Asbestos-Induced Lung Cancer
Epidemiologic and experimental analyses of the relationship between asbestos exposure and lung cancer: A large number of epidemiologic studies have established a definite relationship between heavy asbestos exposure and an excess risk of lung cancer [1, 2] . The latency period (time between first exposure and the appearance of disease) is relatively long: increases in lung cancer incidence do not appear until about 10 years after first exposure, and the peak incidence occurs around 30 years after first exposure [3]. At these high occupational exposure levels lung cancer incidence is in general a linear function of cumulative exposure. Even with high exposures, there are quite marked differences in lung cancer incidence by type of industry,with the lowest rates seen in chrysotile mining and milling and chrysotile friction products manufacture; greater rates in cement and mixed products work; and very high rates in chrysotile textile workers [4]. The latter may reflect use of long fibers and consequently greater incidences of asbestosis. Additionally there is evidence that exposure to amphiboles (amosite and crocidolite) increases the risk of lung cancer compared to exposure to chrysotile. A recent statistical analysis [5] suggests that the difference between chrysotile and amphiboles is in the range of 10 to 50 fold for a given fiber dose. Virtually all asbestos-related lung cancers occur in cigarette smokers, although some studies show an excess risk for nonsmokers as well [6, 36] . Excess risk appears to be confined to those with heavy exposure (many of whom have asbestosis), and in this setting most studies show that the combination of cigarette smoke and asbestos produces a more than additive risk and in some instances a clearly multiplicative risk [6, 36] :

Table 2: Relative risk of dying of lung cancer in asbestos insulation workers [6]

Group	Relative Risk
Nonsmokers, no asbestos exposure	1.00
Nonsmokers with asbestos exposure	5.17
Smokers, no asbestos exposure	10.85
Smokers with asbestos exposure	53.24

There is general agreement about the data just discussed, but there is marked disagreement about the circumstances in which one can associate a lung cancer with asbestos exposure. Broadly speaking, there are three schools of thought on this issue: 1) Risk of lung cancer is increased with any exposure to asbestos, no matter how small 2) Risk is only increased with a relatively high level exposure, an exposure in the range that produces asbestosis, but asbestosis itself is not required; 3) Only asbestosis increases risk [7, 8, 9, 10] .

Theory one, that any exposure to asbestos increases lung cancer risk, is based in large part on observations in experimental tissue culture systems, because asbestos is able, under certain conditions, to damage DNA or to affect cell proliferation. This theory also depends on extrapolations of dose response curves from the high exposure levels where actual increases in lung cancer risk have actually been found, to exposure levels several orders of magnitude less; ie, low level exposures where no increases in rates have actually been demonstrated, and there is considerable doubt that such extrapolations are valid.

In contrast, several recent studies have shown that quite significant levels of exposure fail to increase lung cancer risk. Camus et al [11] examined women who lived in the Quebec chrysotile mining townships but did not work in the chrysotile mining and milling industry. Because of environmental contamination these women were estimated to have received cumulative exposures of about 100 fiber/cc-yrs, (an amount at the bottom of the asbestosis-risk range) but they had no increased risk of lung cancer. Similarly, Liddell et al [12] examined lung cancer risk in those employed in the Quebec chrysotile mining and milling industry and found no increased risk of lung cancer below an exposure of about 800 to 1000 fiber/cc-yr.

Theory number two states, in effect, that asbestos-induced lung cancers do not appear until a threshold cumulative exposure has been reached and that this threshold cumulative exposure is in the range required to produce asbestosis. There is considerable epidemiologic support for this theory [7, 8, 11, 12, 13] . Since the level of exposure required to produce asbestosis is quite high, these observations support a requirement for high exposure as a minimum condition for the development of lung cancer.

However, various animal and human studies support the idea that it is actually asbestosis and not just high exposure by itself that increases risk. Animal experiments show that increases in lung cancer rates require very long high level exposure to asbestos and that tumors only appear when there is abnormal fibrosis (asbestosis); fibers that do not cause fibrosis do not cause cancers [14]. In humans there is no doubt that the presence of asbestosis increases the risk of developing lung cancer. In older series of workers receiving compensation for asbestosis, lung cancers were seen in an average of 30% of deaths. More recently Weiss [9] analyzed 38 worker cohorts and demonstrated a strong correlation between excess (above that expected from smoking) lung cancer rate and asbestosis rate.

