Malignant Pleural Mesothelioma in Turkey

The “Fairy Chimneys” of Cappodocia are remnants of lava rock containing carcinogenic minerals.

Turkey has one of the highest prevalence rates for endemic asbestos-related pulmonary disease in the world¹. This can be attributed primarily to the geology of the country, which includes numerous outcrops of asbestos (Fig. 1). Central Anatolia is covered with a think layer of volcanic ashes, larva and rocks resulting from the repeated eruptions of two volcanoes up the present era. This soft rock has been eroded into a variety of exotic shapes and in the past provided residences and places of worship, since the outcrops could be easily hollowed out, or mined for various domestic purposes, including building. Malignant Mesothelioma in Turkey, then, is an environmental hazard, related to the use of various naturally occurring minerals and rocks by villagers, rather than by exposure related to the commercial use of asbestos.

Epidemiology

Asbestos is a group of naturally-occurring silicate minerals. Silicates are the most abundant minerals (comprising at least 30% of all minerals), which consist of various metals associated with silica and oxygen – the silicate part of the molecule. Asbestos includes several different types of fiber, all of which are strong, last for a long time, and are resistant to heat and fire. They are, however, long, thin (approximately 1,000 times thinner than a human hair) and sufficiently flexible to be woven into cloth. Asbestos has, therefore, been used in a broad range of commercial products. The main types of fiber used commercially are 1) Chrysotile, or white asbestos, white-gray in color and found in serpentine rock (a silicate mineral; 2) Amosite, or brown asbestos, mined mostly from southern Africa; and 3) Crocidolite, or blue asbestos, which comes from southern Africa and Australia.

Fig. 1. Map of Turkey showing areas of asbestos and erionite deposits. Black indicates areas where there is high exposure, red shows areas of moderate exposure and pink indicates low, but still appreciable degrees of exposure to mineral fibers.

Tremolite, actinolite and anthophyllite are types of asbestos fibers that have not been used commercially, although they are sometimes found as contaminants in asbestos-containing products. These types of asbestos, however, are often responsible in Turkey for health problems, since these so-called “white soils” were traditionally used in rural areas to make a whitewash or stucco to surface the walls, floors, and roofs of houses and also as a substitute for baby powder and gripewater. The health hazard from asbestos results from inhalation – the fibres are so small that they can remain suspended in the air for long periods.

Mineralogical analysis has revealed that tremolite is the most prominent type of asbestos found as a contaminant of white stucco. In addition, chrysotile asbestos and in some districts, anthophyllite asbestos have also been found as contaminants of white stucco².

A different mineral fiber has also been found, particularly in three villages located in the Cappadocian region of Central Anatolia³. This has been identified as the fibrous zeolite, erionite, another form of silicate. This fiber, which looks and feels like wool, is present in certain volcanic rocks (tuffs), from which stones have been cut to build houses in these villages.

Experimental studies have shown that erionite is 300-800 times more carcinogenic than chrysotile, and 100-500 times more potent than crocidolite when given by the intrapleural route to hamsters⁴.

Homes constructed with bricks containing erionite fibers pose a health hazard to the inhabitants.

Both asbestos and erionite can cause a variety of benign and malignant chest diseases. Among the latter, pleural mesothelioma is the most serious public health problem in central and eastern Anatolia. It has been estimated that about 16 million people living in rural parts of Anatolia have been environmentally exposed to mineral fibers. In such subjects, the cumulative retention of fibers in the lung is comparable to that found in patients occupationally exposed to asbestos in Belgium^5,6. This indicates that environmental exposure in Turkey is a serious health hazard and is not comparable to that in other western countries where it does not pose a significant health risk to the general population.

