ANNALS of Internal Medicine SEPTEMBER 1975 • VOLUME 83 • NUMBER 3 Published Monthly by the American College of Physicians

Focal Nodular Hyperplasia of the Liver and Intrahepatic Hemorrhage in Young Women on Oral Contraceptives J. Q. STAUFFER, M.D., M. W. LAPINSKI, M.D., D. J. HONOLD, M.D., and J. K. MYERS, M.D., Syracuse, New York

Focal nodular hyperplasia of the liver may occur with increased frequency in young women who have been taking oral contraceptives. Patients may present with massive intraperitoneal hemorrhage requiring immediate surgical intervention. These nodules may be multiple and occasionally pedunculated, mimicking ovarian cysts. Liver function tests are nondiagnostic. A liver scan and arteriogram are often helpful in determining a diagnosis. Percutaneous liver biopsy is contraindicated. Large nodules should be resected, and continued use of oral contraceptives is contraindicated.

speculate on a possible etiologic role of the long-term use of oral contraceptives. In 1974 Mays, Christopherson, and Barrows (8) reviewed three more patients and described the histologic features of these tumors. They stressed that the tumors resembled focal nodular hyperplasia of the liver and not benign hepatic adenomas. We are reporting 3 additional cases to emphasize new clinical features of this recently recognized syndrome and again raise the suspicion of the etiologic role of long-term use of oral contraceptives. Case Reports PATIENT 1

R ECENT REPORTS have brought attention to a possible relation between use of oral contraceptives and the development of benign tumors of the liver. Baum and colleagues (1) in 1973 presented the clinical features in seven patients and suggested a relation with long-term use of oral contraceptives. In five of these patients the initial manifestation of the hepatic tumor was massive intraperitoneal hemorrhage and shock. Subsequently, O'Sullivan and Wilding (2), Contostavols ( 3 ) , Horvath, Kovacs, and Ross ( 4 ) , Kelso (5), Knapp and Ruebner (6) and Berg and associates (7) reported a total of 11 more cases of hepatic tumors arising in young women on oral contraceptives. In many of these patients massive intraperitoneal hemorrhage, as well as large solitary tumors, were noted as the initial clinical manifestations. The rarity of hepatic tumors in young women (1, 7) led these authors (2-7) to also • From the Departments of Medicine, Pathology, and Surgery, State University of New York, Upstate Medical Center, Syracuse, New York. Annals of Internal Medicine 83:301-306, 1975

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A 25-year-old white woman, gravida 1, para 1, was admitted to the hospital in June 1973 for evaluation of an abdominal mass. Before this the patient had been in excellent health. Her only medications were various oral contraceptives taken for the preceding 7 years, except when these were withdrawn in 1972 so that she could become pregnant. The patient had an uncomplicated pregnancy without jaundice or pruritus and delivered a full-term infant in March 1973. After the delivery she was again placed on oral contraceptives. One month later she noted a mass in her lower abdomen. A routine pelvic examination revealed a moveable, firm, nontender mass in the right lower quadrant, suggestive of an ovarian cyst. Preoperative evaluation included a plain film of the abdomen, an intravenous pyelogram, and a barium enema. A large extrinsic mass was noted in the lower abdomen with displacement of the inferior aspect of the transverse colon and indentation of the right ureter. Liver function tests were within normal limits. The patient underwent exploratory laparotomy, at which time a 10cm pedunculated mass arising from the left lobe of the liver was noted. The tumor mass was richly vascular, but bleeding was controlled at the time of resection by ligatures at the base of the stalk as it arose from the left lobe of the liver. The remainder of the exploratory laparotomy was normal, and no other mass lesions were noted in the liver. Liver function tests, 301

Figure 1 . Gross specimen, Patient 2. A. Left lobe of the liver (open arrow) and cross section through the largest tumor nodule (so//d arrows). Note the area of ischemic necrosis in the large mass (so//d arrows). B. Cross section of left lobe (portion indicated by open arrow in A). Note the multiple areas of nodular hyperplasia (solid arrows) and the area of ischemic necrosis with hemorrhage in one nodule (large solid arrow).

including hepatitis B surface antigen and alpha fetoglobulin, showed normal results 2 and 8 months later. The histologic appearance of the tumor is discussed below. PATIENT 2

