The story of the discovery of this rare tumor and of the subsequent controversies that arose about its causation by specific forms of com-mercial asbestos is long and complex. It could fill an entire book.
This chapter focuses on the early history of the discovery, from 1767 to 1900; on the histologic controversies, from 1900 to 1942; and on the diagnostic controversies and the role of asbestos, from 1943 to 1973 (Table 1.1).
The period from 1972 through the 1980s and 1990s could be character-ized by advances in the industrial hygiene assessment of exposures, case-control studies, and other major epidemiologic studies concerning health effects in asbestos end-product users, paraoccupational expo-sures, household exposures, school and building exposures, and the
role of specific asbestos fiber types, fiber characteristics, and lung fiber burden analysis.
The 1970s to 1990s was also the period when the role of environmental exposure to erionite, tremolite, and ceramic fibers was discovered, and molecular and cellular biology focused on the
characteristics of fiber carcinogenicity. In the final period, from the late 1990s to the present, the focus has been on the viral contribution to pathogenesis such as SV40 and human genetics and treatment strate-gies. The history of the discoveries after 1973 is covered by other
authors in other chapters in this research.
The period from 1972 through the 1980s and 1990s could be character-ized by advances in the industrial hygiene assessment of exposures, case-control studies, and other major epidemiologic studies concerning health effects in asbestos end-product users, paraoccupational expo-sures, household exposures, school and building exposures, and the
role of specific asbestos fiber types, fiber characteristics, and lung fiber burden analysis.
The 1970s to 1990s was also the period when the role of environmental exposure to erionite, tremolite, and ceramic fibers was discovered, and molecular and cellular biology focused on the
characteristics of fiber carcinogenicity. In the final period, from the late 1990s to the present, the focus has been on the viral contribution to pathogenesis such as SV40 and human genetics and treatment strate-gies. The history of the discoveries after 1973 is covered by other
authors in other chapters in this research.
The History of Mesothelioma
Early Discovery, 1767 to 1900
The history of the term mesothelioma has entailed more than 100 years of controversy. The earliest mention of a possible tumor of the chest wall was by Joseph Lieutaud (1), generally regarded as the founder of pathologic anatomy in France according to Wolf (2), as quoted by
Robertson (3). Lieutaud published a study of 3000 autopsies, among which were two cases of “pleural tumors.” The published account men-tions a boy who suffered from marked dyspnea following trauma, who at postmortem showed fleshy masses adherent to the pleura and the
ribs. Laennec (4) in 1819 is also said by Robertson to have suggested that there was an entity of primary malignancy of the pleura based on Chapter 1 The History of Mesothelioma
The history of the term mesothelioma has entailed more than 100 years of controversy. The earliest mention of a possible tumor of the chest wall was by Joseph Lieutaud (1), generally regarded as the founder of pathologic anatomy in France according to Wolf (2), as quoted by
Robertson (3). Lieutaud published a study of 3000 autopsies, among which were two cases of “pleural tumors.” The published account men-tions a boy who suffered from marked dyspnea following trauma, who at postmortem showed fleshy masses adherent to the pleura and the
ribs. Laennec (4) in 1819 is also said by Robertson to have suggested that there was an entity of primary malignancy of the pleura based on Chapter 1 The History of Mesothelioma
Table 1.1. Important historical events between 1767 and 1972
Year Researcher Event
1767 Lietaud Report of first possible case of pleural
mesothelioma
1854 von Rokitansky First pathologic description of peritoneal
mesothelioma
1870 Wagner First pathologic description of pleural
mesothelioma
1890 Biggs First American case
1920 Du Bray, First use of the term mesothelioma
Rosson
1924 Robertson Best review of literature up to that time
1942 Stout, Murray Further evidence on histogenesis
1953 Weiss Association with pleural mesothelioma made in
Germany
1954 Leichner Association of asbestosis with peritoneal
mesothelioma
1957 Godwin Clear pathologic criteria for pleural
mesothelioma
1960 Winslow, Taylor Clear pathologic criteria for peritoneal
mesothelioma
1960 Wagner Mesothelioma associated with northwest Cape
crocidolite
Year Researcher Event
1767 Lietaud Report of first possible case of pleural
mesothelioma
1854 von Rokitansky First pathologic description of peritoneal
mesothelioma
1870 Wagner First pathologic description of pleural
mesothelioma
1890 Biggs First American case
1920 Du Bray, First use of the term mesothelioma
Rosson
1924 Robertson Best review of literature up to that time
1942 Stout, Murray Further evidence on histogenesis
1953 Weiss Association with pleural mesothelioma made in
Germany
1954 Leichner Association of asbestosis with peritoneal
mesothelioma
1957 Godwin Clear pathologic criteria for pleural
mesothelioma
1960 Winslow, Taylor Clear pathologic criteria for peritoneal
mesothelioma
1960 Wagner Mesothelioma associated with northwest Cape
crocidolite
crocidolite
1964 Enticknap, Association of asbestos and peritoneal
Smither mesothelioma
1965 Selikoff New York Academy of Science Symposium,
report on U.S. insulators
1969 Wagner Animal model further perfected
1972 Stanton, Wrench Stanton hypothesis on the importance of fiber
size/length
1964 Enticknap, Association of asbestos and peritoneal
Smither mesothelioma
1965 Selikoff New York Academy of Science Symposium,
report on U.S. insulators
1969 Wagner Animal model further perfected
1972 Stanton, Wrench Stanton hypothesis on the importance of fiber
size/length
the epithelial nature of these pleural cells. In 1843, von Rokitansky (5) actively opposed the idea of primary cancer of the pleura, and stated that pleural cancer always was secondary to a primary focus elsewhere.
