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MedGenMed. 2007; 9(2): 32.
Published online May 10, 2007.
PMCID: PMC1994863

Peritoneal Mesothelioma: A Review

Alessio Bridda, MD, Third-year Resident in General Surgery, Ilaria Padoan, MD, Third-year Resident in Pathology, Roberto Mencarelli, MD, Staff Physician, and Mauro Frego, MD, Assistant Professor of Surgery

Abstract

Background

Malignant peritoneal mesothelioma (MPM) is a rare aggressive tumor of the peritoneum, regarded as a universally fatal disease. It is poorly described and the knowledge of its natural history is very limited. Occupational and environmental asbestos exposure still remains a public health problem around the world. The incidence has increased in the past 2 decades. Only 20% to 33% of all mesotheliomas arise from the peritoneum itself; the pleura is the most common site of origin.

Epidemiology

Mesotheliomas are aggressive tumors arising from serous surfaces: pleura (65%-70%), peritoneum (30%), tunica vaginalis testis, and pericardium (1%-2%).[1] Peritoneal mesothelioma was first described in 1908 by Miller and Wynn. It is a rare neoplasm with a rapid fatal course (median survival 6-12 months,[2] mean symptoms-to-survival time 345 days[3]). In the United States, the overall prevalence is 1-2 cases per million, with an estimated incidence of 200-400 new cases annually. It was exceedingly rare until 1930, when industry increased the use of asbestos, which is the principal risk factor for the disease. It can occur in any age group, although the 50- to 69-year age group is the most affected[4,5]: only an estimated 2% to 5% of all cases present in the first 2 decades of life.[6] It is more common in men, possibly because of the higher male occupational exposure to asbestos.[7] The main risk factor is asbestos exposure, primarily the crocidolite variety, although some tumors have arisen in ports of prior radiation,[8] or after thorium, talc, erionite or mica exposure,[7,9,10] as well as in patients affected by familial Mediterranean fever[1012] and diffuse lymphocytic lymphoma.[10] Only 50% of patients with a peritoneal origin of MPM have a history of asbestos exposure.[13,14] This association increases to 80% in mesotheliomas with the more common pleural origin. A reported association with simian virus (SV) 40 remains controversial.[8]

Clinical Picture

Mesothelioma can arise both from visceral and parietal peritoneum. It is diagnosed in advanced stages in most cases, and it often takes considerable time to arrive at the correct diagnosis, as the mean symptoms-to-diagnosis time reported is 122 days.[3] The most frequently reported initial symptoms are abdominal pain (35%), abdominal swelling (31%), anorexia, marked weight loss, and ascites[3,1517]; less frequently night sweats and hypercoagulability.[18] Clinical presentation with fever of unknown origin,[15] intestinal obstruction,[19] or surgical emergency (due to acute inflammatory lesions)[3,20] have been reported. In particular, compression of the gastrointestinal tract can complicate the disease, but it is rarely the presenting symptom. Occasionally the diagnosis has been made incidentally during laparoscopy.[21] Paraneoplastic syndromes associated with mesothelioma, and in particular with peritoneal mesothelioma, are thrombocytosis,[3] hypoglycemia,[9] venous thrombosis,[22] paraneoplastic hepatopathy, and a wasting syndrome.[23]

Diagnosis

The clinical and radiologic presentation of mesotheliomas is nonspecific. History can be very elusive because the most frequent symptom at presentation is abdominal pain. Routine laboratory tests are not useful in making the diagnosis, and abdominal radiographs will show signs such as abdominal distension.

Potentially useful serum markers for diagnosis and follow-up are the serum mesothelin-related protein (SMRP), which is elevated in more than 84% of mesotheliomas, and has a 60% sensitivity at diagnosis; CA-125, CA 15-3, hyaluronic acid, and osteopontin[2426] are other potential markers.

Computed tomography (CT) findings of peritoneal mesothelioma are nonspecific and not sufficient to establish a diagnosis; however, CT is useful for the detection, characterization, staging, and guiding biopsy of peritoneal masses.[27] At CT, MPM appears as solid, heterogeneous, enhancing soft-tissue masses. Its growth pattern is expansive more than infiltrating.[13] There are 3 types of CT appearances described. 'Dry-painful' type is the most common, in which CT shows 1 large mass or multiple small peritoneal masses in 1 abdominal quadrant, with no signs of ascites. The 'wet' type is associated with intestinal distension and ascites, widespread small nodules and plaques, and no solid masses. Finally, there is the 'mixed' type.[28] Few data have been published about the sonographic and magnetic resonance imaging manifestations of peritoneal mesothelioma.

