sign in sign up
<<
Home , Gross Anatomy, Hepatic diverticulum, Histology, Interlobular bile ducts

, , 1 AND

EMBRYOLOGY intimate contact with the portal At the beginning of fetal development (to- surrounding a portal branch (2). In the ward the latter part of the third week of gesta- weeks that follow, certain parts of the ductal tion), the hepatic diverticulum buds from the plates are duplicated by a second layer of cells, ventral . The hepatic diverticulum then to become double-layered ductal plates, which gives rise to the transverse septum (septum then dilate to form cylindrical structures to be transversum), a structure situated between integrated into the mesenchyme of the newly the pericardial and peritoneal cavities (1,2). formed portal region (fig. 1-1). When they are Mesenchymal elements of the transverse sep- integrated into the portal space, the immature tum, which already exist, are invested by tubules evolve into bile ducts that are embraced formed from hepatic endodermal by connective and gradually situated in cells (also known as hepatoblasts) of the he- their usual location in the portal tracts as the patic diverticulum to give rise to the liver buds portal tracts increase in size (2,7–9). (3). During fetal development the liver buds as a hematopoietic , which is composed of hepatocytic cords, venous-sinusoi- The liver can be divided into the right and dal plexus, and hematopoietic precursor cells, left lobes by the middle hepatic vein and a plane including Kupffer cells ( residing between the inferior vena cava and the gallblad- in liver). The umbilical vein supplies most of der fossa. Anteriorly, this division is visible by the during development of the liver. The the falciform . Viewed from the under remaining smaller amount of blood is supplied surface, there are also the quadrate lobe in the by the portal vein and hepatic . vicinity of the fossa and the caudate During fetal development, the placenta ex- lobe which in part encases the vena cava. ecutes the major functions performed by the There are dual afferent blood supplies in adult liver, including the absorption of nutri- the liver: hepatic artery and portal vein. The ents and the excretion of bile containing waste hepatic artery (branches from the celiac artery) products; bile by fetal liver is negligible transports 30 to 40 percent and the portal vein before birth. Nonetheless, the fetal liver produc- (drains the intestine) transports up to 70 per- es alpha-fetoprotein and other plasma , cent of the oxygenated blood to the liver. The synthesizes bile , and stores fat, glycogen, sinusoids then carry blood from hepatic iron, and copper. and portal to the terminal hepatic , The anterior portion of the hepatic diver- and subsequently through the hepatic vein to ticulum forms the liver and intrahepatic bile the inferior vena cava. ducts, while the posterior portion gives rise Functionally, the liver is better divided into to the gallbladder and extrahepatic bile ducts eight segments based on the blood supply, (2,4–6). The ultimate formation of intrahepatic known as the Couinaud classification, or Cou- bile ducts occurs late during development, and is inaud scheme (fig. 1-2). The segments are num- completed after birth, during the first year of life. bered in Roman numerals I to VIII. ­Segment I The development of small intrahepatic bile ducts essentially represents the caudate lobe, which begins when the ductal plate is formed, which drains directly into the inferior vena cava. Seg- is a single-layered sheath of small flat epithelial ments II to VIII are then numbered in a clockwise cells assembled by the periportal hepatoblasts in manner in a frontal plane beginning superiorly

1 Tumors of the Liver

Figure 1-1 FETAL LIVER Left: The embryonic ductal plate, composed of cytokeratin-rich cells, forms a layer that surrounds the portal area. This immunostain for cytokeratin (CK) 18 shows that the ductal plate is discontinuous and in a few places forms a double layer of cells with small lumina. Right: Higher magnification of another portal area shows the bile forming from the ductal plate, which will eventually disappear as the liver grows.

Figure 1-2 SEGMENTAL ANATOMY OF THE LIVER The segments, designated by Ro­ man numerals, can be resected surgically­­ because each is sup­ plied by a major branch of the hepatic artery and portal vein and drained by a major tributary of the hepatic vein.

from the left lobe. These segments are bounded ing to the Couinaud scheme allows the surgical by the three main branches of the hepatic veins: removal of a single segment, or two or more the left, middle, and right hepatic veins. Each adjacent segments en bloc, in such a fashion to segment drains into branches of the hepatic veins avoid damaging the remaining segments. The and then into the inferior vena cava. Overall, seg- Couinaud scheme also serves as a common ter- ments I to IV represent the functional left lobe, minology for communicating among physicians whereas segments V to VIII are considered the of different disciplines:­ surgeons, hepatologists, functional right lobe. Division of the liver accord- oncologists, radiologists, and pathologists (10).