Ironically von Rokitansky in 1854 described what were called primary tumors of the peritoneum, which he called “colloid cancer” and most likely were peritoneal mesotheliomas. This strong opinion on the metastatic origin of pleural mesotheliomas by the German pathologists
was to remain the opinion of many pathologists up through the mid-20th century as stated by Willis (6). There were further reports in the early 19th century of what could be considered pleural-based cancers.
It was Wagner in 1870 who first described a lesion, which he classified as “Das Tuberkelähnliche Lymphadenom.” He felt this was a primary malignancy of the pleura in a 69-year-old woman in whom an epithelial-based malignancy was found. Wagner had described lymph channels filled with tumor. Schultz (7) in 1875 reexamined the prepa-rations of Wagner and emphasized the neoplastic nature of the process and renamed it endothelial cancer. The tumor was thought to arise from the lymph vessels and was commonly called an endothelioma.
This was not questioned until 1891, when Engelbach (8) first raised the question of whether these tumors arose from the endothelium of the lymph vessels or from the surrounding serosal surfaces.
was to remain the opinion of many pathologists up through the mid-20th century as stated by Willis (6). There were further reports in the early 19th century of what could be considered pleural-based cancers.
It was Wagner in 1870 who first described a lesion, which he classified as “Das Tuberkelähnliche Lymphadenom.” He felt this was a primary malignancy of the pleura in a 69-year-old woman in whom an epithelial-based malignancy was found. Wagner had described lymph channels filled with tumor. Schultz (7) in 1875 reexamined the prepa-rations of Wagner and emphasized the neoplastic nature of the process and renamed it endothelial cancer. The tumor was thought to arise from the lymph vessels and was commonly called an endothelioma.
This was not questioned until 1891, when Engelbach (8) first raised the question of whether these tumors arose from the endothelium of the lymph vessels or from the surrounding serosal surfaces.
During the late 19th century and early 20th century, there was general acceptance that some sarcomas arose from the pleura when there was no evidence of a primary elsewhere, and it was generally accepted that the only tumor that might be primary to the pleura or the subpleura was a primary sarcoma. This was generally the Italian view as summarized by De Renzi (9). In 1890 Biggs (10) was the first American to report two cases of “endothelioma of the pleura” at the
New York Pathological Society. Primary fibrous sarcomas of the pleura were generally accepted as arising from the fibroblast but not the pleural tissue itself. The fact that the pleural lining was capable of pro-ducing tumors that were both epithelial and of connective tissue origin
was first pointed out by Paltauf (11), Borst (12), and Kaufmann (13). By 1909 Patterson (14) found 96 cases in the literature and added two of his own. The disease occurred twice as frequently in men than inwomen, and the greatest number of cases was found in patients
between the ages of 40 and 60 years.
New York Pathological Society. Primary fibrous sarcomas of the pleura were generally accepted as arising from the fibroblast but not the pleural tissue itself. The fact that the pleural lining was capable of pro-ducing tumors that were both epithelial and of connective tissue origin
was first pointed out by Paltauf (11), Borst (12), and Kaufmann (13). By 1909 Patterson (14) found 96 cases in the literature and added two of his own. The disease occurred twice as frequently in men than inwomen, and the greatest number of cases was found in patients
between the ages of 40 and 60 years.
Histologic Controversy, 1900 to 1942 Miller and Wynn (15) were the first to advance the opinion that a peri-toneal neoplasm was able to present both epithelial and fibroblastic characteristics because of the embryologic relationship of these cells to the mesoderm. Later, Maximow (16) was able to demonstrate via tissue culture direct transitions from the mesothelioma cell to fibroblast.
In 1924 Robertson’s (3) article on endothelioma of the pleura was probably the most thorough review of the literature that had been done up until that time. At the time of that publication, endotheliomas or primary pleural malignancies were certainly rare, in that Clarkson (17)
in 1914 stated that out of 10,829 postmortem exams performed in Munich, Germany, there were only two cases of primary endothelioma of the pleura, although he could find records of only 41 cases. Later, Robertson quotes Keilty (18), who reviewed the records of the pathol-
ogy department at the University of Pennsylvania and found nine cases of primary endothelioma of the pleura in 5000 postmortem examinations.
In 1924 Robertson’s (3) article on endothelioma of the pleura was probably the most thorough review of the literature that had been done up until that time. At the time of that publication, endotheliomas or primary pleural malignancies were certainly rare, in that Clarkson (17)
in 1914 stated that out of 10,829 postmortem exams performed in Munich, Germany, there were only two cases of primary endothelioma of the pleura, although he could find records of only 41 cases. Later, Robertson quotes Keilty (18), who reviewed the records of the pathol-
ogy department at the University of Pennsylvania and found nine cases of primary endothelioma of the pleura in 5000 postmortem examinations.
Bayne-Jones (19) described a 16-year-old boy with a pleural-based malignancy that Bayne-Jones thought was a primary neoplasm of the lining cells of the pleura and an epithelial tumor, which he described as a carcinoma of the pleura. Bayne-Jones thought this tumor was not an endothelioma or it did not arise from the endothelium of the lym-phatics but from the mesothelial cells and therefore was an epithelial carcinoma. In 1920 Du Bray and Rosson (20) proposed the term primary mesothelioma of the pleura. They thought the term pleural carcinoma or endothelioma was not appropriate, but that the term mesothelioma was
most appropriate. In 1921 Eastwood and Martin (21) agreed that the term should be mesothelioma. Zeckwer (22) also used the term mesothelioma in his report of 1928. The issue as to whether there was such athing as a primary endothelial malignancy arising from the pleura wascarefully discussed by Robertson (3) in his seminal paper, and he rejected the idea that the epithelial tumors were primary tumors of the mesothelium; he thought that these tumors were most likely metasta-tic tumors of some other origin. He thought that only sarcomas could
be classified as primary malignant tumors, and that all other types of growth were secondary tumors with implementations or metastasis from unrecognized, latent primary malignancies elsewhere. In 1931 Paul Klemperer and Coleman Rabin (23) published a report
of five cases from Mt. Sinai Hospital in New York City, including one case with both epithelial and mesenchymal characteristics. They thought that diffuse neoplasms of the pleura arose from the surface lining cells, the mesothelium, and should be designated mesothelioma as previously suggested by others.
