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1671
Primary Hepatocellular Carcinoma in Workers
Exposed to Vinyl Chloride
A Report of Two Cases
Jean-C. Saurin, M.D.1
Philippe Tanière, M.D.2
François Mion, M.D.1
Philippe Jacob, M.D.1
Christian Partensky, M.D.1
Pierre Paliard, M.D.1
Françoise Berger, M.D.2
BACKGROUND. Vinyl chloride (VC), an industrial toxic gas, has a dose-dependent
carcinogenicity in rodents and has been responsible for multiple cases of liver
angiosarcoma in humans. The aim of this study was to describe histopathologic
1
Fédération des Spécialités Digestives, Hôpital
Edouard Herriot, Lyon Cedex, France.
2
Laboratoire d’Anatomie Pathologique, Hôpital
Edouard Herriot, Lyon Cedex, France.
liver alterations and to evaluate risk factors for hepatocellular carcinoma in two
workers from the same plant, both of whom had primary nonangiosarcoma liver
tumors and were exposed to VC.
METHODS. Clinical, biochemical, serologic, and pathologic data were reviewed at
the time of hepatic resection. Clinical and biologic follow-up were available for
several years before the diagnosis of hepatocellular carcinoma.
RESULTS. Liver alterations distant from the tumor site were compatible with ongoing exposure to VC in both cases. Several areas containing dysplastic hepatocytes
were present in nontumoral liver in one patient. Both patients are alive after partial
liver resection, and 1 has had 5 years of follow-up without recurrence.
CONCLUSIONS. Exclusion of classic risk factors for noncirrhotic hepatocellular carcinoma of the liver in both patients suggests a relationship between VC exposure
and observed tumors. Systematic long term follow-up with biology and ultrasonography for workers exposed to VC may result in relatively early diagnoses of liver
tumors and long term survival in some cases. Cancer 1997;79:1671–7.
q 1997 American Cancer Society.
KEYWORDS: vinyl chloride, toxic, professional exposure, hepatocellular carcinoma,
liver, histopathology, surgery.
V
Address for reprints: Jean-C. Saurin, M.D., Fédération des Spécialités Digestives, Pavillon O,
Hôpital Edouard Herriot, 5 place d’Arsonval,
69437 Lyon Cedex, France.
Received July 12, 1996; revisions received October 28, 1996, and December 16, 1996; accepted December 16, 1996.
inyl chloride (VC) is a toxic gas extensively used to manufacture
a variety of polyvinyl chloride products. VC has been shown to be
mutagenic in several bacterial species.1 VC also possesses carcinogenic properties in rats, inducing various type of tumors, including
angiosarcomas of the liver.2,3 VC exposure in humans may lead to
circulatory disorders, sclerodermia, hematologic diseases, and cancer.1,4,5 A slight increase in lung, brain, bladder, and skin carcinoma
incidence has been reported in retrospective series of workers exposed to VC, but no statistically significant association has been observed for these cancers. In contrast, primary liver angiosarcoma is
closely associated with VC exposure in a time- and dose-dependent
manner. The association between VC exposure in humans and primary hepatocellular carcinoma (HCC) remains controversial. In contrast, primary HCC is a common finding in rats exposed to high concentrations of VC.6 This discrepancy may be explained by an exposure
during the neonatal period in rats in contrast with humans. Only a
few cases of VC-associated HCC in exposed workers have been reported, with poor data available regarding other risk factors such as
q 1997 American Cancer Society
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CANCER May 1, 1997 / Volume 79 / Number 9
TABLE 1
Work History in Two Vinyl Chloride Workers
Work history
Case 1
VC autoclave development, laboratory
VC polymer handling (residual VCM),
laboratory
Same work, half time
Case 2
VC polymer manufacturing, including
autoclave cleaning
Same work after 1974
Outside VC polymer manufacturing area
Exposure
duration (mos)
Exposure
index a
24
5
102
58
4
3
117
66
4
6
4
2
VC: vinyl chloride; VCM: vinyl chloride monomer.
a
Exposure index was evaluated following the method of Greenberg and Tamburro,7 with the help of
an occupational physician working in the same plant as the two patients.
chronic viral hepatitis. In cohort studies, primary HCC
is not always clearly delineated from angiosarcoma,
and the status of the liver is not available in most
cases. In this study, the authors report two cases of
primary HCC in noncirrhotic livers from workers exposed to VC, who had no evidence of associated risk
factors for HCC.
