdominal cavity [39,40]. Common complaints include abdominal distention and/or increasing abdominal girth, abdominal pain or discomfort, nausea, anorexia, and weight loss. Gastrointestinal complications such as bowel obstruction are usually a manifestation of advanced disease.

Due to the nonspecific nature of the presenting symptoms, many patients already have an advanced disease burden at diagnosis. A minority are asymptomatic and diagnosed incidentally, often as the result of a palpated abdominal mass [36,37].

Abdominal distention (increased abdominal girth), the most frequent initial symptom, is present in 56 to 82 percent of patients. It can cause early satiety, dysphagia, and shortness of breath, all of which contribute to weight loss, impaired performance status, and overall inanition. Abdominal distension may also manifest as a new or worsening abdominal wall hernia, whose repair may reveal the unsuspected diagnosis of a mesothelioma.

Increased abdominal girth by itself does not portend a poor prognosis; however, weight loss is a poor prognostic sign [41]. Most patients with abdominal distention due to excess energy intake or who develop progressive accumulation of ascites associated with a nonmalignant conditions gain weight. Decreasing weight associated with loss of lean body mass in a patient with progressively increasing abdominal girth should raise suspicion for malignant ascites secondary to a peritoneal surface malignancy.

Pain is the second most common initial symptom, and is present at diagnosis in 27 to 58 percent of patients [36,41-43]. In most cases, the pain is diffuse and nonspecific, although a small minority present with an acute abdomen secondary to perforation or obstruction [44].

Morbidity and mortality from MPM are almost invariably due to disease progression within the peritoneal cavity. However, MPM may also extend into the pleural cavity during the latter stages of disease progression. While MPM may metastasize to the abdominal and pelvic lymph nodes, distant metastases are very uncommon.

Localized malignant mesothelioma — The less common localized form of MPM presents as a focal, circumscribed mass that may invade locally and extend into adjacent organs, but typically does not spread diffusely throughout the peritoneal cavity [38]. Patients may complain of localized abdominal pain, or have a palpable abdominal or pelvic mass [38].

Paraneoplastic phenomena — A number of paraneoplastic phenomena have been described in the setting of mesothelioma, including [45-49]:

Fever
Thrombocytosis
Malignancy-related thrombosis
Hypoglycemia
Rarely, Coombs-positive hemolytic anemia

Radiographic imaging — Computed tomography (CT) is the most useful initial diagnostic study. The peritoneal masses and nodules may enhance on CT after intravenous injection of iodinated contrast material. However, CT and other imaging modalities tend to underestimate the actual burden of disease.

The imaging patterns and features of malignant mesothelioma are shown equally well on magnetic resonance imaging (MRI). Limited reports describe the signal intensity of MPM as intermediate to low on T1-weighted images and intermediate to high on T2-weighted images [50]. However, MRI is not used as commonly to evaluate patients whose signs or symptoms are thought to reflect a diffuse abdominal process. MRI may be the primary assessment method in a patient who cannot receive iodinated contrast, or in a woman with a pelvic mass found at clinical examination or ultrasound.

Diffuse MPM produces two patterns on cross-sectional imaging:

Diffuse and widespread involvement of the peritoneal cavity tumor infiltration and irregular/nodular thickening of the peritoneum in a sheetlike fashion.

Less commonly, there is a focal pattern of involvement with a dominant intraperitoneal mass and associated peritoneal studding [51]. In some studies, this pattern has been more common with the sarcomatous subtype [52].

In addition to the primary tumor, moderate to extensive (rarely massive) ascites is present in 60 to 100 percent of newly diagnosed patients [42,52,53]. Other findings include omental caking/thickening, scalloping or direct invasion of intraabdominal organs such as the liver, and diaphragmatic involvement. Cystic areas may be present.

The sheetlike pattern of growth may extend to the visceral peritoneal surfaces of the small bowel, encasing it and leading to the appearance of a thick intestinal wall on cross sectional images [51]. Infiltration of the small bowel mesentery can lead to fixation of the position of the bowel loops and the mesentery, with apparent straightening of the course of the mesenteric vessels
[51,54-56]. These findings, in conjunction with a linearly oriented tumor in the mesentery, produce a characteristic "pleated" appearance on cross-sectional imaging [51].

Calcifications within diffuse MPM are considered rare. Calcified plaques are seen less often than with pleural mesothelioma; however, calcified pleural plaques and other signs associated with asbestos exposure may be present in the chest in up to 50 percent of patients [56].

Published frequencies of positive CT findings are summarized in the table. For patients being considered for aggressive locoregional therapy, results from the initial staging CT scan can be used to predict the likelihood of complete surgical cytoreduction.

Localized mesothelioma — Localized mesothelioma is an uncommon manifestation of the disease. The localized type of MPM appears as a heterogeneous, solid intraperitoneal mass on cross sectional imaging. The margins are often irregular, and there may be scalloping or direct invasion of adjacent visceral structures such as the liver, spleen, or pelvic organs. Localized, loculated ascitic fluid may be present, but manifestations of diffuse peritoneal involvement (generalized ascites, omental caking, peritoneal nodularity) are characteristically absent [51].