most appropriate. In 1921 Eastwood and Martin (21) agreed that the term should be mesothelioma. Zeckwer (22) also used the term mesothelioma in his report of 1928. The issue as to whether there was such athing as a primary endothelial malignancy arising from the pleura wascarefully discussed by Robertson (3) in his seminal paper, and he rejected the idea that the epithelial tumors were primary tumors of the mesothelium; he thought that these tumors were most likely metasta-tic tumors of some other origin. He thought that only sarcomas could
be classified as primary malignant tumors, and that all other types of growth were secondary tumors with implementations or metastasis from unrecognized, latent primary malignancies elsewhere. In 1931 Paul Klemperer and Coleman Rabin (23) published a report
of five cases from Mt. Sinai Hospital in New York City, including one case with both epithelial and mesenchymal characteristics. They thought that diffuse neoplasms of the pleura arose from the surface lining cells, the mesothelium, and should be designated mesothelioma as previously suggested by others.
In 1933 S. Roodhouse Gloyne (24) reviewed his series of asbestosis cases and stated, “Of the complications unrelated to the asbestosis the following have been noted: (a) abdominal carcinoma; (b) mitral steno-sis; (c) cerebral hemorrhage, and (d) cholelithiasis. There has been one case of squamous carcinoma of the pleura. There is no evidence at the moment that this was in any way related to asbestosis.” It is open to speculation as to whether these were the earliest cases of mesothe-liomas in asbestos-exposed workers! Ewing (25) in 1940 raised the question of the influence of chronic irri-tation or trauma and low grades of inflammation in causing connec-tive tissue changes in the pleura, and wondered if some of the cases of
pleural malignancy were connected with tuberculosis. Many of the previously reported cases had evidence of coexistent tuberculosis, in several attacks of pleurisy on the involved side. The trauma and chronic inflammation as a cause of pleural transformation were reviewed by Ewing (25). Ewing’s comments were amplified by an excellent review of the literature by Andrea Saccone and Aaron Coblenz (26) from New York City in 1943. The authors were able to
identify 41 cases in seven published series between 1910 and 1938 from a total of 46,000 autopsies or 0.09% mesotheliomas. They concluded from their review of the case reports that some of these tumors were misdiagnosed and were metastatic from other sites. Certainly the con-fusion in making the pathologic diagnosis would continue for many years. From 1960 to 1968 only one half of Canadian mesothelioma cases on death certificates could be confirmed by an expert panel (27).
pleural malignancy were connected with tuberculosis. Many of the previously reported cases had evidence of coexistent tuberculosis, in several attacks of pleurisy on the involved side. The trauma and chronic inflammation as a cause of pleural transformation were reviewed by Ewing (25). Ewing’s comments were amplified by an excellent review of the literature by Andrea Saccone and Aaron Coblenz (26) from New York City in 1943. The authors were able to
identify 41 cases in seven published series between 1910 and 1938 from a total of 46,000 autopsies or 0.09% mesotheliomas. They concluded from their review of the case reports that some of these tumors were misdiagnosed and were metastatic from other sites. Certainly the con-fusion in making the pathologic diagnosis would continue for many years. From 1960 to 1968 only one half of Canadian mesothelioma cases on death certificates could be confirmed by an expert panel (27).
Further support for the idea that these tumors arose from the mesothelium rather than from the endothelium was provided by Stout and Murray (28) of New York City in 1942. They used their studies on tissue cultures to support the idea that malignant cells arose primarily from the mesothelial cell. Their concept of histogenesis was so contro-versial at that time that their Department of Pathology chairman required them to publish a statement of his disbelief in their paper.
Stout was later to become professor of pathology at Columbia Univer-sity in New York City. He was able to accumulate pathologic material on 156 mesotheliomas between July 1919 and June 1964. This was the largest series from a single institution in the world as of 1964 and yet
Stout (29) later commented that in retrospect he was unaware of a single case associated with asbestosis.
Stout was later to become professor of pathology at Columbia Univer-sity in New York City. He was able to accumulate pathologic material on 156 mesotheliomas between July 1919 and June 1964. This was the largest series from a single institution in the world as of 1964 and yet
Stout (29) later commented that in retrospect he was unaware of a single case associated with asbestosis.
Further support for Stout’s theory of histogenesis came from Canada in a paper by Postoloff (30) entitled “Mesothelioma of the Pleura,” in which he concluded that, indeed, the mesothelioma is capable of trans-forming into both an epithelioid malignancy and a sarcomatous malig-nancy. He emphasized the importance of an osteoid matrix in the histologic features of mesothelioma. He also mentioned that his team found only seven mesotheliomas out of 7878 consecutive autopsies covering a 20-year period between 1923 and 1942.
