Oral contraceptives and intrahepatic biliary cystadenoma having an increased level of estrogen receptor.

We report a case of intrahepatic biliary cystadenoma in a young woman who had no prior history of liver disease and who had taken oral contraceptives for one year. A 27-year-old woman was admitted to our hospital with a firm epigastric mass. At laparotomy, a large cystic mass was resected from the left hepatic lobe, and diagnosed as biliary cystadenoma. In the tumor tissue, the estrogen receptor content was 14.0 fmol/mg cytosol protein, which was much higher than the 3.0 fmol/mg cytosol protein in the surrounding liver tissue. This is the first case of biliary cystadenoma in which the estrogen receptor content was increased.

PIP: A 27-year-old woman with a 1-year history of oral contraceptive (OC) use presented to a Japanese medical center with a firm epigastric mass. The patient had no prior history of liver disease. Biliary cystadenoma was diagnosed on the basis of the cystic nature of the mass, several mural nodules, and the presence of large amounts of mucinous fluid. At laparotomy, a cystic mass 7.2 x 5.8 x 6.2 cm was rejected from the left hepatic lobe. Several smaller cysts, lined by a layer of columnar mucinous epithelium, were contained within the wall of the larger cyst. The estrogen receptor content of the tumor tissue was 14 fmol/mg cytosol protein compared to less than 3 fmol/mg in the surrounding liver tissue. Biliary cystadenoma accounts for under 5% of all solitary cysts of biliary origin. This is the 4th known case of such a tumor in an OC user. Although the precise etiology of this woman's biliary cystadenoma cannot be ascertained, the high estrogen receptor content in her cystadenoma suggests that these tumors are sensitive to estrogen and that estrogen-containing OCs may serve as tumor promoters.

[Co-occurring liver cell adenoma and focal nodular hyperplasia due to contraceptives. Case report]. / Koinzidenz von Leberzelladenom und fokaler nodulrer Hyperplasie unter Ovulationshemmern.

The case is presented of a female patient who developed two pill-associated tumors in the liver, a liver cell adenoma in the right lobe and focal nodular hyperplasia in the left lobe. The pathological, clinical and prognostic features are discussed.

PIP: A case is presented of a female patient who developed 2 pill-associated tumors in the liver, 1 liver cell adenoma in the right lobe and the other a focal nodular hyperplasia in the left lobe. The pathological, clinical, and prognostic features are discussed. (Authors' modified)

[Benign hepatic tumours and oral contraception. Pathophysiology (author's transl)]. / Tumeurs hépatiques bénignes et contraceptifs oraux. Physiopathologie.

PIP: If the relation between OC (oral contraception) and hepatic tumors is well established, the pathogeny of such neoplasms is not well known. Estrogens exercise different metabolic actions on the liver, and progesogens contribute with a synergic action, especially on cholestasis. Other possible phenomena, however, are not yet explained, such as the role of acetylenic bindings, or the interference of OCs with other drugs, an interference which can become potentially toxic when metabolized in the liver.^ieng

Studies on the role of oral contraceptive use in the etiology of benign and malignant liver tumors.

PIP: Studies involving the role of OCs (oral contraceptives) in the etiology of benign and malignant liver tumors are reviewed. Although the number of reported cases is comparatively small (1 study cited an incidence rate of 1 case in 10,000 users after 5-10 years of contraceptive use), the available evidence strongly suggests that there is a relationship between the use of OCs and benign liver tumors. The acutal risk seems to be related to duration of usage, age of the woman, and type of contraceptive steroid used. 1 study showed the risk to be greater for those users who took pills with high doses of estrogens and progestogens. Analysis of liver tumors histologically showed the tumors among nonusers to be distributed among all the histologic types; there was a preponderance of hepatic cell adenomas (HCA) and focal modular hyperplasia (FNH) among users. Further evidence for an etiologic role for OCs in liver tumor formation can be derived from several cases of tumor regression or dormancy following OC discontinuance. Further etiologic studies should focus on other factors, e.g., female hormone balance, number of pregnancies, and liver disease. It is possible that FNH develops in women susceptible to hormonal stimulation. The malignant potential of benign tumors should also be studied.^ieng

Liver tumours.