Differential diagnosis — Based on imaging findings, the differential diagnosis for a typical diffuse MPM includes peritoneal carcinomatosis, serous surface papillary (primary peritoneal) carcinoma, ovarian carcinoma in women, lymphomatosis, and tuberculous peritonitis. There are no imaging features that are specific for MPM [57], although some features may help to suggest a specific diagnosis:

Liver metastases and lymphadenopathy are more common with peritoneal carcinomatosis from a gastrointestinal tract primary neoplasm as compared to MPM [58].

The finding of diffuse adenopathy with a lack of omental involvement should raise suspicion for lymphomatosis.

Tuberculous peritonitis is usually characterized by smooth peritoneal thickening, mesenteric lymphadenopathy with central necrosis, ascites with high attenuation and splenomegaly.

In women, the main differential is between diffuse MPM and papillary serous carcinoma of the peritoneum [59]. This entity is a primary neoplasm arising within the peritoneum but is not likely of mesothelial cell origin. Instead, it is considered to arise from ovarian epithelial rests that are a remnant of the ovary's descent into the pelvis. Any of the pelvic adnexa may, in fact, be a source of these cells. These tumors are histologically, immunophenotypically, and clinically distinct from mesothelioma, but similar to epithelial carcinomas of the ovary.

DIAGNOSIS AND STAGING — The diagnosis can be established cytologically or histologically.

Cytology — In general, cytologic fluid analysis is of limited diagnostic utility. Although a diagnosis of mesothelioma can be made cytologically [60], fluid cytology is often inconclusive and has a low yield [41]. The differentiation between benign or malignant causes of mesothelial cell proliferation can be especially difficult. Cytology does not allow for assessment of true stromal invasion into the peritoneum or the underlying viscera, the defining parameter of malignancy [61]. Invasion can only be seen on histologic study of solid tumor material.

Biopsy — CT-guided core needle biopsy or laparoscopic biopsy may both provide sufficient material to make a tissue diagnosis. Features seen on hematoxylin and eosin (H&E)-stained sections and immunohistochemical staining characteristics usually allow the differentiation of mesothelioma from other tumors. There is a propensity for mesothelioma to seed needle tracts or trocar sites [41]. Therefore, the site of the biopsy/laparoscopic port sites are usually excised at the time of surgery.

Histology and immunohistochemistry — MPM is characterized macroscopically by hundreds to thousands of individual tumor nodules of varying size and consistency that are usually diffusely disseminated throughout the peritoneal cavity. The lesions may range from diffuse subcentimeter gray hard nodules to large nodular masses which spread in sheets and coalesce to form plaques and masses, replacing the omentum, circumferentially encasing the bowels, and invading solid organs, mesentery, and diaphragm. These tumors may have a gelatinous consistency, depending on the hyaluronic acid content, and as they progress, they interrupt peritoneal lymphatics and produce exudative fluid from their surfaces, resulting in ascites.

Upon microscopic examination, there are four histologic subtypes:

Epithelial
Sarcomatoid
Biphasic
Tubulopapillary (well-differentiated)

Epithelial malignant mesotheliomas are composed of cells that resemble normal mesothelial cells [38]. Architecturally, they form a tubulopapillary or trabecular pattern. Flattened or cuboidal cells with monotonous nuclei line the papilla or tubules. Mitotic figures are uncommon. The tumor infiltrates submesothelial connective tissue, fat, and/or muscle. There may be other characteristics, such as signet-ring cell structure or a desmoplastic response, that makes it difficult to distinguish from another adenocarcinoma on histologic analysis alone.

The sarcomatous pattern, which is less common in the peritoneum as compared to the pleura, is typically composed of tightly packed spindle cells. Malignant osteoid, chondroid, or muscular elements may be present within the tumor [38]. A biphasic tumor is defined as one with both epithelial and sarcomatous components, each contributing more than 10 percent to the overall histology.

The well-differentiated or tubulopapillary type is discussed below.

Distinction among the morphologic subtypes is prognostically significant. Tumors with a sarcomatoid component have a worse prognosis [41,62]. In one report, the median survival for the epithelial subgroups of MPM was significantly higher than that of the combined groups of sarcomatoid and biphasic subtypes (55 versus 13 months) [41].

Immunohistochemistry — Although immunohistochemical staining (IHC) for several markers can assist in identifying mesothelial cells, none is specific for mesothelioma. Instead, a panel of markers is generally used to help differentiate a mesothelioma from more common tumors such as metastatic adenocarcinoma, primary peritoneal serous carcinoma, and soft tissue sarcoma, which might have a similar histologic appearance [51,55,63,64]. The most useful of these are summarized below:

In contrast to adenocarcinomas, MPM produces large amounts of hyaluronic acid, and the distinction can be easily made with the use of colloidal iron or alcian blue and hyaluronidase.

Another differentiating feature is the presence or absence of neutral mucin as determined by the periodic acid Schiff (PAS) stain and diastase; MPM is invariably devoid of neutral mucin [65-67].