A precise diagnosis based on imaging findings alone is not possible. Furthermore, distinguishing a benign from a malignant process as well as a primary from a metastatic process is also challenging. Therefore, the definitive diagnosis of peritoneal mesothelioma depends on histologic and immunohistochemical examination.

Cytologic analysis of ascites has a low diagnostic potential, due to high cytologic diversity of tumor cells and to small number of malignant cells within the fluid. When there is no effusion, sampling by fine-needle aspiration of the tumour can be used to reach a diagnosis. Immunohistochemistry uses some cytological markers: calretinin and Wilms' tumor 1 antigen (WT1) are used to determine whether the tissue is mesothelial; epithelial membrane antigen (EMA) is used to determine whether the tissue is malignant. In experienced hands, the diagnosis of malignant peritoneal mesothelioma can be made in approximately 80% of cases with an adequate cytologic sample of the tumor.[29]

When cytologic findings are inconclusive or ascitic fluid is absent, tumor biopsy is more likely to yield a diagnosis. Immunohistochemical expression of tumor markers is not homogeneous within the same solid tumor section, so diagnostic accuracy increases with core sample size.[30]

Pathology

Mesotheliomas have 3 basic histologic forms: epithelioid (the most frequent), sarcomatoid or mixed (biphasic). More often, areas showing features and admixtures of these three types may be encountered within a single tumor; a sarcomatoid component is observed in 25% of cases,[31,32] but a pure sarcomatoid variety is extremely rare and only 32 cases have been reported in the literature since 2006 (Table 1).

Table 1
Reported Cases of Pure Sarcomatoid MPM as of 2006

The epithelioid MPM can grow with 4 different patterns: tubular, papillary (the most common, often found in association with other patterns), diffuse, and deciduoid (cells with abundant glassy eosinophilic cytoplasm). Atypia is a frequent feature but is typically mild; only a few cases have moderate or severe atypia.[16] Unusual histologic features include lymphoid follicles, striking myxoid stroma, prominent foamy histiocytes, and marked vascular proliferation. Multicystic mesotheliomas and well-differentiated papillary mesothelioma are histological types associated with a long survival in the absence of treatment.[8]

Sarcomatoid mesothelioma is extremely rare: Neumann and colleagues[33] in a series of 53, and Deraco and colleagues[34] in a series of 49 MPM reported no sarcomatoid histotypes. It is composed of a fascicular proliferation of spindle cells with oval nuclei, scant amphophilic cytoplasm and occasionally prominent nucleoli. In general, sarcomatoid mesotheliomas show more atypia than their epithelioid counterparts, and often display mitotic activity and foci of necrosis. The tumor cells can display a fibrosarcoma-like appearance; therefore, sarcomatoid MPM must be differentiated from the rare variant of extra-intestinal gastrointestinal stromal tumors (GISTs) with sarcomatoid features or from true retroperitoneal sarcomas.

A large number of immunohistochemical markers have been suggested for diagnostic aid, but none of the markers alone is diagnostic. However, they become very useful when used as a panel. Malignant MPM is characterized by positive staining for EMA, calretinin, WT1, cytokeratin 5/6, antimesothelial cell antibody-1, and mesothelin. Cytokeratins help to confirm invasion and to distinguish mesothelioma from sarcoma and melanoma. Mesotheliomas are characterized by the absence of antigens such as carcinoembryonic antigen (CEA), thyroid transcription factor-1, B72.3, MOC-31, Ber-EP4, and BG8.[29] Immunohistochemistry is also useful to distinguish peritoneal mesotheliomas from primary papillary serous carcinoma of peritoneum, serous ovarian carcinomas, colorectal adenocarcinoma diffusely involving the peritoneum, and borderline serous tumors. In particular, calretinin, cytokeratin, and thrombomodulin are typically positive in patients with mesotheliomas and negative in those with serous carcinomas.