Humans are remarkably resistant to many carcinogens that readily produce liver tumours in rodents, particularly the rat. The neoplastic process has been extensively studied in animal experiments, but little is known so far of how it evolves in humans. Few drugs have been shown to cause liver tumours in humans, and the risk appears to be low. The best-known examples are C17-alkylated or ethinylated gonadal sex steroids. Oral contraceptives have now been in use by millions for thirty years, but only a few hundred cases at most of liver cell adenoma have been observed. The role of these substances in liver cell carcinoma remains controversial, and the evidence is weaker still in relation to focal nodular hyperplasia and other tumour-like conditions. Anabolic-androgenic steroids stand out as the major cause of peliosis, but liver cell tumours induced by them seem to be adenomas and not carcinomas as originally suggested. The effect that both oral contraceptives and anabolic-androgenic steroids have on liver vasculature is of great clinical importance as the most important complication of liver tumours is rupture, leading to life-threatening haemorrhage. For this reason, liver tumours arising in users of these drugs should be removed whenever feasible. Thorium dioxide will remain a risk factor for the development of angiosarcoma, liver cell carcinoma and bile duct carcinoma for some time yet, and the number of patients who have been exposed is high--tens of thousands at least. The evidence of a carcinogenic role for many other drugs is anecdotal or weak. Neoplasia in the liver seems to be the least important side-effect of drugs in clinical use.

PIP: The role of oral contraceptives (OCs) in liver cell carcinoma remains controversial, although OCs, anabolic-androgenic steroids, and thorium dioxide are the best known causative agents of liver tumors in medical practice. The magnitude of the risk of liver cell adenoma in OC users is yet to be defined, but is considered to be dose- and time-dependent. The annual incidence rate in the US is estimated at 3.4/100,000 OC users, or 288 cases of liver cell adenoma/year. The epidemiological evidence has failed to confirm any association between OC use and focal nodular hyperplasia. The few studies that have collected data on liver cell carcinoma have neither confirmed nor refuted an association with OC use, although intraperitoneal hemorrhage seems to be a more common complication of liver cancer in OC users. Case-control studies have alleged a relative risk for developing liver cell carcinoma in OC users of 7.2-20.1; however, there is general agreement that the risk is low. Anabolic-androgenic steroids are the major cause of peliosis, but liver cell tumors induced by these agents tend to be adenomas rather than carcinomas. Even though the risk of liver tumors seems to be low in OC users, the effect of sex steroids on liver vasculature deserves serious attention since the major complication of liver tumors is rupture. For this reason, liver tumors in users of sex steroids should be removed whenever feasible.

Spontaneous resolution of oral-contraceptive-associated liver tumor.

Follow-up by computed tomography (CT) was quite useful in a woman with an oral-contraceptive-associated benign hepatic cell adenoma. Follow-up by CT without therapy (except to stop the oral contraceptives) was sufficient to show spontaneous regression of the lesion.

PIP: A case report of a woman diagnosed with an oral contraceptive-associated liver tumor who experienced spontaneous remission upon cessation of therapy is presented. The use of computed tomography for follow-up showed the regression, which was confirmed by histological examination. Use of computed tomography to visualize the lesion is an aid in diagnosing hepatic cell adenoma, but biopsy must be performed for confirmation. The patient had taken Enovid for 10 years without a break in therapy when the tumor was diagnosed.

Increased UDP-glucuronyltransferase in putative preneoplastic foci of human liver after long-term use of oral contraceptives.

