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The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of
the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an interna-
tionally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a
standardized nomenclature and differential diagnosis for classifying microscopic lesions observed in the hepatobiliary system of laboratory rats and
mice, with color microphotographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available
for society members electronically on the internet (http://goreni.org). Sources of material included histopathology databases from government,
academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure
to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions of the hepatobiliary system in laboratory
animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to
increase and enrich international exchanges of information among toxicologists and pathologists.
Keywords: diagnostic pathology; hepatobiliary system; histopathology; liver; nomenclature; rodent pathology.
Address correspondence to: Bob Thoolen, Global Pathology Support, Benoordenhoutseweg 23, The Hague 2596 BA, Netherlands; e-mail: bob.thoolen@
gpstoxpath.com.
Financial Disclosure: No money was paid for the preparation of this manuscript. During the construction of this manuscript salaries of contributors were paid by
their respective companies. None of the content of the manuscript contains any information that could be patentable or claimed as intellectual property of the
contributors or their respective companies.
Abbreviations: AE1/AE3, Two clones of anti-cytokeratin monoclonal antibodies; a.k.a., Also known as; AS, Anterior Segment; a-SMA, a-smooth muscle actin;
Bcl-2, B-cel lymphoma 2 - apoptosis regulator protein; BSTP, British Society of Toxicological Pathologists; CD (31, 34, 68), Cluster differentiation (31, 34, 68);
CEA, Carcinoembryonic antigen; CK, Cytokeratin; ED1, Rat homologue of human CD68; EM, Electron microscopy; ESTP, European Society of Toxicologic
Pathology; Factor VIII, Blood clotting factor/anti-hemophilic factor; F4/80, Rat anti-mouse macrophage monoclonal antibody; H&E, Hematoxylin and Eosin;
IHC, Immunohistochemistry; JSTP, The Japanese Society of Toxicologic Pathology; Ki-67, Nuclear protein associated with proliferation; LAMP, Lysosome-
associated protein; LLL, Lef lateral lobe; LML, Left medial lobe; MIB-1, Monoclonal antibody that detects K-67 antigen on formalin fixed paraffin embedded
sections; MS, Middle Segment; NTP, National Toxicology Program; NLDC-145, Rat anti-mouse dendritic cell monoclonal antibody; NOS, Not otherwise
specified; OX-6, MHC Class II Ia antibody; PAS, Periodic acid-Schiff; PC, Caudate Process; PCNA, Proliferator Cell Nuclear Antigen; PCR, Polymerase
Chain Reaction; PP, Papillary Process; PPA, Processus papillaris anterior; PPAR, Peroxisome Proliferator-Activated Receptor; PS, Posterior Segment; RER,
Rough Endoplasmic Reticulum; RLL, Right lateral lobe; RML, Right medial lobe; SRA-E5, Mouse monoclonal anti-macrophage antibody for Scavenger
Receptor A; SOPs, Standard Operating Procedures; STP, Society of Toxicologic Pathology.
5S
6S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
LLL ¼ Left lateral lobe; RLL ¼ Right lateral lobe; PC ¼ Caudate Process; LML ¼ Left medial lobe; RML ¼ Right medial lobe; PP ¼ Papillary Process; PPA ¼ Processus papillaris
anterior; AS ¼ Anterior Segment; MS ¼ Middle Segment; PS ¼ Posterior Segment.
Gray, Williams, and Bannister (1995); Browning, Schroeder, and Berringer (1974); König, Sautet, and Liebich (2004); Rajtová, Horák, and Popesko (2002); Vons et al., 2009.
a
(Number of lobes / Number of lobes including segments).
1. Blood Supply and Bile Flow lymphocytes that have natural killer activity and are primarily
located in periportal areas (Wright and Stacey 1991).
The liver has a dual blood supply, the hepatic portal vein and
the hepatic artery. The hepatic artery supplies oxygenated
3. Immunohistochemistry
blood. Approximately 75% of the blood is delivered to the liver
via the hepatic portal vein that drains the spleen, stomach, Immunohistochemistry (IHC), utilizing fluorescent or chro-
intestines, and pancreas. Branches of the hepatic artery and mogen tagged antibodies, is a useful adjunct for identification
portal vein are seen in the portal triads along with bile ducts and of different cell types in the liver. Selected examples are pro-
are separated from the hepatic cords by a ‘‘limiting plate’’ of vided in Table 2.
hepatocytes. The bile ducts join to form the hepatic duct lead- Use of IHC can be helpful for diagnostic purposes and is
ing to the small intestine in rats and to the gallbladder in mice. common in human pathology where panels of immunohisto-
Blood flows from the portal areas to the central vein in the cen- chemical stains are used for supporting diagnoses. Not all com-
ter of each lobule while bile flows from the center of the hepa- mercially available preparations of a given antibody will react
tic lobule to the portal areas and on to the hepatic duct. the same way between different laboratories and between
different species. Furthermore, expertise is required for
2. Histology tissue handling to unmask cellular antigens that may be
cross-linked during tissue fixation. Diagnostic evaluation of
The two most commonly used descriptions for the structural
immunostains typically requires inclusion of both positive and
and functional units of the liver are the hepatic lobule (Kiernan
negative controls. The interpretations of IHC results are usually
1883) and the acinus (Rappaport et al., 1954) (Figure 2). The
performed in conjunction with histopathological findings and
structural unit, the hepatic lobule, is modeled on the blood flow
sometimes also with consideration of gross findings and/or
within the liver and is commonly used for descriptive pathol-
clinical pathology or other relevant study results.
ogy and morphological diagnoses. The functional unit, the
hepatic acinus, is modeled on blood flow and metabolism
IV. PHYSIOLOGY
within the liver. More recently a parenchymal unit in the liver
has been described as a cone-shaped three-dimensional struc- The liver is responsible for maintenance of many homeo-
ture comprised of approximately fourteen hepatic lobules sup- static and physiological functions. Liver size is governed both
plied and drained by common vascular tributaries (Malarkey by genetic factors and by the rate of biochemical activity to
et al. 2005; Teutsch, Schuerfeld, and Groezinger 1999; Teutsch maintain optimal functional mass. It is an organ system capable
2005). This parenchymal unit more closely explains the ran- of rapid responses to a variety of noxious stimuli. Following
dom size and shape distribution of the more classical hepatic loss of hepatocytes from stimuli such as transient toxic insult,
lobule as seen in a conventional two-dimensional histology infection, or partial hepatectomy, the liver is rapidly restored
slide. It also provides a basis for understanding the heteroge- to its optimal mass to maintain normal function.
neous response of various hepatic lobules to chemical insult. Liver functions are complex and diverse including endo-
In addition to hepatocytes, the liver is comprised of a variety crine and exocrine activity, metabolism, conjugation, detoxifi-
of cell types, including biliary cells, endothelial cells, Kupffer cation, and hematopoiesis in early embryonic and fetal
cells, Ito cells (stellate cells), fat-storing cells, and pit cells in development (Harada et al. 1999). The liver is continuously
addition to hematopoietic cells in the sinusoids and blood ves- exposed to all ingested substances absorbed through the intest-
sels. Polyhedral hepatocytes comprise approximately 60% of inal tract via the portal vein and systemically via the arterial
the liver arranged in plates or cords that radiate from the central blood supply. A pivotal hepatic function in toxicologic pathol-
vein to the portal areas. In two-dimensional sections they are ogy is xenobiotic biotransformation that leads to detoxification
typically one cell layer thick and form anastomoses (Miyai of materials absorbed in the intestinal tract. Xenobiotic
1991). On one surface they are separated from the sinusoidal metabolism by hepatocytes can occur by phase I (often the
wall by a peri-sinusoidal space, the space of Disse, where cytochrome oxidase series) and phase II reactions (often the
they are exposed to tissue fluids. On the opposite side of formation of the water soluble glucuronide) (Graham and Lake
the hepatocyte bile canaliculi are formed with hepatocytes in 2008; Martignoni, Groothuis, and de Kanter 2006). Hepatic
an adjacent hepatic cord. Desmosomes, gap junctions, and metabolic processes may also cause indirect toxicity by gener-
stud-like protrusions connect contiguous hepatocytes within a ating electrophilic species capable of reacting with proteins,
cord. Biliary cells form bile ducts in the portal areas and nucleic acids, and other cytoplasmic organelles (Xu, Li, and
constitute the portal triad with a hepatic artery and a portal Kong 2005). Intrinsic and induced enzymes responsible for
vein. Fenestrated endothelial cells line the sinusoids and hepatic function may be unevenly distributed throughout the
synthesize prostaglandins. Kupffer cells are a self-renewing hepatic lobule and between the different lobes (Greaves 2007).
fixed macrophage comprising approximately 10% of all liver The presence of background changes and undercurrent dis-
cells (Eustis et al. 1990). Kupffer cells are phagocytic, secrete ease states affects the hepatic and biliary morphology, for
mediators of inflammation, and catabolize lipids and proteins. Ito example, caloric restriction diminishes hepatocellular size and
cells (stellate cells) are peri-sinusoidal cells that store vitamin A can make interpretation of test-article–related changes more
and are also a major source of collagen in the liver. Pit cells are challenging. Other factors that influence the liver morphology
8S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
TABLE 2.—Selected immunohistochemical stains that have been Most toxicologic pathologists use a common grading scale
used to identify different cell types in liver sections. such as marginal or minimal, slight, moderate, marked, and
severe for inflammatory, necrotizing, or other degenerative and
Immunohistochemical stains of liver cells responsive lesions. Tissue-specific locators are often used, such
Cell type Antibody as portal, periportal, midzonal, centrilobular, hilar, ductal, peri-
ductal, peri-canalicular, or subcapsular to indicate the lesion
Hepatocytes CK8, CK18
distribution within the liver. Focal, multifocal, and diffuse are
Bile canaliculi Polyclonal CEA
Bile duct epithelium CK7, CK19, AE1/AE3 commonly used modifiers in the morphological diagnosis for
Endothelial cell Factor VIII, CD31, CD34 distribution parameters. Based on the formal definition, a focal
Exudate macrophages (monocytes) ED1 lesion refers to one specific area, or focus, whereas multifocal
Kupffer cells CD68, F4/80, ED2, SRA-E5 refers to more than one focus (foci). However, some patholo-
Hepatic stellate cells (activated), a-SMA
gists use focal for both focal and multifocal, referring to the
myofibroblasts and smooth muscle cells
Dendritic cells NLDC-145, OX-6 nature of the lesion rather than its actual distribution and using
Oval cells a-fetoprotein (AFP), CK20 grading to reflect the extent of the multifocality. Schemes for
Apoptosis Bcl-2, Caspase 3 and 7 scoring lesion severity vary widely and no single system is
Proliferation markers Ki67/MIB-1, PCNA likely to be accepted by all pathologists. While a sample grad-
ing scheme for focal and multifocal liver lesions is provided in
Geller, Dahll, and Alsabeh (2008); Malhotra, Sakhuja, and Gondal (2004); Hurlimann
and Gardiol (1991); Davenport et al. (2001); Kashiwagi, Kaidoh, and Inoué (2001); Faa Table 3, this should not be regarded as a universal or specific
et al. (1998). INHAND-recommended grading scheme.
are: body weight loss, blood flow, food intake, vascular and TABLE 3.—A sample grading scheme for focal and multifocal
hemodynamic changes, timing and duration of exposure, with- liver lesions (modified from Hardisty and Eustis 1990; World
drawal effects, and functional heterogeneity. Functional hetero- Health Organization 1978; Derelanko 2000).
geneity expresses itself via differences in metabolism, oxygen
supply, b-oxidation, amino acid metabolism, gluconeogenesis, Proportion of Quantifiable
Severity liver affected Grade finding
glycolysis, ureagenesis, liponeogenesis, and bile acid and biliru-
bin secretion. These factors can affect occurrence of nonproli- Marginal or minimal Very small amount 1 1-2 foci
ferative as well as proliferative liver lesions in rodents. Slight or few Small amount 2 3-6 foci
Moderate or several Medium amount 3 7-12 foci
Marked or many Large amount 4 >12 foci
V. LIVER NECROPSY AND TRIMMING PROTOCOL Severe Very large amount 5 Diffuse
At necropsy, rat and mouse liver may be weighed and
individual liver lobes examined carefully for gross lesions. In VII. NOMENCLATURE, DIAGNOSTIC CRITERIA, AND DIFFERENTIAL
conventional preclinical rodent studies, gross lesions must be DIAGNOSIS
correlated with the histopathological findings. Liver-specific
A. Congenital Lesions
trimming protocols (see Figure 1) according to standard oper-
ating procedures (SOPs) are used (e.g., see Ruehl-Fehlert Introduction
et al. 2003). Dissected lobes and trimmed liver pieces can be
Developmental anomalies occasionally occur in the liver of
fixed in 10% neutral buffered formalin (no more than 1 cm
rodents. These malformations might be expressed in different
thick in 1:10 tissue: formalin).
forms and be of different origin. They mostly occur as isolated
effects and are considered by the pathologist in distinguishing
VI. GRADING OF LIVER LESIONS
background hepatic lesions versus xenobiotic-induced lesions
Interpretation of hepatic lesions in safety assessment studies that occur in rodent preclinical toxicity studies.
requires consideration of gross and microscopic findings,
hematology, clinical chemistry, and liver weights in the con- Hepatodiaphragmatic Nodule (Figures 3 and 4)
current control groups of animals and should take into account
Pathogenesis: Developmental alteration.
species and strain, age, caging, diet, and tissue sampling.
