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Hepatic Tumors: Possible Relationship to Use of Oral Contraceptives
Vol. 73 , No.2 Printed in U.S.A.
GASTROENTEROLOGY 73:386-394, 1977 Copyright © 1977 by the American Gastroenterological Association
PROGRESS IN HEPATOLOGY HEPATIC TUMORS: POSSIBLE RELATIONSHIP TO USE OF ORAL CONTRACEPTIVES GERALD KLATSKIN'
M.D.
Liver Study Unit, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
In 1970, Janet Baum of Ann Arbor submitted a paper to the Journal of the American Medical Association suggesting, on the basis of 3 cases, that oral contraceptives might be implicated in the development of benign hepatic tumors in young women. 1 To her annoyance, the editors rejected the paper with the comment that her suggestion was ridiculous! The first two published reports of hepatic cell adenoma in women on oral contraceptives appeared in 1971 (Reference 2 and S. Kay, personal communication, December 15, 1976) * and 1972. 3 • 4 However, in neither case did the authors comment on a possible etiological relationship between oral contraceptives and hepatic tumors, so that credit must go to Baum and her colleagues5 for drawing attention to this possibility in their report of 7 cases which appeared in Lancet in 1973. This paper excited great interest and touched off an avalanche of similar reports, which continue to appear in ever increasing numbers. As shown in table 1, the number of cases reported annually has risen dramatically, so that by September 1976 at least 117 had been described. In addition, 120 have been cited in the literature but not documented, bringing the total of 237 . The number in the latter group may represent an overestimate, because most have been reported from large registries for such tumors and may include tumors previously reported by others. Nevertheless, the number of documented cases is impressive. Most of the cases have been reported from the United States (table 1). If, indeed, oral contraceptives play a role in the pathogenesis of hepatic tumors, it may be anticipated that reports will begin to appear in increasing numbers from other parts of the world where these agents are in common use. Moreover, if the present Received February 7, 1977. Accepted February 28, 1977. This paper was presented at a meeting held on October 23, 1976 at Kurume University, Japan, to honor Professor Tashiro Nakashima on the 15th anniversary of his appointment as Professor of Pathology. Address requests for reprints to: Dr. Gerald Klatskin, Department of Medicine, Yale University, 333 Cedar Street, New Haven, Connecticut 06510. * Patient reported in Reference 2 started using oral contraceptives (Enovid E) in 1963, 4 years before appearance and resection of first hepatic cell adenoma in 1967; she continued on oral contraceptives (Ortho-Novum) until1973, 3 years after appearance and biopsy of second hepatic cell adenoma in 1970. She is alive and well in 1976, and showed no evidence of a tumor on liver scan in October 1976. 386
trend in reporting continues, hepatic tumors may prove to be an even more serious problem than thromboembolic disease as a complication of oral contraceptive therapy. Initially, the tumors encountered were benign, being variously classified as hepatic cell adenoma (S. Kay, personal communication, and References 2 and 6 through 26), benign hepatoma,~5 • 27- 33 focal nodular hyperplasia, 16 • 25• 26• 3 4-4 1 or hamartoma. 26• 42-4 4 • However, more recently, malignant tumors of several types have been reported, including hepatocellular carcinoma (References 25, 37, 42, and 45 through 48, and A. H. Baggenstoss, personal communication), mixed hepatocellular and ductular carcinoma, 49 and hepatoblastoma50 (table 2). Because most authorities 5 L 52 consider the terms hepatic cell adenoma and benign hepatoma on the one hand and focal nodular hyperplasia and hamartoma on the other as synonymous, I have, for the purposes of of this discussion, regrouped the benign tumors associated with oral contraceptives into two categories, hepatic cell adenoma and focal nodular hyperplasia. Although some of the reported tumors do not meet generally accepted criteria for distinguishing between hepatic cell adenoma and focal nodular hyperplasia, 51. 52 as pointed out by others, 22 • 53 I have made no attempt to reclassify any of the lesions, particularly because these criteria may be open to question, a point that is considered later. As can be seen in table 3, over one-half of the patients had used oral contraceptives for more than 5 years. However, in 10% the period of exposure had been as brief as 6 to 12 months, and in 9 cases the tumor was discovered 6 months to 10 years after cessation of oral contraceptive therapy.6, !Ht, 31, 34, 38,41 The contraceptive agents employed in this group included almost all combinations of synthetic estrogens and progestogens in common use (table 3). However, it will be noted that those containing mestranol as the estrogenic component outnumbered those containing ethinyl estradiol. This has led Edmondson et al. 18 to propose that mestranol has a greater oncogenic potential than ethinyl estradiol. However, as pointed out by others, 54 • 55 this view is open to question, because mestranol has been in use significantly longer than ethinyl estradiol, so that women on oral contraceptives for over 5 years were more likely to have received mestranol. In patients with hepatic cell adenoma (table 4), the major presenting complaint in over two-thirds of the
TABLE 1. Hepatic tumors encountered in women using
oral contraceptives Year and origin Year reported 1971 1972 1973 1974 1975 1976 Origin of reports United States United Kingdom Canada Sweden Hungary France Italy Greece Norway Total
Case reports
Cases cited: no details
Total
90 30
1 1 11 14 121 89
1 1 11 14 31 59
216 7 4 4 2 1 1 1 1
96 7 4 4 2 1 1 1 1
120
117
120
237
TABLE 2. Types of hepatic tumor encountered in women using
oral contraceptives Tumor type Diagnoses reported Hepatic cell adenoma Benign hepatoma Focal nodular hyperplasia Hamartoma Malignant hepatic tumor Current diagnostic classification Benign tumors Hepatic cell adenoma Focal nodular hyperplasia Malignant tumors Hepatocellular carcinoma Hepatoblastoma Mixed hepatocellular-ductular Total a
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August 1977
Case reports
62 17 21 7 10
Cases cited: no details 41 61 7 11
79 28
41 68
8 1 1
11
117
120
Total"
103 17 82 14 21
120 (51) 96 (41) 19 (8) 1 (0.4) 1 (0.4) 237
Percentages are given in parentheses.
group was acute abdominal pain, often accompanied by shock, attributable to either rupture of the tumor with hemoperitoneum or hemorrhage into the tumor. By contrast, in those with focal nodular hyperplasia, one-half had asymptomatic tumors that were discovered unexpectedly during laparatomy for other unrelated diseases. Nevertheless, in this group too, 21% presented with acute abdominal pain caused by rupture of the tumor with hemoperitoneum or hemorrhage into the tumor. Except for the absence of cirrhosis in all cases, the clinical features in women with malignant hepatic tumors associated with the use of oral contraceptives were similar to those that usually accompany such tumors, so that they will not be discussed further . Hepatic function in patients with benign tumors was
remarkably well preserved, even when the tumors were large. Thus, in only a minority of the patients tested were slight elevations in serum bilirubin, alkaline phosphatase, and transaminase noted, and invariably, tests for a-fetoprotein yielded negative results (table 5). Technetium sulfur colloid scans of the liver revealed defects in most but not all cases of hepatic cell adenoma and focal nodular hyperplasia (table 5). As might be anticipated, all tumors less than 4 em in diameter escaped detection. The defects did not appear to depend on the presence within the tumor of fibrosis, hemorrhage, or necrosis. Observations in one of our own patients with a large area of focal nodular hyperplasia in the left lobe of the liver suggested that the defect demonstrated on technetium sulfur colloid scan was attributable to TABLE 3. Use of oral contraceptives by women with hepatic tumors Focal Heyatic nodular Maligeel ad- hyperTotal nant enoma Parameter (10 (117 cases)" plasia (79 (28 cases) cases) cases) Years <1 1-5 >5 Not reported Type employed Mestranol, plus: Norethynodrel Norethindrone Lynestrenol Ethynodiol Chlormadinone N orethisterone Progestogen type? Ethinyl estradiol, plus: Dimethisterone Norgestrel Norethindrone Progestogen type? Not reported Total Mestranol Ethinyl estradiol a
8 23 43 5
2 10 15 1
1 7 2
11 (10) 40 (36) 60 (54) 6
7 8 1 3 2
6 8 3 5
1
14 16 5 8 2 3 29
1
2
1
1 1
2
2
5
29 1 6 1 2 19
1 9 2 2 26 77 (85) 14 (15)
Percentages are given in parentheses.
TABLE 4. Presenting complaints in women with benign hepatic tumors
associated with the use of oral contraceptives• Presenting complaints Acute abdominal pain, shock Tumor rupture, hemoperitoneum Tumor hemorrhage Palpable mass Chronic or intermittent pain Hepatomegaly Asymptomatic: tumor an unexpected finding at laparotomy a
Hepatic cell adenoma (79 cases)
Focal noduJar hyperplasia (28 cases)
Total (107 cases)
32 (41)
4 (14)
36 (34)
21 17 1 1 7
(27) (22) (1) (1)
(9)
Percentages are given in parentheses.
