Multicentric study on malignant pleural mesothelioma and non-occupational exposure to asbestos
C Magnani, A Agudo, CA González, A Andrion, A Calleja, E Chellini, P Dalmasso, A Escolar, S Hernandez, C Ivaldi, D Mirabelli, J Ramirez, D Turuguet, M Usel and B Terracini

Cancer Epidemiology Unit, S Giovanni B Hospital and Regional Centre for Cancer Epidemiology and Prevention, Torino, Italy; Department of Epidemiology and Cancer Registration, Catalan Institute of Oncology (ICO), Av. Gran Via s/n, Km 2.7, E-08907, L’Hospitalet de Llobregat, Spain; Department of Pathology, Ospedale Martini, Torino, Italy; entre de Seguretat i Condicions de Salut en el Treball (CSCST), Barcelona, Spain; Epidemiology Unit, Center for Study and Prevention of Cancer Firenze (CSPO), AO Careggi, Firenze, Italy; Department of Preventive Medicine and Public Health, Hospital Universitario Puerta del Mar, Cádiz, Spain; Agency for Environmental Protection (ARPA) Piemonte, Torino, Italy; Department of Pathology, Hospital Clinic, Barcelona, Spain; Former Documentation Services, Instituto Nacional de Seguridad e Higiene en el Trabajo, and Centro de Investigación y Desarrollo de Barcelona (CSIC), Barcelona, Spain; Geneva Medical Inspectorate of Factories (OCIRT) and Geneva Cancer Registry, Geneva, Switzerland

Summary Insufficient evidence exists on the risk of pleural mesothelioma from non-occupational exposure to asbestos. A population-based case–control study was carried out in six areas from Italy, Spain and Switzerland. Information was collected for 215 new histologically confirmed cases and 448 controls. A panel of industrial hygienists assessed asbestos exposure separately for occupational, domestic and environmental sources. Classification of domestic and environmental exposure was based on a complete residential history, presence and use of asbestos at home, asbestos industrial activities in the surrounding area, and their distance from the dwelling. In 53 cases and 232 controls without evidence of occupational exposure to asbestos, moderate or high probability of domestic exposure was associated with an increased risk adjusted by age and sex: odds ratio (OR) 4.81, 95% confidence interval (CI) 1.8–13.1. This corresponds to three situations:
cleaning asbestos-contaminated clothes, handling asbestos material and presence of asbestos material susceptible to damage. The estimated OR for high probability of environmental exposure (living within 2000 m of asbestos mines, asbestos cement plants, asbestos textiles, shipyards, or brakes factories) was 11.5 (95% CI 3.5–38.2). Living between 2000 and 5000 m from asbestos industries or within 500 m of industries using asbestos could also be associated with an increased risk. A dose–response pattern appeared with intensity of both sources of exposure. It is suggested that low-dose exposure to asbestos at home or in the general environment carries a measurable risk of malignant pleural mesothelioma. © 2000 Cancer Research Campaign

Keywords: asbestos; environmental exposure; mesothelioma; case–control studies

There is convincing evidence that pleural malignant mesothelioma is associated with occupational exposure to all commercial forms of asbestos (Landrigan, 1998; WHO, 1998). Although most cases of mesothelioma show a definite history of asbestos exposure at work, in population studies there is a proportion of cases that do not report any occupational exposure throughout their working life. Therefore, attention has turned to the potential risk associated with exposure at the lower doses in the general environment (Landrigan 1998).

Two circumstances for possible non-occupational exposure to asbestos have been investigated: domestic and environmental exposure. The former results from asbestos fibres brought home by workers exposed in the workplace (Gardner and Saracci, 1989). Environmental exposure may result from residence in the vicinity of asbestos mines, mills, or factories using asbestos. In many studies there is a single well-identified source of asbestos pollution termed a ‘neighbourhood exposure’. Another kind is due to residence in areas where the soil is naturally rich in asbestos or similar fibres. Both sets of circumstances have led to localized outbreaks of pleural mesotheliomas, large enough to be first recognized in the absence of formal epidemiological studies (Gardner and Saracci, 1989). The latter are needed, however, to investigate whether the industrial use of asbestos may produce sufficient environmental pollution to cause asbestos-related disease. Rarely, mesotheliomas may occur in recognizable geographical or temporal clusters when the exposure is relatively high, but they will go unnoticed when exposure is low. Although asbestos is widely found in the environment, insufficient evidence exists on the risk of mesothelioma as a consequence of general environmental exposure (Siemiatycki and Boffeta, 1998). The extent to which the general population is exposed and the potential effects of such low-dose exposure are a matter of controversy.

