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mesothelioma survivor

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mesothelioma survivor

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									Tumori, 88: 1-9, 2002


NON-ASBESTOS RELATED DIFFUSE MALIGNANT MESOTHELIOMA

Michael Huncharek
Division of Radiation Oncology, Department of Clinical Oncology, Marshfield Clinic, Marshfield, WI; Meta-Analysis Research Group, Stevens
Point, WI



Aims: The association between asbestos exposure and the de-            factors, (4) childhood mesothelioma and (5) the role or
velopment of malignant mesothelioma is well known.                     SV40.
Nonetheless, a proportion of patients suffering from this dis-         Result: Available information suggests that genetic factors
ease do not appear to have documented exposure to as-                  may play a larger role in the etiology of this disease than cur-
bestos fibers from any known source. Available information             rently appreciated. The interplay of genes and environment re-
suggests that a true “background” incidence of this disease            quire further elucidation in the pathogenesis of mesothe-
exits raising the possibility that other factors contribute to its     lioma. The role of diet is poorly understood with few studies
etiology. This paper will review existing data related to non-as-      directly addressing this issue. Whether other environmental
bestos related mesothelioma and suggest avenues for further            or infectious agents are involved in mesothelioma develop-
research.                                                              ment remains speculative.
Methods and study design: A comprehensive electronic MED-              Conclusion: The biology of mesothelioma is an enigma. Al-
LARS search of the literature pertinent to non-asbestos re-            though this disease appears to occur in the absence of as-
lated malignant mesothelioma was performed including the               bestos exposure, the genetic and biological differences be-
years 1996-2001. Hand searches were also carried out to                tween asbestos related and non-asbestos related tumors is
supplement electronically derived information and literature           unclear. Additional epidemiological and laboratory studies
pre-dating 1996. The resulting references were stratified in-          are needed to provide a better understanding of the relation-
to the following categories and reviewed; (1) radiation asso-          ship between environmental and non-environmental causes
ciated mesothelioma, (2) familial mesothelioma, (3) dietary            of mesothelioma.
Key words: asbestos, diet, pleural neoplasms, radiation, SV40.




IIntroduction                                                          suggests that a true “background” incidence of non-as-
                                                                       bestos related mesothelioma exists7. The incidence rate
   Although malignant mesothelioma remains a rela-                     among women is considered one possible measure of
tively uncommon malignancy, it continues to represent                  this rate since females often report no known source of
an important cause of mortality in numerous areas                      asbestos exposure. Occupational asbestos exposure in
worldwide (eg England and Wales, Australia)1. Recent                   women is relatively uncommon. These facts raise the
estimates, for instance, suggest that in coming decades,               possibility that other factors are associated with
as much as one percent of deaths among men in the
                                                                       mesothelioma development in addition to asbestos.
United Kingdom currently aged 49-54 may be due to
this tumor2. Much of this increase is due to the wide-                    Although the medical literature related to malignant
spread use of asbestos and asbestos containing materials               mesothelioma has expanded considerably over the past
on an international scale. Asbestos fibers have been in-               decade, the biology of this tumor and the mechanisms
corporated into thousands of products including pipes,                 of asbestos induced cancer remain poorly understood.
roofing tiles, brakes shoes, insulating materials, floor               Clinical management of this tumor remains almost
coverings, fire proof clothing, among many others.                     purely palliative with few, if any patients, experiencing
Widespread use has vastly increased opportunities for                  durable control or cure of their disease. A better under-
exposure in a variety of occupational and non-occupa-                  standing of the path physiology of mesothelioma may
tional settings3.                                                      result in the development of improved treatment and
   The association between asbestos exposure and ma-                   preventive strategies for this devastating disease. This
lignant mesothelioma is well known and documented in                   paper will discuss the issue of non-asbestos related
numerous epidemiological studies4. Although asbestos                   mesothelioma in the hope of elucidating possible av-
is considered the primary etiologic factor for this tumor,             enues for future work.
most published series contain a substantial minority of
subjects without known exposure5,6. Under-reporting of                 Radiation associated mesothelioma
exposure may partially account for this since exposure
in a variety of settings is sometimes unrecognized by                    The etiologic link between asbestos exposure and
both patients and investigators3. Available information                mesothelioma was firmly established in 1960 by Wagn-


