Authors Bob Thoolen Robert R.Maronpot Takanori Harada Abraham Nyska Colin Rousseaux Thomas Nolte David E.Malarkey Wolfgang Kaufmann Karin Küttler Ulrich Deschl Dai Nakae Richard Gregson Michael P.Vinlove Amy E.Brix Bhanu Singh Fiorella Belpoggi Jerrold M.Ward
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 internationally-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.
Diagnostic pathology; hepatobiliary system; histopathology; liver; nomenclature; rodent pathology.
AE1/AE3, Two clones of anti-cytokeratin monoclonal antibodies; a.k.a., Also known as; AS, Anterior Segment; α-SMA, α -smooth muscle actin; Bcl-2, B-cell 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, Left 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.
LLL = Left lateral lobe; RLL = Right lateral lobe; PC = Caudate Process; LML = Left medial lobe; RML = Right medial lobe; PP = Papillary Process; PPA = Processus papillaris anterior; AS = Anterior Segment; MS = Middle Segment; PS = 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).
The liver is a major target organ in safety assessment of preclinical toxicity and oncogenicity studies with rodents; hence, hepatic pathology is central to many toxicological pathology studies. As toxicologic pathologists sometimes experience difficulties in distinguishing the wide variety of liver lesions in the rodents for safety evaluation purposes, this document is a consensus of senior toxicologic pathologists regarding suggested nomenclature that should be used for specific lesions.
Standardized diagnostic criteria and nomenclature are essential to harmonize the classification and reporting of hepatic non-proliferative as well as proliferative lesions. This INHAND document serves as a framework that can be used for the harmonization of diagnostic criteria of hepatic lesions in laboratory rats and mice. These recommendations for diagnostic criteria and preferred terminology should not be considered mandatory; proper diagnoses are ultimately based on the discretion of the toxicologic study pathologist.
The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) initiative creates a framework for the harmonization of diagnostic nomenclature (classification of lesions using the same terminology) in different rodent organ systems. It is a joint initiative between Societies from the United States (STP), Great Britain (BSTP), Japan (JSTP), and European countries (ESTP).
This document is organized to provide introductory material that reviews comparative interspecies differences in anatomy and liver function, followed by a listing of liver lesions in a standardized format. The liver lesions descriptions include differential diagnoses to aid in distinguishing primary diagnoses from similar appearing lesions. Throughout the document, comparisons are made with respect to similar liver lesions that may occur in humans. It should be noted that the preferred diagnostic terminology for some lesions in this document might represent departures from traditional nomenclature schemes found in standard textbooks. Furthermore, illustrative photomicrographs for a given diagnostic entity may occasionally depict additional tissue changes as this reflects actual situations frequently observed in pathological evaluation of toxicity studies.
The liver occupies the cranial third of the abdominal cavity and is comprised of multiple lobes; however, the nomenclature for the liver lobes varies among authors. There are basically left, middle, right, and caudate lobes (Harada et al. 1999; Eustis et al. 1990). A thin connective tissue capsule that is externally lined by peritoneal mesothelial cells covers the parietal and visceral surfaces of the liver. The middle lobe has an incomplete fissure where the falciform ligament attaches. In mice the gallbladder is located in the middle lobe fissure, whereas the rat does not have a gallbladder. The right lobe has an anterior and posterior component and the small caudate lobe consists of two or more disc like sublobes (See Figure 1).
Nomenclature for liver lobes varies among species and sometimes among authors. A table showing differences in liver lobes between species is included based on current anatomic features (Table 1).
The two-dimensional microarchitecture of the liver has been categorized in at least three perspectives (Figure 2). The anatomic model is the classical lobule, a hexagonal structure divided into concentric centrilobular, midzonal, and periportal segments. The triangular portal lobule is based on bile flow and is centered on the portal triad (portal canal). The elliptical or diamond shaped liver acinus is a functional sub unit of the liver. It incorporates blood flow and metabolic functions and is divided in zone 1 (periportal), zone 2 (transitional; midzonal), and zone 3 (centrilobular). Functionally, zone 1 hepatocytes are specialized for oxidative liver functions such as gluconeogenesis, β-oxidation of fatty acids, and cholesterol synthesis, while zone 3 cells are more important for glycolysis, lipogenesis, and cytochrome P-450–based drug detoxification.
The liver has a dual blood supply, the hepatic portal vein and the hepatic artery. The hepatic artery supplies oxygenated blood. Approximately 75% of the blood is delivered to the liver via the hepatic portal vein that drains the spleen, stomach, intestines, and pancreas. Branches of the hepatic artery and portal vein are seen in the portal triads along with bile ducts and are separated from the hepatic cords by a ‘‘limiting plate’’ of hepatocytes. The bile ducts join to form the hepatic duct leading to the small intestine in rats and to the gallbladder in mice. Blood flows from the portal areas to the central vein in the center of each lobule while bile flows from the center of the hepatic lobule to the portal areas and on to the hepatic duct.
