INTRODUCTION — Malignant mesothelioma is a highly lethal malignancy of the serosal membranes of the pleura, peritoneum, pericardium, or tunica vaginalis testes. This is a rare disease. As an example, of the approximately 3300 cases of mesothelioma diagnosed in the United States every year, only 10 to 15 percent are peritoneal [1-3]. 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. (See "Epidemiology of malignant pleural mesothelioma", section on 'Asbestos exposure'.)
Malignant peritoneal mesothelioma (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 [4,5].
This topic review will cover the epidemiology, histology, clinical features, diagnosis, and staging of MPM. Treatment of MPM and the epidemiology, pathology, clinical presentation, diagnosis, and staging of pleural, pericardial, and testicular mesothelioma are presented elsewhere. (See "Malignant peritoneal mesothelioma: Treatment" and "Epidemiology of malignant pleural mesothelioma" and "Presentation, initial evaluation, and prognosis of malignant pleural mesothelioma" and "Cardiac tumors", section on 'Mesothelioma' and "Testicular sex cord stromal tumors", section on 'Other tumor types'.)
EPIDEMIOLOGY AND RISK FACTORS — In the United States, malignant peritoneal mesothelioma (MPM) accounts for approximately 10 to 15 percent of all cases of mesothelioma, and there are approximately 600 new cases diagnosed annually [6,7]. Mesothelioma rates are rising worldwide, largely a reflection of occupational asbestos exposure [1,2,6,8,9]. The incidence is expected to peak between 2015 and 2025 [10]. However, pleural mesothelioma accounts for most of the rising number of cases. In the United States and elsewhere, incidence rates of MPM have remained stable over the last 30 years [1,2,11,12]. (See "Epidemiology of malignant pleural mesothelioma".)
In contrast to pleural mesothelioma, which has a male predominance (male to female ratio of between four and five to one), women comprise approximately one-third to one-half of all cases of MPM [1,6,7,12-14].
The higher proportion of females who develop MPM is generally interpreted to reflect a higher background rate of mesothelioma that is unrelated to asbestos exposure [6,15]. (See 'Asbestos' below.)
The median age at presentation is 51 to 59, younger than that of the average patient with pleural mesothelioma [1,14,16,17]. Although MPM is typically a disease of adults, childhood cases have been reported [18-20].
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 20 to 40 years [21,22]. (See "Epidemiology of malignant pleural mesothelioma", section on 'Asbestos exposure'.)
However, the link between exposure to asbestos and MPM is less strong than it is for pleural mesothelioma, particularly among women [15,23-25]. 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 [15]. The reason for this gender difference is unclear, but misclassification of exposure history in women may be in part responsible.
Nevertheless, asbestos is the best defined risk factor for MPM, 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 [26].
●The role of occupational asbestos exposure in causing MPM was confirmed in several community-based studies [15,22,27]. In one, the odds ratio of a peritoneal cancer was 180 (95% CI 23.5-1375) for insulation workers and 7.6 (95% CI 2.3-25.5) for manufacturers of non-metallic mineral products, including asbestos.
●Two studies provide evidence for an increased risk of MPM with non-occupational (ie, household or residential) exposure [28,29].
MPM induced by asbestos generally requires a higher cumulative dose than its pleural counterpart [30-32]. 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 [30]. 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 an early study examining the relative risk (RR) of developing pleural or peritoneal mesothelioma based upon the type of occupation [31]. Relative risks (RRs) ranged from 2.6 in construction workers to 46.1 in insulation workers. 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.
The main fiber type implicated in the United States is amosite (an amphibole); in contrast to pleural mesothelioma, chrysotile has not been convincingly shown to cause MPM [26]. (See "Epidemiology of malignant pleural mesothelioma", section on 'Asbestos exposure'.)
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 [33-35]. The association between radiation exposure and mesothelioma was investigated in a longitudinal analysis of long-term solid cancer survivors derived from the SEER database [36]. They found a modest increased risk of developing peritoneal mesothelioma in cancer patients who received direct peritoneal external beam radiation, but not in those who received scattered radiation delivered to other areas. Overall, the clinical impact of radiation exposure on the development of peritoneal mesothelioma is limited. (See "Epidemiology of malignant pleural mesothelioma", section on 'Radiation'.)
