Focal Nodular Hyperplasia of the Liver: Possible ...

Focal

N o d u l a r

H y p e r p l a s i a

o f

the

Liver

Possible R e l a t i o n s h i p to O r a l C o n t r a c e p t i v e s E. T R U M A N M A Y S , M.D.,

W I L L I A M M. C H R I S T O P H E R S O N ,

A N D G E O R G E H. B A R R O W S ,

M.D.,

M.D.

Departments of Surgery and Pathology, University of Louisville School of Medicine, Health Sciences Center, Louisville, Kentucky 40201 ABSTRACT

RECENTLY, Baum, and associates reported seven cases of benign hepatoma, all occurring in women who were taking oral contraceptives. 2 Shortly thereafter, Contostavlos reported an additional case. 5 In these reports the clinical and radiographic aspects of the lesion were emphasized without illustrations of the histopathology. In recent years we have had the opportunity to study in detail the resected specimens from three patients with solitary hepatic masses in non-cirrhotic livers, all of whom were young women taking oral contraceptives. It is our conclusion that these solitary tumor masses represent focal nodular hyperplasia and not hepatic adenomas, or benign

hepatomas. It would be presumptuous for us to assume we are dealing with the same tumor as those previously described. However, the morphologic features of our three tumors were so similar—one to the other—and the clinical setting so similar to those reported by Baum and associates and Contostavlos, that the possibility at least exists. T h e purpose of this communication is to describe in detail the morphologic features of focal nodular hyperplasia of the liver and to present a theory as to its pathogenesis. Report of Three Cases

Case 1. A 42-year-old woman, gravida 6, para 4, ab. 2, had been taking norethynodReceived February 5, 1974; accepted for publication February 11, 1974. rel and mestranol from 1964 to 1968. T h e Address reprint requests to: W. M. Christopherson, M.D., Health Sciences Center, Louisville, Kentucky only other medication had been desiccated thyroid, 3 gr./day, for the past 5 or 6 years. 40201. 735

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Mays, E. Truman, Christopherson, William M., and Barrows, George H.: Focal nodular hyperplasia of the liver. Possible relationship to oral contraceptives. Am. J. Clin. Pathol. 6 1 : 735-746, 1974. T h e possible association between oral contraceptives and benign hepatomas has recently been reported. A study of three hepatic masses, all surgically resected, leads us to the conclusion that our lesions represent focal nodular hyperplasia, and may be similar to those reported as adenomas. The possibility that the vascular changes found in these lesions play an etiologic role is suggested. T h e vascular lesions, in turn, could be related to oral contraceptives. A fairly definite syndrome consisting of oral contraceptive ingestion, intrahepatic or intraperitoneal hemorrhage, or both, shock or syncope, acute abdomen, and focal nodular hyperplasia of the liver (or benign hepatoma) has predominated in the cases thus far reported. (Key words: Focal nodular hyperplasia; Benign hepatoma; Liver cell adenoma; Oral contraceptives.)

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FIG. 1. Nodular liver mass, after fixation, from Case 1. Note the coarse nodularity of the tumor mass and the adjacent hematoma. There is a surrounding shell of normal liver.

There was no history of previous hepatic disease or exposure to known hepatotoxic agents. In May 1972, a cholecystogram, performed because of pain in the right upper quadrant, was normal. A subsequent liver scan revealed a defect in the right lobe of the liver. An exploratory operation and

liver biopsy were performed. Following this, the patient was referred to one of us (E.T.M.) for resection. A right lobectomy was successfully performed. T h e postoperative course was uneventful. T h e surgical specimen weighed 757 Gm. There was a subcapsular hematoma 2.5 cm.


FIG. 2. The multinodular mass with large hematoma is shown. The surrounding liver is normal (Case 2).