Mesotheliomas usually stain negative for other adenocarcinoma markers, including CEA, LeuM1, Ber-Ep4, B72.3, Bg8, and MOC-31.

Most mesotheliomas stain positively for calretinin, cytokeratins 5/6, WT-1, thrombomodulin, and mesothelin.

Overall, IHC for cytokeratin 5/6, calretinin, and WT-1 (positive markers for mesothelioma), and CEA, Ber-Ep4, LeuM1 and Bg8 (negative in mesothelioma) is the most useful panel of markers [51,55].

Occasionally, when an epithelial mesothelioma is extremely dedifferentiated or if it is a desmoplastic variant, ultrastructural analysis via electron microscopy may be beneficial, although it is rarely needed. Electron microscopy is less helpful for the differentiation of sarcomatous mesothelioma from soft tissue sarcoma [38].

The distinction between benign and malignant mesothelial proliferations is sometimes more challenging:

As noted above, histologic evidence of invasion is the defining parameter in the distinction between malignant or benign mesothelial proliferations. However, even in biopsy or surgical specimens, mesothelial cells are frequently subject to entrapment in adhesions, fat lobules and inflammatory tissue which may falsely suggest stromal invasion [68]. In particular, the pelvic adnexae are notorious for granulomatous and adhesive mesothelial entrapment, due to the intense inflammatory conditions that frequent this part of the anatomy. Also, cells in ascites can sediment onto a mesothelial surface which, when biopsied, resembles a mesothelial proliferation that has subserosal invasion [61].

Atypia and necrosis are more common in malignant tumors but are nether sufficiently sensitive nor specific for distinguishing between benign and malignant mesothelium [65]. As an example, in a review of 217 cases by the US-Canadian Mesothelioma Reference Panel, there was virtually total agreement on mesothelial origin but disagreement regarding malignancy in 22 percent of the cases [61].

A promising but still new area of investigation that may help to differentiate benign from malignant mesothelium is immunohistochemical labeling of telomerase [69-71].

Staging — There is no uniformly accepted staging system for MPM. Because of the low frequency of disease spread outside of the peritoneum, staging for distant metastases is generally not needed, unless there are symptoms suggesting metastases to a distant organ. For patients who present with a pleural effusion, further diagnostic testing with thoracentesis or video-assisted thoracoscopic surgery (VATS) is improtant to eliminate the possibility of tumor spread into the pleural cavity.

Tumor markers — Serum chemistries and tumor markers are of no value in establishing a diagnosis of MPM. Elevated levels of hyaluronan, CA-125, alpha fetoprotein, carcinoembryonic antigen, and mesothelin are found in some patients, and there is often a correlation between elevated levels and disease progression. However, for diagnostic purposes, the specificity of all of these tumor markers is low [42,72].

Some of these markers (particularly CA-125 [72] and mesothelin) may prove useful to follow response to therapy or for posttreatment surveillance, if they are initially elevated.

Mesothelin and mesothelin-related peptides — Mesothelin is a glycoprotein that is expressed on the surface of normal mesothelial cells and highly overexpressed in malignant mesothelioma. Soluble mesothelin-related peptides (SMRPs) are believed to be either cleaved peptide fragments of mesothelin, or abnormal variants of mesothelin that are unable to bind to membranes and are found in the serum. Mesothelin and its associated peptide fragments appear to be of some value as tumor markers in mesothelioma, although limited to the epithelial and biphasic subtypes. The bulk of the data are in patients with the pleural variant.

An ELISA is commercially available (Mesomark™ assay) to measure serum levels of SMRPs that are shed into the circulation [73]. In one report, elevated levels (≥9 ng/mL) were seen in 40 of 56 (71 percent) of patients with mesothelioma (primary site not specified). Using this cutoff, elevated levels were also found in 13 percent of randomly selected hospitalized patients without a diagnosis of cancer and in 8 of 21 patients with advanced ovarian cancer, illustrating the problems with specificity and the lack of utility of this assay for diagnostic purposes.

However, out of the six patients with peritoneal mesothelioma who underwent surgery, four had elevated serum mesothelin levels preoperatively; levels decreased in three of four patients who successfully underwent cytoreduction plus heated intraperitoneal chemotherapy, and they were undetectable by day 7. These data suggest that assay of SMRPs may be a useful and sensitive marker for response and disease recurrence in patients with MPM. Further data are needed.

TREATMENT

General principles — There is no consensus as to the optimal treatment for MPM. Several factors have hampered the evaluation and comparison of different treatment options for this disease. MPM is uncommon, and most clinical trials are small; randomized studies are challenging to accrue. The disease itself is heterogeneous in its clinical behavior (particularly in women [74,75]), and there are many prognostic variables, some of which are only evident at surgical evaluation. The different histologic types have different natural histories, and there are two variants in particular, both of which arise predominantly in women, which have indolent clinical behavior.

The following sections will focus on diffuse MPM, the most common type of clinical presentation. Management of the well-differentiated papillary and multicystic variants is described below.

