Hepatoadenoma and Focal Nodular Hyperplasia: Pitfalls in Radiocolloid Imaging 1

Nuclear Medicine

Anthony F. Salvo, M.D., 2 Alan Schiller, M.D., Chrlstos Athanasoulis, M.D., James Galdablnl, M.D., and Kenneth A. McKuslck, M.D. Both hepatoadenoma and focal nodularhyperplasia must be considered in the differential diagnosisof right upper quadrant pain or massin youngwomentaking oral contraceptives. Three new cases are presented, and the radionuclide scan findingsof 35 additional cases reviewed. There is great variability in the radiocolloid liver scans of these entities. Hepatoadenomas often develop along the inferior marginof the liver, and may therefore go undetected by radiocolloid imaging. INDEX TERMS: (Liver, adenoma, 7[61] .3192) • Liver, focal nodular hyperplasia. Liver neoplasms, radionuclide diagnosis. (Liver, pseudotumor, 7[61] .3197) Radiology 125:451-455, November 1977

OCAL LIVER DEFECTS larger than 2 cm are usually

F

rounded by areas of fibrosis. The size anddensityof venouschannels in the tumor exceededthose in the surrounding liver. Partsof the periphery contained large, thick-walled blood vessels which coursed circumferentially and delimited it from the adjacent parenchyma.

resolved by 99mr c sulfur colloid liver scanning (1). Two focal benign lesions of the liver-hepatoadenoma and focal nodular hyperplasia-may grow extensively and yet have a variable liver scan appearance, including normal, absent, or increased activity. Hepatoadenoma is a potentially lethal benign tumor. The incidences of both hepatoadenoma and focal nodular hyperplasia are increasing (2). Thirty-five previously reported cases have included radionuclide liver scans. These cases are reviewed and three additional cases added.

CASE II: A 45-year-old woman was found by routine physical examination to havehepatomegaly. Shehada history of oralcontraceptive medication, although the specific medication andthe duration were not known. A histologicaldiagnosis of hepatoadenoma of the right lobe of the liver was madeat open liver biopsy. Shewas transferredfor a definitive surgical procedure. The physical examination at the time of admission wasnormal except for a firm liver edge, palpable four fingerbreadths belowthe right costal margin. Laboratory findings were normal. Abdominal angiography revealeda massively enlarged right lobeof the liver with a hypervascular mass approximately 20 em in vertical height. It appeared to be a discrete lesioncompressing the surrounding liver parenchyma. The99mTc sulfur colloid liver scan showed a large liver with irregularly shaped areasof decreased activity involving 1/2 of the right lobeanda portion of the left lobe (Fig. 2). The original operative plan was to evaluatethe extent of the tumor at surgery andremove it as effectivelyaspossible; the left hepaticartery wasto be spared. An attemptwas made to remove a soft largevascular tumor involving the lower half of the right lobe, but dissection revealed extension into the left lobe(needle biopsyof the left lobeconfirmed the diagnosis of hepatoadenoma). Extensions of the tumorwere found, with multiple projections into normal liver across the surgical planes of dissection. Copious bleeding from the resection margin could not be comroued, andthe patient diedduring surgery. Postmortem examination revealed a 5 X 6 X 4-cm green tumor in the right lobe which was not encapsulated but appeared sharply demarcated from the liver. Histological examination showedthe tumor to be similar to that of CASE I, except for a slightly lobulatedcontour, a more pronounced increase in tumor cell glycogen content, and the presence of many randomly scattered necroticfoci. Whilesome of thesefoci hadundergone fibrous organization, others showed a dropoutof tumor cells, leaving clusters of rounded blood-filled spaces in direct continuity with the sinusoids of the surrounding tissue (the appearance of peliosis hepatis). Transition stages withevidence of tumorcell necrosis confirmed thatthesespaces resulted from an attrition of parenchymal elements. No thick-walled circumferential venous channelswere present.