The two most commonly used descriptions for the structural and functional units of the liver are the hepatic lobule (Kiernan 1883) and the acinus (Rappaport et al., 1954) (Figure 2). The structural unit, the hepatic lobule, is modeled on the blood flow within the liver and is commonly used for descriptive pathology and morphological diagnoses. The functional unit, the hepatic acinus, is modeled on blood flow and metabolism within the liver. More recently a parenchymal unit in the liver has been described as a cone-shaped three-dimensional structure comprised of approximately fourteen hepatic lobules supplied and drained by common vascular tributaries (Malarkey et al. 2005; Teutsch, Schuerfeld, and Groezinger 1999; Teutsch 2005). This parenchymal unit more closely explains the random size and shape distribution of the more classical hepatic lobule as seen in a conventional two-dimensional histology slide. It also provides a basis for understanding the heterogeneous response of various hepatic lobules to chemical insult.
In addition to hepatocytes, the liver is comprised of a variety of cell types, including biliary cells, endothelial cells, Kupffer cells, Ito cells (stellate cells), fat-storing cells, and pit cells in addition to hematopoietic cells in the sinusoids and blood vessels. Polyhedral hepatocytes comprise approximately 60% of the liver arranged in plates or cords that radiate from the central vein to the portal areas. In two-dimensional sections they are typically one cell layer thick and form anastomoses (Miyai 1991). On one surface they are separated from the sinusoidal wall by a peri-sinusoidal space, the space of Disse, where they are exposed to tissue fluids. On the opposite side of the hepatocyte bile canaliculi are formed with hepatocytes in an adjacent hepatic cord. Desmosomes, gap junctions, and stud-like protrusions connect contiguous hepatocytes within a cord. Biliary cells form bile ducts in the portal areas and constitute the portal triad with a hepatic artery and a portal vein. Fenestrated endothelial cells line the sinusoids and synthesize prostaglandins. Kupffer cells are a self-renewing fixed macrophage comprising approximately 10% of all liver cells (Eustis et al. 1990). Kupffer cells are phagocytic, secrete mediators of inflammation, and catabolize lipids and proteins. Ito cells (stellate cells) are peri-sinusoidal cells that store vitamin A and are also a major source of collagen in the liver. Pit cells are lymphocytes that have natural killer activity and are primarily located in periportal areas (Wright and Stacey 1991).
Immunohistochemistry (IHC), utilizing fluorescent or chromogen tagged antibodies, is a useful adjunct for identification of different cell types in the liver. Selected examples are provided in Table 2.
Use of IHC can be helpful for diagnostic purposes and is common in human pathology where panels of immunohistochemical stains are used for supporting diagnoses. Not all commercially available preparations of a given antibody will react the same way between different laboratories and between different species. Furthermore, expertise is required for tissue handling to unmask cellular antigens that may be cross-linked during tissue fixation. Diagnostic evaluation of immunostains typically requires inclusion of both positive and negative controls. The interpretations of IHC results are usually performed in conjunction with histopathological findings and sometimes also with consideration of gross findings and/or clinical pathology or other relevant study results.
The liver is responsible for maintenance of many homeostatic and physiological functions. Liver size is governed both by genetic factors and by the rate of biochemical activity to maintain optimal functional mass. It is an organ system capable of rapid responses to a variety of noxious stimuli. Following loss of hepatocytes from stimuli such as transient toxic insult, infection, or partial hepatectomy, the liver is rapidly restored to its optimal mass to maintain normal function.
Liver functions are complex and diverse including endocrine and exocrine activity, metabolism, conjugation, detoxification, and hematopoiesis in early embryonic and fetal development (Harada et al. 1999). The liver is continuously exposed to all ingested substances absorbed through the intestinal tract via the portal vein and systemically via the arterial blood supply. A pivotal hepatic function in toxicologic pathology is xenobiotic biotransformation that leads to detoxification of materials absorbed in the intestinal tract. Xenobiotic metabolism by hepatocytes can occur by phase I (often the cytochrome oxidase series) and phase II reactions (often the formation of the water-soluble glucuronide) (Graham and Lake 2008; Martignoni, Groothuis, and de Kanter 2006). Hepatic metabolic processes may also cause indirect toxicity by generating electrophilic species capable of reacting with proteins, nucleic acids, and other cytoplasmic organelles (Xu, Li, and Kong 2005). Intrinsic and induced enzymes responsible for hepatic function may be unevenly distributed throughout the hepatic lobule and between the different lobes (Greaves 2007). The presence of background changes and undercurrent disease states affects the hepatic and biliary morphology, for example, caloric restriction diminishes hepatocellular size and can make interpretation of test-article-related changes more challenging. Other factors that influence the liver morphology are: body weight loss, blood flow, food intake, vascular and hemodynamic changes, timing and duration of exposure, withdrawal effects, and functional heterogeneity. Functional heterogeneity expresses itself via differences in metabolism, oxygen supply, β-oxidation, amino acid metabolism, gluconeogenesis, glycolysis, ureagenesis, liponeogenesis, and bile acid and bilirubin secretion. These factors can affect occurrence of non-proliferative as well as proliferative liver lesions in rodents.
Geller, Dahll, and Alsabeh (2008); Malhotra, Sakhuja, and Gondal (2004); Hurlimann and Gardiol (1991); Davenport et al. (2001); Kashiwagi, Kaidoh, and Inoué (2001); Faa et al. (1998).