A multicentric population-based case–control study was therefore carried out with the main aim of measuring risk associated with low-intensity, non-occupational exposure to asbestos.

A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomes
Michele Carbone, Salih Emri, A. Umran Dogan, Ian Steele, Murat Tuncer, Harvey I. Pass and Y. Izzettin Baris

Abstract | In Cappadocia, Turkey, an unprecedented mesothelioma epidemic causes 50% of all deaths in three small villages. Initially linked solely to the exposure to a fibrous mineral, erionite, recent studies by scientists from Turkey and the United States have shown that erionite causes mesothelioma mostly in families that are genetically predisposed to mineral fibre carcinogenesis. This manuscript reports, through the eyes of one of the researchers, the resulting scientific advances that have come from these studies and the social improvements that were brought about by both the scientists and members of the Turkish Government.

Mesothelioma is a cancer arising from the mesothelial cells that line the pleural, pericardial and peritoneal surfaces1,2. Although there are rare benign variants of mesothelioma, such as multicystic mesothelioma or mesothelioma of the atrioventricular node, which are not related to asbestos exposure1,2, this article focuses on the relatively more common malignant mesothelioma. In the United States there are approximately 2,500 cases and deaths per year of malignant mesothelioma, which is often related to asbestos exposure (BOX 1). Median survival is approximately 1 year from diagnosis because current therapies have only marginal effects in altering the natural course of the disease1. Although the link between asbestos exposure and mesothelioma was established in 1960, it is still unclear whether all types of asbestos cause mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-related tumor which is increasing in incidence and causes an estimated 15,000 to 20,000 deaths per annum worldwide. Malignant pleural mesothelioma has a median survival of seven to ten months and a clinical pattern that usually involves substantial pain and dyspnea. It presents at a clinically advanced stage in most patients so there is a need for new methods of early detection. The fact that asbestos is the main etiologic agent for MPM means that at-risk populations can be readily identified and studied, and these populations represent ideal cohorts in which to undertake early cancer detection studies.

There have been a number of studies attempting to define biomarkers that could predate symptoms in a “high risk for MPM” population and also distinguish MPM from other malignancies. Unfortunately, the majority of these studies have had very few patients of various stages of MPM and the markers have not been prospectively evaluated. Some of these biomarkers include tissue polypeptide antigen, carcinoembryonic antigen, hyaluronic acid, and ferritin [1] as well as hyaluronic acid levels [2]. Other markers such as cytokeratins [3] and cancer antigen 125 (CA-125) [4] have been evaluated in MPM but have been inconclusive. One must conclude, therefore, that until recent reports of soluble mesothelin-related protein (SMRP) [5] and osteopontin [6] in MPM, there have been no reliable, validated serum or pleural effusion markers that can distinguish a highrisk, asbestos-exposed population without MPM from patients with established MPM, or to distinguish other malignancies from MPM.

Case Report

Malignant mesothelioma of the tunica vaginalis: a case with an unusually indolent course following radical orchidectomy and radiotherapy
1J L HARMSE, 1A T EVANS and 2P M WINDSOR

Directorates of 1Pathology and 2Radiotherapy and Oncology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK

Abstract. Malignant mesothelioma (malignant adenomatoid tumour) of the tunica vaginalis testis is a very rare neoplasm with highly aggressive biological behaviour. Treatment is di¤cult, and widespread local invasion and/or metastatic disease at presentation are associated with a poor prognosis. In this case report we describe for the first time a patient who, despite presenting with locally advanced disease, remains well 10 years after diagnosis and treatment with radical orchidectomy and high dose radiotherapy.

Case report
A 70-year-old man presented in November 1988 with a right scrotal mass. A right hydrocele had been repaired 18 years earlier, but otherwise there was no significant medical or surgical history. On examination, three cysts were palpable above the right testicle, but the organ itself was hard and craggy, which suggested the possibility of a tumour. In view of this, a radical orchidectomy was performed as the primary procedure.