Many pathologists use a grading system to document lesion Diagnostic features:
severity. In toxicological pathology, the generation of ordinal
data using a scoring system allows statistical analysis for Visible grossly and tinctorially similar to normal
effects and trends (Gad and Rousseaux 2002). However, not all hepatic parenchyma.
grading systems are the same and may differ in how they incor- Rounded extensions usually of the medial lobe(s).
porate distribution, stage, and extent of lesions. The problem of Increased mitoses, cytological alterations, and
harmonization as it relates to lesion severity has been recog- nuclear alterations may be present.
nized and discussed in some detail (Hardisty and Eustis Linear chromatin structures with small lateral projec-
1990; World Health Organization 1978). tions are pathognostic.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 9S
indicative of more serious hepatic dysfunction but can also Differential diagnosis:
result from nutritional disturbances (Greaves 2007).
Specific xenobiotics can induce either macrovesicular or Fatty change—round clear vacuoles tend to be single
microvesicular lipidosis in humans (Kanel and Korula 2005). or multiple and discrete.
In animal studies, it is common to see a mixture of macrovesi- Glycogen accumulation—irregular and poorly
cular and microvesicular lipidosis. In those situations one can defined clear spaces in the cytoplasm (rarefaction)
either diagnose the most prevalent form or record the findings usually with centrally located nuclei; positive stained
as mixed. Commentary in the pathology narrative report might with periodic acid-Schiff staining.
be appropriate, especially if recording the most prevalent form
of lipidosis. Liver with admixed presence of glycogen and fatty Comment: Definitive diagnosis of phospholipidosis is not pos-
change can be observed (Figures 8 and 9). sible based strictly on H&E-stained liver sections. A diagnosis
Fatty change and necrosis may appear together although of cytoplasmic vacuolation of hepatocytes will typically be an
they may differ in proportion. A number of causes other than acceptable descriptive diagnosis. Since the cytoplasmic
xenobiotic exposure, such as chronic hepatic injury, diet, vacuolation may mimic microvesicular fatty change, a descrip-
metabolic and hormonal status, debilitation of animals, and tive diagnosis of cytoplasmic vacuolation is recommended in
fasting before necropsy, should be taken into consideration the absence of electron microscopy or special immunostaining.
in reviewing these changes (Vollmar et al. 1999; Katoh and Phospholipidosis can be induced by xenobiotics with a
Sugimoto 1982; Nagano et al. 2007; Denda et al. 2002). The cationic amphophilic structure (Halliwell 1997; Anderson and
distribution can be either diffuse (e.g., ethionine) or zonal Borlak 2006; Reasor, Hastings, and Ulrich 2006; Chatman
(e.g., centrilobular in CCl4; periportal in phosphorus toxicity; et al. 2009) (Figures 14 and 15). It is a lipid storage disorder
midzonal in choline deficiency). Inadequate fixation proce- seen when complexes between xenobiotics and phospholipids
dures may sometimes give rise to artifacts with microvesicu- accumulate within lysosomes. Phospholipidosis refers to a spe-
lar vacuolation, although mostly with less clear cytoplasm cific form of hepatic vacuolation with the occurrence of con-
(Li et al. 2003). centric membrane bound lysosomal myeloid bodies/lamellar
Focal fatty change can sometimes be seen spontaneously and bodies that can be confirmed by specific staining and electron
is usually described as such. A specific variation occurs near the microscopy (Hruban, Slesers, and Hopkins 1972; Obert et al.
attachment of the falciform ligament and gallbladder in mice and 2007) (Figure 16). Definitive diagnosis requires electron
is referred to as ‘‘tension lipidosis’’ (Harada et al. 1999) (Figures microscopy or positive immunostaining. Immunohistochem-
10 and 11). Spontaneous fatty change can differ between strains ical staining for a lysosomal-associated protein and adipophilin
and is a normal finding in BALB mice. Livers of these mice are may be used to differentiate phospholipidosis from conven-
typically paler than in other strains. Focal fatty change in the tional fatty change (Obert et al. 2007). Both preexisting neutral
liver of rodents has previously been categorized as vacuolated fat and phospholipids can be observed in combination. The
altered hepatic foci (Eustis et al. 1990), but current practice is macrovesicular and the microvesicular fatty change (vacuola-
to diagnose this change as focal fatty change rather than as a tion) generally located at the cell periphery stains positively for
focus of hepatic alteration (Figures 12 and 13). Oil Red-O and the membranes surrounding these lipid
Fatty change can also be observed in combination with other vacuoles stain positively for adipophilin (a protein that forms
hepatotoxic injuries (e.g., chronic liver toxicity, degeneration, the membrane around non-lysosomal lipid droplets) but neg-
inflammation, and necrosis) or nutritional disturbance (e.g., ative for LAMP-2 (a lysosome-associated protein) by immu-
diet, vitamin A excess) in both animals and man. Special stains nohistochemical techniques (Obert et al. 2007). This indicates
on cryostat sections can demonstrate fat (e.g., Oil red O or that this vacuolation was due to accumulation of non-
Sudan Black) (Jones 2002). lysosomal neutral lipid. Cytoplasmic microvesiculation
located centrally in hepatocytes that exhibit positive immuno-
histochemical staining for LAMP-2 (Figure 17) but is nega-
Phospholipidosis2 tive for Oil-Red-O and adipophilin is indicative of
phospholipid accumulation (Obert et al. 2007).
Synonym: Cytoplasmic vacuolation, foam cells.
Amyloidosis (Figures 18 and 19)
Pathogenesis: Induced by xenobiotics with a cationic ampho-
philic structure. Pathogenesis: Cellular process related to misfolding of protein.
Diagnostic features: Diagnostic features:
Multiple irregular to round clear membrane-bound Deposition of pale, homogeneous, amorphous eosi-
vacuoles. nophilic material.
Tends to be a diffuse change affecting hepatocytes. Deposition often peri-sinusoidal, periportal, or
involving blood vessel walls.
2
Electron microscopy or special staining needed for a definitive diagnosis. Localization is extracellular.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 11S
Comment: This is a rare condition in rats but is a more com- Spencer et al. 1997; Yasui, Yase, and Ota 1991; DePass
mon age-related phenomenon in hamsters and mice et al. 1986). Mineralization can sometimes be observed in
(Greaves 2007; BSTP 2007). The basis of the pathological combination with inflammation or neoplasia (Harada et al.
change is the cell’s inability to prevent protein misfolding, 1999; Kanel and Karuda 2005). Mineral deposits can be
to revert misfolded proteins to normal, or to eliminate mis- demonstrated by using additional stains (Alizarin Red, von
folded proteins by degradation. This can result in deposition Kossa) (Churukian 2002).
of potentially cytotoxic protein aggregates of amyloid as in
other protein aggregation diseases (Aigelsreiter et al. 2007).
The amyloid is predominantly composed of protein in a
Pigmentation (Pigment Deposition) (Figures 21–25)
beta-pleated sheet conformation.
The incidence of spontaneous amyloidosis usually Pathogenesis: Incidental occurrence and secondary to cellular
increases with age and is common in CD-1 mice (Harada and erythryoid breakdown products; lipid peroxidation of cel-
et al. 1996). Amyloid observed in the liver often is referred lular membranes; altered heme metabolism.
to as secondary amyloidosis (serum amyloid A protein) and
is seen in the sinusoids and within the portal vessel walls. Diagnostic features:
Hepatocytes adjacent to sinusoidal amyloid deposits are often
atrophic. A number of factors (e.g., species, age, strain, gen- Lipofuscin:
der, endocrine status, diet, stress, and parasitism) can influ-
ence the occurrence of amyloidosis (Beregi et al. 1987; Coe Pigment can be seen in hepatocytes as well as in
and Ross 1990; Lipman et al. 1993; Harada et al. 1996; Liu Kupffer cells.
et al. 2007). Other organs are often involved in the deposition May vary from pale yellow to deep granular
of amyloid (e.g., kidney, nasal submucosa, lamina propria brown.
intestines, heart, salivary gland, thyroid, adrenal cortex, lung, May be sudanophilic with autofluorescence under
tongue, testis, ovary, and aorta). ultraviolet light.
Amyloidosis can be confirmed with additional histo- Often located adjacent to bile canaliculi.
chemical staining (Congo red) where it shows pink-red stain-
ing and apple green birefringence under polarized light
(Vowles and Francis 2002; Kanel and Korula 2005) and by Iron/hemosiderin:
immunohistochemistry.
Can be yellow to brown.
May be finely granular.
Mineralization (Figure 20) Usually appears intracellularly in Kupffer cells and
hepatocytes.
Pathogenesis: Hypercalcemia secondary to diet or abnormal
calcium metabolism; hepatocellular necrosis (dystrophic
mineralization). Porphyrin:
cystic degeneration, that are more clearly established in tradi- formation (Gonzalez-Quintela et al. 2000; NTP Toxicology and
tional pathology literature. The preferred diagnosis will be Caracinogenesis Studies Ethylene Glycol 1993; Peters et al.
influenced by morphological features, conventional pathology 1983; Bruni 1960; Shea 1958; Omar, Elmesallamy, and Eassa
practice, and the experience of the pathologist. 2005; Lin et al. 1996), but is rarely used as a separate description
Glycogen accumulation in hepatocytes is a type of cytoplas- since a combination of findings is often present. Cytoplasmic
mic alteration manifested on H&E-stained paraffin sections as alteration reflecting plasma influx is an artifact seen in non-
clear spaces in the cytoplasm and a centrally located nucleus. exsanguinated rats in a postmortem time-dependent manner
Intracellular accumulation of glycogen is a normal physiological (Li et al. 2003) (see Figure 33).
response following food ingestion. Since rodents eat primarily in
the evening hours, the largest amount of glycogen will be present Degeneration, Hydropic (Figure 45)
during early morning hours. Intrahepatocyte glycogen is mobi-
Synonyms: Cytoplasmic alteration, cytoplasmic change, hydro-
lized throughout the day, initially being removed from centrilob-
pic change, cloudy swelling.
ular hepatocytes. Consequently the amount present varies
depending upon whether the animals were fasted and on the time
Pathogenesis: Intracytoplasmic fluid accumulation secondary
of necropsy during the day. Failure to accumulate glycogen
to disturbance of cell membrane integrity.
because of inanition or abnormal glycogen retention may result
from treatment-induced metabolic perturbations. Diagnostic features:
necrosis, may occur within hours after exposure to a xenobio- seen after anoxia, or exposure to tannic acid, chloroform, or
tic, and should not be diagnosed as single cell necrosis (apop- other hepatotoxic agents (Gopinath, Prentice, and Lewis
tosis). A more appropriate diagnosis for this situation is focal 1987). This zone (Rappaport zone 3) is particularly vulnerable
necrosis (see the following). to ischemic damage because of its low oxygen gradient and
generation of toxic metabolites due to high content of xenobio-
Necrosis, Focal/Multifocal (Figures 51–53) tic metabolizing enzymes (Comporti 1985; Walker, Racz, and
McElligott 1985).