The estimated incidence of malignant pleural mesothelioma has been reported to be 43 per million inhabitants in the southeast of Turkey⁷ and is extremely high - 996 per 100,000 inhabitants - in the population exposed to erionite, in the so-called “erionite villages” of Cappadocia³, where more than 50% of deaths are caused by malignant pleural mesothelioma⁸. In Sweden, in a cohort of 162 Turkish emigrants from Karain (one of the erionite villages), Metintas et al. reported 14 deaths due to mesothelioma among the 18 (78%) deaths occurring between 1965 and 1997 ⁹. The standardized incidence rates were 135 times higher among men and 1336 times higher among women, compared with the general population of Sweden. The risk correlated with the duration of residence in the village.

A recent survey of the incidence and distribution of malignant mesothelioma in Turkey revealed a total of 506 new cases (464 pleural, 42 peritoneal) for the year 2000 ¹⁰. The female-to-male ratio was 213:293. The mean age at diagnosis was 56 years (range: 24-88 years), for both men and women. In none of these cases was there a history of occupational exposure to either asbestos or erionite. Six percent of cases (30/506) were reported from the erionite villages. The mean age of patients with mesothelioma at diagnosis in all cases was higher than that reported in a previously published study in 1992 (48.3 years) ¹¹. Recent mortality data from villages near to the three known erionite villages in the Cappadocian area (Tuzkoy, Karain, and Sarihidir) for the years 1994 to 1997 suggest that malignant mesothelioma might also occur at high incidence in some of these villages ¹². These include Karacaören, Boyali, Cökek, Karlik, and Yesilöz. Fifty-three of the total of 64 reported deaths due to mesothelioma in this region were from the three erionite villages, six were from Karacaören, and five from the other four villages. No mesotheliomas were found in Karlik. Thus, mesothelioma cases are more prevalent in the erionite villages compared to other villages nearby¹³.

The interiors of homes, as well as the exteriors, are plastered with asbestos-containing “white soil.”

Individuals in adjacent houses in the same village seem to have a very different incidence of mesothelioma, despite similar exposure, which suggests that other factors also contribute. In a recent genetic-epidemiologic study addressing this issue, the possibility of a genetic factor determining susceptibility to carcinogenicity of erionite in this area was investigated¹⁴. The study showed that mesotheliomas are much more frequent in certain families compared to others and in one extended pedigree of 526 individuals, appeared to be transmitted as an autosomal dominant. Further studies are in progress to identify the gene(s) that predispose individuals to malignant mesothelioma.

Recent studies have shown that Simian virus 40 (SV40), a DNA tumor virus that contaminated polio vaccines distributed worldwide in the late 1950’s and early 1960’s, is a cofactor in the development of human mesotheliomas in the USA ¹⁵. However, this does not seem to be the case in the context of environmentally related malignant mesothelioma in Turkey ¹⁶. SV40-contaminated vaccines were never administered in Turkey.

Clinical Features and Treatment

The biologic behavior of malignant pleural epithelioma is difficult to predict. The disease is initially limited to the parietal pleura and then advances, mainly through local spread within the thoracic cavity. In the final stages, chest wall invasion and distant metastases can occur. The reason for the relative rarity of distant metastases may be related to the rapidity of tumor growth, which generally results in death within 9-10 months after diagnosis.

Author Salih Emri (second from left) poses with villagers and a fellow scientist in front of the first 50 homes constructed in Tuzköy with erionite-free bricks.

Therapeutic results remain poor and cure of the disease is exceptional¹⁷. Unusually long survival without any treatment is, however, occasionally observed. In a retrospective study, Selcuk et al. showed a relatively better survival in patients with malignant pleural mesothelioma caused by exposure to asbestos, compared to erionite (median survival 13.5 months versus 21.5 months respectively. Mantel-Cox regression, p<0.01) 11. The reason for this is unknown.

Objective response rates with single or multiple chemotherapeutic drugs have so far been disappointing. Our current therapeutic approach is combined modality treatment consisting of surgery (pleurectomy/decortication), intracavitary chemotherapy with cisplatin, irradiation and systemic chemotherapy with gemcitabine, cisplatin , taxol and carboplatin.