The orchidectomy was performed through an inguinal incision. When the testicle was examined, the lower pole was found to be adherent to the over-lying dartos muscle and skin. A disc of skin and muscle tissue was excised in continuity with the testicle and the specimen was submitted for histo-pathological examination.

Pathological Findings
Macroscopic
The specimen comprised the right testis together with coverings and attached spermatic cord. On section a tumorous mass was seen arising from the tunica vaginalis, and consisting of dense white tissue. An adherent disc of skin and dartos muscle was included and this appeared to be widely infiltrated by pale tumour.

Microscopic
Sections from the tumour showed tubular and glandular structures set in a fibrous stroma. The gland spaces were lined by cuboidal epithelial cells displaying cytological features of malignancy and a brisk mitotic rate (Figure 1a). The tumour
invaded the testicular parenchyma and overlying muscle and skin (Figure 1b). In places, perineural invasion was a conspicuous feature (Figure 1c).

The results of previous histochemistry, immuno-histochemistry and electron microscopy examinations, performed in 1988, gave support to a diagnosis of a malignant mesothelioma, and an expert opinion also agreed with this conclusion.
Reviewoftheoriginalhistologyandrecentimmuno-histochemistry with currently available markers confirm the original diagnosis of primary malignant mesothelioma arising in the tunica vaginalis.

Multicystic Mesothelioma of the Peritoneum
Liem T. Bui-Mansfield1, Gina Kim-Ahn2, Larry K. O’Bryant3

During a pelvic examination, a 44-year-old woman was found to have an abdominal mass. Pelvic sonography revealed a complex multiseptate cystic mass (Fig. 1A). MR imaging showed a 15x9x7 cm mass arising from the uterine fundus; on T2-weighted images, the mass exhibited intermediate and high signal intensity. Fine septations were seen in the cystic component of the
mass (Fig. 1B). The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. The hysterectomy specimen showed an irregular multilocular cystic mass attached to the uterine fundus (Fig. 1C). Microscopic examinations found multiple mesothelium-lined cysts surrounded by a fibrovascular stroma with adenomatoid changes (Fig. 1D). The pathologic diagnosis was multicystic mesothelioma of the peritoneum.

Mesotheliomas are mesenchymal neoplasms originating in the serous lining of the pleura, pericardium, or peritoneum. Multicystic mesothelioma of the peritoneum is an intermediate form of mesothelioma: the severity of the disorder is greater than that of the localized, benign adenomatoid mesothelioma but is less than that of the highly lethal form of diffuse epithelial mesotheliomas [1]. Multicystic mesothelioma occurs predominantly (84% of cases) in young or middle-aged women (mean age, 37 years 10 months) [1, 2]. The tumor chiefly affects the pelvic peritoneum, particularly the uterus, cul-de-sac, bladder, and rectum, growing along the serosa as multiple translucent fluidfilled cysts. Multicystic mesothelioma is made up of mesothelium-lined cysts embedded in fibrovascular stroma. The mesothelial cells are typically flattened or cuboidal. In one third of patients, adenomatoid change or squamous metaplasia of the mesothelium is found [1]. Unlike the malignant form of mesothelioma, multicystic mesothelioma has no association with asbestos exposure [1]. The most common presenting symptoms are abdominal pain (46% of patients) and abdominal mass (29% of patients) [2]. In 18% of patients, the tumor is an incidental finding [2].

On sonography, multicystic mesothelioma appears as a multiseptate cystic mass [3]. Typically, CT reveals a well-defined, noncalcified multilocular cystic mass [2], although a case of calcification in a benign cystic peritoneal mesothelioma has been reported [4]. MR imaging shows well-defined lesions that are hypointense on T1-weighted images and have intermediate signal intensity on T2-weighted images, isointense to urine. This finding correlates with the clear watery fluid seen at gross pathologic examination [2].

Differential diagnoses include lymphangioma, endometriosis, ovarian cystadenoma or cystadenocarcinoma, teratoma, pseudomyxoma peritonei, necrotic leiomyoma or leiomyosarcoma, and epithelial inclusion cysts [1, 2]. Because of the rarity of multicystic mesothelioma, a correct preoperative diagnosis is almost never rendered [1]. Multicystic mesothelioma is not chemo- or radiosensitive. No correlation exists between the extent of the tumor and the patient’s survival. Treatment for localized lesions is total surgical excision, and for more extensive lesions, debulking procedures are performed.