2 Embryology, Histology, and Anatomy

Figure 1-3 HISTOLOGIC ORGANIZATION OF THE LIVER Left: Hepatic Architecture. Two views of the architecture of the liver as seen in microscopic sections. The lobules have a central vein at the center and portal spaces at the corners. A cross section of an superimposed on two lobules shows that zone 3 tends to be centrilobular, zone 2 midzonal, and zone 1 periportal, but all three are crescent shaped and may extend into other parts of the classic lobule. Bottom: Liver Blood Flow. Figure from “Gastrointestinal­ Tract—Liver Development” from embryology. med.unsw.edu.au.

portal tracts at the center. The spherical area of HISTOLOGIC ORGANIZATION those surrounding the portal tract The liver is structurally organized into pa- is referred to as zone 1, which has the richest renchymal, vascular, bile ductal, and interstitial oxygenated blood. The area outside of zone 1 components (11). Traditionally, the smallest is referred to as zone 2. Zone 3 is further out, functional unit has been conceptualized as corresponding to the region surrounding the the hepatic lobule or three dimensionally as terminal hepatic vein, where the oxygen con- the hepatic acinus, as defined by Rappaport tent in blood is the lowest (fig. 1-3). (12). Most oxygenated blood flows from the The two-dimensional concept of the lobule, terminal branches of portal veins and hepatic as seen on slides, serves the purpose of histo- arteries in the portal tracts, via the sinusoids to logic visualization, but zonal subdivision of the supply the hepatocytes, and finally draining acinus incorporates the physiologic concept into the terminal branches of the hepatic (cen- into histologic organization and facilitates the tral) veins at the peripheral part of the acinus recognition of certain liver injury patterns. (11). The acinus can also be conceptualized as These patterns include the gradual increasing a three-dimensional­ spherical structure with vulnerability to ischemic and toxic/metabolic

3 Tumors of the Liver

Figure 1-4 HEPATOCYTES AND ENDOTHELIAL CELLS Left: Normal hepatocytes are polyhedral cells arranged in plates that are one thick. They have granular, and usually one nucleus. The sinusoids between the hepatocytes are lined by inconspicuous endothelial cells. Right: The hepatocytic plates are normally one cell layer in thickness and are separated by the sinusoidal space (). injuries from zone 1 through zone 2 to zone 3, Bile ductules and canals of Hering are struc- as well as the distinction between adult nonal- tures at the periphery of the portal tracts and coholic steatohepatitis (zone 3 accentuated) and are not conspicuous by hematoxylin and pediatric nonalcoholic steatohepatitis (zone 1 (H&E) stain in normal liver. They are the con- accentuated) (13–15). duits between the biliary tree and Hepatocytes are formed in plates of one cell canaliculi. The canals of Hering drain bile from in thickness, which can be highlighted by a bile canaliculi into bile ductules, and then into reticulin stain (fig. 1-4, right). The hepatocytic the interlobular bile ducts. Canals of Hering plates are organized in a radial fashion between are important for liver regeneration since the the portal tracts and terminal hepatic venules hepatic progenitor cells reside here (16,17). (fig. 1-5), and are separated by sinusoids lined by endothelial cells, with oxygenated blood HISTOLOGY flowing from the portal tracts to the terminal Cells of the Liver hepatic venules. The radial alignment is most pronounced in the hepatocyte plates surround- Hepatocytes. Hepatocytes, which originate ing the terminal hepatic venules. In normal from endoderm, comprise the primary cell pop- liver, the portal tracts are composed of at least ulation in liver, accounting for 75 to 80 percent one hepatic artery branch, one portal vein of the liver volume (18). They are hexagonal or branch, and one interlobular (fig. 1-6). polyhedral in cross section, and have an eosin- The boundary between the portal tracts and the ophilic cytoplasm containing a centrally placed first layer of hepatocytes in the parenchyma is round nucleus; occasional hepatocytes may be termed the limiting plate. binucleatic. In the adult liver, hepatocytes are