PIP: Previous research by the authors had suggested that uridine-diphosphate-glucuronyl-transferase (UDP-GT) is a useful preneoplastic marker in chemical carcinogenesis. Recently the authors report that they found typical clear cell foci in a macroscopically normal liver surrounding focal nodular hyperplasia with a 6 cm diameter in a 27-year old woman who had been using oral contraceptives (OCs) containing ethinyl-estradiol and lynestrenol for 9 years. These foci were further characterized by a reduction of canalicular and cytoplasmic ATPase activity, an increased glycogen content, and a positive immunohistochemical reaction for UDP-GT. OC users develop 2 basic types of benign liver tumors: hepatic adenoma and focal nodular hyperplasia. Hepatic adenoma appears to be caused by OCs, whereas the relationship between OC use and focal nodular hyperplasia is less clear. The tumorigenic action of OCs has been ascribed to a promotor action on liver cells; however, there is no evidence that OCs are initiators of liver tumors. The case reported shows 2 manifestations of toxic lesions promoted by OC use: the development of focal nodular hyperplasia and enzyme-altered foci comparable to those seen in experimental liver carcinogenesis. Further studies are needed to get more information about the preneoplastic potential of these foci in humans. Since enzyme-altered foci could not be identified in the liver tissue of healthy women, these foci may be of prognostic significance in longterm OC users.^ieng

Abnormal sex-steroid milieu in young adults with hepatocellular carcinoma.

PIP: Analysis of 7 patients 20-30 years of age treated for hepatic cell carcinoma during the past 15 years at Massachusetts General Hospital indicated that 5 had an androgenous or exogenous disturbance of gonadal function. The 2 men in this series were taking methyltestosterone. Of the women, 2 had been taking oral contraceptives (OCs) for long durations, 1 had Stein-Leventhal syndrome, and 1 was infertile for 18 months. 3 of the 4 women with altered reproductive function had fibrolamellar carcinomas. These cases suggest that abnormalties of hypophyseal-gonadal endocrine metabolism can predispose to the development of hepatic cell carcinoma. Cessation of methyltestosterone or OC use and major hepatectomy apparently cured 3 of these patients. Although the data are consistent with a role for sex steroids in some cases of hepatic carcinogenesis, a case-control study would be needed to eliminate chance occurrence of fibrolamellar-variant cancer in the age group most likely to be using OCs. It is likely that hepatic carcinogenesis is a complex process involving genetic susceptibility, drug potency, regenerative urges, and the cooperation of promoters and co-carcinogens.^ieng

Oral contraceptive use and liver cancer.

The risk of liver cancer in relation to use of oral contraceptives was evaluated in a hospital-based case-control study conducted in five US cities from 1977 to 1985. Twelve new cases of liver cancer were identified in women aged 19-54 years; five controls selected from among patients hospitalized for acute conditions unrelated to oral contraceptive use were matched to each case on age (five-year categories), date of interview (three-year categories), and geographic location of the hospital. Among nine cases classified as having hepatocellular carcinoma, eight (89%) had used oral contraceptives; only 16 (36%) of 45 matched controls had used oral contraceptives. Among three other cases (two with cholangiocarcinomas and one with liver cancer of undetermined type), all had used oral contraceptives, compared with four of 15 matched controls. The results confirm the strong positive association between oral contraceptive use and hepatocellular carcinoma observed in earlier studies. Such an association is consistent with evidence that oral contraceptive use is associated with benign hepatic tumors in young women. However, the number of cases of liver cancer in the United States that are attributable to oral contraceptive use is probably small, because liver cancer is extremely rare in the United States.

Transformation of hepatic cell adenoma to hepatocellular carcinoma due to oral contraceptive use.

PIP: Unlike the proven causal association between oral contraceptive (OC) use and hepatic cell adenoma, the link between OCs and hepatocellular carcinoma remains speculative. The case history of a 53-year-old US woman suggests, however, that hepatic cell adenomas may transform into hepatocellular carcinoma. The patient, who had used Ovral continuously since 1966, presented in 1985 with vague abdominal pain and a palpable right upper quadrant mass. Computed tomography revealed a 12 x 8 cm mass in the right hepatic lobe and 2 small lesions in the left lobe. Serum alpha-fetoprotein and ferritin levels were normal and tests for hepatitis B were negative. A needle biopsy of the right lobe mass indicated benign hepatic adenoma. OC use was discontinued and the patient was examined at bimonthly intervals. Although she continued to report vague pain, there were no significant changes in radiologic findings or levels of alpha-fetoprotein over the next 18 months. At the 18-month follow-up visit, the alpha-fetoprotein level showed an increase to 227 mcg/L and had risen to 2300 mcg/L by the 30-month follow-up visit. At this time, computed tomography showed slight enlargement of the right lobe mass and inhomogeneity, while biopsy revealed sclerosing hepatocellular carcinoma. This is the 3rd case reported in the literature in which there is evidence of a transformation of hepatic cell adenomas into hepatocellular carcinoma in longterm OC users. Thus, the premalignant potential of hepatic cell carcinomas in OC users should be considered by physicians who follow such cases.^ieng

Hepatocellular carcinoma and oral contraceptives.