Case Reports
Patient 1 was a 50-year-old man (height: 170 cm;
weight: 80 kg), who underwent a systematic followup (biology, and ultrasonography) from 1983 to 1991
because of a known exposure to VC. The patient was
exposed to VC between 1959 and 1970 at several
places, but mostly in laboratory work and not directly
in the polymerization process. Exposure was estimated at 50 to 100 parts per million (ppm) during
these 11 years, which corresponds to an intermediate
ranked level of exposure according to Simonato et al.4
Total cumulative exposure rank months, with each exposure index being evaluated with help of an occupational physician following the method of Greenberg
and Tamburro,7 was estimated at 702 (Table 1). During
this follow-up, there was no alteration in liver function
tests. In 1991, a hepatic segment III nodular lesion
measuring 3 cm in greatest dimension was detected on
ultrasonography and confirmed by tomodensitometry.
Physical examination showed neither jaundice nor hepatomegaly. A fine-needle aspiration biopsy was performed, which yielded the diagnosis of primary HCC.
At time of diagnosis, liver function tests showed no
increase in transaminases, bilirubin, prothrombin
time, gamma-glutamyl transferases, and a-fetoprotein
(AFP). There was a slight increase in ferritin level (537
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mg/L, N õ 320); however, the serum iron level and
saturation of the serum iron were normal. Serum cholesterol level was measured at 3.6 mmol/L (N õ 6) and
the triglyceride level at 2.34 mmol/L (N õ 2).
A left lobectomy was performed after a hepatic
lipiodol arteriography showing no associated hepatic
lesion. Pathologic examination of the resected liver
revealed a 4 cm 1 4.5 cm 1 4 cm multinodular, incompletely encapsulated well differentiated HCC with
moderate cellular atypia (Fig. 1). There were two identical satellite nodules, each approximately 1 cm in
greatest dimension. Examination of the liver distant
from the tumor site revealed noncirrhotic liver with
diffuse, predominantly centrilobular, macrovesicular
steatosis (Fig. 2). Other observed lesions included
moderate sinusoidal dilatation (Fig. 2), and mild lobular and periportal fibrosis (not shown) with no or mild
portal or lobular inflammation. There was no evidence
of active alcoholic disease (absence of polymorphonuclear leukocyte infiltration and of Mallory’s bodies)
and no hepatic iron overload on Perls’ staining.
Patient 2 was a 61-year-old man (height: 179 cm;
weight: 90 kg) with a higher exposure to VC (200 –
500 ppm) from 1964 to 1979, at several stages in the
polymerization process. Total cumulative exposure
rank months was evaluated at 974 (Table 1). During
follow-up, a slight elevation in gamma-glutamyl transferases was observed (95 IU, N õ 65) with no other
alteration of liver function tests (transaminases, bilirubin, alkaline phosphatases, or prothrombin time) and
normal mean corpuscular volume. Serum lipid profile
was as follows: cholesterol, 5.3 mmol/L (N õ 6) and
triglycerides, 2.67 mmol/L (N õ 2). Ultrasonography
showed a 5-cm left hepatic mass (segments III – IV).
There were no symptoms and clinical examination was
normal. AFP was measured at 110 mg/L (N õ 5). Diagnosis was confirmed by fine-needle aspiration biopsy
(well differentiated HCC). Hepatic arterial chemoembolization with doxorubicin and lipiodol was performed, and no other hepatic tumor was visualized.