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FIG. 3 (upper, left). Low-power view of an area of infarction below, with hemorrhage and fibrosis immediately above, and regenerating liver on top. (Hematoxylin and eosin. X55) FlG. 4 (upper,right).Note uniform cells withfinelygranular cytoplasm arranged in cords. No organization about central veins or portal triads were present over a large area. (Hematoxylin and eosin. X130) FlG. 5 (lower, left). Higher-power view of the same tumor, showing bile duct formation in center and vacuolated liver cells (presumably containing fat). (Hematoxylin and eosin. x340) FlG. 6 (lower,right).Another area of the same specimen, showing formation of tubular structures in the central portion. Note uniformity of nuclei and distinct nucleoli. (Hematoxylin and eosin. X340)

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in diameter. Near the margin of excision was a pink, lobulated, circumscribed tumor, 4.5 cm. in diameter. Adjacent to this was a 5 cm. cyst filled with old blood. T h e cyst wall varied from 2 to 3 mm. in thickness. T h e remainder of the liver appeared normal (Fig. 1).


lapsed. A large mass, thought to be a hepatic tumor, was palpable in the epigastrium. Exploration disclosed a line of demarcation between the left and right lobes after ligation of the left branch of die portal vein and the right hepatic artery and duct. Using this demarcation line, the left lobe was resected. T h e patient has been Case 2. A 26-year-old woman, gravida 2, followed regularly since. Liver function para 2, had taken norethynodrel and remains normal, and a radioscan showed mestranol for the past seven years. She had regeneration of the liver. taken medication for a duodenal ulcer T h e resected specimen weighed 1,150 intermittently. There had been no previous Gm. There was an outer rim of normalsymptoms of hepatic disease, and no appearing liver tissue. Most of the specimen exposure to known hepatotoxic agents. In consisted of a bosselated mass with indiMay 1973, the patient was thought to have a perforated peptic ulcer of die duodenum. vidual lobules as large as 7 cm. in diameter. At operation a hemoperitoneum was found On cut section there was a large blood clot; and a second incision was made to look for a adjacent to this were mottled, yellow-tan ruptured tubal pregnancy. Both tubes and areas. Near the periphery of the hematoma ovaries were normal; therefore, the upper were several pale yellow, tan nodules, abdominal incision was extended to explore surrounded by more deeply reddishthe liver. A large, solid tumor in the right brown, normal-appearing liver tissue. No lobe was found to be the source of the true capsule was demonstrated. bleeding. Hemorrhage was controlled by sutures. Histopathology After recovery, the patient was referred T h e three lesions were histologically for definitive surgery. T h e right lobe of the similar, the changes varying only quantitaliver was resected. T h e postoperative tively. T h e bosselated or lobulated apcourse was uneventful, and subsequent pearance was due to areas of fibrosis, most scintiscan revealed hepatic regeneration. marked centrally. All three tumors conLiver function remained normal. tained areas of infarction necrosis, T h e surgical specimen weighed 1,275 hemorrhage, and surrounding fibrosis Gm. There was a central, 10 cm., lobulated (Fig. 3). T h e nodules were composed of mass. T h e r e was considerable hemorrhagic liver cells arranged in either cords or necrosis, and the mass contained a blood sheets, usually without orientation to cenclot. Throughout the lesion were yellowtral veins or portal triads. T h e liver cells gray areas thought to resemble necrosis. appeared relatively normal, but in the T h e surrounding liver appeared normal larger regenerating areas the cells were (Fig. 2). somewhat smaller. A sparsity of portal Case 3. A 25-year-old woman, gravida 2, triads and irregular arrangement of the para 2, had been taking norethynodrel and cells presented an adenomatous appearmestranol for five years. She had taken no ance. In areas of good cellular preservaother medication. There was no history of tion, the cell outlines were sharp, and die prior hepatic disease and no history of cytoplasm was usually finely granular (Fig. exposure to hepatotoxic agents. In July 4), but at times it was vacuolated. T h e 1968, while bending over, she experienced larger vacuoles appeared to contain fat sudden severe epigastric pain and col- (Fig. 5), although no unprocessed tissue

June 1974

739

FOCAL NODULAR HYPERPLASIA AND ORAL CONTRACEPTIVES "¿vk ni' : ..V: ^.•fc-.y.',*» i l FlG. 9. Note regenerative area above, and adjacent relatively normal liver, lower right. There is sharp demarcation but lack of encapsulation. Also note that the cells of the "tumor" are smaller than the adjacent liver cord cells. (Hematoxylin and eosin. X130)