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 [37]. (See "Epidemiology of malignant pleural mesothelioma", section on 'Asbestos exposure'.)
MPM has been reported in three separate cohorts of patients who received thorotrast for radiological examinations [38-40]. 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. (See 'Asbestos' above.)
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 [41]. However, the causal nature of this association has been questioned, and laboratory contamination may explain some of the findings [42]. (See "Epidemiology of malignant pleural mesothelioma", section on 'Viral oncogenes'.)
Cases of MPM have also been reported in the setting of chronic peritonitis [43], and an increased risk of MPM has been associated with a diet low in vegetable consumption [44].
Inherited susceptibility — It has been shown that a tumor suppressor gene previously identified in pleural mesothelioma, BRCA-associated protein 1 (BAP1), is frequently mutated in MPM [45]. Others have shown an increased susceptibility to MPM in germline BAP1 heterozygous mice [46], leading to speculation that patients with BAP1 mutations may have a predisposition to develop malignant mesothelioma after environmental exposure to asbestos. (See 'Molecular pathogenesis' below.)
A subset of mesotheliomas arise in carriers of BAP1 and other germline mutations that predispose to other cancers. In one report of 79 patients with malignant mesothelioma who were identified because they had a family history of malignant mesothelioma, a different BAP1-associated cancer (uveal melanoma, cutaneous melanoma, clear cell renal cancer, or breast cancer), a history of multiple malignancies, or age younger than 50 years, 43 (16 probands and 27 relatives) were found to have a deleterious germline BAP1 mutation [47]. Notably, only 22 (28 percent) reported possible asbestos exposure. Among the remaining 36 patients with no germline BAP1 mutation, 12 had deleterious mutations of additional genes linked to cancer (including mutL homolog 1 [MLH1], which is linked to Lynch syndrome). Patients with mesothelioma and a germline mutation in a cancer susceptibility gene had a better prognosis relative to expected outcomes in a cohort of patients derived from the SEER database. Identification of these individuals is important because they and their relatives may be susceptible to additional cancers, and they may benefit from genetic counseling and cancer screening. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management".)
MOLECULAR PATHOGENESIS — The molecular pathogenesis of peritoneal mesothelioma is largely unknown. However, this is an area of active research:
●It has been shown that a tumor suppressor gene previously identified in pleural mesothelioma, BRCA-associated protein 1 (BAP1), is frequently mutated in malignant peritoneal mesothelioma (MPM) [45]. Some evidence suggests that patients with BAP1 mutations have improved survival compared with those without them [47]; this association is independent of histologic type, age, or gender [48].
●A group from Pittsburgh has analyzed various genetic alterations in almost 90 patients with MPM and identified homozygous cyclin-depended kinase inhibitor 2A (CDKN2A) deletions in 29 percent, hemizygous loss of NF2 in 35 percent, and loss of BAP1 protein expression in 79 percent [49]. Combined CDKN2A deletion and NF2 loss was a negative prognostic factor for both progression-free and overall survival, independent of other known prognostic factors, including patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion.
●In one study, 11 of 88 patients (13 percent) with peritoneal mesothelioma were found to have anaplastic lymphoma kinase (ALK) gene rearrangements in tumors tested by immunohistochemistry or fluorescent in situ hybridization [50]. Loss of chromosomal region 9p or 22q, or genetic alterations in BAP1 or NF2 that are typically identified in peritoneal mesothelioma were not observed in ALK-rearranged tumors. ALK-positive tumors were more likely in women and younger patients than in those without ALK rearrangements, but other parameters, including survival, were not different between groups.
CLINICAL PRESENTATION AND IMAGING FEATURES — There are no signs or symptoms that are specific for malignant peritoneal mesothelioma (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 [51-53]. In a review of 35 MPM patients treated at a single center, the most frequent symptoms were abdominal distention/pain, weight loss, dyspnea, and chest pain. The average time between the onset of symptoms and diagnosis was approximately five months [17].
The majority of cases of MPM present with diffuse peritoneal involvement and are variably referred to as diffuse peritoneal mesothelioma, MPM or just peritoneal mesothelioma. However, a minority of cases has localized disease, and they have a different presentation and natural history [54,55]:
●Diffuse MPM is highly aggressive, with a few exceptions (such as the well-differentiated papillary mesotheliomas that occur in women). (See 'Well-differentiated papillary mesothelioma' below.)