A 29-year-old white woman, gravida 0, para 0, had been on 2 mg of norethindrone and 0.1 mg of mestranol (OrthoNovum® 2 mg) for 6 years before admission in December 1974 for evaluation of an abdominal mass. The patient had been in excellent health without any antecedent liver disease or medical problems until October 1974, at which time she noted a nontender mass in the left upper quadrant, which could be moved into the epigastrium and right upper quadrant. One month before admission a routine abdominal and gynecologic evaluation confirmed the presence of a mobile mass, and diagnosis of an ovarian or mesenteric cyst was made. Preoperative evaluation included normal upper gastrointestinal and small bowel roentgenograms and a complete blood count; liver function tests showed normal results except for an abnormal serum alkaline phosphatase of 120 IU (normal, < 85 IU). Exploratory laparotomy revealed a large lobulated mass lesion in the left lobe of the liver (Figure 1). A wedge biopsy from the

Figure 2. Liver scan from Patient 3. A. Initial liver scan showing a large defect of uptake of radiopharmaceutical (technetium-99m sulfur colloid, 10 millicuries) in the lateral aspect of the right lobe. Note the increased uptake on the border of the defect, which suggested compression of normal parenchymal tissues (so//d arrows). B. Follow-up liver scan 3 months later showing gradual resolution of the defect. 302

tumor revealed well-differentiated hepatocytes without evidence of malignant transformation. A left partial hepatectomy was done, and the remaining hepatic tissue seemed normal. The patient had an uneventful postoperative course, and repeat liver function tests at 1 and 3 months after surgery, including alpha fetoglobulin and hepatitis B surface antigen were within normal limits. PATIENT 3

In October 1974 a 29-year-old white woman, gravida 0, para 0, who had been on 1 mg of ethynodiolacetate and 0.1 mg of mestranol (Ovulen-21®) for approximately 6 years before her admission, had sudden onset of severe right upper quadrant pain that radiated into her back. Her initial physical examination revealed tenderness in the right upper quadrant with a suggestion of involuntary muscle guarding. She suddenly became hypotensive, and her hematocrit fell precipitously from 33% to 24%. At this time her serum glutamic oxalacetic transaminase was 402 IU; serum glutamic pyruvic transaminase, 212 IU; bilirubin, 1.2 mg/100 ml, alkaline phosphatase, 22 IU (normal, < 13 IU), and the leukocyte count was elevated to 15 600 mm3. Four units of whole blood were given, with correction of the hypotension. Over the next several days she had fever to 40 °C [104 °F], but blood cultures were negative. She developed a right pleural effusion and continued to have fever. The patient was started on broad spectrum antibiotics, with a gradual decrease in her temperature to normal. However, as the patient continued to have severe right upper quadrant pain and tenderness, a liver scan was done that showed a large filling defect in the right lobe of the liver, and she was referred to the Upstate Medical Center for further evaluation. At this time her liver was palpable 5 cm below the right costal margin and was tender. Repeat liver function tests were not significantly changed, and an hepatitis B surface antigen, alpha fetoglobulin, and hemagglutination inhibition titers for amebiasis were negative. A repeat liver scan (Figure 2A) suggested expansion of the mass lesion in the lateral aspect of the right lobe of the liver, and a sonogram (Figure 3) showed that this liver mass was cystic. A preoperative diagnosis of a hepatic abscess was entertained, and the patient underwent exploratory laparotomy, at which time a large hematoma was found in the lateral aspect of the right lobe of the liver and was drained. A careful examination of the right and left

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Figure 3. Sonogram from Patient 3. A large cystic filling defect in the right lobe of the liver is shown. A = anterior; P = posterior; C = cephalad; RL = right lobe of liver. Open arrows indicate the border of the cystic mass.

of the largest nodule and hemorrhagic necrosis in one of the smaller nodules (Figure 1). The finding of multiple hyperplastic nodules in Patient 2 is a unique observation in this syndrome. The histologic appearance of the nodules from Patients 1 and 2 were similar, consisting of altered hepatocytes with vacuolated to clear cytoplasm without evidence of nuclear atypia (Figures 4 and 5). There was loss of a normal lobular pattern and absence of the normal plates of hepatocytes. In some areas there was a pseudorosette pattern, but this was not a dominant feature of the nodules. Kupffer cells were present, but a sparsity of bile ducts and portal areas was a characteristic feature in these specimens. Many randomly distributed fibrous tracts were present, which contained vascular channels and large vessels (Figure 4). In several areas hemorrhage into the adjacent normal hepatic tissue was noted. Additionally, focal areas of ischemic necrosis were present, particularly in the large tumor nodules. Normal hepatic tissue adjacent to the nodules showed dilated sinusoids and some ischemic necrosis. The tumor nodules were not encapsulated. The absence of cellular atypia and the resemblance of these lesions to focal nodular hyperplasia suggested that these lesions were benign. No nodules were present in Patient 3. Discussion

lobes of the liver failed to reveal any nodules. Scrapings from the wall of the cystic cavity were negative for Entamoeba histolytica, and cultures of aerobic and anaerobic bacteria, fungi, and mycobacterium were negative. Cytologic and histologic evaluation of material taken from a border of the cystic cavity showed only necrotic tissue. Postoperatively, her liver has returned to normal size, and serial liver scans (Figure IB) done over the next 3 months have demonstrated a gradual decrease in the size of the filling defect in the right lobe of the liver. Liver function tests showed normal results within 1 month, and the patient has completely recovered. HISTOPATHOLOGY