PIP: This article reports 11 new cases of liver cancer in US born women ages 18-39 occurring in 1975-80 obtained from the population-based cancer registry for Los Angeles County, California. 2 matched controls were obtained for each case. 10 cases had used OCs for periods ranging from 6-168 months, and 1 was given unspecified hormone shots for menstrual regulation during the 9 months preceding hormone shots for menstrual regulation during the 9 months preceding diagnosis of liver cancer. 6 were taking hormones at the time of diagnosis. The average duration of OC use among the 10 cases was 64.7 months compared with 27.1 months in controls (p0.005). Review of histopathologic material indicated that 3 cases had typical fibrolamellar carcinomas and 1 had a typical microtrabecullar carcinoma. 1 other case was a typical well-differentiated hepatocellular carcinoma. In 3 additional cases, the carcinoma was more undifferentiated but some trabecullar pattern was evident. The remaining 3 cases had distinctly unusual liver neoplasms, including a giant cell carcinoma, a sclerosing duct forming carcinoma, and a papillary carcinoma. The latter tumor occurred in a woman who had used OCs for 168 months. There was no evidence of exposure to other potential causes for liver cell carcinoma. The clinical, pathological, and epidemiological data strongly suggest that longterm OC use may cause hepatocellular carcinoma.^ieng

[Contraception and hepatogastroenterology]. / Contraception et hepato-gastro-enterologie.

PIP: Complications of oral contraceptives (OCs) affecting the gastrointestinal tract, liver and pancreas are rare but potentially serious. Hepatobiliary complications are by far the most frequent and varied. Hepatic lesions will probably decline in frequency as low-dose OCs replace higher dosed pills. Intrahepatic cholestasis induced by OCs resembles that of pregnancy. There may be a genetic predisposition to both conditions involving a dose-dependent estrogen effect of decreasing bile secretion. Intrahepatic cholestasis appears within 6 cycles of OC use. Symptoms include pruritus with anorexia, asthenia, vomiting, and weight loss without fever, rash or abdominal pain. Termination of OCs clears the condition without sequelae within 1-3 months, sometimes after a temporary aggravation. A moderate and asymptomatic cytolysis may appear when OC treatment is begun. Sinusoidal dilatation has been conclusively linked to OCs although few cases have been published. Clinical manifestations other than hepatomegaly are variable. Abdominal pain and fever are the most common. The condition is not related to duration of use and disappears 5-15 days after OC use is terminated. The relative risk of Budd-Chiari syndrome in OC users is estimated at 2.37. OCs increase the prevalence of hepatic adenomas as a function of duration of treatment. They are usually discovered fortuitously but may be revealed by vague abdominal pains. Hemorrhagic complications are more likely in OC users. It may be difficult to distinguish between adenomas, hepatocellular carcinoma, and focal nodular hyperplasia. A puncture biopsy guided by sonography may aid diagnosis. The natural history of adenomas is poorly understood and treatment remains controversial. OCs do not appear to increase the risk of focal nodular hyperplasia but they increase the size of the tumor and the risk of hemorrhage. OCs should be terminated because of risk of hemorrhage. Surgical resection is not indicated unless there are complication or diagnostic doubts. While hepatocellular carcinoma is very rare, its risk is increased by a factor of 7-20 in women using OCs for 8 years or more. Use of combined OCs appears to speed development of lithiasis in predisposed women. Risk of lithiasis is linked to estrogen content in women under 30. Several cases of acute pancreatitis in the 1st 3 months of treatment have been reported in women with preexisting lipid metabolic anomalies. Cases of ischemic lesions of the small intestine or colon have been reported in OC users with A positive blood type. Such lesions can be fatal without early diagnosis and termination of OCs. Gastric esophageal reflux is increased by progestins. Preexisting constipation may be aggravated and the incidence of Crohn's disease increased by OCs. It is advisable to rule out preexisting hepatic pathology before prescribing OCs. OCs should be stopped in case of viral hepatitis.^ieng

[The pill and the liver]. / Pilule et foie.

