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Dr. Bignon on Historical Overview of Malignant Mesothelioma - Imig Conference - May, 1997

It is for me an honor to introduce the IMIG conference. Summarizing the whole story of mesothelioma in fifteen minutes is a difficult challenge, so, I will focus on different aspects and questions relating to causal factors.

In 1992, Christ Wagner opened the Paris conference focusing on the early period (from 1870 to 1930), when pathologists were discussing the exact origin and nature of the so called primary neoplasms of the pleura.

Several hypothesis were debated: metastatasis? endothelioma? sarcoma? and finally primary neoplasms, derived from pleural mesothelioma cells?

Actually, it was only in 1931 that Klemperer and Rabin used for the first time the term "mesothelioma", when reporting five cases of pleural malignancy. Thereafter, we had to wait until the fifties to find case reports of "primary diffuse pleural mesotheliomas" in Europe, as well as in North America.

Indeed, before 1950, mesotheliomas was unknown in medical practice, as confirmed by the review of fifty thousand autopsy records during one century at the Massachusetts General Hospital. All mesothelioma cases occurred in the last forty five years and none before.

Actually, it was in 1960 that Christ Wagner reported 33 cases of mesothelioma in Northwest Cape, South Africa, mainly in crocidolite miners and in their family contacts...In the sixties, the pioneering work of pathologists had reached a consensus for considering that mesothelioma was a primary neoplasm arising from pluripotential mesothelial cells, as demonstrated in cell culture by Maximov (1927) and Stout and Murray (1942).

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That mesothelioma was a highly job-related disease is demonstrated by this figure from McDonald: for the period from 1961 to 1983, the number of fatal cases reported by pathologists in Canada increased regularly in males, whereas it remained stable in females.

In the seventies and eighties, several authors, particularly Amstrong, McDonald and others, stressed upon the existence of gradient in the relationship of mesotheliomas according to asbestos types. ***

Since the pioneering work of Langer and Pooley in the early 70's several laboratories equipped with electron microscopy have been involved in identification and counting of asbestos fibers in respiratory tissue samples.

Shown here, the unexpected data obtained by Sebastien in 1989 in the lungs of workers exposed essentially to chrysotile at Thedford mine (Quebec). Curiously, a significant proportion of long tremolite fibers were present whereas this fiber type represented only a 1% contaminant of the Quebec chrysotile ore. By contrast, there remained few chrysotile fibers in the lung.

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Another track was the search for the presence of asbestos fibers in the parietal pleural tissue, where starts usually mesothelioma. Such studies have been carried out in 3 laboratories.

Sebastien in 1979, when studying the fiber burden in parietal pleura, specimen, found only short chrysotile, fibers, less than 5mm in length, but no significant amphibole fiber.

Later Dodson (1990) published approximately the same results, mentioning few fibers with a length >8mm.

But recently Boutin (1996) could demonstrate the presence of significant amount of long amphibole fibers, mainly crocidolite or tremolite (in a patient from Corsica), at the level of black spots of the parietal pleura.

Thus, in my opinion, the hypothesis of focal accumulation of the long durable fibers in close contact with the target mesothelial cells is worthy of serious consideration.

Since the seventies, many long term animal experiments by inhalation have been carried out in the several laboratories, particularly in UK and in North America. The results have positively contributed to a better understanding of fiber-related carcinogenesis and identification of dose-response.

However, most of these experiments failed to confirm a striking difference between chrysotile/amphiboles for inducing mesotheliomas in the rat. The reasons remained obscure; doses inhaled?, short life duration?

The seventies was the historical time when Stanton in US and Pott in Germany developed the intraserosal inoculation of fibers in the rat. These studies, reproduced in other laboratories, have clearly identified size parameters, that is length and diameter, which are responsible for the carcinogenic potential of natural, as well as man-made fibers.

In the 70's, industrialized countries, particularly in the UK, tried to register all cases of mesothelioma. But, as recently reviewed by Iwatsubo et al (1994), the percentage of pathologically confirmed diagnosis of mesothelioma ranged from 26% to 96% in different studies.

As the French Mesothelioma Register, set up in 1975, did not appear capable to provide valid information on the true incidence of mesothelioma, in January 1987 we shifted to a case control study to investigate dose-response for occupational exposure.

This study including 405 cases and 387 controls has shown a significant excess of mesothelioma observed for levels of cumulative exposure far below the limits adopted in most industrial countries in the 1980's (down to 0.5 flcc. years).

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These cases of mesothelioma without known occupational exposure may be related either to:

  1. Occult occupational exposure.
  2. Environmental exposure:

    Particularly outdoor, in the vicinity of asbestos factories or in rural areas, with a special historical mention for the discovery in Karien (Turkey) by Baris of the most powerful carcinogenic fiber for the pleura: erionate-ziolite.
  3. Passive indoor exposure at low concentrations in buildings with friable asbestos. Indeed, in cases where insulation is damaged, critical levels exceeding 25 F/L may occur, particularly during maintenance operations. Thus, there is a possibility that such saturation might be responsible for mesothelioma cases, as recently projected by J. Peto for the forthcoming years.

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I will end my historical overview by showing this original 1984 figure from J. Peto comparing mortality by lung cancer and mesothelioma in the cohort of American insulation workers followed by I. Selikoff. These curves suggested to Peto totally different mechanisms for these two locations of carcinogenesis.

  • For lung cancer, we see the well known multiplicative effect of smoking when associated with asbestos exposure and also of age at first exposure.

By contrast, for a mesothelioma, the incidence was determined by time since first exposure, irrespective of age or smoking, suggesting to J. Peto that asbestos worked as complete carcinogen at the level of mesothelia cells.

Thus presently, we need to reach a better understanding of pleural mesothelial cells transformation:

  • are we dealing with a "hit and run" model, as suggested by the in vitro studies?
  • or with a multi step process, with repeated hits by mineral fibers, in association with inflammatory cells releasing mediators and oxy-radicals.

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I hope that this meeting will contribute to solving some of these problems and bring new advances for thet clinical and therapeutic managements of those unfortunate patients.