●By contrast, patients with a localized MPM usually have a good prognosis following complete surgical excision.
Clinical features
Diffuse versus localized peritoneal mesothelioma — Clinical manifestations of diffuse MPM are related to ascites or tumor progression within the abdominal cavity [14,56,57]. 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 is asymptomatic and diagnosed incidentally, often as the result of a palpated abdominal mass [52,53].
Abdominal distention (increased abdominal girth), the most frequent initial symptom, is present in 30 to 80 percent of patients [57,58]. 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, which, if subject to attempted surgical repair, may reveal the unsuspected diagnosis of a mesothelioma.
Most patients with abdominal distention due to excess energy intake or who develop progressive accumulation of ascites associated with non-malignant conditions (eg, cirrhosis) 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. (See "Malignancy-related ascites", section on 'Clinical manifestations'.)
Pain is the second most common initial symptom and is present at diagnosis in 27 to 58 percent of patients [52,58-60]. In most cases, the pain is diffuse and nonspecific, although a small minority present with an acute abdomen secondary to perforation or obstruction [61].
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 [54,55]. Patients may complain of localized abdominal pain or have a palpable abdominal or pelvic mass [54].
Pattern of spread — 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, causing a pleural effusion [62].
Uncommonly, MPM metastasizes to the abdominal and pelvic lymph nodes. Lymph node metastases are found in approximately 20 to 28 percent of patients undergoing cytoreductive surgery for diffuse MPM [63,64]. Notably, the majority of clinically suspicious lymph nodes are not pathologically positive [64]. In other registry series, the incidence of lymph node metastases is <5 percent [12].
Distant metastases are very uncommon [12,65-69]. In a multi-institutional registry-based series of 294 patients with MPM, only 12 had extra-abdominal metastases (4 percent) [69].
Paraneoplastic phenomena — A number of paraneoplastic phenomena have been described in the setting of mesothelioma, including [70-74]:
●Fever
●Thrombocytosis
●Malignancy-related thrombosis (see "Risk and prevention of venous thromboembolism in adults with cancer")
●Hypoglycemia
●Rarely, Coombs-positive hemolytic anemia (see "Warm autoimmune hemolytic anemia (AIHA) in adults")
The presence of baseline thrombocytosis has been shown to be an independent factor strongly associated with shortened survival in patients with diffuse MPM [75].
Radiographic imaging
Diffuse mesothelioma — Computed tomography (CT) is the most useful initial diagnostic study and is typically the first test ordered in a patient with abdominal pain and increasing abdominal girth. The peritoneal masses and nodules may enhance on CT after intravenous injection of iodinated contrast material. However, CT, as with other imaging modalities, tends to underestimate the actual burden of disease. Positron emission tomography (PET scanning) has been used for staging, but it is not reliable for assessing disease extent in MPM [76].
The imaging patterns and features of MPM 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 [77]. More recently, diffusion-weighted and dynamic gadolinium-enhanced MRI have been shown to accurately reflect disease burden in the abdominal cavity both initially and during post-treatment follow-up evaluation of patients with MPM [78]. MRI may become the primary assessment method in a patient undergoing long-term follow-up evaluation after initial treatment for MPM who cannot receive iodinated contrast or in a woman with a pelvic mass found at clinical examination or ultrasound.
Diffuse MPM can produce a variety of patterns on cross-sectional imaging:
●Diffuse and widespread involvement of the peritoneal cavity, tumor infiltration, and irregular/nodular thickening of the peritoneum in a sheet-like fashion.
●Less commonly, there is a focal pattern of involvement with a dominant intraperitoneal mass with or without associated peritoneal studding [79]. In some studies, this pattern has been more common with the sarcomatous subtype [80].
In addition to the primary tumor, moderate to extensive (rarely massive) ascites is present in 60 to 100 percent of newly diagnosed patients (image 1) [58,80]. Other findings include omental caking/thickening, scalloping or direct invasion of intra-abdominal organs such as the liver, and diaphragmatic involvement; multiloculated large cystic areas may also be present [81].