There are two retrospective pathology studies which shed light on this issue. Kipen et al [15] and Newhouse et al [16] evaluated the lungs of workers who had heavy asbestos exposure. Cases were selected because they had lung cancer, and the presence or absence of asbestosis noted. Histologic asbestosis was documented in 100% and 90% of the cases. Thus these data indicate that the presence of asbestosis accounts for all the excess lung cancer risk.

Even more interesting are two prospective studies in which data on both the presence or absence of asbestosis and cumulative exposure exist. Hughes and Weill [17] examined asbestos cement workers using chest radiographs and Sluis-Cremer and Bezuidenhout [18] documented asbestosis in autopsy lungs from amosite asbestos miners. In both studies increased lung cancer rates were found only in the presence of asbestosis (Table 3). These studies also provided data on measured cumulative asbestos exposure, but cumulative exposure did not account for the presence or absence of lung cancer. Thus these data strongly support the idea that asbestosis is required to link a lung cancer to asbestos exposure.

Table 3: Relationship of Asbestosis and Lung Cancer in Two Prospective Studies

Report	Asbestosis	SMR	Significant Increase?
Hughes & Weill [17] Chest x-ray asbestos cement workers	None Present	1.06 4.32	No Yes
Sluis-Cremer & Bezuidenhout [18] Autopsy pathology - amosite asbestos miners	None Mild Mod/severe	0.89 4.17 5.65	No Yes Yes

Practical approach for the pathologist
Pathologists are commonly asked to determine whether a lung cancer is caused by asbestos exposure. As indicated above, the weight of the evidence suggests that a lung cancer should be attributed to asbestos exposure only if asbestosis is present, either radiographically or pathologically (the pathologic features of asbestosis are discussed by Victor Roggli in this symposium and will not be repeated here).

There is considerable discussion in the literature about whether histologic subtype and tumor location provide any useful information for attribution. One can find claims in the literature that asbestos-induced carcinomas are more frequent in the lower lobes, but equal numbers of claims that they are more frequent in the upper lobes. Similarly, the literature supports and denies the idea that asbestos-related carcinomas are peripheral rather than central.

The same types of contradictions apply to attempts to use histologic subtype for attribution, with reports claiming that one or another histologic type of tumor is or is not increased. A number of years ago I compiled a listing of the frequency of different cell types in asbestos workers with lung cancer from different reports; overall there was no difference compared to nonexposed individuals [19]. Thus I do not believe that either tumor location or tumor cell type are of any use in this situation.

A few claims exist in the literature that the presence of k-ras mutations can be used to determine which lung cancers are caused by asbestos exposure. Given the high frequency of k-ras mutations in non-small cell lung cancers from ordinary cigarette smokers, this approach does not appear to be useful.

Malignant Mesothelioma

Incidence
In the United States the current incidence of mesothelioma is about 20/million in men and 2 to 3/million in women [20]. In men incidence rates have increased steadily over the last 30 to 40 years, but in women incidence rates are essentially unchanged over this period. These differences are believed to reflect gender differences in asbestos exposure. Recent data from the SEER cohort [20] indicate that the peak incidence rate for mesothelioma was reached in the US in the early 1990's and that there is now a slow decline, a phenomenon that probably reflects decreasing amphibole use starting in the 1970's [21].

Location of Tumors
The majority of mesotheliomas are pleural in origin, followed by peritoneal primaries; pericardial and tunica vaginalis primaries are rare. For men, the ratio of pleural:peritoneal tumors in the US is about 9:1, but for women only 2:1 [22]. This difference probably reflects the additional tumors produced in men in the pleural cavity by asbestos exposure. The same histologic patterns are seen in all locations, although sarcomatous lesions are relatively uncommon in the peritoneal cavity.