4 Embryology, Histology, and Anatomy

Figure 1-5 Figure 1-6 HEPATIC ARCHITECTURE PORTAL TRACT Plates of hepatocytes extend from the portal area (lower A normal portal tract has at least one portal vein, one left) to the terminal hepatic or central vein (upper hepatic artery, and one bile duct. The interlobular bile duct right). Blood that enters the liver through branches of the is approximately the same diameter as the hepatic artery portal vein and hepatic artery perfuses the sinusoids and and is approximately the same distance as its own diameter exits through tributaries of the hepatic vein. away from it. aligned as anastomosing plates, normally one cell layer in thickness (fig. 1-4). The hepatocytic plates are separated by sinusoids, in which the oxygenated blood flows from the portal tracts to the terminal hepatic venules. Bile is produced exclusively by hepatocytes and secreted into the bile canaliculi, which are gutter-like structures between two or three adja- cent hepatocytes in the hepatocytic plates (11). The canalicular surface is lined by glycoprotein I, which cross reacts with polyclonal carcinoembry- onic antigen (CEA), an immunohistochemical marker specific for hepatocytic differentiation (fig. 1-7), although its sensitivity is not optimal and its interpretation requires experience. Can- alicular is also observed using a CD10 immunostain (19). Immunohistochemical stains for cytokeratin (CK) 8 and 18 are positive in he- patocytes, as is CAM5.2 (20). Since the hepatocytes are rich in urea cycle proteins, against some urea cycle have been used widely as hepatocytic markers, such as hepatocyte paraf- fin-1 (HepPar1) (21) and arginase-1 (22). Various Figure 1-7 cytoplasmic contents, pigments, and materials are also present within the hepatocytes, including HEPATOCYTES fat, glycogen, bile, lipofuscin, and hemosiderin. Canalicular structures between the hepatocytes are However, they are not always seen nor are they highlighted by polyclonal carcinoembryonic antigen (CEA) due to cross reaction with the glycoprotein on the absolutely specific for hepatocytic differentiation. canalicular surface.

5 Tumors of the Liver

Figure 1-8 Figure 1-9 INTERLOBULAR BILE DUCTS PERIBILIARY GLANDS Lining cells of the interlobular bile ducts are cuboidal Small glands in the walls of large bile ducts are composed and form a circular structure in cross section. Their nuclei of small acini of cuboidal cells with clear cytoplasm. are round and regular, without prominent nucleoli.

Biliary Epithelial Cells. The lining epithe- in the hilar bile ducts, , and periamp- lial cells of the septal or larger intrahepatic ullary areas (24–28). Peribiliary glands are com- bile ducts are tall columnar to cuboidal, while posed of glandular and branched tubuloalveolar those of the interlobular bile ducts are typically structures that form small acini that surround cuboidal (fig. 1-8). These cells are encased by a the intrahepatic and extrahepatic large bile layer of periodic –Schiff (PAS)-positive base- ducts. The glandular cells are cuboidal, clear ment membrane and are further surrounded­ by (fig. 1-9), and seromucinous in , secreting ­ of variable amount, depend- lactoferrin and lysozyme (26). ing on the size of the bile ducts. The interlobular Ductular Cells. Bile ductules are also known bile duct and hepatic artery are typically adja- as cholangioles. The terms bile ductules and ca- cent to each other, with a similar diameter and nals of Hering are sometimes used interchange- a distance apart approximately the same as their ably, however, they represent two different own diameters. The bile ducts are connected physiologic and histologic structures. The canals to the bile canaliculi via the canals of Hering. of Hering are the physiologic link between the On cross section, the configuration of the bile biliary tree and hepatocyte canaliculi (29). They duct appears as a chain of pearls (fig. 1-8). Bile are lined partially by cholangiocytes and par- ductal cells express CK7 and CK19, reflected tially by hepatocytes. They continue into bile by immunohistochemical staining. Like the ductules, which represent the conduits between hepatocytes, they also express CK8 and CK18. canals of Hering and the interlobular bile ducts. Peribiliary Gland Cells. Peribiliary glands Bile ducts are lined entirely by cholangiocytes. are small accessory glands of the bile ducts in The bile ductules are situated at the edge of liver. They communicate with the lumens of the the portal tracts. They may also penetrate the intrahepatic and extrahepatic large bile ducts via limiting plate so they not only have an intra- specialized conduits (7,23,24), densely populated portal segment, but also have an intralobular

