Macroregenerative Nodules and Hepatocellular Carcinoma in Forty-four Sequential Adult Liver Explants with Cirrhosis NEILD. THEISE,’MYRONSCHWARTZ,2 CHARLES MILLER^ AND SWAN N. THUNG’ IThe Lillian and Henry M . Stratton-Hans Popper Department of Pathology and 2Department of Surgery, Mount Sinai Medical Center of the City University of New York, New York 10029

Macroregenerative nodules, also called nodules of adenomatous hyperplasia, have been well documented in Japan. Extensive studies support the hypothesis that in the Japanese population these lesions represent a pogeible pathway for hepatocarcinogenesis. However, reporting of these lesions in non-Japanese populationm has so far been rare. We examined 44 sequemtial cirrhotic hepatectomy specimens from adult patients who underwent orthotopic liver transplantation at our institution. All livers were serially 88ctioned every 0.5 cm. Macroregenerative nodules were defined am regenerative nodules at least 1 cm in diameter. Forty-eight macroregenerative nodules were found in 11livers (26% of livers). The antecedent diseasem in these livers included hepatitis C (3). alcoholism (a), primary biliary cirrhosis (2) (one with iron overload),cryptogenic cirrhosis (2), hepatitis B (1) and u,-antitryprdn ddciency (1). The macroregenerative nodalee often differed from the surrounding nodular parenchyma in color, texture or the degree to which they bulged beyond the cut liver surface. Three livers contained grossly apparent hepatocellular carcinomas. Microscopically, macroregenerative nodules could be clamifled as those with (type 2) and without (type 1) dysplasia. Four livers had type 1 lesions, two had type 2 lesions and five had lesions of both types. We found 36 type 1 lesions in all and 12 type 2 lesions, 3 containing foci of microscopic carcinoma. All hepatocellular carcinomas arose in livers containing macroregenerative nodules (either type). Liver cell dysplasia, large-cell or small-cell, was o b r v e d in cirrhotic nodules of 27 livers. Microscopic or macroscopic

hepatocellular carcinoma occurred in three livers with large-cell but not small-cell dysplasia and in one liver without dysplasia. We conclude that macroregenerative nodulea are common in non-Japanese cirrhotic patients, occur in a wide range of chronic liver diseases and may represent precancerous lesions in this population. ( I ~ E P ~ L . o G1992;18:949-965.) Y

Reeeived January 21, 1992;accepted May 25, 1992. Thie study was initiated 88 a result of discussions held at the inaugural meeting of the International Liver Pathology Study Group at the Royal Free Hospital of London, July 1990.Generous support for the meeting was gratefully received from Ortho Diagnostics,Dako Ltd.,and Roche Produets Ltd.(Members of the study group:Charles Balabaud, Krzystof Bardadin,Paulette Bioulae-Sage, Romano Colombari, James Crawford, Amar Paul Dhillon, Linda FerreU, Yasuni Nakanuma, BernardPortmann, Jurgen Rode, Peter Scheuer, Dale Snover, Neil Theise, Swan “hung and Dirk van Leeuwen). Thispeper was OTiginallypresented, under the same title, at the 42nd Annual Meeting of the American Association for the Study of Liver Diseases, held on November 4,1991, in Chicago and was published in abstract form (Hepatology 1991;14:49A). Addreas reprint requests to: Neil Theise, M.D., Mount Sinai Medical Center, Department of Pathology, Box 1194.One Gustave L.Levy Place, New York, New York 10029. 31/1/3@827

In recent years, the body of literature from Japan has expanded rapidly with regard to nodular lesions of the liver, referred to variously as “adenomatous hyperplasia” (1,2),“macroregenerative nodules” (MRNs) (3), or “pseudotumors” (4). The importance of these lesions lies in the growing evidence that they are precancerous. The nodules are often, though not always, found in cirrhotic livers (3). They are larger than 1 cm in their greatest diameter and are distinct from the surrounding parenchyma in color, texture or degree of bulge beyond the cut surface of the liver. Microscopically, the nodules contain relatively intact architecture, including portal tracts. A subgroup contains atypical cytological or architectural features that may be sufficient to warrant its members’ classification as foci of HCC.