2 4 4 0 14
(7) (14) (14) (50)
23 21 5 1 21
(21) (20) (5) (1) (20)
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TABLE 5. Functional, scintiscan, and arteriographic findings in women with hepatic tumors associated with the use of oral contraceptives Findings
Hepatic functional abnormalities Serum bilirubin Serum alkaline phosphatase Serum transaminase a-Fetoprotein Hepatic scintiscan defects Patients Tumors Tumors 1-3 em Tumors >3 em Tumor fibrosis No fibrosis Tumor hemorrhage No hemorrhage Tumor necrosis No necrosis Arteriographic abnormalities Patients Tumors Enlarged hepatic artery Peripheral arterial supply Increased vascularity Avascularity Tumor "blush"
Hepatic Focal cell ade- nodular noma hyperplas1a
Total(%)
1118 5/17 7/17 0/9
0!3 113 0/3 0/2
1121 (5) 6/20 (30) 7/ 20 (35) 0!11
11/15 15/18 0/3 13/16 2/5 10/13 9/12 3/6 6/6 5/11
6/6 7/9 0/2 7/7 4/5 3/4 4/4 3/5 3/3 4/6
17/21 (81) 22/27 (81) 0/5 20/23 (87) 6/10 (60) 13/ 17 (76) 13/16 (81) 6/11 (55) 9/9 (100) 9/17 (53)
15/ 15 17/19 7/16 8/16 14/18 2/17 7/16
4/6 5/7 0/5 115 4/5 0/5 115
19/21 (90) 22/26 (85) 7/21 (33) 9/21 (43) 18/23 (78) 2/22 (9) 8/21 (38)
failure of the reticuloendothelium to take up the colloid, because the tumor incorporated selenomethionine normally and exhibited a normal distribution of intravenously injected indium-113m, indicating normal hepatocellular synthetic activity and normal blood flow , respectively. Arteriographic abnormalities were demonstrable in most but not all of the tumors investigated (table 5). As previously pointed out by Goldstein et al. ,56 the findings in hepatic cell adenoma and focal nodular hyperplasia were indistinguishable. The principal features included enlargement of the hepatic artery, a peripheral arterial blood supply, increased vascularity, and a tumor "blush" during the venous phase. Rarely, the tumor appeared avascular, owing to intramural hemorrhage, necrosis, or infarction. Long term follow-up data on the clinical course are available in only a minority of the patients with hepatic tumors associated with the use of oral contraceptives (table 6). However, of the 107 with hepatic cell adenomas or focal nodular hyperplasia, 99 (93%) were still alive at the time of reporting, 2 months to 6 years after detection of the tumor. All8 deaths occurred in patients with hepatic cell adenomas, and were attributable to rupture with hemoperitoneum in 7, 5· 8· 15· 27· 28· 30 and intramural hemorrhage in 1. 7 Of those who died, 4 had undergone lobectomy or resection of the tumor5· 7· 28· 30 , 1 had been subjected to packing and suture of a ruptured tumor followed by hepatic artery ligation, 8· 15 and 3 had died of tumor rupture and hemoperitoneum before surgical treatment could be instituted. 27· 30
Surgery was remarkably well tolerated in this group; the survival rate was 96% in the 92 subjected to resection or lobectomy, 67% in the 3 whose tumors were packed, drained, and/or sutured, .and 100% in the 7 nonhemorrhagic tumors subjected to biopsy alone. Two of the 88 successfully resected tumors recurred, both in patients who continued to use oral contraceptives. In the first case (Reference 2 and S. Kay, personal communication), a large hepatic cell adenoma was discovered in the right lobe 21/2 years after resection of a similar tumor in the same lobe. In the second, 42 a large tumor classified as focal nodular hyperplasia was found in the right lobe 6 years after lobectomy for a similar large hemorrhagic tumor in the contralateral lobe. Both recurrent tumors, which were subjected to biopsy alone, regressed after withdrawal of oral contraceptives. In the first case (8. Kay, personal communication), the tumor was no longer evident on scan 5 years later, and in the second,42 it was significantly smaller on scan 5 months later. Of 12 other tumors left in situ, u , 12, 1s, 22, 24, 32, 35, 38, 40, 42 · 44 the four largest, including two classified as hepatic cell adenoma22· 32 and two as focal nodular hyperplasia,35· 40 showed significant regression as documented by scan 22 · 35· 40 or arteriography32 after cessation of oral contraceptive therapy over periods ranging from 3 months to 3 years. In none of the tumors left in situ was there evidence of progression or malignant transformation. Of the patients with malignant hepatic tumors associated with oral contraceptives, 5 have died, 1 during the course of lobectomy, 42 1 a year after lobectomy (Reference 50 and G. Klatskin, personal follow-up on case reported in Reference 50) and 3 who were not treated. 42 · 48 Three patients with hepatocellular carcinoma were still alive and well at the time of reporting1 2 months42 and 2 1 year after lobectomy.45· 46 The duration of survival of the 2 remaining cases, 1 given chemotherapy4 7 and the other subjected to hepatic artery ligation followed by chemotherapy, 49 has not been reported. According to authoritative sources, 5L 52 hepatic cell adenoma and focal nodular hyperplasia are unrelated tumors, each with distinctive morphological features, TABLE 6. Clinical course of women with benign hepatic tumors associated with the use of oral contraceptives Clinical course
Survived Died After surgery Resection Packing or drainage Biopsy No surgery Total Recurrence of tumor after successful resection Regression of unresected tumors Progression of unresected tumors Malignant transformation of unresected tumors
No. (%)
99/107 (93)
4/92 (4) 1/3 (33)
017 3/5 (60) 8/107 (7) 2!88 4/14 0/14 0/14
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that show no tendency to undergo malignant transformation. If, then, oral contraceptives are implicated in the pathogenesis of hepatic tumors, it is surprising that they produce lesions of such diverse structure and biological behavior. This raises two questions: first, do currently accepted morphological criteria clearly distinguish between hepatic cell adenoma and focal nodular hyperplasia, and, second, is it conceivable that, at least under conditions of oral contraceptive therapy, hepatic cell adenoma and focal nodular hyperplasia represent two phases in the development of the same lesion, and that such lesions may undergo malignant transformation? As usually described, 51· 52 hepatic cell adenoma presents as a solitary, relatively soft, sharply circumscribed mass of variable size. Multiple tumors are not rare, and occasionally the tumor may be pedunculated. On cross-section, the tumor is lighter in color than the adjacent intact liver, has a fleshy appearance, and may show foci of hemorrhage. Occasionally, it is yellow or green in color because of bile staining and/or fatty infiltration. The cut surface may show ill-defined lobulation, but is never frankly nodular or fibrotic. Microscopically, the neoplastic cells closely resemble normal hepatocytes and show no features suggestive of malignancy. However, particularly at the periphery of the tumor, they may be larger and paler than normal hepatocytes, owing to increased deposition of glycogen, and often are arranged in the form of thick plates , rosettes, or pseudoducts, some of which may contain inspissated bile. Deeper in the tumor, the neoplastic cells tend to be smaller and darker and often show an irregular plate pattern with an unusually delicate reticulin network. Frequently, the tumor contains numerous thin-walled vessels resembling central veins, but characteristically there is a paucity or absence of portal triads and bile ducts. In contrast to hepatic cell adenoma, focal nodular hyperplasia usually presents as a firm, grossly nodular mass of variable size which, on cross-section contains a central stellate fibrous core with radiating branching septa that subdivide the tumor into nodules. Microscopically, the lesion closely resembles that of an inactive cirrhosis. Characteristically, the fibrous septa contain numerous ductules, vessels, and mononuclear inflammatory cells. In some cases, the larger vessels are thickened as a result of subintimal fibrosis or hypertrophy of the media, occasionally leading to obliteration of their lumens. Although these morphological criteria usually serve to differentiate between hepatic cell adenoma and focal nodular hyperplasia, it is evident from our own experience and that reported in the literature that they do not do so in all cases. Indeed, of six benign hepatic tumors that we have studied recently, only two could be adequately classified on the basis of these criteria. Thus, of three with the typical gross and microscopic features of hepatic cell adenoma, two were lobulated and traversed by septa containing tightly packed islands of small neoplastic cells interpersed with numerous ductules, small vessels, and delicate fibrous bands, features suggestive
389
of focal nodular hyperplasia. Indeed, these 2 cases were previously reported by Stauffer et al. 40 as examples of focal nodular hyperplasia. Similar difficulty was encountered in classifying two of our tumors which had the typical microscopic features of focal nodular hyperplasia but which, on gross inspection, were smooth in contour and soft in consistency, and, on cut section, showed no evidence of nodulation or central stellate scarring. Recently, Goldfarb 23 has described 2 similar cases of focal nodular hyperplasia, 1 of which was localized within a hepatic cell adenoma. Observations such as these suggest that hepatic cell adenoma and focal nodular hyperplasia may be related lesions, at least in the case of those associated with the use of oral contraceptives, or, alternatively, that the stimulus to tumor growth affects both entodermal and mesenchymal elements in the liver to a variable degree in different tumors. The fact that both benign and malignant hepatic tumors have been encountered in women on oral contraceptives invites speculation that, at least in some case, the former may undergo malignant transformation. Although no examples of such transformation have been reported in nonusers of oral contraceptives, 51· 52 there is suggestive evidence that this may have occurred in several cases associated with the use of such agents. Thus, in 2 women on oral contraceptives seen at the Mayo Clinic, unequivocal areas of hepatocellular carcinoma were found within a hepatic cell adenoma (A. H . Baggenstoss, personal communication ). Similarly, in the case reported by Davis et al. 46 hepatocellular carcinoma was encountered within a benign tumor which was classified as focal nodular hyperplasia but, on subsequent review (H. Popper, personal communication) , was reclassified as a typical example of hepatic cell adenoma. In addition, both Galloway et al. 32 and Goldfarb23 have described foci of hepatic cellular dysplasia and atypia within hepatic cell adenomas considered premalignant. The possibility that the other malignant hepatic tumors reported in women on oral contraceptives may have evolved from benign lesions cannot be assessed on the basis of available evidence. · Because the suggestive evidence of malignant transformation in benign hepatic tumors appears to be limited to women on oral contraceptives, the possibility that such tumors differ in other respects from those encountered in non-"pill" users merits consideration. For purposes of comparison I have culled from the literature 138 cases of hepatic cell adenoma6· 18· 21. 30· 32 · 41. 45, 52 · 54 · 57- 73 and 234 cases of focal nodular hyperplasia38, 39, 41. 52, 54, 64, 69, 72 • 74-87 reported in patients with no history of exposure to oral contraceptives. Although these do not comprise a complete inventory, they do include most cases reported between 1938 and 1976. It is recognized that orne of the patients in this group may have received oral contraceptives that were not reported. However, if a significant number fell into this category, it would tend to obscure rather than exaggerate any differences between users and nonusers of such agents. Also, the classification of some of the tumors may be open to question, but this is equally true of the
PROGRESS IN HEPATOLOGY
390
oral contraceptive-associated tumors. As shown in table 7, 10% of the patients with non-pill related hepatic cell adenomas were male, and 14% were children. However, it is noteworthy that 59% were women of childbearing age. The most striking clinical difference between the two groups was the significantly higher incidence of tumor rupture with hemoperitoneum or hemorrhage into the tumor in users of oral contraceptives (66%) than in nonusers (25 %). In contrast, whereas 20 % of the tumors unrelated to the pill were asymptomatic and discovered unexpectedly at laparotomy or necropsy, only 9% of those associated with oral contraceptives were asymptomatic. In general, the hepatic cell adenomas in users of the pill were larger than those in nonusers, being 5 em or larger in diameter in 97% of the former and 73 % of the latter. In addition, the tumors in the users exhibited rupture (39 %) and intramural hemorrhage (71 %) more frequently than in nonusers (14 and 38 % respectively) , and were the only ones occasionally accompanied by peliosis hepatis (table 7). As shown in table 8, although 30% of the nonusers of oral contraceptives with focal nodular hyperplasia were male, 60% were women of childbearing age. PresentaT A BLE
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tion with acute abdominal pain due to rupture of the tumor with hemoperitoneum or hemorrhage into the tumor was significantly more frequent in users (21 %) than in nonusers (less than 1%) , although the incidence in the former was significantly lower than in users with hepatic cell adenoma (66 %). In contrast, asymptomatic focal nodular hyperplasia was less common in users (50 %) than in nonusers (76%). As in the case of hepatic cell adenoma, tumors classified as focal nodular hyperplasia were significantly larger in users than in nonusers, being 5 em or larger in 79 % of the former and only 24% in the latter. Similarly, the incidence ofrupture (14 %) and hemorrhage into the tumor (21 %) in those associated with oral contraceptives was significantly higher than in those unassociated with such agents (less than 1% and 2%, respectively). Also, the only instance of peliosis hepatis was encountered in a patient on oral contraceptives. The larger size and the propensity of the benign hepatic tumors to bleed in women on oral contraceptives suggest that such agents may affect the vasculature of these lesions. Indeed, this appears to be the case. As previously noted by others, almost all of the hepatic cell adenomas we have studied exhibited significant patchy
7. Hepatic cell adenomas: comparison of features in women on oral contraceptives and in patients with no reported use of such agen ts P arameter
Sex Ma le Female Age, yr < 1- 15 19-50
No oral contraceptives (138 cases) "
14 (10) 124 (90)
0 79 (100)
7 (14)
0 78 (99)
F
>50 N ot r epor ted Presenting complaint Acute abdominal pain, shock Hemoperitoneum Hemorrhage into tumor Palpa ble mass Chroni c or intermittent pain Hepatomegaly Asymptomatic tumor found at: Laparotomy Necropsy Tumor Number Single 2 or more Not reported Size, em <5 5-10 > 10 Not reported Gross appearance Pedunculated Ruptured Hemorrhagic Peliosis hepatis a Percentages are given in parentheses. ' NS, not significant.