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FIG. 10 (upper). Note the occlusive changes in both the hepatic artery and the portal vein. This is adjacent to an area of infarction, lower left. (Hematoxylin and eosin. X55) FIG. 11 (lower). Phlebitis with intimai thickening and a fresh non-obturating thrombus are shown in an otherwise unidentified vein. This was adjacent to a large area of infarction. (Hematoxylin and eosin. x55) slide of the larger areas of regeneration. Thin-walled veins were present throughout, but usually organization of lobules about a central vein was lacking. Abortive attempts at small bile duct formation were noted, especially near the junction of normal liver with these hyperplastic

nodules (Figs. 5 and 6). In a single case small blood-filled lakes were evident, but there were not found throughout the entire mass, nor in adjacent normalappearing hepatic tissue (Fig. 8). T h e margins of the lesions were sharply demarcated from the surrounding hepatic

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FIG. 12 (upper). Verhoff's elastic stain, showing vascular lesions andfibrosisin the portal triad. (x55) FIG. 13 (lower). Obliterative phlebitis of the portal vein with organizing thrombus. Chronic inflammatory cells are scattered throughout the fibrous septa. (Hematoxylin and eosin. X55) tissue, but there was no capsule (Fig. 9). Because of the areas of infarction necrosis and hemorrhage in all three tumors, a careful search was made for vascular lesions. T h e interlobular branches of both the afferent veins and arteries were involved in limited areas in each of the

three cases, usually near (within a 4X field or two) areas of infarction necrosis (Fig. 10). There was phlebitis of the portal veins, together with varying stages of thrombosis (Figs. 11 and 12). At times the lumen was totally, or near totally, oce l u d e d (Fig. 13). T h e i n t e r l o b u l a r

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MAYS ET AL.

Discussion T h e rarity of true liver-cell adenomas is well documented. 4,6,I ° T h e absence of definite histologic criteria for their diagnosis has r e s u l t e d in e r r o r s a n d confusion. 6 Our own experience is limited to a single case, later accepted by Edmondson. 7 T h e patient was a 13-

61

month-old girl. T h e tumor was an encapsulated mass weighing 460 Gm. T h e patient survived 25 years after surgical removal of the tumor and had no residual tumor at autopsy. 4 Re-evaluation of this case showed many dissimilarities from the solitary regenerating nodules under discussion. T h e capsule of the adenoma was so definite it served as the plane for resection or enucleation. T h e r e were no Kupffer cells, vascular changes, areas of necrosis, or hemorrhage. Furthermore, there were neither bile ducts nor abortive attempts at duct formation. At that time we were influenced by the writings of Warvi, 18 who emphasized encapsulation in liver-cell adenomas. Our conclusion that these lesions represent focal nodular hyperplasia rather than liver-cell adenomas, while based mainly on morphology, has support from other considerations. Multiple areas of nodular hyperplasia represent the most commonly encountered regenerative lesion of the liver. It is generally agreed that a wide variety of agents that damage the liver can result in multiple nodular hyperplasia. The lesion is most apt to occur when extensive hepatic necrosis is present. T h e association of multinodular hyperplasia with malignant hepatoma is widely documented and universally accepted. Focal nodular hyperplasia, on the other hand, is much less common and differs considerably from the aforementioned cirrhotic type of nodular hyperplasia. There is a wide difference of opinion as to whedier the solitary form is a regenerative phenomenon, a hamartoma, or a neoplasm. Some type of focal injury with interference with, or disruption of, blood supply have been suggested as playing a part in the etiology. 6 Women are commonly affected, and many of the lesions have been seen in children. 7 Edmondson states the lesion usually occurs in the right lobe, as did eight of the 11 oral contraceptive-associated cases. He