6 Embryology, Histology, and Anatomy

Figure 1-10 BILE DUCTULES A: The ductules, or cholangioles, are normally incon­ spicuous, but they become apparent and increased in number in reaction to various pathologic conditions. In this case of primary sclerosing cholangitis, the ductules are apparent and increased in number in reaction to biliary obstruction. B: Immunohistochemical staining for CK19 highlights the reacting ductules. C: Ductular reaction in a case of submassive hepatocellular necrosis due to acetaminophen overdose. The ductules reflect a regenerative phenomenon in response to liver injury.

segment (11,29). Unlike the interlobular bile circulating cells such as marrow-derived), duct, the bile ductules are not accompanied or biliary of hepatocytes (rare) (29). by a hepatic artery branch (11). Their lumens Endothelial Cells. The endothelial cells are also smaller than those of interlobular bile lining the portal veins, hepatic arteries, and ducts (29). The lining cells of the canals of Her- terminal hepatic venules share the same prop- ing stain for CK7, CK19, and the hepatic stem erties and immunophenotype as the endothelial cell marker NCAM/CD56, demonstrating the cells lining the arteries, veins, and scattered presence of hepatic progenitor cells in other organs. Their single layer of flattened in these structures (16,17). endothelial cells is attached above a basement Ductular reaction is a phenomenon seen in membrane and lines the vascular spaces of these diseased liver, either acute or chronic disease (fig. vessels. They are immunoreactive to antibodies 1-10). It is a reaction of ductular phenotype, but against CD31, CD34, and factor VIII-related not necessarily of ductular origin (29), as it may antigen (von Willebrand factor). arise from proliferation of preexisting cholan- In contrast, endothelial cells lining the sinu- giocytes, progenitor cells (either local and/or soidal spaces do not have a basement membrane

7 Tumors of the Liver

Figure 1-11 Figure 1-12 SINUSOIDAL ENDOTHELIAL CELLS KUPFFER CELLS The endothelial cells lining the sinu­soidal spaces are Kupffer cells enlarge and become apparent when they inconspicuous (arrows). engulf and phagocytose debris resulting from liver injury. They are highlighted by a CD68 immunostain.

(fig. 1-11). In normal liver, the sinusoidal spaces enlarge and become noticeable when they en- are fenestrated and are lined by endothelial cells gulf and phagocytose debris resulting from liver that are immunohistochemically nonreactive to injury (fig.­ 1-12). Hemosiderin pigments may CD31 or CD34. The fenestration allows plasma be deposited in Kupffer cells, due to secondary to be transported between the sinusoidal spaces , or more rarely, hereditary hemo- and the hepatocytes underneath the subendo- chromatosis due to in the SLC40A1/ thelial space of Disse. When there is neoplastic ferroportin 1 gene (33). Lipofuscin pigment may change of the hepatocytes, the fenestration is also appear in Kupffer cells. decreased, and the sinusoidal endothelial cells Kupffer cells are variably PAS positive and become reactive to CD31 or CD34, a phenom- diastase resistant since they contain many ly- enon known as capillarization of the sinusoids. sosomes. They are also positive for These changes are also observed in preneoplastic markers such as CD68 (KP1). , i.e., dysplastic nodules (30–32). Capillar- Hepatic Stellate Cells. The compartment ization also occurs in with chronic injury between the hepatocyte cytoplasmic membrane or cirrhosis, beginning at the periportal region and the sinusoidal space, underneath the fenes- and extending to the hepatic lobules, although trated sinusoidal endothelial cells, is the space the changes are not as significant as in neoplasia. of Disse, where hepatic stellate cells reside. A Kupffer Cells. Kupffer cells are specialized number of synonyms were previously used for macrophages of the mononuclear phagocyte these cells, such as Ito cells, fat-storing cells, system that line the walls of the sinusoidal perisinusoidal cell lipocytes, and parasinusoidal spaces. Normally they are not prominent, but cells, but the preferred nomenclature by the