Detecting characteristic ultrastructural features by electron microscopy may help the diagnosis of malignant mesothelioma.[31] Typical mesothelioma show tall and thin microvilli on the cell surface. It has been suggested that only microvilli whose length exceeds the width by a margin of 15:1 are diagnostic of mesothelioma.[35] Because the microvilli are often poorly developed in the sarcomatoid variety, electron microscopy is generally not useful in their diagnosis.[36]

Peritoneal mesothelioma usually remains confined to the peritoneal cavity for most of its natural history. Typical growth pattern of peritoneal mesothelioma is locally expansive masses. Hematogenous or lymphatic metastasis is unusual. However, parasternal,[37] retroperitoneal,[38] mediastinal,[39,40] axillary, supraclavicular,[41] and cervical[40] lymph nodes; lung,[42] bone,[41,43] liver,[40] and umbilical ('Sister Mary Joseph's nodule')[44] metastases have all been reported.

Treatment

For patients with confirmed MPM, radical resection is associated with better prognoses and should be pursued when possible. Other treatments for peritoneal mesothelioma include intensive loco-regional therapeutic strategies: cytoreductive surgery, hyperthermic intraoperative or early postoperative intraperitoneal chemotherapy, and immunotherapy.

Surgery can achieve a complete or incomplete resection. The aim of cytoreductive surgery is to remove as much tumor as possible, as it is often not possible to achieve a complete resection. After surgical debulking, the resection can be classified according to the Completeness of Cytoreduction Score,[45] which evaluates the residual peritoneal seeding within the operative field: complete (CC-0) or partial with a diameter of the residual nodules < 0.25 cm (CC-1), 0.25-2.5 cm (CC-2), > 2.5 cm or confluence of tumor nodules (CC-3). The CC-1 tumor nodule size is thought to be penetrable by intracavitary chemotherapy and is, therefore, designated as complete cytoreduction if perioperative intraperitoneal chemotherapy is used. The limitation of this score is the fact that it can be evaluated only after surgery; therefore, no preoperative informations can be obtained about the resectability of the tumor. Survival after cytoreductive surgery and intraperitoneal chemotherapy is 35.8 months for patients treated with a CC-0 or CC-1 resection, and only 6.5 months for those treated with a CC-2 or CC-3 resection.[46] Widely used in both noninvasive and invasive peritoneal surface malignancy, the completeness of cytoreduction score is thought to be the principle prognostic indicator.

Chemotherapy has an important role in palliation. It can be administered systemically or directly into the abdomen. The overall response rate reported with a single agent chemotherapy, combined chemotherapy, intraperitoneal chemotherapy, continuous hyperthermic peritoneal perfusion are 13.1%, 20.5%, 47.4%, and 84.6%, respectively.[47] Cisplatin is the most studied agent, with activity in 25% of patients.[18]

Direct exposure of antitumor agent to the peritoneal surface is considered to be most effective against malignant peritoneal mesothelioma. Intraperitoneal chemotherapy can be instilled after surgery or without surgery through an abdominal catheter. Advantages of intraperitoneal chemotherapy include greatly enhanced drug concentrations in the peritoneal cavity and decreased systemic toxicity.

Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion is the standard treatment for resectable tumors at diagnosis. A preheated (42.5 degrees C) perfusate with 2 or 3 antineoplastic agents (cisplatin, mitomycin C, fluorouracil, doxorubicin, and/or paclitaxel) is infused continuously into the closed or semi-closed abdomen after surgery. In a recent Phase II study[48] with cisplatin, mitomycin C and doxorubicin, the major morbidity rate reported was 12%: the most significant complications were anastomotic leaks (11%), abdominal bleeds (1.9%) and sepsis (1.9%). Operative mortality rate was 12%. In another study, after cytoreductive surgery and continuous hyperthermic peritoneal perfusion with cisplatin, fluorouracil, and paclitaxel, peritoneal progression-free and overall survival were reported to be 17 and 92 months, respectively. Deraco and colleagues reported 5-year overall survival, disease-free survival, and progression-free survival of 70%, 63%, and 51% respectively.[49]

Systemic chemotherapy has also been investigated. Pemetrexed in combination with cisplatin has shown survival improvement in patients with pleural mesothelioma. Data from uncontrolled studies suggest similar antineoplastic efficacy in patients with peritoneal mesothelioma,[50,51] and should be the standard of care for patients with unresectable malignant mesothelioma. The disease control rate reported is 71.2%: it includes partial responses or stable disease. No complete responses are reported for this chemotherapy.[52]

Other drug regimens used for unresectable disease are vinorelbine and gemcitabine, either alone or combined with platinum compounds.[51] The response rate of vinorelbine alone is 24%.[53] Irinotecan[54] and gefinitib[55] have not been shown to be effective when used alone.