branches of the hepatic artery often showed marked hypertrophy of the media, with varying degrees of occlusion (Fig. 14). Two types of early lesions were occasionally noted. One was fresh organizing thrombosis of small vessels not otherwise identified (Fig. 15); the other appeared to be intimai proliferation and swelling (Fig. 16). While the afferent veins, and to a lesser degree, the arteries, could be identified as being involved, we could not prove involvement of die hepatic veins. In some of the fibrous septa numerous lymphocytes were present, and in a single case there was heavy eosinophilic infiltrate adjacent to an area of infarction. Several special stains were done, but did not prove very rewarding. PAS stains without diastase on paraffin-embedded material showed extensive PAS-positive content of the cytoplasm of the Kupffer cells. Although there was some faint staining of cytoplasmic granules in the regenerative areas, this was insufficient to permit the conclusion that the cells contained glycogen. Reticulin and iron hematoxylin stains were of no help. Stains for iron showed none in the regenerating cells, or normal liver, but were positive in some of the areas of old hemorrhage. Verhoff s elastic stain and trichrome stains showed the previously described vascular lesions to advantage. Previous processing of all available tissue prevented us from proving the presence of suspected fat droplets in some of the regenerating cells, and from further studying their glycogen content.

A.J.C.P.—Vol.

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FIG. 14 (left). Hypertrophy and obliterative changes in the hepatic artery are shown, lower right. Liver cells are arranged in cords, lower left, and an adenomatous mass of regenerating liver cells is visible above (Hematoxylin and eosin. X55) FIG. 15 (right). Fresh obturating thrombosis of small vessels (Hematoxylin and eosin. X340)

further states that they are usually solitary, as were all eleven. They are usually superficial, as were all of our cases. He further mentions that they may be pedunculated. He goes on to describe them as light brown to yellow-gray, sharply circumscribed, "but hardly can be said to have a true capsule." His description of the histologic features, including the blood vessel changes, strengthens the case for the diagnosis of focal nodular hyperplasia. Quite aside from the pathologic interpretation of these lesions, several clinical features have been relatively constant in the 11 cases of hepatic masses under discussion. T h e evidence all points to their benign nature. They have all been soli> FIG. 16. A rare finding was what we interpret as endothelial proliferation and swelling occluding small vessels, not otherwise identified. (Hematoxylin and eosin. x 130)


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tary. Eight patients had presenting symptoms of hemorrhage and/or shock, while an additional patient had intrahepatic hemorrhage and syncope. Nine of ten patients treated by resection are currently well. T h e tenth died of cardiac arrest following resection. T h e other patient, seen because of acute epigastric pain radiating to the right shoulder, had the diagnosis made at necropsy.


taining both an estrogen and a progestogen may alter hepatic function, cholestasis has been the principal abnormality found in women. 1 This was not described in the reported cases of liver-cell adenoma associated with oral contraceptives, or in any of our cases. Because of the close structural relationship between some progestogens utilized in oral contraceptives and anabolic steroids, potential danT h e most constant and no doubt the gers of oral contraceptives are apparent. Recendy, there has been great interest most provocative feature of these lesions is that they occurred in women 25 to 42 in evidence relating clear-cell carcinomas years old, who were, or had been, taking of the vagina and cervix to intrauterine oral contraceptives, most for five or more exposure to stilbesterol and related nonyears (Table 1). T h e possibility that focal steroidal estrogens. 9,13,14 These are most nodular hyperplasia is related to hepato- often observed in patients 14 to 22 years toxic effects of oral contraceptives is old. Stilbesterol has also been associated certainly intriguing. T h e association of with more common vaginal and cervical androgenic anabolic steroid therapy with abnormalities (congenital cervical erosion the development of hepatocellular car- and vaginal adenosis) in young girls cinoma has been observed. 3,15 Of the five whose mothers took the drug early in patients reported, all had aplastic anemia. pregnancy. 12 Currently there are about T h e hepatotoxic effects of oxymetholone 100 vaginal and 70 cervical carcinomas in and the other C17-alkylated testosterone patients less than 30 years of age in the derivatives have been described. There clear-cell carcinoma registry. Not all pawas, however, no real evidence from that tients were exposed in utero to one of the study that morphologic hepatic changes three DES-related drugs. 11 In each of our attributable to metabolic steroids were cases there was a negative history of intrauterine exposure to stilbesterol. Two present. 16 of the mothers, however, had had signs of In the case reported by Contostavlos, toxemia during the pregnancy. After conpeliosis hepatis was present. 5 Yanoff and sidering the role that oral contraceptives Rawson reported parenchymal peliosis to might play in the pathogenesis of focal be present in two patients receiving nodular hyperplasia, we are most imnorethandrolone reported since 1950, pressed with vascular lesions involving the and added a case of their own. 20 In mice afferent vessels, especially the interlobular 19 bearing interstitial-cell testicular tumors branches of the portal vein. Fatal endo8 or granulosal tumors, a lesion similar to phlebitis and thrombosis of the hepatic peliosis was found. In one of our cases veins with hepatic infarction has been rethere were a few blood lakes which hisported in a woman taking oral contraceptologically were indistinguishable from tives.17 We are fully aware that some of the those described as occurring in peliosis vascular changes described and illustrated hepatis. 19 However, it should be emhere could conceivably be secondary to phasized that these were apparently focal; the process of infarction, necrosis and at least, we have no evidence that the scarring. On the other hand, the focal lesion was generalized. nature of the vascular lesions, variation in Although there appears to be little, if stage of development, and location in the any, doubt that oral contraceptives con-