1 (1)
0
32 (41)} 20 (25) 18 (23) 1 (1) 1 (1)
~ (9)
=
31 (61) 30 13 (25) 87
21 14 51 23
(15)} (10) (37) (17)
2 (1) }
62 (78) 17 (22)
Significance of differ ence, Yates correction (P )'
15 (11) } 12 (9)
100 (75) 33 (25) 5
8.92 ( < 0.01) 30.95 ( < 0.001) 16.48 ( < 0.001)
32.57 ( < 0.001) 4.02 ( < 0.05) 10.59 (< 0.01) NS
NS
NS NS
2 (3) 28 (39)} 42 (58) 7
35 (27) 43 (33) } 54 (41) 6
16.11 ( < 0.001)
2 31 56 3
16 (12) 20 (14) 53 (38) 0
4.29 ( < 0.05) 15.76 ( < 0.001) 19.92 ( < 0.001) NS
(3) (39) (71) (4)
16.11 ( < 0.001)
x',
August 1977 TABLE
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8. Focal nodular hyperplasia: comparison of features in women on oral contraceptives and in patients with no reported use of such agents Parameter
Oral contraceptives (28 cases)a
No oral contraceptives (234 cases)a
Significance of difference Yates correction (P)•
x',
Sex Male
Female Age, yr < 1-15 19-50 > 50 Not reported Presenting complaint Acute abdominal pain, shock Hemoperitoneum Hemorrhage into tumor Palpable mass Chronic or intermittent pain Hepatomegaly Asymptomatic tumor found at: Laparotomy Necropsy Others Tumor Number Single 2 or more Size, em <5 5-10 > 10 Not reported Gross appearance Pedunculated Ruptured Hemorrhagic Peliosis hepatitis
0 28 (100) 0
27 (96) 1 (4) 0
4 (14)} 2 (7)
4 (14) 4 (14) 0
1~ (50)} 0
24 (86) 4 (14)
4 (21) 12 (63)} 3 (16)
70 (30) 164 (70) 11 (5)
174 (84) F = 124 22 (11) 27
~ (<1)} 22 (9) 17 (7) 7 (3)
83 (35)} 96 (41)
NS NS NS
34.72 (< 0.001)
NS NS NS 7. 73 (< 0.01)
8 (3)
190 (81) 44 (19)
NS NS
168 (76) 41 (19) }
23 .85 ( < 0.001)
11 (5)
9
14
0
0
4 (14) 6 (21)
1 (<1) 5 (2)
1 (4)
0
23 .85 ( < 0.001)
NS 26 .86 ( < 0.001) 27.86 ( < 0.001) NS
" Percentages are given in parentheses. • NS, not significant.
congestion of the sinusoids. In addition, two of the tumors had numerous unusual vascular lesions leading to hemorrhage, peliosis hepatis, scarring, and infarction. The earliest vascular lesion in these cases was an eccentric hemorrhage around a thin-walled vein resulting in or associated with dissolution of adjacent tumor cells. In more advanced lesions, the hemorrhage encircled the vein, ultimately producing cyst-like cavities typical of peliosis hepatis. Some of the larger areas of hemorrhage showed evidence of organization and fibrosis. A second and apparently unrelated type of vascular lesion was characterized by subintimal fibrosis and medial hypertrophy in medium-sized arterioles resulting in constriction of their lumens, and, in some instances, the development of infarction. There is suggestive evidence that oral contraceptives may affect normal liver tissue as well. Thus, in 4 women on such agents, Winkler and Poulsen88 observed hepatomegaly and periportal and midzonal congestion, which, in 3 cases, receded after cessation oftherapy. In another case, reported by Pliskin, 89 hepatic arteriography revealed numerous focal collections of contrast material scattered through the liver, which appeared during the
late arterial phase and became more prominent during the parenchymal and venous phases. These were interpreted as evidence of peliosis hepatis, although wedge biopsy of the liver showes only dilation ofthe sinusoids. We too have observed hepatomegaly associated with peripheral and midzonal sinusoidal congestion in 2 women on oral contraceptives. In 1 of these, hepatic arteriography demonstrated the same type of pooling of contrast material described by Pliskin. 89 Although laparotomy revealed numerous small bluish areas on the surface of the liver, wedge biopsy showed congestion of the sinusoids but no peliotic cavities. Such observations suggest that the vascular changes observed in hepatic tumors associated with oral contraceptives may be due to the direct hormonal effects of these agents rather than to tumor growth. Several lines of circumstantial evidence are consistent with this interpretation, and include: (1) the greater frequency of vascular lesions in users than in nonusers of oral contraceptives (tables 7 and 8), (2) the occasional occurrence of hemorrhage and rupture in oral contraceptive-associated tumors during menstruation/ 8 pregnancy, 31 or the postpartum period, 10• 2 1. 25 (3) reports of sinusoidal
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congestion and peliosis hepatis in individuals given synthetic androgenic-anabolic steroids closely related in structure to those used in oral contraceptives, 9 (}-95 and (4) the occurrence of sinusoidal congestion in female rats given norethynodrel. 96 Currently available evidence implicating oral contraceptives in the pathogenesis of hepatic tumors, although impressive, must be regarded as circumstantial rather than conclusive. Considering that only approximately 400 case~ of hepatic cell adenoma and focal nodular hyperplasia were reported in non-pill users between 1937 and 1976 (tables 7 and 8), the fact that over 200 cases have been encountered in women on oral contraceptives in the past 3 years (table 1) strongly suggests an etiological relationship. However, relatively large numbers of undocumented cases have been reported from four centers that have organized registries for oral contraceptive-associated hepatic tumors. 1 • 5 • 16 ' 18 • 2'· 26 ·0bviously, this introduces a bias in reporting that favors the relationship, as illustrated by the fact that 168 (96 %) of the 177 cases :r:eported from these centers were pill-associated. Another potential source of bias that may inflate the number of cases stems from the failure of these registries to indicate whether or not any of their cases have been previously reported by others. What may be rriore realistic data on the relative frequency of benign hepatic tumors in users and nonusers of oral contraceptives have been reported from Sweden by Grabowski et alY These investigators, who reveiwed all of the biopsy and autopsy material in the files of .the only hospital in Malmo and the two major hospitals in Lund that together serve a population of over 1112 million individ· uals, found that between 1964 and 1974, there were 8 cases of focal nodular hyperplasia in women of childbearing age, only 4 of whom had used oral contraceptives. Kay 9 7 suggests that the incidence may be even lower, because in the 8-year prospective study of oral contraceptives being conducted by the Royal College of General Practitioners in Great Britain, not one hepatic tumor has been encountered in women receiving such ag-ents with a total exposure of 54,850 patient-years, or in any of their controls. Obviously, a study of this type does not exclude the possibility of a relationship between oral contraceptives and hepatic tumors, but does suggest that if these agents are oncogenic, they produce tumors only rarely. Two clinical observations that point to an etiological role for oral contraceptives are the reported regression of benign hepatic tumors after the cessation of such therapy (References 2, 22, 32, 35, 40, and 42, and S. Kay, personal communication) and the recurrence of the tumor after resection in the same (Reference 2 and S. Kay, personal communication) or contralateral lobe42 in patients who continued to use such agents. That hormonal factors may play a role in the pathogenesis of hepatic tumors is strongly suggested by the fact that approximately 60% of spontaneous hepatic cell adenomas and focal nodular hyperplasia are encountered in women of childbearing age (tables 7 and 8), and that occasionally such tumors appear during preg-
nancy4 1• 69 • 71• 85• 86 or the postpartum period. 25 • 30 • 69 Other evidence consistent with such a relationship includes reports of both benign and malignant hepatic neoplasms in patients with endocrine tumors, such as adenocarcinoma of the ovary4 1 and carcinoma of the adrenal, 44 and in patients receiving various hormonal agents for purposes other than contraception, including conjugated natural estrogens 25 • 3 7 synthetic estrogens, 98 • 99 and synthetic androgenic-anabolic steroids. 10(}- 104 Of probable significance is the fact that all of these synthetic steroids, like those in oral contraceptives, are C17 a-alkyl derivatives .of testosterone. The results of animal experiments have been inconsistent. In strains of mice highly susceptible to spontaneous hepatic neoplasms, Enovid, a commonly employed Contraceptive containing norethynodrel and mestranol, failed to increase the incidence of hepatic tumors, even when large doses were administered. 105 However, in susceptible rats, a number of C 17 a-alkyl derivatives of testosterone increased the expected frequency ofJiver ceU tumors. 106 Because such agents are known to induce proliferation ofthe endoplasmic reticulum and the production of microsomal hydroxylating enzymes, it has been suggested that their oncogenic effects may be mediated by this adaptive process. 107 In the last analysis, the question of whether or not oral contraceptives are oncogenic cannot be resolved until accurate data are available on the relative incidence of hepatic tumors in users and nonusers of such agents. Nothing short of a national or large regional registry of all hepatic tumors, including those encountered in both sexes and at all ages, can provide such iriformation. In addition, it is reasonable to expect that the panel of expert pathologists seleeted to review all cases would clarify the interrelationships among hepatic cell adenoma, focal nodular hyperplasia; and hepatocellular carcinoma and provide more uniform and acceptable criteria for their differentiation. Although this is a formidable and costly undertaking, health authorities would be well advised to organize such a registry as soon as possible, because the problem involved is a potentially serious one that will be of concern to millions of women, particularly once reports of hepatic tumors in users of oral contraceptives reach the public press, which they are bound to do. To reassure their patients and to provide sound advice on the risks involved, physicians will need more precise information on the oncogenic potential of oral contraceptives than is currently available. REFERENCES 1. Baum JK: Liver tumors and oral contraceptives. JAMA 232:1329, 1975