A left lobectomy was performed. Macroscopic examination showed a large (5 cm 1 4.5 cm 1 4 cm)
necrotic tumor. Microscopic examination of this tumor revealed an encapsulated, well differentiated HCC
(Fig. 3) with a predominantly trabecular pattern, and
moderate cellular atypia. Histopathologic examination
of the liver distant from the primary tumor revealed
bridging and portal fibrosis but no cirrhosis (Fig. 4),
variable, diffuse, mainly centrilobular macrovesicular
steatosis (Fig. 4); diffuse sinusoidal dilatation; focal,
mostly centrilobular, areas of enlarged sinusoids with
hyperplastic lining endothelial cells and hepatocytes
(Fig. 5), and high hepatocyte density in focal areas
(Fig. 6) with small, monomorphic cells (hepatocyte
W: Cancer
Liver Carcinoma in Vinyl Chloride Workers/Saurin et al.
1673
FIGURE 1. Case 1. Left: well differentiated hepatocellular carcinoma (trabecular pattern) with a thin capsule.
Right: normal adjacent liver (H & E, original magnification 1160).
FIGURE 2.
Case 1. Sinusoidal dilatation in the periportal area. Centrilobular macrovesicular steatosis
(H & E, original magnification 1160).
small cell dysplasia). The AFP level decreased to 4.8
mg/L after surgery.
Laboratory and clinical investigation revealed no
classic risk factor for HCC or chronic hepatitis in either
patient. There was no history of alcohol abuse. Repeated serologic tests were negative for viral hepatitis
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B (negative for hepatitis B surface antigen [HBs Ag]
anti-hepatitis B core antigen, anti-hepatitis B surface
[HBS] and hepatitis B virus [HBV] DNA by dot blot)
and C viruses (anti-hepatitis C virus first-generation
enzyme-linked immunoadsorbent assay, viral RNA by
polymerase chain reaction). There was no evidence of
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CANCER May 1, 1997 / Volume 79 / Number 9
FIGURE 3. Case 2. Well differentiated hepatocellular carcinoma (trabecular pattern) with a thick fibrous
capsule, and (top) adjacent liver (H & E, original magnification 160).
FIGURE 4. Case 2. Low-power view of periportal and bridging fibrosis without cirrhosis. There is diffuse
macrovesicular steatosis (chromotrope-aniline blue).
autoimmune diseases (antinuclear, antimitochondrial, smooth muscle, or liver/kidney microsomal antibodies), metabolic disease (such as a-1 antitrypsine
deficiency), Wilson’s disease, or hemochromatosis;
there was a normal serum iron level, normal saturation
of the serum iron, and normal ferritin level (except a
slight increase was observed in Patient 1), and absence
of hepatic iron overload on pathologic examination.
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DISCUSSION
In published cohorts of workers exposed to VC, a statistically significant excess of liver carcinoma has been
observed, in contrast with other cancer sites (lung,
brain, and hematopoietic). The risk of liver carcinoma
increases with the total cumulative exposure (ppmyear) and the time since first exposure.4,8 However,
this increased risk is mainly related to liver angiosar-
W: Cancer
Liver Carcinoma in Vinyl Chloride Workers/Saurin et al.
1675
FIGURE 5.
Case 2. High-power view of factor VIII immunostaining (Dako Co., Carpinteria, CA) in the area of dilated
sinusoids, showing hyperplasia of stained sinusoidal lining cells (arrowhead) and hyperplastic hepatocytes (arrows). Revelation
by immunoperoxidase (streptavidin-biotin, Dako duet) (counterstained with hematoxylin, original magnification 1400).
FIGURE 6. Case 2. Hepatocyte small cell dysplasia (right) and proliferative hepatocytes (arrows) without
dysplasia (left), (H & E, original magnification 1160).
coma, a very rare disease in the general population,
with an annual incidence estimated to be 2 in 10 million.4 Thus, angiosarcoma was the final diagnosis in
77 – 94% of histologically proven primary liver tumors
in workers exposed to VC.4,8 Only few primary HCCs
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were diagnosed (2 of 36 liver carcinomas in a cohort
of 14,351 VC-exposed workers4). However, liver status
and details of other risk factors were not available in
these studies.