Diagnostic features:
Diagnostic features:
Single or multiple foci of a few pale staining
hepatocytes. Early necrotic hepatocytes are swollen.
Usually retain normal morphological outline. Cytoplasm has increased eosinophilia.
May be associated with inflammation. Nucleus undergoing lysis, not pyknosis.
May have an irregular distribution but can also occur in May have a minimal associated inflammatory
the subcapsular areas with minimal or no inflammation. reaction.
Early lesions typically consist of three or four hepa- Can be accompanied by glycogen depletion, hydro-
tocytes, but as the lesions progress more hepatocytes pic degeneration, fatty change, hemorrhage, and
may be involved. ‘‘ballooning’’ of hepatocytes.
Subcapsular necrosis may sometimes be observed in
combination with hypertrophy. Midzonal (Figures 60–61)
Differential diagnosis: This necrosis is the least common form of zonal necrosis and
is mediated by specific toxicants (e.g., furan, concavalin-A,
beryllium) (Wilson et al. 1992; Boyd 1981; Seawright 1972;
Foci of extramedullary hematopoiesis—mature and/
or immature erythroid and myeloid cell aggregates Satoh et al. 1996; Cheng 1956). The location is considered
without accompanying hepatocyte necrosis. specific and has a metabolic basis.
Foci of inflammatory cell infiltrate—aggregates of Diagnostic features:
cells, usually mononuclear cells, in absence of obvi-
ous hepatocellular necrosis. Seen as a band of swollen and eosinophilic cells
Infectious disease (MHV, Ectromelia, Clostridium intermediate to the central vein (zone III) and the por-
pilliforme, Helicobacter hepaticus, Parvo virus, tal triad (zone I).
Noro virus)—a spectrum of acute to chronic active Nucleus undergoing lysis.
inflammation, degenerative, and proliferative changes Two to three cells in thickness in the middle of the
specific for the infectious disease entity. lobule.
Comment: Some pathologists use focal for both focal and mul- Periportal (Figure 62)
tifocal, referring to the nature of the lesion rather than its actual
distribution. A severity grade can be used to reflect the multi- Hepatic necrosis in the periportal zone is observed follow-
focal nature of the lesion. Focal, multifocal, and subcapsular ing a variety of agents (e.g., phosphorus, ferrous sulphate,
necrosis is occasionally seen in untreated rodents and may be allyl alcohol) (Kanel and Korula 2005; Atzori and Congiu
a terminal event potentially due to hypoxic change secondary 1996; Sasse and Maly 1991). Affected cells may encircle the
to impaired blood flow. Subcapsular necrosis has also been portal tract (Popp and Cattley 1991) and may be associated
reported from direct pressure secondary to gastric distention with inflammatory and other changes (Ward, Anver, et al.
and from some types of restraint (Parker and Gibson 1995; 1994; Ward, Fox, et al. 1994; NTP Technical Report on the
Nyska et al. 1992) Toxicology and Carcinogenesis Studies of a Binary Mixture
2006; NTP Technical Report on the Toxicology and Carcino-
Necrosis, Zonal (Centrilobular, Midzonal, Periportal, genesis Studies of 2, 3, 7, 8-tetracholorodibenzo-p-dioxin
Diffuse) 2006).
can also be induced by xenobiotics (Schoental and Magee are often referred to as simple or multiloculated biliary cysts
1959; Jones and Butler 1975; Singh et al. 2007; Nyska et al. (Goodman et al. 1994). Polycystic liver can be observed in
2002; Guzman and Solter 2002; Lalwani et al. 1997; Travlos the rat (Muff et al. 2006; Sato et al. 2006) and hamster (Percy
et al. 1996; Kari et al. 1995; Herman et al. 2002). In addition, and Barthold 2001), resembling Caroli’s disease in humans
multinucleated cells (formed by cell fusion rather than divi- (Clemens et al. 1980; Numan et al. 1986; Serra, Recalde, and
sion) can be formed in rats after administration of 2, 3, 7, 8- Martellotto 1987). The cysts seen in polycystic disease are mul-
tetrachloro-dibenzo-p-dioxin (Gopinath, Prentice, and Lewis tiple and seen diffusely throughout the liver and are of variable
1987; Jones and Butler 1975). Eosinophilic cytoplasmic inclu- size but generally large compared to the smaller biliary cysts.
sions may be seen in affected hepatocyte nuclei because of cell
membrane invaginations.
C. Inflammatory Cell Infiltrates and Hepatic Inflammation
Cysts, Biliary (Hepatic Cysts) (Figures 67–69) (Hepatitis)
Pathogenesis: More common in aging animals occurs as a Introduction
dilation of biliary structures.
A variety of focal, multifocal, and more generalized infiltra-
Diagnostic features: tions of inflammatory cells are frequently present in liver tis-
sue. Changes range from acute inflammatory cell infiltrate(s)
Range in size from small to very large. or occasional aggregates of lymphocytes/lymphohistiocytic
Single or multiple cysts. cells/foci of mononuclear cells without associated alterations
Macroscopically may contain clear to pale yellow of adjacent hepatocytes, to large panlobular patches of distinct
fluid. hepatocyte necrosis accompanied by polymorphonuclear and
May occur anywhere in the liver and may be unilocu- mononuclear (lymphocytes, plasma cells, macrophages) cellu-
lar or multilocular. lar infiltrates. ‘‘Mononuclear cell’’ can be used when there is a
Multilocular cysts are divided into variably sized mixture of cell types (lymphocytes; less often macrophages and
compartments by partial or complete connective plasma cells) or the cell type is mononuclear but cannot be
tissue septa. unequivocally identified in H&E stain. If a cell type predomi-
Cyst walls are characteristically lined by flattened to nates, then the infiltrate should be classified as lymphocytic,
cuboidal epithelium. plasmacytic, or histiocytic. While etiological agents (e.g., bac-
May be mild compression of adjacent hepatic teria, virus, parasite) may be present, in most safety assessment
parenchyma. studies the causes of significant inflammation are either cryptic
or are attributed to a specific treatment regimen. Inflammatory
Differential diagnosis: reactions in the liver may be accompanied by oval cell and
fibroblast proliferation and the propensity for hepatocellular
Cystic degeneration—consists of markedly enlarged proliferative responses to replace lost parenchyma.
cells with finely flocculent pale eosinophilic cytoplasm. It is recommended that use of the diagnostic term
Angiectasis (Peliosis hepatis)—dilated vascular spaces ‘‘inflammation’’ for the liver should be used sparingly. Liver
lined by endothelial cells; may contain blood cells. inflammation (hepatitis) is operationally defined as a constella-
Bile duct dilation—dilated bile ducts lined by cuboi- tion of changes that represent a severe and generalized liver
dal epithelium; not multiloculated. reaction and would require multiple diagnostic terms to ade-
Parasitic cyst—may have thickened wall and contain quately characterize (Figure 70). This type of reaction is not
parasite tissue. typically encountered in conventional rodent toxicity studies.
Cholangioma—may cause compression of adjacent Traditionally, hepatic inflammatory responses have been
parenchyma and spaces lined by more endothelial classified as acute, subacute, chronic, granulomatous, and so
cells than in biliary cysts. on. These terms are somewhat interpretative, lack precise def-
initions, vary depending upon study duration, usually do not
Comment: Biliary cysts are commonly seen in older rats (Burek consist of a singular cell type, and do not have exclusive
1978; Greaves 2007; Harada et al. 1999). Solitary cysts can be pathognomic features. A more descriptive approach is recom-
observed without major adjacent morphology changes of the sur- mended and can be qualified by lesion distribution or use of
rounding tissue. However, depending on the location, adjacent subclassification and discretionary qualifiers (Figure 71).
parenchyma may contain pressure atrophy of the hepatic cords
of the liver, fibrosis, hemosiderin deposition, proliferation of bile
Infiltration, Inflammatory Cell
ducts, or periportal lymphocytic infiltration. Single cysts are
often caused by cystic dilatation of the intrahepatic bile ducts Pathogenesis: Infiltration of different inflammatory cells is
(Sato et al. 2005). Multiple cysts are observed also in hepatic typically a response to parenchymal cell death with causes
polycystic disease, where they occur alone or in combination ranging from infectious agents, exposure to toxicants, genera-
with polycystic kidney disease (Masyuk et al. 2004, 2007). They tion of toxic metabolites, and tissue anoxia.
20S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
there are typically fewer neutrophils seen in chronic lesions and system is active. Others may consider chronic active inflamma-
there is more involvement of portal areas with infiltrating mono- tion simply as a form of chronic inflammation with areas of
nuclear cells and disruption of limiting plates. Granulomatous neutrophilic infiltration in the inflammatory process and
inflammation with characteristic focal or multifocal nodular col- prefer to address that in their accompanying pathology narra-
lections of mononuclear epitheloid cells and occasional giant tive. A combined neutrophilic and mononuclear infiltrate
cells associated with areas of hepatocyte necrosis can be consid- (chronic active inflammation) is a common response found in
ered a specific subtype of mononuclear cells infiltration and part mice chronically infected with Helicobacter hepaticus.
of the spectrum comprising chronic inflammation of the liver
(Figures 74–77). Some pathologists consider granulomatous Infiltration, Peribiliary (Intrahepatic) (Figure 81)
inflammation of the liver to be a form of chronic inflammation Pathogenesis: Age associated change that may be exacerbated
when there is a prolonged duration with predominant presence of by treatment.
epitheloid cells/macrophages and prefer to address the fact that
there may be areas containing mononuclear epitheloid cells and Diagnostic features:
multinucleated giant cells in the chronic inflammatory process in
an accompanying narrative. Fatty material and cholesterol Peribiliary aggregates of inflammatory cells affecting
deposits may accumulate in some granulomatous inflammatory a few to many portal areas.
reactions. Such localized accumulations of abundant cholesterol Sometimes accompanied by fibrosis.
have been referred to as cholesterol granulomas (Figures 78 and May be associated with some degree of bile duct
79). hyperplasia.
When only few isolated collections of mononuclear cells are
Differential diagnosis:
present, some pathologists may diagnose them as focal mononuc-
lear cell aggregates. These focal accumulations are considered
Cholangiofibrosis—proliferative and metaplastic
by some to be a background lesion, and for these aggregates
biliary response plus fibrosis extending into the hepa-
using the cell type in the diagnosis, instead of inflammation or
tic parenchyma; may be subcapsular.
inflammatory cell infiltrate, may be preferable and less mislead-
ing. The frequency of these mononuclear cell aggregates may
Comment: A minimal to moderate peribiliary inflammatory
be exacerbated by treatment. Helicobacter sp. and murine noro-
cell infiltration consisting primarily of mononuclear cells can
virus infections in mice may cause these incidental lesions.
occur commonly in the livers of rats and mice and increases
in incidence with animal age. Persistent obstruction to biliary
Infiltration, Mixed (Figure 80)
flow may also lead to bile duct inflammation in hepatic portal
Synonym: Infiltration, purulent, and mononuclear; chronic areas. Although this background lesion may be considered a
active inflammation; mixed inflammatory cell focus/foci. subtype of mononuclear cell infiltration (see previous), it is fre-
Diagnostic features: quently diagnosed separately when exacerbated by treatment.