2. Kay S, Shatzki PF: Ultrastructure of a benign liver cell adenoma. Cancer 28:755-762, 1971 3. Horvath E, Kovacs K, Ross RC: Ultrastructural findings in a well-differ entiated hepatoma. Digestion 7:74-82, 1972 4. Horvath E, Kovacs K , Ross RC: Benign hepatoma in a young woman on cotraceptive steroids. La ncet 1:357-358, 1974 5. Baum JK, Holtz F , Bookstein JJ, et al: Possible association between benign hepatomas and oral contraceptives. Lancet 2:926-929, 1973
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6. Davis JB, Schenken JR, Zimmerman 0 : Massive hemoperitoneum from rupture of benign hepatocellular adenoma. Surgery 73:181-184, 1973 (see also Schenken21 ) 7. Knapp WA, Ruebner BH: Hepatomas and oral contraceptives. Lancet 1:270-271, 1974 8. Vosnides G, Brander W, O'Keefe B, et al: Liver hamartomas in patients on oral contraceptives. Br Med J 3:580, 1974 (see also Clinicopathological Conference 15 ) 9. Bisson A, Duron PL, Fagniez PL, et al: Adenomatose hepatique et contraceptifs oraux. Nouv Presse Med 3:2079-2082, 1974 10. Antoniades K, Brooks CE Jr: Hemoperitoneum from liver cell adenoma in a patient on oral contraceptives. Surgery 77:137139, 1975 11. Model DG, Fox JA, Jones RW: Multiple hepatic adenomas associated with an oral contraceptive. Lancet 1:865, 1975 12. Ameriks JA, Thompson NW, Frey CF, et al: Hepatic cell adenomas, spontaneous liver rupture, and oral contraceptives. Arch Surg 110:548-556, 1975 13. Block GE: Discussion of paper by Ameriks et al. 12 Arch Surg 110:556-557, 1975 14. Large AM: Discussion of paper by Ameriks et al.' 2 Arch Surg 110:557' 1975 15. Clinicopathological Conference: A patient's life. Br Med J 3:209-213, 1975 16. Nissen ED, Kent DR: Liver tumors and oral contraceptives. Obstet Gynecol 46:460-467, 1975 17 . Antoniades K, Campbell WN, Hecksher RH, et al: Liver cell adenoma and oral contraceptives: double tumor development. JAMA 234:628-629, 1975 18. Edmondson HA, Henderson B, Benton B: Liver cell adenomas associated with use of oral contraceptives . N Eng! J Med 294:470-472, 1976 19. Baek SM, Sloane CE, Futterman SC: Benign liver cell adenoma associated with use of oral contraceptive agents. Ann Surg 183:239-242, 1976 20. Littman I, Berentey E, Magyar E, Balazs M: Anticoncipiens kezeles kapcsan letrejovo maj-adenoma operalt esete. Orv Hetil 117:159-161, 1976 21. Schenken JR: Hepatocellular adenoma: relationship to oral contraceptives? JAMA 236:559, 1976 22. Hilliard JL, Graham DY, Spjut HJ: Hepatic adenoma: a possibl€ complication
wB:
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Med J 74:113, 1975 34. Mays ET, Christopherson WM, Barrows GH: Focal nodular hyperplasia of the liver:possible relationship to oral contraceptives. Am J Clin Pathol 61:735-746, 1974 35. Ross D, Pina J, Mirza M, et al: Regression of focal nodular hyperplasia after discontinuation of oral contraceptives. Ann Intern Med 85:203-204, 1976 36. Christopherson WM, Mays ET, Barrows GH: Liver tumors in women on contraceptive steroids. Obstet Gynecol 46:221-223 , 1975 37. Christopherson WM: Liver tumours and the pill. Br Med J 4:756, 1975 38. Fisher AWF, Curry B, Jacques J: Solitary liver nodules. Can Med Assoc J 112:1196-1200, 1975 39. Shojania NG, Hogg GR: Isolated liver nodules. Gastroenterology 69:28-34 , 1975 40. Stauffer JQ , Lapinski MW, Honold DJ, et al: Focal nodular hyperplasia of the liver and intrahepatic hemorrhage in young women on oral contraceptives. Ann Intern Med 83:301-306 , 1975 41. Grabowski M, Stenram U, Berqvist A: Focal nodular hyperplasia of the liver, benign hepatomas, oral contraceptives and other drugs affecting the liver. Acta Pathol Microbiol Scand (A) 93:615-622, 1975 42. Mays ET, Christopherson WM, Mahr MM, et al: Hepatic changes in young women ingesting contraceptive steroids: hepatic hemorrhage and primary hepatic tumors. JAMA 235:730732, 1976 43 . Bartok I, Garas S, Szabo L: Oral contraceptives and benign liver tumour. Lancet 1:479-480 , 1976 44. O'Sullivan JP, Wilding RP: Liver hamartomas in patients on oral contraceptives. Br Med J 3:7-10, 1974 45. Hermann RE, David TE: Spontaneous rupture of the liver caused by hepatomas. Surgery 74:715-719, 1973 46 . Davis M, Portmann B, Searle M, et al: Histological evidence of carcinoma in a hepatic tumour associated with oral contraceptives . Br Med J 4:496-498 , 1975 47 . Glassberg AB, Rosenbaum EH: Oral contraceptives and malignant hepatoma. Lancet 1:479, 1976 48. Tigarid F, Ferlazzo B, Barrile A: Oral contraceptives and malignant hepatoma. Lancet 2:196, 1976 49 . O'Sullivan JP, Rosswick RP: Oral contraceptives and malignant hepatic tumours. Lancet 1:1124-1125, 1976 50. Meyer P, LiVolsi VA, Cornog JL: Hepatoblastoma associated with an oral contraceptive. Lancet 2:1387 , 1974 51. Edmonson HA: Tumors of the Liver. Washington, DC, Armed Forces Institute of Pathology, 1958 52. Ishak KG, Rabin L: Benign tumors of the liver. Med Clin North Am 59:995-1013, 1975 53. Mays ET: Standard nomenclature for primary hepatic tumors. A critical need . JAMA 236:1469-1470, 1976 54. Barnes AC: Liver-cell adenomas and oral contraceptives. New Eng! J Med 294:1061, 1976 55. Evrard JR: Liver-cell adenomas and oral contraceptives. New Erigl J Med 294:1061, 1976 56. Goldstein HM, Neimari HL, Mena E, et al: Angiographic findings in benign liver cell tumors. Radiology 110:339-343, 1974 57 ~ Wilens G: Adenoma of the liver. Am J Dis Child 55:792-797, 193,8 58 . PackaJ;"d GB , StevensonAW: Hepatoma in infancy and childhoocl: discussion arid. report of a patient treated by operation. St,rrgery 15: 292~306, i944 59. Duckett JY/, Montgomery HG: Resection of primary liver tumors .. Surgery 2!.4.55-469, 1947 60. ~tunipf HH, Liber. FL: Hepatocellular adenomatosis: report of a case .with liver function studies. Am J Med 17:887-890, 1954 61. Henson SW ~r, ·Gray HK, Dockerty MB: Benign tumors of the liver. 1. Adenomas. Surg Gynecol Obstet 103:23-30, 1956
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62. Jager BV, Nugent CA: Solitary benign adenoma of the liver associated with progressive hepatic insufficiency: report of a case with autopsy findings . Arch Intern Med 101:645-649, 1958 63 . Berkheiser SW: Recurrent liver cell adenoma. Gastroenterology 37:760-765, 1959 64. Longmire WP Jr, Marable SA: Clinical experiences with major hepatic resections. Ann Surg 154:460-472, 1961 65. Largiader A: Leberzelladenoma ohne Zirrhose. Gastroenterologia 99: 1-21, 1963 66. Pa lubinskas AJ, Baldwin J, McCormack KR: Liver cell adenoma: angiographic findings and report of a case. Radiology 89:444-447' 1967 67. Scorer GG: Spontaneous rupture of a hepatic adenoma: a possible hazard of flying. Br J Surg 56:633-635, 1969 68. Garancis JC , Tang T , Panares R, et al: Hepatic adenoma: biochemical and electron microscopic study. Cancer 24:560-568, 1969 69 . Malt RA, Hershberg RA , Miller WL: Experience with benign tumors of the liver. Surg Gynecol Obstet 130:285-291, 1970 70. Sackett JF, Mosenthal WT, House RK , et a!: Scintillation scanning of liver cell adenoma. Am J Roetgenol Radium Ther Nucl Med 113:56-50, 1971 71. Motsay GJ, Gamble WG: Clinical experience with hepatic adenomas. Surg Gynecol Obstet 134:415-418, 1972 72. Phillips MJ, Langer B, StoneR, eta!: Benign liver cell tumors: classification and ultrastructural pathology. Cancer 32:463470, 1973 73. Albritton DR, Tompkins RK , Longmire WP Jr: Hepatic cell adenoma: report of four cases. Ann Surg 180:14-19, 1974 74. Schrager VL: Surgical aspects of adenoma of the liver. Ann Surg 105:33-43, 1937 75. Hoffman HS: Benign hepatoma: review of the literature and report of a case. Ann In tern Med 17:130-139, 1942 76. Benson CD , Pemberthy GC: Surgical excision of primary tumor ofliver (hamartoma) in infant seven months old with recovery. Surgery 12:881-886, 1942 77. Franklin RG, Dowling CF: Primary liver tumors. Am J Surg 73:390-395, 1947 78. Hunter WR: A case of benign hepatoma. Br J Surg 36:425-428, 1949 79. Kay S, Talbert PC: Adenoma of the liver, mixed type (hamartoma): report of two cases. Cancer 3:307-315, 1950 80. McBurney RP, Woolner LB , Wollaeger EE: Solitary hyperplastic nodule of the liver simulating a neoplasm: reportof a case. Proc Staff Meet May Clin 25:606-611, 1950 81. Gerding WJ, Popp MF, Martineau PC: Hamartomatous cholangiohepatoma: report of a case. JAMA 145:821-822, 1951 82. Begg CF, Berry WH: Isolated nodules of regenerative hyperplasia of the liver: the problem of their differentiation from neoplasm. Am J Clin Pathol 23:447-463 , 1953 83. Benz EJ, Baggenstoss AH: Focal cirrhosis of the liver: its relation to the so-called hamartoma (adenoma, benign hepatoma). Cancer 6:743-755, 1953 84. Ramchand S, Suh HS, Gonzales-Crussi F: Focal nodular hyperplasia of the liver. Can J Surg 13:22-26, 1970 85. Whelan TJ Jr, Baugh JH , Chandor S: Focal nodular hyperpla-