PIP: Combined oral contraceptives (OCs) modify different factors implicated in blood coagulation in the direction of encouraging thromboses. Patients with thrombotic antecedents or with reduced antithrombin III should not receive combined pills, and surgical intervention should be avoided in others until the patient has discontinued use for 3 weeks, long enough for the modifications to disappear. Combined preparations are inducers of certain hepatic enzyme systems and their use may alter the parameters of substances such as alpha 1 antitrypsine or gamma-glutamyltransferase, with little clinical effect. Combined OCs favor the formation of delta-aminolevulinic acid and should be avoided in case of porphyrie. Although the optical microscope discloses no histologic modifications except those existing in a clinical syndrome, the electron microscope may demonstrate modifications which can later attain clinical significance. Among clinical manifestations of pill use are biliary symptomatologies including cholestatic jaundice, which is rare, more common in women of Scandinavian origin, and apparently due to both the estrogen and progestagen. Biliary lithiasis is another possible clinical effect and is twice as common in pill users as in the control population. Vascular symptomatology attributable to pill use includes the Budd-Chiari syndrome and hepatic peliose, which may be reversed on discontinuation of pill use if the lesions are nonnecrotic. The use of OCs is known to be associated with the appearance of primitive hepatic tumors, but the exact incidence is unknown. Among 55 cases occurring in women aged 15-50 years identified in France between 1975-79, 5 were malignant and 50 were benign. 47 of the women had definitely used OCs. 47 of the 55 tissues were reviewed by the same pathologist. Of the 42 benign tumors, 31 were focal nodular hyperplasias, 9 were adenomas, and 2 were unclassifiable. Although the etiology of hepatic tumors in users of combined OCs is controversial, such women should be followed carefully and episodes of pain or other symptoms should be fully evaluated.^ieng

Hepatic tumors induced by sex steroids.

Our study of more than 250 women with hepatic tumors, accessioned in our tumor registry at the University of Louisville, disclosed three types of tumor: FNH , HCA, and HCC. The ingestion of sundry kinds of sex steroids by the majority of these women, chiefly for purposes of preventing conception, warrants the suspicion that such hormones induced these different types of hepatic tumors. Publications by others reporting similar hepatic tumors in men using male sex steroids lends support to this hypothesis. Rupture of the hepatic tumor and consequent hemorrhage, producing hemoperitoneum, is a major risk factor. Other presenting symptoms are pain and palpable mass. Symptomatic women using OCs should be subjected to a CT or technetium hepatic scan as an initial screening assessment. Because of the imminent possibility of rupture, large turgid vascular tumors should be resected without biopsy. Biopsy-proved HCC should also be removed surgically. All other tumors, including small multiple tumors, will usually regress when exogenous sex steroids are withdrawn and pregnancy avoided. Other significant hepatic changes observed in this study are peliosis hepatis, periportal sinusoidal dilation, and vascular lesions. The branches of the hepatic artery and the tributaries of the portal vein show combinations of intimal and smooth muscle proliferation, vascular thickening, occlusive intimal thickening, and, at times, obstructing thrombosis. Similar smooth muscle proliferation in the afferent vessels of the livers of animals treated with sex steroids suggests that there is a cause and effect relationship in women using OCs.