Murine Norovirus Hepatitis (See Figure 73) Comment: Mouse hepatitis virus (MHV), a coronavirus, infects
hepatocytes, endothelium, and macrophages. In mouse liver,
Pathogenesis: Infection by murine norovirus.
virus strains may have different pathogenicities in the
Diagnostic features: various mouse strains and in mice of different ages (Percy
and Barthold 2007). Focal and multifocal necrosis is seen
Focal, multifocal to diffuse areas of inflammation with multinucleated (syncytial) hepatocytes, endothelium, and
sometimes with vasculitis in immunodeficient mice. macrophages. Immunodeficient mice may develop a chronic
Focal to multifocal small areas of inflammation in persistent infection with chronic lesions in liver (Ward, Collins,
most lines of mice. and Parker 1977).
Inflammatory foci contain macrophages and Clinical MHV infection may be most commonly seen in
lymphocytes. young mice. Adult mice may have serum antibodies but no
Immunohistochemistry shows that inflammatory clinical signs and few, if any, histopathologic lesions. Some
cells, especially macrophages in lesions and Kupffer cases show lesions in liver only. MHV is one of the most
cells, can be positive for murine norovirus antigens. prevalent murine viruses in the United States and Europe
(Homberger 1996) but appears less common today.
Differential diagnosis:
Tyzzer’s Disease (Clostridium piliforme Infection)
Helicobacter hepatitis can appear similar but may
Pathogenesis: Infection by Clostridium piliforme (Bacillus
contain silver positive bacteria.
piliforme).
Helicobacter hepatitis is more common in A, BALB/
c, and C3H strains that are not susceptible to MNV Diagnostic features:
infection.
Inflammation, focal or multifocal, acute or chronic, Focal or multifocal necrosis, coagulation to caseous
unknown etiology. with neutrophilic infiltration.
Intrahepatocyte bundles of long basophilic bacilli.
Comment: Murine norovirus (MNV) may cause severe hepa- Bacteria seen in Warthin-Starry, Giemsa stains, or by
titis in some lines of immunodeficient mice but only minimal the PAS method.
hepatitis or no lesions in most lines of infected immunocom-
petent mice (Ward et al. 2006). MNV infection is the most Differential diagnosis:
common viral infection in mouse colonies today. The impli-
cations for interfering in experimental results are not known. Necrosis, of other known causes or unknown causes.
It can be assumed that chemicals or infectious agents involv-
ing the immune system or liver may be influenced by MNV Comment: Named after Ernest Tyzzer who first described it
infection. in a colony of Japanese walzing mice (Fox et al. 2002). Clos-
tridium piliforme (Bacillus piliformis) is a long, thin, spore-
forming (intracellular) bacterium. Rare lesion with sudden
Mouse Hepatitis Virus Hepatitis (See Figures 63, 64, and 70) death, with or without diarrhea. Often infection of the colon
with dissemination to the liver (focal hepatitis) and occasion-
Pathogenesis: Infection by mouse hepatitis virus affecting
ally heart (myocarditis). Special stains (e.g., Giemsa or
hepatocytes, endothelium, and macrophages (Kupffer cells).
Warthin-Starry Silver stain) can reveal intracytoplasmic fila-
Diagnostic features: mentous bacteria.
Tyzzer’s disease is rare in rodents. It is usually sporadic.
Focal or multifocal hepatic necrosis. The gerbil is known to be extremely susceptible to infection
Multinucleated cells (syncytia) from hepatocytes, (Fox et al. 2002).
endothelium, and macrophages. Gross lesions can include hepatomegaly, focal necrosis, sin-
MHV lesions in other tissues, including peritoneum, gle or multifocal, small or large lesions sometimes associated
CNS, blood vessels. with lesions in other tissues, especially intestines (Percy and
Chronic hepatitis and postnecrotic cirrhosis in immu- Barthold 2007). Multiple foci of necrosis (coagulative necro-
nodeficient mice. sis) and/or multifocal necrotizing hepatitis can be observed
microscopically.
Differential diagnosis:
E. Vascular Lesions
Necrosis caused by toxins.
Introduction
Necrosis caused by murine norovirus.
Necrosis caused by Helicobacter sp. The liver has a dual blood supply consisting of a relatively
Necrosis caused by C. piliforme. major (about 75%) venous (portal) supply via the hepatic portal
24S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
vein, which carries venous blood that is largely depleted of Angiectasis (Figures 86 and 87)
oxygen, and relatively minor (about 25%) arterial blood sup-
Synonyms: Peliosis hepatis, telangiectasis, sinusoidal dilation.
ply, via the hepatic artery. The portal blood contains toxic
materials absorbed in the intestine, and therefore the liver is the Pathogenesis: Perturbations in blood flow and/or drainage;
first tissue to be exposed to toxic substances that have been weakening of sinusoidal walls.
absorbed through the gastro-intestinal tract.
Diagnostic features:
Within the hepatic parenchyma, the hepatocytes are in
intimate contact with the sinusoidal capillaries, which are car-
Macroscopically—seen on the surface as blood-
rying the mixture of blood originating from ramifications of
filled, thin walled cavities projecting above the sur-
the portal vein and hepatic artery to the central vein. The
face (Bannasch et al. 1997).
sinusoids are lined by modified endothelial cells containing
Microscopically—There are two morphological
fenestrations, which allow passage of lipoproteins and other
types, as follows:
large molecules but provide a barrier to blood cells. Kupffer
1. Cystic (‘‘Phlebectatic’’)—Focal dilation (disten-
cells reside in the lumen of the sinusoids and are anchored
sion) of endothelial lined channels (photographic
to their wall.
presentation contributed by Hardisty et al. 2007).
The morphological aspect of the hepatic pathology during
Can be an isolated lesion or have a multicentric
circulatory disorders depends on the location of the vascular
form. The lacunae are densely packed with blood
structure being affected (i.e., lobular sinusoids, the outflow
and are coated by a single layer of endothelium
hepatic vein, or the inflow portal vein).
and separated from one another by cords of liver
parenchyma (Bannasch, Wayss, and Zerban
1997). The endothelial cells appear to be unal-
Congestion (Figure 85)
tered, and there is no increase of mitotic figures.
Synonym: Chronic passive congestion. The tissue adjacent to the dilated sinusoids is
well preserved and free of necrotic cells.
Pathogenesis: Circulatory failure, typically right-sided heart 2. Cavernous (‘‘Parenchymal’’)—The peliotic cysts
failure. are not, or are only partially, lined by endothelium.
Thus, the cysts involve not only the sinusoidal
Diagnostic features:
lumen, but also the space of Disse, and the blood
comes in direct contact with the neighboring par-
Increase prominence (number) of erythrocytes in the
enchymal cells. The parenchyma undergoes focal
capillary bed or larger vessels of an organ.
necrosis without a zonal distribution. This lesion is
No appreciable distention (angiectasis) of the vessel
much less likely to be preneoplastic and a few tox-
wall.
ins have been shown to induce the lesion. When
Diagnosis often correlates with gross observation
endothelial lining is absent, the term Peliosis
(e.g., reddened, darkened focus).
Hepatis instead of Angiectasis is indicated.
May be associated with centrilobular necrosis.
Differential diagnosis:
Differential diagnosis:
Hemangioma—expansile structure lined by flattened
Angiectasis—dilated vascular spaces lined by endothelial cells; may be associated with parenchy-
endothelial cells; dilated vascular channels and mal compression.
spaces frequently contain erythrocytes. Cystic degeneration (Spongiosis hepatis)—cavities
Massive necrosis. are not filled with blood but with a finely flocculent
Hemorrhage-irregular patchy lakes of blood not con- acidophilic material.
tained within defined vascular channels.
Autolysis-altered cellular texture and loss of staining Comment: Angiectasis is a cystic or cavernous widening of the
intensity. liver sinusoids that can occur in a variety of pathological
insults. In human, sinusoidal dilatation has been reported fol-
Comment: Congestion may result from circulatory disturbance lowing hypoxia or hyperperfusion as a result of right-sided
such as right-sided heart failure and is usually associated with heart failure, thrombosis of hepatic veins, amyloid deposition,
necrosis of the centrilobular areas (Burt, Portmann, and granulomatous, or neoplastic disease (Greaves and Faccini
MacSween 2002). Presence of blood in hepatic sinusoids seen 1992; Bruguera et al. 1978). Although these lesions can also
in animals that die or in situations where there is incomplete occur spontaneously in different rodents with different diseases
exsanguination should not be diagnosed as congestion. If it is or with certain neoplasms causing hemodynamic changes, it
absolutely necessary to record such findings, it is important can also be induced by different compounds. Focal sinusoidal
to qualify the blood stasis in the liver as passive congestion. dilatation and peliosis hepatis have been observed in the rodent
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 25S
liver after treatment with nitrosamines, pyrrolizidine alkaloids Comment: There are several potential mechanisms leading to
or glucocorticoids (Greaves 2007; Ruebner, Watanabe, and liver thrombosis. Activation of the coagulation system associ-
Wand 1970; Ungar 1986; Wolstenholme and Gardner 1950). ated with fibrin deposits and hypoxia located in the centrilob-
Altered hemodynamic and changes in the hepatic microcircula- ular sinusoids was reported to occur in the livers of rats
tion have been proposed to be of importance in the pathogen- exposed to monocrotaline (MCT) (Copple et al. 2002). It was
esis of sinusoidal dilatation (Slehria et al. 2002). Subcapsular suggested that the fibrin thrombi were formed following
sinusoidal dilatation can also be found a postmortem finding chemical-induced hepatic endothelial cell damage. In studying
in rats (Kimura and Abe 1994). an endotoxin-exposure model, it was suggested that the noted
Angiectasis is defined by multiple blood-filled cystic spaces focal and random hepatocellular necrosis was caused by circu-
of different size and shape occurs after suspected loss or weaken- latory disturbances due to fibrin thrombi in clusters of adjacent
ing of sinusoidal walls and/or supporting tissue. The two subtypes sinusoids. Using a rat model of 2-butoxyethanol induced hemo-
may occur in combination. The cystic spaces are devoid of lytic anemia associated with systemic thrombosis, fibrin
endothelial lining in the cavernous subtype (‘‘parenchymal’’) thrombi were noted in the central vein and sinusoids of the
although controversy still exists (Greaves 2007; Edwards, liver, in addition to the presence of thrombi seen in several
Colombo, and Greaves 2002). Angiectasis can be found in aged other organs (Ramot et al. 2007).
rats (Lee 1983). However, these lesions can also be induced in
both rats and mice after viral infection (Bergs and Scotti 1967) Infarction (Figures 89 and 90)
or exposure to certain drugs or chemicals (Mendenhall and Pathogenesis: Interruption of blood flow in a major vessel.
Chedid 1980; Husztik, Lazar, and Szabo 1984). Torsion of hepatic lobe.
Angiectasis has also been reported in animals or humans
Diagnostic features:
infected with Bartonella spp. (Wong et al. 2001; Breitschwerdt
and Kordick 2000) and it has been associated with a number of
Extensive area of necrosis may be associated with
diseases in humans as well as administration of anabolic steroids
inflammation.
and oral contraceptives (Naeim, Cooper, and Semion 1973;
The necrosis does not have acinar pattern.
Zimmerman 1998; Tsokos and Erbersdobler 2005).