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sia of the liver. Ann Surg 177:150-158, 1973 86. McMullen CT, Montgomery JL: Arteriographic findings offocal nodular hyperplasia of the liver and review of the literature. Am J Roentgenol Radium Ther Nucl Med 108:380-387, 1973 87. McLoughlin MJ, Colapinto RF, Gilday DL, et al: Focal nodular hyperplasia of the liver: angiography and radioisotope scanning. Radiology 107:257-263 , 1973 88. Winkler K , Poulsen H: Liver disease with periportal sinusoidal dilatation: a possible complication to contraceptive steroids. Scand J Gastroenterol10:699-704, 1975 89 . Pliskin M: Peliosis hepatis. Radiology 114:29-30, 1975 90. Kintzen W, Silny J: Peliosis hepatis after administration of fluoxymesterone. Can Med Assoc J 83:860-862, 1960 91. Gordon BS, Wolf J , Krause T, et al: Peliosis hepatis and cholestasis following administration of norethandrolone. Am J Clin Pathol 33:156-165, 1969 92. McGiven AR: Peliosis hepatis: a case report and review of pathogenesis. J Pathol 101:283-285, 1970 93. Naeim F, Copper PH, Semion AA: Peliosis hepatis: possible etiologic role of anabolic steroids. Arch Pathol 95:284-285, 1973 94. Bagheri SA , Boyer JL: Peliosis hepatis associated with androgenic-anabolic steroid therapy: a severe form of hepatic injury. Ann Intern Med 81:610-618, 1974 95. Groos G, Arnold OH , Brittinger G: Peliosis hepatis after longterm administration of oxymethalone. Lancet 1:874, 1974 96. Beaconsfield P: Liver tumours and steroid hormones. Lancet 1:516-517, 1974 97. Kay CR: Liver-cell adenomas and oral contraceptives. Lancet 2:52-53 , 1976 98. Thallasinos NC, Lymberatos C, Hadjioannou J, eta!: Liver-cell carcinoma after long-term oestrogen-like drugs. Lancet 1:270, 1974 99. Sotaniemi EA, Alavaikko MJ, Kaipainem WJ: Primary liver cancer associated with long-term oestrogen therapy. Ann Clin Res 7:287-289, 1975 100. Johnson FL, Feagler JR, Lerner KG, et a l: Association of androgenic-anabolic steroid therapy with development of hepatocellular carcinoma. Lancet 2:1273-1276, 1972 101. Henderson JT, Richmond J : Androgenic-anabolic steroid therapy and hepatocellular carcinoma. Lancet 1:934, 1973 102. Farrell GC, Joshua DE , Uren RF, et a!: Androgen-induced hepatoma. Lancet 1:430-431, 1975 103. Mulvihill JJ, Ridolfi RL, Schultz FR, et al: Hepatic adenoma in Fanconi anemia treated with oxymethalone. J Pediat 87:122124, 1975 104. Sweeney EC, Evans DJ: Liver lesions and androgenic steroid therapy. Lancet 2:1042, 1975 105. Heston WE , Vlahakis G, Desmukes B: Effects of the antifertility drug En ovid in five strains of mice, with particular regard to carcinogenesis. J Nat! Cancer Inst 51:209-224, 1973 106. Carcinogenicity Tests of Oral Contraceptives. A Report by the Committee on Safety of Medicines. London, Her Majesty's Stationery Office, 1972 107. Lingeman CH: Liver-cell neoplasm and oral contraceptives. Lancet 1:64, 1974
GASTROENTEROLOGY 73:386-394, 1977 Copyright © 1977 by the American Gastroenterological Association
PROGRESS IN HEPATOLOGY HEPATIC TUMORS: POSSIBLE RELATIONSHIP TO USE OF ORAL CONTRACEPTIVES GERALD KLATSKIN'
M.D.
Liver Study Unit, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
In 1970, Janet Baum of Ann Arbor submitted a paper to the Journal of the American Medical Association suggesting, on the basis of 3 cases, that oral contraceptives might be implicated in the development of benign hepatic tumors in young women. 1 To her annoyance, the editors rejected the paper with the comment that her suggestion was ridiculous! The first two published reports of hepatic cell adenoma in women on oral contraceptives appeared in 1971 (Reference 2 and S. Kay, personal communication, December 15, 1976) * and 1972. 3 • 4 However, in neither case did the authors comment on a possible etiological relationship between oral contraceptives and hepatic tumors, so that credit must go to Baum and her colleagues5 for drawing attention to this possibility in their report of 7 cases which appeared in Lancet in 1973. This paper excited great interest and touched off an avalanche of similar reports, which continue to appear in ever increasing numbers. As shown in table 1, the number of cases reported annually has risen dramatically, so that by September 1976 at least 117 had been described. In addition, 120 have been cited in the literature but not documented, bringing the total of 237 . The number in the latter group may represent an overestimate, because most have been reported from large registries for such tumors and may include tumors previously reported by others. Nevertheless, the number of documented cases is impressive. Most of the cases have been reported from the United States (table 1). If, indeed, oral contraceptives play a role in the pathogenesis of hepatic tumors, it may be anticipated that reports will begin to appear in increasing numbers from other parts of the world where these agents are in common use. Moreover, if the present Received February 7, 1977. Accepted February 28, 1977. This paper was presented at a meeting held on October 23, 1976 at Kurume University, Japan, to honor Professor Tashiro Nakashima on the 15th anniversary of his appointment as Professor of Pathology. Address requests for reprints to: Dr. Gerald Klatskin, Department of Medicine, Yale University, 333 Cedar Street, New Haven, Connecticut 06510. * Patient reported in Reference 2 started using oral contraceptives (Enovid E) in 1963, 4 years before appearance and resection of first hepatic cell adenoma in 1967; she continued on oral contraceptives (Ortho-Novum) until1973, 3 years after appearance and biopsy of second hepatic cell adenoma in 1970. She is alive and well in 1976, and showed no evidence of a tumor on liver scan in October 1976. 386
trend in reporting continues, hepatic tumors may prove to be an even more serious problem than thromboembolic disease as a complication of oral contraceptive therapy. Initially, the tumors encountered were benign, being variously classified as hepatic cell adenoma (S. Kay, personal communication, and References 2 and 6 through 26), benign hepatoma,~5 • 27- 33 focal nodular hyperplasia, 16 • 25• 26• 3 4-4 1 or hamartoma. 26• 42-4 4 • However, more recently, malignant tumors of several types have been reported, including hepatocellular carcinoma (References 25, 37, 42, and 45 through 48, and A. H. Baggenstoss, personal communication), mixed hepatocellular and ductular carcinoma, 49 and hepatoblastoma50 (table 2). Because most authorities 5 L 52 consider the terms hepatic cell adenoma and benign hepatoma on the one hand and focal nodular hyperplasia and hamartoma on the other as synonymous, I have, for the purposes of of this discussion, regrouped the benign tumors associated with oral contraceptives into two categories, hepatic cell adenoma and focal nodular hyperplasia. Although some of the reported tumors do not meet generally accepted criteria for distinguishing between hepatic cell adenoma and focal nodular hyperplasia, 51. 52 as pointed out by others, 22 • 53 I have made no attempt to reclassify any of the lesions, particularly because these criteria may be open to question, a point that is considered later. As can be seen in table 3, over one-half of the patients had used oral contraceptives for more than 5 years. However, in 10% the period of exposure had been as brief as 6 to 12 months, and in 9 cases the tumor was discovered 6 months to 10 years after cessation of oral contraceptive therapy.6, !Ht, 31, 34, 38,41 The contraceptive agents employed in this group included almost all combinations of synthetic estrogens and progestogens in common use (table 3). However, it will be noted that those containing mestranol as the estrogenic component outnumbered those containing ethinyl estradiol. This has led Edmondson et al. 18 to propose that mestranol has a greater oncogenic potential than ethinyl estradiol. However, as pointed out by others, 54 • 55 this view is open to question, because mestranol has been in use significantly longer than ethinyl estradiol, so that women on oral contraceptives for over 5 years were more likely to have received mestranol. In patients with hepatic cell adenoma (table 4), the major presenting complaint in over two-thirds of the
TABLE 1. Hepatic tumors encountered in women using
oral contraceptives Year and origin Year reported 1971 1972 1973 1974 1975 1976 Origin of reports United States United Kingdom Canada Sweden Hungary France Italy Greece Norway Total
Case reports
Cases cited: no details
Total
90 30
1 1 11 14 121 89
1 1 11 14 31 59
216 7 4 4 2 1 1 1 1
96 7 4 4 2 1 1 1 1
120
117
120
237
TABLE 2. Types of hepatic tumor encountered in women using
oral contraceptives Tumor type Diagnoses reported Hepatic cell adenoma Benign hepatoma Focal nodular hyperplasia Hamartoma Malignant hepatic tumor Current diagnostic classification Benign tumors Hepatic cell adenoma Focal nodular hyperplasia Malignant tumors Hepatocellular carcinoma Hepatoblastoma Mixed hepatocellular-ductular Total a
387
PROGRESS IN HEPATOLOGY
August 1977
Case reports
62 17 21 7 10
Cases cited: no details 41 61 7 11
79 28
41 68
8 1 1
11
117
120
Total"
103 17 82 14 21
120 (51) 96 (41) 19 (8) 1 (0.4) 1 (0.4) 237
Percentages are given in parentheses.