Acknowledgments: The author thanks Lamar Wheeler for manuscript preparation.
Correspondence to: Michael Huncharek, MD, MPH, Department of Clinical Oncology Marshfield Clinic Cancer Center, c/o St Michael’s Hospi-
tal Cancer Center, 900 Illinois Avenue Stevens Point, WI 54481. Tel +715-343-3035; fax +715-343-3080; e-mail metaresearch@hotmail.com
Received August 28, 2001; accepted October 31, 2001
2                                                                                                       M HUNCHAREK


er and associates8. In this report, the authors described   multiple exposures experienced total doses of radiation
33 cases of pleural mesothelioma occurring in the           ranging from 2.1 to 250 Gy. Control rats were either un-
Northwestern Cape Province of South Africa. Crocido-        exposed, sham exposed or exposed to stable CeO2. Rats
lite asbestos was implicated as the etiologic agent         exposed to the highest radiation doses developed a large
among this group. This relationship has been confirmed      number of squamous cell carcinomas of the lung as well
by numerous other investigators9,10.                        as a lower percentage of adenocarcinomas. Among 566
   The possibility of mesothelioma induction by ioniz-      study animals, 4 mesotheliomas were found. All
ing radiation dates back several decades. Early animal      mesotheliomas occurred in animals exposed repeatedly
experiments in the 1970’s demonstrated that inhaled or      to cerium-144 dioxide with doses ranging from 32 to
implanted plutonium in rodents and dogs could induce        190 Gy. It is interesting to note that four other animals
epithelial and mensenchymal tumors in the lungs and         developed osteosarcomas of the ribs probably due to the
thorax11. Park et al. exposed 35 beagle dogs to res-        concentration of cerium in the subpleural region of the
pirable plutonium oxide. Twenty-two subsequently died       lungs.
with epithelial lung tumors while 3 developed thoracic         In addition to the experimental evidence for radiation
sarcomas “derived from the pleura, mediastinum or           induced mesothelioma, numerous clinical reports have
lymph nodes”11.                                             been published over the last two decades. An early re-
   In a 1972 report12, Sanders et al. studied the effects   port by Mauer et al.15 described a case of peritoneal
of intraperitoneal injection of plutonium oxide in          mesothelioma developing in a patient after thorotrast
Sprague-Dawley rats (approx. 2.8 uCi, sub-micron            administration. Thorotrast is a colloidal solution of tho-
sized PuO2 particles). Thirty-six animals received intra-   rium dioxide and was widely used as an X-ray contrast
abdominal injections of the radioactive material sus-       agent in the 1930’s and 1940’s. This substance was sub-
pended in 1mL of saline. Animals were examined for          sequently linked to a variety of human tumors and clini-
number of tumors, location and tumor histology. Twen-       cal use was discontinued. Mauer et al. described a pa-
ty-seven percent of study animals developed peritoneal      tient undergoing cholecystectomy in 1937. A cholan-
mesothelioma with an additional 38% found to harbor         giogram was performed with accidental spillage of
sarcomas of other histologies eg, liposarcomas, rhab-       thorotrast around the bile duct, contaminating the peri-
domyosarcomas, estrogenic sarcomas, among others.           toneal cavity. In 1962, the patient underwent surgery for
Analysis of the micro-distribution of plutonium in the      a non-functioning kidney and massive fibrosis involv-
