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Benign hepatic lesions and orally administered contraceptives
BENIGN HEPATIC LESIONS AND ORALLY ADMINISTERED CONTRACEPTIVES A Report of Seven Cases and a Critical Analysis of the Literature Robert E. Fechner, M.D.*
Abstract A consecutive series of 12 benign he'patic lesions in women consisted of six cases of focal nodular hyperplasia and six cases of liver cell adenoma. Five o f the six women.with liver cell adenoma and two of the six with focal nodular hyperplasia had taken orally active contraceptive horntones. These few cases reflect a similar impression gained from a critical analysis of the literature, namel)', tlmt focal nodular hyperplasia may be unrelated to the oral administration of contraceptive hormones, whereas rite increase in liver cell adenoma reported in recent )'ears is probably related to such therapy. Two women with fiver cell adenomas were asymptomatic six and four years after incomplete resection of the tumor. These are tim longest intervals thus far reported for uncomplicated survival in incompletely resected liver cell adenoma.
In 1973 Baum et al? reported seven women with benign hepatic ttnnors who were taking contraceptive hormones orally. T h r e e of these patients were from a single hospital where no other benign hepatic tumors could be found in a search back to 1913. Therefore, the cluster of cases was considered significant and the common denominator of oral contraceptive hormone therapy suggested that the hormones might be causal. A flurry of additional reports of lmpatic ttunors in women taking orally active contraceptive hormones has ensued, totaling nearly 100 cases. Seven have been diagnosed as either hepatoma or hepatoblastoma, 2-5 but the
majority of liver lesions have been considered benign. Diagnoses in the latter group have included focal nodular hyperplasia, hamartoma, adenoma, and benign hepatonla. When one stndies tim papers dealing with benign lesions, it is obvious tlmt these several terms are being applied to two pathologically distinct lesions, to wit, focal nodular hyperplasia and liver cell adenoma. Many authors have not made tim distinction, and this clouds tile understanding of the possible relation of orally administered contraceptive hormones to these two different entities. Tbe basic problem of inaccurate classification is especially unnecessary, since Edmond-
*Professor, BaylorCollege of Medicine. Surgical Pathologist,Tile Methodist Hospital, Houston, Texas.
255
HUMAN P A T H O L O G Y - V O L U M E 8, NUMBER 3 May 1977 son 6"~ separated a n d defined focal n o d u lar hyperplasia and liver cell a d e n o m a in the late 1950s. His criteria are clear a n d recently have been reaffirmed by others. 8-n T i m p u r p o s e o f this c o m m u n i c a t i o n is to present a consecutive series o f benign lesions in patients f r o m a single ltospital. Altlmugh a small g r o u p , it is tim first consecutive series o f patients with benign hepatic lesions in w h o m a history of oral contraceptive l t o r m o n e t h e r a p y has been specifically obtained. T l m Anglo-American literature dealing with focal n o d u l a r hyperplasia and liver cell a d e n o n m was reviewed from 1940 to the present in an effort to place recent r e p o r t s in perspective. In this discussion the phrases " b e f o r e 1960" and "after 1960" are used repeatedly. T h e )'ear 1960 is crucial because it m a r k e d ttte beginning o f the oral use o f contraceptives on a large scale. T h e literature prior to 1960 serves as an effective "control," since patients r e p o r t e d b e f o r e t h e n were not taking contraceptives orally. In addition, the literature between 1960 a n d 1973 is valuable because hepatic lesions r e p o r t e d in those )'ears were not selected for publication because o f a history o f oral contraceptive h o r m o n e therapy. Tiffs is important because papers on benign hepatic lesions going to press a f t e r late 1973 have dealt almost exclusively with lesions in w o m e n taking contraceptives orally. It is obvious that the first criterion for publication is that the patient be taking h o r m o n e s , resulting in selected case reports r a t h e r
than series o f consecutive patients unselected as to h o r m o n e history o r sex. Anecdotal literature may detect a genuinely new t r e n d , but it also becomes selffldfilling a n d is weighted toward an apparently positive association between two events. DEFINITION OF TERMS. Focal nodular hyperplasia and liver cell a d e n o m a are not morphologically complex, and by adltering to a few criteria it is possible to definitely identify cases in the literature if sufficient description is given, regardless o f tlte n a m e used by tire original authors. An)" case in tim literature that did not clearly fnlfill the criteria to be listed was placed into the category o f " t u m o r o f uncertain type." A lesion was classified as liver cell a d e n o t n a when tim t u m o r was c o m p o s e d o f liver ceils with nuclear variation n o g r e a t e r tlmn that o f n o r m a l liver and specifically lacked bile ducts or ductules (Figs. 1, 2). A case was accepted as focal n o d u l a r hyperplasia wlten all tim following criteria were met: o n e o r m o r e grossly visible localized nodules in an otherwise n o r m a l liver, a p r e d o m i n a n c e o f normal hepatic cells but with some bile ducts or multiple ductules, a n d fibrous sepia in the nodule, which usually radiate f r o m a central stellate fibrous area (Figs. 3, 4). T h e s e criteria exclude nodules in cirrhotic livers, n o d u l a r regenerative hyperplasia, hepatocellular adenomatosis, and partial n o d u l a r transformation, alt h o u g h all share some microscopic features witlt focal n o d u l a r hyperplasia, e.g.,
Figure 1. Cut surface of liver cell adenoma has finely granular appearance. Darker areas are recent hemorrhage. The mass is 8 cm. wide. (Case 3.)
256
BENIGN HEPATIC
Figure 2. Liver cell adenoma cousists of liver cells without bile ducts or ductules. (Hematoxyliu and eosin stain, x 300.)
LESIONS AND ORAL CONTRACEPTIVES--FEclINER
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HUMAN P A T H O L O G Y - V O L U M E 8, NUMBER 3 May 1977 hepatic cell h y p e r p l a s i a attd the p r e s e n c e o f bile ducts within nodules. T h e differentiations are m a d e readily because the grossly detectable masses o f partial n o d u lar r e g e n e r a t i v e h y p e r p l a s i a and hepatocelhdar a d e n o m a t o s i s involve the liver diffusely. 12
METHODS A N D MATERIALS T h e benign hepatic lesions in the surgical p a t h o l o g y files b e t w e e n 1968 and 1976 at T h e Methodist Hospital were re,~'iewed. T h i s search yielded six cases o f liver cell a d e n o m a and six cases o f focal n o d u l a r hyperplasia, all in w o m e n (Table I). Five o f the six w o m e n with liver cell a d e n o m a s w e r e taking orally active contraceptive h o r m o n e s at the time the lesion was diagnosed, as were two o f the six w o m e n with focal n o d u l a r hyperplasia. T h e negative histories were c o n f i r m e d by specific interviews with the w o m e n . T h e clinical px:esentation in o u r cases parallels that o f cases iri the literature. T h r e e w o m e n with liver cell a d e n o m a s p r e s e n t e d with pain s e c o n d a r y to intrahepatic h e n t o r r h a g e ; two h a d a palpable mass a n d in o n e the finding was incidental at l a p a r o t o m y . O n the o t h e r h a n d , f o u r o f the lesions o f focal n o d u l a r hyperplasia
were u n e x p e c t e d l y e n c o u n t e r e d at laparo t o m y e i t h e r at the time o f gynecologic p r o c e d u r e s (three cases) or at ileocolic bypass (one case). T w o p r e s e n t e d as painless masses. T w o patients with liver cell a d e n o m a s did not u n d e r g o total r e m o v a l o f an aden o m a . O n e patient (case 3) had two masses, o n e o f which was totally resected. T h e second mass was located n e a r the h i l u m o f the liver a n d was incompletely r e m o v e d by piecenteal blunt dissection. A p o s t o p e r ative scan s h o w e d a defect in the hilum, which has persisted u n c h a n g e d for three )'ears. She c o n t i n u e d to take Enovid E but has n o w b e e n advised to stop. A n o t h e r patient (case 2) had a lesion located in the hilum that was partially r e m o v e d . She received 5-fluorouracil (250 mg. p e r d a y for 30 days) t h r o u g h a catheter in the c o m m o n hepatic artery. Oral contraceptive horm o n e t h e r a p y was c o n t i n u e d for four )'ears a n d t h e n stopped, a n d she was well six )'ears a f t e r the initial diagnosis.