Etiologies
Asbestos: By far the most extensively investigated etiology is asbestos exposure. A report by Spirtas et al [23] using data from a set of cancer registries in the United States concluded that asbestos exposure was the cause of 90% of the pleural tumors, and about 60% of the peritoneal tumors in men, but only about 20% of all mesotheliomas in women. Other countries where amphibole use was extensive have higher rates and a greater proportion of asbestos associated tumors in women; however, in all studies some proportion of mesotheliomas are not associated with asbestos exposure.

Mesotheliomas typically are seen in workers who had significant amphibole asbestos exposure, particularly pipefitters and insulators, shipyard workers, amphibole asbestos miners, and individual working in factories that used amphibole or mixtures of amphiboles and chrysotile. Construction workers of many types also have been shown to have an increased risk. Pleural mesotheliomas may occur as a result of household contact exposure such as washing amphibole-asbestos contaminated workclothes. Exposure to chrysotile asbestos carries a much lower risk of pleural mesothelioma and enormous doses of chrysotile are required before mesotheliomas develop. Hodgson and Darnton [5] estimated that the relative risk is 1 (chrysotile): 100 (amosite): 500 (crocidolite). Peritoneal mesotheliomas are only associated with high level amphibole exposure.

The latency period for mesothelioma after asbestos exposure is long, with a mean value of 30 to 40 years [24]; latencies less than 20 years are uncommon and even with heavy amphibole exposure mesotheliomas rarely if ever occur within about 15 years of first exposure [24].

Other causes of mesothelioma
A few cases of mesothelioma have been reported in persons who received therapeutic radiation as treatment for a malignant neoplasm [25], although a recent epidemiologic survey has challenged the idea that therapeutic radiation actually increases mesothelioma risk [26]. A handful of cases have been reported after plombage therapy for tuberculosis. In Turkey a high incidence mesothelioma is seen in villages where the soil and rocks contain an asbestos-sized (but not asbestos) biopersistent fiber called erionite [27]. It has also been proposed that Simian Virus 40 (SV40) contamination of polio vaccines in the 1950's might have lead to widespread infection of the population and a subsequent role for SV40 in human mesotheliomas. While there is increasing evidence that SV40 genomic sequences can be found in some mesotheliomas, epidemiologic studies have failed to show an increased risk in individuals believed to have received SV40 contaminated polio vaccines [28]. At this point the association of SV40 and human mesothelioma, if any, is unclear.

Short summary of pathologic features
The pathologic features of asbestos-induced malignant mesothelioma and mesothelioma induced by other agents are identical. This talk will only briefly mention a few important points but considerable detail is provided in the general references at the beginning of the reference list:

1) Gross findings
Mesothelioma typically surrounds viscera (lung or bowel) and invades from the external surface. The presence of diffuse tumor on a serosal membrane and the absence of a solid organ primary are crucial pieces of information for the diagnosis of mesothelioma. This information can be obtained from radiographic report, operative reports, or surgical specimens. Although most mesotheliomas have a distinctive appearance, far greater diagnostic accuracy results if the pathologist has information available on tumor distribution.

2) Microscopic findings
A wide variety of microscopical appearances are seen in mesotheliomas. In a broad sense they may be divided into epitheial, sarcomatous, and mixed epithelial and sarcomatous forms, and this distinction is useful because survival is best in the epithelial forms and worst in the sarcomatous forms.. Within each of these categories there are numerous morphologic variants but their importance is purely one of recognition for diagnosis; the different variants have no independant prognostic implications.

3) Immunohistochemical findings
This is a confusing topic because of the vast number of stains which have been proposed as shown in Table 4. However, the literature needs to be examined with caution and a certain amount of testing is required to see what stains work in one's own laboratory.