rat carcasses showed significant uptake in the omentum      ing the right renal pelvis, renal vessels and peritoneum
with formation of fibrotic adhesions measuring up to a      was noted. The authors state that: “In the scare tissue at
millimeter in diameter. Autoradiograms indicated that a     the pyeloureteral junction, large amounts of thorium
large fraction (approx. 35%) of the injected plutonium      dioxide could be identified microscopically and by auto
concentrated in these adhesions. Soft tissue sarcomas as    radiography”15. The patient died several years later with
well as mesothelioma were often found adjacent to           a pulmonary embolism and at autopsy was found to
these “hot spots” of plutonium concentration. Among         have a diffuse peritoneal mesothelioma (mixed histol-
control animals not injected or injected with saline, no    ogy). The autopsy failed to show other primary tumor.
mesenchymal tumors were seen.                               It should also be noted that experimental animal data
   Sanders published a subsequent study in 1992 13          exist demonstrating the ability of thorotrast to induce
which examined both inhaled and intrapluerally inject-      peritoneal tumors in rodents16.
ed plutonium dioxide. The activity median aerodynamic          Since publication of the above paper, numerous case
diameter of the aerosol was 1.6+/-0.11 microns. Only 5      report of mesothelioma occurring in patients years after
animals developed pleural mesothelioma with lung ra-        radiation therapy for various malignancies appeared in
diation doses ranging from 0.06 to 22 Gy. Only one of       the medical literature. For instance, Stock et al. de-
27 rats given an intrapleural injection of 30kBq sub mi-    scribed a case of peritoneal mesothelioma occurring in
cron sized PuO2 developed pleural mesothelioma. Au-         the patient 16 years following radiation therapy for
toradiographs were performed which indicated that the       seminoma17. The patient was diagnosed with seminoma
radioactive particles were rapidly cleared from the         of the right testicle at age 50 and underwent a right or-
pleural cavity. The authors concluded that the failure of   chiectomt and post operative radiation therapy. No doc-
PuO2 to aggregate on the pleural surfaces resulted in       umented history of asbestos exposure was noted. Total
the low incidence of mesotheliomas in the experimental      radiation dose was 32 Gy to the pelvis and abdomen.
animals. These findings contrast with data from studies     Sixteen years later, the patient developed a right groin
examining intraperitoneally injected PuO2, as previous-     mass measuring 3 cm in greatest diameter. Histologic
ly described.                                               examination as well as ultra structural characteristics by
   In an additional 1992 report, Hahn and Lundgren ex-      electron microscopy were felt consistent with malignant
posed F344 rats to an inhaled beta emitter ie cerium-       mesothelioma. The tumor showed multiple microvilli,
144 dioxide, either once or repeatedly14. The animals       tonfibrils and desmosomes. Following exicision of the
were observed over their entire lifetime and necropsied     groin mass, exploratory laparotomy showed diffuse
at death. Rats exposed only once received doses ranging     peritoneal implants of tumor on the serosal surfaces and
from 0.26 Gy to 46 Gy to the lung. Animals receiving        parietal peritoneum. Microscopic examination of the
NON-ASBESTOS RELATED MESOTHELIOMA                                                                                      3