Angiectasis may refer to a vascular lesion formed by dilatation Differential diagnosis:
of a group of small blood vessels. It can be observed in transgenic
mouse models (Srinivasan et al. 2003; Bourdeau et al. 2001) or Hepatocellular necrosis resulting from direct toxicity
related to xenobiotic administration in rats and mice (Robison may have a diffuse or lobular distribution but also may
et al. 1984; Kim et al. 2004). It can be found as an incidental find- be accompanied by infarction; not mutually exclusive.
ing in aging mice and is sometimes associated with hepatocellu-
lar neoplasms (Harada et al. 1996, 1999). Angiectasis can be Comment: Aside from torsion of liver lobes, which can occur
chemically induced (Bannasch, Wayss, and Zerban 1997) and spontaneously in rodents, infarction is a very rare lesion that
has been suggested to be preneoplastic in some animal models. can be induced only under very specific experimental condi-
tions. The combined injection in mice of NG-monomethyl-L-
Thrombosis (Figure 88) arginine and aspirin after lipopolysaccharide exposure resulted
in significant hepatocellular enzyme release, characterized his-
Pathogenesis: Activation of the coagulation system associated tologically by intravascular thrombosis with diffuse infarction
with arteritis or phlebitis or secondary to atrial thrombosis. and necrosis (Harbrecht et al. 1994). Intraperitoneal injections
Diagnostic features: in rats of vasoconstrictor xenobiotics such as phenylephrine
produced infarcts of the spleen regularly and infarcts of the
It is characterized by the formation of a thrombus liver occasionally (Levine and Sowinski 1985). Isolated perfu-
within the lumen of a blood vessel, like sinusoids and sion with 1.0 g/kg of the cytotoxic xenobiotic 5-FU or
central veins. hyperthermia of 41 degrees C 10 min resulted in 90% to
Amorphous mass attached to the endothelium or free 100% mortality in rats, with extensive, patchy necrosis, and
within the blood vessel lumen (due to plane of section). infarction on histologic examination (Miyazaki et al. 1983).
Contains fibrin, platelets, and entrapped blood cells.
Damaged endothelium can be seen. Endothelial Cell Hypertrophy/Karyomegaly3 (Figure 91)
May occur with histiocytic sarcoma in rats or mice. Synonyms: Endothelial cell enlargement, cytomegaly.
Pathogenesis: Continued DNA synthesis and cell cycle arrest Pathogenesis: Proliferation of normally present sinusoidal lin-
following exposure to certain xenobiotics. ing endothelial cells without sinusoidal dilation.
Irregularly shaped karyomegalic nuclei. Focal, located to the portal triad, consisting of
Nuclei and cells appear larger than normal. increased number of capillaries.
Secondary changes related to the endothelial Blood may not be present within the capillaries.
cell damage and/or obstruction of the sinusoids lead- Absence of supporting tissue.
ing to local ischemia may be seen. Such changes May have mitotic figures and nuclear atypia.
include sinusoidal congestion, hemorrhage, thrombi
formation, hepatocytic fatty change/degeneration, Differential diagnosis:
and necrosis (Lailach et al. 1977; Nyska et al. 2002).
Hemangioma—expansile structure lined by flattened
Differential diagnosis: endothelial cells; may be associated with parenchy-
mal compression.
Endothelial cell hyperplasia characterized by Angiectasis—dilated vascular spaces lined by
increased number of endothelial cells. endothelial cells; dilated vascular channels and
Hepatocytic cytomegaly and karyomegaly. spaces frequently contain erythrocytes.
Anisokaryosis—variation in the size of nuclei and/or
binuclearity admixed with diploid appearing hepato- Comment: Endothelial derivation and proliferation can be
cyte nuclei. confirmed by dual immunostaining for CD31/KI-67 (Ohnishi
Reactive Kupffer cells—enlarged histiocytic cells et al. 2007). Comparative endothelial cell kinetic studies in
with visible cytoplasm lining sinusoids. human, mice, and rats indicated that the labeling index (LI)
Histiocytic sarcoma—hepatic parenchyma infiltrated in the male and female B6C3F1 mouse liver was significantly
and replaced by collections of histiocytic cells that higher (p < .01) compared to the LI in male and female rat
can be pleomorphic. and human liver, and the LI in the male and female rat liver
was significantly greater (p < .05) than the LI in human liver.
It was suggested that the increased rate of spontaneous
Comment: In a study of monocrotaline (Wilson et al. 2000) it hemangiosarcoma formation in mice may be related to the
was suggested that the endothelial karyomegaly was the result increased proliferation rate of endothelial cells normally
of continued DNA synthesis and concentration-dependent cell- present in the B6C3F1 strain of mice compared to rats and
cycle arrest. The exposed cells undergo a process of multiplica- humans (Ohnishi et al. 2007).
tion of chromosomal copies, defined as endopolyploidy, with
nuclear and cytoplasmic gigantism. A direct correlation
between cytoplasmic volume and nuclear DNA content was F. Non-Neoplastic Proliferative Lesions
suggested.
Introduction
A similar pathogenesis was suggested in the case of
ridelliinne-induced endothelial cytomegaly and karyomegaly A variety of non-neoplastic proliferative lesions of different
(Nyska et al. 2002). Administration of riddelliine, a naturally origin(s) occurs spontaneously in the liver of rodents and may
occurring pyrrolizidine alkaloid, to rats results in cytomegaly and also be induced by treatment with chemicals. Incidences and
karyomegaly of hepatic endothelial cells as one of its pleotrophic morphological characteristics vary considerably by animal spe-
responses to cell-specific cytotoxicity. A metabolite of this cies, strain, and sex. Some of these lesions might be regarded as
pyrrolizidine alkaloid is believed to directly interact with pre-neoplastic alterations.
endothelial cell DNA. As a non-neoplastic proliferative response, increased
Sometimes this change is interpreted as prominent hepatocyte mitoses (Figure 92) above normal background
Kupffer cells or Kupffer cell hypertrophy on H&E sections levels or increased above what is seen in control animals can
and warrants further characterization for confirmation of occur in rodent livers. Causes vary from physiological
the endothelial cell origin. Immunohistochemical stains responses such as during early growth, during pregnancy, and
and electron microscopy can be used to identify the cell type following partial hepatectomy to post-necrotic repair. This
involved. change may be diagnosed as cytologic alteration or mitotic
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 27S
alteration with a description in the pathology narrative. Portal areas and central veins not present in small foci
In some laboratories diagnosis of ‘‘increased mitoses’’ is but can be seen in larger foci.
used. Sinusoids within focus may be compressed, so
typical parenchymal plates are difficult to detect.
Tortuous hepatic cords may occur due to increased
Focus of Cellular Alteration number of cells.
Size of cells and cytoplasmic tinctorial variation
Introduction: Foci of cellular alteration are common in rodent
depend on type of focus.
studies greater than duration of twelve months and may be
Normally absence of cellular atypia.
seen in short duration toxicity studies following exposure
Cystic degeneration (spongiosis hepatis) and
to certain xenobiotics. Foci of cellular alteration can be iden-
angiectasis (peliosis hepatis) may occur within foci
tified by special stains. In H&E-stained slides they may be
of altered cells.
subclassified based on the predominant cell type present.
Cytoplasmic lipid may be present.
Diagnosis of the mixed cell subtype of altered hepatic focus
Intracytoplasmic inclusions of various types may be
varies among different laboratories. One viewpoint defines a
present.
mixed focus of cellular alteration as consisting of a combina-
tion of basophilic, vacuolated, eosinophilic, and/or clear cell
hepatocytes without a predominant cell type. An alternative
viewpoint defines a mixed cell focus as containing any two Basophilic (Figures 93–97)
phenotypes of cells in approximately a 50%/50% proportion.
Basophilic, diffuse (Figures 93 and 94).
Others regard a ‘‘true’’ mixed focus as one that contains
clearly identified basophilic and eosinophilic cells regardless Hepatocytes of normal size or slightly enlarged with
of the proportions of each. Because of this diverse set of homogeneously staining cytoplasmic basophilia due
diagnostic opinions regarding focus subtypes, the pathologist to abundant free ribosomes.
is encouraged to describe the morphological features Cells may be pleomorphic with enlarged vesiculated
of documented foci in detail, especially if they are altered nuclei and prominent nucleoli.
by treatment. Dissociation of cells may occur.
Mitotic figures may occur.
Synonyms: Areas of cellular alteration; focus of altered
Basophilic, tigroid (Figure 95).
hepatocytes; hyperplastic focus; preneoplastic focus; enzyme
altered focus; phenotypically altered focus. Cells are usually smaller; enlarged cells may
occur.
Pathogenesis: A localized proliferation of hepatocytes pheno- Cells are often arranged as tortuous cords.
typically different from surrounding hepatocyte parenchyma. Cells display large abundant basophilic bodies often
arranged in clumps or long bands with striped pattern
Diagnostic features: in paranuclear or peripheral regions of cytoplasm
(due to increased rough endoplasmic reticulum).
May occasionally be observed grossly as small white
Mitotic rate may be increased.
foci on the liver surface, but not round nodules.
Size may range from less than one lobule to multiple Basophilic, NOS (Figure 96).
lobules in diameter.
Foci that are not clearly tigroid or diffusely
Circular or ovoid shape; irregular formed foci may
basophilic.
occur.
Peliosis or spongiosis may occur within these foci.
Distinguished into types of foci by virtue of tinctorial
variation, size of hepatocytes, and textural appear- Basophilic (no further classification in mice) (Figure 97).
ances from surrounding parenchyma.
May be subclassified based on predominant cell type. Consist of cells larger or smaller than normal hepato-
The fact that 80% of the focus is composed of one cytes, in general they are smaller.
morphologic cell type (basophilic, eosinophilic, etc.) Cytoplasm exhibits distinct basophilia due to free
or a mixed cell type. ribosomes or rough endoplasic reticulum.
Normally no or only minimal compression of the sur- Often cells contain obvious glycogen.
rounding liver tissue. Intracytoplasmic basophilic clumps with relatively
Liver plates merge imperceptible with surrounding clear intervening cytoplasm or the cytoplasmic baso-
hepatic parenchyma; nevertheless foci are sharply philia may be distributed homogeneously.
demarcated from the adjacent normal hepatocytes Vascular pseudo-invasion may be present.
by the appearance and staining reaction of its cells. Eosinophilic cytoplasmic inclusions may be found
Lobular architecture preserved. occasionally within hepatocytes.
28S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
Harada, Maronpot, Morris, and Boorman, 1989; Squire 1989; treatment-associated and consists of a proliferative collection
Schulte-Hermann et al. 1989). Most importantly, types of of hepatocytes spanning several lobules and without evidence
foci in controls should be compared to those found in treated ani- of prior hepatic damage. This lesion is not associated with any
mals. Some pathologists regard vacuolated foci as focal fatty evidence of existing or prior hepatocellular injury. Diagnostic
change and do not consider them a subtype of focus of cellular difficulties occur when preneoplastic foci and hepatocellular
alteration. adenomas occur in the same liver sections of older rodents.
This lesion may be similar to that of hepatic nodular hyperpla-
Hyperplasia, Hepatocellular, Non-Regenerative (Figures sia in dogs.
109 and 110) There are basically two variations of non-regenerative
hepatocellular hyperplasia. One is relatively smaller and is
Synonyms: Hyperplasia, hepatocellular, focal hepatocellular accompanied by angiectasis and/or spongiosis hepatis and the
hyperplasia. other tends to be larger than several lobules. The former
occurs in both sexes and the latter predominantly in untreated
Pathogenesis: A spontaneous or treatment-associated prolif- female control F344 rats but occasionally reported in treated
erative collection of hepatocytes spanning several lobules and rats (Tasaki et al. 2008; Hailey et al. 2005; Bach et al.
without evidence of prior hepatic damage. 2010). When present near the capsular surface, this type of
Diagnostic features: nodular hyperplasia may be evident grossly as a raised area.
The proliferating cell nuclear antigen (PCNA) labeling index
A relatively large lesion that is often greater than sev- in these nodules is increased in comparison with surrounding
eral adjacent lobules and is occasionally accompa- parenchyma and the lesion is glutathione S-transferase pla-
nied by angiectasis and/or spongiosis hepatis (cystic cental form (GSTP) immunonegative.
degeneration). Very early non-regenerative hyperplasia may be the size of
Comprised of slightly enlarged hepatocytes. small foci of cellular alteration and are identified by their
Hepatocytes are tinctorially similar to surrounding altered growth pattern and tinctorial similarity to surrounding
parenchyma. parenchyma (see Figure 109).