The specimen obtained from Patient 1 was a large solitary tumor weighing 350 g and measuring 10 cm in maximal diameter. There was abundant vascularization of the tumor, giving it a spongy characteristic. Sectioning the tumor revealed numerous large vascular channels. The gross appearance of this solitary tumor was similar to the nodules in the left lobe of the liver in Patient 2. In Patient 2, however, there were five areas of nodular hyperplasia, with central ischemic necrosis


The clinical features of this syndrome are important in that the mode of presentation of many patients requires immediate efforts for control of hemorrhage (1-8). Sixty percent of the patients previously reported presented with sudden onset of abdominal pain and right upper quadrant peritoneal signs, followed soon thereafter by hypotension and shock. At emergency exploratory laparotomy, massive intraperitoneal hemorrhage from rupture of the hepatic nodules was found. Survival in these patients was probably related to immediate surgical intervention with resection of the hemorrhagic nodules and adequate hemostasis of liver tissues. In the cases reported previously (1-8), areas of hepatic nodular hyperplasia have resulted in solitary masses so that a partial hepatectomy has been feasible. However, in one of our patients there were multiple areas of nodular hyperplasia, which fortuitously were restricted to the left

Figure 4. Microscopic sections from Patient 1. Note the marked vascularity and loss of normal lobular architecture. There is a suggestion of pseudorosette formation in some areas (solid arrow). (Magnification (left), X 170; magnification (right), X 340.) Stauffer et at. • The Liver and Oral Contraceptives

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Figure 5. Microscopic sections from Patient 2. A. Note the large blood vessel in this nodule. (Magnification, x 50.) B. The hepatocytes in several areas have vacuolated cytoplasm. (Magnification, x 360.)

lobe so that a partial left lobectomy was done without difficulty. The finding of multiple nodules, however, should alert the surgeon to examine all lobes carefully for other nodules, even if a solitary lesion has been identified. Most of these mass lesions are readily apparent on inspection of the surface of the liver. In our series two of the three patients presented with minimal clinical symptoms and a palpable mobile mass, which was misdiagnosed as either an ovarian or mesenteric cyst. The insidious presentation, most striking in our patients, emphasizes the important point that the physician must consider this entity in any young woman with an abdominal mass who has been taking oral contraceptives, in order to establish the correct diagnosis before hemorrhage occurs. The patients usually have normal liver function tests, blood counts, a negative alpha fetoglobulin and hepatitis B surface antigen, as well as nondiagnostic radiologic findings of the gastrointestinal tract. Thus, the suspicion of focal nodular hyperplasia of the liver can be raised only by awareness of this important clinical entity, so that the clinician can proceed to more definitive diagnostic tests. In some cases reported (1, 8) the liver scan has been helpful. The extensive vascularity of these lesions would suggest that the liver scan may be helpful in showing the mass lesions, particularly if flow studies are combined with routine scanning methods. When a mass lesion is strongly suspected, arteriography is indicated to define the site and size of the nodules. In view of our finding of multiple nodules, arteriography would provide a means of excluding nodules in several areas of the liver and provide needed information before resection. Any residual doubt as to the origin of abdominal mass lesions might be resolved by peritoneoscopy. If peritoneoscopy is done, a liver biopsy through the peritoneoscope would be contraindicated in view of the vascularity of these lesions. Furthermore, routine percutaneous liver biopsies of mass lesions in the liver in young women who are currently taking or have recently used oral 304