To date, very few documented cases of primary
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CANCER May 1, 1997 / Volume 79 / Number 9
HCC in workers exposed to VC have been reported.9–13
Gokel et al.10 reported one case with a previous suspicion
of cirrhosis and no data regarding other risk factors except negative intrahepatic HBs Ag staining. Puech et al.9
reported two cases, one with a previous diagnosis of
alcoholic cirrhosis and one with chronic hepatitis with
cirrhosis of unknown origin diagnosed 5 years after the
first VC exposure. Koischwitz et al.11 described one case
of associated liver angiosarcoma and HCC in a liver that
was probably cirrhotic. Evans et al.12 described one case
of primary HCC and one case of associated primary liver
carcinoma and angiosarcoma. In this last report, morphologic abnormalities of hepatocytes (hyperplastic
nodules and dysplasia) were described and considered
to be preneoplastic lesions. Dietz et al.13 reported three
cases with no cirrhosis, pathologic abnormalities of endothelial cells previously described in workers exposed
to VC, and absence of intrahepatic and serologic HBs
Ag. However, most classic risk factors for HCC were not
excluded in these reports. The latency period between
first VC exposure and the diagnosis of HCC ranged between 13 and 39 years (mean, 22 years), which was significantly longer than the observed latency for liver angiosarcomas.8,10,12 Thus, the reported latency in the cases
in the current study (31 years in both) is compatible with
previous reports.
An important argument in favor of the role of VC
in these two cases of HCC is the absence of an other
identified risk factor. In large series, 10 – 20% of primary HCC arose in noncirrhotic livers. A variety of
potential etiologic factors have been considered in
these carcinomas, including estrogen, chronic viral B
and C hepatitis, aflatoxin, alcohol abuse, cigarette
smoking, drug, toxins, and metabolic diseases such as
genetic hemochromatosis.14 – 17
The usual etiologies of chronic hepatitis (viral, autoimmune, and metabolic) were ruled out by corresponding laboratory investigations in the patients in
the current study. The authors cannot exclude the role
of serologically negative HBV because no polymerase
chain reaction amplification of HBV DNA in liver tissue was performed. The absence of consistent portal
inflammation, hypergammaglobulinemia, or previous
history of transfusion, and the close biologic followup without any observed increase in transaminases
argue against a hypothetical chronic viral hepatitis.
Alcohol intake was considered as moderate in the patient in Case 2 and as none or occasional in the patient
in Case 1. Height and weight in both cases, as well as
the lipid profile, suggest that nonalcoholic steatohepatitis (NASH) could be partly responsible for the observed steatosis and fibrosis.18,19 However, there was
no significant inflammation, either periportal or lobular, which is part of the definition of NASH18; more-
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over, NASH without cirrhosis has not been associated
with HCC. There was also no evidence of alcoholic
liver disease on histologic examination. The patient in
Case 1 stopped smoking 20 years before the diagnosis
of primary HCC and the patient in Case 2 was a nonsmoker. Exposure to other toxins are usually professional in nature and were carefully excluded by clinical
history in both patients because of the close professional medical follow-up. Finally, both patients presented with no classic risk factors for HCC.
Associated lesions of nontumoral liver in the two
reported cases are compatible with previous VC exposure. Several histopathologic lesions of the liver have
been described in VC-exposed humans and animals6,20 – 24 including degenerative changes (focal hydropic degeneration of hepatocytes, and disseminated
large-sized fat vacuoles); fibrosis (portal fibrosis, slight
focal intralobular fibrosis, and thickening of the hepatic capsula); and sinusoidal dilatation with marked
proliferative activity of sinusoidal lining cells and associated nodular areas of hypertrophic and hyperplastic
hepatocytes. Pathologic examination of the resected
nontumoral liver showed these lesions (degenerative
changes, sinusoidal dilatation, and fibrosis) in both
reported patients. These lesions corresponded to focal
mixed hyperplasia, which has previously been described as characteristic of chemical injury.25 Interestingly, sinusoidal cell changes were mild in both patients, with mild hyperplasia of sinusoidal lining cells
without clear dysplasia in the patient in Case 2, and
no sinusoidal cells with hyperplasia or dysplasia in the
patient in Case 1. In contrast, focal areas of dysplastic
hepatocytes in the patient in Case 2 were frequent.
