ANNALS OF CLINICAL AND LABORATORY SCIEN CE, Vol. 8, No. 6Copyright © 1978, Institute for Clinical Science

Liver Tumors and Oral Contraceptives: Pathology and Pathogenesis

THOMAS D. GINDHART, M.D.

Department o f Pathology, University o f California,

San Francisco, CA 94143

ABSTRACT

Since 1973, over 200 cases of liver masses associated with oral contracep­tive usage have been reported. Nearly 100 have been liver cell adenomas and 11 have been hepatocellular carcinomas. Focal nodular hyperplasia (FNH) appears only coincidentally associated, but with a particular hemor­rhagic tendency. Bile duct proliferation distinguishes FN H from liver cell adenoma. Two typical cases are presented. Right upper quadrant pain with intra-abdominal hemorrhage is the single most common clinical presenta­tion. M estranol-containing preparations appear more hazardous. Liver en­zymes are usually normal or slightly elevated. Most cases are resectable. Lesions have regressed following discontinuation of pill use; however, close observation is required. Although mammalian liver possesses estrogen re­ceptors, these agents have induced few or no liver tumors in numerous animal studies. Mutagenicity tests indicate that estrogenic compounds do not damage DNA. However, diethylstilbestrol can promote the growth of rat hepatomas initiated by a carcinogen. Further experimental studies may better characterize estrogens as hepatoma promoters.

Since 1973 over 200 cases of liver tumors associated with oral contraceptive usage have been reported.3-4,6,19 Over 100 have been identified as hepatocellular adenomas (HCA) and at least 11 hepato­cellular carcinomas have been related to use of oral contraceptives.3,17,19 Focal nodular hyperplasia (FNH) appears only coincidentally associated but with a par­ticu la r hem orrhag ic ten d e n c y .10 Two cases are reported to illustrate the differ­ing pathological features of HCA and FNH. Available experimental evidence

suggests th a t e s trogens act as tum or growth promoters rather than as carcino­gens.

Case HistoryCASE 1

A 33 year old housewife on oral contraceptives for seven years presented with right upper abdominal pain of five months duration. For the last 30 months, she had taken C-Quens® which contains 2 mg of chlormadinone acetate and 80 fig of mestranol. De­tails of the radiologic features of her liver hepato­cellular adenomas have been previously reported but without the history of oral contraceptive use.20

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4 4 4 G IN D H A R T

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F ig u r e 1. Case 1. Hepatocellular adenomas in the right hepatectomy specimen: the larger, darker mass consists of viable tumor with a 2 cm diameter focus of lighter, necrotic tissue, the site of a previous operative biopsy. The smaller, lighter tumor has spontaneously undergone necrosis.

Serum alkaline phosphatase was slightly elevated (5.4 Bodansky units) and other serum indicators of liver condition were normal. Two masses in the right lobe of the liver were evident on liver scans with both sulfur colloid and rose bengal. A large 9 cm posterior-inferior mass took up tracer as readily as normal liver while a smaller 6 cm medial mass ap­peared as a defect. By arteriography, the first mass was highly vascular but the second avascular. A right hepatic lobectomy was performed, with successful outcome (figure 1). The patient is alive and well eight years later. Microscopically, the viable tumor consisted predominantly of large hepatocytes ar­ranged in haphazard plates two to three cells thick accompanied by Kuppfer cells lining inconspicuous sinusoids (figure 2). Scattered dysplastic liver cells

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F ig u r e 2. Case 1. Hepatocellular adenoma with enlarged hepatocytes forming plates with in­conspicuous sinusoids. Several prominent vascular channels are present. Focal mild dysplasia is noted. No scar tissue or bile ducts occur. Granules with the staining properties of alpha^antitrypsin could not be demonstrated in the case. Hematoxylin and eosin stain, 400x.

F ig u r e 3. Case 1. Portal triad in zone of diffuse hepatocellular hyperplasia. Hematoxylin and eosin stain, 160x.

occurred with enlarged, dark nuclei and prominent nucleoli. Numerous endothelial lined vascular channels occurred but portal triads and especially bile ducts were absent. The only fibrosis present was the thick collagenous capsule which surrounded the tumor. Adjacent liver was normal except for com­pression and a band of diffuse hepatocellular hyperplasia along one edge (figure 3).

CASE 2

A 28 year old woman who died of carcinoma of the cervix had taken Ovulen 21® intermittently for nine years until ten months prior to death. A 1.5 cm diame­ter well demarcated lesion which proved to be focal nodular hyperplasia was an incidental finding in the liver at autopsy. Grossly, it was pale tan with a cen­tral stellate white scar. Microscopically it resembled a collection of regeneration nodules of cirrhosis (fig­ure 4). Enlarged hepatocytes arranged into plates two cells thick formed round nodules which lacked central veins. Fibrous septa with prominent bile duct proliferation occupied much of the center of the lesion (figure 5). There was little vascularity and few foci of dysplasia. Adjacent liver was normal but fre­quently compressed.