group was acute abdominal pain, often accompanied by shock, attributable to either rupture of the tumor with hemoperitoneum or hemorrhage into the tumor. By contrast, in those with focal nodular hyperplasia, one-half had asymptomatic tumors that were discovered unexpectedly during laparatomy for other unrelated diseases. Nevertheless, in this group too, 21% presented with acute abdominal pain caused by rupture of the tumor with hemoperitoneum or hemorrhage into the tumor. Except for the absence of cirrhosis in all cases, the clinical features in women with malignant hepatic tumors associated with the use of oral contraceptives were similar to those that usually accompany such tumors, so that they will not be discussed further . Hepatic function in patients with benign tumors was
remarkably well preserved, even when the tumors were large. Thus, in only a minority of the patients tested were slight elevations in serum bilirubin, alkaline phosphatase, and transaminase noted, and invariably, tests for a-fetoprotein yielded negative results (table 5). Technetium sulfur colloid scans of the liver revealed defects in most but not all cases of hepatic cell adenoma and focal nodular hyperplasia (table 5). As might be anticipated, all tumors less than 4 em in diameter escaped detection. The defects did not appear to depend on the presence within the tumor of fibrosis, hemorrhage, or necrosis. Observations in one of our own patients with a large area of focal nodular hyperplasia in the left lobe of the liver suggested that the defect demonstrated on technetium sulfur colloid scan was attributable to TABLE 3. Use of oral contraceptives by women with hepatic tumors Focal Heyatic nodular Maligeel ad- hyperTotal nant enoma Parameter (10 (117 cases)" plasia (79 (28 cases) cases) cases) Years <1 1-5 >5 Not reported Type employed Mestranol, plus: Norethynodrel Norethindrone Lynestrenol Ethynodiol Chlormadinone N orethisterone Progestogen type? Ethinyl estradiol, plus: Dimethisterone Norgestrel Norethindrone Progestogen type? Not reported Total Mestranol Ethinyl estradiol a
8 23 43 5
2 10 15 1
1 7 2
11 (10) 40 (36) 60 (54) 6
7 8 1 3 2
6 8 3 5
1
14 16 5 8 2 3 29
1
2
1
1 1
2
2
5
29 1 6 1 2 19
1 9 2 2 26 77 (85) 14 (15)
Percentages are given in parentheses.
TABLE 4. Presenting complaints in women with benign hepatic tumors
associated with the use of oral contraceptives• Presenting complaints Acute abdominal pain, shock Tumor rupture, hemoperitoneum Tumor hemorrhage Palpable mass Chronic or intermittent pain Hepatomegaly Asymptomatic: tumor an unexpected finding at laparotomy a
Hepatic cell adenoma (79 cases)
Focal noduJar hyperplasia (28 cases)
Total (107 cases)
32 (41)
4 (14)
36 (34)
21 17 1 1 7
(27) (22) (1) (1)
(9)
Percentages are given in parentheses.
2 4 4 0 14
(7) (14) (14) (50)
23 21 5 1 21
(21) (20) (5) (1) (20)
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PROGRESS IN HEPATOLOGY
TABLE 5. Functional, scintiscan, and arteriographic findings in women with hepatic tumors associated with the use of oral contraceptives Findings
Hepatic functional abnormalities Serum bilirubin Serum alkaline phosphatase Serum transaminase a-Fetoprotein Hepatic scintiscan defects Patients Tumors Tumors 1-3 em Tumors >3 em Tumor fibrosis No fibrosis Tumor hemorrhage No hemorrhage Tumor necrosis No necrosis Arteriographic abnormalities Patients Tumors Enlarged hepatic artery Peripheral arterial supply Increased vascularity Avascularity Tumor "blush"
Hepatic Focal cell ade- nodular noma hyperplas1a
Total(%)
1118 5/17 7/17 0/9
0!3 113 0/3 0/2
1121 (5) 6/20 (30) 7/ 20 (35) 0!11
11/15 15/18 0/3 13/16 2/5 10/13 9/12 3/6 6/6 5/11
6/6 7/9 0/2 7/7 4/5 3/4 4/4 3/5 3/3 4/6
17/21 (81) 22/27 (81) 0/5 20/23 (87) 6/10 (60) 13/ 17 (76) 13/16 (81) 6/11 (55) 9/9 (100) 9/17 (53)
15/ 15 17/19 7/16 8/16 14/18 2/17 7/16
4/6 5/7 0/5 115 4/5 0/5 115
19/21 (90) 22/26 (85) 7/21 (33) 9/21 (43) 18/23 (78) 2/22 (9) 8/21 (38)
failure of the reticuloendothelium to take up the colloid, because the tumor incorporated selenomethionine normally and exhibited a normal distribution of intravenously injected indium-113m, indicating normal hepatocellular synthetic activity and normal blood flow , respectively. Arteriographic abnormalities were demonstrable in most but not all of the tumors investigated (table 5). As previously pointed out by Goldstein et al. ,56 the findings in hepatic cell adenoma and focal nodular hyperplasia were indistinguishable. The principal features included enlargement of the hepatic artery, a peripheral arterial blood supply, increased vascularity, and a tumor "blush" during the venous phase. Rarely, the tumor appeared avascular, owing to intramural hemorrhage, necrosis, or infarction. Long term follow-up data on the clinical course are available in only a minority of the patients with hepatic tumors associated with the use of oral contraceptives (table 6). However, of the 107 with hepatic cell adenomas or focal nodular hyperplasia, 99 (93%) were still alive at the time of reporting, 2 months to 6 years after detection of the tumor. All8 deaths occurred in patients with hepatic cell adenomas, and were attributable to rupture with hemoperitoneum in 7, 5· 8· 15· 27· 28· 30 and intramural hemorrhage in 1. 7 Of those who died, 4 had undergone lobectomy or resection of the tumor5· 7· 28· 30 , 1 had been subjected to packing and suture of a ruptured tumor followed by hepatic artery ligation, 8· 15 and 3 had died of tumor rupture and hemoperitoneum before surgical treatment could be instituted. 27· 30
Surgery was remarkably well tolerated in this group; the survival rate was 96% in the 92 subjected to resection or lobectomy, 67% in the 3 whose tumors were packed, drained, and/or sutured, .and 100% in the 7 nonhemorrhagic tumors subjected to biopsy alone. Two of the 88 successfully resected tumors recurred, both in patients who continued to use oral contraceptives. In the first case (Reference 2 and S. Kay, personal communication), a large hepatic cell adenoma was discovered in the right lobe 21/2 years after resection of a similar tumor in the same lobe. In the second, 42 a large tumor classified as focal nodular hyperplasia was found in the right lobe 6 years after lobectomy for a similar large hemorrhagic tumor in the contralateral lobe. Both recurrent tumors, which were subjected to biopsy alone, regressed after withdrawal of oral contraceptives. In the first case (8. Kay, personal communication), the tumor was no longer evident on scan 5 years later, and in the second,42 it was significantly smaller on scan 5 months later. Of 12 other tumors left in situ, u , 12, 1s, 22, 24, 32, 35, 38, 40, 42 · 44 the four largest, including two classified as hepatic cell adenoma22· 32 and two as focal nodular hyperplasia,35· 40 showed significant regression as documented by scan 22 · 35· 40 or arteriography32 after cessation of oral contraceptive therapy over periods ranging from 3 months to 3 years. In none of the tumors left in situ was there evidence of progression or malignant transformation. Of the patients with malignant hepatic tumors associated with oral contraceptives, 5 have died, 1 during the course of lobectomy, 42 1 a year after lobectomy (Reference 50 and G. Klatskin, personal follow-up on case reported in Reference 50) and 3 who were not treated. 42 · 48 Three patients with hepatocellular carcinoma were still alive and well at the time of reporting1 2 months42 and 2 1 year after lobectomy.45· 46 The duration of survival of the 2 remaining cases, 1 given chemotherapy4 7 and the other subjected to hepatic artery ligation followed by chemotherapy, 49 has not been reported. According to authoritative sources, 5L 52 hepatic cell adenoma and focal nodular hyperplasia are unrelated tumors, each with distinctive morphological features, TABLE 6. Clinical course of women with benign hepatic tumors associated with the use of oral contraceptives Clinical course
Survived Died After surgery Resection Packing or drainage Biopsy No surgery Total Recurrence of tumor after successful resection Regression of unresected tumors Progression of unresected tumors Malignant transformation of unresected tumors
No. (%)
99/107 (93)
4/92 (4) 1/3 (33)
017 3/5 (60) 8/107 (7) 2!88 4/14 0/14 0/14
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that show no tendency to undergo malignant transformation. If, then, oral contraceptives are implicated in the pathogenesis of hepatic tumors, it is surprising that they produce lesions of such diverse structure and biological behavior. This raises two questions: first, do currently accepted morphological criteria clearly distinguish between hepatic cell adenoma and focal nodular hyperplasia, and, second, is it conceivable that, at least under conditions of oral contraceptive therapy, hepatic cell adenoma and focal nodular hyperplasia represent two phases in the development of the same lesion, and that such lesions may undergo malignant transformation? As usually described, 51· 52 hepatic cell adenoma presents as a solitary, relatively soft, sharply circumscribed mass of variable size. Multiple tumors are not rare, and occasionally the tumor may be pedunculated. On cross-section, the tumor is lighter in color than the adjacent intact liver, has a fleshy appearance, and may show foci of hemorrhage. Occasionally, it is yellow or green in color because of bile staining and/or fatty infiltration. The cut surface may show ill-defined lobulation, but is never frankly nodular or fibrotic. Microscopically, the neoplastic cells closely resemble normal hepatocytes and show no features suggestive of malignancy. However, particularly at the periphery of the tumor, they may be larger and paler than normal hepatocytes, owing to increased deposition of glycogen, and often are arranged in the form of thick plates , rosettes, or pseudoducts, some of which may contain