DISCUSSION T h e review o f the literature dealing with b e n i g n hepatic lesions b e t w e e n 1940 a n d 1960 yielded 37 surgically treated
TABLE 1. THE METHODISTHOSPITALCASES (1968--1976) Case Age
Liver cell adenoma 1 27 9 2 26 3 4 5 6
33 38 29 28
Duration of Oral ContraceptiveTherapy
Treatment
Outcome
Enovid, 3 yr.
Mass
Excision
Enovid, 1 yr. Ovulen, 4 yr. Enovid E, 3 yr. None Several, 5 yr. Ovulen, 5 yr.
Acnte pain
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Well 3 yr. (then lost) Well 6 yr.
Mass (2 lesions) Incidental Acute pain Acute pain
Biopsy, excision Excision Excision Excision
Well 4 yr. Well 1 yr. Well 6 too. Well 3 too.
Incidental Mass
Biopsy Excision
Well 5 yr. Well 4 yr.
Incidental Incidental Incidental Mass
Excision Excision Excision Excision
Well 3 yr. Well 2 yr. Well 2 yr. Well 6 too.
Focal nodular hyperplasia 7 44 None 8 26 Oracon, 3 yr. Ovral 9 37 None 10 38 None 11 34 None 12 35 Norinyl, 5 yr. Ovulen Enovid Ovral
258
Presentation
BENIGN HEPATIC LESIONS AND ORAL CONTRACEPTIVES--FECHNER masses, excluding mesenchymal hantartomas and hemangiomas. O f these, 24 were thought to be clearcut examples of focal nodular hyperplasia. ~3--~rSeven adtflts and one child were accepted as representing tmequivocal cases of liver cell adenoma.,7, .~s-3~_ Since 1960, 125 cases of benign liver lesions diagnosed during life have been reported individually or in small series. Thirty-seven were definitely focal nodular hyperplasia, 3~z 36 were liver cell adenomas, 3,42,4~'Sz-Tz and 52 were of uncertain type? "4'r~z There was a positive history of usage of orally active contraceptive hormones in 59 cases, o f which nine were identifiable as focal nodular hyperplasia, 19 as liver cell adenomas, and 31 as uncertain type (Table 2). T h e pathology study of Phillips et al. s~ had 15 cases of liver cell adenoma and focal nodular hyperplasia but is not included in further analysis in this presentation because clinical information was not a part of the report. In addition, Ishak and Rabin s3 briefly summarized their experience with 130 cases of focal nodular hyperplasia and 75 cases of liver cell adenoma collected at tile Armed Forces Institute of Pathology. Their report, published in 1975, spans ~ses before and afte~ 1960 but does not provide detailed histories. Finally Edmondson et al. s4 published in 1976 a stud), of 42 cases of liver cell adenoma in women, six of which had already been published. Since focal nodular hyperplasia and liver cell adenQmas are morphologically distinct lesions, they will be discussed separately.
Focal Nodular Hyperplasia The 24 cases of focal nodular hyperplasia diagnosed during life reported between 1940 and 1960 include 11 in children and 13 in adults: 10 women and three l n e n . 1 4 , 20, 93, 24,213 Tile w o n l e n were 23, 28, 28, 28, 32, 38, 39, 46, 47, and 63 years old. Since 1960, 37 cases of focal nodular hyperplasia diagnosed during life have been published, of which 26 patients were older th,~n 19 )'ears. Twenty-three were women between 21 and 51 years of age, 13 of whom were between 21 and 29 )'ears of age. (The subsequent discussion ex-
cludes the survey by Ishak and Rabin since it includes autopsy as well as snrgical material.) In comparing the adults surgically treated for focal nodular hyperplasia before 1960 and after 1960, there are many similarities and only a single difference that may be related to oral contraceptive hormone therapy. Both groups had a similar age range: 23 to 64 )'ears before 1960 and 21 to 51 years after 1960. Almost exactly half the female patients in both groups were in the third decade. Focal nodular hyperplasia in adults is predominately a disease detected in young women even when they are not taking orally active cont~ceptive hormones, Tile lesions in adults were evenly distributed between the left and right lobes both before and after 1960, a finding that is also borne out in the subgroup known to be t a k i n g orally active contraceptive hormones. Tile freqnency of multiple lesions in adults was virtually identical before 1960 (two of 13) and after 1960 (three of 24). Moreover, in five of 34 cases of focal nodular hyperplasia there were multiple nodules in an autopsy series studied before the hormone era, 85 a proportion similar to that in the surgical groups. Against tltis background, the fact that two of the three patients with multiple lesions reported since 1960 were taking orally active contraceptive hormones is unimpressive and can be considered coincidental. No major gross or microscopic differences can be discerned between tile lesions of focal nodular hyperplasia in women taking orally active contraceptive ltormones and those in women having a negative history. Nevertheless there is one feature, alterations in the vasculature, that deserves further comment as it has been emphasized in several papers. Mays et al. 43 discuss a variety of abnormalities, including arterial medial hypertrophy and varying degrees of occlusion, phlebitis, fresh organizing thrombi, attd intintal proliferation and swelling in small vessels not otherwise identified. The authors tlaought that tile changes might have caused hemorrhagic necrosis, but were aware that tltey might be merely secondary to such necrosis. Similar changes were described in two other le-
259
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BENIGN HEPATIC LESIONS AND ORAL CONTRACEPTIVES--FEcu,,,'ER sions of focal nodular l~yperplasia in women taking orally active contraceptive hormones in whom hemorrlmge was absent.4G,47 Therefore, vascular changes can exist without producing bleeding and were not secondary to hemorrhage in these particular instances. It is also of note that arterial and venous hypertrophy was described by Edmondson in 1958 before orally active contraceptive hormones were available, and Benz and Baggenstoss 85 found "occasional venous thrombi" in their lesions of noninfarcted focal nodular hyperplasia in auto'psy material before these drugs were available. For these reasons, one slmuld not too quickly attribute to oral contraceptive hormone therapy the rare thronabi or changes in the vessel walls. However, even though there are no qualitative differences in the vascular changes in lesions of focal nodular hyperplasia in women taking orally active contraceptive hormones, there appears to be a quantitative difference in a few lesions that may be attributable to these drugs. The one clinical difference that stands out since 1960 is the dramatic complication of acute life threatening hemorrlmge. Prior to 1960 no patient with focal nodular hyperplasia had presented with bleeding, although occasional small foci of old or recent hemorrhage were found in resected lesions. ~4 In 1967 a 25 )'ear old woman was reported who had hemorrhage from focal nodular hyperplasia, but there is no information regarding orally administered contraceptive hormones. 4~ O f the nine women with focal nodular hyperplasia known to be taking contraceptive hormones orally, two presented with intrahepatic or intraperitoneal bleeding. 43 That a woman taking orally active contraceptive hormones might be more susceptible to hemorrhage than a nonuser is possible in view of the increased frequency of thrombotic episodes in other organs during such therapy. In cases o f hepatic lesions this complication may be a direct consequence of oral contraceptive hormone therapy and could occur even if the underlying lesion itself were not caused by hormone therapy. The incidence of focal nodular hyperplasia is not known, and accurate statistical