lungs failed to show interstitial fibrosis or ferruginous        An additional interesting association documented in
bodies. Histologically and histochemically, the peri-         the literature is the occurrence of mesothelioma in pa-
toneal implants were consistent with a diagnosis of ma-       tients treated for Wilm’s tumor as children28-30. This is a
lignant mesothelioma.                                         rare malignancy of the kidney usually diagnosed in
   The recent literature contains additional cases of pa-     children less than 5 years of age although it can occur in
tients treated with external beam radiation for various       older children and rarely in adults. Currently, multi-
cancers and subsequent mesothelioma. Almost all of the        modality treatment provides cure in the majority of pa-
reports describe patients treated for one of 4 tumor          tients. Several studies suggests that Wilm’s tumor pa-
types ie breast cancer, Hodgkins disease, cervical can-       tients are at increased risk of second malignancies al-
cer or Wilm’s tumor. One additional documented case           though the role of radiation and chemotherapy in this
of peritoneal mesothelioma following radiation therapy        increased risk is unclear31,32.
for testicular seminoma was published by Gilks et al. in         Austin et al. 28 reported a fatal case of malignant
198818. This latter patient was diagnosed with peri-          pleural mesothelioma in a 28 years old female treated
toneal mesothelioma at age 61, 26 years after abdomi-         with a left nephrectomy and radiation to the left renal
nal radiotherapy for seminoma of the right testicle. The      fossa at age four for Wilm’s tumor. The patient also re-
patient worked his entire lifetime in sales and mangage-      ceived radiation treatment to the right lung for metastat-
ment positions and thorough history did not elicit any        ic disease although the dose was not specified. Accord-
possible source of asbestos exposure. According to the        ing to the authors, she subsequently underwent resec-
authors, “…the patient received 38 Gy to the pelvis and       tion of metastatic disease in the right chest. At age 28
lower abdomen and 36 Gy to the upper abdomen”18.              the patient presented with a left sided pleural mesothe-
Autopsy did not reveal another primary tumor or elevat-       lioma and died shortly after diagnosis prior to the insti-
ed lung asbestos fiber burden.                                tution of any therapy. Since the patients mesothelioma
   Weisman et al., Cavazza et al., Hoffman et al., Ler-       did not arise in the irradiated field, a causal association
man et al., Flachero et al., and Pappo et al. report either   must be regarded with caution. Anderson et al. and
single cases or small case series of patients with            Antman et al.29,30 report similar cases (3 total) 2 with
mesothelioma following treatment for Hodgkin’s                contra lateral chest disease and one with ipsilateral
disease19-24. Hodgkin’s lymphoma has bimodal age dis-         pleural mesothelioma.
tribution with one peak at ages 15-34 and another after          Although the above case reports suggest a relation-
age 60. Other types of second malignancies have been          ship between therapeutic radiation and mesothelioma,
described in patients with Hodgkin’s disease following        such reports are anecdotal and may represent purely
initial therapy25,26. Van Leeuwen et al.25 found an in-       chance associations. The occurrence of several of these
creased risk of lung cancer, non-Hodgkin’s lymphoma           tumors outside the radiation field raises additional
and leukemia among these patients. The overall relative       doubts concerning the causal connection. In an attempt
risk for lung cancer was 4.9 while leukemia showed a          to provide a more substantial evaluation of this issue,
relative risk of 45.7. All lung cancers arose in the radia-   Neuget et al. recently conducted a retrospective cohort
tion fields used to treat the initial tumor. For non-         study utilizing data on over 250,000 women registered
Hodgkin’s lymphoma, combined modality therapy ap-             with breast cancer and Hodgkin’s dDisease in the US
peared to be the most important risk factor. Similar find-    National Cancer Institute’s Surveillance, Epidemiology,
ings were reported by Tucker et al. in a cohort of over       and End Results Program between 1973 and 199333. Al-
1500 Hodgkin’s patients treated at Stanford University26.     most 25% of the patients with breast cancer received ra-
   Weissman et al. report 4 cases of pleural mesothe-         diation therapy as part of their initial management as
lioma in Hodgkin’s patients treated at the Dana Farber        did 50.6% of patients with Hodgkin’s disease.
Cancer Institute19. No patient had a history of asbestos         The relative risk of developing pleural mesothelioma
exposure and one patient had lung fiber studies per-          following thoracic radiation therapy was 1.6 with a non-
formed which did not show elevated levels of asbestos         statistically significant 95% confidence interval of 0.2-
fibers. Three of the four received combined modality          5.6. In the absence of radiation therapy the relative risk
therapy for their Hodgkin’s disease ie chemo-radiation.       was 0.9 (0.2-2.2). No pleural mesothelioma occurred
The mean interval between initial treatment and devel-        among the patients with Hodgkins disease while only
opment of the mesothelioma was 15 years. These data           six cases were found among 252,000 women treated for
are consistent with most of the other reports cited           breast cancer. This study provided no support for a rela-
above. That is, most patients do not have a documented        tionship between chest irradiation and mesothelioma
asbestos exposure history, a long latent period between       risk.
initial treatment and mesothelioma development and tu-
mor occurring in the prior radiation field.                   Familial mesothelioma/genetic predisposition
   Shannon et al. describe two patients developing
pleural mesothelioma 10 and 35 years following radia-            Newhouse and Thompson were the first to report
tion therapy for breast cancer27. These tumors arose in       family contact asbestos-associated mesothelioma34. In a
the irradiated hemi thorax in the absence of occupation-      later report, Anderson and collegues assessed household
al or para-occupational exposure to asbestos.                 asbestos-contact disease risk35. At that time, 37 cases of
4                                                                                                        M HUNCHAREK