CASE REPORTS CASE I: A 39-year-Old womanpresented with a rightupperquadrant abdominal masspalpated on routinephysicalexamination. The patient hadno historyof jaundice, fever, or chills. Sherarely ingested alcohol. She had been taking oral contraceptives (ethynodiol diactetate with mestranOl) for the previous four years. An uppergastrointestinal series, oral cholecystogram, bariumenema, and intravenous pyelogram were normal. At exploratory laparotomy, a tumor estimatedat 20 em was found in the rightlobeof the liver.A biopsy wasperformed andthetissue was consistent with hepatoadenoma. The patient was transferred for definitive surgical resection. Angiography revealed a 12-cmvascular masswhichextended from the right lobe of the liver into the pelvis. A 99mTc sulfur colloid liver scan (Fig. 1)demonstrated that the inferior margin of the right lobe of the liver, in a position corresponding to that of the mass, was indented. The tumor was foundto be 8 em in diameterat exploratory laparotomy, with 3 em of surrounding induration nearthe midline posteriorto the gallbladder. The tumor was a well-demarcated but nonencapsulated smooth round mass which compressed the surrounding hepatic parenchyma. It was composedof cords of uniform cells which, except for a somewhatgreater glycogen content, closely resembled normal hepatocytes. The cells were arranged in irregular trabeculae from one to five cells thick andwere separated by sinusoids linedby endothelium and Kupffer cells. Occasional foci of canalicular bile stasis were observed. Noportaltractsor bileduets werepresent; tumorcell trabeculae around irregularly spaced venous channels occasionally were sur-

1 From the Departments of Radiology and Pathology, Massachusetts General Hospital and Harvard Medical School. Boston,Mass. Accepted for publication in May, 1977. 2 Presentaddress: Departmentof Pathology, Maine MedicalCenter, Portland, Maine04102. ss

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TABLE I: HEPATOADENOMA REFERENCE

YEAR

PT.

AGENT

SCAN

Monaco Palubinskas Sackett

1964 1967 1971

21 F 22 F 33 F

McLoughlin

1972

Motsay Horvath Baum Lerona Tountas Antoniades Belanger

F F F F F

Rose bengal Gold colloid Rose bengal & Tc colloid Tccolloid Tc colloid

1974

Large defect, R. lobe Large defect, R. lobe Defect in necrotic area but normal for 1250-g mass Defect edge R. lobe (superficially normal) Defect edge R. lobe (superficially normal) Normal Defect, R. lobe Equivocal defect, L. lobe Uniform colloid accumulation Defect, L. lobe Two defects, R. lobe Defect, L. lobe Focal increased activity Normal Normal Normal Defects, R. lobe, hilum Defect, R. lobe Possible defect, edge R. lobe Multiple defects, R. lobe

Ameriks Jhingran CASE I CASE II

32 22 197~ 38 197? 28 1973 25

19H· 30 F 197'i 32 F 1975 23 F 1975 44 F 44 F 28 F 1977 32 F 39 F 1977 32 F 1977 45 F

Gold colloid Tccolloid Tc colloid Gallium Tc colloid Tc colloid Tc colloid Tc colloid Tc colloid Tc colloid Tc colloid

CASE III: A 43-year-old woman was admitted because of uterine fibroids which had increased in size over the previousone-yearperiod. No hepatomegaly was noted on abdominal examination. Routine admission laboratory studies, including liver function tests, were normal. At abdominal hysterectomy, a large liver mass (6 em in diameter) was palpablewithin the right lobe.Postoperatively, a 99"'Tc sulfurcolloid liver scan demonstrated a normal-sized liver with a slight increase in radioactivity in its central portion (Fig. 3). No other abnormalitieswere otherwise noted in the liver or spleen. An angiogram demonstrateda large irregular vascular mass within the right lobe of the liver and two smaller areas which demonstrated a tumor blush (about 1.5 em in diameter) separated from the larger mass. Laparotomy was done with the surgicalgoalof a partialhepatectomy if the lesion proved to be anything except focal nodularhyperplasiaor a widely disseminated malignant tumor. The tumor, found principally in the medial segment of the left lobe, also extended across to the medial portion of the anterior segment of the right lobe. A needle biopsy histological examination disclosed essentially unremarkable hepatic parenchyma traversed by thick, densely fibrotic collagenousbandsin which were dispersed tortuous largethick-walled venous channels showing marked fibrosis of the intima and media. Small bile ducts and proliferated bile ductuleswere also present within

REMARKS 1,770-g mass L. lobe replaced bytumor, nodefect

R.E. cellspresent histologically 9-cmdiameter 9-cmdiameter s-cm diameter L. lobe 870-g mass 500-g pedunculated Almost replaced R. lobe Almost replaced L. lobe Two masses, 14-cm & 7-cm diameter 580-g mass 10-cm diameter 10-cm diameter 21-cm diameter 8-cmdiameter 20-cm diameter

the fibrous trabeculae, and there were focal collections of chronic inflammatory cells. The parenchyma subdividedby the trabeculae was not nodular, and there was no histologic evidence of liver cell regeneration of necrotic areas. A diagnosisof focal nodularhyperplasiawas made. No further surgery on the liver was undertaken, and the abdomen was closed. The patient recovered uneventfully, and because of the lack of malignant potential associated with focal nodularhyperplasia, the patient was followed conservatively. Follow-up scanning again demonstrated the localized area of increasedactivity in the right lobe, corresponding to the region of known focal nodular hyperplasia. The patient has continued to be well 24 months since the original admission.