Table 4: Histochemical and Immunnohistochemical Techniques for the Diagnosis of Mesothelioma

Test	Usual Finding
	Adenoca	Meso
Mucin Stains
Digested PAS	+	-
Intermediate Filament Stains
Cytokeratin	+	+
Vimentin	+/-	+
Cytokeratin 5/6	-	+
Carcinoma Markers
CEA	+	-
B72.3	+	-
LeuM1	+	-
BEREP4	+	-
MOC31	+	-
Thyroid transcription factor	+	-
Mesothelioma Markers
Calretinin	-	+
WT-1	-	+

Practical approach for the pathologist
Pathologists often worry about whether a patient has a history of asbestos exposure when dealing with a case that might be a mesothelioma. As indicated in the foregoing discussion, mesotheliomas occur in persons who have had asbestos exposure and those who did not; the importance of a history of exposure to asbestos is in assigning causation to a given tumor. However, a history of exposure to asbestos is of no importance in diagnosis: diagnosis depends only on the gross, microscopic, and special technique observations, as it does with any other tumor.

Other Cancers
This presentation considers only carcinoma of the lung and malignant mesothelioma. The various associations listed under the Association Doubtful column in Tabel 1 are generally not accepted, and are clearly confounded by exposures to other known carcinogens, particularly alcohol and cigarette smoke, and likely confounded well as by misclassification of mesotheliomas (for intra-abdominal tumors). These issues are purely epidemiologic and there are no pathologic features in a given case that could be used to support an association, even if one existed. Reviews of the various topics in Association Doubtful are listed in references: [29, 30, 31, 32, 33, 34, 35] .

General References
(can be consulted for additional references and greater detail)

Churg A: Neoplastic asbestos induced disease. In, Churg A, Green FHY: Pathology of Occupational Lung Disease, 2nd Edition. Baltimore, Williams and Wilkins, 1998. Churg A, Green FHY: Occupational Lung Disease, in Thurlbeck=s Pathology of the Lung, 3rd Edition. Edited by Churg A, Myers J, Tazelaar H, Wright JL. New York, Thieme Medical Publishers, in press. Battifora H, McCaughey WTE: Tumors of the Serosal Membranes. Atlas of Tumor Pathology, Third Series, Fascicle 15. Washington, DC, Armed Forces Institute of Pathology, 1995. Churg A, Cagle PT, Roggli VL: Tumors of the Serosal Membranes. Atlas of Tumor Pathology, Fourth Series. Washington, DC, Armed Forces Institute of Pathology, in press. Roggli VL, Oury TD, Sporn TA: Pathology of Asbestos-Associated Disease, 2nd Ed. NewYork, Springer, 2004, in press.

