A mixed hamartoma of the liver: Light and electron microscopy

A MIXED HAMARTOMA OF THE LIVER: LIGHT AND ELECTRON MICROSCOPY Roy H. Rhodes, Ph.D., M.D.,* Michael B. Marchildon, j\1.D.,t Donald C. Luebke, M.DA Hugh A. Edmondson, M.D.,§

and Victor G. Mikity, M.D.II

Abstract The gross , microscopic, and ultrastructural features ofa mixed liver hamartoma occurring in a three month old infant are reported. The differentiation from two other solid liver masses, focal nodular hyperplasia and liver cell adenoma, is emphasized. Mesenchymal hamartomas, though usually cystic rather than solid masses , share the histologic feature of fibroductular tissue with mixed liver hamartomas and focal nodular h yperplasia. Only the mixed liver hamartoma has extremely broad fields of ductules and an embryonic type of hepatocyte at the ultrastructural level. These and other hepatic lesions show morphologic evidence of transformation of liver cells into biliary epithelial cells in association with vascular connective tissue.

There are few clinical features or radiologic criteria that are helpful in the diagnosis and treatment of a large, relatively vascular mass in the liver of a young child. Benign growths and inflammatory masses may resemble hepatocellular malignant tumors angiographically;' leaving the clinician with the uncertainties of noninvasive procedures or with the pros-

pect of undertaking a biopsy for a definitive diagnosis. The child presented here became symptomatic while under clinical investigation for a liver mass and required operative inter ven tion. The pathologic findings are unique in our experience, but are clearly delineated from those of other solid mass lesions of the liver both grossl y

*Clinical Instructor. Department of Pathology. University of Southern California School of Medicine. Resident, Los Angeles County-University of Southern California Medical Center, Los Angeles , California. t Assistant Professor. Uni versity of Miami School of Medicine . Assistant Professor. Division of Pediatric Surgery. University of Miami Hospitals. Miami , Florida.

:j:Resident, Department of Surgery. Universit y of Southern California School of Medicine and Los Angeles County-University of Southern California Medical Center. Los Angeles. California. §Professor, Department of Pathology, University of Southern California School of Medicine. Senior Pathologist, Section of Laboratories and Pathology. Los Angeles County-University of Southern California Medical Center, Los Angeles California. [Professor. Department of Radiology, University of Southern California School of Medicine. Senior Pediatric Radiologist, Los Angeles County-University of Southern California Medical Center, Los Angel es, California.

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and microscopically." These other lesions have not been uniformly defined or described and include benign masses of differing etiologies but with commonalities in their histologic makeup. :J-5 The present case is compared to this group of differing lesions. Case Report

A three month old Spanish American male was admitted to the Los Angeles County-University of Southern California Medical Center on February 11, 1975, for evaluation of an abdominal mass noted the previous day during a well baby examination. The mother was a healthy young primagravida who reported an unremarkable pregnancy and neonatal period. She had taken no medications. The child ate well and gained 2.5 kg. over the birth weight. The stools had been normal, there was no vomiting, and no jaundice had been noted. Physical examination revealed a healthy appearing baby with a weight in the 50th percentile and height in the 90th percentile. No icterus was present. There was a 2 by 2 em. capillary hemangioma in the left axillary region. Other positive physical signs were confined to the abdomen where the liver edge was palpable 3 cm. below the right costal margin and extended across the epigastrium. A large midline mass, palpable inferior to the liver edge for about 8 cm., extended into the right upper quadrant. The mass was firm and slightly nodular, could not be separated from the liver itself, and was only slightly movable. The spleen was not palpable. Admission laboratory results showed normal serum electrolyte levels; hemoglobin, I 1.3 gm. per dl.; white blood cells, 19,000 per cu. mm. with 39 neutrophils, 2 bands, 49 lymphocytes, and 9 eosinophils; total serum protein, 6.5 gm. per dl.; albumin, 4.0 gm. per ell.; total bilirubin, 0.5 mg. per dl.; alkaline phosphatase, 6.0 Bessey-Lowry-Brock units (normal, ] to 3); and normal serum creatine phosphokinase and serum transaminase levels. The prothrombin time was 90 per cent of the control value. Urinary catecholamine, vanilmandelic acid, and metanephrine