By 1946 Arnold Piatt (31), a radiologist at the Newark Hospital, reviewed the radiologic aspects of primary mesothelioma or endothe-lioma of the pleura. By then over 200 authors had discussed and offered opinions on the entity, which at that time was called primary mesothe-
lioma or endothelioma of the pleura. Piatt points out that it was a very difficult diagnostic problem for pathologists, who argued among themselves as to the type and histologic origin of the neoplasm. By then there were as many as 30 different terms used to describe this
clinical entity, including endothelioma, mesothelioma, endothelial carci-noma, pleural carcinoma, primary papillary endothelioma of the pleura, adenoendothelioma, sarcoendothelioma, pleural sarcoma, round cell sarcoma, spindle cell sarcoma, angiosarcoma, lipomyxosarcoma, giant cell sarcoma of the visceral pleura, sarcomatous malignancy of the pleura, malignant tumor of the pleura, mesothelial carcinoma, perithelioma, endothelioma, carcinoma-todes, lymphangioendothelioma, fibroendotheliosis of the pleura, lymphangitis
proliferans, pleuroma, abdominal colloid tumor, and tubercle-like lymphadenoma (32).
lioma or endothelioma of the pleura. Piatt points out that it was a very difficult diagnostic problem for pathologists, who argued among themselves as to the type and histologic origin of the neoplasm. By then there were as many as 30 different terms used to describe this
clinical entity, including endothelioma, mesothelioma, endothelial carci-noma, pleural carcinoma, primary papillary endothelioma of the pleura, adenoendothelioma, sarcoendothelioma, pleural sarcoma, round cell sarcoma, spindle cell sarcoma, angiosarcoma, lipomyxosarcoma, giant cell sarcoma of the visceral pleura, sarcomatous malignancy of the pleura, malignant tumor of the pleura, mesothelial carcinoma, perithelioma, endothelioma, carcinoma-todes, lymphangioendothelioma, fibroendotheliosis of the pleura, lymphangitis
proliferans, pleuroma, abdominal colloid tumor, and tubercle-like lymphadenoma (32).
Definition and Suspicion, 1943 to 1960
In the confusion about whether mesothelioma was truly a separate clinical entity, there were five different opinions as to the source of the tumor: (1) an aberrant nest of lung epithelium became malignant within the lining of the pleura; (2) the endothelial lining of the subpleural lymphatics was the source of the tumor, hence the name endothelioma; (3) the tumor arose from the pleural capillary endothe-lium or endothelial lining of the subpleural lymphatics, or both; (4) the
tumor arose from the mesothelial lining of the pleura itself, or was a mesothelial-derived tumor or a mesothelioma; (5) those tumors of epithelial origin always arose from a primary tumor elsewhere that had metastasized to the pleura. These primary tumors could be so small
that they were easily missed on a routine autopsy. A sarcoma was a primary from the subpleural connective tissue. It is because of the dif-ferences in opinion about the origin of the tumor that there was such a large number of terms used to describe the same process.
In the confusion about whether mesothelioma was truly a separate clinical entity, there were five different opinions as to the source of the tumor: (1) an aberrant nest of lung epithelium became malignant within the lining of the pleura; (2) the endothelial lining of the subpleural lymphatics was the source of the tumor, hence the name endothelioma; (3) the tumor arose from the pleural capillary endothe-lium or endothelial lining of the subpleural lymphatics, or both; (4) the
tumor arose from the mesothelial lining of the pleura itself, or was a mesothelial-derived tumor or a mesothelioma; (5) those tumors of epithelial origin always arose from a primary tumor elsewhere that had metastasized to the pleura. These primary tumors could be so small
that they were easily missed on a routine autopsy. A sarcoma was a primary from the subpleural connective tissue. It is because of the dif-ferences in opinion about the origin of the tumor that there was such a large number of terms used to describe the same process.
In this setting of confusion, early reports began to filter out that some patients with asbestosis developed an unusual form of pleural malig-nancy. The first report was by Wedler (33), who reported the results of 30 autopsies on asbestos workers in Germany. He excluded one case,
and of the 29 remaining autopsies, four had bronchial cancers, and two others had a malignant pleural growth. He commented about his own
and of the 29 remaining autopsies, four had bronchial cancers, and two others had a malignant pleural growth. He commented about his own
impression that the incidence of cancer, which was 20% for malignant tumors in this population, was much too high to be by chance, and that the lung cancer was due to the asbestos exposure. He reviewed all the known studies at that time, and pointed out that the first mention of a
lung cancer associated with asbestosis was made in 1933 by Gloyne (34), who stated, “There has also been one case of squamous cancer of the pleura. There is no evidence at the moment this was in any way related to asbestosis.” In 1935 Gloyne (35) was able to report two addi-
tional patients with lung cancer and asbestosis. Wedler did not discuss whether the pleural cancers he found were true mesotheliomas or were related to an underlying lung cancer; he simply reported these findings and called them pleural growths of epithelial origin. He stated that
lung cancer was the most common complication encountered in cases of asbestosis.
lung cancer associated with asbestosis was made in 1933 by Gloyne (34), who stated, “There has also been one case of squamous cancer of the pleura. There is no evidence at the moment this was in any way related to asbestosis.” In 1935 Gloyne (35) was able to report two addi-
tional patients with lung cancer and asbestosis. Wedler did not discuss whether the pleural cancers he found were true mesotheliomas or were related to an underlying lung cancer; he simply reported these findings and called them pleural growths of epithelial origin. He stated that
lung cancer was the most common complication encountered in cases of asbestosis.
While the report of Wedler was readily accepted in Germany, the information was generally ignored elsewhere. In retrospect, Harrington (36) stated, “Of particular interest is the apparent influence of politics, given that the earliest published accounts emanated from Nazi Germany, thus received less attention and credence than was their due. Furthermore, there was the skepticism—presumably natural rather than biased—on the part of many early scientific observers in both the United States and Britain.” In 1947 a patient with a mesothelioma of the pleura and pericardium who worked with asbestos cutting insulation board was reported as chronic pulmonary congestion (CPC)by the Massachusetts General Hospital, but the association with the asbestos exposure was not made (37). In 1952 Cartier (38) reported in
a scientific meeting via an abstract of a discussion of a paper by W.E. Smith seven cases of respiratory cancer in 4000 asbestos workers working in the Quebec chrysotile mining and milling industry, and included in the cohort were two cases of pleural mesothelioma. Cartier
thought that since the two mesothelioma cases did not have asbesto-sis, causation from asbestos exposure could not be made. The detailsof these cases were never published.
a scientific meeting via an abstract of a discussion of a paper by W.E. Smith seven cases of respiratory cancer in 4000 asbestos workers working in the Quebec chrysotile mining and milling industry, and included in the cohort were two cases of pleural mesothelioma. Cartier
thought that since the two mesothelioma cases did not have asbesto-sis, causation from asbestos exposure could not be made. The detailsof these cases were never published.