The sheet-like 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 (image 2) [79]. 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 [79,82-84]. These findings, in conjunction with a linearly oriented tumor in the mesentery, produce a characteristic "pleated" appearance on cross-sectional imaging (image 3) [79].
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 [84].
Published frequencies of positive CT findings are summarized in the table (table 1). 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. (See "Malignant peritoneal mesothelioma: Treatment", section on 'Cytoreductive surgery and intraperitoneal chemotherapy'.)
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, and peritoneal nodularity) are characteristically absent [79].
Differential diagnosis — Based on imaging findings, the differential diagnosis for a typical diffuse MPM includes peritoneal carcinomatosis, serous peritoneal carcinoma, ovarian carcinoma in women, lymphomatosis, and tuberculous peritonitis. There are no imaging features that are specific for MPM [58], although some features may help to suggest a specific diagnosis (see "Abdominal tuberculosis" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis"):
●Liver metastases and lymphadenopathy are more common with peritoneal carcinomatosis from gastrointestinal tract primary neoplasms than they are with MPM [81].
●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 serous carcinoma of the peritoneum [83]. 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. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Histopathology".)
●Two related primary malignancies of the peritoneum with distinctive characteristics on CT are well-differentiated papillary mesothelioma, and multicystic mesothelioma. These tumors are important to distinguish from diffuse peritoneal mesothelioma because their treatment strategy is primarily surgical and the clinical course is largely benign. (See 'Peritoneal mesothelioma variants' below.)
Laboratory findings — 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 [58,85].
Although one study has shown that baseline serum CA-125 has prognostic significance in patients with MPM undergoing operative cytoreduction [86], this parameter has not been adopted in clinical decision making regarding selection of treatment. CA-125 [85] and mesothelin may prove useful to follow response to therapy or for post-treatment surveillance if they are initially elevated.
Mesothelin and soluble mesothelin-related peptide — 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 epithelioid 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 in patients with mesothelioma. Lack of sensitivity and specificity limits the utility of this marker for diagnostic purposes [87,88]. As an example, in one report, elevated levels (≥9 ng/mL) were seen in 40 of 56 (71 percent) of patients with mesothelioma (primary site not specified), in 13 percent of randomly selected hospitalized patients without a diagnosis of cancer, and in 8 of 21 patients with advanced ovarian cancer [87].
Serum levels of SRMP are potentially more useful as a marker of disease activity in patients with an established diagnosis [87,89].
DIAGNOSIS AND HISTOLOGY — The diagnosis of peritoneal mesothelioma should be considered in any individual with evidence of a diffuse malignant process in the abdomen on initial clinical and radiographic evaluation, and it can usually be established cytologically or by biopsy.
In general, cytologic analysis of ascitic fluid is of limited diagnostic utility. Although a diagnosis of mesothelioma can be made cytologically [90], fluid cytology is often inconclusive and has a low yield [59,73]. 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 [91]. Invasion can only be seen on histologic study of solid tumor material. (See "Malignancy-related ascites", section on 'Cytology'.)
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. Because of the propensity for mesothelioma to seed needle tracts or trocar sites [59], the site of the biopsy/laparoscopic port sites are usually excised at the time of surgery. (See "Malignant peritoneal mesothelioma: Treatment", section on 'Technique'.)
Histology — Grossly, malignant peritoneal mesothelioma (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 (picture 1). The lesions may range from diffuse subcentimeter gray hard nodules to large nodular masses that 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.
Histologic examination of routine hematoxylin-eosin stained sections allows the classification of MPM into one of three broad histologic subtypes, epithelioid, sarcomatoid, and biphasic (mixed); the characteristic histologic patterns are similar to those encountered in pleural mesothelioma (picture 2) [92]. Tubulopapillary (well-differentiated) mesothelioma, a rare variant that is seen more often in the peritoneum than in the pleura, is discussed below. (See 'Well-differentiated papillary mesothelioma' below and "Pathology of malignant pleural mesothelioma", section on 'Histology'.)
●The most common, epithelioid malignant mesotheliomas, are composed of cells that resemble normal mesothelial cells [54]. 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, which makes it difficult to distinguish from another adenocarcinoma on histologic analysis alone.