DISCUSSION

In his classic monograph, Edmundson (3) classified hepatoadenomas and focal nodular hyperplasia in separate categories : hepatoadenomas under tumors of epithelial origin, and focal nodular hyperplasia under tumor-like conditions. The major differences between the two are shown by simplified histological descriptions of each. Hepatoadenomas are benign, usually solitary tumors

Fig. 1. A and B. CASE I. Hepatoadenoma: Anterior and right lateral views of Tc colloid liver scan. The only indication of the tumor on the inferior surface of the liver is the indentation of the right lobe which corresponds to the palpated mass (arrow).

TABLE II: REFERENCE Wilson McLoughlin McLoughlin

Whelan McMullen

Pasquier Mays O'Sullivan Stauffer Uszler Jhingran CASE III

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YEAR

PT.

1969 33 M 1972 18 F 1973 32 F 26 F 9 F 1973 21 F 7 F 1973 21 F 28 F 1974 1974 1974 1975 1975 1977 1977

37 42 51 29 27 35 43

F F F F F F F

FOCAL NOOVcAR HYPERPLASIA

AGENT

SCAN

Rose bengal Tc colloid Tc colloid Tc colloid Tc colloid colloid Gold collo id Gold colloid Tccolloid Rose bengal colloid collo id

Defect, L. lobe Normal Normal Normal Delect, R. lobe Delect, L. lobe Delect, L. lobe Irregular detect , L. lobe Delect, R. lobe Defect, R. lobe Focal increased activity Detect, R. lobe oetect, R. lobe Delect, R. lobe Normal activity in pedunculated tumor Normal Focal increased activity

Tc colloid Tc colloid Tccolloid Tc colloid

Nuclear Medicine

without lobular architecture, usually encapsulated, composed of slightly ,larger vacuolated hepatocytes in cords and sheets. True lobules are not well developed. Bile ducts are absent. Lesions of focal nodular hyperplasia are spherical nodules of hepatocytes arranged about a central stellate scar with fibrous trabeculae radiating to the periphery. Bile ducts are found in the fibrosis trabeculae. Both types may have increased vascularity. Kupffer cells are sparse in hepatoadenoma, whereas they are present in the sinusoids in focal nodular hyperplasia. There has been much confusion in the literature regarding these two entities because of the lack of uniform classification. Formerly , these lesions were considered uncommon. Edmundson (3) found only two hepatoadenomas in 197 benign liver tumors, and 14 cases of focal nodular hyperpasia in 50,000 consecutive autopsies. Malt (4) reviewed benign liver neoplasms over a 20-year period and found 4 lesions which he classified as hepatoadenomas and 3 cases of focal nodular hyperplasia. More recent papers emphasize the rising incidence of these lesions. Baum (5) reported 7 cases, and recently (6) reported 6 more patients with hepatoadenomas who have undergone surgery between 1973 and 1975. Berg (7) reported 4 hepatoadenomas between 1969 and 1971, four times the statistical prediction. Since Baum's first article in 1973 suggesting an association of oral contraceptives and hepatoadenoma, 14 additional reports have been published supporting this concept, suggesting a possible association between oral contraceptives and focal nodular hyperplasia (2, 8-20). Clinically, these two lesions usually present in one of three ways: (a) a right upper quadrant mass noted by the patient or by the physician either at routine physical examination or incidentally at surgery; (b) right upper quadrant pain simulating gallbladder disease; and (c) pain, shock , and hemoperitoneum in a patient on oral contraceptives. Laboratory data are usually normal. Most mass lesions of the liver do not contain Kupffer cells and are, therefore, " cold" on radiocolloid scanning. The exception is focal nodular hyperplasia (21). Phillips et el. (22), in reporting on the ultrastructure of the two lesions under discussion, stated that the hepatocytes, biliary