TABLE1. Liver explants containingMRNs and HCCs No. of MRNB NO.

1 2 3 4

5 6

Underlying disease

Age (yr)

Hepatitis C Hepatitis C Hepatitis C PBC PBC Alcoholicliver

No. of HCCB

TypeII+ Hcc

(W-) 2 0 1 0 0 0

Type1

TypeII

53 46 61 53 60 52

6 0 0 1 6

0 3 0

1

0

0 0 1 0 0 2

55

1

1

0

0

57

4

4

0

1

50

4

0

0

0

30 39

7 6

0 0

0 0

0 0

1 1

disease 7

8 9 10 11

949

Alcoholicliver disease Cryptogenic cirrhosis Cryptogenic cirrhosis HepatitisB a,-Antitrypsin deficiency

950

THEISE ET AL.

HEPATOLOGY

FIG.1. Cross section of a cirrhotic liver from a patient who underwent transplantation for end-stage PBC.Two macroregenerativenodules (arrowheads), measuring 1.0 and 1.7 cm in diameter, differ from other nodules in the degree to which they bulge from the cut surface of the liver and in their texture (bar = 1 cm).

FIG.2. A typical macroregenerative nodule, measuring 1.8 cm in diameter, is well circumscribed though unencapsulated. This patient had

PBC.(bar = 1 cm) (whole mount, trichrome stain).

One of the intriguing aspects of the lesions is that, despite the fact that they have been extensively reported in Japanese patients, they have only rarely been described in nondapanese populations (5). The extensive and rigorous screening programs in Japan of patients at high risk for HCC (6) may have led to an unusually high rate of identification of the nodules. To assess the actual incidence of these lesions in a nonJapanese population, we carefully examined adult patients’ cirrhotic liver explants from our institution’s liver transplantation program. Furthermore, because the importance of identifying these lesions lies in their relationship with the development of HCC, we carefully noted the presence of HCC in these livers, as well as the

presence of liver cell dysplasia (LCD),both large-cell and small-cell types -the other putative precancerous or HCC-associated lesions of the liver (7, 8). MATERIAL AND METHODS We examined all adult liver explants from our institution’s liver transplantation program over 6 mo (July 1990to January 1991). Livers removed because of fulminant liver failure (resulting from acute viral or drug-induced hepatitis) or Budd-Chiari syndrome were excluded from the study; the remaining 44 livers had cirrhosis, which was characterized as micronodular, macronodular or of a mixed pattern. These livers were serially sectioned and examined every 0.5 cm. Any nodules greater than 1 cm in diameter that were distinct from

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95 1

FIG.3. (A) A field of hepatocytes exhibiting features of large liver cell dysplasia, including nuclear and cellular enlargement and nuclear pleomorphism. These cells were identified in a macroregenerative nodule, which ww then classified as type 2 (original magnification x 100; H & E).(B)An expanding nodule of small hepatocytes (bounded by arrows)with hyperchromatic nuclei exhibit the features of small-cell LCD. These cells were identified in a macroregenerative nodule, which was then classified as type 2 (original magnification x 200; H & E).

the surrounding parenchyma in color, texture or degree of bulge beyond the cut surface were classified as macroregenerative nodules and sampled (Fig. 1). Grossly apparent foci of HCC were sampled. Routine sectioning of the liver explants, consisting of five sections each from the right and left lobes and one section from the caudate lobe was also performed. Sections of all specimenswere stained with hematowlin and eosin. The classification of MRN was confirmed by identifi-

cation of portal tracts in the nodule. The nodules were always well circumscribed,though unencapsulated (Fig. 2). They were further classified as type 1 when architectural or cytological atypia was absent or type I1 when atypia was observed (3). Large-cell LCD was defined, following the classification system of Anthony et al. (7), as hepatocytes with cellular enlargement, nuclear pleomorphism and multinucleation occurring in groups or occupying whole cirrhotic nodules (Fig.

952

THEISE ET AL.

HEPA!rOLoGY

FIG.4. Cross sections of a liver resected for end-stage chronic alcoholic liver disease. Two grossly apparent HCCs (arrowheads) and one macroregenerative nodule (arrow) are present (bar = 1 cm).