PIP: Previous reports describing the oncogenic capacity of estrogens and endrogens and reports suggesting a relationship between primary liver tumors and oral contraceptives (OCs) prompted a meticulous evaluation of the lifestyle and medication usage of each patient accessioned by the registry at the University of Louisville School of Medicine. More than 250 cases of hepatocyte tumors in young women, not all steroid related, have been collected since 1973. The data are sufficient for analysis in 201 patients. The intention was to assess etiological factors and critically classify the histologic features. 3 separate tumors were distinguishable: hepatocelluar adenoma (HCA), focal nodular hyperplasia (FNH), and hepatocellular carcinoma (HCC). In 9 tumors a histologic classification could not be made, generally because of massive hemorrhage and infarction of the tumor. 1 tumor was removed several weeks after hepatic artery ligation was done to stop hemorrhage from the ruptured tumor. Only dense scar tissue remained. Currently, none of the patients in the unclassified group has developed a recurrence nor have any developed metastases. None have died. HCA is relatively soft and usually solitary. The usual description of HCA stresses encapsulation. This is true of 5 tumors in the registry; in these cases the HCA occurred in women not exposed to exogenous reproductive steroids. In contrast, in women ingesting sex steroids the HCA were frequently not encapsulated. Nonencapsulation was characteristic of multiple small tumors in the group taking OCs. The typical FNH has a central scar with radiating septa and a coarsely nodular appearance. In contrast to HCA, necrosis and hemorrhage are less frequently encountered. The presence of bile duct epithelium is the single most distinguishing characteristic differentiating FNH from CHA. In women taking exogenous sex steroids, HCA and FNH may be related lesions or may be different histologic manifestations of a stimulus affecting mesenchymal and entodermal elements of the liver in variable degrees. HCC is grossly indistinguishable from FNH, having a well formed central scar, fibrous septa, and coarse nodulation. Despite the fact that all HCCs were fairly well differentiated tumors, there were no longterm survivors. There is no conclusive evidence that a cause and effect relationship exists between primary tumors of the liver and OCs. A history of prolonged sex steroid administration, usually OCs, was present in the majority of the cases studied. Similar smooth muscle proliferation in the afferent vessels of the livers of animals, treated with sex steroids suggests that there is a cause and effect relationship in women using OCs.

Hepatocellular carcinoma associated with oral contraceptive use and pregnancy.

Numerous undesirable side effects have been attributed to oral contraception, from mild breast discomfort to thromboembolism. The authors present a case report of hepatocellular carcinoma associated with oral contraceptive use and pregnancy and discuss the potentially fatal association of malignant liver tumors with usage of oral contraception.

PIP: The possible association of hepatocellular carcinoma with oral contraceptive (OC) use is supported by the case of a 33-year old black female, gravida 5, para 4. She presented in April 1978 with right upper quadrant pain, nausea, vomiting, and fatty food intolerance. The case had been taking norethindrone, 1 mg with mestranol 0.05, for 2 years. There was no history of liver disease, alcohol abuse, or exposure to chemical toxins. The preoperative diagnosis was subacute cholecystitis; however, an unresectable primary liver tumor of both lobes was detected on surgery. OC use was discontinued, and the case refused chemotherapy. On December 1, 1978, she presented with a 9-week pregnancy which was aborted. Physical examination revealed an enlarged liver and mass in the upper right quadrant. The patient was readmitted December 11 with intractable pain and discharged. She died December 28, 1978. At autopsy the liver tumor appeared as a moderate to poorly differentiated hepatoma with irregular hyperchromatic nuclei. There was no evidence of coexistent benign lesions. The rapid progression of the disease following pregnancy suggests that hepatic growth was stimulated by the high estrogen levels of pregnancy. Earlier diagnosis and improved management are required in such cases. Ultrasonography can be used to confirm the presence of a mass, and liver scan or hepatic angiogram may be useful. Liver biopsy is required for definitive diagnosis. Treatment involves discontinuation of OC use and complete excision of the tumor where possible. If tumors have progressed beyond the stage of resectability, as in this case, the prognosis is poor.

Oral contraceptives and benign tumors of the liver.