malignant mesothelioma related to domestic asbestos          system was used. Production occurred between 1944
exposure were described in the literature. Of 326            and 1961. The father died in 1984 at age 74 years, the
healthy household contacts of amosite asbestos workers       son in 1985 at age 45 years and the mother at age 79
examined 2-3 decades after the onset of presumed             years in 1987. Two other sons and one daughter were
household contamination, 35% showed X-ray abnor-             unaffected at the time of the report.
malities characteristic of amosite exposure. At the time        Martensson and colleagues described malignant
of this report, 4 deaths due to mesothelioma had oc-         mesothelioma in two pairs of siblings, ie a brother and
curred. The investigators concluded that domestic cont-      sister and identical twin brothers41. The former pair had
amination with asbestos from industrial sources com-         no direct occupational asbestos exposure, although they
monly occurs. They postulated that a small fraction of       reported domestic exposure during childhood from their
contacts so exposed could develop asbestos related ma-       father. The father worked at a foundry where asbestos
lignancies.                                                  insulation was used. His work clothes, which were
   In 1978, Vianna and Polan36 published a case-control      brought home daily, were often contaminated with as-
analysis of occupational histories of 52 females with        bestos fibers. Both patients had documented pleural
malignant mesothelioma in order to evaluate the risk of      plaques as well as pleural mesothelioma. The latter pair
this disease secondary to indirect asbestos exposure.        of identical twin brothers were employed in a shipyard
Data on parental cancer history was also obtained for        for approximately 7 years. Both developed pleural
analysis. Having a father or spouse employed in an as-       mesothelioma 16 years from first exposure resulting in
bestos-related occupation increased the risk of mesothe-     their deaths within 18 months from diagnosis. The oc-
lioma by a factor of 10. Of particular interest, the fre-    currence of this rare tumor in a pair of identical twins is
quency of parental cancer, particularly of the gastroin-     intriguing, particularly given the relatively short dura-
testinal tract, was significantly greater among cases        tion of asbestos exposure.
than controls. This finding led authors to hypothesize          Several additional case control and genetic epidemi-
that a genetic predisposition to mesothelioma may exist.     ology studies suggest a possible role for genetic predis-
   In the same year, Li and associates37 described a wife    position in this disease. In 1996, Huncharek et al.42
and daughter of an asbestos insulator both developing        published the results of a case-control study examining
mesothelioma at ages 50 and 34 years, respectively. No       parental cancer history among patients with malignant
other source of asbestos exposure was noted other than       pleural mesothelioma. The study enrolled thirty nine
from the husband’s (father) work clothes which were          mesothelioma patients and 259 age matched controls
laundered at home.                                           seen at the Massachusetts General Hospital (MGH) be-
   A very unusual description of familial clustering of      tween 1978 and 1993. Control patients consisted of
this tumour is that of Risberg and colleagues38. Five        spouses/friends of lung cancer cases presenting to the
cases were reported, ie three sons, one daughter and         surgical service of the MGH between November 1992
their father. Asbestos exposure may have occurred in 4       and May 1995. Medical records were reviewed for each
of the 5 cases via work in the building trades. With this    case and next of kin were identified. A standard ques-
striking aggregation of mesothelioma, the possible role      tionnaire was used to obtain demographic information
of genetic predisposition was suggested.                     and parental cancer history. Data for the control group
   More recently, Hammer and associates reported fa-         were obtained by trained interviewer at the time of pre-
milial mesothelioma in two families39. In the first, three   sentation for surgery of the spouse/friend. Since most of
brothers developed pleural mesothelioma more than 25         the mesothelioma patients (cases) were deceased at the
years from the first reported exposure to asbestos. All      time the study was initiated, questionnaire data were
three were insulators and were diagnosed at ages 54, 58      obtained via telephone interview of next of kin, usually
and 66 years. In the second family, a father developed       a spouse.
peritoneal mesothelioma of the epithelial subtype at age        Seventy one percent of cases reported having a parent
63. During world war II, he worked in a shipyard which       with some form of cancer versus 44% among controls.
was his source of asbestos exposure. This patient’s son      This difference was highly statistically significant (P
developed a similar epithelial peritoneal tumor at age       <0.01). Tumors of the gastrointestinal tract accounted for
44, 11 years after the death of his father. The son’s only   40% of tumors seen among the parents of mesothelioma
known asbestos exposure was from his father’s work           cases while only 25% of parents of controls reported
clothes.                                                     such a history (P <0.01). No other tumor site showed an
   Finally, two other studies provide additional informa-    increased frequency among cases. The authors suggest
tion on 7 cases of this tumor occurring in two separate      that the presented data provide evidence that family his-
families. In the report by Otte and associates40, a Danish   tory (predisposition) may play an important role in the
family was involved in home manufacturing of an as-          development of pleural mesothelioma. The possible rela-
bestos containing compound called “Rollfix” used to fix      tionship between gastrointestinal malignancies and
screws in drilled holes. Amosite asbestos was used           mesothelioma risk requires further elucidation.
along with gypsum and sand. The mixture was mixed               Heineman et al.43 provide further support for the
and packaged by hand in the basement of the family           above cited data. Using a case-control design, these au-
home. No protective equipment or special ventilation         thors collected data on 196 patients with malignant
NON-ASBESTOS RELATED MESOTHELIOMA                                                                                      5