TABLE2. Underlying diseases of cirrhotic livers Disease

TOTAL

Hepatitis C PBC Alcoholic liver disease Primary sclerosing cholangitis Cryptogenic cirrhosis Hepatitis B Primary hemochromatosis a,-Antitrypsin deficiency Autoimmune chronic hepatitis Secondary biliary cirrhosis

13

TOTAL

No. of livers

No. of livers

withMRNs

withHCCs

9 8 4 4

2

1

2 1

1 0

0 0

1

1

0

1

0

0

1

0

0

44

11

4

3B). Small-cell LCD was defined, following the classification method of Watanabe et al. (8),as small hepatocytes with nuclear pleomorphism and an increased nucleocytoplasmic ratio (Fig. 3A). HCC, either microscopic or macroscopic, was defined as cellular or architectural atypia conformingto grades I to IV of the Edmondson grading system (9). Clinical data of the patients from whom the livers were taken-including age, sex and hepatitis B and C serological status-were obtained. Diagnosis of the underlying chronic liver disease was based on correlation of clinical, serological and histological findings. Statistical analyses were performed with Student’s t test or the x2 test.

RESULTS Eleven of 44 livers (25%) contained MRNs (Table 1). Four of 15 livers with micronodular cirrhosis contained MRNs, as did 5 of 19 with macronodular cirrhosis and 2 of 10 with a mixed pattern (the association of MRNs with any pattern of cirrhosis was not significant).A total of 48 MRNs was identified, averaging approximately 4/liver (range = 2 to 8). The sizes of the MRNs ranged from 1 cm to 2.2 cm in their greatest diameters. Ninety percent of MRNs were 1.5 cm or smaller in diameter. Four livers contained only type 1 MRNs, two contained only type 2 MRNs and five contained both types of MRN. Thirty-six were type 1(75%) and 12 were type 2. No significant difference was found in mean size between type 1 and type 2 lesions. Three MRNs were classified as type 2 because of small expanding clusters of hepatocytes (a nodule-within-nodule pattern): one cluster with clear cytoplasm (in a background of hepatitis C), one with fatty change (in cryptogenic cirrhosis) and one containing Mallory’s hyaline (in PBC). In one liver with grade 1 hemosiderosis, from a patient with chronic alcoholic liver disease, three nodules were found to be resistant to iron uptake. HCC was identified grossly in three livers that also contained MRNs (Fig. 4). One of these livers also had a microscopic focus of HCC in a type 2 MRN (Fig. 5). Another liver, without grossly apparent HCC, had two MRNs that contained microscopic foci of HCC. Thus all HCCs, microscopic or macroscopic, arose in livers containing MRNs. This association was statistically significant (p < 0.0025 with Yates’ correction) (Fig. 6). All grossly apparent HCCs had areas corresponding to

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MACROREGENERATIVE NODULES AND HCC

FIG.5. (A) This macroregenerative nodule, from a liver with hepatitis Cpositive cirrhosis, contains subnodules compressing surrounding tissue-a “nodule-within-nodule”effect (bar = 1 cm) (whole mount, trichrome stain). (B) High-power examination reveals two areas of carcinoma arising in the nodule, one with a trabecular growth pattern (upper right) and one with clear cell features flower left), cornpressing nonneoplastic hepatocytes between them (arrows) (original magnification x 100; H & E).

Edmondson grades I1 to IV.MicroscopicHCCs arising in MRNs had areas corresponding to Edmondson grades I1 and 111. Large-cell LCD was present in 27 livers (61%); small-cell LCD was present in 3 livers (7%). Three of the livers with microscopic or macroscopic HCCs contained large-cell LCD; one did not. The association of HCC with

LCD was not statistically significant. None of the livers with HCC contained small-cell LCD (Fig. 7). The mean age of the patients without MRNs was 46 -+ 11yr (mean S.D.);that of patients with MRNs but without HCC was 48 9 yr and the mean age of patients with microscopic or macroscopic HCC was 56 4 yr. The differences in these mean ages were not

*

*

*

954

HEPATOLOGY

THEISE ET AL.

DISCUSSION

CIRRHOT IC LIVE RS

FIG.6. The association of HCC and macroregenerative nodules in our series of adult cirrhotic livers was significant on x2 analysis (p < 0.0025 with Yates’ correction).