REMARKS 7-cm diameter mass 4.5 X 3.5 cm 2-cm diameter-2 lesions z-orn diameter-3 lesions a-em diameter 10-cm diameter 1.280g 2.5-cm diameter 6-cm diameter-L. lobe 757-g. subcapsular hematoma 5-cm diameter Necrotic tissue. hematoma Tumor extends beyond edge of R. lobe Mass projections inferior R. lobe 6-cm diameter

epithelium, and Kupffer cells of focal nodular hyperplasia were almost identical to those in the surrounding normal liver, while Kupffer cells were commonly deficient in hepatoadeonomas . TABLES I and \I summarize the radiocolloid scan findings in our 3 cases and in previous reports . Scan results have been reported in 19 cases of hepatoadenomas and in 16 cases of focal nodular hyperplasia . In the hepatoadenomas, 13 scans have been positive, two equivocal , and four normal. In focal nodular hyperplasia, 9 scans have shown detects in activity,S were considered normal, and 2 showed focal areas of increased activity . One previously reported case of hepatoadenoma (30) caused a large defect in the right lobe of the liver , but a tumor replaced the whole left lobe, with no corresponding defect demonstrated by a scan. Sackett 's (32) case of hepatoadenomashowed a defect in a necrotic area of the tumor, but both the rose bengal and radiocolloid scans were normal for the non-necrotic tumor mass. Reticuloendothelial cells were present in this tumor (32). Hepatoadenomas frequently occur at the free edge of the right lobe of the liver, thus giving the radiocolloid scan a normal appearance on superficial examination. This dif-

Fig. 2. CASE II. Hepatoadenoma: Anterior view shows irregularly shaped areas of decreased activity invo lv ing the right and left lobes.

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ANTHONY F. SALVO AND OTHERS

ficulty is shown in the cases reported by McLoughlin (26), Baum (5), and in our first case. Those cases of hepatoadenoma which were not demonstrable on colloid scanning were all greater than 6 em in size, and therefore large enough to be resolved if a defect had been present. The sean findings in foealnodular hyperplasia have been variable (TABLE II). Despite the presence of Kupffer cells in focal nodular hyperplasia, it seems likely that some abnormality exists to result in defects in the radiocolloid scan in 60% of the cases; among the possibilities are necrosis and hemorrhage (13). Although 10 of 16 cases have shown defects in the radiocolloid scan, 4 seans were normal. One important feature of this disease is the finding of increased activity in these lesions in 2 of the 15 scans (31, and CASE III). CONCLUSIONS

Because precipitous clinical presentations frequently necessitated surgical intervention, liver scanning was performed in approximately 30 % of the reported cases . Awareness of these lesions when there is a less than catastrophic onset of symptoms should lead to earlier diagnosis. Since there is such a great variability in the radiocolloid scan findings, careful attention must be paid to technique. Palpating the patient under the gamma camera and the recording of multiple projections are helpful in correctly interpreting the scan. Focally increased activity has been seen in 2 of the 15 reported scans of focal nodular hyperplasia. This finding is a very important factor in the differential diagnosis of liver mass lesions, especially for patients taking oral contraceptive medication. A specific diagnosis cannot be made on the basis of the radiocolloid scan alone, but requires the clinical settings described above. Even if the radiocolloid liver scan is normal,

November 1977

the diagnosis of hepatoadenoma or focal nodular hyperplasia should be considered. ACKNOWlEDGt..£NTS: The authors gratefully recognize the extensive contributions made by the medical , surgical , and technological staffs of the Massachusetts General Hospitalln the evaluation and the care of these patients .

REFERENCES 1. Holder LE, Saenger EL: The use of nuclear medicine in evaluating liver disease. Semin RoentgenoI10:215-222, Jul 1975 2. Mays E, ChristophersonWM, Mahr MM, et al: Hepatic changes in young women ingesting contraceptive steroids. Hepatic hemorrhage and primary hepatic tumors. JAMA 235:730-732, 16 Feb 1976 3. Edmundson HA: Tumors of the liver and intrahepaticbile ducts. [In) : AFIP Atlas of Tumor Pathology, sect VII, fasc 25, 1958 4. Malt RA, Hershberg ra, Miller WL: Experience with benign tumors of the liver. Surg Gynecol Obstetr 130:285-291, Feb 1970 5. Baum J, Bookstein JJ, Holtz F, et al: Possible association between benign hepatomas and oral contraceptives. Lancet 2:926-929, 27 Oct 1973 6. Baum JK: Letter: liver tumors and oral contraceptives. JAMA 232:1 ,329,30 Jun 1975 7. Berg J, Ketelaar R, Rose EF, et al: Letter: hepatomas and oral contraceptives. Lancet 2:349-350, 10 Aug 1974 8. Antoniades K, Brooks CE Jr: Hemoperitoneum from liver cell adenoma in a patient on oral contraceptives. Surgery 77:137-139, Jan 1975 9. Antoniades K, Campbell WN, Hecksher RH, et al: Liver cell adenoma and oral contraceptives. Double tumor development. JAMA 234:628-629, 10 Nov 1975 10. Contostavlos DL: Letter: benign hepatomas and oral contraceptives. Lancet 2:1,200,24 Nov 1973 11. Kelso DR: Letter: Benignhepatomas and oral contraceptives. Lancet 1:315-316, 23 Feb 1974 12. Knapp WA, Ruebner BH: Letter: hepatomas and oral contraceptives. Lancet 1:270-271, 16 Feb 1974 13. Mays ET, Christopherson WM, Barrows GH: Focal nodular hyperplasia of the liver. Possible relationship to oral contraceptives. Am J Clin PathoI61:735-746, Jun 1974