At necropsy, rat and mouse liver may be weighed and individual liver lobes examined carefully for gross lesions. In conventional preclinical rodent studies, gross lesions must be correlated with the histopathological findings. Liver-specific trimming protocols (see Figure 1) according to standard operating procedures (SOPs) are used (e.g., see Ruehl-Fehlert et al. 2003). Dissected lobes and trimmed liver pieces can be fixed in 10% neutral buffered formalin (no more than 1 cm thick in 1:10 tissue: formalin).
Interpretation of hepatic lesions in safety assessment studies requires consideration of gross and microscopic findings, hematology, clinical chemistry, and liver weights in the concurrent control groups of animals and should take into account species and strain, age, caging, diet, and tissue sampling.
Many pathologists use a grading system to document lesion severity. In toxicological pathology, the generation of ordinal data using a scoring system allows statistical analysis for effects and trends (Gad and Rousseaux 2002). However, not all grading systems are the same and may differ in how they incorporate distribution, stage, and extent of lesions. The problem of harmonization as it relates to lesion severity has been recognized and discussed in some detail (Hardisty and Eustis 1990; World Health Organization 1978).
Most toxicologic pathologists use a common grading scale such as marginal or minimal, slight, moderate, marked, and severe for inflammatory, necrotizing, or other degenerative and responsive lesions. Tissue-specific locators are often used, such as portal, periportal, midzonal, centrilobular, hilar, ductal, periductal, peri-canalicular, or subcapsular to indicate the lesion distribution within the liver. Focal, multifocal, and diffuse are commonly used modifiers in the morphological diagnosis for distribution parameters. Based on the formal definition, a focal lesion refers to one specific area, or focus, whereas multifocal refers to more than one focus (foci). However, some pathologists use focal for both focal and multifocal, referring to the nature of the lesion rather than its actual distribution and using grading to reflect the extent of the multifocality. Schemes for scoring lesion severity vary widely and no single system is likely to be accepted by all pathologists. While a sample grading scheme for focal and multifocal liver lesions is provided in Table 3, this should not be regarded as a universal or specific INHAND-recommended grading scheme.
Developmental anomalies occasionally occur in the liver of rodents. These malformations might be expressed in different forms and be of different origin. They mostly occur as isolated effects and are considered by the pathologist in distinguishing background hepatic lesions versus xenobiotic-induced lesions that occur in rodent preclinical toxicity studies.
Pathogenesis: Developmental alteration.
Comment: Hepatodiaphragmatic nodules can be seen in rats at any age and their occurrence in fetuses is considered presumptive evidence of a congenital origin. While they appear to be protruding through the diaphragm and extending into the thoracic cavity, they actually are attached to and covered by a thin fibrous portion of the diaphragm (Eustis et al. 1990).
An incidence ranging from 1% to 11% has been reported for hepatodiaphragmatic nodules in Fischer 344 rats (Eustis et al. 1990), with few cases reported in other rat stocks and strains. Mice do not develop such nodules but may have focal lesions similar to those in rat hepatodiaphragmatic nodules and with large nuclei with large central nucleoli-like basophilic bodies.
The function and structure of most liver cells are relatively constrained by their genetic programs of metabolism, differentiation, and specialization. While the cells of the hepatic parenchyma have the flexibility to adapt to changing physiological demands with reversible functional and morphological alterations, sufficient stress, or noxious stimuli may lead to inability to maintain homeostasis and adverse cellular adaptations. The morphological response to injurious stimuli depends on the nature of the injury and its severity and duration. Often at high doses, targeted cells go through a sequence of cellular degeneration followed by cell death, but at lower doses degenerative changes do not necessarily lead to cell death. Consequentially, cellular changes that do not lead to cell death or death of the animal may be called ‘‘adaptive’’ changes that can be considered either adverse or not adverse reactions, depending on the nature of the change. There are cellular adaptations involving metabolic or functional alterations that lead to increases in cellular organelles and intracellular accumulations of a variety of endogenous and exogenous substances but allow the cell and animal to survive and often live normally. Similar changes may occur in human liver, such as cholestasis, a common lesion in human liver after long-term drug therapy. However, in animals, when the limits of adaptive responses are exceeded or do not occur in response to chemical exposure, irreversible cellular injury and cellular death occurs, with possible subsequent illness and death.
Adaptive changes or doses of chemicals that induce adaptive changes usually do not result in illness or death of rodents. Often these processes are dose and chemical related.
Synonyms/subtypes: Lipidosis, vacuolation, lipid, macrovesicular and/or microvesicular steatosis, phospholipidosis.1
1 Electron microscopy or special staining needed for a definitive diagnosis.
Pathogenesis: Perturbations in lipid metabolism and disposition.
Macrovesicular fatty change (Figures 5 and 6).
Microvesicular fatty change (Figure 7).
Comment: There is a difference in preferred nomenclature among pathologists for this change. Based strictly on an H&E-stained section, a diagnosis of cytoplasmic vacuolation of hepatocytes is a universally acceptable descriptive diagnosis. Based on the experience of the observer, the specific morphological features of the cytoplasmic vacuolation may be sufficiently consistent with intracytoplasmic lipid accumulation to warrant a presumptive diagnosis of fatty change. The unequivocal demonstration of intracytoplasmic fat, however, requires a special stain.