Benign hepatoma Benign hepatoma Benign hepatoma Benign hepatoma Benign hepatoma

Benign hepatoma Benign hepatoma

1

6

Focal nodular hyperplasia Focal nodular hyperplasia Focal nodular hyperplasia

9

25 (gravida 2)

26 (gravida 2)

42 (gravida 6)

37

39

30

29

25

25

27

26

Norethynodrel and mestranol

Norethynodrel and mestranol 5

7

5

Many years

Noresterol and ethinylestradiol


7

7

5

Vi

6

Unknown

2

Duration of Contraceptive (Years)


Multiple


Norgestrol and ethinylestradiol

Unknown

Norethynodrel and mestranol Dimethisterone and ethinylestradiol

Oral Contraceptive

* Cases 1-7, ref. 2; Case 8, ref. 5; Cases 9-11, Mays, Christopherson, Barrows.

11

10

Benign hepatoma

8

7

5

4

3

2

Diagnosis

Case

Patient's Age (Years)

Intraperitoneal hemorrhage, shock Intrahepatic hemorrhage

Abdominal pain

Massive intraperitoneal hemorrhage

Intraperitoneal hemorrhage

Intraperitoneal hemorrhage, shock

Abdominal pain, shock, anemia Right upper quadrant mass, self-detected

Right upper quadrant mass



Presenting Problem

Table 1. Summary of 11 Cases*


Dead, cardiac arrest Alive

Right hepatectomy Excision of tumor of left lobe through pedicle Right hepatectomy

Alive 2 mo. Right hepatectomy

Alive 2 yr. Alive 1 yr. Alive 5 yr.

Lobectomy, right Lobectomy, right Lobectomy, left

Necropsy, right lobe

Alive 15 mo.

Excision of tumor of right lobe with rim of normal hepatic tissue Right hepatectomy

Alive 3'/4 yr.

Alive 2 mo.

Alive 4 yr.