PIP: The prevalence of benign tumors of the liver in users of oral contraceptives (OCs) has increased to the point that they must be considered in the differential diagnosis of a variety of symptoms in women at risk. It is important to distinguish hepatic adenoma from focal nodular hyperplasia because the former may be complicated by severe hemorrhage and is clearly linked to prolonged OC use. The annual incidence of hepatic adenoma has been estimated at 3.4 cases/100,000 OC users. Focal nodular hyperplasia generally appears as a single nodule (78%) measuring less than 5 cm in diameter (84%). On cut section there is a characteristic central, stellate, fibrous core that radiates to the periphery of the lesion, dividing the tumor into a number of nodules. Proliferating bile ducts and inflammatory cells are often seen in the fibrous areas. Hepatic adenoma is easily distinguished by gross and microscopic inspection. It usually appears as a single (71%), large (36% larger than 10 cm), fleshy tumor without any internal structure. The absence of bile ducts is noteworthy. Data show strong association between OCs and the development of hepatic adenoma but no association with focal nodular hyperplasia. If women use OCs for more than 6 years, hepatic adenoma is 25 times more likely to develop than in nonusers. Patients with hepatic adenoma usually present with life-threatening hemorrhage as the initial manifestation of the tumor. Hormonal factors are very important in the pathogenesis and clinical presentation of hepatic adenoma; hemorrhage frequently occurs in association with menstruation. By contrast, patients with focal nodular hyperplasia generally have no symptoms and the prognosis is excellent. Use of OCs should be stopped in all patients who may have hepatic tumors because tumor regression usually occurs after withdrawal of the drug. Evidence indicates that synthetic estrogens do not cause tumors directly but can enhance the growth of neoplastic cells.^ieng

Hepatocellular carcinoma coexisting with hepatic adenoma. Incidental discovery after long-term oral contraceptive use.

PIP: In March 1989, ultrasonography revealed a hepatic mass in a 40 year old nulliparous woman who was then referred to the University of Southern California--Los Angeles (UCLA) Liver Unit. She exhibited no symptoms of a liver condition. From 19-28 years old, she took the combined oral contraceptive (OC) Ovulen 21 for irregular menses. After a brief period of taking Ortho Novum 1/80, she took Demulen 1/35-24 between ages 28-34. Her physician diagnoses endometriosis at 34. He stopped OC therapy and prescribed the progestin Norlutate. She had no history of hepatitis, toxin exposure, and previous liver disease. Further no one in her family had had liver disease or neoplasms. Computer tomography identified a 6.5 cm x 3.5 cm mass in the right lobe of the liver which matched a cold defect on a liver scan using technetium Tc 99m sulfur colloid. The mass selectively took up gallium. Arteriography revealed the mass to be a vascular tumor, but it did not exhibit a typical vascular pattern of an adenoma or the neovascularity of hepatocellular carcinoma. Physicians at UCLA used peritoneoscopy to take percutaneous needle biopsies of the right lobe which confirmed a hepatic adenoma. they then removed the right lobe of the liver. The remaining part of the liver was normal. Histologic examinations of the removed section showed features of a well differentiated hepatocellular carcinoma. Further tumor cells had invaded normal hepatic parenchyma. The physicians believed that hepatic adenoma was in the process of transforming into hepatocellular carcinoma in this patient. They thought that long term OC use, and possibly long term progestin use, may have contributed to the formation of the liver neoplasms. They emphasized the need for a pilot study to develop guidelines on surveillance ultrasonography of women taking OCs over a long period.^ieng

Resolution of a contraceptive-steroid-induced hepatic adenoma with subsequent evolution into hepatocellular carcinoma.

PIP: The very rare event of 3 types of liver neoplasia occurring at different times and locations in a user or oral contraceptives is reported. The woman developed benign hepatic adenoma at 36 years of age in 1977 after using pills for 14 years. She had taken a combination of norethindrone and mestranol for the last 7 years. The tumor was 13 cm in diameter and extensively involved the inferior suface of the right lobe. She discontinued pills, the tumor resolved, and she remained well. In 1984 a necrotic hemorrhagic mass with a thick fibrous capsule was then found at the same site. It was a poorly differentiated hepatocellular carcinoma. During a second laparotomy 2 months later for curative resection, another nodular mass 2 cm in diameter was found on the left lobe, apparently a focal nodular hyperplasia. 9 months later several tumor implants appeared on the serosal surface of the transverse colon, metastatic hepatocellular carcinoma. After partial colectomy the woman has been free of tumors for 2 years. The literature on the few cases of malignant transformation of adenomas associated with contraceptive steroids is discussed. Even though such adenomas usually resolve after discontinuation of the pill, patients should probably be followed with ultrasound over several years.^ieng

Hepatocellular carcinoma in the non-cirrhotic liver: a comparison with that complicating cirrhosis.