In the past, diffuse MPM was treated at most cancer centers with a combination of systemic chemotherapy, palliative surgery, and sometimes, whole abdominal irradiation [76]. Median survival was uniformly less than one year, and long-term survival was uncommon [76-78]. More recent experience with chemotherapy alone demonstrates a median survival of 13 months and a 66 percent one-year survival rate among 66 patients treated with pemetrexed plus cisplatin, versus month month median survival and zero percent one-year survival in 32 patients treated with pemetrexed monotherapy [79].

These results provide a "benchmark" against which other therapies, such as cytoreductive surgery and intraperitoneal chemotherapy, can be compared.

Cytoreduction surgery and intraperitoneal chemotherapy — Over the last decade, aggressive regional therapy using a combination of cytoreduction surgery (CRS) and intraperitoneal (IP) chemotherapy has been increasingly applied to patients with peritoneal surface malignancies, including pseudomyxoma peritonei and malignant peritoneal mesothelioma (MPM). (See "Cancer of the appendix and pseudomyxoma peritonei", section on Aggressive cytoreduction and intraperitoneal chemotherapy).

The rationale for this therapy in MPM is as follows:

MPM remains confined to the peritoneal cavity in the majority of cases. Because the peritoneal implants are typically superficial and do not invade the underlying tissues deeply until the late stages of disease, the disease is amenable to complete or near complete gross cytoreduction in over one-half of all patients undergoing exploration. The completeness of surgical cytoreduction is a major prognostic factor for outcomes (see below).

Direct IP administration of chemotherapy can permit a several-fold increase in drug concentration in the abdominal cavity compared to systemic administration [80]. Despite this regional advantage, direct penetration into tumor tissue is limited to a few millimeters. This his may be enhanced by heating the perfusate containing chemotherapy, but even so, this form of therapy is best restricted to small volume disease.

IP chemotherapy used in the operating room with hyperthermia has many nomenclatures, including continuous hyperthermic peritoneal perfusion, heated intraoperative peritoneal chemotherapy, and intraperitoneal hyperthermic chemotherapy (IPHC). The remainder of this topic review will use the term IP hyperthermic chemotherapy (IPHC). Some centers also extend the period of IP chemotherapy beyond the operating room, an approach termed early postoperative intraperitoneal chemotherapy (EPIC).

Although randomized trials have not been conducted, as the number of centers utilizing this approach has expanded, particularly over the last five years, dramatic improvements in outcome of MPM have been reported compared to historical controls. In several series, median survival approaches five years.

However, these results are achieved with optimally selected patient populations and with treatment delivery in a center with expertise in these technically demanding procedures:

This approach is best suited for patients with no evidence of extraperitoneal spread, a good performance status, and a disease burden that is amenable to complete cytoreduction to minimal residual disease (deposits smaller than 2 to 2.5 mm) [81]. It is unlikely that even a heated solution of chemotherapy could penetrate large tumor deposits.

Patients with MPM should be managed at an institution with demonstrated experience in this therapy. The quality of the CRS is dependent upon the skills and level of experience of the surgeon [82]. The favorable results (particularly with regard to treatment-related toxicity) achieved by international experts in the field may not be replicated in routine clinical practice. Guidance as to centers with expertise in treatment of peritoneal mesothelima is available from the nonprofit Mesothelioma Applied Research Foundation (MARF) [83].

Patient selection — Several factors are associated with better outcomes after cytoreduction surgery and IPHC, some of which are useful for stratifying patients into groups that are more or less likely to benefit this aggressive approach. These include disease extent and depth of tumor invasion beyond the mesothelial surface, completeness of surgical cytoreduction, histology (epithelial better than sarcomatoid), age (less than 60 better than older), presence or absence of weight loss, and possibly gender (women tend to do better than men) [39,40,62,84,85].

Results from the initial staging CT scan can be used to predict the likelihood of complete surgical cytoreduction.

Sugarbaker's group at the Washington Hospital Center systematically scored findings on preoperative CT scans from 30 patients undergoing CRS and IPHC for MPM, and identified features associated with adequacy of cytoreduction [86]. The presence of a >5 cm mass in the epigastric region and loss of normal architecture of the small bowel and its mesentery (matted adjacent small bowel loops, distorted and thickened configuration, segmental small bowel obstruction, small bowel mesenteric vessels difficult to define due to obliteration of mesenteric fat) were the radiographic features that were most strongly associated with suboptimal cytoreduction. Patients who had neither of these two findings had a 94 percent probability of adequate cytoreduction (defined as all residual tumor nodules <2.5 cm in diameter), while no patient with both findings had a successful surgical cytoreduction.

Radiographic criteria such as these are one of the selection factors used by Sugarbaker and other groups to select patients with a peritoneal surface malignancy who are most likely to benefit from aggressive surgical debulking and IPHC. His group uses four preoperative and intraoperative features to select patients for combined treatment [87,88]:

Preoperative contrast (oral and IV)-enhanced CT of the chest, abdomen and pelvis — In addition to excluding liver or other systemic metastases, the finding of segmental obstruction of the small bowel and tumor nodules >5 cm in diameter on small bowel surfaces or directly adjacent to the small bowel mesentery in the jejunum or upper ileum predict a poor outcome from CRS and IPHC.