Discussion

H ep ato ce llu lar adenom as are clearly associated w ith oral contraceptive use ,19 b u t focal n o d u la r h y p erp la sia appears only co inciden ta lly associa ted .10 O f 88 cases of HCA occurring in w om en, in the files o f the A rm ed Forces In s titu te of Pathology, 92 percen t had taken oral con­traceptives for one year or longer.19 In 1976, only an estim ated 17 percen t of all U.S. w om en aged 15 to 44 used oral con­tracep tives.lfi D evelopm ent of HCA is as­sociated w ith prolonged pill use and, for w om en over 27 years old, the relative risk

LIV ER TUM ORS AND ORAL CON TRA CEPTIV ES 4 4 5

rises rapidly w ith duration of pill use. In over one half of the cases, oral contracep­tives have been taken for five years or m ore and in 90 percen t of the cases for 14 m onths or m ore.3,19

M estranol-containing preparations are c o n s id e re d p a r tic u la r ly h a z a rd o u s .3,6 R ight u p p er quadran t pain w ith abdom i­nal hem orrhage is the single m ost com ­m on clinical p resen tation .3 Right u pper quadran t masses w ith or w ithout gastro­in te s tin a l sym ptom s acco u n t for tw o- th irds of cases.19 L iver enzym es are usu­ally norm al or only s lig h tly e lev a ted . A lpha-fetoprotein levels have not been e leva ted . T he risk of hem orrhage p re ­cludes percu taneous liver biopsy. L iver m asses found incidentally or because of pain require preoperative liver scan and arteriography. A bdom inal u ltrasound and CAT scan are also useful diagnostic aids. O ver tw o-thirds of lesions have been soli­tary and resectable, although m ultip le le­sions have occurred in nearly 10 percen t of cases.3,19 Several lesions have regres­sed following discontinuation of oral con­traceptive use, b u t careful observation is w a rran te d e sp e c ia lly a f te r p reg n an cy w hen d e lay ed ru p tu re m ay occur.3,7,12 A pproxim ately tw o-th irds of th e HCA have occurred in the right lobe of the liver.

M icroscopically, b ile duct proliferation, usually in fibrous septa b etw een nodules, d istinguishes FN H from HCA.8 No lipo- fuscin p igm ent is usually found in the p ro­liferating hepatocytes in both HCA and FN H . G ranular diastase resistant periodic acid-Schiff positive deposits of a lp h a^ antitrypsin have been described in ap­proxim ately tw o-thirds o f cases of HCA and FN H in the absence of serum alpha,- antitrypsin abnorm alities.13

In m ost anim al studies, fem ale sex ste­ro id s a lo n e in d u c e d few or no l iv e r tum ors.1,21 In vitro m utagenicity assays ind icate that estrogenic com pounds do not dam age DNA and should not be re­garded as tum or in itiators,5,11 including m estranol.14 On the o ther hand, diethyl-

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F ig u r e 4. Case 2. Focal nodular hyperplasia with liver cells arranged as in regeneration nodules of cirrhosis, but around a central stellate scar. Hematoxylin and eosin stain, 25 x .

stilbestrol can prom ote the growth of rat hepatom as in itia ted by a ca rc in o g en .18 M am m alian liver is know n to possess es­trogen re cep to rs9 w hich m ed ia te gene regulation by estrogens in classic target tissues through re la tive ly w ell-defined m echanism s.2

A prom oter or co-carcinogen is defined as a com pound w hich increase the growth of tum ors induced by another agent bu t w hich cannot induce tum ors by itself. A curren t p roblem in the biology of tum ors induced by carcinogenic chem icals is the m echanism of action of prom oters.15 Such

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Figure 5. Case 2. Proliferating bile ducts in the central scar are the distinguishing feature of focal nodular hyperplasia. Hematoxylin and eosin stain, 6 0 x .

4 4 6 G IN D H A R T

agents are though t to prom ote tum or growth by a lte rin g the expression of genes. The two best studied promoters of rat hepatomas, partial hepatectomy and phénobarbital, have no obvious mecha­nism of gene regulation.15,22 Chemically in d u ced rat hepa tom as are th e b e s t studied animal model system for human chemical carcinogenesis and experimen­tal id en tif ica tio n o f es trogens as rat hepatoma promoters should lead to in­formation of broad significance in basic tumor biology.