●The sarcomatous pattern, which is less common in the peritoneum as compared with the pleura, is typically composed of tightly packed spindle cells. Malignant osteoid, chondroid, or muscular elements may be present within the tumor [54].
●A biphasic tumor is defined as one with both epithelioid and sarcomatous components, each contributing more than 10 percent to the overall histology.
As in the pleura, peritoneal mesotheliomas with a sarcomatoid component have a worse prognosis [59,93,94]. In one report, the median survival for the epithelioid subgroups of MPM was 55 months, compared with 13 months for the combined sarcomatoid and biphasic subtypes [59].
The distinction between benign and malignant mesothelial proliferations is sometimes challenging:
●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 that may falsely suggest stromal invasion. In particular, the pelvic adnexa 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 [91].
●A promising but still new area of investigation that may help to differentiate benign from malignant mesothelium is immunohistochemical labeling of telomerase. (See "Pathology of malignant pleural mesothelioma", section on 'Immunohistochemistry'.)
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, peritoneal serous carcinoma, and soft tissue sarcoma, which might have a similar histologic appearance [79,83,95,96]. The most useful of these are summarized below (see "Pathology of malignant pleural mesothelioma", section on 'Immunohistochemistry'):
●Most mesotheliomas stain positively for calretinin, cytokeratins 5/6, Wilms tumor-1 (WT-1), epidermal growth factors receptor (EGFR), CA125, thrombomodulin, and mesothelin.
●Mesotheliomas usually stain negative for other adenocarcinoma markers, including CEA, LeuM1, Ber-Ep4, B72.3, Bg8, PAX-8, and MOC-31.
●Staining patterns appear to be similar across histologic subtypes. In a histologic study of 64 tumors of various subtypes, CA125 was positive in 94 percent, EGFR was positive in 94 percent, and calretinin was positive in 93 percent. Tumors also stained positive for p16 in 85 percent, cytokeratin 5/6 in 76 percent, D2-40 in 71 percent, and WT-1 in 47 percent [97].
●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 [98-100].
●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.
Overall, IHC staining for cytokeratin 5/6, calretinin and WT-1 (positive markers for mesothelioma), and CEA, Ber-Ep4, LeuM1 and Bg8 (negative in mesothelioma) represents the most helpful panel of markers for MPM [79,83,92]. The use of at least two mesothelioma markers and two carcinoma markers is recommended [92].
Occasionally, when an epithelioid mesothelioma is extremely dedifferentiated or if it is a desmoplastic variant, ultrastructural analysis via electron microscopy may be beneficial, although it is rarely needed. Among patients who have a peritoneal primary tumor, electron microscopy is less helpful for the differentiation of a sarcomatous mesothelioma from a soft tissue sarcoma [54]. (See "Pathology of malignant pleural mesothelioma", section on 'Electron microscopy'.)
STAGING AND THE STAGING WORKUP — There is no uniformly accepted staging system for malignant peritoneal mesothelioma (MPM). The peritoneal cancer index, which is derived from radiographic imaging and intraoperative evaluation, is discussed elsewhere. (See "Malignant peritoneal mesothelioma: Treatment", section on 'Patient selection'.)
Because of the low frequency of disease spread outside of the peritoneum, a staging evaluation 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 important to eliminate the possibility of tumor spread into the pleural cavity, which might alter the therapeutic approach. A novel Tumor, Node, Metastasis or "TNM" staging system has been proposed that takes into account the extent of disease in the peritoneum (T stage), the presence of intra-abdominal lymph node metastases (N), and the absence or presence of extra-abdominal disease (M) [69]. T stage is calculated based on the peritoneal cancer index (PCI [101]), a measure of the volume and extent of tumor deposits as follows:
●T1 – PCI 1-10
●T2 – PCI 11-20
●T3 – PCI 21-30
●T4 – PCI 31-39
Stage groupings, which were associated with a progressive decrease in survival, were as follows:
●Stage I – T1 N0 M0; five-year survival 87 percent
●Stage II – T2-3 N0 M0; five-year survival 53 percent
●Stage III – T4 N0-1 M0, T1-4 N1 M01-, and T1-4 N0-1 M1; five-year survival 29 percent
(See "Malignant peritoneal mesothelioma: Treatment".)