inspissated bile. Deeper in the tumor, the neoplastic cells tend to be smaller and darker and often show an irregular plate pattern with an unusually delicate reticulin network. Frequently, the tumor contains numerous thin-walled vessels resembling central veins, but characteristically there is a paucity or absence of portal triads and bile ducts. In contrast to hepatic cell adenoma, focal nodular hyperplasia usually presents as a firm, grossly nodular mass of variable size which, on cross-section contains a central stellate fibrous core with radiating branching septa that subdivide the tumor into nodules. Microscopically, the lesion closely resembles that of an inactive cirrhosis. Characteristically, the fibrous septa contain numerous ductules, vessels, and mononuclear inflammatory cells. In some cases, the larger vessels are thickened as a result of subintimal fibrosis or hypertrophy of the media, occasionally leading to obliteration of their lumens. Although these morphological criteria usually serve to differentiate between hepatic cell adenoma and focal nodular hyperplasia, it is evident from our own experience and that reported in the literature that they do not do so in all cases. Indeed, of six benign hepatic tumors that we have studied recently, only two could be adequately classified on the basis of these criteria. Thus, of three with the typical gross and microscopic features of hepatic cell adenoma, two were lobulated and traversed by septa containing tightly packed islands of small neoplastic cells interpersed with numerous ductules, small vessels, and delicate fibrous bands, features suggestive
389
of focal nodular hyperplasia. Indeed, these 2 cases were previously reported by Stauffer et al. 40 as examples of focal nodular hyperplasia. Similar difficulty was encountered in classifying two of our tumors which had the typical microscopic features of focal nodular hyperplasia but which, on gross inspection, were smooth in contour and soft in consistency, and, on cut section, showed no evidence of nodulation or central stellate scarring. Recently, Goldfarb 23 has described 2 similar cases of focal nodular hyperplasia, 1 of which was localized within a hepatic cell adenoma. Observations such as these suggest that hepatic cell adenoma and focal nodular hyperplasia may be related lesions, at least in the case of those associated with the use of oral contraceptives, or, alternatively, that the stimulus to tumor growth affects both entodermal and mesenchymal elements in the liver to a variable degree in different tumors. The fact that both benign and malignant hepatic tumors have been encountered in women on oral contraceptives invites speculation that, at least in some case, the former may undergo malignant transformation. Although no examples of such transformation have been reported in nonusers of oral contraceptives, 51· 52 there is suggestive evidence that this may have occurred in several cases associated with the use of such agents. Thus, in 2 women on oral contraceptives seen at the Mayo Clinic, unequivocal areas of hepatocellular carcinoma were found within a hepatic cell adenoma (A. H . Baggenstoss, personal communication ). Similarly, in the case reported by Davis et al. 46 hepatocellular carcinoma was encountered within a benign tumor which was classified as focal nodular hyperplasia but, on subsequent review (H. Popper, personal communication) , was reclassified as a typical example of hepatic cell adenoma. In addition, both Galloway et al. 32 and Goldfarb23 have described foci of hepatic cellular dysplasia and atypia within hepatic cell adenomas considered premalignant. The possibility that the other malignant hepatic tumors reported in women on oral contraceptives may have evolved from benign lesions cannot be assessed on the basis of available evidence. · Because the suggestive evidence of malignant transformation in benign hepatic tumors appears to be limited to women on oral contraceptives, the possibility that such tumors differ in other respects from those encountered in non-"pill" users merits consideration. For purposes of comparison I have culled from the literature 138 cases of hepatic cell adenoma6· 18· 21. 30· 32 · 41. 45, 52 · 54 · 57- 73 and 234 cases of focal nodular hyperplasia38, 39, 41. 52, 54, 64, 69, 72 • 74-87 reported in patients with no history of exposure to oral contraceptives. Although these do not comprise a complete inventory, they do include most cases reported between 1938 and 1976. It is recognized that orne of the patients in this group may have received oral contraceptives that were not reported. However, if a significant number fell into this category, it would tend to obscure rather than exaggerate any differences between users and nonusers of such agents. Also, the classification of some of the tumors may be open to question, but this is equally true of the
PROGRESS IN HEPATOLOGY
390
oral contraceptive-associated tumors. As shown in table 7, 10% of the patients with non-pill related hepatic cell adenomas were male, and 14% were children. However, it is noteworthy that 59% were women of childbearing age. The most striking clinical difference between the two groups was the significantly higher incidence of tumor rupture with hemoperitoneum or hemorrhage into the tumor in users of oral contraceptives (66%) than in nonusers (25 %). In contrast, whereas 20 % of the tumors unrelated to the pill were asymptomatic and discovered unexpectedly at laparotomy or necropsy, only 9% of those associated with oral contraceptives were asymptomatic. In general, the hepatic cell adenomas in users of the pill were larger than those in nonusers, being 5 em or larger in diameter in 97% of the former and 73 % of the latter. In addition, the tumors in the users exhibited rupture (39 %) and intramural hemorrhage (71 %) more frequently than in nonusers (14 and 38 % respectively) , and were the only ones occasionally accompanied by peliosis hepatis (table 7). As shown in table 8, although 30% of the nonusers of oral contraceptives with focal nodular hyperplasia were male, 60% were women of childbearing age. PresentaT A BLE
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tion with acute abdominal pain due to rupture of the tumor with hemoperitoneum or hemorrhage into the tumor was significantly more frequent in users (21 %) than in nonusers (less than 1%) , although the incidence in the former was significantly lower than in users with hepatic cell adenoma (66 %). In contrast, asymptomatic focal nodular hyperplasia was less common in users (50 %) than in nonusers (76%). As in the case of hepatic cell adenoma, tumors classified as focal nodular hyperplasia were significantly larger in users than in nonusers, being 5 em or larger in 79 % of the former and only 24% in the latter. Similarly, the incidence ofrupture (14 %) and hemorrhage into the tumor (21 %) in those associated with oral contraceptives was significantly higher than in those unassociated with such agents (less than 1% and 2%, respectively). Also, the only instance of peliosis hepatis was encountered in a patient on oral contraceptives. The larger size and the propensity of the benign hepatic tumors to bleed in women on oral contraceptives suggest that such agents may affect the vasculature of these lesions. Indeed, this appears to be the case. As previously noted by others, almost all of the hepatic cell adenomas we have studied exhibited significant patchy
7. Hepatic cell adenomas: comparison of features in women on oral contraceptives and in patients with no reported use of such agen ts P arameter
Sex Ma le Female Age, yr < 1- 15 19-50
No oral contraceptives (138 cases) "
14 (10) 124 (90)
0 79 (100)
7 (14)
0 78 (99)
F
>50 N ot r epor ted Presenting complaint Acute abdominal pain, shock Hemoperitoneum Hemorrhage into tumor Palpa ble mass Chroni c or intermittent pain Hepatomegaly Asymptomatic tumor found at: Laparotomy Necropsy Tumor Number Single 2 or more Not reported Size, em <5 5-10 > 10 Not reported Gross appearance Pedunculated Ruptured Hemorrhagic Peliosis hepatis a Percentages are given in parentheses. ' NS, not significant.
1 (1)
0
32 (41)} 20 (25) 18 (23) 1 (1) 1 (1)
~ (9)
=
31 (61) 30 13 (25) 87
21 14 51 23
(15)} (10) (37) (17)
2 (1) }
62 (78) 17 (22)
Significance of differ ence, Yates correction (P )'
15 (11) } 12 (9)
100 (75) 33 (25) 5
8.92 ( < 0.01) 30.95 ( < 0.001) 16.48 ( < 0.001)
32.57 ( < 0.001) 4.02 ( < 0.05) 10.59 (< 0.01) NS
NS
NS NS
2 (3) 28 (39)} 42 (58) 7
35 (27) 43 (33) } 54 (41) 6
16.11 ( < 0.001)
2 31 56 3
16 (12) 20 (14) 53 (38) 0
4.29 ( < 0.05) 15.76 ( < 0.001) 19.92 ( < 0.001) NS
(3) (39) (71) (4)
16.11 ( < 0.001)
x',
August 1977 TABLE
391
PROGRESS IN HEPATOLOGY
8. Focal nodular hyperplasia: comparison of features in women on oral contraceptives and in patients with no reported use of such agents Parameter
Oral contraceptives (28 cases)a
No oral contraceptives (234 cases)a
Significance of difference Yates correction (P)•
x',
Sex Male
Female Age, yr < 1-15 19-50 > 50 Not reported Presenting complaint Acute abdominal pain, shock Hemoperitoneum Hemorrhage into tumor Palpable mass Chronic or intermittent pain Hepatomegaly Asymptomatic tumor found at: Laparotomy Necropsy Others Tumor Number Single 2 or more Size, em <5 5-10 > 10 Not reported Gross appearance Pedunculated Ruptured Hemorrhagic Peliosis hepatitis
0 28 (100) 0
27 (96) 1 (4) 0
4 (14)} 2 (7)
4 (14) 4 (14) 0
1~ (50)} 0
24 (86) 4 (14)
4 (21) 12 (63)} 3 (16)
70 (30) 164 (70) 11 (5)
174 (84) F = 124 22 (11) 27
~ (<1)} 22 (9) 17 (7) 7 (3)
83 (35)} 96 (41)
NS NS NS
34.72 (< 0.001)
NS NS NS 7. 73 (< 0.01)
8 (3)
190 (81) 44 (19)
NS NS
168 (76) 41 (19) }
23 .85 ( < 0.001)
11 (5)
9
14
0
0
4 (14) 6 (21)
1 (<1) 5 (2)
1 (4)
0
23 .85 ( < 0.001)
NS 26 .86 ( < 0.001) 27.86 ( < 0.001) NS
" Percentages are given in parentheses. • NS, not significant.