A year later, in 1953, Weiss (39) added a third case to the two malig-nant tumors of the pleura described by Wedler, that of a man with asbestosis and pleural mesothelioma who had done insulation work in a naval dockyard from 1920 until 1935. Weiss believed that the associ-
ation between asbestosis and pleural mesothelioma was strong, and therefore he recommended that the German government accept this as a work-related condition. Von Rokitansky (40) in 1854 described what were called primary tumors of the peritoneum, which he called “colloid cancer.” While this tumor was mentioned in the English liter-
ature, first by Miller and Wynn (15) in 1908, the association between peritoneal tumors and possible asbestos exposure was not made until 1954 when another German, Leichner (41), described an autopsy done 2 years earlier on a 53-year-old man who worked in an asbestos factory primarily as a spinner. Leichner reported that the patient had asbesto-sis and tuberculosis, but had what appeared to be an incidental finding of a peritoneal mesothelioma. Leichner found evidence of asbestos fibers in the tumor, and felt that this peritoneal mesothelioma was again work related. Ashort time later, in 1955, Bonser et al (42) reported
72 autopsies of patients with asbestosis in which four were found to have abdominal neoplasms consistent with a peritoneal mesothelioma, but the authors never made the association that these were asbestos-induced peritoneal mesotheliomas.
ation between asbestosis and pleural mesothelioma was strong, and therefore he recommended that the German government accept this as a work-related condition. Von Rokitansky (40) in 1854 described what were called primary tumors of the peritoneum, which he called “colloid cancer.” While this tumor was mentioned in the English liter-
ature, first by Miller and Wynn (15) in 1908, the association between peritoneal tumors and possible asbestos exposure was not made until 1954 when another German, Leichner (41), described an autopsy done 2 years earlier on a 53-year-old man who worked in an asbestos factory primarily as a spinner. Leichner reported that the patient had asbesto-sis and tuberculosis, but had what appeared to be an incidental finding of a peritoneal mesothelioma. Leichner found evidence of asbestos fibers in the tumor, and felt that this peritoneal mesothelioma was again work related. Ashort time later, in 1955, Bonser et al (42) reported
72 autopsies of patients with asbestosis in which four were found to have abdominal neoplasms consistent with a peritoneal mesothelioma, but the authors never made the association that these were asbestos-induced peritoneal mesotheliomas.
In 1956 Ackerman (43) wrote that it was the majority opinion that primary mesotheliomas were rare but do exist. A year later, in 1957, Godwin (44) wrote a very important paper that laid down strict diag-nostic criteria for the diagnosis of pleural mesotheliomas. In 1958 Van
der Schoot (45) reported two mesotheliomas in insulation workers.
In 1958 McCaughey (46) from Belfast, Ireland, reported 11 diffuse and two localized pleural mesotheliomas. He felt there was strong evi-dence to support the belief that diffuse pleural mesothelioma was a clinical entity in spite of opposition to this idea. He did not make the
association in this study to asbestos exposure, but he would do so in retrospect a few years later (47). This paper was a response to an article published by Smart and Hinson (48) of the London Chest Hospital who reported 24 cases of pleural neoplasm and concluded that the occur-rence of a true neoplasm of pleura could not really be denied, that the lesion is produced from known primaries, and that there was no need to postulate an origin from that site (49). In 1956 Eisenstadt (50) of Port Arthur, Texas, reported a patient who worked in a refinery who devel-oped what appeared to be a malignant mesothelioma of the pleura. He pointed out that very experienced pathologists denied the existence of such a tumor, but he felt impelled to report the case anyway.
der Schoot (45) reported two mesotheliomas in insulation workers.
In 1958 McCaughey (46) from Belfast, Ireland, reported 11 diffuse and two localized pleural mesotheliomas. He felt there was strong evi-dence to support the belief that diffuse pleural mesothelioma was a clinical entity in spite of opposition to this idea. He did not make the
association in this study to asbestos exposure, but he would do so in retrospect a few years later (47). This paper was a response to an article published by Smart and Hinson (48) of the London Chest Hospital who reported 24 cases of pleural neoplasm and concluded that the occur-rence of a true neoplasm of pleura could not really be denied, that the lesion is produced from known primaries, and that there was no need to postulate an origin from that site (49). In 1956 Eisenstadt (50) of Port Arthur, Texas, reported a patient who worked in a refinery who devel-oped what appeared to be a malignant mesothelioma of the pleura. He pointed out that very experienced pathologists denied the existence of such a tumor, but he felt impelled to report the case anyway.
A good example of the confusion about what to do with the diag-nosis of mesothelioma is the discussion of the condition by Sir Richard Doll (51) in his classic 1955 study of the association between lung cancer and asbestosis. In Table II of the article he describes 15 patients
with asbestosis and some type of lung cancer, but only uses 11 of the 15 in his analysis. Two of the patients are recorded as having either an endothelioma of the pleura or epithelial carcinoma. Three additional patients with lung cancer were found, but they did not have asbesto-sis. The association between the asbestos exposure and the endothe-lioma of the pleura was not made, and, evidently, was excluded from this statistical analysis.
with asbestosis and some type of lung cancer, but only uses 11 of the 15 in his analysis. Two of the patients are recorded as having either an endothelioma of the pleura or epithelial carcinoma. Three additional patients with lung cancer were found, but they did not have asbesto-sis. The association between the asbestos exposure and the endothe-lioma of the pleura was not made, and, evidently, was excluded from this statistical analysis.