Histopathology — Noninvasive malignancies such as epithelial mesothelioma are more likely to be made visibly disease-free through a peritonectomy procedure and are less likely that other invasive histologies (eg, colonic adenocarcinoma) to have spread to regional nodes, liver or other systemic sites.

Two other clinical indices, the peritoneal cancer index (PCI, a quantitative indicator of prognosis derived from the size and distribution of nodules on the peritoneal surface) and the completeness of cytoreduction score (the size of persisting tumor nodules after maximal cytoreduction) are derived intraoperatively.

Technique — Intraoperative maneuvers or procedures that may be used to achieve complete gross cytoreduction include omentectomy, splenectomy, small and large bowel resection, peritonectomy, hysterectomy, salpingectomy, oophorectomy, and low anterior resection. Implants presenting on the serosal of the small bowel, capsule of the liver or other solid viscera are usually treated with electrical or argon beam coagulation.

IPHC is done selectively, and not always in patients who have had a suboptimal cytoreduction. The treatment parameters for IPHC, including the type of chemotherapy, degree of hyperthermia, and duration of perfusion vary considerably from one institution to another (show table 2), and there are almost no data to support any specific regimen over another. Moreover, the degree to which surgical cytoreduction versus IP chemotherapy contribute to patient outcomes is unclear.

Our approach includes the following:

After maximal surgical debulking, large bore catheters are placed within the peritoneal cavity and connected to an extracorporeal recirculating perfusion circuit consisting of a reservoir, roller pump, and heat exchanger.

4 to 6 L of perfusate containing mitomycin C at a dose of 10 mg per liter perfusate (maximum dose 40 mg) are circulated through the peritoneal cavity for 90 minutes. The perfusate is warmed to achieve target intraperitoneal temperatures between 40 and 42ºC.

We do not typically leave catheters in place for postoperative continuation of IP chemotherapy but others do [39,89,90].

Results — A number of centers in the US and Europe have published phase II or observational experience with cytoreduction surgery (CRS) and IPHC for MPM [39,62,84,90-100]. As noted above, the treatment protocols vary among institutions, with some using IPHC alone and others IPHC in conjunction with EPIC. All studies, however, share two of the most important therapeutic concepts in this disease: maximal CRS to remove macroscopic disease and IP chemotherapy delivered immediately after CRS to eradicate residual tumor cells.

Results from eight published reports (seven expert centers) are summarized in the table (show table 3). The techniques and range of findings from three groups are described in detail below:

Washington Hospital Center — Sugarbaker and colleagues from the Washington Hospital Center have made many important contributions to the field of managing patients with peritoneal surface malignancies, including MPM [84,89,98,101]. The most recent report detailing their experience with 70 consecutive patients was derived from a prospective database of all patients treated by the same surgical team with CRS, IPHC, and early postoperative IP chemotherapy (EPIC) for MPM [89].

The IPHC regimen consisted of cisplatin (50 mg/m2) and doxorubicin (15 mg/m2) delivered under hyperthermic conditions for 90 minutes in the operating room. Closed suction drains remained in place in all patients postoperatively, one beneath the right hemidiaphragm, another beneath the left hemidiaphragm, and two in the pelvis. During postoperative days 1 to 5, 46 patients received IP paclitaxel 20 mg/m2 per day in 1L of 1.5 percent dextrose peritoneal dialysis solution or 6 percent hetastarch solution, with a dwell time of 23 hours, and a turn in patient position every 30 minutes for the first six hours. EPIC was withheld in 24 patients because of postoperative bleeding, respiratory instability or another severe postoperative complication, low white blood cell (WBC) count related to prior chemotherapy, or chemotherapy agent not available (n = 9). Filgrastim was started empirically in the postoperative period if the total WBC count dropped below 2000/microL. Following treatment, all patients were monitored with CT scans every six months.

The mean age at surgery was 48, reflective of the young, otherwise healthy, highly selected patient population. Mean operative duration was eight hours, and the mean length of hospital stay was 23 days. There were two perioperative deaths, one from sepsis and the other from pulmonary embolism. Treatment-related toxicity requiring invasive intervention developed in 41 percent of patients, approximately one-half of which were anemia or central line sepsis. At a median follow-up of 35 months, overall median survival was 58 months, and the one-, three-, and five-year survival rates were 82, 57, and 49 percent, respectively.

Prognostic factors were addressed in a separate report of 62 patients undergoing CRS and IP chemotherapy for diffuse MPM [84]. Although several factors were significant in the univariate analysis (completeness of cytoreduction, cell type, mitotic count, radiographic findings on preoperative CT, and gender among them), the only factor that was independently associated with survival in multivariate analysis was mesothelioma nuclear size.