Fatty change can be induced by a number of different agents and is usually divided into two main types, namely, microvesicular and macrovesicular, although mixed forms can frequently be observed (Greaves 2007; Gopinath, Prentice, and Lewis 1987; Goodman and Ishak 2006; Kanel and Korula 2005). Macrovesicular lipidosis is a reaction to a wide variety of injuries and can also be regarded as a physiological adaptation demonstrated as an imbalance between uptake of lipids from blood and secretion of lipoproteins by the hepatocyte (Goodman and Ishak 2006). Microvesicular lipidosis is usually indicative of more serious hepatic dysfunction but can also result from nutritional disturbances (Greaves 2007).
Specific xenobiotics can induce either macrovesicular or microvesicular lipidosis in humans (Kanel and Korula 2005). In animal studies, it is common to see a mixture of macrovesicular and microvesicular lipidosis. In those situations, one can either diagnose the most prevalent form or record the findings as mixed. Commentary in the pathology narrative report might be appropriate, especially if recording the most prevalent form of lipidosis. Liver with admixed presence of glycogen and fatty change can be observed (Figures 8 and 9).
Fatty change and necrosis may appear together although they may differ in proportion. A number of causes other than xenobiotic exposure, such as chronic hepatic injury, diet, metabolic and hormonal status, debilitation of animals, and fasting before necropsy, should be taken into consideration in reviewing these changes (Vollmar et al. 1999; Katoh and Sugimoto 1982; Nagano et al. 2007; Denda et al. 2002). The distribution can be either diffuse (e.g., ethionine) or zonal (e.g., centrilobular in CCl4; periportal in phosphorus toxicity; midzonal in choline deficiency). Inadequate fixation procedures may sometimes give rise to artifacts with microvesicular vacuolation, although mostly with less clear cytoplasm (Li et al. 2003).
Focal fatty change can sometimes be seen spontaneously and is usually described as such. A specific variation occurs near the attachment of the falciform ligament and gallbladder in mice and is referred to as ‘‘tension lipidosis’’ (Harada et al. 1999) (Figures 10 and 11). Spontaneous fatty change can differ between strains and is a normal finding in BALB mice. Livers of these mice are typically paler than in other strains. Focal fatty change in the liver of rodents has previously been categorized as vacuolated altered hepatic foci (Eustis et al. 1990), but current practice is to diagnose this change as focal fatty change rather than as a focus of hepatic alteration (Figures 12 and 13).
Fatty change can also be observed in combination with other hepatotoxic injuries (e.g., chronic liver toxicity, degeneration, inflammation, and necrosis) or nutritional disturbance (e.g., diet, vitamin A excess) in both animals and man. Special stains on cryostat sections can demonstrate fat (e.g., Oil red O or Sudan Black) (Jones 2002).
Synonym: Cytoplasmic vacuolation, foam cells.
2 Electron microscopy or special staining needed for a definitive diagnosis.
Pathogenesis: Induced by xenobiotics with a cationic amphophilic structure.
Comment: Definitive diagnosis of phospholipidosis is not possible based strictly on H&E-stained liver sections. A diagnosis of cytoplasmic vacuolation of hepatocytes will typically be an acceptable descriptive diagnosis. Since the cytoplasmic vacuolation may mimic microvesicular fatty change, a descriptive diagnosis of cytoplasmic vacuolation is recommended in the absence of electron microscopy or special immunostaining.
Phospholipidosis can be induced by xenobiotics with a cationic amphophilic structure (Halliwell 1997; Anderson and Borlak 2006; Reasor, Hastings, and Ulrich 2006; Chatman et al. 2009) (Figures 14 and 15). It is a lipid storage disorder seen when complexes between xenobiotics and phospholipids accumulate within lysosomes. Phospholipidosis refers to a specific form of hepatic vacuolation with the occurrence of concentric membrane bound lysosomal myeloid bodies/lamellar bodies that can be confirmed by specific staining and electron microscopy (Hruban, Slesers, and Hopkins 1972; Obert et al. 2007) (Figure 16). Definitive diagnosis requires electron microscopy or positive immunostaining. Immunohistochemical staining for a lysosomal-associated protein and adipophilin may be used to differentiate phospholipidosis from conventional fatty change (Obert et al. 2007). Both preexisting neutral fat and phospholipids can be observed in combination. The macrovesicular and the microvesicular fatty change (vacuolation) generally located at the cell periphery stains positively for Oil Red-O and the membranes surrounding these lipid vacuoles stain positively for adipophilin (a protein that forms the membrane around non-lysosomal lipid droplets) but negative for LAMP-2 (a lysosome-associated protein) by immunohistochemical techniques (Obert et al. 2007). This indicates that this vacuolation was due to accumulation of nonlysosomal neutral lipid. Cytoplasmic microvesiculation located centrally in hepatocytes that exhibit positive immunohistochemical staining for LAMP-2 (Figure 17) but is negative for Oil-Red-O and adipophilin is indicative of phospholipid accumulation (Obert et al. 2007).
Pathogenesis: Cellular process related to misfolding of protein.