The seminal year for making the association between asbestos expo-sure and mesothelioma is 1960. The seminal paper is that by Wagner et al (52), entitled “Diffuse Pleural Mesothelioma and Asbestos Expo-sure in the Northwestern Cape Providence.” The paper was very con-
troversial because it described 33 cases of diffuse pleural mesothelioma
with exposure to only one type of asbestos, so-called Cape Blue asbestos mined in the asbestos hills west of Kimberly in the northwest Cape Providence of South Africa. Wagner et al said the tumor was rarely seen elsewhere in South Africa. This means the tumor seemed
to be rather specific to a certain geographic area and a specific type of crocidolite asbestos. The data were considered suspect by many pathol-ogists, in that only four of the patients had full autopsies, the rest having had simple pleural biopsies that were recognized by many as
being unreliable in making the diagnosis of mesothelioma. The other problem was that previously reported patients had heavy industrial exposure and usually asbestosis, and the majority of Wagner et al’s cohort did not have asbestosis or heavy industrial exposure. The
general consensus at that time was that a true mesothelioma diagnosis could not be made unless there was a complete autopsy excluding some primary tumor elsewhere in the body that had metastasized to the pleura and unless there also was concomitant asbestosis. The initial
response was muted, as so eloquently stated by Elliott McCaughey (53) because of “the lack of experimental animal evidence, rejection or lack of knowledge of science conducted outside of the United States, and reluctance of individual writers to change their minds.” In an editorial
written in South Africa in 1968, the relationship between crocidolite exposure and mesothelioma was still thought to be unproven (54).
troversial because it described 33 cases of diffuse pleural mesothelioma
with exposure to only one type of asbestos, so-called Cape Blue asbestos mined in the asbestos hills west of Kimberly in the northwest Cape Providence of South Africa. Wagner et al said the tumor was rarely seen elsewhere in South Africa. This means the tumor seemed
to be rather specific to a certain geographic area and a specific type of crocidolite asbestos. The data were considered suspect by many pathol-ogists, in that only four of the patients had full autopsies, the rest having had simple pleural biopsies that were recognized by many as
being unreliable in making the diagnosis of mesothelioma. The other problem was that previously reported patients had heavy industrial exposure and usually asbestosis, and the majority of Wagner et al’s cohort did not have asbestosis or heavy industrial exposure. The
general consensus at that time was that a true mesothelioma diagnosis could not be made unless there was a complete autopsy excluding some primary tumor elsewhere in the body that had metastasized to the pleura and unless there also was concomitant asbestosis. The initial
response was muted, as so eloquently stated by Elliott McCaughey (53) because of “the lack of experimental animal evidence, rejection or lack of knowledge of science conducted outside of the United States, and reluctance of individual writers to change their minds.” In an editorial
written in South Africa in 1968, the relationship between crocidolite exposure and mesothelioma was still thought to be unproven (54).
In 1960 Eisenstadt and Wilson (55) published a paper describing two patients with pleural mesothelioma. The second patient had a long-term history of exposure to asbestos, and there were asbestos bodies in the lung biopsy specimen. The authors felt there was an association
between the asbestos exposure and the subsequent development of this unusual pleural malignancy.
between the asbestos exposure and the subsequent development of this unusual pleural malignancy.
Association and Causation, 1960 to 1973
Also in 1960 Keal (56) reviewed the records of an English hospital and found 23 women with asbestosis. Four had carcinomatosis of the peri-toneum without a known primary, one had ovarian cancer, and four others had peritoneal malignancy possibly of ovarian origin. The asso-
ciation with asbestosis is glaring, but the connection between asbestos exposure and peritoneal malignancy was not strongly suggested until 4 years later. Winslow and Taylor (57) published a series of 12 cases of peritoneal mesothelioma in 1960 and reviewed 13 previously reported
cases found in the world literature. No association with asbestos expo-sure was mentioned in their paper. However, the association between asbestos exposure and diffuse abdominal tumors was established in the English literature by the paper of Enticknap and Smither (58) in 1964.
Here again, the Germans made the association between asbestos exposure and this rare tumor earlier than other investigators. While attempts to define the tumor mesothelioma were made by earlier investigators such as Klemperer and Rabin (23) in 1931, there was no general agreement among pathologists that such an entity really existed. In 1957 Godwin (44) published strict criteria for the diagnosis of pleural mesotheliomas that placed the pathologic identification on a more firm scientific footing. It was not until 1960 that Winslow and Taylor did the same thing for peritoneal mesothelioma tumors. AfterWagner’s discovery of the association between Cape Blue crocidolite asbestos and the increased risk of mesothelioma in South Africa, the question arose as to whether this was a unique problem limited to South Africa or whether this was a problem occurring in the United States. The American Medical Association Council on Occupational Health (59) published an article on Pneumoconioses in the Archives of Environmental Health in 1963, in which there is a section on asbestosis.
The panel of experts concluded:
ciation with asbestosis is glaring, but the connection between asbestos exposure and peritoneal malignancy was not strongly suggested until 4 years later. Winslow and Taylor (57) published a series of 12 cases of peritoneal mesothelioma in 1960 and reviewed 13 previously reported
cases found in the world literature. No association with asbestos expo-sure was mentioned in their paper. However, the association between asbestos exposure and diffuse abdominal tumors was established in the English literature by the paper of Enticknap and Smither (58) in 1964.