The liver plates in the lesion tend to merge with the
adjacent hepatic parenchyma.
May be minimal to mild compression of adjacent Hyperplasia, Hepatocellular, Regenerative (Figures 111–113)
hepatic parenchyma. Synonyms: Hyperplasia, hepatocellular; hyperplasia, regenera-
Lobular architecture is maintained. tive; hyperplasia, nodular; regeneration, nodular.
Portal triads and central veins are present.
When accompanied by angiectasis/spongiosis hepa-
Pathogenesis: A nodular regenerative response to prior or con-
tis, hepatic cords may be distorted.
tinuous hepatocellular damage.
Differential diagnosis: Diagnostic features:
dose. The intestinal cell metaplasia in cholangiofibrosis hepatocellular neoplasms and may play an important role in
includes goblet and Paneth cells and columnar cells similar hepatocarcinogenesis. Some authors support the concept that
to chief cells identified in H&E-stained paraffin sections and oval cells may participate in the lineage of hepatocellular and
enterochromaffin cells identified by special staining. The cholangiocellular carcinomas and may serve as hepatic stem
metaplastic cells have been confirmed by electron micro- cells. Oval cell hyperplasia diagnosis including grade is rec-
scopy in some cases. While cholangiofibrosis has been ommended, even when it is part of a complex set of hepatic
reported to progress to cholangiocarcinoma with malignant changes.
features (Bannasch and Zerban, 1990; Sirica 1992), unequivo-
cal metastases have not been confirmed in most cases. This
G. Neoplasms
lesion is not observed in humans.
Introduction
Oval Cell Hyperplasia (Figures 127–129)
The rodent liver is the most common target site of chemical
Synonyms: Oval cell proliferation; bile ductule cell hyperplasia. carcinogens (Maronpot et al. 1986; Evans and Lake 1998), per-
haps due to its major function as a metabolizing and detoxifying
Pathogenesis: Arises from terminal ductule epithelial cells organ for xenobiotics. Rodent hepatocarcinogens are usually
(canal of Hering cells) spontaneously, following liver infec- hepatotoxins. The chronic toxicity of these toxins may
tions, and secondary to hepatotoxic injury. contribute to hepatocarcinogenesis although genotoxic liver
Diagnostic features: carcinogens are often also hepatotoxins. There is over a thirty-
year history of experimental induction (Frith and Wiley 1982;
Generally originates from portal areas and is often Malarkey et al. 1995; Evans et al. 1992; Ward et al. 1983,
multifocal. 1986; Ward, Lynch, and Riggs 1988; Popp 1984) and classifica-
Consists of a single or double row of oval to round tion of preneoplastic and neoplastic lesions of the rat and mouse
cells along sinusoids in linear arrays. liver in book chapters (Bannasch and Zerban 1990; Brooks
May form a few or many small ductules with stream- and Roe 1985; Greaves and Faccini 1984; Jones and Butler
ing into the hepatic parenchyma. 1978; Ward 1981; Harada et al. 1999; Eustis et al. 1990) and
Formation of incomplete duct-like structures may by committee (ILAR 1980) or toxicologic pathology
be present. societies (Standardized System of Nomenclature and Diagnos-
Cells are usually uniform in size and shape and may tic Criteria [SSNDC] Guides, http://www.toxpath.org/
be fusiform. ssndc.asp). Terminology has evolved to the present nomencla-
Cells have scant pale basophilic cytoplasm and round ture that is also based on many publications on liver
or oval nuclei. carcinogenesis.
Oval cells express keratin. There is evidence from experimental studies documenting
the regression of proliferative hepatocellular lesions including
Differential diagnosis: foci of cellular alteration, hepatocellular adenomas, and hepato-
cellular carcinomas following cessation of treatment (Maronpot
Hyperplasia, bile duct—several small bile ducts 2009). A dramatic example was reported in mice following
arising in portal region. Biliary epithelium is well cessation of chronic chlordane exposure (Malarkey et al.
differentiated, forming normal ducts. 1995). Similar experience has been reported in rats and mice
Early or mild fibrosis—collagen matrix is evident. in other studies (Lipsky et al. 1984; Greaves, Irisarri, and
Inflammation—presence of mononuclear, polymor- Monro 1986; Marsman and Popp 1994) as well as in humans
phonuclear, or connective tissue cells will be present (Frémond et al. 1987; McCaughan, Bilous, and Gallagher
in inflammation. 1985; Emerson et al. 1980; Steinbrecher et al. 1981). Agents that
require continual administration for the stable presence and
Comment: Oval cell proliferation is considered to arise from
growth of preneoplastic and neoplastic rodent liver lesions can
terminal ductule epithelial cells (canal of Hering cells). It is
be categorized as conditional hepatocarcinogens (Maronpot
a rare spontaneous lesion in rats. Oval cell hyperplasia can
2009).
be observed following severe hepatotoxic injury and treat-
ment with hepatocarcinogens. There is often a close relation
Hepatocellular Adenoma (Figures 130-134)
to the portal tract, although more scattered groups of prolif-
erating oval cells can be seen diffusely throughout the liver Synonyms: Adenoma, hepatic; adenoma, liver parenchymal
following xenobiotic-induced hepatic injury (Engelhardt cell; hepatoma, benign; tumor, liver cell, benign; hepatoma,
1997). benign; type A nodule.
In mice oval cell hyperplasia is a feature of chronic active
hepatitis caused by H. hepaticus and H. bilis and is seen fol- Pathogenesis: Spontaneous and following treatment with
lowing treatment with various hepatocarcinogens. Hyperplas- hepatotoxins that are carcinogenic xenobiotics; with gene
tic oval cells occur in association with a high incidence of alterations in genetically engineered mice.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 33S
Acinar (synonym: glandular): The trabecular type of hepatocellular carcinoma is the most
common form in rats and to a lesser extent in mice.
Neoplastic hepatocytes form a generally single layer Hepatocellular carcinomas may appear to arise within preexist-
around a central clear space. ing adenomas, especially in mice (Figures 139 and 140). While
The acinar structure may vary from tiny to huge cysts. some authors refer to these lesions as focus of carcinoma in
Glandular pattern rarely involves more than 50% of adenoma, such lesions should be diagnosed as hepatocellular
the neoplasm. carcinoma. These carcinomas exhibit the same morphological
Acinar portion is interspersed with areas that have appearance as the carcinomas described earlier and hint toward
either trabecular or solid architecture. a progression of adenoma into carcinoma. Attention should be
paid to hemorrhagic areas, where proliferation of endothelial
Solid: cells or formation of large sinusoidal-like spaces may lead to
the erroneous diagnosis of a vascular tumor.
Well-circumscribed nodule.
A layer of neoplastic cells surrounds luminal structures.
Distinct encapsulation with variable structure may be
Lining cells usually consist of strongly basophilic
present.
cuboidal cells.
Organoid structures are lined by vascular cavities
filled with blood.
Differential diagnosis:
The channels are surrounded by several layers of
tumor cells.
Focus of cellular alteration—liver plates merge
The cells are arranged either radially or concentrically
imperceptibly with surrounding hepatic parenchyma;
forming rosettes, trabeculae, or pseudo-glandular
normal lobular architecture present.
structures.
Regenerative hyperplasia—evidence of prior or
The center of the rosettes sometimes contains ampho-
ongoing hepatocyte damage; normal lobular architec-
philic material or small, endothelium-lined vessel.
ture present, albeit distorted; demarcated from sur-
Cells are small, strongly basophilic, and elongated.
rounding liver tissue.
Sometimes they may be more or less eosinophilic and
Non-regenerative hyperplasia—some evidence of
have smaller, rounder, and less hyperchromatic nuclei.
lobular pattern and presence of central veins and por-
Numerous mitotic figures are present.
tal triads.
Areas of large hemorrhage, pigmentation, fibrosis, or
Hepatocellular adenoma—no local invasiveness, less
necrosis are present.
cellular atypia, sharply demarcated from surrounding
Osteoid, bone, squamous differentiation, and extra-
liver parenchyma. No formation of a trabecular pattern.
medullary hematopoietic foci may be present.
Cholangiocarcinoma—mucus may be present within
the adenoid structures. If there is loss of mucus it is
difficult to distinguish. Differential diagnosis:
Hemangiosarcoma—proliferation of atypical
endothelial cells forming blood spaces. Cholangiocarcinoma (poorly differentiated)—gland-
ular structures with mucus production are present.
Comment: Occur spontaneously with increased incidence in Often evidence is present of extensive fibrosis, but
older rodents and following treatment with carcinogenic and not of osteoid, or bone formation.
hepatotoxic xenobiotics (Bannasch and Zerban 1990; Brooks and Sarcoma, NOS—only mesenchymal structures are
Roe 1985; Greaves and Faccini 1984; Jones and Butler 1978; present.
Ward 1981; Harada et al. 1999; Eustis et al. 1990; Popp 1984, Carcinoma, hepatocellular-only sparse mesenchymal
1985; Vesselinovitch, Mihailovich, and Rao 1978). Diagnosis structures are present. Hepatic cell differentiation is
may be modified based on growth pattern (Frith and Wiley 1982). obvious.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 35S
Comment: Hepatoblastomas consist of organoid structures Hyperplasia, bile duct—multifocal, usually widespread.
often oriented around vascular spaces (Harada et al. 1999; Cholangiofibrosis—central portions become
Nonoyama et al. 1986, 1988; Turusov, Day, et al. 1973; atrophic, collagenized, and avascular whereas the
Turusov, Deringer, et al. 1973). The cells are primitive in actively proliferating portion is at the periphery;
appearance of scant, pale basophilic cytoplasm and ovoid mucus production is common.
hyperchromatic nuclei. They are usually seen with other types Cholangiocarcinoma—proliferation of atypical cells,
of hepatocellular tumors, especially within hepatocellular invasive growth.
adenomas. Rare reports of this lesion in rats appear in litera-
ture. They are seen in certain strains of mice and have also Comment: Cholangioma is rare in control and treated
been induced by certain hepatocarcinogens (Diwan, Ward, rodents (Bannasch and Zerban 1990; Brooks and Roe 1985;
and Rice 1989). Frith and Ward 1979; Greaves and Faccini 1984; Harada
Hepatoblastoma is generally seen within or adjacent to et al. 1999; Jones and Butler 1978; Lewis 1984; Maronpot
hepatocellular neoplasms. In these cases, some preference has et al. 1986).
been expressed for a single diagnosis of hepatoblastoma, rather
than two diagnoses (the hepatoblastoma and the hepatocellular Cholangiocarcinoma (Figures 147 and 148)
neoplasm). If this preferred convention of using the single
diagnosis of hepatoblastoma is not used, then the alternative Synonyms: Adenocarcinoma, bile duct; adenocarcinoma,
convention will need to be defined by the pathologist. Hepato- cholangiocellular; carcinoma, bile duct; carcinoma, cholangio-
blastomas can have high rates of lung metastases in some cellular; cholangioma, malignant.
experiments.
Pathogenesis: Arise from proliferating cholangial cells.
Synonyms: Adenoma, bile duct; adenoma, biliary; adenoma, Biliary structures are usually glandular but may have
cholangiocellular; cholangioma, benign. solid or papillary areas, may be poor in or free of
mucus, and mostly have a minimal connective tissue
Pathogenesis: Proliferation of biliary cells. component.
Diagnostic features: Glandular lining cells are hyperbasophilic and have
large nuclei and nucleoli but occasionally have clear
Glandular acini may vary in size and shape. cytoplasm due to accumulated glycogen.