Comment: This is a rare condition in rats but is a more common age-related phenomenon in hamsters and mice (Greaves 2007; BSTP 2007). The basis of the pathological change is the cell’s inability to prevent protein misfolding, to revert misfolded proteins to normal, or to eliminate misfolded proteins by degradation. This can result in deposition 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 beta-pleated sheet conformation.
The incidence of spontaneous amyloidosis usually increases with age and is common in CD-1 mice (Harada et al. 1996). Amyloid observed in the liver often is referred to as secondary amyloidosis (serum amyloid A protein) and is seen in the sinusoids and within the portal vessel walls. Hepatocytes adjacent to sinusoidal amyloid deposits are often atrophic. A number of factors (e.g., species, age, strain, gender, endocrine status, diet, stress, and parasitism) can influence the occurrence of amyloidosis (Beregi et al. 1987; Coe and Ross 1990; Lipman et al. 1993; Harada et al. 1996; Liu et al. 2007). Other organs are often involved in the deposition of amyloid (e.g., kidney, nasal submucosa, lamina propria intestines, heart, salivary gland, thyroid, adrenal cortex, lung, tongue, testis, ovary, and aorta).
Amyloidosis can be confirmed with additional histochemical staining (Congo red) where it shows pink-red staining and apple green birefringence under polarized light (Vowles and Francis 2002; Kanel and Korula 2005) and by immunohistochemistry.
Pathogenesis: Hypercalcemia secondary to diet or abnormal calcium metabolism; hepatocellular necrosis (dystrophic mineralization).
Comment: Mineralization is rarely seen in the liver and gallbladder in rodents. Dietary factors (mineral content) and disturbance of calcium metabolism commonly influence the process of hepatic mineralization (Harada et al. 1999; Spencer et al. 1997; Yasui, Yase, and Ota 1991; DePass et al. 1986). Mineralization can sometimes be observed in combination with inflammation or neoplasia (Harada et al. 1999; Kanel and Karuda 2005). Mineral deposits can be demonstrated by using additional stains (Alizarin Red, von Kossa) (Churukian 2002).
Pathogenesis: Incidental occurrence and secondary to cellular and erythryoid breakdown products; lipid peroxidation of cellular membranes; altered heme metabolism.
Bile (cholestasis) (Figures 23–25):
Comment: A number of different pigments may be seen as an incidental finding within hepatocytes and Kupffer cells in rodents. Some of them may increase and/or accumulate after treatment. Definitive diagnosis of a specific pigment typically requires special stains.
Lipofuscin or ceroid is sometimes referred to as ‘‘wear and tear’’ or ‘‘aging’’ pigment and therefore is often observed in older animals. It is considered to represent a breakdown of cell membranes. Lipofuscin accumulates in postmitotic and aging cells. It has been shown to be a mixture of oxidized proteins and lipids, carbohydrates, and trace amount of metals (Seehafer and Pearce 2006). A variety of stimuli can accelerate the accumulation of this pigment, such as drug and chemical exposure, trauma and circulatory factors, and diet (Greaves 2007). Lipofuscin accumulation in the liver may be augmented by certain chemicals (Kim and Kaminsky 1988; Marsman, 1995). Treatment of rats with PPAR alpha agonists such as fenofibrate and associated increased lipid peroxidation seen in rodents treated with hypolipidemic agents can induce lipofuscin accumulation in liver after prolonged treatment (Nishimura et al. 2007; Goel, Lalwani, and Reddy 1986; Reddy et al. 1982). Increased lipofuscin accumulation has also been observed in partially hepatectomized liver of rats (Sigal et al. 1999). Lipofuscin is insoluble in alcohols and xylene and other solvents normally used in the preparation of slides. Special stains such as Smorl’s can be used to demonstrate the pigment. Storage granules appear gray with Sudan Black B, may be PAS-positive, and may stain with Luxol fast blue and Ziehl-Neelsen (Jones 2002).
Porphyrin pigment, a precursor of heme protein, is seen with treatment of some xenobiotics. Bile pigment is a common finding when there is cholestasis secondary to obstruction of bile flow or when there is perturbation in bile metabolism. Bile pigment stains green with Hall’s method.
Hemosiderin pigment represents precipitated iron that is most frequently generated as a breakdown product of erythrocytes and is derived from hemoglobin and accumulates in the liver following local or systemic excess of iron. Deposition or iron may occur following excess dietary intake or treatment by xenobiotics (Popp and Cattley 1991; Greaves 2007; Travlos et al. 1996). Excess of iron following injection may be stored as hemosiderin and deposited in the reticuloendothelial component of the liver (and other organs such as spleen and bone marrow) (Bruguera 1999; Pitt et al. 1979). Intraperitoneal injection of aflatoxin B1 can also induce hemosiderosis in hamsters (Ungar, Sullman, and Zuckerman 1976). Endogenous iron deposition can be found following breakdown of blood cells (hemolytic event). Iron pigment can be found in Kupffer cells, macrophages, and hepatocytes. In hepatocytes, the iron is stored in the form of ferritin (ferric iron bound to protein apoferritin) (Popp and Cattley 1991). A spontaneous inherited predisposition for hepatic iron pigmentation has been reported in Sprague-Dawley rats (Masson and Roome 1997), and iron deposition can be found in the aging mouse liver (Harada et al. 1996). Iron can be demonstrated using Perls’ Prussian blue stain in which iron stains blue.