assessment of the influence of orally active contraceptive hormones is not possible. T h e problem can be approached indirectly if one analyzes the years 1960 to 1973, before the rush of selected cases began. There were 26 surgical cases, 15 of which were ill adults (58 per cent). This percentage is not far removed from the series of 24 patients before 1960, which included 13 aduhs (53 per cent). The frequency of focal nodular hyperplasia in childhood is unrelated to orally administered contraceptive hormones and serves as a constant before and after 1960. Since the proportion of adults and childhood cases has stayed about the same, tbis can be interpreted as evidence against an increased frequency of lesions in adults. Another fragment of evidence is provided by the experience at the Armed Forces Institute of Pathology. Exactly half the cases of focal nodular hyperplasia on file occurred before the introduction of orally active contraceptive hormones, and there has not been a conspicuous increase in recent years, s3 Evidence for an association between focal nodular hyperplasia and orally administered contraceptive hormones requires consecutive cases unselected by sex or by hormone history in which the sex ratio overwhelmingly favors women and the majority are taking orally active contraceptive hormones. No such series is available. In fact, the converse was shown in our small group of six consecutive cases of focal nodular hyperplasia seen since 1968. Althougll all were women, only two had a positive history of oral contraceptive hormone usage, which is comparable to the 20 per cent proportion of premenopausal women in our hospital population known to be taking contraceptive hormones orally during these years, s~ At the moment convincing evidence of an association of such hormone usage and focal nodular hyperplasia is lacking, l~ Liver Ceil Adenomas
Liver cell adenomas were rarely reported before 1960. Henson et al. 12 encountered no liver cell adenomas at surgery at the Mayo Clinic between 1907 and 1954. They listed four patients diagnosed
263
HUMAN P A T H O L O G Y - V O L U M E 8, NUMBER 3 May 1977 as having " h e p a t o a d e n o m a s , " but their detailed histologic findings constitute a classic description o f focal nodular h y p e r plasia. Only two a d e n o m a s measuring less than 0.5 cm. were f o u n d in autopsies at the Mayo Clinic between 1922 and 1951. 8~ T h e r e are eight adequately d o c u m e n t e d surgical cases o f liver cell adenonm b e f o r e 1960.1r" 2a-3-~ Since 1960, t h e r e have been reports o f two w o m e n with liver cell adenomas diagnosed at autopsy. O n e was 70 )'ears old 42 and the o t h e r was 37. T h e latter had taken orally active contraceptive h o r m o n e s for " m a n y years" and died at h o m e as a result o f h e m o r r h a g e f r o m an a d e n o m a . 56 T h e literature dealing with liver cell a d e n o m a s diagnosed d u r i n g life includes 42 cases r e p o r t e d by E d m o n d s o n et al. and 36 cases in several smaller series. T h e r e is duplication in these numbers, since six o f the cases o f E d m o n d s o n et al. were previously r e p o r t e d and are included in o u r total o f 36 well p r o v e n cases. 53' ~G,6r T h e 36 cases and the cases o f E d m o n d s o n will be kept separate for the purposes o f this discussion. O f the 36 cases, f o u r were in children, all girls, ages 1, 2, 3, and 15 years? 5' 5r, 71 T h e 32 aduhs r a n g e d in age from 20 to 67 years with 18 patients between 20 and 29 years o f age and 13 m o r e between 30 and 40 years old. With the sole exception o f a 20 year old man, 4z all were women. T h e 31 w o m e n can be divided into three groups: 19 known to be taking orally active contraceptives, seven who never used orally active contraceptives, and five in w h o m no history o f oral usage o f contraceptives was available. T h e age distribution in the w o m e n taking orally acti,;'e contraceptive horm o n e s includes eight in their twenties, 10 in their thirties, a n d one who was 40 years old. T h e single most c o m m o n presenting s y m p t o m was acute pain and collapse d u e to intrahepatic o r intraperitoneal h e m o r rhage, which o c c u r r e d in nine women. Five others had vague pain leading to discovery o f a mass a n d t h r e e had an asymptomatic mass, o n e o f which was f o u n d incidentally at the time o f cholecystectomy. In o n e patient the presenting symptoms are not known. 6~ Cessation o f oral contraceptive hor-
264
m o n e t h e r a p y does not r e m o v e the risk o f fllttlre h e m o r r h a g e f r o m an a d e n o m a , as evidenced in three women, two o f whom had s t o p p e d oral contraceptive t h e r a p y and c o m p l e t e d a subsequent p r e g n a n c y only to i n c u r r u p t u r e o f an a d e n o m a three and five weeks postpartum, respectively. 54' 66 T h e third woman had s t o p p e d oral contraceptive h o r m o n e t h e r a p y and nine m o n t h s later went into shock f r o m h e m o r rhage. TM T h e r e were seven w o m e n with adenomas who had a specifically negative history o f oral contraceptive medication (cases 1, 3, and 4 o f Galloway et al.; 5s case 3 o f Hilliard et al.; 59 case 2 o f Davis et al.; sz and cases f and 3 o f Albritton et al.S8). T h e w o m e n were 22, 24, 25, 26, 34, 35, andt67 )'ears old. T h e patients in case 3 o f Albritton et al. and in case 2 o f Davis et al. p r e s e n t e d with massive h e m o r r h a g e . T h e five women r e p o r t e d b e f o r e 1960 who c o u l d not possibly have used orally active contraceptive h o r m o n e s and the seven w o m e n patients already m e n t i o n e d include two elderly women. However, it is o f interest that nine o f the 10 r e m a i n i n g females were less than 40 years old and seven o f them were between 19 and 27 years o f age. Young w o m e n are the ones most likely to develop liver cell a d e n o m a s even w h e n they are not taking orally active contraceptive hormones. T h e presenting signs o r symptoms in users o f these h o r m o n e s are not particularly different from those in nonusers, with the exception that acute massive h e m o r r h a g e is seen m o r e o f t e n in w o m e n taking orally active contraceptive hormones (eight o f 18 users [44 per cent]) as o p p o s e d to two o f 12 nonusers (17 p e r cent). E d m o n d s o n et al. n o t e d that four o f the 10 w o m e n with r u p t u r e d a d e n o m a s were m e n s t r u a t i n g at the time o f r u p t u r e . T h e y hypothesized that spasm o f arteries in the a d e n o m a might o c c u r at the same time as spasm o f the e n d o m e t r i a l spiral arterioles. T h e sizes o f the lesions in w o m e n who did not use orally active contraceptive h o r m o n e s r a n g e d from 5 to 16 cm. with a m e d i a n o f 10 cm. In w o m e n who did use these d r u g s there was a t e n d e n c y ' f o r the t u m o r s to be slightly larger, r a n g i n g f r o m 8 to 25 cm. with a m e d i a n o f 13 cm.