/CIRRHOTIC

/ /

LIVERS

\

LIVERS WITH LARGE CELL DYSPLASIA

FIG.7. The association of HCC and large-cell or small-cell LCD in our series of adult cirrhotic livers was not significant on x2 analysis.

statistically significant (0.05 < p c 0.10). The difference between the mean ages of patients with type 1 (50 k 10 yr) and type 2 MRNs (55 & 5 yr) was similarly not significant. The underlying diseases in the livers studied are listed in Table 2. Positive hepatitis B and C serological findings, separately or cumulatively, did not correlate with the presence of MRNs or HCC.

Our results demonstrate that MRNs are not an exclusively Japanese phenomenon. Using the same criteria employed by Japanese investigators (31, we found these lesions in 25% of patients undergoing liver transplantation over 6 mo. This figure is somewhat higher than that reported by Furuya et al. (3) in the largest Japanese series (14.2%),though this difference may be related to our comparatively small sample size or the presence in that series of many chronically diseased, though noncirrhotic, livers. The absence of widespread reporting of these lesions outside Japan is probably related not only to the lack of systematic screening to detect early HCCs in high-risk patients but also to inadequate examination of livers after resection or autopsy. Identification, however, first requires attention to what may have previously been regarded simply as large regenerative nodules. More important is the fact that if 90% of MRNs are less than 1.5 cm in greatest diameter, as in this series, then sectioning a liver even every cm would result in a significant number of MRNs remaining undiscovered. The underlying diseases causing cirrhosis in these livers included hepatitis B and C, alcoholic injury and PBC, all of which have been reported by Japanese investigators in association with MRNs (3, 10, 11).We believe our patient with MRNs in the presence of a,-antitrypsin deficiency to be the first such case. Thus hepatitic, cholangitic,toxic and metabolic processes now have all been implicated in the development of MRNs. Our data differ somewhat from those of Furuya et al. (3) in that we found no significant difference in the incidence of MRNs between the different patterns of cirrhosis, in the ages of the patients with and without MRNs or in the sizes of type 1vs. type 2 nodules. These differences from the Japanese population may simply reflect the size of our study and may change as our series expands; however, they may also arise from the comparatively greater diversity of diseases in our series. It may be that such measures are best evaluated by examining uniform populations of patients with the same chronic diseases or at least the same type of disease process. The importance of these lesions, of course, lies in their association with the development of HCC. Our study confirms this association in nondapanese patients because all of our HCCs were found in association with MRNs (p < 0.0025). The possibility that MRNs are premalignant rather than merely associated lesions is further supported by the identification of microscopic foci of HCC in three such lesions. Moreover, changes in clusters of hepatocytes, such as Mallow hyaline formation, clear cell or fatty change and resistance to iron uptake or increased iron uptake-which have all been suggested to represent markers for neoplasia or preneoplasia (12-17)-were identified in several MRNs in this study. Although it is not possible to suggest that MRNs are the only precursor of HCC (18), our study does not support the role of large-cell or small-cell LCD in that