References

1. Barrows, G. H., Christoph erson , W. M., and D r il l , V. A.: Liver lesions and oral con­traceptive steroids. J. Toxicol. Environ. Health 3:219-230, 1977.

2. Chan , L. and O’Malley , B. W.: Mechanism of action of the sex steroid hormones. 3 Parts. New Eng. J. M ed. 294:1322-1328, 1372-1381, 1430-1437, 1976.

3. Ch risto ph erso n , W. M. and Mays, E. T.: Liver tumors and contraceptive steroids: Ex­perience with the first one hundred registry patients. J. Nat. Cancer Inst. 58:167-171, 1977.

4. Christoph erson , W. M.: Personal Communi­cation, Oct., 1977. Two hundred cases of pill associated liver tumors to date.

5. Cleaver , J. E. and Pain ter , R. B.: Absence of specificity in inhibition of DNA repair by DNA-binding agents, co-carcinogens, and ste­roids in human cells. Cancer Res. 35:1773- 1778, 1977.

6. E d m o n d so n , H. A., e t a l .: L iver cell adenomas associated with use of oral contracep­tives. New Eng. J. Med. 294:470-472, 1976.

7. Edmondson, H. A., Reynolds, T. B., Hen ­derson , B., and Ben to n , B.: Regression of Liver Cell Adenomas Associated with Oral Contraceptives. Ann. Int. Med. 86:180-182, 1977.

8. E dmondson, H. A.: Tumors of the liver and intrahepatic bile ducts (Atlas of Tumor Pathol­ogy, Section 7, Fasc. 24). Washington, D. C. Armed Forces Institute of Pathology, 1958.

9. Eisen feld , A. J., St e n , R., Weinberg er , M., Haselbacher , A., H alpern , K., and Krak-

OFF, L.: Estrogen receptor in the mammalian liver. Science 191:862-865, 1976.

10. Fec h n e r , R. E.: Benign hepatic lesions and orally administered contraceptives: A report of seven cases and a critical review of the litera­ture. Human Path. 8:255-268, 1977.

11. I.A.R.C. Monographs on th e Evaluation o f Carcinogenic Risk to Man : Vol. 6, Sex Hormones, 1974.

12. Kay, S.: Nine year follow-up of a case of benign liver cell adenoma related to oral contracep­tives. Cancer 40:1759-1760, 1977.

13. Palmer, P. E., Christoph erson , W. M., and Wo l f e , H. J.: Alpha,-antitrypsin: A tumor pro­tein marker in oral contraceptive associated liver tumors. Lab. Invest. 36:20, 1977.

14. Pain ter , R. B.: Personal communication. Lab­oratory of Radiobiology, University of Califor­nia, San Francisco, 1978.

15. Peraino , C., F ry, M. R. J., St a ffe l d t , E., and Ch r isto ph er , J. P.: Comparative enhancing effects of phenobarbital, am obarbital, diphenylhydantoin, and dichlorodiphenyltri- chloroethone on 2-acetylam inofluorene- induced hepatic tumorogenesis in the rat. Cancer Research 35:2884-2890, 1975.

16. U. S. Morbidity and Mortality T rends Rela tiv e to Oral Co n tr a c eptiv e Us e , 1955-1975. Population Reports, Suppl. Series A, No. 4: A105-A132, May 1977.

17. Pryor, A. C., Co h en , R. J., and Goldman, R. L.: Hepatocellular carcinomas in a woman on long-term oral contraceptives. Cancer 40:884- 888, 1977.

18. Reu ber , M. D.: Influence on hormones on N-2-Fluorenyldiacetamide-induced hyperplas­tic hepatic nodules in rats. J. Nat. Cancer Inst. 43:445-452, 1969.

19. Rooks, J. B., Ory, H. W., Ishak, K. B., et a l .: The association between oral contraception and hepatocellular adenomas—a preliminary re­port. Int. J. Gynaecol. Obstet. 15:143-144,1977.

20. Sacket, J. S., Mosen th a l , W. T., H ouse, R. K., and Jeff r e y , R. F.: Scintillation scanning of liver cells adenomas. Amer. J. Roentg., Rad. Therapy to Nuclear Med. 113:56-60, 1971.

21. Schardein , J. L., Kamp, D. H., Woosley , E. T., and Jellv o , M. M.: Long-term toxicologic and tumorigenesis studies on an oral contracep­tive agent in albino rats. Toxicol. Applied Pharmacol. 61:10-23, 1970.

22. So l t , D. B., Med lin e , A., and Farber, E.: Rapid em ergence of carcinogen-induced hyperplastic lesions in a new model for the se­quential analysis of liver carcinogenesis. Amer. J. Path. 88:595-618, 1977.