Malignant pleural mesothelioma. C. Boutin, M. Schlesser, C. Frenay, Ph. Astoul. ERS Journals Ltd 1998.

ABSTRACT: The incidence of malignant pleural mesothelioma (MPM) has risen for some decades and is expected to peak between 2010 and 2020. Up to now, no single treatment has been proven to be effective and death usually occurs within about 12–17 months after diagnosis. Perhaps because of this poor prognosis, early screening has incited little interest. However, certain forms may have a better prognosis when diagnosed early and treated by multimodal therapy or intrapleural immunotherapy. Diagnosis depends foremost on histological analysis of samples obtained by thoracoscopy. This procedure allows the best staging of the pleural cavity with an attempt to detect visceral pleural involvement, which is one of the most important prognostic factors. Although radiotherapy seems necessary and is efficient in preventing the malignant seeding after diagnostic procedures in patients, there has been no randomized phase III study showing the superiority of any treatment compared with another. However, for the early-stage disease (stage I) a logical therapeutic approach seems to be neoadjuvant intrapleural treatment using cytokines. For more advanced disease (stages II and III) resectability should be discussed with the thoracic surgeons and a multimodal treatment combining surgery, radiotherapy and chemotherapy should be proposed for a randomized controlled study. Palliative treatment is indicated for stage IV. In any case, each patient should be enrolled in a clinical trial. Eur Respir J 1998; 12: 972–981.

The term "mesothelioma" was first used in 1921 by EASTWOOD and MARTIN [1]to describe primary tumours of the pleura. At that time, the primary nature of these tumours was controversial without confirmation by autopsy. Today, the histological diagnosis of mesothelioma remains problematic and differential diagnosis against adenocarcinoma is difficult in 10–15% of cases despite the routine use of histochemistry.

The first evidence implicating asbestos in the pathogenesis of mesothelioma was presented in 1960 by WAGNER [2] in South African miners. The incidence of malignant pleural mesothelioma (MPM) has risen for some decades and is expected to peak sometime between 2010 and 2020 [3, 4]. This increase has been attributed to the widespread use of asbestos in the period from World War II until the end of the 1970s [5]. Pleural mesothelioma is more frequent than peritoneal mesothelioma, possibly because in-halation is the usual route of the pathogenic fibres.

No single treatment has been proven to be effective for malignant mesothelioma. Chemotherapy alone has no effect, radiation therapy simply provides palliation against pain, and surgery (even when performed at a relatively early stage) is controversial [6–10]. The value of the current staging system is questionable: after the first classification by BUTCHART et al. [8] the number of successive classifications provides evidence for the difficulty in distinguishing between the various stages of the disease [11–13].

Recent studies have reported good results using immunotherapy and surgery in patients graded as "early stage" according to a new system of classification [14, 15]. The purpose of the present article is to describe the current knowledge on mesothelioma.

A 10-year-old boy appears at your office with a chief complaint of shortness of breath. Exertional dyspnea has been present for the previous month and is associated with intermittent dry cough. The patient has no associated fever, chills, or chest pain. Chart review indicates no history of asthma or other pulmonary disease, although the patient has been seen several times for “hay fever.”

The patient is accompanied by his mother, who appears quite anxious. The mother emotionally relates that her 65-year-old cousin has recently been diagnosed with mesothelioma and is dying. Furthermore, he had been a custodian at the patient’s school for the previous 3 years, after retiring from his career as a longshoreman. His work at the school involved general cleanup and boiler room maintenance. The mother is afraid that her son’s dyspnea and cough are related to asbestos exposure at the school and that he might be developing mesothelioma, because he often helped her cousin after school. Recent asbestos removal in the school boiler room has increased the mother’s concern.

On physical examination, the patient is in no acute distress. Respirations are unlabored. Lung auscultation reveals a diffuse, expiratory wheeze. Spirometry performed in the office shows a forced vital capacity (FVC) of 95% of predicted value and a forced expiratory volume in 1 second (FEV1) of 88% of predicted value, with an FEV1/FVC of 70%. The remainder of the examination is within normal limits. A chest radiograph is normal.