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levels were normal. Tests showed normal levels of a-I-antitrypsin and no ce-fetoprotein in the serum. Further normal studies included a chest x-ray examination, bone survey radiograms, and an intravenous urogram. Hepatic angiography showed a large, relatively vascular, intrahepatic lesion with large vessels forming an arcade. The blood How through the lesion was slow, as shown by the late vascular phase "blush" and by the delay in appearance of a radioisotope in a later liver scan. Ultrasound studies did not add significant information. These studies could not be used to differentiate between a benign and a malignant process. Within two weeks after admission, ascites was clinically evident. The total serum protein level had fallen to 3.0 gm. per dl. and the albumin level was 1.3 gm. per dl. The moderate eosinophilia had decreasecl and the white blood count varied from 10,000 to 17,000 per cu. mrn. At laparotomy on March 6, 500 ml. of milky ascitic fluid was removed. A large, solid, pale red-brown nodular mass appeared to be arising from the caudate lobe of the liver, extending both anteriorly and posteriorly. The mass involved both the left and the right lobes of the liver, elevating Glisson's capsule in an irregular fashion and fading into grossly normal liver. In the left lobe most of the inferior and posterior portions were replaced; an extension behind the porta hepatis led into the right lobe. A large appendage of the mass was closely applied to the inferior vena cava and, with the part of the mass behind the cava, may have been obstructing it to some degree. At least one sizable arterial branch from the celiac axis entered the mass directly and a few small venous tributaries led from the mass to the inferior vena cava. Because of the location and extent of the lesion, only a partial resection was performed for diagnosis and for possible decompression of the vena cava, and composed perhaps 40 per cent or more of the total lesion. The postoperative course was somewhat difficult with the development of pleural effusion, fever, and ascites, but these gradually subsided. The serum albumin level rose to 2.6 g'm. per dl. The infant was doing well when seen in the

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clinic one year after the operation, with no abdominal masses or organomegaly detected on physical examination. No chemotherapy or radiotherapy was planned and the patient has been lost to further follow-up studies.

MATERIALS AND METHODS A small segment of the biopsy specimen was rapidly diced in the operating room and placed in cold 2 per cent glutaraldehyde in cacodylate buffer, The remainder was divided and placed in Zenker's fixative or in 10 per cent neutral buffered formalin. The latter tissue was prepared routinely for light microscopy and stained with hematoxylin and eosin, periodic acid-Schiff stain with and without prior diastase digestion, and Masson's trichrome and Verhoeff's elastin stains. The glutaraldehyde fixed tissue was postfixed with buffered 1 per cent osmium tetroxide, dehydrated in graded ethanol, and embedded in an Epon-Araldite epoxy resin mixture. Thin sections were stained

with uranyl acetate and lead citrate and examined with either a Hitachi HS-7S.or a Philips 301 electron microscope.

RESULTS Gross Description The specimen was a red-tan, solid, 7 by 5 by 4 em. segment of liver covered on all but the amputated aspect by a thin fibrous capsule. Sectioning revealed the mass to be firm, rubbery, red-tan to graytan, and nodular. After formalin fixation the cut surfaces were distinctly gray with multiple cerebriform nodules with yellowwhite centers separated by opalescent, pearly white fibrous bands of various widths. The nodules were up to 1 em. in greatest diameter (Fig. 1).

L-ight Microscopy Sections of the excised tissue disclose abnormal hepatic parenchyma composed of nodules up to 1 em. in diameter that

Figure 1. Gross appearance of the outer and cut surfaces of the liver mass prior to fixation. There are many nodules. which have white centers and are surrounded by thin septa. (From Edmondson. H. A.: Benign epithelial tumors and uunorlike lesions of the liver. In Okuda, K., and Peters, R, L. [Editors]: Hepatocellular Carcinoma, New York. John Wiley & Sons, Inc., 1976, Chapter 1:1, P: 323.)