8 Embryology, Histology, and Anatomy

Figure 1-13 HEPATIC STELLATE CELLS Left: Hepatic stellate cells are identified with an immunostain for . Right: The hepatic stellate cells become conspicuous in hepatotoxicity due to hypervitaminosis A, which shows bubbly cells due to the deposition of fat in the cytoplasm, with hyperchromatic and scalloped nuclei. consensus of investigators studying this cell is as inhibition of the breakdown of matrix pro- (34). teins, hence leading to liver (36). Within the subendothelial spaces of normal Pit Cells. Another cell residing in the space liver, these cells store vitamin A (retinoid) drop- of Disse is the pit cell. Pit cells are large granule-­ lets in their cytoplasm (35). In their quiescent containing lymphoid cells possessing natural­ phase, they are not conspicuous in formalin-fixed killer cell properties that are liver specific (37). normal liver, but may become discernible by im- Pit cells are not readily identifiable under light munohistochemistry using anti-smooth muscle , but have been characterized by actin (fig. 1-13, left) or anti- antibodies. electron microscopy as cells containing mul- Hepatic stellate cells are also prominent during tivesicular -related dense granules and hepatotoxicity associated with hypervitaminosis rod-cored vesicles (38). A, becoming bubbly cells due to the deposition Inflammatory Cells. In normal liver, in- of fat in the cytoplasm, with hyperchromatic flammatory cells are inconspicuous, except and scalloped nuclei (fig. 1-13, right). for occasional lymphocytes, Kupffer cells, and Hepatic stellate cells are responsible for he- in the sinusoids. The portal tracts patic fibrogenesis. They can transform into my- have few lymphocytes and macrophages, and ofibroblasts when they are activated in response their number appears to correlate with age, to chronic liver disease with activated TGF-b likely reflecting a remnant response to previous and other signaling pathways. This phenotypic injuries in the liver. change triggers a series of accumulation as well

9 Tumors of the Liver

REFERENCES

1. Tremblay KD, Zaret KS. Distinct of 14. Schwimmer JB, Behling C, Newbury R, et al. endoderm cells converge to generate the embry- of pediatric nonalcoholic fatty onic liver bud and ventral foregut tissues. Dev liver disease. Hepatology 2005;42:641-649. Biol 2005;280:87-99. 15. Yeh MM, Brunt EM. Pathological features of fatty 2. Strazzabosco M, Fabris L. Development of the bile liver disease. Gastroenterology 2014;147:754-764. ducts: essentials for the clinical hepatologist. J 16. Theise ND, Saxena R, Portmann BC, et al. The Hepatol 2012;56:1159-1170. canals of Hering and hepatic stem cells in hu- 3. Houssaint E. Differentiation of the mouse hepatic mans. Hepatology 1999;30:1425-1433. primordium. I. An analysis of tissue interac- 17. Turner R, Lozoya O, Wang Y, et al. Human he- tions in hepatocyte differentiation. Cell Differ patic stem cell and maturational liver lineage 1980;9:269-279. biology. Hepatology 2011;53:1035-1045. 4. Tan J, Hytiroglou P, Wieczorek R, et al. Immu- 18. Zhou Z, Xu MJ, Gao B. Hepatocytes: a key cell nohistochemical evidence for hepatic progenitor type for innate immunity. Cell Mol Immunol cells in liver diseases. Liver 2002;22:365-373. 2016;13:301-315. 5. Roskams T, Desmet V. Embryology of extra- and 19. Loke SL, Leung CY, Chiu KY, Yau WL, Cheung intrahepatic bile ducts, the ductal plate. Anat KN, Ma L. Localisation of CD10 to biliary cana- Rec (Hoboken) 2008;291:628-635. liculi by immunoelectron microscopical exam- 6. Lemaigre FP. Mechanisms of liver development: ination. J Clin Pathol 1990;43:654-656. concepts for understanding liver disorders and 20. van Eyken P, Sciot R, van Damme B, de Wolf- design of novel therapies. Gastroenterology Peeters C, Desmet VJ. Keratin immunohisto- 2009;137:62-79. chemistry in normal human liver. Cytokeratin 7. Nakanuma Y, Hoso M, Sanzen T, Sasaki M. Mi- pattern of hepatocytes, bile ducts and acinar crostructure and development of the normal and gradient. Virchows Arch A Pathol Anat Histo- pathologic in humans, including blood pathol 1987;412:63-72. supply. Microsc Res Tech 1997;38:552-570. 21. Butler SL, Dong H, Cardona D, et al. The antigen 8. Libbrecht L, Cassiman D, Desmet V, Roskams for Hep Par 1 is the urea cycle T. Expression of neural cell adhesion carbamoyl phosphate synthetase 1. Lab Invest in human liver development and in congenital 2008;88:78-88. and acquired liver diseases. Histochem Cell Biol 22. Yan BC, Gong C, Song J, et al. Arginase-1: a new 2001;116:233-239. immunohistochemical marker of hepatocytes 9. Fabris L, Cadamuro M, Libbrecht L, et al. Epi- and hepatocellular . Am J Surg Pathol thelial expression of angiogenic growth factors 2010;34:1147-1154. modulate arterial vasculogenesis in human liver 23. Terada T, Nakanuma Y, Ohta G. Glandular ele- development. Hepatology 2008;47:719-728. ments around the intrahepatic bile ducts in man; 10. Majno P, Mentha G, Toso C, Morel P, Peitgen their and distribution in normal HO, Fasel JH. Anatomy of the liver: an outline livers. Liver 1987;7:1-8. with three levels of complexity—a further step 24. Igarashi S, Sato Y, Ren XS, Harada K, Sasaki M, towards tailored territorial liver resections. J Nakanuma Y. Participation of peribiliary glands Hepatol 2014;60:654-662. 10. Zhou Z, Xu MJ, in biliary tract pathophysiologies. World J Hepa- Gao B. Hepatocytes: a key cell type for innate tol 2013;5:425-432. immunity. Cell Mol Immunol 2016;13:301-315. 25. Tsuneyama K, Kono N, Yamashiro M, et al. Ab- 11. Suriawinata A, Thung S. Liver. In: Mills SE, ed. errant expression of stem cell factor on biliary Histology for pathologists, 4th ed. Philadelphia: epithelial cells and peribiliary infiltration of Lippincott Williams & Wilkins; 2012:733-758. c--expressing mast cells in hepatolithiasis 12. Rappaport AM. The structural and functional and primary sclerosing cholangitis: a possi- unit in the human liver (liver acinus). Anat Rec ble contribution to bile duct fibrosis. J Pathol 1958;130:673-689. 1999;189:609-614. 13. Kleiner DE, Brunt EM, Van Natta M, et al. Design 26. Nakanuma Y, Zen Y, Portman B. Diseases of the and validation of a histological scoring system bile ducts. In: MacSween RN, Burt AD, Portman for nonalcoholic . Hepatology B, Ferrell LE, eds. MacSween’s of the 2005;41:1313-1321. liver. Edinburg: Churchill Livingstone/Elsevier; 2012:491-562.