Such lesions have been previously described as hepatocyte small cell dysplasia and considered to be the
most important precancerous lesion in cirrhotic livers.26 This suggests a possible evolution from hepatocyte dysplasia to HCC, as has been proposed in other
reports.12 However, hepatocyte small cell dysplasia has
not been reported earlier in workers exposed to VC,
so that the role of VC remains hypothetical. In the
future, molecular biology may be of help in clarifying
the eventual role of VC in liver tumors or preneoplastic
liver lesions of exposed workers. H-ras, N-ras, c-Ki-ras
2, and p53 mutations have been described in human
(angiosarcoma) and animal (angiosarcoma and HCC)
VC-related liver tumors.2,3,27,28 However, at this time,
no specific oncogenic mutation, such as the reported
mutation at codon 249 of the p53 gene in aflatoxinrelated liver tumors, has been associated with VC exposure.29 Analysis of p53 and ras genes within the primary liver tumor is now under investigation in both
cases.
In conclusion, this study shows that isolated pri-
W: Cancer
Liver Carcinoma in Vinyl Chloride Workers/Saurin et al.
mary HCC may be diagnosed during the follow-up of
workers exposed to VC, in the absence of an associated
risk factor, and with a long latency since first exposure.
In contrast with all previously reported cases of HCC
in workers exposed to VC, which share the same disastrous prognosis as VC-related angiosarcomas,10,12,13
liver tumors in the patients in the current study were
diagnosed early, allowing a potentially curative surgical resection and a long term survival in at least one
patient. Thus, a close and long term morphologic follow-up is justified in these previously exposed workers, even when the cumulative VC exposure is considered to be mild or intermediate. However, the presence of multiple nodular areas of small, dysplastic
hepatocytes in the nontumorous liver of the patient
in the second case suggests a high risk of metachronous liver tumor. These findings raise the issue of a
more aggressive therapeutic modality (i.e., liver transplantation) in such cases to prevent the development
of a metachronous malignant hepatic lesion.
REFERENCES
1.
Giri AK. Genetic toxicology of vinyl chloride—a review. Mutat Res 1995;339:1–14.
2. Froment O, Boivin S, Barbin A, Bancel B, Trepo C, Marion
MJ. Mutagenesis of ras proto-oncogene in rat liver tumors
induced by vinyl chloride. Cancer Res 1994;54:5340–5.
3. Watson MA, Devereux TR, Malarkey DE, Anderson MW,
Maronpot RR. H-ras oncogene mutation spectra in B6C3F1
and C57BL/6 mouse liver tumors provide evidence for
TCDD promotion of spontaneous and vinyl-carbamate-initiated liver cells. Carcinogenesis 1995;16:1705–10.
4. Simonato L, L’abbé KA, Andersen A, Belli S, Comba P, Engholm G, et al. A collaborative study of cancer incidence
and mortality among vinyl chloride workers. Scand J Work
Environ Health 1991;17:159–69.
5. International Agency for Research on Cancer. vinyl chloride,
polyvinylchloride, and vinyl chloride-vinyl acetate polymers.
IARC Monogr 1979;19(Suppl 7):373–5.
6. Popper H, Maltoni C, Selikoff J. Vinyl chloride-induced hepatic lesions in man and rodents. A comparison. Liver
1981;1:7–20.
7. Greenberg RA, Tamburro CH. Exposure indices for epidemiological surveillance of carcinogenic agents in an industrial
chemical environment. J Occup Med 1981;23(5):353–8.
8. Piratsu R, Comba P, Reggiani A, Foa V, Masina A, Maltoni
C. Mortality from liver disease among Italian vinyl chloride
monomer/polyvinyl chloride manufacturers. Am J Ind Med
1990;17:155–61.
9. Puech AM, Fournet A, Laulhere L, Faure J, Cau G, Mallion
JM. Etude des lésions hépatiques observées chez 5 sujets
exposés au chlorure de vinyle dont 3 cas d’angiosarcome
hépatique. Arch Mal Prof 1977;38:787–95.