A separate report from this group addressed the adverse prognostic influence of lymph node involvement. In a total of 100 case of diffuse MPM undergoing CRS with perioperative IP chemotherapy, seven were node-positive, and all died of their disease within two years of surgery [101]. In contrast, the remaining 93 patients with node-negative disease had five- and seven-year survival rates of 50 and 43 percent, respectively. As with all reports from this group, these were highly selected patients.

NCI Bethesda — The most favorable long-term outcomes were reported by the National Cancer Institute (NCI) from a phase II study of 49 patients with MPM treated with CRS and IPHC (cisplatin 250 mg/m2 administered under hyperthermic conditions for 90 minutes) [39]. Systemic sodium thiosulfate was administered to all patients as a nephroprotective agent, and 35 also received a single IP dwell of 5-fluorouracil and paclitaxel in 2 L of saline between postoperative days 7 to 10. Approximately 50 percent of patients were debulked to residual disease <5 mm and 88 percent to residual disease <10 mm.

The median progresion-free and overall survival durations were 17 and 92 months, respectively and the estimated one- and three-year survival rates were 86 and 59 percent, respectively. However, 36 percent of the patients in this series had low-grade histology that was described as "adenomatoid" or tubulopapillary, most of which had no evidence of deep tissue invasion. Nevertheless, in contrast to the findings of others, histology was not associated with outcomes in multivariate analysis. This finding suggests that histology may not be a good surrogate for tumor biology.

Columbia-Presbyterian — Investigators at Columbia-Presbyterian have employed an ambitious multimodality two-staged approach for patients with MPM [62,95]. In a phase II single center trial, 27 patients had initial laparotomy for surgical debulking and placement of an intraperitoneal catheter, followed by intraperitoneal cisplatin, doxorubicin, and gamma interferon for four months. Subsequently, a second laparotomy was performed with attempted complete cytoreduction of residual disease and IPHC using cisplatin and mitomycin C followed by whole abdominal radiotherapy. RT was not received by 13 patients because of the finding of unresectable disease, a complication precluding RT, or patient refusal.

In the most recent report, treatment was remarkably well tolerated [62]. Grade 3 or 4 toxicities during treatment included small bowel obstruction, fistula, chemical peritonitis, and catheter infection in one patient each, and ototoxicity in two patients. There were no perioperative deaths.

The median overall survival was 70 months, with a three-year survival of 67 percent. Seven patients remained alive without evidence of disease at a median follow-up of 90 months, while six others remained alive but with disease, at a median follow-up of 86 months. These results underscore the heterogeneous clinical behavior of MPM.

Treatment-related toxicity — In expert hands, CRS and IPHC treatment is associated with an operative mortality rate that ranges from 0 to 8 percent, and rates of serious perioperative morbidity are between 10 and 25 percent [39,62,84,90-100]. Complications related to chemotherapy are almost invariably related to myelosuppression, while complications related to laparotomy and cytoreduction include fistula, bleeding, wound infection, and sepsis.

In the NCI series of 48 patients described above, the most frequent perioperative complications were wound infection, fascial dehiscence, pleural effusion, prolonged ileus, and catheter sepsis (6, 4, 4, 4, and 4 percent, respectively) [39]. Additional complications with a lower incidence include enterocutaneous fistula, small bowel obstruction, pneumothorax, prolonged mechanical ventilation, acute renal failure, hematologic toxicity, pancreatitis, and abdominal wall herniation.

In one of the reports from Sugarbaker's group, treatment-related toxicity was categorized as grade 1, no intervention reported for resolution; grade 2, medical treatment sufficient for resolution; grade 3, in invasive (eg, radiologic or transfusional) intervention required for resolution; grade 4, urgent definitive intervention (eg, return to the operating room or to the surgical intensive care unit) required for resolution [89].

Grade 3 or 4 morbidity rates were 27 and 14 percent, respectively. Low hemoglobin level was responsible for 26 percent of all grade 3 toxicities, while central line sepsis and urinary tract infection accounted for 17 and 13 percent, respectively. Postoperative bleeding requiring a return to the operative room accounted for 38 percent of the grade 4 adverse events, and respiratory failure requiring intubation was responsible for 22 percent. Risk factors for grade 4 morbidity included primary colonic anastomosis, more than four peritonectomy procedures, and operative duration over seven hours.

Systemic chemotherapy — Cytotoxic chemotherapy is a reasonable treatment option for patients who are not candidates for cytoreduction surgery and IPHC.

The anthracyclines were once considered the "gold standard" drugs for mesothelioma. Early data with doxorubicin-based regimens reported response rates that ranged from 14 to 41 percent, although response durations were short and median survival was usually less than one year [76,102,103]. A meta-analysis concluded that cisplatin was the single most active agent in mesothelioma [104].

Most recently, the combination of pemetrexed plus cisplatin has been associated with dramatic responses in some patients with mesothelioma, although median survival durations are still only about 13 months. For pleural mesothelioma, the combination of pemetrexed and cisplatin has become a standard first-line regimen for patients whose disease is unresectable or who are not otherwise candidates for potentially curative surgery.