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are subdivided into innumerable small pseudolobules. Most of the nodules have a portal tract in the center with radiating smaller branches that tend to subdivide the nodules. The central nidus of biliary and connective tissue surrounded by live~ cells and encircled by a fibrous septum accounts for the gross nodularity. Where the fibrosis is severe. the pseudolobules and nodules are sharply delineated (Fig. 2). With high magnification two distinct changes are noted along' the portal tracts. First, the larger tracts contain wide bands of compact collagen, much of which is present in large bundles (Fig. 3). Many blood vessels encased in this connective tissue have thick myxomatous walls (Fig. 3). An occasional arterial or venous branch has an obliterated lumen. Small lumens are noted in many of the bile ducts surrounded by the dense connective tissue. Secondly, along the smaller branches of the portal system that ramify within the nodules and pseudolobules, the connective tissue is more cellular, the large collagenous bundles are not seen, and a remarkable proliferation of duendes spreads into the pseudolobules, accompanied by diffuse connective tissue proliferation. In

many instances the ductules seem to be derived from conversion of hepatocytes to bile duct epithelium (Figs. 4, 5). In some areas as much as 50 per cent of the tissue is composed of this fibroductular complex. The great expansion of this tissue is responsible for the reduction of the amount of parenchyma in the pseudolobules, so that some areas are composed of fibroductular tissue and only a few hepatocytes. In contrast there are peripheral areas near the capsule where the fibroductular proliferation is much less prominent, and irregularly shaped masses of parenchymal cells are divided by rather thin connective tissue septa, some of which contain ductules whereas others do not. There is a prominent subcapsular venous plexus. The sinusoids and Kupffer cells are fairly normal in appearance, although in some of the pseudolobules the sinusoids are wider than normaL The outflow veins within the pseudolobules are present but rarely have a central location. The larger branches of the hepatic veins are difficult to identify in the septa, but many thick walled, large veins unaccompanied by bile ducts or arteries are present. The hepatocytes are arranged in

Figure 2. Microscopically the nodules consist of liver cells surrounded by a band of connective tissue with the center of the nodule replaced to a variable degree by vascular fibroductular tissue, which includes innumerable cholangioles. Tapering extensions of the central fibroductular area tend to break up the liver cell groupings. (Hematoxylin and eosin stain. X '~5.)

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Figure 3. Within the bands of dense connective tissue there are venous lakes surrounded by mesenchymal tissue, bile ducts, and very thick colJagen bundles (arrow). (Hematoxylin and eosin stain. X lOll.)

strands, which are distinct and variable in thickness. For the most part they have nuclei of normal size and granular acidophilic cytoplasm. A tubular expansion of the canalicular lumen between

hepatocytes at the boundary with the connective tissue is often seen (Fig. 5). The lumen continues across the interface of connective tissue in a cellular bridge of bile epithelial cells and is continuous with

Figure 4. At the point of farthest extension of thin wavy collagen bu ndles along a cord of liver cells, there is a transition of the same continuous cord (arrow) into a cholangiole. The liver cells above the alTOW have round nuclei and a granular cytoplasm; the biliary epithelial cells below the arrow have oval nuclei and a lighter cytoplasm. (Hematoxylin and eosin stain. X :~DO.)

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Figure 5. A. A tubule has hepatocyres on the left side of its lumen and cells cytologically typical of biliary epithelium on the right. Collagen fibrils underlie the biliary portion of the tubule and a capillary is in close relationship. B to D. Tubule elongation and apparent progression into formation of a cholangiole are seen as described in the text. (Hematoxylin and eosin stain. X 500. oil.)

the lumen of a ductule. The cells lining this transitional area are usually distinctly pale staining or mottled and are in direct communication with hepatocytes on one side and biliary epithelial cells on the other (Figs. 4, 5). The nuclei of these pale transitional cells are round to oval, often overlapping the nucleus of an adjacent cell and often polarized toward the ablurninal side of the cell. Liver cell nuclei rarely overlap, but this is a common feature among the ductules, Vascular channels are usually seen at these transition zones and a rare instance of mitosis is also seen here (Fig. 5). The PAS stain reveals glycogen in most hepatocytes. Many hepatocyte tubules bordering on connective tissue are deficient in PAS positive material. There are small amounts of diastase resistant, PAS positive material in the bile duct and ductular epithelial cells.