BENIGN HEPATIC LESIONS AND ORAL CONTRACEPTIVES--FEcHNEt~ All adenomas reported before 1960 were solitary, whereas nine of 36 reported since 1960 were muhiple. T h r e e of the cases of multiple adenomas were in women using orally active contraceptive hormones, but four of seven women with a definitely negative history of oral contraceptive therapy also had multiple lesions. The probability of an increased incidence of liver cell adenomas since 1960 seems likely. We are cognizant of the extreme limitations of trying to judge the incidence o f a lesion by the frequency with which it appears in the literature, but the following observations seem pertinent. There are eight acceptable surgical cases of liver cell adenoma reported between 1940 and 1960, 36 cases since 1960, and the 42 cases of Edmondson et al. The brief reports of Baum et al. and Berg et al. indicated that their sources of material contained no liver cell adenomas until after 1960. As stated before, there were apparently no adenomas as defined by Edmondson's criteria in the surgical files of the Mayo Clinic between 1907 and 1954 and only two tiny lesions were diagnosed at autopsy between 1922 and 1951. A single study relates the frequency of adenomas removed at one institution before and after I960. Albritton et al. 53 report one adenoma removed at the UCLA Health Center in 1948 and four cases between 1965 and 1973 that were diagnosed as adenomas. I f there is an increase in liver cell adenomas since 1960, can it be attributed to oral contraceptive hormone therapy at least in part? There are 20 adults (19 are women) noted in papers published or in press before 1973 when the positive artificial selection factor of orally active contraceptive hormone therapy and liver cell tumors took hold. T h r o u g h the courtesy of several authors, we have been able to obtain histories of oral contraceptive medication in 12 of their patients,sv-gx Nine women are taking orally active contraceptives and three were not. In addition, the report in 1972 by Horvath et al. 6~ included a history of oral contraceptive usage, but this was not the primary reason the case was published. In other words, 10 of the 13 women in whom a history of oral contraceptive usage was available were taking these agents. This is suggestive of a
relation, since only about 16 per cent of American women were taking orally active contraceptives between 1964 and 1972. 90Furthermore, the three cases of liver cell adenoma reported by Hilliard et al. and our six cases provide nine additional consecutive patients with adenomas unselected for oral contraceptive hormone therapy. Seven of these nine had a positive history of such usage. T h e study of adenomas by Edmondson et al. found that 29 of 34 were taking these drugs. Interestingly, a similar number of control subjects (24 of 34) without liver tumors were taking orally active contraceptives. A significant difference did exist between the two groups in that the mean duration of usage was 80 months in the patients with adenomas, but only 38 months in the women without neoplasms. We interpret these observations as being strongly suggestive of an association between liver cell adenomas and oral contraceptive hormone usage. Edmondson et al. noted that the oral contraceptive h o r m o n e therapy in women with adenomas was heavily weighted toward preparations containing mestranol. (All such drugs contain either mestranoi or ethinyl estradiol as the estrogenic component.) They found that over 90 per cent o f the women with adenomas were taking preparations containing mestranol, whereas only 55 per cent of the control users of these hormones were taking mestranol compounds. There are five cases in the literature with well documented liver cell adenomas in which the exact hormone is given, and four of the five were mestranol. In all five of our cases of liver cell adenoma, the orally active contraceptive contained mestranol and not estradiol. Six cases diagnosed as hepatoma have been reported in young women taking orally active contraceptive hormones. In two of these the patients were well three and six years ,after resection? The histologic slides have been reviewed and are now thought to be compatible with adenomas. 9' Davis et al. have reported a hepatic cell tumor with bizarre nuclei, but the follow-up period is too short to j u d g e the biologic potential. 2 Mays et al. 4 listed cases of hepatoma with vein invasion. Two patients had unresectable tumors and died although details were not given. One of
265
H U M A N P A T H O L O G Y - - V O L U M E 8, NUMBER 3 t h e o t h e r two was alive two m o n t h s a f t e r right lobectomy a n d the fourth died duri n g s u r g e r y . It is o f i n t e r e s t t h a t t h r e e o f t h e f o u r p a t i e n t s h a d u s e d orally active c o n t r a c e p t i v e h o r m o n e s for o n e ) ' e a r o r less, c o n t r a s t i n g s h a r p l y with the a d e n o m a s , which o c c u r in w o m e n w h o u s u a l l y h a v e t a k e n h o r m o n e t h e r a p y orally for t h r e e to five )'ears o r l o n g e r . A d d i t i o n a l cases a r e r e q u i r e d to m o r e a c c u r a t e l y assess t h e r e l a t i o n o f oral c o n t r a c e p t i v e h o r m o n e t h e r a p ) ' to e i t h e r b e n i g n o r m a l i g n a n t h e p a t i c lesions. As in the present communication, patients s h o u l d be r e p o r t e d as c o n s e c u t i v e cases a n d n o t p r e s e l e c t e d b e c a u s e o f t h e i r use of oral contraceptive therapy. T h e b e n i g n l e s i o n s m u s t be a c c u r a t e l y classified, bec a u s e two clearly d i f f e r e n t p a t h o l o g i c e n t i t i e s have b e e n r e p o r t e d t h u s f a r a n d it is likely t h a t o n l y o n e , liver cell a d e n o m a , h a s a possible a s s o c i a t i o n with t h e o r a l u s e of contraceptives.
REFERENCES
266
1. Baum, J. K., Holtz, F., Bookstein, j. J., et al.: Possible association between benign hepatomas and oral contraceptives. Lancet, 2:926-929, 1973. 2. Davis, M., Portmann, B., Searle M., et al.: Histological evidence of carcinoma in a hepatic tumor associated with oral contraceptives. Brit. Med. J., 4:496-498, 1975. 3. Hermann, R. E., and David, T. E.: Spontaneous rupture of the liver caused by hepatomas. Surgery, 74:715-719, 1973. 4. Mays, E. T., Christopherson, W. M., Mahr, M. M., et al.: Hepatic changes in young women ingesting contraceptive steroids. Hepatic hemorrlmge and primary hepatic tumors. J.A.M.A., 235:730-732, 1976. 5. Meyer, P., Livolsi, V. A., and Cornog, J. L.: Hepatoblastoma associated with an oral contraceptive. Lancet, 2:1387, 1974. 6. Edmondson, H. A.: Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood. Am. J. Dis. Child., 91:168-186, 1956. 7. Edmondson, H. A.: Tumors of the Liver and Intraheptatic Bile Ducts. Atlas of Tumor Pathology, Section VII, Fascicle 25. Waslfington, D.C., Armed Forces Institute of Pathology, 1958. 8. Ackerman, L. V., and Rosai, J.: Surgical Pathology. Ed. 5. St. Louis, The C. V. Mosby Co., 1974, pp. 533-535. 9. Knowles, D. M., Wolff, M., and Casarella, W. J.: Hepatic cell adenomas (letter). Arch. Surg., 110:1154, 1975.