Most chemotherapy trials have been conducted primarily in patients with pleural mesothelioma, although most include a small number of patients with MPM. Although there are differences in gene expression profile that suggest different pathophysiology for pleural and peritoneal mesothelioma, it is generally assumed (and supported by uncontrolled data [103]) that the efficacy of palliative chemotherapy is similar for both conditions. The following discussion will focus on data obtained in patients with peritoneal mesothelioma. General principles of systemic therapy for pleural and other forms of mesothelioma are discussed elsewhere.

Pemetrexed plus cisplatin — In patients with MPM, the available data suggest that the efficacy of pemetrexed plus cisplatin is comparable to that seen in pleural mesothelioma, and the regimen has generally been well tolerated. Although randomized trials have not been conducted, the value of pemetrexed in patients with peritoneal mesothelioma has been demonstrated in analyses of the pemetrexed expanded access program, both in the US and internationally [105,106]:

The US experience included 98 patients with MPM who received pemetrexed alone (500 mg/m2 every 21 days, n = 26) or the same dose of pemetrexed in combination with cisplatin (75 mg/m2 every 21 days, n = 47) [105]. Folic acid (350 to 600 micrograms daily) and vitamin B12 (1000 microgram IM one to two weeks before the first dose, then every nine weeks) were administered to all patients. Vitamin supplementation improves response to therapy and reduces treatment-related toxicity.

Among 73 evaluable patients, there were 19 objective responses (four complete, objective response rate 26 percent); another 45 percent had stable disease. The median overall survival for previously treated patients was 13.1 months, and it was not reached for those who were chemotherapy-naive. Both the response rate (39 versus 19 percent), and median survival (13.1 versus 8.7 months) were higher with the pemetrexed plus cisplatin combination as compared to pemetrexed alone, and in both cases, the results were comparable to those seen in pleural mesothelioma.

Treatment was extremely well tolerated, with grade 3 or 4 hematologic toxicity (primarily anemia) in only 2 percent of the entire population of 1056 patients treated in the expanded access program and neutropenia in less than 1 percent. The most common grade 3 or 4 nonhematologic toxicities were dehydration, nausea, and vomiting (7, 5, and 5 percent, respectively).

Carboplatin is often substituted for cisplatin, particularly in elderly patients. Although randomized trials have not been undertaken, at least two phase II trials and data from one of the expanded access registries [106] suggest a similar level of antitumor activity for pemetrexed plus carboplatin as with pemetrexed plus cisplatin in patients with advanced mesothelioma.

Pemetrexed plus gemcitabine — For patients who cannot tolerate a cisplatin based regimen, gemcitabine plus pemetrexed is also an active combination. First-line gemcitabine (1250 mg/m2 on days 1 and 8) plus pemetrexed (500 mg/m2 on day 8, before gemcitabine) was administered to 20 patients with advanced MPM [107]. There were three partial responses (response rate 15 percent), but another 35 percent had stable disease for a disease control rate of 50 percent. Median survival was 27 months in the entire population. Hematologic toxicity included grade 3 or 4 neutropenia in 60 percent, but febrile neutropenia in only 10 percent.

Paclitaxel plus cisplatin — Others report an objective response in 10 of 15 women treated with paclitaxel plus cisplatin for diffuse MPM (67 percent) [47]. The high rate of response in this female population raises questions about whether some had a primary peritoneal cancer (a disease that behaves like epithelial ovarian cancer in its natural history and response to platinum and taxane-based chemotherapy) rather than MPM.

Cisplatin plus irinotecan — Responses have been described with cisplatin administered intraperitoneally or IV, in combination with IV irinotecan [108].

Molecularly targeted therapy — Data on therapies that target novel molecular pathways, including mesothelin, the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways, as well as inhibitors of histone deacetylase and ranpirnase, are discussed elsewhere.

PERITONEAL MESOTHELIOMA VARIANTS — Two rare variants of peritoneal mesothelioma are reported, both of which are characterized by indolent behavior and the potential for malignant transformation to MPM.

Well-differentiated papillary mesothelioma — Well-differentiated papillary mesothelioma is a rare clinicopathologic entity that is distinct from MPM. It occurs predominantly in women of reproductive age and most often arises from the peritoneal surfaces of the pelvis [109]. There is no reported associated with asbestos exposure [110].

These indolent tumors are small (most <2 cm) and typically identified as an incidental finding at surgery performed for another indication [111-113]. At histologic analysis, the tumors have a well-developed papillary architecture with uniform, flat or cuboidal epithelium lining the papilla. Invasion is absent. These tumors must be differentiated from ordinary diffuse MPM with focal papillary architecture [16].

The radiologic appearance is rarely described. There may be plaque calcification that diffusely involves the visceral and parietal peritoneum without the presence of an associated soft tissue mass [114]. Rarely, there is peritoneal thickening, multiple peritoneal nodules, omental infiltration, and/or ascites.