Electron Microscopy

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The sinusoidal spaces contain an incomplete lining of endothelial cells. The

space of Disse is filled with long, intertwining liver cell microvilli and with reticular fibers, or unit collagen (Fig. 6). The collagen often forms thick bundles that extend into the juxtasinusoidal intercellular spaces. The hepatocytes are 10 to 20 }.tm. in diameter with intercellular spaces 0.1 to 1.0 usn. in width. Short lateral microvilli project into the intercellular space, and the lateral cell plasma membranes exhibit frequent contacts with junctional complexes. Bile canaliculi are formed where the plasma membranes of several cells contact one another. Small microvilli project into these otherwise empty spaces. The cytoplasm of the hepatocytes contains numerous spherical mitochondria, which are about 1 }.tm. in diameter and have short sparse cristae and electron dense intercristal matrices. The rough endoplasmic reticulum is plentiful and occurs in small stacks and short scattered profiles; the intracisternal spaces contain homogeneous, moderately electron dense material. Single strands of rough endoplasmic reticulum often incompletely

MI XED HA MARTOM A OF THE LIVER-RHODES

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Figure 6. An electro n micro g ra ph sh ows liver cells with mi tochondria and man y small stacks of rough endo plas mic re ticulum. T he nu clei are vesicula r. The relatively wide intercellular spaces have la teral microvilli but 110 collagen . The spa ce of Disse (a rro w) between the sin usoidal end othelial cells and the live r ce lls co ntains collagen. (X 51 00.)

surround a mitochondrion. Beta particles of glycogen are numerous. There are some granules 0.4 p.m. in diameter surrounded by single membranes, which may represent microbodi es altho u gh they have no dense cores. Smaller vesicles, coated vesicles, and dense bodies of various sizes are observed. Hepatocytes ad jacent to fibrosis have a patch y cytoplasm with some relativel y electron lucent areas. These lucent areas co n tain many gl ycogen ro settes and have few organelles , so me o f wh ich ma y be degenerated. Some of these cells and even more electron lu cent cells together form bile canalicu li and lie o n a basement membrane next to ductules, apparently rep resen ting stages of transfor rna tion of hepatocytes into biliary e pithelial cells (Fig. 7). Ductules lie within focall y reduplicated basement m embrane m aterial.

DISCUSSION The presence of a liver mass in a pediatric patient usually requires surgery for definitive diagnosis . Symptomatic lesions,

whether clearly neoplastic or not, should be excised completely whenever possible, e ve n if this requires hepatic lobectomy.v'<" Th ese masses are more likely to be malignant th an benign.?' 8. 9 and a preliminary diagnosis of benignity may be incorr ect. 10-12 The preoperative diagnosis in our case could n ot be made even after careful an giographic stud)'. Angiography of benign and malignant hepa tic masses may giv e similar results, 1. !I, 1;1 and in ou r experience there is no pathognomonic appearance o f an y type of rel atively vascular hepatic mass. A difficult decision ari ses when an as ymptomatic liver mass is in a haz ardous location for surgical r esect ion. 14, 1" The p resent pati en t was no lon ger asy m p tomat ic by the time surgery wa s undertaken and ye t co m p lete resection co u ld not be acco m p lishe d . Resection of the part of the mass th at may have been causing m echanical ca val obstruction has thus far been associated with a favorable r esult. However, so few cases of mixed liver hamartoma are described (vide in fra) that prognostication in a case with partial

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Figure 7. An electron micrograph shows an embryonic type of liver cell (1) forming a bile canaliculus (upper center) with an intermediate cell (2) and a biliary epithelial cell (3), the latter cells lying on a basement membrane (arrows) adjacent to connective tissue. The biliary epithelial cell (3) is part of a cholangiole in the upper right. (X 7000.)

