Peritoneal cancer mesothelioma

Occupational and environmental asbestos exposure continues to represent a public health problem, despite increasingly restrictive laws adopted by most industrialized countries. Peritoneal mesothelioma is a rare and aggressive asbestos-related malignancy. We present the case of a 65-year-old man who developed recurrent ascites after having been exposed to asbestos in the building industry for > 40 years. Liver function and histology were normal. Abdominal computed tomography initially excluded the presence of expansive processes, and no abnormal cells were found in the ascitic fluid. Laparoscopy showed diffuse neoplastic infiltration of the peritoneum. Histopathology of bioptic samples revealed epithelioid neoplastic proliferation with a tubulopapillary pattern, falsely suggesting metastatic adenocarcinomatosis. In consideration of the occupational history, and after further diagnostic procedures had failed to identify the hypothetical primitive tumor, immunostaining of the neoplastic tissue was performed. Results were negative for carcinoembrionary antigen and the epithelial glycoprotein Ber-EP4, whereas results were positive for the mesothelial markers cytokeratins, calretinin, epithelial membrane antigen, and HBME-1, thus leading to the correct diagnosis of peritoneal epithelial mesothelioma. The Italian Workers' Compensation Authority recognized the occupational origin of the disease. Cytoreductive surgery associated with continuous hyperthermic peritoneal perfusion (cisplatin at 42[degrees]C, for 1 hr) was performed. The disease relapsed after 4 months and was later complicated by a bowel obstruction requiring palliative ileostomy. The patient died 23 months after diagnosis. This case illustrates the insidious diagnostic problems posed by peritoneal mesothelioma, a tumor which often simulates other malignancies (e.g., metastatic carcinomas) at routine histopathological examination. Occupational history and immunohistochemistry are helpful for the correct diagnosis, which, in turn, is important in relation to prognosis and treatment (adoption of new integrated procedures that seem to promise prolonged survival and increased quality of life), and in relation to medicolegal issues and occupation-related compensation claims following asbestos exposure. Key words: calretinin, cisplatin, HBME-1, intraperitoneal chemotherapy, occupational cancer, peritonectomy.

Case Presentation

In June 2000 a 65-year-old man was hospitalized for recently developed ascites, indefinite abdominal pain, dyspepsia, and mild hepatomegaly (echographic finding). He reported occasional abuse of alcoholic beverages and lifelong heavy smoking (40 cigarettes/day). The patient had worked in the building industry from 14 to 55 years of age (1949-1990), when he retired. His duties (installation of industrial roofing, pipes, flues, and tanks) required cutting and shaping asbestos-cement panels with an electric saw and a rotating abrasive disk, exposing him to the inhalation of asbestos fibers. Routine blood and urine analyses (including indicators of liver function) were normal. Viral hepatitis (B and C) markers were negative. Chest radiography and lung function tests revealed chronic obstructive pulmonary disease (COPD). Esophagogastroduodenoscopy disclosed mild gastroduodenitis. Abdominal computed tomography (CT) excluded the presence of expansive processes. Evacuative paracentesis was performed: the ascitic fluid was clear, and cytologic analysis did not detect abnormal cells.

In the following months, ascites reformed quickly after repeated paracentesis. Percutaneous liver biopsy (December 2000) showed normal hepatic histology. Laparoscopy (April 2001) revealed diffuse neoplastic infiltration of the peritoneum and greater omentum, with a carcinomatous aspect. Several bioptic samples were collected; standard histopathologic examination demonstrated epithelioid neoplastic proliferation with a tubulopapillary pattern (Figure 1), suggesting metastatic peritoneal adenocarcinomatosis. Further diagnostic procedures (colorectal radiology and endoscopy, magnetic resonance imaging of the abdomen, chest CT, and pelvic, transrectal, and testicular ultrasonography) failed to identify the hypothetical primitive tumor. The occupational history of long-term asbestos exposure prompted us to conduct immunohistochemical tests on the neoplastic tissue samples. Staining for the carcinoembrionary antigen (CEA) and the epithelial glycoprotein Ber-EP4 was negative, whereas results for the mesothelial markers cytokeratins, calretinin (Figure 2), epithelial membrane antigen (EMA), and HBME-1 (Figure 3) were positive, leading to the diagnosis of peritoneal epithelial mesothelioma.