Well-differentiated papillary mesothelioma is generally considered a low-grade malignancy, with a high rate of cure following complete surgical resection [111,115]. Long-term follow-up is required because of the potential to progress to true MPM [115,116]. Extensive debulking surgery and IPHC are not warranted initially because of the indolent nature of the disease, but could be considered for patients with recurrent or more extensive disease [117].

Multicystic mesothelioma — Multicystic mesothelioma is an unusual cystic tumor that most commonly arises from the pelvic surfaces of the peritoneum in young and middle-aged women [38,118-120]. Men represent only 17 percent of cases [119]. There is no association with asbestos exposure.

There is ongoing debate as to the origin of this lesion. This controversy is reflected in the variety of names used to describe this entity, including multicystic mesothelioma (the predominant terminology used), cystic mesothelioma, benign cystic mesothelioma, and peritoneal inclusion cyst. Many women have a history of prior pelvic surgery, endometriosis, or pelvic inflammatory disease, which some consider support for classification as a reactive mesothelial proliferation. Furthermore, the histologic appearance is bland and the biologic behavior is indolent, despite the high rate of recurence after surgical treatment (up 50 percent) [118]. The presence of this lesion has not altered patient survival in the vast majority of cases. However, there have been isolated reports of malignant transformation to aggressive diffuse malignant mesothelioma, a finding that tends to favor (but does not prove) a neoplastic rather than reactive origin [38,59,119-121].

The majority of cases present with chronic or intermittent lower abdominal or pelvic pain, but occasionally, the diagnosis is made incidentally at surgery or on cross-sectional imaging. On CT or MRI scan, the cysts have fluid attenuation values, and the septae enhance with IV iodinated contrast and gadolinium [50]. There may be thick-walled cysts which appear as soft tissue attenuation lesions [122]. On ultrasound, there are multiseptated structures that have an intimate anatomic association with the uterus and ovaries. The fluid within the cysts is usually anechoic. The main differential diagnosis is with cystic lymphangioma, cystic epithelial neoplasms of the ovaries, endometriosis, and pseudomyxoma peritonei.

Pathologically, these tumors are large (mean size at diagnosis 13 cm) and consist of multiple grape-like clusters of mesothelium-lined cysts that grow along the pelvic peritoneum [109,123].

Although the disease is well characterized histologically, pathogenesis, natural history and clinical management are not well defined. The clinical course is usually indolent, and surgical resection is curative. Long-term follow-up is needed, since local recurrence can occur in up to 50 percent from 1 to 27 years after initial diagnosis, and malignant transformation is reported. Surgical cytoreduction and IPHC has been associated with long-term progression-free survival [117,124], and may be best applied when there is evidence of progression after initlal resection.

SUMMARY AND RECOMMENDATIONS — Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm that arises from the lining mesothelial cells of the peritoneum and spreads rapidly within the confines of the abdominal cavity.

As with mesothelioma arising in other sites, there is a strong relationship between asbestos exposure and the development of mesothelioma at any location. However, the link between exposure to asbestos and peritoneal mesothelioma is less strong than it is for pleural mesothelioma, particularly among women.

The majority of cases of MPM present with diffuse peritoneal involvement. Common complaints include abdominal distention and/or increasing abdominal girth, abdominal pain, nausea, anorexia, and weight loss.

The imaging patterns and features of MPM are shown equally well on CT and magnetic resonance (MR) imaging. The pattern of involvement is usually diffuse and widespread involvement of the peritoneal cavity with tumor infiltration and irregular/nodular thickening of the peritoneum in a sheetlike fashion. None of the radiographic findings are sufficiently specific for MPM to avoid the need for tissue diagnosis.

Cytologic analysis of ascites fluid is often inconclusive, especially in distinguishing between malignant and benign mesothelial proliferations. CT-guided core needle biopsy or laparoscopic biopsy may provide sufficient material to establish the diagnosis, which usually requires a panel of immunohistochemical stains.

Treatment — For selected patients with diffuse MPM, no extraperitoneal disease spread, a good performance status, and who can be predicted to achieve maximal surgical cytoreduction, we recommend regional therapy using cytoreduction surgery (CRS) and hyperthermic intraoperative intraperitoneal perfusion with chemotherapy.

Although randomized trials have not been conducted, as the number of centers utilizing this approach has expanded, particularly over the last five years, marked improvements in outcome have been reported compared to historical controls. Among centers with expertise in this form of therapy, reported median survival approaches five years. Referral of these patients to a center with expertise in the management of MPM is preferred [83].

Cytotoxic chemotherapy is a reasonable treatment option for patients who are not candidates for cytoreductive surgery and IPHC. We suggest pemetrexed plus cisplatin rather than pemetrexed or cisplatin alone for first line therapy as long as a patient's performance status and general health is adequate to tolerate it. Pemetrexed plus carboplatin or pemetrexed plus gemcitabine are reasonable alternative regimens for patients in whom cisplatin toxicity is a particular concern.

We suggest initial surgical resection alone rather than CRS and IPHC for patients with the indolent well-differentiated peritoneal mesothelioma and multicystic mesothelioma variants (Grade 2C). Long-term follow-up is warranted.

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