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resection is not possible. The etiology of the progressive hypoalbuminemia in this case is not clear. Lesions similar to the liver mass in the three month old infant described here are often termed hamartomas, adenomas, or focal nodular hyperplasia. 4,5 These terms have been used interchangeably. However, when the lesion is congenital, contains abnormal arrangements of all the cells of the normal organ, and shows no inherently aggressive behavior, it is preferably called a hamartoma. J(; Because the lesion in our patient was a part of the liver and contained all the types of cells of that organ, with each represented quite prominently, we chose the term mixed liver hamartoma. The term mixed hepatic hamartoma is also acceptable and would conform to a recently discussed standard nomenclature of hepatocellular lesions. s The congenital nature of this hamartoma is underscored by the unique immature ultrastructural characteristics of its hepatocytes. They show cell to cell relation-

ships, organellar content, and plasma membrane specializations consistent with embryonic human liver cells. 17,18 Adult human liver cells, in contrast, have a smaller intercellular space, only infrequently have stacks of rough endoplasmic reticulum, have dense cores in most of their microbodies, and have only a few lateral microvilli. 19 Other entities that have been called hamartomas of the liver, but in most cases are not, do not have embryonic types of liver cells at the electron microscopic level. Focal nodular hyperplasia, a lesion described by Edmondson": 1~, so as a specific entity, has a prominent radiating stellate central scar grossly and has no central veins microscopically; its liver cells are ultrastructurally adult in type. ~1, 2~ The lesion contains only a few bile ductules associated with portal structures located in the center of nodules as in a mixed liver hamartoma. Extremely broad fields of ductules and central outflow veins in mixed liver hamartomas distinguish the

MIXED HA1\IARTOMA OF THE LIVER- RHOD ES

hamartomas from focal nodular hyperplasia. Von Meyenber g com p lexes are fibroductular ham artomas of a focal type. Although the y have a histologic similarity to mixed liver hamartomas, they seem histogeneticall y close r to polycystic liver disease. " Liver cell adenomas . which usually contain only liver cells and minimal stroma but which can have an occasional biliary structure.s?' 2:l. ~ ~ a r e characterized by an ultrastructural picture of altered neoplastic liver cells, which resemble neither developing' nor a d ult types. 22.2 1 Mesenchymal hamartom as undergo cysti c degeneration anel are not p art of the spectrum of solid hepatic masses even though they contain a minor co m po ne n t of paren chy ma."- I ~ , 20 However. the mixed liver hamartoma, fo cal n odular h yp erplasia, and mesench ymal ham artomas all have large vessel s surrou nd ed by loose mes ench ymal tissue . 2 , 1 ~ , 20 T his is also a feature or' so me solid hepatic ma sses associated with orally administered contraceptives. ~ 5 -27 There a re only a few acceptable cases of mixed liver hamartoma. Benson and Penberth y" described th e lesion in a seven month old female , Franklin and Downingw described seve r al large entering vessels in a mixed liver hamartoma in a 2g year old male. Kay an d Tulbert'" furnished an excellent descr ip tio n of two pediatric cases, previous! y classified as focal nodular hyperplasia . -I, I~ . 1(\ Experie n ce with ))0 cas es of focal nodular hype rplasia now shows a clear d ifference betwee n the two en tities, both grossly and microscopicall y. ~ The hepatic mass in Kay and Talbert's secon d case was associated with major abd omin a l vessels a n d had a palpable thrill intra op eratively, Ours is the fifth case; it is sim ilar in its excellent a rterial supply, in th e g ross ap pearance of its cut section , and in its m icroscopic detail to th e other Iou r cas es. Ladd and Gross." I-I uuter.:" Bartlett a nd Shellito. i" and Knowles and WolH'-1 disc u sse d cases th a t might be m ixed hamartomas , but adequat e documentation is lacking. Many (cystic or so lid ) hepatic masses have important biliary co m pon e nts. such as cystic bile du ct s in mesenchymal hamartomas" and th e many eluctules in