Selected References

1. McDonald JC: Cancer risks due to asbestos and man-made fibres. Recent Results Cancer Res 1990; 120: 122-133.
2. Health Effects Institute: Asbestos in public and commercial buildings: A literature review and synthesis of current knowledge. Cambridge, MA; Health Effects Institute, 1991.
3. Selikoff IJ, Hammond EC, Seidman H. Latency of asbestos disease among insulation workers in the United States and Canada. Cancer 1980; 46: 2736-40.
4. McDonald JC: Unfinished business: the asbestos textiles mystery. Ann Occup Hyg 1998; 42: 3-5.
5. Hodgson JT, Darnton A: The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure. Ann Occup Hyg 2000; 44: 565-601.
6. Hammond EC, Selikoff IJ, Seidman H. Asbestos exposure, cigarette smoking, and death rates. Ann NY Acad Sci 1979; 330: 473-491.
7. Browne K: A threshold for asbestos related lung cancer. Br J Indust Med 1986; 43: 556-558.
8. Browne K: Is asbestos or asbestosis the cause of the increased risk of lung cancer in asbestos workers. Br J Indust Med 1986; 43: 145-149.
9. Weiss W: Asbestosis: a marker for the increased risk of lung cancer among workers exposed to asbestos. Chest 1999; 115: 536-549.
10. Jones RN, Hughes JM, Weill H: Asbestos exposure, asbestosis, and asbestos-attributable lung cancer. Thorax 1996; 51 (Suppl 2): 59-515.
11. Camus M, Siemiatycki J, Meek B: Nonoccupational exposure to chrysotile asbestos and the risk of lung cancer. NEJM 1998; 338: 1565-1571.
12. Liddell FDK, McDonald AD, McDonald JC: Dust exposure and lung cancer in Quebec chrysotile miners and millers. Ann Occup Hyg 1998; 42: 7-20.
13. Health and Safety Executive: Review of Fiber Toxicology. Sudbury, England, HSE Books, 1996.
14. Hesterberg TW, Hart GA: Synthetic vitreous fibers: a review of toxicology research and its impact on hazard classification. Crit Rev Toxicol 2001; 31: 1-53.
15. Kipen HM, Lilis R, Suzuki Y, Valciukas JA, Selikoff IJ: Pulmonary fibrosis in asbestos insulation workers with lung cancer: A radiological and histopathological evaluation. Br J Indust Med 1987; 44: 96-100.
16. Newhouse ML, Berry G, Wagner JC: Mortality of factory workers in east London 1933-80. Br J Indust Med 1985; 42: 4-11.
17. Hughes JR, Weill H: Asbestosis as a precursor of asbestos related lung cancer. Br J Ind Med 1991; 48: 229-233.
18. Sluis-Cremer GK, Bezuidenhout BN: Relation between asbestosis and bronchial cancer in amphibole asbestos miners. Br J Indust Med 1989; 46: 537-540.
19. Churg A: Lung cancer cell type and asbestos exposure. JAMA 1985; 253: 2984-2985.
20. seer.cancer.gov/csr/1973_1999/overview/overview21.pdf (this site is updated periodically)
21. Weill H, Hughes JM, Churg A: Changing trends in US mesothelioma incidence. Occup Environ Med, in press.
22. Spirtas R, Beebe GW, Connelly RR et al: Recent trends in mesothelioma incidence in the United States. Amer J Indust Med 1986; 9: 397-407.
23. Spirtas R, Heineman EF, Bernstein L et al: Malignant mesothelioma: attributable risk of asbestos exposure. Occup Environ Med 1994; 51: 804-811.
24. Lanphear BP, Buncher CR: Latent period for malignant mesothelioma of occupational origin. JOM 1992; 34: 718-721.
25. Cavazza A, Travis LB, Travis WD, Wolfe JT, Foo ML, Gillespie DJ, Weidner N, Colby TV: Post-irradiation malignant mesothelioma.Cancer 1996; 77: 1379-1385.
26. Neugat AI, Ahsan H, Antman KH: Incidence of pleural mesothelioma after thoracic radiotherapy. Cancer 1997; 80: 948-950.
27. Artvinli M, Baris YI, Sahin AA: Environmental mesothelioma in Turkey. Ann NY Acad Sci 1979; 330: 423-432.
28. Strickler HD, Goedert JJ, Devesa SS, Lahey J, Fraumeni JF, Rosenberg PF: Trends in US pleural mesothelioma incidence rates following simian virus 40 contamination of early poliovirus vaccines. JNCI 2003; 95: 38-45.
29. Browne K: Asbestos-related disorders. In, Parkes WR, editor: Occupational Lung Disorders, 3rd Edition. Pages 411-504.
30. Homas DM, Garabrant DH, Gillespie BW: A meta-analysis of colorectal cancer and asbestos exposure. Amer J Epidmiol 1994; 139: 1210-1222.
31. Weiss W: The lack of causality between asbestos and colorectal cancer. J Occup Environ Med 1995; 37: 1364-1373.
32. Liddell FDK: Laryngeal cancer and asbestos. Br J Indust Med 1990; 47: 289-291.
33. Browne K, Gee JB: Asbestos exposure and laryngeal cancer. Ann Occup Hyg 2000; 44: 239-250.
34. Becker N, Berger J, Bolm-Augdorff U: Asbestos exposure and malignant lymphomasB a review of the epidemiological literature. Int Arch Occup Environ Hlth 2001; 74: 459-469.
35. Weisenburger DD and Chiu BCH: Does asbestos exposure cause non-Hodgkin's lymphoma or related hematolymphoid cancers. Clinical Lymphoma 2002; 3: 36-40.
36. Erren TC, Jacobsen M, Peikarski C: Synergy between asbestos and smoking on lung cancer risks. Epidemiology 1999; 10: 405-411.