Hemosiderin slowly dissolves in acids, especially oxalic acid. Non-aldehyde fixatives can remove hemosiderin or alter it in such a way that reactions for iron are (false) negative (Churukian 2002). Malarial pigment is seen in hepatocytes and Kupffer cells of Plasmodium sp experimentally infected mice. It is the pigment from the organism and not hemosiderin.
Porphyrin pigment normally occurs in tissues only in small amounts and is a precursor of the heme portion of hemoglobin (Churukian 2002). Porphyrin deposition in the liver of rodents is found after administration of a number of compounds including griseofulvin where it can be seen in association with hepatocellular neoplasia (Stejskal et al. 1975; Zatloukal et al. 2000; Knasmuller et al. 1997; Tschudy 1962). Griseofulvin administration in mice may result in inhibition of the mitochondrial enzyme ferrochelatase and (compensatory) induction of ALA synthetase. Griseofulvin-induced accumulation of porphyrins in mouse liver is followed by cell damage and necrotic and inflammatory processes (Knasmuller et al. 1997). Proto-porphyrin pigment in liver of rats and mice is mainly found in the bile ducts and leads to bile duct proliferation and portal inflammation, but can also occur in hepatocytes, Kupffer cells, and portal macrophages (Hurst and Paget 1963). The birefringence of porphyrin appears to be associated with bilamellar components within the pigment (Stejskal et al. 1975). This pigment is also seen in combination with liver fibrosis and cirrhosis, bile duct proliferation, periportal inflammation, and hepatocarcinogenesis (Kanel and Korula 2005; Hurst and Paget 1963; Greaves 2007; Rank, Straka, and Bloomer 1990).
Pathogenesis: Hyperlipidemia (cholesterol crystals), Chi313 (Ym1) protein (eosinophilic biliary crystals).
Comment: In hyperlipidemia, cholesterol crystals can deposit in the liver with or without granulomatous inflammation (Greaves 2007; Graewin et al. 2004; Handley, Chien, and Arbeeny 1983). During gall stone formation, in addition to classical rhomboid-shape monohydrate crystals, cholesterol can also crystallize transiently as needle-, spiral-, and tubule- shaped crystals of anhydrous cholesterol (Dowling 2000). Eosinophilic crystals have been described in intrahepatic bile ducts and gallbladder of different laboratory mice strains, and some of these crystals have been shown to contain chitinase-like proteins confirmed by immunohistochemistry for Ym1 protein (now Chi313) (Ward et al. 2001; Harbord et al. 2002).
Crystal formation may be associated with inflammatory and/or proliferative bile duct changes and fibrosis in mice and may also occur spontaneously (Lewis 1984; Rabstein, Peters, and Spahn 1973; Enomoto et al. 1974). Numerous crystals can be demonstrated using a simple system of polarizing microscopy. Crystals are capable of producing plane-polarized light, thus showing birefringence.
Synonyms: Inclusion bodies, intranuclear cytoplasmic invagination, acidophilic inclusions, globular bodies.
Pathogenesis: Protrusion of cytoplasm into an invagination of the hepatocyte nuclear membrane without the actual protrusion necessarily being present in the plane of section. Seen in specific viral infections. Deposition of protein material within hepatocyte cytoplasm.
Comment: Both intranuclear and intracytoplasmic inclusions are common findings in the aging mouse liver and may be seen in normal as well as neoplastic hepatocytes (Percy and Barthold 2001; Frith and Ward 1988; Irisarri and Hollander 1994). When the intranuclear inclusions represent invaginations of the cytoplasm into the nucleus, they may contain cytoplasmic organelles in electron micrographs (van Zwieten and Hollander 1997). Ultrastructurally, three types of cytoplasmic inclusions have been described: dense reticulated substance in the dilated cisternae of rough endoplasmic reticulum, fine granular substance in rough endoplasmic reticulum, and non–membrane bound dense granulofibrillar in the cytoplasm (Helyer and Petrelli 1978).
Kakizoe, Goldfarb, and Pugh (1989) have correlated the incidences of cytoplasmic inclusion with hepatocellular tumors in different mice strains. C57BL/6 mice are relatively more resistant to hepatocarcinogens than C3H and C57BL/6 x C3H F1 mice. The tumors in the C57BL/6 mice were unique in their early focal development of cells containing inclusions. The authors suggested that the higher incidence of inclusions in liver might be related to slowing of the tumor growth leading to lower incidence of hepatocellular tumors in C57BL/6 mice. Other types of intracytoplasmic inclusions such as Mallory bodies, lamellated, and crystalloid inclusions have been described in mice treated with different chemicals and in lysosomal storage diseases (Gebbia et al. 1985; Meierhenry et al. 1983; Rijhsinghani et al. 1980; Shio et al. 1982).
Cytoplasmic vacuoles can occur in hepatocytes and endothelial cells in a postmortem time-dependent manner in fasted and non-fasted rats (Li et al. 2003). This artifact is especially common in rats that are not exsanguinated at necropsy and the cytoplasmic vacuoles represent plasma influx into to affected cells (Figure 33). This artifact is more common in males than in females.