PERITONEAL MESOTHELIOMA VARIANTS — There are two rare variants of peritoneal mesothelioma. Both are characterized by indolent behavior and the potential for malignant transformation to malignant peritoneal mesothelioma (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 [79]. There is no reported association with asbestos exposure [102].
These indolent tumors are small (most <2 cm) and typically identified as an incidental finding at surgery performed for another indication [103-105]. On 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 [23].
The radiologic appearance is rarely described. There may be plaque-like calcification that diffusely involves the visceral and parietal peritoneum without the presence of an associated soft tissue mass [106]. 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, although long-term follow-up is required because of the potential to recur and progress to true MPM. (See "Malignant peritoneal mesothelioma: Treatment", section on 'Well-differentiated papillary mesothelioma'.)
Multicystic mesothelioma — Multicystic mesothelioma is an unusual cystic tumor that most commonly arises from the pelvic peritoneal surfaces in young and middle-aged women [54,107-109]. Men represent only 17 percent of cases [108]. This lesion is associated with a history of previous abdominal surgery, endometriosis, or pelvic inflammatory disease [110,111]. There are no reports addressing asbestos exposure as a risk factor.
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 recurrence after surgical treatment (up 50 percent) [107]. The presence of this lesion has not altered patient survival in the vast majority of cases. However, local recurrences are frequent, leading to morbidity [110], and 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 [54,108,109,112,113].
The majority of cases present with chronic or intermittent lower abdominal or pelvic pain [110]. Occasionally, the diagnosis is made incidentally at surgery or on ultrasound or cross-sectional imaging:
●On ultrasound, there are multiseptated structures that have an intimate anatomic association with the uterus and ovaries [110]. The fluid within the cysts is usually anechoic.
●On CT or MRI scan, the cysts have fluid attenuation values, and the septae enhance with IV iodinated contrast and gadolinium [77,110]. There may be thick-walled cysts that appear as soft tissue attenuation lesions [114].
The main differential diagnosis is with cystic lymphangioma, mesenteric or omental cysts, cystic epithelial neoplasms of the ovaries, endometriosis, malignant mesothelioma, 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 [79,115].
Although the disease is well characterized histologically, the pathogenesis, natural history, and clinical management are not well defined. The clinical course is usually indolent, and surgical resection can be curative. However, as with the well-differentiated papillary mesothelioma, 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 rarely reported. (See "Malignant peritoneal mesothelioma: Treatment", section on 'Multicystic mesothelioma'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Peritoneal mesothelioma".)
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. (See 'Introduction' above.)
●As with mesothelioma arising in other sites, there is a strong relationship between asbestos exposure and the development of MPM. However, the link between exposure to asbestos and peritoneal mesothelioma is less strong than it is for pleural mesothelioma, particularly among women. A germline BRCA-associated protein 1 (BAP1) mutation may predispose individuals to develop MPM. (See 'Epidemiology and risk factors' above.)
●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. Rarely, patients present with a paraneoplastic syndrome (fever, thrombocytosis, hypoglycemia). (See 'Clinical features' above.)
●The imaging patterns and features of MPM are shown equally well on CT and magnetic resonance 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 sheet-like fashion, usually with moderate to extensive ascites. Less commonly, there is a focal pattern of involvement with a dominant intraperitoneal mass with or without associated peritoneal studding. (See 'Radiographic imaging' above.)
●None of the radiographic findings is sufficiently specific for MPM to avoid the need for tissue diagnosis. Ascitic fluid cytology 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. (See 'Diagnosis and histology' above.)
●There are no tumor markers with sufficient sensitivity or specificity to be useful in the diagnostic evaluation of a patient with suspected MPM. (See 'Laboratory findings' above.)
●There is no uniformly accepted staging system for MPM. Given the very low risk of extra-abdominal spread, a radiographic staging workup is generally not needed in the absence of symptoms. (See 'Staging and the staging workup' above.)
●There are two rare variants of peritoneal mesothelioma, well-differentiated papillary mesothelioma and multicystic mesothelioma (peritoneal inclusion cyst), which are both characterized by a localized presentation and indolent behavior. (See 'Peritoneal mesothelioma variants' above.)
Do you want to add Medilib to your home screen?