mesothelioma and 511 controls using population based           were patients who did not have cancer and were hospi-
cancer registries. As in the study by Huncharek et al.42       talized for conditions unrelated to tobacco use and to di-
telephone interviews were conducted to gather data us-         etary intake. Control patients were frequency matched
ing a standardized questionnaire. The authors found a          to cases by sex, age (+/- 5 years), race and year of diag-
two-fold, statistically significant, increase in the risk of   nosis. A standardized questionnaire was administered to
malignant mesothelioma for patients reporting cancer in        subjects by trained interviewers. The dietary section
two or more first degree relatives (OR = 2.2, 95% con-         consisted of a 35 item food frequency assessment in
fidence interval 1.1-4.4). No increase was seen among          which subjects were asked to describe their usual eating
men without asbestos exposure or among women. The              habits. Responses were elicited in terms of daily, week-
authors acknowledge that the presented data are limited        ly or monthly food intake.
but the findings suggest a possible role for genetic pre-         The analysis demonstrated that subjects consuming
disposition in the development of this disease.                tomatoes or tomato juice had a reduced by non-signifi-
                                                               cant risk of mesothelioma compared with subjects who
Dietary factors                                                never consumed tomatoes (OR = 0.5, (95% CI 0.2-1.4).
                                                               The odds ratio associated with carrot consumption (> or
   The mortality from cancer is considerably lower in          = one per month) was 0.2 (95% CI 0.1-0.8) compared
countries that have a high per capita consumption of           with subjects who never consumed carrots. No associa-
fruits and vegetables44. In epidemiological studies, a         tion was found with consumption of spinach, broccoli,
lower risk of several types of cancer, including lung          cabbage, cantaloupe, sweet potatoes, cauliflower, or-
cancer, has been related to diets rich in cruciferous veg-     ange juice and red meat. When the highest and lowest
etables and vitamin containing foods45. Unfortunately,         quartiles of the vitamin A and Beta-carotene indices
few data are available examining the possible influence        were compared, a reduced but non-significant risk of
of dietary factors on mesothelioma risk.                       cancer was observed.
   In 1988, Schiffman et al. conducted a case-control             The issue of dietary intake and mesothelioma risk re-
study of diet and mesothelioma in Louisiana46. Fifty-          mains uncertain. Both of the studies cited above are
eight cases of malignant mesothelioma were identified          limited by small sample size and therefore the lack of
from two population based cancer registries as well as         statistical power to detect an effect. Additional studies
local hospital records. Eleven cases were excluded for         are needed to clearly define the possible influence of di-
various reasons leaving thirty-seven for analysis. One         etary factors in the development of this tumor.
control subject was selected for each case. Trained in-
terviewers administered a standardized questionnaire to        Mesothelioma in children
respondents or next-of-kin for those who had died. The
questionnaire included demographic characteristics,               One of the more perplexing characteristics of malig-
smoking practices, lifetime residential history and a          nant mesothelioma is its occurrence in children. Since
food frequency section in which respondents were               this tumor remains relatively rare in adults, childhood
asked how often per month (prior to illness) each of 58        cases represent a even rarer event. The majority of the
food items were eaten. Subjects were classified as hav-        available literature consists of single case reports or
ing either “definite” or “uncertain” occupational as-          small case series. Three of the largest series were pub-
bestos exposure. Subjects were also asked about use of         lished by Grundy and Miller48, Brenner et al.49 and
vitamin supplements.                                           Fraire et al.50.
   Overall, cases reported less frequent consumption of           Grundy and Miller48 reviewed 42, 597 death certifi-
homegrown produce (P = 0.005), cruciferous vegetables          cates for all children under 15 years of age who died in
(P = 0.005) and all vegetables combined (P = 0.09) than        the United States between 1960 and 1964 and for those
did controls. Beta-carotene intake was also lower              under 20 dying between 1965 and 1968. Although a to-
among cases. Although the relative risks across intake         tal of 31 cases of mesothelioma were initially identified,
categories showed significant inverse trends with in-          only 13 could be confirmed. Ten of the cases in this re-
creasing intake for home grown produce, cruciferous            port occurred in males with all but two tumors arising
vegetables and carotene, the relative risks for each in-       in the pleura. The majority were histological sarcomata
take category were not statistically significant. The very     with none of the tumors being exclusively epithelia. As
limited sample size clearly contributed to this finding.       in adults, the natural history was that of a highly malig-
The strongest statement that can be made regarding             nant neoplasm with relatively short survival times from
these data is that they are suggestive for a possible pro-     diagnosis. The longest survivor reported in this group
tective effect for vegetables or some vegetable-related        lived twenty-four months from the onset of symptoms.
constituents on mesothelioma development.                         Unfortunately, little information was available that
   The only other epidemiological study directly ad-           could implicate specific environmental exposures to
dressing this issue is a case-control study by Muscat          disease development, including asbestos exposure. Data
and Huncharek47. This report included ninety-four sub-         existed regarding the father’s occupation in seven cases.
jects and 64 controls without cancer obtained from the         Job descriptions included plumber, electrician, mechan-
Memorial Sloan-Kettering Cancer Center. Controls               ical engineer, farmer, building construction, lumber
6                                                                                                         M HUNCHAREK