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6. Takayasu K,Moriyama N, Muramatsu Y, Makuuchi M, Hasegawa H, Okazaki N, Hirohashi S. The diagnosis of small hepatocellular carcinomas: efficacy of various imagingprocedures in 100 patients. AJR Am J Roentgenol 1990;155:49-54. 7. Anthony PP, Vogel CL, Barker LF. Liver cell dysplasia, a premalignant condition. J Clin Path01 1973;26:217-223. 8. Watanabe S, Okita K, Harada T, Kodama T, Numa Y,Takemoto T, Takahashi T. Morphologic studies of the liver cell dysplasia. Cancer 1983;51:2197-2205. 9. Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer 1954;7: 462-503. 10. Terada T, Kurumaya H, Nakanuma Y, Hayakawa Y, Matsuda H. Macroregenerative nodules of the liver in primary biliary cirrhosis: report of two autopsy cases. Am J Gastroenterol 198984: 418-421. 11. Wada K, Kondo F, Kondo Y. Large regenerative nodules and dysplastic nodules in cirrhotic livers: a histopathologic study. 1988;8:1684-1688. HEPATOLOGY Acknowledgments: We thank Mr. Glenn MafYei and 12. Terada T, Hoso M, Nakanuma Y. Mallory body clustering in Dr. Pamela Unger for their assistance with the prepaadenomatous hyperplasia in human cirrhotic livers: report of four ration of the photographs used in this manuscript. We cases. Hum Path01 1989;20:886-890. are particularly indebted to Mr. Wayne Dewell, whose 13. Terada T, NakanumaY, Hoso M, Saito K, Sasaki M, Nonomura A. Fatty macroregenerative nodule in non-steatotic liver cirrhosis: a skill and patience supported every computer-generated morphologic study. Virchows Arch Pathol [A] 1989;415:131-136. aspect of this work. 14. Terada T, Nakanuma Y. Survey of iron-accumulative macroregenerative nodules in cirrhotic livers. HEPATOLOGY 198910: REFERENCES 851-854. 1. Arakawa M, Kage M, Sughara S, Nakashima T, Suenaga M, 15. Terada T, Kadoya M, Nakanuma Y, Matsui 0. Iron-accumulating adenomatous hyperplastic nodule with malignant foci in the Okuda K. Emergence of malignant lesions within an adenomatous cirrhotic liver. Cancer 1990;65:1994-2000. hyperplastic nodule in a cirrhotic liver. Gastroenterology 1986; 16. Nakanuma Y, Ohta G. Is Mallory body formation a preneoplastic 91:198-206. change? A study of 181 cases of liver bearing hepatocellular 2. Sakamoto M, Hirohashi S, Shimosata Y. Early steps of multistep carcinoma and 82 cases of cirrhosis. Cancer 1985;55:2400-2404. hepatocarcinogenesis: adenomatous hyperplasia and early hepa17. Nakanuma Y, Ohta G. Small hepatocellular carcinoma containing tocellular carcinoma. Hum Path01 1991;22:172-178. many Mallory bodies. Liver 1984;4:128-133. 3. Furuya K, Nakamura M, Yamamoto Y, Togei K, Otsuka H. Macroregenerativenodule of the liver: a clinicopathologicstudy of 18. Kondo F, Ebara M, Sugiura N, Wada K, Kita K, Hirooka N, Nagato Y, et al. Histologic features and clinical course of large regener345 autopsy cases of chronic liver disease. Cancer 1988;62:99-105. ative nodules: evaluation of their precancerous potentiality. 4. Nagasue N, Akamizu H, Yukaya H, Yuuki I. Hepatocellular HEPATOLOGY 1990;12:592-598. pseudotumor in the cirrhotic liver: report of three cases. Cancer 19. Altman HW.Pathology of human liver tumors. In: Remmer H, 1984;54:2487-2494. Bolt HM, Bannash P, Popper H, eds. Primary liver tumors. 5. Grigioni WF, D’Errico A, Bacci F, Carella R, Mancini AM. Small Lancaster, UK: MTP Press, 197753-71. liver mas= in cirrhotic patients: a pathological clue for the morphogenesis of human hepatocellular carcinoma. Acta Pathol 20. Cohen C, Berson SD. Liver cell dysplasia in normal cirrhotic and hepatocellular carcinoma patients. Cancer 1986;57: 1535-1538. Jpn 1989;39:520-527.

capacity, either. As has been noted by others (19,20), the widespread nature of large-cell LCD (61%in our series) weakens its status as a premalignant lesion to that of a marker of chronic liver injury. On the other hand, our finding of small-cell LCD in only three livers (7%) may perhaps reflect inadequate sampling. Thus, despite the lack of an association between small-cell LCD and HCC in this study, we cannot conclude that small-cell LCD does not represent an alternate pathway of hepatocarcinogenesis, as has been suggested by others (8). Therefore we conclude that MRNs are common in end-stage cirrhotic livers of nondapanese patients, that they Mxur in a wide range of chronic liver diseases and that they may represent precancerous lesions.

Macroregenerative nodules and hepatocellular carcinoma in forty-four sequential adult liver explants with cirrhosis.

Macroregenerative nodules, also called nodules of adenomatous hyperplasia, have been well documented in Japan. Extensive studies support the hypothesi...
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