Pathogenesis: Metabolic enzyme induction causing increase in endoplasmic reticulum; increase in peroxisomes; increase in mitochondria.
Comment: Hepatocellular hypertrophy, secondary to increase in microsomal enzymes often occurs with a zonal or specific lobular pattern and commonly occurs following exposure to enzyme inducing xenobiotics. There is enlargement of the hepatocyte cytoplasm secondary to increase in the cytosolic protein or number of organelles (e.g., smooth endoplasmic reticulum, peroxisomes, mitochondria). Classically hepatocyte hypertrophy occurs without increase in hepatocyte numbers or DNA (i.e., hyperplasia or polyploidy), however, combinations with increased mitoses do occur (e.g., PPAR-alpha agonists).
Hepatocellular hypertrophy following enzyme induction is considered an adaptive response to chemical stress. Strain differences in responsiveness occur. While typically an adaptive response, excessive hypertrophy from enzyme induction of hypertrophy can lead to hepatocellular degeneration and necrosis. Hepatocellular hypertrophy may be associated with increase in absolute liver weights. Enzyme induction leading to hepatocellular hypertrophy may be accompanied by some evidence of transient mitogenesis. Hypertrophy that is panlobular may be difficult to appreciate histologically because the contrast provided by a sublobular pattern is not evident. In some cases, hepatocyte hypertrophy related to metabolic enzyme induction may not be evident to the pathologist when liver weight increase is small for a group, for example, less than 20%.
Hepatocellular enlargement or swelling may occur from accumulation of glycogen, fat, or other substances and may also be a feature of degeneration and some forms of hepatocellular necrosis. To avoid confusion with the more common usage of hepatocyte hypertrophy for physiological enzyme induction, it is recommended that alternative forms of hepatocyte enlargement not be diagnosed as hepatocellular hypertrophy.
Pathogenesis: Inanition, starvation, hemodynamic changes, or pressure atrophy from neoplasia.
Comment: Hepatocellular atrophy can be caused by a number of factors such as inanition, starvation, hemodynamic changes, or pressure atrophy from neoplasia (Yu et al. 1994; Gruttadauria et al. 2007; Belloni et al. 1988). Hepatocyte atrophy may be associated with decrease in absolute liver weights in rats (Belloni et al. 1988). Ultrastructurally atrophic hepatocytes have reduced amounts of glycogen and decreased numbers of mitochondria.
Introduction: In the diagnostic lexicon, degeneration is a nonspecific diagnosis that provides limited useful information unless qualified to reflect the dominant morphological features. It is often at the borderline between adaptation with resolution back to normal structure and function and inability to adapt leading to cell death. In human clinical medicine degenerative disease most often refers to chronic debility involving organs and tissues that slowly accumulate damage over time. In rodent studies, degeneration may also be applicable to chronic debility, but more often it is used to reflect acute or chronic cytological alterations with characteristic morphological features. Combinations of different degenerative features may occur with or without inflammation and/or necrosis.
Based on H&E-stained sections, distinction between different forms of degeneration, hepatocellular hypertrophy secondary to enzyme induction, other forms of hepatocellular enlargement such as glycogen accumulation/retention, and even early necrosis (a.k.a. onconosis) may be difficult. In some cases, special stains may be required to more clearly delineate the nature of the cytologic alteration. Based strictly on H&E staining, a descriptive diagnosis of cytoplasmic alteration is recommended in lieu of interpretative diagnosis such as granular degeneration and hyaline degeneration. However, there are some degenerative lesions, such as hydropic degeneration and cystic degeneration, that are more clearly established in traditional pathology literature. The preferred diagnosis will be influenced by morphological features, conventional pathology practice, and the experience of the pathologist.
Glycogen accumulation in hepatocytes is a type of cytoplasmic alteration manifested on H&E-stained paraffin sections as clear spaces in the cytoplasm and a centrally located nucleus. Intracellular accumulation of glycogen is a normal physiological response following food ingestion. Since rodents eat primarily in the evening hours, the largest amount of glycogen will be present during early morning hours. Intrahepatocyte glycogen is mobilized throughout the day, initially being removed from centrilobular hepatocytes. Consequently, the amount present varies depending upon whether the animals were fasted and on the time of necropsy during the day. Failure to accumulate glycogen because of inanition or abnormal glycogen retention may result from treatment-induced metabolic perturbations.
Synonyms: Cytoplasmic alteration, cytoplasmic change, granular change, granular degeneration, hyaline degeneration, glycogen accumulation; ground glass change.
Pathogenesis: Often xenobiotic-induced and may be associated with other forms of liver damage.
Comment: What has been described as granular degeneration can be seen in combination with other forms of liver damage (e.g., necrosis, hydropic degeneration, inflammation) (Huang et al. 2007; Gokalp et al. 2003; Datta et al. 1998; Xu et al. 1992; Aydin et al. 2003). Hepatocellular granularity may be due to swelling of cell organelles or increase in the numbers of cell organelles including peroxisomes, mitochondria, and smooth endoplasmic reticulum. Some pathologists do not consider granular degeneration to be a distinct entity and do not include it in their diagnostic lexicon.