The best characterised novel agent for the treatment of malignant mesothelioma is pemetrexed (LY 231514, ALIMTA), an antimetabolite which inhibits multiple folate-dependent enzymes (thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). Pemetrexed has shown activity as a single agent as well as in combination with cisplatin and carboplatin. In a recent randomized study involving 456 patients, Pemetrexed and cisplatin improved median survival to 12.1 months compared to 9.3 months with cisplatin alone¹⁸.

Salih Emri*, Murat Tuncer**, Y. Izzettin Baris***
* Hacettepe University, School of Medicine, and Member of National Mesothelioma Study Commitee Ankara, Turkey.
** Director of National Cancer Control Department, Ministry of Health, Ankara, Turkey .
*** Güven Medical Centre, and Chief of National Mesothelioma Study Committee, Ankara, Turkey.

References:

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2. Dogan M, Emri S. Environmental health problems related to mineral dusts in Ankara and Eskisehir, Turkey.Yerbilimleri 2000; 22: 149-161.

3. Baris YI, Simanato l, Artvinli M, Pooley F, Saracci R, Skidmore J, Wagner C. Epidemiological and environmental evidence of health effect of exposure to erionite fibers: A four-year study in the Cappadocian region of Turkey. Int J Cancer 1987; 39: 10-17.

4. Cartthew P, Hill RJ, Edwards RE, Lee PN. Intrapleural admistration of fibers induces mesothelioma in rats in the same relative order of hazards as occurs in man after exposure. Human Exp Toxicol 1992; 11: 530-534.

5. Dumortier P, Çoplü L, de Maertelaer V, Emri S, Baris I, De Vuyst P. Assessment of environmental asbestos exposure in Turkey by bronhoalveolar lavage. Am J Respir Crit Care Med 1998;158:1815-1824.

6. Dumortier P, Çoplü L, Broucke I, Emri S, Selcuk T, De Maertelaer V, De Vuyst P, Baris I. Erionite bodies and fibres in bronhoalveolar lavage fluid (BALF) of residents from Tuzköy, Cappadocia, Turkey. Occup Environ Med 2001;58:261-266.

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10. Baris YI. Lung diseases related to asbestos and fibrous zeolite esposure in Turkey. The symposium on nutrition, environment, and cancer. March 31-April 3, 2002, Ankara, Turkey.

11. Selcuk ZT, Çöplü L, Emri S, Kalyoncu AF, Sahin AA, Baris YI. Malignant pleural mesothelioma due to environmental mineral fiber exposure in Turkey. Analysis of 135 cases. Chest 1992; 102: 790-796.

12. Emri S, Demir A, Dogan M and et al. Lung diseases due to environmental exposures to erionite and asbestos in Turkey. Toxicology Letters 2002;127/1-3: 251-257.

13. Dogan AU. Cappadocian mesothelioma villages. The symposium on nutrition, environment, and cancer. March 31-April 3, 2002, Ankara, Turkey.

14. Hammady I-Roushdy, Siegel J, Emri S, Testa JR, Carbone M. Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey. Lancet 2001; 357:444-445.

15. Carbone M, Fisher S, Powers A, Pass HI and Rizzo P. New molecular and epidemiological issues in mesothelioma: Role of SV40. J Cell Physiol 1999; 180:167-172.

16. Emri S, Kocagoz T, Olut A, Güngen Y, Mutti L, Baris YI. Simian virus 40 is not a cofactor in the pathogenesis of environmentally induced malignant pleural mesothelioma in Turkey. Anticancer Research 2000; 20: 891-894.

17. Emri S, Akbulut H, Zorlu F, Dinçol D, Akay H, Güngen Y, Içli F. Prognostic significance of flow cytometric DNA analysis in patients with malignant pleural mesothelioma. Lung Cancer 2001;33: 109-114.

18. Vogelzang NJ, Rusthoven J, Paoletti P, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer MJ, Emri S, Niyikiza C. Phase III single-blinded study of pemetrexed+cisplatin vs. cisplatin alone in chemonaive patients with malignnat pleural mesothelioma. ASCO proceedings 2002 abstract no 5.