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a mi xed liver hamartoma. T hese biliary structures develop from portal bile ducts , wh ich them selve s are derived embryologically f rom transformed hepatocytes in a process strikingly simil ar to the apparent transformation se en in the present case. :l~ -:l~ Hepatocellular- bile ductular transformation not only is a ke y to understanding the histologic findings in many hepatic lesions, but is also an im p or ta n t clue to pathogenesis. Although it may play little or no part in the evolu tion of such lesions as adenomas, hepatocellular-bile d uctu lar transformation appears to be responsible for the maj or findings in mixed liver hamartomas and for some of the changes in vario u s oth e r hepatic le sions and ca n be seen in tissu e culture.": 2 7. -IO- -W Th e parench yma in the h amartoma is apparentl y being re p laced through this process by fibrodu ctular tissue , leading to the appearance of the n odul es a n d pseudolobules as described . The re placement of hepatocytes by fibroductular tissu e may acco u nt for the lack of a palpable mass in our patient one year after surgery. This assu mes a "contraction" of the lesion. Liver parench ymal cells are co m m itte d to certain morphologic expressi ons early in development from the yolk sa c and maintain th ese features e ven after seve re experimental and pathological change.":': ~ 7 , ~ 8 It is not, then, a surp rise that a mixe d liver hamartoma so clo sely imitates the theme o f normal histogenesis. There is a consensus th at an a bno r mality in a chemical organizer in the portal o r subcapsular co n nec t ive tissue, 0 1- in the respo nse to the organizer, causes the pathol ogic va r iatio ns in the les ions of the histologic spectrum under discussion.": ~ ~I­ :i l Other factors influencing liver and conne ctive tissu e growth t hat m a y define the ultimate fo r m taken in the spectrum of these liver masses incl u de lo cal a n d humoral factors, exogenous hormones , mesenchymal-epitheli al interactions. an d me ch anical-fluid d ynamic force s. 27 . ~ 8 . 5~ -58 The initial ce llula r lesion in a mixed liver ham artoma could be lo calized in the co nnect ive tissu e or pa ren chym a or in an abno r ma l exchange of metabolic information. suggestions made by Albrecht!" in 1904 regarding hamartomas in general.

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ACKNOVVLEDGMENTS

Dr. R. L. Wood kindly reviewed some of the electron micrographs and commented on the data. Mr. Dale Carriere provided assistance from the Electron Microscopy Unit of the Department of Pathology. Mr. Lloyd Matlovsky took the photomicrographs. REFERENCES 1. Novy, S., Wallace, S., Medellin, H., and Mcbride, C.: Angiographic evaluation of primary malignant hepatocellular tumors in children. Am. J. Roentgenol., 120:353, 1974. 2. Edmondson, H. A.: Benign epithelial tumors and tumorlike lesions of the liver. In Okuda, K., and Peters, R. L. (Editors): Hepatocellular Carcinoma. New York, John Wiley & Sons, Inc., 1976, p. 309. 3. Ein, S. H., and Stephens, C. A,: Benign liver tumors and cysts in childhood. J. Pediat, Surg., 9:847,1974. 'l. Knowles, D. M., II, and Wolff, M,: Focal nodular hyperplasia of the liver. A clinicopathologic study and review of the literature. Hum. Pathol., 7:533,1976. 5. Mays, E. T.: Standard nomenclature for primary hepatic tumors. A critical need. J.A.M.A., 236: 1469,1976. 6. Clatworthy, H. W., Jr., Boles, E. T.,Jr., and Kottmeier, P. K.: Liver tumors in infancy and childhood. Ann. Surg., 154:'175,1961. 7. Malt, R. A., Hershberg, R, A., and Miller, W. L,: Experience with benign tumors of the liver. Surg. GynecoI. Obstet., 130:285, 1970. 8. Clatworthy, H. W.,lr., Schiller, M., and Grosfeld, J L.: Primary liver tumors in infancy and childhood, Arch. Surg., 109:143, 1974. 9. Kim, D. K, McSweeney, J., Yeh, S. D. J., and Fortner, J. G.: Tumors of liver as demonstrated by angiography, scan and laparotomy. Surg. Gynecol. Obstet., 141:409, 1975. 10. Schrager, V. L.: Surgical aspects of adenoma of the liver. Ann. Surg., 105:33,1937. 11. Packard, G. B., and Stevenson, A. W.: Hepatoma in infancy and childhood: discussion and report of patient treated by operation. Surgery, 15:292,1944. 12. Edmondson, H. A.: Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood. Am. J. Dis. Child., 91: 168,1956. 13, Caffey, J.: Pediatric X-ray Diagnosis. Ed. 6. Chicago, Year Book Medical Publishers, Inc., 1972. Vol. 2, p. 1407. 14. Raffucci, F. L., and Ramirez-Schon, G.: Management of tumors of the liver. Surg. Gynecol. Obstet., 130:371,1970. 15. Shah, J. T., Goldsmith, H, S., and Huvos, A. G.: Hamartomas of the liver. Surgery, 68:778, 1970.