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31. Wallace, R. H.: Resection of the liver for hepatoma. Arch. Surg., 43:14-20, 19,tl. 32. Warvi, W. N.: Prinmry tumors of the liver. Surg. Gynecol. Obstet., 80:643-650, 1945. 33. Duckett, J. w., and Montgomery, H. G.: Resection of primary liver tumors. Surgery, 21: 455-469, 1947. 34. Hershey, C. D.: Partial hepatectomy in certain primary tumors of the liver. South. Surg., 12:245-252, 1946. 35. Levenson, R. M., and Mason, D. G.: Mixed adenoma (hamartoma) of the liver: report of a case. Ann. Intern. Med., 38:136-141, 1953. 36. Aronsen, K. F., Ericssou, B., Lunderquist, A., et al.: A case of operated focal nodular cirrhosis of the liver. Scand. J. Gastroenterol., 3:58-64, 1968. 37. Crispin, H. A.: A case of hepatic adenoum. Acta Clair. Belg., 70:91-110, 1971. 38. Field, C. A.: Hanmrtoma of the liver in a pregnant woman. Minn. Med., 52:639-641, 1969. 39. Garancis, J. C., Tang, T., Panares, R., et al.: Hepatic adenoma. Biochemical and electron microscopic study. Cancer, 24:560-568, 1969. 40. Hertzer, N. R., Hawk, W. A., and Hernmnn, R. E.: Inflammatory lesions of the liver which simulate tumor: report of two cases in children. Surgery, 69:839-846, 1971. 41. Kwittken, J.: Hamartoma of the liver. N.Y. State J. Med., 67:3254-3257, 1967. 42. Mah, R. A., Hershberg, R. A., and Miller, W. L.: Experience with benign tumors of the liver. Surg. Gynecol. Obstet., 130:285-291, 1970. 43. Mays, E. T., Christopherson, W. M., and Barrows, G. H.: Focal nodular hyperplasia of the liver. Possible relationship to oral contraceptives. Am. J. Clin. Pathol., 61:735-746, 1974. 44. McLougldin, M. J., Colapinto, R. F., Gilday, G. L., et al.: Focal nodular hyperplasia of the liver. Angiography and radioisotope scanning. Radiology, 107:257-263, 1973. 45. Nikaido, H., Boggs, J., and Swenson, O.: Liver tumors in infants and children. Clinical and pathological analysis of 22 cases. Arch. Surg., 101:245-257, 1970. 46. Nissen, E. D., and Kent, D. R.: Liver tumors and oral contraceptives. Obstet. Gynecol., 46:460-467, 1975. 47. O'Sullivan, J. P., and Wilding, R. P.: Liver hamartomas in patients on oral contraceptives. Brit. Med. J.,2:7-10, 1974. 48. Ramchand, S., Sub, H. S., and Gonzalez-Crussi, F.: Focal nodular hyperplasia of the liver. Can. J. Surg., 13:22-26, 1970. 49. Thonaas, P. A., McCusker, J.J., Merrigan, E. H., and Conte, N. F.: Lobar cirrhosis with nodular hyperplasia (hamartoma) of the liver treated by left hepatic Iobectomy. Am. J. Surg., 112: 831-834, 1966. 50. Westbrook, R. I., and Raines, *1.: Hamartoma: case report. Nebr. Med. J., 54:588-591, 1969. 51. Whelan, T. J., Baugh, J. H., and Chandor~ S.: Focal nodular hyperplasia of the liver. Ann. Surg., 177:150-158, 1973. 52. Wilson, T. S., and MacGregor, J. W.: Focal nodular hyperplasia of the liver: the solitary
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and children. Am. J. Surg., 123:346-350, 1972. Tountas, C., Paraskevas, G., and Deligeorgi, H.: Benign hepatoma and oral contraceptives (letter). Lancet, 1:1351-1352, 1974. Ameriks, J. A., Thompson, N. W., Frey C.F., et al.: Hepatic cell adenomas, spontaneous liver rupture, and oral contraceptives. Arch. Surg., 110:548-557, 1975. Berg, J. W., Ketalaar, R. J., Rose, E. F., et al.: Hepatomas and oral contraceptives (letter). Lancet, 2:349-350, 1974. Goldstein, H. M., Neiman, H. L., Mena, E., et al.: Angiogi-aphic findings in benign liver cell tumors. Radiology, 110:339-343, 1974. Model, D. G., Fox, J. A., and Jones, R. W.: Muhiple hepatic adenomas associated with an oral contraceptive. Lancet, 1:865, 1975. Mosonyi, L.: Muhiple benign hepatomas and virilization by ovarian tumor. Lancet, 2: 1263-1264, 1973. O'Reilly, K.: Focal nodular hyperplasia of the liver. Aust. New Zeal. J. Surg., 44:142-143, 1974. O'Reilly, K.: Focal nodular hyperpIasia o f the liver: a further contribution. Anst. New Zeal. J. Surg., 45:76-77, 1975. Phillips, M. J., .Langer, B., Stone, R., et al.: Benign liver cell tumors. Classification and uhrastructural pathology. Cancer, 32:463470, 1973.
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81. Pollice, L.: l'rimary hepatic tumors in infancy and childhood. Am. J. Clin. Path., 60:512521, 1973. 82. Vosnides, G., O'Keefe, B., Brander, W., et al.: Liver hamartomas in patients on oral contraceptives. Brit. Med., J., 5:580, 1974. 83. Ishak, K. G., and Rabin, L.: Benign tumors of the liver. Med. Clin. North Am., 59:995-1013, 1975. 84. Edmondson, H. A., Henderson, B., and Benton, R.: Liver-cell adenomas associated with use of oral contraceptives. New Eng. J. Med., 294: 470-472, 1976. 85. Benz, E. J., and Baggenstoss, A. H.: Focal cirrhosis of the liver: its relation to the socalled hamartoma (adenoma, benign hepatoma). Cancer, 6:743-755, 1953. 86. Fechner, R. E.: Fibroadenomas in patients receiving oral contraceptives. A clinical and pathologic stud)'. Am. J. Clin. Path., 53: 857-864, 1970. 87. Schenken, J. R.: Personal communication, 1975. 88. AIbritton, D. R.: Personal communication, 1975. 89. Gamble, W. G.: Personal communication, 1975. 90. Kay, S.: Personal communication, 1975. 91. Hermann, R. E.: Personal communication, 1976. 92. Tyler, E. T.: International aspects of the use of norgestrel, lh Fairweather, D.V.I. (Editor): International Norgestrel Symposium. New York, American Elsevier Publishing Co., 1974, pp. 1-8. Department of Pathology Baylor College of Medicine 1200 Moursnnd Avenue Houston, Texas 77030
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Abstract A consecutive series of 12 benign he'patic lesions in women consisted of six cases of focal nodular hyperplasia and six cases of liver cell adenoma. Five o f the six women.with liver cell adenoma and two of the six with focal nodular hyperplasia had taken orally active contraceptive horntones. These few cases reflect a similar impression gained from a critical analysis of the literature, namel)', tlmt focal nodular hyperplasia may be unrelated to the oral administration of contraceptive hormones, whereas rite increase in liver cell adenoma reported in recent )'ears is probably related to such therapy. Two women with fiver cell adenomas were asymptomatic six and four years after incomplete resection of the tumor. These are tim longest intervals thus far reported for uncomplicated survival in incompletely resected liver cell adenoma.
In 1973 Baum et al? reported seven women with benign hepatic ttnnors who were taking contraceptive hormones orally. T h r e e of these patients were from a single hospital where no other benign hepatic tumors could be found in a search back to 1913. Therefore, the cluster of cases was considered significant and the common denominator of oral contraceptive hormone therapy suggested that the hormones might be causal. A flurry of additional reports of lmpatic ttunors in women taking orally active contraceptive hormones has ensued, totaling nearly 100 cases. Seven have been diagnosed as either hepatoma or hepatoblastoma, 2-5 but the
majority of liver lesions have been considered benign. Diagnoses in the latter group have included focal nodular hyperplasia, hamartoma, adenoma, and benign hepatonla. When one stndies tim papers dealing with benign lesions, it is obvious tlmt these several terms are being applied to two pathologically distinct lesions, to wit, focal nodular hyperplasia and liver cell adenoma. Many authors have not made tim distinction, and this clouds tile understanding of the possible relation of orally administered contraceptive hormones to these two different entities. Tbe basic problem of inaccurate classification is especially unnecessary, since Edmond-
*Professor, BaylorCollege of Medicine. Surgical Pathologist,Tile Methodist Hospital, Houston, Texas.