10. Gokel JM, Liebezeit E, Eder M. Hemangiosarcoma and hepatocellular carcinoma of the liver following vinyl chloride exposure. Virchows Arch A Pathol Anat Histopathol 1976;
372:195–203.
/ 7b55$$1037
04-02-97 14:23:20
cana
1677
11. Koischwitz VD, Lelbach WK, Lackner K, Hermanuntz D. Das
vinylchloridinduziert Leberangiosarkom und hepatozellulare karzinom. Fortschr Rontgenstr 1981;134:283–90.
12. Evans DMD, Jones WW, Kung ITM. Angiosarcoma and hepatocellular carcinoma in vinyl chloride workers. Histopathology 1983;7:377–88.
13. Dietz A, Langbein G, Permatter W. Das Vinylchloride-induzierte hepatocellulare karzinoma. Klin Wochenschr 1985;
63:325–31.
14. Okuda K, Nakashima T, Kojiro M, Kondo Y, Wada K. Hepatocellular carcinoma without cirrhosis in Japanese patients.
Gastroenterology 1989;97:140–6.
15. El-Refaie A, Savage K, Bhattacharya S, Khakoo S, Harrison
TJ, El-Batanony M, et al. HCV-associated hepatocellular carcinoma without cirrhosis. J Hepatol 1996;24:277–85.
16. Deugnier Y, Guyader D, Crantock L, Lopez JM, Turlin B,
Yaouano J, et al. Primary liver cancer in genetic hemochromatosis: a clinical, pathological and pathogenetic study of
54 cases. Gastroenterology 1993;104:228–34.
17. Smalley SR, Moertel CG, Hilton JF, Weiland LH, Weiand HS,
Adson MA, et al. Hepatoma in non cirrhotic liver. Cancer
1988;62:1414–24.
18. Powell EE, Cooksley WGE, Hanson R, Searle J, Halliday JW,
Powel LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21
years. Hepatology 1990;11:74–80.
19. Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri
BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994;107:1103–9.
20. Popper H, Thomas LB. Alteration of the liver and spleen
among workers exposed to vinyl chloride. Ann NY Acad Sci
1975;246:172–91.
21. Popper H, Thomas LB, Telles NC, Falk H, Selikoff IJ. Development of hepatic angiosarcoma in man induced by vinyl
chloride, thorotrast, and arsenic. Am J Pathol 1978;92:349–
76.
22. Thomas LB, Popper H, Berk PD, Selikoff I, Falk H. Vinylchloride-induced liver disease. From idiopathic portal hypertension (Banti’s syndrome) to angiosarcomas. N Engl J
Med 1975;292:17–22.
23. Berk PD, Martin JF, Young RS, Creech J, Selikoff IJ, Falk H,
et al. Vinyl chloride-associated liver disease. Ann Intern Med
1976;84:717–31.
24. Gedigk P, Müller R, Bechtelsheimer H. Morphology of liver
damage among polyvinyl chloride production workers. A
report of 51 cases. Ann NY Acad Sci 1975;246:278–85.
25. Tamburro CH, Makk L, Popper H. Early hepatic histologic
alterations among chemical (vinyl monomer) workers. Hepatology 1984;4:413–8.
26. Watanabe S, Okita K, Harada T, Kodama T, Numa Y, Takemoto T, et al. Morphologic studies of the liver cell dysplasia.
Cancer 1983;51:2197–2205.
27. Hollstein M, Marion MJ, Lehman T, Welsh J, Harris CC, Martel-Planche G, et al. p53 mutations at A:T base pairs in angiosarcomas of vinyl chloride-exposed workers. Carcinogenesis
1994;15:1–3.
28. Marion MJ, Froment O, Trepo C. Activation of Ki-ras gene
by point mutations in human liver angiosarcoma associated
with viny chloride exposure. Mol Carcinog 1991;4:450–4.
29. Ozturk M, Bressac B, Puisieux A, Kew M, Volkmann M, Bozcall S, et al. p53 mutation in hepatocellular carcinoma after
aflatoxine exposure. Lancet 1991;338:1356–9.
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