Outcome

Left hepatic lobectomy

Management and Location

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female sex hormones and the liver. Am J Med 49:630-648, 1970 2. Baum JK, Holtz F, Bookstein JJ, et al: Possible association between benign hepatomas and oral contraceptives. Lancet 11:926-929, 1973 3. Bernstein MS, Hunter RL, Yachnin S: Hepatoma and peliosis hepatis developing in a patient with Fanconi's anemia. N Engl J Med 284:1135-1136, 1971 4. Christopherson WM, Collier HS: Primary benign liver cell tumors in infancy and childhood. Cancer 6:853-861, 1953 5. Contostavlos, DL: Hepatomas and oral contraceptives. Lancet II: 1200, 1973 6. Edmondson H.A.: Atlas of Tumor Pathology; Tumors of the Liver and Intrahepatic Bile Ducts. Fascicle 25, p 193-206. Armed Forces Institute of Pathology, Washington, D.C., 1958 7. Edmondson HA: Differential diagnosis of tumors and tumor-like lesions of liver in Acknowledgments. Drs. Robert S. Howell, Jewish infancy and childhood. Am J Dis Child Hospital, John D. Allen, Kentucky Baptist Hospital, 91:168-186, 1956 and Edward J. Fadell, Methodist-Evangelical Hospi8. Furth J, Sobel H: Hypervolemia secondary to tal, Louisville, Kentucky provided the material for grafted granulosa-cell tumor. J Natl Cancer pathological examination. Inst 7:103-113, 1946 9. Greenwald P, Barlow JJ, Nasca PC, et al: Vaginal cancer after maternal treatment with ADDENDUM synthetic estrogens. N Engl J Med 285:390Since submitting the manuscript, two addi392, 1971 tional reports of benign hepatomas in young 10. Henson SW, Jr, Gray HK, Dockerty MD: Benign tumors of the liver. I Adenomas. Surg women on oral contraceptives have appeared in Gynecol Obstet 103:23-30, 1956 the literature. One woman* presented with AL: Personal communication, 9 January abdominal pain. A hemorrhagic hepatic mass 11. Herbst 1974 was resected and was diagnosed as hepatic- 12. Herbst AL, Kurman RJ, Scully RE: Vaginal and cell adenoma and peliosis hepatis. The othert cervical abnormalities after exposure to stilbesterol in utero. Obstet Gynecol 40:287-298, presented with pain and syncopy. She had mas1972 sive introperitoneal hemorrhage. The pathologic diagnosis was benign hepatoma. Both 13. Herbst AL, Scully RE: Adenocarcinoma of the vagina in adolescence: A report of 7 cases women died postoperatively. including 6 clear-cell carcinomas (so-called Through the courtesy of Drs. Hugh Williams mesonephromas). Cancer 25:745-757, 1970 and Elton Heaton we have had the opportunity 14. Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinoma of the vagina: Association of to examine an additional specimen from a 22maternal stilbesterol therapy with tumor apyear-old woman who had been taking Orthopearance in young women. N Engl J Med riovum for 7 years. She presented with severe 284:878-881, 1971 abdominal and shoulder pain and shock. There 15. Johnson FL, Feagler JR, Lerner KC, et al: was massive introperitoneal hemorrhage. The Association of androgenic-anabolic steroid resected specimen was 520 Gm. of hemorrhagic therapy with development of hepatocellular carcinoma. Lancet 11:1273-1276, 1972 and necrotic liver tissue. There was peliosis hepatis and nodular regeneration without 16. Santhez-Medal L, Gomez-Leal A, Duarte L, et al: Anabolic androgenic steroids in the treatfibrosis or vascular changes. She is well two ment of acquired aplastic anemia. Blood years later. 34:283-300, 1969 17. Sterup K, Mosbech J: Budd-Chiari syndrome after taking oral contraceptives. Br Med J References 4:660, 1967 1. Adlercreutz H, Tenhuen R: Some aspects of the 18. Warvi WM: Primary neoplasms of the liver. Arch Pathol 37:367-382, 1944 interaction between natural and synthetic 19. Wolstenholme ST, Gardner WU: Sinusoidal dilatation occuring in livers of mice with * Knapp WA, Ruebner BH: Hepatomas and oral transplanted testicular tumor. Proc Soc Exp contraceptives. Lancet 1:270-271, 1974 Biol Med 74:657-661, 1950 t Kelso DR: Benign hepatomas and oral con- 20. Yanoff M, Rawson AJ: Peliosis hepatis. Arch traceptives. Lancet 1: 315-316, 1974 Pathol 79:159-165, 1964

afferent vessels lead to the logic of postulating an etiologic role. While present evidence strongly suggests an association between contraceptives and focal nodular hyperplasia of the liver, the causative relationships should await additional study. Considering the millions of women taking oral contraceptives, the risk of developing focal nodular hyperplasia must be extremely low, and with the recent development of lowerdosage contraceptives, the risks might be suspected of becoming even less, if indeed a causative relationship does exist.