255
HUMAN P A T H O L O G Y - V O L U M E 8, NUMBER 3 May 1977 son 6"~ separated a n d defined focal n o d u lar hyperplasia and liver cell a d e n o m a in the late 1950s. His criteria are clear a n d recently have been reaffirmed by others. 8-n T i m p u r p o s e o f this c o m m u n i c a t i o n is to present a consecutive series o f benign lesions in patients f r o m a single ltospital. Altlmugh a small g r o u p , it is tim first consecutive series o f patients with benign hepatic lesions in w h o m a history of oral contraceptive l t o r m o n e t h e r a p y has been specifically obtained. T l m Anglo-American literature dealing with focal n o d u l a r hyperplasia and liver cell a d e n o n m was reviewed from 1940 to the present in an effort to place recent r e p o r t s in perspective. In this discussion the phrases " b e f o r e 1960" and "after 1960" are used repeatedly. T h e )'ear 1960 is crucial because it m a r k e d ttte beginning o f the oral use o f contraceptives on a large scale. T h e literature prior to 1960 serves as an effective "control," since patients r e p o r t e d b e f o r e t h e n were not taking contraceptives orally. In addition, the literature between 1960 a n d 1973 is valuable because hepatic lesions r e p o r t e d in those )'ears were not selected for publication because o f a history o f oral contraceptive h o r m o n e therapy. Tiffs is important because papers on benign hepatic lesions going to press a f t e r late 1973 have dealt almost exclusively with lesions in w o m e n taking contraceptives orally. It is obvious that the first criterion for publication is that the patient be taking h o r m o n e s , resulting in selected case reports r a t h e r
than series o f consecutive patients unselected as to h o r m o n e history o r sex. Anecdotal literature may detect a genuinely new t r e n d , but it also becomes selffldfilling a n d is weighted toward an apparently positive association between two events. DEFINITION OF TERMS. Focal nodular hyperplasia and liver cell a d e n o m a are not morphologically complex, and by adltering to a few criteria it is possible to definitely identify cases in the literature if sufficient description is given, regardless o f tlte n a m e used by tire original authors. An)" case in tim literature that did not clearly fnlfill the criteria to be listed was placed into the category o f " t u m o r o f uncertain type." A lesion was classified as liver cell a d e n o t n a when tim t u m o r was c o m p o s e d o f liver ceils with nuclear variation n o g r e a t e r tlmn that o f n o r m a l liver and specifically lacked bile ducts or ductules (Figs. 1, 2). A case was accepted as focal n o d u l a r hyperplasia wlten all tim following criteria were met: o n e o r m o r e grossly visible localized nodules in an otherwise n o r m a l liver, a p r e d o m i n a n c e o f normal hepatic cells but with some bile ducts or multiple ductules, a n d fibrous sepia in the nodule, which usually radiate f r o m a central stellate fibrous area (Figs. 3, 4). T h e s e criteria exclude nodules in cirrhotic livers, n o d u l a r regenerative hyperplasia, hepatocellular adenomatosis, and partial n o d u l a r transformation, alt h o u g h all share some microscopic features witlt focal n o d u l a r hyperplasia, e.g.,
Figure 1. Cut surface of liver cell adenoma has finely granular appearance. Darker areas are recent hemorrhage. The mass is 8 cm. wide. (Case 3.)
256
BENIGN HEPATIC
Figure 2. Liver cell adenoma cousists of liver cells without bile ducts or ductules. (Hematoxyliu and eosin stain, x 300.)
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HUMAN P A T H O L O G Y - V O L U M E 8, NUMBER 3 May 1977 hepatic cell h y p e r p l a s i a attd the p r e s e n c e o f bile ducts within nodules. T h e differentiations are m a d e readily because the grossly detectable masses o f partial n o d u lar r e g e n e r a t i v e h y p e r p l a s i a and hepatocelhdar a d e n o m a t o s i s involve the liver diffusely. 12
METHODS A N D MATERIALS T h e benign hepatic lesions in the surgical p a t h o l o g y files b e t w e e n 1968 and 1976 at T h e Methodist Hospital were re,~'iewed. T h i s search yielded six cases o f liver cell a d e n o m a and six cases o f focal n o d u l a r hyperplasia, all in w o m e n (Table I). Five o f the six w o m e n with liver cell a d e n o m a s w e r e taking orally active contraceptive h o r m o n e s at the time the lesion was diagnosed, as were two o f the six w o m e n with focal n o d u l a r hyperplasia. T h e negative histories were c o n f i r m e d by specific interviews with the w o m e n . T h e clinical px:esentation in o u r cases parallels that o f cases iri the literature. T h r e e w o m e n with liver cell a d e n o m a s p r e s e n t e d with pain s e c o n d a r y to intrahepatic h e n t o r r h a g e ; two h a d a palpable mass a n d in o n e the finding was incidental at l a p a r o t o m y . O n the o t h e r h a n d , f o u r o f the lesions o f focal n o d u l a r hyperplasia
were u n e x p e c t e d l y e n c o u n t e r e d at laparo t o m y e i t h e r at the time o f gynecologic p r o c e d u r e s (three cases) or at ileocolic bypass (one case). T w o p r e s e n t e d as painless masses. T w o patients with liver cell a d e n o m a s did not u n d e r g o total r e m o v a l o f an aden o m a . O n e patient (case 3) had two masses, o n e o f which was totally resected. T h e second mass was located n e a r the h i l u m o f the liver a n d was incompletely r e m o v e d by piecenteal blunt dissection. A p o s t o p e r ative scan s h o w e d a defect in the hilum, which has persisted u n c h a n g e d for three )'ears. She c o n t i n u e d to take Enovid E but has n o w b e e n advised to stop. A n o t h e r patient (case 2) had a lesion located in the hilum that was partially r e m o v e d . She received 5-fluorouracil (250 mg. p e r d a y for 30 days) t h r o u g h a catheter in the c o m m o n hepatic artery. Oral contraceptive horm o n e t h e r a p y was c o n t i n u e d for four )'ears a n d t h e n stopped, a n d she was well six )'ears a f t e r the initial diagnosis.
DISCUSSION T h e review o f the literature dealing with b e n i g n hepatic lesions b e t w e e n 1940 a n d 1960 yielded 37 surgically treated
TABLE 1. THE METHODISTHOSPITALCASES (1968--1976) Case Age
Liver cell adenoma 1 27 9 2 26 3 4 5 6
33 38 29 28
Duration of Oral ContraceptiveTherapy
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Biopsy Excision
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Well 3 yr. Well 2 yr. Well 2 yr. Well 6 too.
Focal nodular hyperplasia 7 44 None 8 26 Oracon, 3 yr. Ovral 9 37 None 10 38 None 11 34 None 12 35 Norinyl, 5 yr. Ovulen Enovid Ovral
258
Presentation
BENIGN HEPATIC LESIONS AND ORAL CONTRACEPTIVES--FECHNER masses, excluding mesenchymal hantartomas and hemangiomas. O f these, 24 were thought to be clearcut examples of focal nodular hyperplasia. ~3--~rSeven adtflts and one child were accepted as representing tmequivocal cases of liver cell adenoma.,7, .~s-3~_ Since 1960, 125 cases of benign liver lesions diagnosed during life have been reported individually or in small series. Thirty-seven were definitely focal nodular hyperplasia, 3~z 36 were liver cell adenomas, 3,42,4~'Sz-Tz and 52 were of uncertain type? "4'r~z There was a positive history of usage of orally active contraceptive hormones in 59 cases, o f which nine were identifiable as focal nodular hyperplasia, 19 as liver cell adenomas, and 31 as uncertain type (Table 2). T h e pathology study of Phillips et al. s~ had 15 cases of liver cell adenoma and focal nodular hyperplasia but is not included in further analysis in this presentation because clinical information was not a part of the report. In addition, Ishak and Rabin s3 briefly summarized their experience with 130 cases of focal nodular hyperplasia and 75 cases of liver cell adenoma collected at tile Armed Forces Institute of Pathology. Their report, published in 1975, spans ~ses before and afte~ 1960 but does not provide detailed histories. Finally Edmondson et al. s4 published in 1976 a stud), of 42 cases of liver cell adenoma in women, six of which had already been published. Since focal nodular hyperplasia and liver cell adenQmas are morphologically distinct lesions, they will be discussed separately.