congestion of the sinusoids. In addition, two of the tumors had numerous unusual vascular lesions leading to hemorrhage, peliosis hepatis, scarring, and infarction. The earliest vascular lesion in these cases was an eccentric hemorrhage around a thin-walled vein resulting in or associated with dissolution of adjacent tumor cells. In more advanced lesions, the hemorrhage encircled the vein, ultimately producing cyst-like cavities typical of peliosis hepatis. Some of the larger areas of hemorrhage showed evidence of organization and fibrosis. A second and apparently unrelated type of vascular lesion was characterized by subintimal fibrosis and medial hypertrophy in medium-sized arterioles resulting in constriction of their lumens, and, in some instances, the development of infarction. There is suggestive evidence that oral contraceptives may affect normal liver tissue as well. Thus, in 4 women on such agents, Winkler and Poulsen88 observed hepatomegaly and periportal and midzonal congestion, which, in 3 cases, receded after cessation oftherapy. In another case, reported by Pliskin, 89 hepatic arteriography revealed numerous focal collections of contrast material scattered through the liver, which appeared during the
late arterial phase and became more prominent during the parenchymal and venous phases. These were interpreted as evidence of peliosis hepatis, although wedge biopsy of the liver showes only dilation ofthe sinusoids. We too have observed hepatomegaly associated with peripheral and midzonal sinusoidal congestion in 2 women on oral contraceptives. In 1 of these, hepatic arteriography demonstrated the same type of pooling of contrast material described by Pliskin. 89 Although laparotomy revealed numerous small bluish areas on the surface of the liver, wedge biopsy showed congestion of the sinusoids but no peliotic cavities. Such observations suggest that the vascular changes observed in hepatic tumors associated with oral contraceptives may be due to the direct hormonal effects of these agents rather than to tumor growth. Several lines of circumstantial evidence are consistent with this interpretation, and include: (1) the greater frequency of vascular lesions in users than in nonusers of oral contraceptives (tables 7 and 8), (2) the occasional occurrence of hemorrhage and rupture in oral contraceptive-associated tumors during menstruation/ 8 pregnancy, 31 or the postpartum period, 10• 2 1. 25 (3) reports of sinusoidal
392
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PROGRESS IN HEPATOLOGY
congestion and peliosis hepatis in individuals given synthetic androgenic-anabolic steroids closely related in structure to those used in oral contraceptives, 9 (}-95 and (4) the occurrence of sinusoidal congestion in female rats given norethynodrel. 96 Currently available evidence implicating oral contraceptives in the pathogenesis of hepatic tumors, although impressive, must be regarded as circumstantial rather than conclusive. Considering that only approximately 400 case~ of hepatic cell adenoma and focal nodular hyperplasia were reported in non-pill users between 1937 and 1976 (tables 7 and 8), the fact that over 200 cases have been encountered in women on oral contraceptives in the past 3 years (table 1) strongly suggests an etiological relationship. However, relatively large numbers of undocumented cases have been reported from four centers that have organized registries for oral contraceptive-associated hepatic tumors. 1 • 5 • 16 ' 18 • 2'· 26 ·0bviously, this introduces a bias in reporting that favors the relationship, as illustrated by the fact that 168 (96 %) of the 177 cases :r:eported from these centers were pill-associated. Another potential source of bias that may inflate the number of cases stems from the failure of these registries to indicate whether or not any of their cases have been previously reported by others. What may be rriore realistic data on the relative frequency of benign hepatic tumors in users and nonusers of oral contraceptives have been reported from Sweden by Grabowski et alY These investigators, who reveiwed all of the biopsy and autopsy material in the files of .the only hospital in Malmo and the two major hospitals in Lund that together serve a population of over 1112 million individ· uals, found that between 1964 and 1974, there were 8 cases of focal nodular hyperplasia in women of childbearing age, only 4 of whom had used oral contraceptives. Kay 9 7 suggests that the incidence may be even lower, because in the 8-year prospective study of oral contraceptives being conducted by the Royal College of General Practitioners in Great Britain, not one hepatic tumor has been encountered in women receiving such ag-ents with a total exposure of 54,850 patient-years, or in any of their controls. Obviously, a study of this type does not exclude the possibility of a relationship between oral contraceptives and hepatic tumors, but does suggest that if these agents are oncogenic, they produce tumors only rarely. Two clinical observations that point to an etiological role for oral contraceptives are the reported regression of benign hepatic tumors after the cessation of such therapy (References 2, 22, 32, 35, 40, and 42, and S. Kay, personal communication) and the recurrence of the tumor after resection in the same (Reference 2 and S. Kay, personal communication) or contralateral lobe42 in patients who continued to use such agents. That hormonal factors may play a role in the pathogenesis of hepatic tumors is strongly suggested by the fact that approximately 60% of spontaneous hepatic cell adenomas and focal nodular hyperplasia are encountered in women of childbearing age (tables 7 and 8), and that occasionally such tumors appear during preg-
nancy4 1• 69 • 71• 85• 86 or the postpartum period. 25 • 30 • 69 Other evidence consistent with such a relationship includes reports of both benign and malignant hepatic neoplasms in patients with endocrine tumors, such as adenocarcinoma of the ovary4 1 and carcinoma of the adrenal, 44 and in patients receiving various hormonal agents for purposes other than contraception, including conjugated natural estrogens 25 • 3 7 synthetic estrogens, 98 • 99 and synthetic androgenic-anabolic steroids. 10(}- 104 Of probable significance is the fact that all of these synthetic steroids, like those in oral contraceptives, are C17 a-alkyl derivatives .of testosterone. The results of animal experiments have been inconsistent. In strains of mice highly susceptible to spontaneous hepatic neoplasms, Enovid, a commonly employed Contraceptive containing norethynodrel and mestranol, failed to increase the incidence of hepatic tumors, even when large doses were administered. 105 However, in susceptible rats, a number of C 17 a-alkyl derivatives of testosterone increased the expected frequency ofJiver ceU tumors. 106 Because such agents are known to induce proliferation ofthe endoplasmic reticulum and the production of microsomal hydroxylating enzymes, it has been suggested that their oncogenic effects may be mediated by this adaptive process. 107 In the last analysis, the question of whether or not oral contraceptives are oncogenic cannot be resolved until accurate data are available on the relative incidence of hepatic tumors in users and nonusers of such agents. Nothing short of a national or large regional registry of all hepatic tumors, including those encountered in both sexes and at all ages, can provide such iriformation. In addition, it is reasonable to expect that the panel of expert pathologists seleeted to review all cases would clarify the interrelationships among hepatic cell adenoma, focal nodular hyperplasia; and hepatocellular carcinoma and provide more uniform and acceptable criteria for their differentiation. Although this is a formidable and costly undertaking, health authorities would be well advised to organize such a registry as soon as possible, because the problem involved is a potentially serious one that will be of concern to millions of women, particularly once reports of hepatic tumors in users of oral contraceptives reach the public press, which they are bound to do. To reassure their patients and to provide sound advice on the risks involved, physicians will need more precise information on the oncogenic potential of oral contraceptives than is currently available. REFERENCES 1. Baum JK: Liver tumors and oral contraceptives. JAMA 232:1329, 1975
2. Kay S, Shatzki PF: Ultrastructure of a benign liver cell adenoma. Cancer 28:755-762, 1971 3. Horvath E, Kovacs K, Ross RC: Ultrastructural findings in a well-differ entiated hepatoma. Digestion 7:74-82, 1972 4. Horvath E, Kovacs K , Ross RC: Benign hepatoma in a young woman on cotraceptive steroids. La ncet 1:357-358, 1974 5. Baum JK, Holtz F , Bookstein JJ, et al: Possible association between benign hepatomas and oral contraceptives. Lancet 2:926-929, 1973
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6. Davis JB, Schenken JR, Zimmerman 0 : Massive hemoperitoneum from rupture of benign hepatocellular adenoma. Surgery 73:181-184, 1973 (see also Schenken21 ) 7. Knapp WA, Ruebner BH: Hepatomas and oral contraceptives. Lancet 1:270-271, 1974 8. Vosnides G, Brander W, O'Keefe B, et al: Liver hamartomas in patients on oral contraceptives. Br Med J 3:580, 1974 (see also Clinicopathological Conference 15 ) 9. Bisson A, Duron PL, Fagniez PL, et al: Adenomatose hepatique et contraceptifs oraux. Nouv Presse Med 3:2079-2082, 1974 10. Antoniades K, Brooks CE Jr: Hemoperitoneum from liver cell adenoma in a patient on oral contraceptives. Surgery 77:137139, 1975 11. Model DG, Fox JA, Jones RW: Multiple hepatic adenomas associated with an oral contraceptive. Lancet 1:865, 1975 12. Ameriks JA, Thompson NW, Frey CF, et al: Hepatic cell adenomas, spontaneous liver rupture, and oral contraceptives. Arch Surg 110:548-556, 1975 13. Block GE: Discussion of paper by Ameriks et al. 12 Arch Surg 110:556-557, 1975 14. Large AM: Discussion of paper by Ameriks et al.' 2 Arch Surg 110:557' 1975 15. Clinicopathological Conference: A patient's life. Br Med J 3:209-213, 1975 16. Nissen ED, Kent DR: Liver tumors and oral contraceptives. Obstet Gynecol 46:460-467, 1975 17 . Antoniades K, Campbell WN, Hecksher RH, et al: Liver cell adenoma and oral contraceptives: double tumor development. JAMA 234:628-629, 1975 18. Edmondson HA, Henderson B, Benton B: Liver cell adenomas associated with use of oral contraceptives . N Eng! J Med 294:470-472, 1976 19. Baek SM, Sloane CE, Futterman SC: Benign liver cell adenoma associated with use of oral contraceptive agents. Ann Surg 183:239-242, 1976 20. Littman I, Berentey E, Magyar E, Balazs M: Anticoncipiens kezeles kapcsan letrejovo maj-adenoma operalt esete. Orv Hetil 117:159-161, 1976 21. Schenken JR: Hepatocellular adenoma: relationship to oral contraceptives? JAMA 236:559, 1976 22. Hilliard JL, Graham DY, Spjut HJ: Hepatic adenoma: a possibl€ complication
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