dealer and salesman. Domestic asbestos exposure via         zens to SV40. The preparation of vaccine using
father’s husband’s work clothes has been previously re-     macaque monkey cells was abandoned and African
ported in the medical literature. Although some of the      Green monkey cells were subsequently employed.
above noted occupations are associated with exposure        These cells were found to be free of indigenous viruses.
to asbestos, eg plumber, electrician, mechanical engi-         The relationship and concern over SV40 and malig-
neer and construction worker, the remainder are not. It     nant mesothelioma stems from early work that identi-
is unclear whether domestic asbestos exposure could         fied SV40 like DNA in human tumors. Bersagel et al. in
have played a role in any of the cases of mesothelioma      1992 58 found DNA sequences in childhood choroid
in this series.                                             plexus tumors and ependymomas identical to a portion
   Brenner et al.49 reported on seven cases of this tumor   of the SV40 large T antigen (Tag). Their initial studies
seen at Memorial Sloan-Kettering Cancer Center in           were repeated using PCR primers for SV40, similar re-
New York City. All but one of these patients had disease    sults were found. Seven of eleven tumor samples also
originating in the pleura. As in adults, the children in    stained immunohistochemically for Tag. Since SV40
the Brenner series experienced short survival times al-     was found to induce pleural mesotheliomas in ham-
though two patients survived more than five years. In-      sters59, Carbone et al. extended their findings to human
terestingly, three of the seven children developed brain    tumors60. In a series of 48 human mesotheliomas, SV40
metastases that were clinically apparent prior to death.    like DNA sequences were found in 29 of 48 samples
Although brain metastases have been reported in             but in only 1 of 28 lung tissue samples from the same
adults51, symptomatic brain metastases are unusual. As      patients. No such sequences were identified in 48 other
in the report by Grundy and Miller, parental asbestos       non-mesothelial solid tumors.
exposure was investigated as a possible source of              Since this early work was first published, numerous
household contamination. The authors found no clear         other laboratories have reported the presence of SV40
parental asbestos exposure via the occupational or non-     in human mesotheliomas61,62. For instance, Cristaudo et
occupational route.                                         al.63 studies 18 paraffin embedded mesotheliomas using
   A series of pediatric mesothelioma cases published       PCR and Southern blot hybridization for the DNA regu-
by Fraire et al.50 largely supports the findings of the     latory region of SV40. Approximately 55% of the tumor
above cited authors. Unfortunately, only ten of eighty      samples contained SV40 regulatory sequences with
cases initially identified could be histological con-       80% containing Tag sequences.
firmed. Four of the ten cases were of mixed histology          McLaren et al.64 examined malignant mesothelioma
while the remaining six were all epithelioid, in contrast   cell lines and tumor tissue derived from Australian pa-
to the two previously reviewed series. Nonetheless, se-     tients. Five cell lines were established in the investigators
lection factors play a role since only ten of eighty ini-   laboratory from pleural fluid of mesothelioma patients.
tially identified tumors were pathologically document-      Seven tumor biopsy specimens were also obtained via
ed. Survival times ranged from eight to fifty-nine          Tru-cut biopsy needles. The investigators employed three
months with only one subject identified with known as-      different sets of primers, ie Svfor2/Svrev, Svfor3/Svrev
bestos exposure.                                            and Sv8/9. These primers allowed amplification of DNA
   More recent literature on childhood mesothelioma         from the five mesothelioma cell lines and demonstrated
supports the earlier findings noted above52. Short sur-     the presence of SV40 like sequences. Likewise, SV40
vival and resistance to conventional therapy are typical.   like sequences were also found in all seven biopsy speci-
At present, little is known regarding the etiology of ma-   mens. The authors noted the existence of differences in
lignant mesothelioma in children although it would ap-      sensitivity across primers used with the Svfor2/Svrev
pear that asbestos exposure plays little role.              primers the least sensitive. Such differences may con-
                                                            tribute to varying inter-laboratory detection rates.
SV-40 and mesothelioma                                         Several studies provide some indirect support for the
                                                            theory that SV40 exposure is, in fact, related to exposure
   SV40 is a polyomavirus that causes asymptomatic          via contaminated polio vaccine. Hirvonen et al.65 exam-
infections in Asiatic macaques53. This virus is known to    ined tumor tissue from 49 Finnish mesothelioma patients
induce tumors in rodents54 and is related to the human      born between 1912 and 1953. Most of these patients had
polyomaviruses BKV and JCV5. These latter two virus-        been occupationally exposed to asbestos. In Finland, po-
es commonly cause asymptomatic human infection with         lio vaccination began in 1957 and no SV40 contaminat-
70-80% of adults being seropositive56. Although poly-       ed vaccine was used. None of the Finnish samples tested
omavirus are considered species specific, SV40 was          positive for SV40 like sequences using PCR and South-
demonstrated to infect and transform human cell in          ern blotting. Five mesothelioma samples from US pa-
vitro by Shein and Enders57. By the time these findings     tients were also blindly analyzed with three found posi-
were discovered, poliovirus vaccines were prepared in       tive for SV40 DNA. A similar study was conducted by
the United States using Rhesus monkey kidney cells. It      Emri et al. in Turkey66. Both asbestos and environmental
is estimated that contamination of Salk poliovirus vac-     exposure to fibrous zeolite are the major causes of
cine (IPV) in the mid-1950’s and early 1960’s may have      mesothelioma in Turkey. As in Finland, polio vaccines
resulted in exposure of upwards of 100 million US citi-     distributed in Turkey were apparently SV40 free, as po-
NON-ASBESTOS RELATED MESOTHELIOMA                                                                                      7