Focal Nodular Hyperplasia The 24 cases of focal nodular hyperplasia diagnosed during life reported between 1940 and 1960 include 11 in children and 13 in adults: 10 women and three l n e n . 1 4 , 20, 93, 24,213 Tile w o n l e n were 23, 28, 28, 28, 32, 38, 39, 46, 47, and 63 years old. Since 1960, 37 cases of focal nodular hyperplasia diagnosed during life have been published, of which 26 patients were older th,~n 19 )'ears. Twenty-three were women between 21 and 51 years of age, 13 of whom were between 21 and 29 )'ears of age. (The subsequent discussion ex-
cludes the survey by Ishak and Rabin since it includes autopsy as well as snrgical material.) In comparing the adults surgically treated for focal nodular hyperplasia before 1960 and after 1960, there are many similarities and only a single difference that may be related to oral contraceptive hormone therapy. Both groups had a similar age range: 23 to 64 )'ears before 1960 and 21 to 51 years after 1960. Almost exactly half the female patients in both groups were in the third decade. Focal nodular hyperplasia in adults is predominately a disease detected in young women even when they are not taking orally active cont~ceptive hormones, Tile lesions in adults were evenly distributed between the left and right lobes both before and after 1960, a finding that is also borne out in the subgroup known to be t a k i n g orally active contraceptive hormones. Tile freqnency of multiple lesions in adults was virtually identical before 1960 (two of 13) and after 1960 (three of 24). Moreover, in five of 34 cases of focal nodular hyperplasia there were multiple nodules in an autopsy series studied before the hormone era, 85 a proportion similar to that in the surgical groups. Against tltis background, the fact that two of the three patients with multiple lesions reported since 1960 were taking orally active contraceptive hormones is unimpressive and can be considered coincidental. No major gross or microscopic differences can be discerned between tile lesions of focal nodular hyperplasia in women taking orally active contraceptive ltormones and those in women having a negative history. Nevertheless there is one feature, alterations in the vasculature, that deserves further comment as it has been emphasized in several papers. Mays et al. 43 discuss a variety of abnormalities, including arterial medial hypertrophy and varying degrees of occlusion, phlebitis, fresh organizing thrombi, attd intintal proliferation and swelling in small vessels not otherwise identified. The authors tlaought that tile changes might have caused hemorrhagic necrosis, but were aware that tltey might be merely secondary to such necrosis. Similar changes were described in two other le-
259
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BENIGN HEPATIC LESIONS AND ORAL CONTRACEPTIVES--FEcu,,,'ER sions of focal nodular l~yperplasia in women taking orally active contraceptive hormones in whom hemorrlmge was absent.4G,47 Therefore, vascular changes can exist without producing bleeding and were not secondary to hemorrhage in these particular instances. It is also of note that arterial and venous hypertrophy was described by Edmondson in 1958 before orally active contraceptive hormones were available, and Benz and Baggenstoss 85 found "occasional venous thrombi" in their lesions of noninfarcted focal nodular hyperplasia in auto'psy material before these drugs were available. For these reasons, one slmuld not too quickly attribute to oral contraceptive hormone therapy the rare thronabi or changes in the vessel walls. However, even though there are no qualitative differences in the vascular changes in lesions of focal nodular hyperplasia in women taking orally active contraceptive hormones, there appears to be a quantitative difference in a few lesions that may be attributable to these drugs. The one clinical difference that stands out since 1960 is the dramatic complication of acute life threatening hemorrlmge. Prior to 1960 no patient with focal nodular hyperplasia had presented with bleeding, although occasional small foci of old or recent hemorrhage were found in resected lesions. ~4 In 1967 a 25 )'ear old woman was reported who had hemorrhage from focal nodular hyperplasia, but there is no information regarding orally administered contraceptive hormones. 4~ O f the nine women with focal nodular hyperplasia known to be taking contraceptive hormones orally, two presented with intrahepatic or intraperitoneal bleeding. 43 That a woman taking orally active contraceptive hormones might be more susceptible to hemorrhage than a nonuser is possible in view of the increased frequency of thrombotic episodes in other organs during such therapy. In cases o f hepatic lesions this complication may be a direct consequence of oral contraceptive hormone therapy and could occur even if the underlying lesion itself were not caused by hormone therapy. The incidence of focal nodular hyperplasia is not known, and accurate statistical
assessment of the influence of orally active contraceptive hormones is not possible. T h e problem can be approached indirectly if one analyzes the years 1960 to 1973, before the rush of selected cases began. There were 26 surgical cases, 15 of which were ill adults (58 per cent). This percentage is not far removed from the series of 24 patients before 1960, which included 13 aduhs (53 per cent). The frequency of focal nodular hyperplasia in childhood is unrelated to orally administered contraceptive hormones and serves as a constant before and after 1960. Since the proportion of adults and childhood cases has stayed about the same, tbis can be interpreted as evidence against an increased frequency of lesions in adults. Another fragment of evidence is provided by the experience at the Armed Forces Institute of Pathology. Exactly half the cases of focal nodular hyperplasia on file occurred before the introduction of orally active contraceptive hormones, and there has not been a conspicuous increase in recent years, s3 Evidence for an association between focal nodular hyperplasia and orally administered contraceptive hormones requires consecutive cases unselected by sex or by hormone history in which the sex ratio overwhelmingly favors women and the majority are taking orally active contraceptive hormones. No such series is available. In fact, the converse was shown in our small group of six consecutive cases of focal nodular hyperplasia seen since 1968. Althougll all were women, only two had a positive history of oral contraceptive hormone usage, which is comparable to the 20 per cent proportion of premenopausal women in our hospital population known to be taking contraceptive hormones orally during these years, s~ At the moment convincing evidence of an association of such hormone usage and focal nodular hyperplasia is lacking, l~ Liver Ceil Adenomas
Liver cell adenomas were rarely reported before 1960. Henson et al. 12 encountered no liver cell adenomas at surgery at the Mayo Clinic between 1907 and 1954. They listed four patients diagnosed
263
HUMAN P A T H O L O G Y - V O L U M E 8, NUMBER 3 May 1977 as having " h e p a t o a d e n o m a s , " but their detailed histologic findings constitute a classic description o f focal nodular h y p e r plasia. Only two a d e n o m a s measuring less than 0.5 cm. were f o u n d in autopsies at the Mayo Clinic between 1922 and 1951. 8~ T h e r e are eight adequately d o c u m e n t e d surgical cases o f liver cell adenonm b e f o r e 1960.1r" 2a-3-~ Since 1960, t h e r e have been reports o f two w o m e n with liver cell adenomas diagnosed at autopsy. O n e was 70 )'ears old 42 and the o t h e r was 37. T h e latter had taken orally active contraceptive h o r m o n e s for " m a n y years" and died at h o m e as a result o f h e m o r r h a g e f r o m an a d e n o m a . 56 T h e literature dealing with liver cell a d e n o m a s diagnosed d u r i n g life includes 42 cases r e p o r t e d by E d m o n d s o n et al. and 36 cases in several smaller series. T h e r e is duplication in these numbers, since six o f the cases o f E d m o n d s o n et al. were previously r e p o r t e d and are included in o u r total o f 36 well p r o v e n cases. 53' ~G,6r T h e 36 cases and the cases o f E d m o n d s o n will be kept separate for the purposes o f this discussion. O f the 36 cases, f o u r were in children, all girls, ages 1, 2, 3, and 15 years? 5' 5r, 71 T h e 32 aduhs r a n g e d in age from 20 to 67 years with 18 patients between 20 and 29 years o f age and 13 m o r e between 30 and 40 years old. With the sole exception o f a 20 year old man, 4z all were women. T h e 31 w o m e n can be divided into three groups: 19 known to be taking orally active contraceptives, seven who never used orally active contraceptives, and five in w h o m no history o f oral usage o f contraceptives was available. T h e age distribution in the w o m e n taking orally acti,;'e contraceptive horm o n e s includes eight in their twenties, 10 in their thirties, a n d one who was 40 years old. T h e single most c o m m o n presenting s y m p t o m was acute pain and collapse d u e to intrahepatic o r intraperitoneal h e m o r rhage, which o c c u r r e d in nine women. Five others had vague pain leading to discovery o f a mass a n d t h r e e had an asymptomatic mass, o n e o f which was f o u n d incidentally at the time o f cholecystectomy. In o n e patient the presenting symptoms are not known. 6~ Cessation o f oral contraceptive hor-