[FIGURES 1-3 OMITTED]

In May 2001 the patient underwent bilateral subphrenic peritonectomy, partial pancreasectomy, splenectomy, appendicectomy, and cytoreductive debulking of neoplastic nodules larger than 3 mm. This was followed by peritoneal perfusion with cisplatin heated at 42[degrees]C for 1 hr. After overcoming severe postoperative complications (delayed adynamic ileus, Candida tropicalis septicemia, and Clostridium difficile bowel infection), the patient was discharged in fairly good conditions (July 2001). He remained apparently free of disease for 4 months, after which ascites reformed. Abdominal ultrasonography indicated disease relapse.

In February 2003 the subject was readmitted to the hospital with a clinical picture suggestive of intestinal obstruction, which was confirmed at colonoscopy. Surgery revealed the presence of diffuse peritoneal neoplastic infiltration involving the intestinal loops. Palliative ileostomy was performed. The subject died 1 month later at 67 years of age.

Discussion

Malignant peritoneal mesothelioma was first described in 1908 by Miller and Wynn; it is a rare, locally aggressive neoplasm arising from the abdominal serosal lining, and exposure to asbestos fibers has been recognized as a principal etiopathogenetic agent (Antman 1993; Vogelzang 2002). The disease is more common in men, possibly because of the higher male occupational exposure to asbestos (Antman 1993; Attanoos and Gibbs 1997).

Diagnosis of peritoneal mesothelioma (particularly the differentiation from the more common metastatic peritoneal cancers) is often difficult and delayed, both for the nonspecific clinical manifestations of the disease (abdominal pain, ascites, abdominal masses) and its extreme morphologic variability (Attanoos and Gibbs 1997; Sugarbaker et al. 2002). In the reported patient, the clinical picture was dominated by recurrent ascites. Normality of both liver function and histology excluded the presence of hepatic disease. Definition of the neoplastic nature of ascites required exploratory laparoscopy. Routine histologic examination of neoplastic tissue was initially misleading, suggesting metastatic invasion of the peritoneum by occult adenocarcinoma. Besides mesothelioma, a variety of other abdominal and pelvic malignancies (e.g., gastrointestinal or genitourinary cancer) may in fact present with peritoneal seeding. With hematoxylin-eosin staining, epithelial (epithelioid) mesothelioma (the most common histopathological subtype, 50-75% of cases) may present the same morphology of glandular carcinomas, as in this case. Sarcomatous (or sarcomatoid) mesothelioma (15-20%) may in turn simulate sarcomas originating from connectival tissue (e.g., fibrosarcoma). The only pathognomonic phenotype is the mixed (or biphasic) mesothelioma (20-30%), where epithelioid and sarcomaroid tissues coexist. Histologic diagnosis of rare morphologic variants (e.g., small-cell, desmoplastic, or lymphohistiocytoid mesothelioma) may also be problematic (Attanoos and Gibbs 1997; Sugarbaker et al. 2002).

In this patient, the negative results of CEA and Ber-EP4 immunohistochemistry allowed us to exclude reactivity of the bioptic samples with epithelial-binding antibodies, whereas results of immunohistochemistry for cytokeratins, calretinin, EMA and HBME-1 indicated reactivity of the neoplastic tissue with antibodies that preferentially bind cells of mesothelial origin (Attanoos and Gibbs 1997; King and Hasleton 2001). As a discrminant marker, calretinin (a calcium-binding protein) shows high sensitivity and specificity for mesothelioma (Doglioni et al. 1996; Leers et al. 1998), particularly for the epithelial subtype (Attanoos et al. 2001). Thus, immunostaining allowed us to formulate the correct diagnosis of primary peritoneal mesothelioma (epithelial subtype) excluding metastatic adenocarcinomatosis.