The clinicopathological features of 50 patients with hepatocellular carcinoma arising in a non-cirrhotic liver are described and compared with those of 100 patients in whom the tumour arose as a complication of cirrhosis. The non-cirrhotic patients were significantly younger, more often female and had a less strong association with serum markers of hepatitis B virus infection. Liver function tests and serum AFP were less often abnormal and survival was significantly better than in the cirrhotic group. The different aetiological factors, clinical features and prognosis of hepatocellular carcinoma arising in the non-cirrhotic liver compared to the more common form of hepatocellular carcinoma which complicates cirrhosis justifies detailed investigation by liver biopsy and other techniques.

PIP: The clinicopathological features of 50 patients with hepatocellular carcinoma arising in a noncirrhotic liver are described and compared with those of 100 patients in whom tumors arose as a complication of cirrhosis. The noncirrhotic patients were significantly younger, more often female, and had a less strong association with serum markers of hepatitis B virus infection. Liver function tests and serum alpha fetoproteins were less often abnormal and survival was significantly better than in the cirrhotic group. The different etiological factors, clinical features, and prognosis of hepatocellular carcinoma arising in the noncirrhotic liver compared to the more common form of hepatocellular carcinoma which complicates cirrhosis justifies detailed investigation by liver biopsy and other techniques.

[Hepatic and biliary repercussions of estrogens: dose or duration of treatment effect]. / Retentissement hepatobiliaire des oestrogenes: effet-dose ou effet-duree.

PIP: The effects of dose and duration of estrogen treatment on cholestasis, hepatic regeneration, and the genesis of liver tumors are evaluated in this work. Estrogens, especially at high doses during pregnancy or after long use of oral contraceptives (OCs), cause a constant diminution of bile secretion which remains subclinical in the great majority of cases. Ethinyl estradiol causes a constant but reversible cholestasis in the rat. 2 categories of cholestasis related to estrogens are distinguished in clinical practice; cholestasis induced by estrogens in pregnancy or in OCs, and cholestasis aggravated or revealed by estrogens, such as primitive biliary cirrhosis. Cholestasis induced by estrogens is dose-dependent, but few clinical data are available on this point. Experience has shown that a woman predisposed to cholestasis due to condition even with low-dose combined OCs. OCs are contraindicated for women genetically predisposed to cholestasis. Evidence has been found of an interaction between estrogen and DNA in the initiation of regenerative processes after experimental hepatectomy. 2 benign liver tumors, hepatic adenomas and focal nodular hyperplasias, have become more common with widespread diffusion of OCs. The role of estrogens in the genesis of hepatic adenomas is well established, but is more controversial with focul nodular hyperplasia. The appearance of low- dose OCs does not seem to have decreased the incidence of benign liver tumors. On the other hand, 2 series totalling 113 cases have demonstrated that the risk of adenoma increases significantly with the duration of treatment, and another study of 32 cases of focal nodular hyperplasia and 12 adenomas showed that most of the women had used OCs for more than 5 years. Both types of tumor carry risks of hemorrhagic accidents, and adenomas at least also carry carcinoma appears more significant in a country like Great Britain with a very low prevalence of such cancers. Benign liver tumors are very rare and should not affect prescription of OCs. A hepatobiliary sonogram should be obtained for women seeking OCs. A sonographic image of a tumor less than 5 cm in diameter with the characteristics of a benign tumor should prompt termination of OCs and reexamination in 4 weeks. If the tumor is over 5 cm in diameter the diagnosis should be confirmed by another technique. The nodular hyperplasias that are large, painful, and easily accessible. Recent epidemiologic studies suggest that the prevalence of asymptomatic lithiases is not very different in OC users and nonusers, but the frequency of complications leading to cholecystectomy is greater in women receiving longterm estrogen treatment. An asymptomatic lithiasis in a young OC user does not necessarily require termination of OCs.^ieng