lio vaccination programs did not begin until 1970 at          ined among infants born between 1956 and 1962, chil-
which time all preparations were uncontaminated. Using        dren born between 1947 and 1952 (childhood exposure)
PCR, none of 29 Turkish specimens tested positive for         and unexposed children born between 1964 and 1969.
SV40 DNA while a positive control mesothelioma sam-           Statistical methods were used to determine whether in-
ple obtained from Italy tested positive. A caveat that        cidence rates varied according to birth cohort. Overall,
needs to be considered regarding the Turkish data is a re-    there were at least 45 million person-years of observa-
cent study by Roushdy-Hammady et al.67. Some areas of         tion for each of the three cohorts. The exposed groups
Turkey suffer extremely high incidence rates of malig-        did not experience increased incidence of cancer com-
nant mesothelioma such as Karain where incidence rates        pared to the non-exposed groups. None of the relative
can range from 5,000 to 50,000 cases per million68. Zeo-      risks for ependymoma, brain tumors of all types, os-
lite used in building materials as well as asbestos expo-     teosarcomas or mesotheliomas showed statistically sig-
sure contributes to this high rate of disease. Nonetheless,   nificant associations with SV40 exposure. The authors
the study by Roushdy-Hammady et al. suggests that ge-         point out that, “The birth cohorts of interest… have not
netic susceptibility may play an important role in the        yet reached the age at which most mesotheliomas occur,
pathogenesis of mesothelioma in this region. The au-          resulting in few cases and imprecise estimates of risk.
thors constructed genetic epidemiology maps and ana-          Incidence data show that mesothelioma rates have been
lyzed a six-generation pedigree of 526 individuals. Their     increasing during the past several decades. It is impor-
analysis suggested that mesothelioma might be geneti-         tant to note, though, that similar increases have also oc-
cally transmitted in an autosomal dominant fashion. It is     curred in Sweden, where adults never received SV-40
questionable though, whether reliable pedigrees could be      contaminated poliovirus vaccines, suggesting that other
constructed over so many generations. Mesothelioma re-        factors common to industrialized nations. …Appear ad-
mains a difficult pathological diagnosis under the best of    equate in explaining the observed increases in mesothe-
circumstances. The Roushdy-Hammady data should                lioma incidence rates71”.
therefore be interpreted caustiously.                            Geissler et al.72 reported a study conducted in Ger-
    As reviewed earlier, the available data on the role       many following immunization of over 700,000 infants
that genetic susceptibility may play in the development       with SV40 contaminated polio vaccine between 1959
of malignant mesothelioma is sparse. Genetic factors          and 1961. With twenty-two years of follow up, no in-
may be more important than currently appreciated. In-         crease in cancer incidence was found among the SV40
terpretation of the SV40 data is difficult in the absence     exposed birth cohort versus an unexposed birth cohort
of more definitive information of the genetic character-      from 1962-1964. The long observation period and large
istics of this disease.                                       sample size are particularly important features of this
    Other work argues against a clear role for vaccine de-    study.
rived SV40 and mesothelioma. In a report by Butel et             Overall, the data linking SV40 exposure and malig-
al.69 the authors follow up on a previous study from          nant mesothelioma are equivocal. Differences in viral
their laboratory dealing with human brain and bone tu-        detection across laboratories suggests that technical dif-
mors58. These authors examined brain and bone tumors          ferences influence the “yield” of positive findings. The
(osteosarcomas) using PCR using primers from four             demonstration of SV40 in tumors from patients not ex-
separated regions of the SV40 genome. SV40 DNA was            posed to contaminated virus suggests other routes of
found in both human and bone tumors and sequencing            human infection exist. In the case of children with
studies ruled out contamination as a source. There also       ependymomas for instance, maternal fetal transmission
were differences across samples in the C-terminal se-         may account for such findings73. The work of Butel et
quences of the T-ag genes, which argues against conta-        al. presents an interesting argument of the existence of
mination from a single source. The authors were unable        other strains of SV40 that can infect humans69. These
to determine the source of SV40 DNA. All tumors ana-          data require confirmation and have important implica-
lyzed were from patients born after 1965 with some            tions for drawing causal connections between “authen-
born as late as the mid-1980’s. Therefore, exposure via       tic SV40” exposure and human tumors.
contaminated polio vaccine could not have occurred.
Their data suggest that humans may be infected by vari-       Conclusions
ous “strains” of SV40 that have previously been unrec-
ognized. There was no indication that a particular viral         The causal association between occupational and en-
strain was tumor specific.                                    vironmental asbestos exposure and malignant mesothe-
    Supporting evidence from large-scale epidemiologi-        lioma is well established4. Despite stabilizing incidence
cal studies would provide much needed additional evi-         rates in the United States, the exportation and use of as-
dence to support a causal connection between SV40             bestos containing products in the developing world en-
from polio vaccine and malignant mesothelioma.                sures that this highly fatal disease will continue to rep-
Strickler et al.70 published the results of large-scale co-   resent a serious public health problem world-wide.
hort study of birth cohorts dating back to the 1950’s.           Despite the fact that most cases of malignant mesothe-
The incidence of ependymoma, osteosarcoma and                 lioma are secondary to the inhalation of asbestos fibers, a
mesothelioma incidence and mortality data were exam-          proportion of patients present with no known source of
8                                                                                                                       M HUNCHAREK


asbestos exposure. While it is true that some exposures              the setting of a “genetically predisposed” host. In the
fail to be recognized and therefore not reported, other              latter instance, the genetic predisposition is only mani-
cases are clearly non-asbestos related (eg mesothelioma              fested in concert with asbestos exposure. This gene-en-
in young children). This suggests that a true “back-                 vironment hypothesis requires further investigation
ground” incidence of this tumor may exist independent                since it is recognized that not all exposed individuals
of asbestos exposure.                                                develop mesothelioma.
   As pointed out in this review, little is understood re-              The role played by diet in the etiology of this disease
garding the genetic features of mesothelioma. Recent                 is also poorly understood. Few studies are available ad-
work suggests that genetics might play a more impor-                 dressing this question precluding substantive conclu-
tant role in the etiology of this tumor than currently ap-           sions. Whether other environmental or infectious agents
preciated. Some tumors may arise secondary to an auto-               are involved in mesothelioma pathogenesis remains
somally transmitted gene while other cases may arise in              speculative.



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