contraceptives should be avoided in view of the possibility of initiating massive hemorrhage. Spontaneous hemorrhage from liver cell carcinoma has been reported (9) but is a rare event. The third patient in our series presents somewhat different clinical features than other patients reported thus far. This patient presented with massive intrahepatic hemorrhage, and, although no nodules were identified, we suspect that this is a variant of the syndrome. The multiple nodules identified in Patient 2 showed hemorrhagic necrosis of small areas of focal nodular hyperplasia. We suspect that the intrahepatic hemorrhage in Patient 3 was related to necrosis of a small nodule, with subsequent massive intrahepatic hemorrhage such that the area of nodular hyperplasia could no longer be recognized grossly. This patient survived her massive intrahepatic hemorrhage, probably because it occurred in the lateral aspect of the right lobe with compression of the area of bleeding by the chest wall. This unusual case is included in our report to stress that massive intrahepatic hemorrhage may occur in young women who are on oral contraceptives, and that focal nodular hyperplasia may not be readily apparent at exploration. In retrospect, arteriography at the onset of her abdominal pain might have identified an area of nodular hyperplasia. At the time of exploration, drainage of the large hematoma did not initiate any further bleeding, so that a right lobectomy was avoided. Therefore, on the basis of our experience and the cases previously reported, it seems clear that large areas of focal nodular hyperplasia should be resected, if clinically possible. Nodules that are pedunculated or restricted to the surface of the liver may be locally resected, but large intrahepatic lesions may require partial hepatectomy. There is no experience thus far with asymptomatic patients; therefore, it is difficult to make specific recommendations in this group. It may be possible to withdraw the oral contraceptives and obtain serial lever scans to assess regression

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of the hyperplastic nodules. This may be the best approach if nodules are found throughout the liver. Prospective studies are needed to define the natural history of these hyperplastic nodules when oral contraceptive use is withdrawn.

may arise with use of oral contraceptives. These now include impaired sulfobromophthalein transport (17, 18), a slight but reversible rise in serum glutamic oxalacetic transaminase or alkaline phosphatase, or both, (18), and jaundice (17, 18, 21, 22). Impairment of bilirubin excretion may be more pronounced in women who have had HISTOPATHOLOGY cholestatic jaundice of pregnancy, and oral contraceptives The prominent feature of these nodules relates to the may be contraindicated in this group of patients (23). increased vascularity of the lesions, with extensive proRecent reports have also suggested that there may be an liferation of large and small thin-walled vessels. The hepaincreased incidence of gallstone formation in patients who tocytes are altered with marked vacuolation of the cytohave had long-term use of oral contraceptives (24). Rarely, plasm and, in some areas, clear cytoplasm. The loss of a thrombosis of hepatic veins may also occur in young normal lobular pattern, the absence of plates of hepatocytes women on oral contraceptives (25). with some areas of pseudorosette formation, and the The increasing frequency of reports of focal nodular paucity of bile ducts and central veins gives certain porhyperplasia of the liver in association with oral contrations of these nodules features of benign hepatic adenomas ceptive use raises the likelihood that this entity is more (10-14). However, the total appearance of these nodules common than initially suspected. Detailed prospective is not that of a hepatic adenoma. Our specimens did not studies with careful physical examination of the liver for have fibrous tracts coalescing in the center of the lesions, masses, in combination with liver scanning methods, should as is often seen in cases of true focal nodular hyperplasia be undertaken to determine the true incidence and preva(15, 16). There were some areas offibroblasticproliferalence of this clinical entity and provide definitive recomtion in association with proliferation of the previously demendations for management of asymptomatic patients. scribed thin-walled vessels, so that the tumor had some ACKNOWLEDGMENTS: The authors thank the Department of features of a liver hamartoma. The term focal nodular Pathology, Crouse-Irving Memorial Hospital, Syracuse, New York, hyperplasia of the liver perhaps best defines the features for assistance in preparation and review of pathologic specimens obpresented by these nodules and avoids the confusing term tained from Patients 1 and 2. Grant support: in part by grant RR-229, General Clinical Reof "benign hepatoma." Review of multiple sections taken search Centers Program of the Division of Research Resources, Nathrough the nodules obtained from our patients confirmed tional Institutes of Health. Received 5 May 1975; accepted 29 May 1975. the histology, as reported by other investigators, that these lesions are not hepatocellular carcinomas. In the patients • Requests for reprints should be addressed to John Q. Stauffer, M.D., Gastroenterology Section, Department of Medicine, State Unidescribed there has been no evidence of metastatic disease. versity Hospital, 750 E. Adams St., Syracuse, NY 13210. The survivors have had no recurrent nodule formation, but they have not reinstituted oral contraceptive use. References Chemotherapy or radiation treatment is not indicated as 1. BAUM JK, HOLTZ F, BOOKSTEIN J J, et al: Possible association either a preoperative or postoperative adjunct to surgical between benign hepatomas and oral contraceptives. Lancet 2: resection of massive lesions (2). 926-929, 1973 2. O'SULLIVAN JP, WILDING RP: Liver hamartomas in patients on ORAL CONTRACEPTIVES AND LIVER DISEASE