Expansively growing with compression. Glands lined by single or multilayered cuboidal or
Nucleus is round or oval occasionally vesicular with cylindrical cells.
one or two conspicuous nucleoli. Clear-cut invasion into vascular and lymphatic struc-
Cytoplasm is somewhat basophilic. tures and surrounding parenchyma may be present.
Two types can be distinguished: May appear as a large solid mass.
Evidence of metastasis or likelihood of metastasis is
Simple: expected.
Butler 1978; Lewis 1984; Narama et al. 2003). A specific Carcinoma, hepatocholangiocellular—features of
phenotype of cholangiocarcinoma with features of hepatocellular carcinoma and cholangiocarcinoma
cholangiofibrosis consisting of dilated biliary glands, mucus are present. Hepatocytes arranged in nests, solid, tra-
production, intestinal metaplasia, inflammatory cell infil- becular, or glandular patterns. Stratification and aty-
trates, and fibrosis has been diagnosed in rats treated with a pia of biliary epithelial component is present.
variety of hepatotoxic xenobiotics (Bannasch and Zerban
1990; Bannasch, Brenner, and Zerban 1985; Sirica 1992; Comment: Rare spontaneous lesion. A proliferative mixture of
Kimbrough and Linder 1974; Maronpot et al. 1986). The hepatocytes and intrahepatic bile duct epithelium with neither
distinction between cholangiofibrosis and this phenotype of component being malignant comprise to this tumor type
cholangiocarcinoma is difficult and controversial and is pri- (Deschl et al. 2001; Frith and Ward 1979; Harada et al.
marily based on extent of liver involvement since unequivocal 1999; Narama et al. 2003).
metastasis is rare.
These rare lesions of cholangiocarcinoma can contain para- Carcinoma, Hepatocholangiocellular (Figures 151 and 152)
meters of cholangiofibrosis but show less inflammation and
less mucus cyst(s) but with atypical ductular structures and can Pathogenesis: Proliferation of admixture of hepatocytes and
metastasize. It has been proposed to diagnose this specific form intrahepatic bile duct epithelium. Stem cell origin speculated.
of cholangiocarcinoma as ‘‘cholangiocarcinoma, intestinal Diagnostic features:
type’’ (Greaves 2007), but that nomenclature as a separate
(sub-) diagnosis was not favorably encouraged at a recent Features of hepatocellular carcinoma and cholangio-
scientific workshop (NTP Satellite Symposium 2010). carcinoma are present.
The hepatocytic component may be arranged in tra-
becular, glandular, or solid patterns.
Adenoma, Hepatocholangiocellular (Figures 149 and 150) The biliary component may form acini or small nests
Pathogenesis: Proliferation of admixture of hepatocytes and without lumen. Stratification or cellular atypia may
intrahepatic bile duct epithelium. Stem cell origin speculated. occur.
Occasionally ducts lined by both cell types, hepato-
Diagnostic features: cytic and biliary epithelial cells, may be present.
Areas of hemorrhage and necrosis may be present.
Features of hepatocellular adenoma and cholangioma Mitotic figures may be numerous.
are present.
Areas composed of cords of neoplastic hepatocellular Differential diagnosis:
cells merge with areas composed of ducts lined by
neoplastic epithelium that resembles bile duct epithe- Carcinoma, hepatocellular—composed of malignant
lium. Hepatocytes may be seen forming ductules or hepatocytes.
ducts. Cholangiocarcinoma—composed of malignant duct
The neoplastic biliary epithelium forms slightly epithelium.
dilated acini lined by cuboidal cells. Adenoma, hepatocholangiocellular—features of
Stratification and atypia of the biliary epithelium is hepatocellular adenoma and cholangioma are pres-
minimal or absent. ent. Hepatocytic component has typical cord-like
Stromal component may be absent. arrangement of cells. Evidence of stratification and
Hepatocytes may have some alteration in staining atypia of biliary epithelial component is minimal or
(eosinophilic, basophilic, or clear cell) compared to absent.
surrounding parenchyma.
Mitotic figures are rare. Comment: Rare spontaneous lesion. This neoplasm contains
neoplastic elements of both hepatocytes and bile duct epithe-
Differential diagnosis: lium (Deschl et al. 2001; Frith and Ward 1979; Harada et al.
1999; Narama et al. 2003; Teredesai, Wohrmann, and Schlage
Adenoma, hepatocellular—composed of neoplastic 2002). A diagnosis of malignancy may be based on just one of
hepatocytes. Loss of normal lobular architecture with the components being malignant.
irregular growth pattern. Liver plates often impinge
perpendicular or obliquely on the surrounding par-
Tumor, Ito Cell, Benign (Figures 153 and 154)
enchyma. Distinct compression is present.
Cholangioma—composed of neoplastic duct Synonyms: Fat-storing cell tumor; stellate cell tumor, lipoma.
epithelium. Well demarcated; usually solitary. The
acini are lined by cuboidal uniform and well- Pathogenesis: Arises from fat-storing perisinusoidal cells,
differentiated epithelium. so-called Ito cells.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 37S
Proliferative Lesions
Gallbladder, Calculi (Figures 175 and 176)
Hyperplasia, Gallbladder (Figures 179 and 180)
Synonyms: Stones, gallstones, choleliths.
Pathogenesis: Irritation of gallbaldder mucosa and after xeno-
biotic exposure.
Pathogenesis: Excess dietary factors and altered metabolism.
Diagnostic features:
Diagnostic features:
Lesion is often small.
Grossly visible concretion(s) in the gallbladder of Lesion varies from a few cells on papillary folds to
mice. small papillary projections.
Grossly, may be solid or soft, single or multiple, and Epithelium is usually single layered.
of various colors including white and pigmented (yel- Cells are well differentiated.
low, grey). Minimal atypia may be present.
Depending on the etiology, the stone may be com-
posed of a mixture of cholesterol, calcium salts, Differential diagnosis:
hemoglobin, and occasionally as a pure stone com-
posed of just one of these substances. Adenoma—growth pattern is disordered. May exhi-
Often associated with inflammatory lesions of the bit some atypia
gallbladder. Adenocarcinoma—increased cellular atypia. Disor-
dered growth pattern. Invasive growth.
Differential diagnosis: Adenomatoid change/glandular metaplasia—focal or
diffuse proliferation of epithelial cells forming gland-
Mineralization—associated with necrosis, necrotic ular structures. Cells are well differentiated, usually
benign or malignant tumor, and inflammatory columnar, and eosinophilic, with little or no cellular
conditions. atypia. Distinct eosinophilic crystals are present in
Neoplasia (Gross) —histologically, it is neoplastic. cytoplasm, or in lumen of glands.
Inflammation—inflammatory exudates may be seen
without gallstone formation. Comment: Details related to gallbladder hyperplasia can be
Parasites—can be seen histologically as parasites. found in several references (Deschl et al. 2001; Harada et al.
42S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
1996, 1999; Yoshitomi, Alison, and Boorman 1986; Yoshitomi et al. 2001; Harada et al. 1996, 1999; Lewis 1984; Yoshitomi,
and Boorman 1994). Alison, and Boorman 1986; Yoshitomi and Boorman 1994).
FIGURE 1.—Gross appearance and tissue trimming recommendations for a normal rodent liver. Ref. to http://reni.item.fraunhofer.de/reni/trimming/
index.php. FIGURE 2.— Two-dimensional microarchitecture of the liver. FIGURE 3.—Rat liver. Hepatodiaphragmatic nodule. FIGURE 4.—Rat liver.
Hepatodiaphragmatic nodule with intranuclear inclusions (chromatin). Higher magnification of Figure 3. FIGURE 5.—Rat liver. Macrovesicular fatty
change. FIGURE 6.—Rat liver. Macrovesicular fatty change. Higher magnification of Figure 5.
44S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 7.—Mouse liver. Fatty change, microvesicular. FIGURE 8.—Mouse liver. Mixture of fatty change and cytoplasmic glycogen. FIGURE 9.—
Mouse liver. Mixture of fatty change and cytoplasmic glycogen. Higher magnification of Figure 8. FIGURE 10.—Mouse liver. Tension lipidosis.
FIGURE 11.—Mouse liver. Tension lipidosis. Higher magnification of Figure 10. FIGURE 12.—Rat liver. Focal fatty change.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 45S
FIGURE 13.—Rat liver. Focal fatty change. Higher magnification of Figure 12. FIGURE 14.—Rat liver. Phospholipidosis. FIGURE 15.—Rat liver.
Phospholipidosis. Higher magnification of Figure 14. FIGURE 16.—Rat liver. Phospholipidosis. EM concentric membrane bound lysosomal myeloid
bodies/lamellar bodies. FIGURE 17.—Rat liver. Phospholipidosis. Central microvesiculation; positive LAMP-2 staining. FIGURE 18.—Mouse liver.
Amyloidosis.
46S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 19.—Mouse liver. Amyloidosis. Higher magnification of Figure 18. FIGURE 20.—Mouse liver. Focal mineralization associated with centri-
lobular necrosis. FIGURE 21.—Mouse liver. Pigment deposition in a focus of histiocytes. FIGURE 22.—Rat liver. Pigmentation. FIGURE 23.—Mouse
liver. Centrilobular hypertrophy with cholestasis. FIGURE 24—Mouse liver. Cholestasis.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 47S
FIGURE 25.—Rat liver. Pigment in hypertrophic hepatocytes consistent with bile. Cholestasis. FIGURE 26.—Mouse liver. Hyalinosis of hyper-
plastic bile ducts with crystal formation and peribiliary inflammatory cell infiltrate. FIGURE 27.—Mouse liver. Hyalinosis of hyperplastic bile
ducts with crystal formation and peribiliary inflammatory cell infiltrate. Higher magnification of Figure 26. FIGURE 28.—Mouse liver.
Hyalinosis of hyperplastic bile ducts with crystal formation. FIGURE 29.—Mouse liver. Numerous intracytoplasmic hyaline bodies in an hepa-
tocellular adenoma. FIGURE 30.—Mouse liver. Intranuclear inclusion body, cytoplasmic invagination.
48S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 31.—Mouse liver. Intranuclear inclusion bodies. FIGURE 32.—Mouse liver. Cytoplasmic inclusions in an hepatocellular adenoma. FIGURE
33.—Mouse liver. Plasma influx. FIGURE 34.—Mouse liver. Centrilobular hepatocellular hypertrophy. FIGURE 35.—Mouse liver. Higher magni-
fication of centrilobular hepatocellular hypertrophy. FIGURE 36.—Mouse liver. Hepatocellular hypertrophy.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 49S
FIGURE 37.—Mouse liver. Hepatocellular hypertrophy. FIGURE 38.—Mouse liver. Centrilobular hepatocellular hypertrophy. FIGURE 39.—Rat
liver. Hepatocellular hypertrophy with eosinophilic granular cytoplasm following treatment with a peroxisome proliferating xenobiotic.
FIGURE 40.—Rat liver. Hepatocellular hypertrophy following treatment with a peroxisome proliferating xenobiotic. FIGURE 41.—Rat liver.
Hepatocyte enlargement confirmed as mitochondrial hypertrophy. FIGURE 42.—Rat liver. Atrophy.
50S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 43.—Mouse liver. Hepatic atrophy. FIGURE 44.—Mouse liver. Cytoplasmic alteration. FIGURE 45.—Mouse liver. Hydropic degeneration.
FIGURE 46.—Rat liver. Cystic degeneration. FIGURE 47.—Rat liver. Cystic degeneration. FIGURE 48.—Mouse liver. Apoptosis.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 51S
FIGURE 49.—Mouse liver. Apoptosis. FIGURE 50.Mouse liver. Apoptosis. FIGURE 51 and 53 Mouse liver. Necrosis, focal. FIGURE 52. Mouse liver.
Necrosis, multifocal. FIGURE 54. Rat liver. Bridging centrilobular necrosis.