264
m o n e t h e r a p y does not r e m o v e the risk o f fllttlre h e m o r r h a g e f r o m an a d e n o m a , as evidenced in three women, two o f whom had s t o p p e d oral contraceptive t h e r a p y and c o m p l e t e d a subsequent p r e g n a n c y only to i n c u r r u p t u r e o f an a d e n o m a three and five weeks postpartum, respectively. 54' 66 T h e third woman had s t o p p e d oral contraceptive h o r m o n e t h e r a p y and nine m o n t h s later went into shock f r o m h e m o r rhage. TM T h e r e were seven w o m e n with adenomas who had a specifically negative history o f oral contraceptive medication (cases 1, 3, and 4 o f Galloway et al.; 5s case 3 o f Hilliard et al.; 59 case 2 o f Davis et al.; sz and cases f and 3 o f Albritton et al.S8). T h e w o m e n were 22, 24, 25, 26, 34, 35, andt67 )'ears old. T h e patients in case 3 o f Albritton et al. and in case 2 o f Davis et al. p r e s e n t e d with massive h e m o r r h a g e . T h e five women r e p o r t e d b e f o r e 1960 who c o u l d not possibly have used orally active contraceptive h o r m o n e s and the seven w o m e n patients already m e n t i o n e d include two elderly women. However, it is o f interest that nine o f the 10 r e m a i n i n g females were less than 40 years old and seven o f them were between 19 and 27 years o f age. Young w o m e n are the ones most likely to develop liver cell a d e n o m a s even w h e n they are not taking orally active contraceptive hormones. T h e presenting signs o r symptoms in users o f these h o r m o n e s are not particularly different from those in nonusers, with the exception that acute massive h e m o r r h a g e is seen m o r e o f t e n in w o m e n taking orally active contraceptive hormones (eight o f 18 users [44 per cent]) as o p p o s e d to two o f 12 nonusers (17 p e r cent). E d m o n d s o n et al. n o t e d that four o f the 10 w o m e n with r u p t u r e d a d e n o m a s were m e n s t r u a t i n g at the time o f r u p t u r e . T h e y hypothesized that spasm o f arteries in the a d e n o m a might o c c u r at the same time as spasm o f the e n d o m e t r i a l spiral arterioles. T h e sizes o f the lesions in w o m e n who did not use orally active contraceptive h o r m o n e s r a n g e d from 5 to 16 cm. with a m e d i a n o f 10 cm. In w o m e n who did use these d r u g s there was a t e n d e n c y ' f o r the t u m o r s to be slightly larger, r a n g i n g f r o m 8 to 25 cm. with a m e d i a n o f 13 cm.
BENIGN HEPATIC LESIONS AND ORAL CONTRACEPTIVES--FEcHNEt~ All adenomas reported before 1960 were solitary, whereas nine of 36 reported since 1960 were muhiple. T h r e e of the cases of multiple adenomas were in women using orally active contraceptive hormones, but four of seven women with a definitely negative history of oral contraceptive therapy also had multiple lesions. The probability of an increased incidence of liver cell adenomas since 1960 seems likely. We are cognizant of the extreme limitations of trying to judge the incidence o f a lesion by the frequency with which it appears in the literature, but the following observations seem pertinent. There are eight acceptable surgical cases of liver cell adenoma reported between 1940 and 1960, 36 cases since 1960, and the 42 cases of Edmondson et al. The brief reports of Baum et al. and Berg et al. indicated that their sources of material contained no liver cell adenomas until after 1960. As stated before, there were apparently no adenomas as defined by Edmondson's criteria in the surgical files of the Mayo Clinic between 1907 and 1954 and only two tiny lesions were diagnosed at autopsy between 1922 and 1951. A single study relates the frequency of adenomas removed at one institution before and after I960. Albritton et al. 53 report one adenoma removed at the UCLA Health Center in 1948 and four cases between 1965 and 1973 that were diagnosed as adenomas. I f there is an increase in liver cell adenomas since 1960, can it be attributed to oral contraceptive hormone therapy at least in part? There are 20 adults (19 are women) noted in papers published or in press before 1973 when the positive artificial selection factor of orally active contraceptive hormone therapy and liver cell tumors took hold. T h r o u g h the courtesy of several authors, we have been able to obtain histories of oral contraceptive medication in 12 of their patients,sv-gx Nine women are taking orally active contraceptives and three were not. In addition, the report in 1972 by Horvath et al. 6~ included a history of oral contraceptive usage, but this was not the primary reason the case was published. In other words, 10 of the 13 women in whom a history of oral contraceptive usage was available were taking these agents. This is suggestive of a
relation, since only about 16 per cent of American women were taking orally active contraceptives between 1964 and 1972. 90Furthermore, the three cases of liver cell adenoma reported by Hilliard et al. and our six cases provide nine additional consecutive patients with adenomas unselected for oral contraceptive hormone therapy. Seven of these nine had a positive history of such usage. T h e study of adenomas by Edmondson et al. found that 29 of 34 were taking these drugs. Interestingly, a similar number of control subjects (24 of 34) without liver tumors were taking orally active contraceptives. A significant difference did exist between the two groups in that the mean duration of usage was 80 months in the patients with adenomas, but only 38 months in the women without neoplasms. We interpret these observations as being strongly suggestive of an association between liver cell adenomas and oral contraceptive hormone usage. Edmondson et al. noted that the oral contraceptive h o r m o n e therapy in women with adenomas was heavily weighted toward preparations containing mestranol. (All such drugs contain either mestranoi or ethinyl estradiol as the estrogenic component.) They found that over 90 per cent o f the women with adenomas were taking preparations containing mestranol, whereas only 55 per cent of the control users of these hormones were taking mestranol compounds. There are five cases in the literature with well documented liver cell adenomas in which the exact hormone is given, and four of the five were mestranol. In all five of our cases of liver cell adenoma, the orally active contraceptive contained mestranol and not estradiol. Six cases diagnosed as hepatoma have been reported in young women taking orally active contraceptive hormones. In two of these the patients were well three and six years ,after resection? The histologic slides have been reviewed and are now thought to be compatible with adenomas. 9' Davis et al. have reported a hepatic cell tumor with bizarre nuclei, but the follow-up period is too short to j u d g e the biologic potential. 2 Mays et al. 4 listed cases of hepatoma with vein invasion. Two patients had unresectable tumors and died although details were not given. One of
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H U M A N P A T H O L O G Y - - V O L U M E 8, NUMBER 3 t h e o t h e r two was alive two m o n t h s a f t e r right lobectomy a n d the fourth died duri n g s u r g e r y . It is o f i n t e r e s t t h a t t h r e e o f t h e f o u r p a t i e n t s h a d u s e d orally active c o n t r a c e p t i v e h o r m o n e s for o n e ) ' e a r o r less, c o n t r a s t i n g s h a r p l y with the a d e n o m a s , which o c c u r in w o m e n w h o u s u a l l y h a v e t a k e n h o r m o n e t h e r a p y orally for t h r e e to five )'ears o r l o n g e r . A d d i t i o n a l cases a r e r e q u i r e d to m o r e a c c u r a t e l y assess t h e r e l a t i o n o f oral c o n t r a c e p t i v e h o r m o n e t h e r a p ) ' to e i t h e r b e n i g n o r m a l i g n a n t h e p a t i c lesions. As in the present communication, patients s h o u l d be r e p o r t e d as c o n s e c u t i v e cases a n d n o t p r e s e l e c t e d b e c a u s e o f t h e i r use of oral contraceptive therapy. T h e b e n i g n l e s i o n s m u s t be a c c u r a t e l y classified, bec a u s e two clearly d i f f e r e n t p a t h o l o g i c e n t i t i e s have b e e n r e p o r t e d t h u s f a r a n d it is likely t h a t o n l y o n e , liver cell a d e n o m a , h a s a possible a s s o c i a t i o n with t h e o r a l u s e of contraceptives.
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