Fig. 3. CASE III. Focal nodular hyperplasia: A. Anterior view shows increased activity (arrow) in central portion of right lobe. B. and C. Angiogram shows the vascular mass with tumor blush in the central portion of the right lobe, corresponding to the area of abnormality on the liver scan.

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14. O'Sullivan JP, Wilding RP: Liver hamartomas in patients on oral contraceptives. Br Mad J 2:7-10, 6 Jul1974 15. Stauffer JO, Lapinski MW, Honold OJ, at al: Focal nodular hyperplasia of the liver and intrahepatic hemorrhage in young women on oral contraceptives. Ann Intern Med 83:301-306, Sep 1975 16. Tountas C, Paraskevas G, Deligeorgi H: Letter: benign hepatoma and oral contraceptives. Lancet 1:1,351-1,352, 29 Jun 1974 17. UszlerJM, SwansonLA: Focal nodularhyperplasiaof the liver: case report. J Nucl Med 16:831-832, Sep 1975 18. Edmondson HA, Henderson B, Benton B: Liver-eell adenomas associatedwith use of oral contraceptives. N Engl J Med 294:470-472, 26 Feb 1976 19. Ameriks JA, Thompson NW, Frey CF, et al: Hepatic cell adenomas, spontaneousliver rupture, and oral contraceptives. Arch Surg 110:548-557, May 1975 20. Jhingran S, Mukhopadhyay A, Ajmani S, et al: Hepatic adenomas and focal nodular hyperplasia of the liver in young females on oral contraceptives: case reports. J Nucl Med 18:263-266, Mar 1977 21. Mcloughlin MJ, ColapatinoRF, GildayDL, et al: Focal nodular hyperplasia of the liver. Radiology 107:257-263, May 1973 22. Phillips MJ, Langer B, Stone R, et al: Benign liver cell tumors. Classification and ultrastructure pathology. Cancer 32:463-470, Aug 1973 23. Belanger MA, Beauchamp JM, Neitzschman HR: Gallium uptake in benign tumor of the liver: case report. J Nucl Med 16: 470-471, Jun 1975 24. Horvath E, Kovacs K, Ross RC: Ultrastructural findings in a well differentiated hepatoma. Digestion 7:74-82, 1972

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25. Lerona PT, Go RT, Cornell SH: Limitations of angiography and scanning in diagnosis of liver masses. Radiology 112:139-145, Jul 1974 26. McLoughlin MJ, Gilday DL: Angiography and colloid scanning of benign mass lesions of the liver. Clin RadioI23:377-391, 1972 27. McMullenCT, MontgomeryJL: ·Arteriographicfindings of focal nodular hyperplasia of the liver and review of the literature. Am J Roentgenol 117:380-387, Feb 1973 28. Monaco A, Hallgrimsson J, McDermott WV Jr: Multiple adenoma (hamartoma) of the liver treated by subtotal(90 percent) resection: morphological and functional studies of regeneration. Ann Surg 159: 513-519, Apr 1964 29. Motsay G, Gamble WG: Clinical experience with hepatic adenomas. Surg Gynecol Obstetr 134:415-418, Mar 1972 30. Palubinskas AJ, Baldwin J, McCormack KR: Liver cell adenoma, angiographic findings. Radiology 89:444-447, Sep 1967 31. Pasquier J, Dorta T: Letter: focal hyperfixation of radiocolloid by the liver. J Nucl Med 15:725, Aug 1974 32. Sackett J, MosentholW, HouseR, et al: Scintillation scanning of liver cell adenoma. Am J RoentgenoI113:56-60, Sep 1971 33. WhelanTJ Jr, BaughJH,ChandorS: Focal nodularhyperplasia of the liver. Ann Surg 177:150-158, Feb 1973 34. Wilson TS, Macgregor JW: Focal nodular hyperplasia of the liver: the solitary cirrhotic liver nodule. Canad Med Assoc J 100: 567-572,22 Mar 1969 Kenneth A. McKusick, M.D. Division of Nuclear Medicine Massachusetts General Hospital Boston, Mass. 02114