Immunotherapy is used on an experimental basis, mainly for pleural mesothelioma.[56] Humanized anti-CD3 antibodies (OKT3),[57] cytotoxic T lymphocytes (CTL),[58] interferon alfa-2a,[59] and autovaccine[60] have all been used anecdotally for palliation of advanced peritoneal mesothelioma, but more data are needed before this therapy can be recommended. Radiation therapy has a limited role in peritoneal mesothelioma and it is not currently used.[61]

Outcome and Prognosis

Mesotheliomas are almost universally considered a fatal neoplasm, and until recently the treatment options were very limited and ineffective. The overall median survival was only 1 year. Nevertheless, a few cases of long-term survivors have been reported (longest survival reported is 19 years[23]).

After the introduction of cytoreductive surgery followed by intraperitoneal hyperthermic perfusion, a significant prolongation in the median survival has been achieved, with approximately half the patients alive at 5 years.[48,62] Tumor histopathology, previous surgical score, lesion size, gender, distribution (assessed with Gilly classification and peritoneal cancer index), and completeness of cytoreduction score[45,62] represent the main prognostic index.

Multicystic mesothelioma and well-differentiated peritoneal mesothelioma typically occur in the peritoneum of women without a history of asbestos exposure and show low malignant potential. Multicystic mesothelioma predominantly affects the pelvic peritoneum of young women, has a high tendency to recur locally, but no tendency to metastasis, and consequently requires only surgical treatment.[63,64] Some theories link this type of mesothelioma to fibromatoses, suggesting a reactive hyperplastic process more than a neoplastic one.[65] A familial form of multicystic mesothelioma has also been described.[66] Sarcomatoid mesothelioma, although rare, is the most aggressive histotype, with a median survival reported of only 3.8 months.[67,68]

Conclusions

Malignant mesothelioma is a highly lethal neoplasm, and diagnosis is difficult because of the frequency of vague symptoms present over a long time. Given the rarity of peritoneal mesotheliomas, it is difficult to obtain precise information regarding their incidence, natural history and optimal management. Despite many histopathologic similarities between peritoneal and pleural mesotheliomas, clinical and prognostic features may be quite different, and the precise nature of MPM cannot be extrapolated from the pleural form.

In those patients diagnosed and treated early with a multimodality approach, including cytoreductive surgery and postoperative intraperitoneal hypothermic chemotherapy, a relatively long survival can be expected, with a median survival of 50-60 months.[69,70] This represents a significant advance due to treatment improvements. As the incidence of MPM begins to decrease as asbestos exposure is eliminated, the prognosis for those diagnosed with mesothelioma will continue to improve.

Footnotes

Readers are encouraged to respond to the author at moc.enozainmo@xela or to Paul Blumenthal, MD, Deputy Editor of MedGenMed, for the editor's eyes only or for possible publication via email: ude.drofnats@nemulbp

Contributor Information

Alessio Bridda, Clinica Chirurgica I, Department of Surgical and Gastroenterological Sciences, University of Padua, School of Medicine, Via Giustiniani 2, Policlinico III Piano, 35128 Padova, Italy.

Ilaria Padoan, Department of Pathology, University of Padua, School of Medicine, Via Gabelli 61, 35128, Padova, Italy.

Roberto Mencarelli, Department of Pathology, University of Padua, School of Medicine, Via Gabelli 61, 35128, Padova, Italy.

Mauro Frego, Clinica Chirurgica I, Department of Surgical and Gastroenterological Sciences, University of Padua, School of Medicine, Via Giustiniani 2, Policlinico III Piano, 35128 Padova, Italy Author's Email: moc.enozainmo@xela.

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