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16. Albrecht. E.: Ueber Hamartome. Verh. Dtsch. Pathol. Ges .. 7: 153, 1904. 17. Phillips, M. ]., and Steiner, .J. W.: Electron microscopy of liver cells in cirrhotic nodules. 1. The lateral cell membranes. Am. J. Pathol., 46 :985, 1965. 18. Koga, A.: Morphogenesis of intrahepatic bile ducts of the human fetus: light and electron microscopic study. Z. Anal. Entwicklungsgesch., 135:156,1971. 19. Ma, M. H., and Biernpica, L.: The normal human liver cell: cytochemical and ultrastructural studies. Am.]. Pathol.,62:353, 1971. 20. Edmondson, H. A.: Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology, Fascicle 25: Washington, D.C., Armed Forces Institute of Pathology, 1958. 21. Carancis, J. C., Tang, T., Panares, R., and Jurevics, 1.: Hepatic adenoma: biocherriical and electron microscopic study. Cancer, 24: 560.1969. 22. Phillips, M. J., Langer, B., Stone, It, Fisher, M. M., and Ritchie, S.: Benign liver cell tumors: classification and ultrastructural pathology. Cancer. 32:463, 1973. 23. Palubinskas, A. J, Baldwin, J., and McCormack, K, R.: Liver-cell adenoma. Angiographic findings and report of a case. Radiology, 89:444, 1967. 24. Kay, S., and Schatzki, P. F.: Ultrastructure of a benign liver cell adenoma. Cancer, 28:755, 1971. 25. Mays, E. T., Christopherson, W. M., and Barrows, G. H.: Focal nodular hyperplasia of the liver: possible relationship to oral contraceptives. Am. J. Clin. Pathol., 61 :735, 1974. 26. O'Sullivan, J. P., and Wilding', R P.: Liver hamartomas in patients on oral contraceptives. Br. Med . .J.,3:7, 1974. 27. Arneriks, J. A., Thompson, N. W., Frey, C. F., Appelman, H, D.; and Walter, J. F.: Hepatic cell adenomas, spontaneous liver rupture, and oral contraceptives. Arch. Surg., 1l0:548, 1975. 28. Benson. C. D., and Penberthy, G. C.: Surgical excision of primary tumor of liver (hamartoma) in infant seven months old with recovery. Surgery, 12:881, 1942. 29. Franklin, R. G., and Downing, C. F.: Primary liver tumors. Am. ]. Surg., 73:390, 1947. 30. Kay, S., and Talbert, P. C.: Adenoma of the liver, mixed type (hamartoma). Report of two cases. Cancer, 3 :307, 1950. 31. Ladd, W. E., and Gross, R. E.: Abdominal Surgery of Infancy and Childhood. Philadelphia, W. B, Saunders Company, 1941, pp. 289-290. 32. Hunter, W. R: A case of benign hepatoma. Br. J. Surg., 36:425, 1949. 33. Bartlett, W. C., and Shellito, J. G.: Hamartoma of the liver. Surgery, 29:593, 1951. 34. Kolliker, A.: Manual of Human Histology. (Translators and Editors: Busk, G., and Huxley, T.) London, Sydenham Society, 1854, Vol. 2, pp. 132-134. 35. Bloom, W.: The embryogenesis of human bile capillaries and ducts. Am. l. Anat.. 36 :451, 1926.

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Department of Pathology Los Angeles County- University of Southern California Medical Center 1200 North State Street Los Angeles. California 90033 (Dr. Rhodes)

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