The recognition in the last 2 years of focal nodular hyperplasia of the liver in young women, at an incidence much higher than one would predict on the basis of the known prevalence of tumor nodules in women in this age group (1, 7, 8, 14), suggests a possible etiologic relation to long-term use of oral contraceptives. This association is circumstantial but seems to be a common feature in the cases reported to date. In the three patients reviewed in this article, no other etiologic agent could be ascertained. The suspicion of this relation to use of oral contraceptives is heightened by recognition of the effect on liver function and structure of steroids, which have been modified by an additional alkyl group in the alpha configuration at the C-17 position (17). Use of these drugs may lead to cholestasis (17, 18) or, in some circumstances, to angiomatous transformation of vessels in the liver with the formation of hemorrhagic cysts, an entity known as peliosis hepatis (19, 20). It is speculated that some of the agents used in oral contraceptives may have an effect similar to the androgenic-anabolic steroids (8, 17, 18). Thus, it seems clear that focal nodular hyperplasia should be added to the growing list of hepatic abnormalities that

oral contraceptives. Br Med J 3:7-10, 1974 3. CONTOSTAVOLS DL: Benign hepatomas and oral contraceptives (letter). Lancet 2:1200, 1973 4. HORVATH E, KOVACS K, Ross RC: Benign hepatoma in young woman on contraceptive steroids (letter). Lancet 1:357-358, 1974 5. KELSO DR: Benign hepatomas and oral contraceptives (letter). Lancet 1:315-316, 1974 6. KNAPP WA, RUEBNER BH: Hepatomas and oral contraceptives

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contraceptives (letter). Lancet 2:349-350, 1974 8. MAYS ET, CHRISTOPHERSON WM, BARROWS GH: Focal nodular

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a misdiagnosed emergency. Am Surg 179:133-135, 1974 10. CHRISTOPHERSON WM, COLLIER HS: Primary benign liver cell tumors in infancy and childhood. Cancer 6:853-861, 1953 11. EDMONDSON HA: Tumors of the Liver and Intrahepatic Bile Ducts: Benign Epithelial Tumors. Armed Forces Institute of Pathology, Washington, D.C., 1958, pp. 193-206 12. GARANCIS JC, TANG T, PANARES R, et al: Hepatic adenoma:

biochemical and electron microscopic study. Cancer 24:560-568, 1969 13. CRISPIN HA: A case of hepatic adenoma. Acta Chir Belg 70:91110, 1971 14. PHILLIPS MJ, LANGER B, STONE R, et al: Benign liver cell

tumors: classification and ultrastructure pathology. Cancer 32: 463-470, 1973 15. BEGG CF, BERRY WH: Isolated nodules of regenerative hyperplasia of the liver. Am J Clin Pathol 23:447-463, 1953 Stauffer et al. • The Liver and Oral Contraceptives

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16. BENZ EJ, BAGGENSTOSS AH: Focal cirrhosis of the liver: its

relation to the so-called hamartoma (adenoma, benign hepatoma). Cancer 6:743-755, 1953 17. ADLERCREUTZ H, TENHUNEN R: Some aspects of the interaction

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between natural and synthetic female sex hormones and the liver. Am J Med 49:630-648, 1970 OCKNER RK, DAVIDSON CS: Hepatic effects of oral contraceptives. N Engl J Med 276:331-334, 1967 KINTZEN W, SILNY J: Peliosis hepatis after administration of fluoxymesterone. Can Med Assoc J 83:860-862, 1960 BAGHERI SA, BOYER JL: Peliosis hepatis associated with androgenic-anabolic steroid therapy. A severe form of hepatic injury. Ann Intern Med 81:610-618, 1974 THULIN KE, NERMARK J: Seven cases of jaundice in women


taking an oral contraceptive, anovlar. Br Med J 5487:584-586, 1966 22. SOMAYAJI BN,






tives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumors. Lancet 1:1399-1404, 1973 25. HOYUMPA AM, SCHIFF L, HELFMAN EL: Budd-Chiari syndrome

in women taking oral contraceptives. Am J Med 50:137-140, 1971

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jaundice in two sisters. Br Med J 2:281-283, 1968 23. DRILL VA: Benign cholestatic jaundice of pregnancy and benign cholestatic jaundice from oral contraceptives. Am J Obstet Gynecol 119:165-174, 1974

Focal nodular hyperplasia of the liver and intrahepatic hemorrhage in young women on oral contraceptives.

Focal nodular hyperplasia of the liver may occur with increased frequency in young women who have been taking oral contraceptives. Patients may presen...
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