Histologic Controversy, 1900 to 1942

Miller and Wynn (15) were the first to advance the opinion that a peritoneal 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 pathology 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 lymphatics 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 a thing as a primary endothelial malignancy arising from the pleura was carefully 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 metastatic 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 stenosis; (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 mesotheliomas in asbestos-exposed workers!

Ewing (25) in 1940 raised the question of the influence of chronic irritation or trauma and low grades of inflammation in causing connective 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 confusion 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 controversial 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 University 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 transforming into both an epithelioid malignancy and a sarcomatous malignancy.

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 endothelioma of the pleura. By then over 200 authors had discussed and offered opinions on the entity, which at that time was called primary mesothelioma 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 carcinoma, 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, carcinomatodes, lymphangioendothelioma, fibroendotheliosis of the pleura, lymphangitis proliferans, pleuroma, abdominal colloid tumor, and tubercle-like lymphadenoma (32). 

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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 mentions 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 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 mid20th 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 preparations 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 producing 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 in women, and the greatest number of cases was found in patients between the ages of 40 and 60 years.
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