10 Embryology, Histology, and Anatomy

27. Terada T, Nakanuma Y, Ohta G. Glandular ele- 32. Bedossa P, Hytiroglou P, Yeh M. Vascular Dis- ments around the intrahepatic bile ducts in man; orders. In: Burt A, Ferrell LD, Hubscher S, eds. their morphology and distribution in normal MacSween’s pathology of the liver, 7th ed: Phil- livers. Liver1987;7:1-8. adelphia: Elsvier; 2018:636-672. 28. Lim JH, Zen Y, Jang KT, Kim YK, Nakanuma Y. 33. Pietrangelo A. The ferroportin disease. Blood Cyst-forming intraductal papillary Cells Mol Dis 2004;32:131-138. of the bile ducts: description of imaging and 34. Friedman SL. Hepatic stellate cells: protean, pathologic aspects. AJR Am J Roentgenol multifunctional, and enigmatic cells of the liver. 2011;197:1111-1120. Physiol Rev 2008;88:125-172. 29. Roskams TA, Theise ND, Balabaud C, et al. No- 35. Wake K. “Sternzellen” in the liver: perisinusoidal menclature of the finer branches of the biliary cells with special reference to storage of vitamin tree: canals, ductules, and ductular reactions in A. Am J Anat 1971;132:429-462. human livers. Hepatology 2004;39:1739-1745. 36. Hernandez-Gea V, Friedman SL. Pathogenesis of 30. Ruck P, Xiao JC, Kaiserling E. Immunoreactivity liver fibrosis. Annu Rev Pathol 2011;6:425-456. of sinusoids in hepatocellular . An 37. Wisse E, Luo D, Vermijlen D, Kanellopoulou C, immunohistochemical study using lectin UEA- De Zanger R, Braet F. On the function of pit cells, 1 and antibodies against endothelial markers, the liver-specific natural killer cells. Semin Liver including CD34. Arch Pathol Lab Med 1995;119: Di. 1997;17:265-286. 173-178. 38. Nakatani K, Kaneda K, Seki S, Nakajima Y. Pit cells 31. Park YN, Yang CP, Fernandez GJ, Cubukcu O, as liver-associated natural killer cells: morphol- Thung SN, Theise ND. Neoangiogenesis and si- ogy and function. Med Electron Microsc 2004; nusoidal “capillarization” in dysplastic nodules 37:29-36. of the liver. Am J Surg Pathol 1998;22:656-662.

11