Here again, the Germans made the association between asbestos exposure and this rare tumor earlier than other investigators. While attempts to define the tumor mesothelioma were made by earlier investigators such as Klemperer and Rabin (23) in 1931, there was no general agreement among pathologists that such an entity really existed. In 1957 Godwin (44) published strict criteria for the diagnosis of pleural mesotheliomas that placed the pathologic identification on a more firm scientific footing. It was not until 1960 that Winslow and Taylor did the same thing for peritoneal mesothelioma tumors. AfterWagner’s discovery of the association between Cape Blue crocidolite asbestos and the increased risk of mesothelioma in South Africa, the question arose as to whether this was a unique problem limited to South Africa or whether this was a problem occurring in the United States. The American Medical Association Council on Occupational Health (59) published an article on Pneumoconioses in the Archives of Environmental Health in 1963, in which there is a section on asbestosis.
The panel of experts concluded:
The relationship between cancer of the lung and asbestosis constitutes a problem of great current interest. There is no doubt that the two diseases appear in the same lung. Whether that occurrence is one of mere coincidence, or of direct cause–effect, the relationship cannot be resolved on the basis of a single case. The total body of evidence favors a relationship, especially as it involves certain kinds of asbestos and possibly only those that contain specific
chemical substances have the capacity to cause cancer. Attention is invited toexperiences in the union of South Africa where pleural mesotheliomas have been discovered in appreciable numbers of persons exposed to the inhalation of crocidolite-amosite asbestos. Certainly detailed epidemiologic clinical and experimental studies are required for the ultimate resolution of the problem. [p. 37]
chemical substances have the capacity to cause cancer. Attention is invited toexperiences in the union of South Africa where pleural mesotheliomas have been discovered in appreciable numbers of persons exposed to the inhalation of crocidolite-amosite asbestos. Certainly detailed epidemiologic clinical and experimental studies are required for the ultimate resolution of the problem. [p. 37]
In 1962 Wagner (60) was able to produce mesothelial tumors of the pleura by direct implantation of asbestos dusts in laboratory animals. In 1963 Wagner reported at the 14th International Congress of Occu-pational Health on 120 cases of mesothelioma, but curiously less than one half of the patients directly worked with asbestos; they just lived in the area where there was environmental exposure. The question at that time was whether this was a localized group of mesothelioma patients or the forerunner of an international epidemic. This question
was answered at the International Meeting on Biological Effects of Asbestos held at the New York Academy of Sciences in New York City in October 1964 but not published until December 31, 1965 (61). Reports at the New York meeting from Newhouse and Thompson in
London, Elmes and Wade in Ireland, Jacob and Anspach in Germany, Hammond, Selikoff, and Churg in the United States, and Viliani and coworkers in Italy confirmed the global extent of the problem.
was answered at the International Meeting on Biological Effects of Asbestos held at the New York Academy of Sciences in New York City in October 1964 but not published until December 31, 1965 (61). Reports at the New York meeting from Newhouse and Thompson in
London, Elmes and Wade in Ireland, Jacob and Anspach in Germany, Hammond, Selikoff, and Churg in the United States, and Viliani and coworkers in Italy confirmed the global extent of the problem.
Selikoff et al (62) reported their working experience with the relationship between asbestos exposure and mesothelioma in the New England Journal of Medicine in 1965, further cementing the relationship between asbestos exposure and mesothelioma and raising the question
of whether others types of asbestos might also cause mesotheliomas. The authors did not believe that American workers had significant exposure to crocidolite. They thought that the emergence of mesotheliomas in their cohort of asbestos insulators represented mainly expo-
sure to chrysotile and amosite. All patients had heavy exposure and asbestosis. This article was followed by an editorial in the New England Journal of Medicine on March 18, 1965 (63). The editorial mentions that amosite, the third commercially used form of asbestos, has yet to be
incriminated, but there are no definitive studies to date to confirm or deny such a connection.
Sluis-Cremer (64) of the Miner’s Medical Bureau in Johannesburg, South Africa, gave a report to the New York Academy of Science in 1965. Sluis-Cremer in his discussion of mesotheliomas pointed out that his epidemiologic studies found mesotheliomas only in the northwest
cape area of South Africa. The Transvaal amosite deposits had been actively developed for longer than this period, and he mentioned that in the 1940s amosite was produced in three times the amount of the northwest crocidolite, yet no mesotheliomas were seen in the north-
west area related to amosite exposure.
Of particular interest was the case control study of Newhouse and Thompson (65). They diagnosed 83 patients, 41 men and 43 women, with mesothelioma in association with a Cape Blue asbestos factory that opened in London in 1913. There were 27 peritoneal tumors and
56 pleural tumors. The factory used Cape crocidolite exclusively until 1926, when small amounts of amosite and chrysotile were added. Eigh-teen patients were employed in the asbestos factory and eight as insu-lators and laggers. An additional nine patients lived in the same house
as an asbestos worker. Particularly distressing was the discovery of 36 patients with no known work or domestic exposure to asbestos. Eleven of these patients lived within one-half mile of the asbestos factory, suggesting neighborhood exposure. This case-control study and one
by Elmes et al (66) were the first two case-control studies to confirm the earlier report of Wagner from South Africa. The concern about neighborhood exposure was echoed by Lieben and Pistawka (67) of the Pennsylvania Health Department, who reported that of 42
patients with mesothelioma only 20 had occupational exposure, eight lived within the vicinity of an asbestos plant, and three had family exposure.
of whether others types of asbestos might also cause mesotheliomas. The authors did not believe that American workers had significant exposure to crocidolite. They thought that the emergence of mesotheliomas in their cohort of asbestos insulators represented mainly expo-
sure to chrysotile and amosite. All patients had heavy exposure and asbestosis. This article was followed by an editorial in the New England Journal of Medicine on March 18, 1965 (63). The editorial mentions that amosite, the third commercially used form of asbestos, has yet to be
incriminated, but there are no definitive studies to date to confirm or deny such a connection.