52S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 55.—Rat liver. Bridging centrilobular necrosis. Higher magnification of Figure 54. FIGURE 56.—Rat liver. Centrilobular necrosis with early
bridging. FIGURE 57.—Rat liver. Centrilobular necrosis with early bridging. Higher magnification of Figure 56. FIGURE 58.—Rat liver. Centrilob-
ular bridging necrosis with mineralization. FIGURE 59.—Rat liver. Centrilobular bridging necrosis with mineralization. Higher magnification of
Figure 58. FIGURE 60.—Rat liver. Midzonal necrosis.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 53S
FIGURE 61.—Rat liver. Midzonal necrosis. Higher magnification of Figure 60. FIGURE 62.—Mouse liver. Periportal necrosis. FIGURE 63.—Mouse
liver. Diffuse necrosis with inflammation and bile duct hyperplasia in lower left of figure. FIGURE 64.—Mouse liver. Diffuse necrosis.
Multinucleated giant cells in MHV infection. Higher magnification of Figure 63. FIGURE 65.—Mouse liver. Karyocytomegaly. FIGURE 66.—Mouse
liver. Multinucleated hepatocytes. Karyocytomegaly.
54S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 67.—Rat liver. Biliary cysts. FIGURE 68.—Rat liver. Biliary cysts. FIGURE 69.—Rat liver. Biliary cysts. Higher magnification of Figure 68.
FIGURE 70.—Mouse liver. Generalized inflammation, postnecrotic mild fibrosis. Mouse hepatitis virus infection. FIGURE 71.—A descriptive
approach for classifying inflammatory responses in the liver. FIGURE 72.—Mouse liver. Focal neutrophil infiltrate associated with hepatocyte
necrosis.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 55S
FIGURE 73.—Mouse liver. Multifocal mononuclear cell infiltrates. Norovirus infection. FIGURE 74.—Rat liver. Infiltration, mononuclear. Granu-
lomatous inflammation with pigment-laden histiocytes and multinucleated giant cells. FIGURE 75.—Rat liver. Mixed inflammatory cell infiltrate
and granulomatous inflammation. FIGURE 76.—Infiltration, mononuclear (microgranulomas). FIGURE 77.—Rat liver. Infiltration, mononuclear.
FIGURE 78.—Rat liver. Infiltration, mononuclear. Granulomatous inflammation (cholesterol granuloma).
56S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 79.—Rat liver. Infiltration, mononuclear. Granulomatous inflammation (cholesterol granuloma). Higher magnification of Figure 78.
FIGURE 80.—Mouse liver. Focal neutrophil infiltrate. FIGURE 81.—Mouse liver. Periportal inflammatory cell infiltrate. FIGURE 82.—Rat liver.
Fibrosis. Early bridging between lobules. FIGURE 83.—Rat liver. Fibrosis. Higher magnification of Figure 82. FIGURE 84.—Mouse liver. Silver
stain demonstrating Helicobacter sp.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 57S
FIGURE 85.—Rat liver. Chronic passive congestion. FIGURE 86.—Rat liver. Angiectasis. FIGURE 87.—Rat liver. Angiectasis. FIGURE 88.—Rat liver.
Thrombosis with associated area of necrosis. FIGURE 89.—Mouse liver. Infarcted lobe. FIGURE 90.—Mouse liver. Infarct.
58S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 91.—Rat liver. Endothelial karyomegaly (sinusoidal cell karyomegaly). FIGURE 92.—Mouse liver. Increased mitoses. FIGURE 93.—Rat
liver. Diffuse basophilic focus. FIGURE 94.—Rat liver. Diffuse basophilic focus. Higher magnification of Figure 93. FIGURE 95.—Rat liver. Baso-
philic (tigroid) focus of cellular alteration. FIGURE 96.—Rat liver. Basophilic focus of cellular alteration with cystic degeneration.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 59S
FIGURE 97.—Rat liver. Basophilic focus of cellular alteration. FIGURE 98.—Rat liver. Eosinophilic focus of cellular alteration. FIGURE 99.—Rat
liver. Eosinophilic focus of cellular alteration. Higher magnification of Figure 98. FIGURE 100.—Rat liver. Eosinophilic focus of cellular alteration
with pale pink cytoplasm. FIGURE 101.—Mouse liver. Large basophilic focus of cellular alteration with glycogen present in centrally located hepa-
tocytes. FIGURE 102.—Mouse liver. Large basophilic focus of cellular alteration with glycogen present in centrally located hepatocytes. Higher
magnification of the edge of Figure 102.
60S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 103.—Rat liver. Mixed cell foci. FIGURE 104.—Rat liver. Mixed cell focus. Higher magnification of Figure 103. FIGURE 105.—Mouse liver.
Clear cell focus. FIGURE 106.—Mouse liver. Clear cell focus. Higher magnification of Figure 105. FIGURE 107.—Rat liver. Clear cell focus of
cellular alteration. FIGURE 108.—Rat liver. Amphophilic focus.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 61S
FIGURE 109.—Rat liver. Early non-regenerative hyperplasia. FIGURE 110.—Rat liver. Non-regenerative hyperplasia. FIGURE 111.—Rat liver.
Regenerative hyperplasia. FIGURE 112.—Rat liver. Regenerative hyperplasia. Higher magnification of Figure 111. FIGURE 113.—Rat liver. Regen-
erative hyperplasia. Higher magnification of Figure 111. FIGURE 114.—Mouse liver. Kupffer cell hyperplasia.
62S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 115.—Mouse liver. Kupffer cell hyperplasia. FIGURE 116.—Mouse liver. Ito cell hyperplasia. FIGURE 117.—Mouse liver. Ito cell hyper-
plasia. Higher magnification of Figure 116. FIGURE 118.—Mouse liver. Ito cell hyperplasia, multifocal. FIGURE 119.—Rat liver. Bile duct hyper-
plasia. FIGURE 120.—Rat liver. Bile duct hyperplasia with associated mononuclear inflammatory cell infiltrate.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 63S
FIGURE 121.—Rat liver. Bile duct hyperplasia with mononuclear inflammatory cell infiltration and early fibrosis. FIGURE 122.—Rat liver. Bile
duct hyperplasia. FIGURE 123.—Rat liver. Cholangiofibrosis. FIGURE 124.—Rat liver. Cholangiofibrosis. FIGURE 125.—Rat liver. Cholangiofibro-
sis. FIGURE 126.—Rat liver. Cholangiofibrosis.
64S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 127.—Rat liver. Oval cell hyperplasia. FIGURE 128.—Mouse liver. Oval cell hyperplasia. FIGURE 129.—Mouse liver. Oval cell hyperplasia.
FIGURE 130.—Mouse liver. Large hepatocellular adenoma. FIGURE 131.—Mouse liver. Hepatocellular adenoma, eosinophilic. FIGURE 132.—
Mouse liver. Hepatocellular adenoma, eosinophilic. Higher magnification of Figure 131.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 65S
FIGURE 133.—Mouse liver. Hepatocellular adenoma. FIGURE 134.—Mouse liver. Hepatocellular adenoma. High magnification of Figure 133.
FIGURE 135.—Mouse liver. Hepatocellular carcinoma. FIGURE 136.—Mouse liver. Hepatocellular carcinoma. Prominent glandular formation.
Higher mignification of Figure 135. FIGURE 137.—Mouse liver. Hepatocellular carcinoma. Prominent glandular and trabecular formation. Higher
mignification of Figure 135. FIGURE 138.—Mouse liver. Hepatocellular carcinoma with trabecular and glandular formation.
66S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 139.—Mouse liver. Hepatocellular carcinoma arising in an hepatocellular adenoma. FIGURE 140.—Mouse liver. Hepatocellular carcinoma
arising in a hepatocellular adenoma. Higher magnification of Figure 139. FIGURE 141.—Mouse liver. Hepatoblastoma. FIGURE 142.—Mouse liver.
Hepatoblastoma. Higher magnification of Figure 141. FIGURE 143.—Mouse liver. Hepatoblastoma. Osseous metaplasia is present. FIGURE 144.—
Mouse liver. Hepatoblastoma. High magnification of Figure 143.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 67S
FIGURE 145.—Mouse liver. Cholangioma. FIGURE 146.—Mouse liver. Cholangioma. Higher magnification of Figure 145. FIGURE 147.—Mouse liver.
Cholangiocarcinoma. FIGURE 148.—Mouse liver. Cholangiocarcinoma. Higher magnification of Figure 147. FIGURE 149.—Rat liver. Hepatocholan-
gioma (adenoma, hepatocholangial). FIGURE 150.—Rat liver. Hepatocholangioma (adenoma, hepatocholangial). Higher magnification of Figure 149.
68S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 151.—Rat liver. Hepatocholangiocarcinoma (Carcinoma, hepatocholangial). FIGURE 152.—Rat liver. Hepatocholangiocarcinoma
(Carcinoma, hepatocholagial). High magnification of Figure 151. FIGURE 153.—Mouse liver. Ito cell tumor. FIGURE 154.—Mouse liver. Ito cell tumor.
Higher magnification of Figure 153. FIGURE 155.—Mouse liver. Histiocytic sarcoma. Perivascular infiltration. FIGURE 156.—Mouse liver.
Hemangioma.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 69S
FIGURE 157.—Mouse liver. Hemangioma. High magnification of Figure 156. FIGURE 158.—Mouse liver. Hemangiosarcoma. FIGURE 159.—Mouse
liver. Hemangiosarcoma. Higher magnification of Figure 158. FIGURE 160.—Mouse liver. Hemangiosarcoma. Higher magnification of Figure 159.
FIGURE 161.—Mouse liver. Extramedullary hematopoiesis. FIGURE 162.—Mouse liver. Extramedullary hematopoiesis. Myelopoiesis.
70S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 163.—Mouse liver. Intrahepatic erythrocytes. FIGURE 164.—Rat liver. Pancreatic acinar metaplasia. FIGURE 165.—Rat liver. Ectopic
acinar pancreas. FIGURE 166.—Rat liver. Hepatocyte glandular metaplasia. FIGURE 167.—Rat liver. Hepatocyte glandular metaplasia. FIGURE
168.—Mouse liver. Subintimal intravascular hepatocyte proliferation.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 71S
FIGURE 169.—Mouse gallbladder. Heterotopic acinar pancreas. FIGURE 170.—Mouse gallbladder. Heterotopic acinar pancreas. Higher magni-
fication of Figure 169. FIGURE 171.—Mouse gallbladder. Hyalinosis. Part of a biliary calculus is present. FIGURE 172.—Mouse gallbladder.
Hyalinosis with crystal formation. FIGURE 173.—Mouse gallbladder. Hyalinosis and mucosal hyperplasia. Higher magnification of Figure 172.
FIGURE 174.—Mouse gallbladder. Hyalinosis with crystal formation. Higher magnification of Figure 172.
72S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
FIGURE 175.—Mouse gallbladder. Biliary calculus (biliary stone). FIGURE 176.—Mouse gallbladder. Hyalinosis and biliary calculus.
FIGURE 177. Mouse gallbladder. Cholecystitis. FIGURE 178.—Mouse gallbladder. Submucosal edema. FIGURE 179.—Mouse gallbladder. Mucosal
hyperplasia. FIGURE 180.—Mouse gallbladder. Mucosal hyperplasia. Higher magnification of Figure 179.
Vol. 38, No. 7S, 2010 LESIONS OF THE HEPATOBILIARY SYSTEM 73S
FIGURE 181.—Mouse gallbladder. Papillary adenoma. FIGURE 182.—Mouse gallbladder. Papillary adenoma. FIGURE 183.—Mouse gallbladder.
Papillary adenoma. Higher magnification of Figure 182.
74S THOOLEN ET AL. TOXICOLOGIC PATHOLOGY
ACKNOWLEDGEMENTS Bergs, V. V., and Scotti, T. M. (1967). Virus-induced peliosis hepatitis in rats.
Science 158, 377–78.
The authors wish to express their thanks for the excellent Binhazim, A. A., Coghlan, L. G., and Walker, C. (1994). Spontaneous heman-
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