Sluis-Cremer (64) of the Miner’s Medical Bureau in Johannesburg, South Africa, gave a report to the New York Academy of Science in 1965. Sluis-Cremer in his discussion of mesotheliomas pointed out that his epidemiologic studies found mesotheliomas only in the northwest
cape area of South Africa. The Transvaal amosite deposits had been actively developed for longer than this period, and he mentioned that in the 1940s amosite was produced in three times the amount of the northwest crocidolite, yet no mesotheliomas were seen in the north-
west area related to amosite exposure.
Of particular interest was the case control study of Newhouse and Thompson (65). They diagnosed 83 patients, 41 men and 43 women, with mesothelioma in association with a Cape Blue asbestos factory that opened in London in 1913. There were 27 peritoneal tumors and
56 pleural tumors. The factory used Cape crocidolite exclusively until 1926, when small amounts of amosite and chrysotile were added. Eigh-teen patients were employed in the asbestos factory and eight as insu-lators and laggers. An additional nine patients lived in the same house
as an asbestos worker. Particularly distressing was the discovery of 36 patients with no known work or domestic exposure to asbestos. Eleven of these patients lived within one-half mile of the asbestos factory, suggesting neighborhood exposure. This case-control study and one
by Elmes et al (66) were the first two case-control studies to confirm the earlier report of Wagner from South Africa. The concern about neighborhood exposure was echoed by Lieben and Pistawka (67) of the Pennsylvania Health Department, who reported that of 42
patients with mesothelioma only 20 had occupational exposure, eight lived within the vicinity of an asbestos plant, and three had family exposure.
The general medical community had believed that if asbestosis could be avoided by reducing exposure to friable asbestos, then asbestos-related malignancy would also be avoided. The early mesothelioma cases were generally heavily exposed in the early 1900s prior to the
promulgation of dust control measures. Selikoff (68) stated in 1969, “I have yet to see a mesothelioma in a man who began work after 1930 or a case of lung cancer in an asbestos worker who had worked in that industry less than twenty years.” However, the data of Wagner, New-house and Thompson, Lieben, and others challenged this. Thompson
(69,70) reported in 1963 asbestos bodies in the lungs of people who were not asbestos workers and called it a modern urban hazard.
promulgation of dust control measures. Selikoff (68) stated in 1969, “I have yet to see a mesothelioma in a man who began work after 1930 or a case of lung cancer in an asbestos worker who had worked in that industry less than twenty years.” However, the data of Wagner, New-house and Thompson, Lieben, and others challenged this. Thompson
(69,70) reported in 1963 asbestos bodies in the lungs of people who were not asbestos workers and called it a modern urban hazard.
In 1968 Utidjian et al (71) reported that almost 100% of urban dwellers had asbestos bodies in their lungs. By 1970 Thompson’s orig-inal observations were widely confirmed in Montreal, Milan, London, Newcastle, Glasgow, Belfast, Dresden, Pittsburgh, Miami, and New York (68). A paradigm shift had occurred; by 1970 it was generally accepted that low-level exposure to northwest Cape Blue crocidolite was capable of causing mesothelioma. By 1966 the importation of cro-cidolite asbestos had been voluntarily abandoned in England, and new
asbestos regulations accepting the relationship between asbestos and mesothelioma were adopted in 1969. The standard for asbestos exposure in England was set at 0.2 f/mL (F is the degree of fineness of abrasive particles) for crocidolite or one-tenth the acceptable level of
exposure to other forms of commercial asbestos at 2 f/mL (72). The question remained how much exposure was too much. The next 30 years would be focused on the role of other types of commercial asbestos and noncommercial asbestiform materials. Wagner and Berry (73) by 1969 had perfected an animal model that would help answer many of these questions. Stanton and Wrench (74) had demonstrated in 1972 that the carcinogenic potential of asbestos was related to its diameter and length.
In 1965 Sir Bradford Hill (75) proposed criteria for assessing causa-tion in chronic diseases. His seminal paper presented at the Royal Society of Medicine provided a systematic approach to evaluate the association between asbestos exposure and mesothelioma. The main
requirements were strength of association, consistency of association, dose-response relationship, and biologic plausibility. The acceptance of new ideas moves slowly. Biologic plausibility of carcinogenesis is meant primarily to be based on animal and cell tissue modeling or by analogy to other human tumors. Unfortunately, biologic plausibility for many in the 1960s and early 1970s meant that if I can’t understand it, I don’t believe it.
asbestos regulations accepting the relationship between asbestos and mesothelioma were adopted in 1969. The standard for asbestos exposure in England was set at 0.2 f/mL (F is the degree of fineness of abrasive particles) for crocidolite or one-tenth the acceptable level of
exposure to other forms of commercial asbestos at 2 f/mL (72). The question remained how much exposure was too much. The next 30 years would be focused on the role of other types of commercial asbestos and noncommercial asbestiform materials. Wagner and Berry (73) by 1969 had perfected an animal model that would help answer many of these questions. Stanton and Wrench (74) had demonstrated in 1972 that the carcinogenic potential of asbestos was related to its diameter and length.
In 1965 Sir Bradford Hill (75) proposed criteria for assessing causa-tion in chronic diseases. His seminal paper presented at the Royal Society of Medicine provided a systematic approach to evaluate the association between asbestos exposure and mesothelioma. The main
requirements were strength of association, consistency of association, dose-response relationship, and biologic plausibility. The acceptance of new ideas moves slowly. Biologic plausibility of carcinogenesis is meant primarily to be based on animal and cell tissue modeling or by analogy to other human tumors. Unfortunately, biologic plausibility for many in the 1960s and early 1970s meant that if I can’t understand it, I don’t believe it.
The History of Mesothelioma .. Dorsett D. Smith
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