Hyaline degeneration has been described by a number of authors, sometimes in combination with Mallory body formation (Gonzalez-Quintela et al. 2000; NTP Toxicology and Carcinogenesis Studies Ethylene Glycol 1993; Peters et al. 1983; Bruni 1960; Shea 1958; Omar, Elmesallamy, and Eassa 2005; Lin et al. 1996), but is rarely used as a separate description since a combination of findings is often present. Cytoplasmic alteration reflecting plasma influx is an artifact seen in nonexsanguinated rats in a postmortem time-dependent manner (Li et al. 2003) (see Figure 33).
Synonyms: Cytoplasmic alteration, cytoplasmic change, hydropic change, cloudy swelling.
Pathogenesis: Intracytoplasmic fluid accumulation secondary to disturbance of cell membrane integrity.
Comment: Because of disturbance of the cell membrane integrity, accumulation of intracytoplasmic fluid may occur. This causes vacuolation and ‘‘ballooning’’ of cells. This change can be caused by a number of xenobiotics with differing lobular localization and may be a precursor to hepatocyte necrosis (Gkretsi et al. 2007; Wang et al. 2007; Peichoto et al. 2006; Matsumoto et al. 2006; Chengelis 1988).
Synonyms: Spongiosis hepatis (traditional diagnostic term preferred by many pathologists).
Pathogenesis: Cystic enlargement of perisinusoidal stellate cells (Ito cells) particularly observed in aging rats.
Comment: Spontaneous and xenobiotic-induced cystic degeneration/spongiosis hepatis may occur in rats (Karbe and Kerlin 2002; Bannasch 2003; Babich et al. 2004; Newton et al. 2001). It is more common in aging rats with some male predilection. It is less common in mice. This lesion may be seen in or associated with other hepatic lesions (necrosis, regeneration; foci of cellular alteration; hepatocellular neoplasms). The pathogenesis is not fully understood (Bannasch, Block, and Zerban 1981; Karbe and Kerlin 2002).
Introduction: In the fully developed organism, cell death is the ultimate result of irreversible cellular injury. Cellular death in the liver is manifested by a spectrum of morphological patterns that can occur alone or in combinations. However, there are two primary manifestations of cell death: necrosis and apoptosis. For decades a form of necrosis involving individual isolated hepatocytes has been diagnosed as ‘‘single cell necrosis.’’ This particular change is now regarded as ‘‘apoptosis’’ by most pathologists (Levin 1999; Levin et al. 1999; Elmore 2007) when the majority of injured cells have the typical apoptotic morphology. Provided that there is no accompanying inflammatory reaction, the two terms are synonymous. However, since a diagnosis of ‘‘apoptosis’’ implies a specific sequence of biochemical and morphological events and should ideally be supported by electron microscopy, it may be more prudent to diagnose single cell necrosis unless there is definitive proof of apoptosis provided by electron microscopy (Levin et al. 1999). It can be mentioned in the pathology narrative that the observed ‘‘single cell necrosis’’ is morphologically consistent with ‘‘apoptosis.’’
Pathogenesis: Direct or indirect cellular damage, including anoxia. Apoptosis (a.k.a., single cell necrosis) can occur spontaneously in liver and may also be exacerbated or induced by treatment.
Comment: Apoptosis is a form of genetically controlled ‘‘programmed cell death.’’ Microscopically in H&E-stained tissue sections, apoptosis appears as dense eosinophilic shrunken cell bodies with maintenance of membrane integrity, nuclear fragmentation and cytoplasmic budding, and without an inflammatory response. Definitive diagnosis of apoptosis can be made by histological findings and confirmed by distinctive electron microscopic features. Consequently, use of a diagnosis of ‘‘single cell necrosis’’ is appropriate based strictly on H&E staining. The use of TUNEL kits or caspase immunostaining may assist in diagnosing apoptosis and enumerating affected cells, but necrosis may also be immunopositive. Inhibition of apoptosis also plays a key role in the process of carcinogenesis (Foster 2000). Although apoptosis can be observed spontaneously in the liver, certain chemicals may be able to trigger direct stimulation of pro-apoptotic pathways in hepatocytes (Feldmann 1997; Reed 1998). Apoptosis can also accompany treatment-related zonal necrosis in the liver, especially in situations where there may be a xenobiotic induced effect (Cullen 2005; Greaves et al. 2001).
While apoptosis represents a specific genetically programmed form of cell death unaccompanied by an inflammatory response, there are situations where small numbers of cells and even occasional single cells characterized by cell swelling can undergo necrosis without an inflammatory response. This represents an early stage of conventional necrosis, may occur within hours after exposure to a xenobiotic, and should not be diagnosed as single cell necrosis (apoptosis). A more appropriate diagnosis for this situation is focal necrosis (see the following).
Comment: Some pathologists use focal for both focal and multifocal, referring to the nature of the lesion rather than its actual distribution. A severity grade can be used to reflect the multifocal nature of the lesion. Focal, multifocal, and subcapsular necrosis is occasionally seen in untreated rodents and may be a terminal event potentially due to hypoxic change secondary to impaired blood flow. Subcapsular necrosis has also been reported from direct pressure secondary to gastric distention and from some types of restraint (Parker and Gibson 1995; Nyska et al. 1992).
Pathogenesis: Secondary to direct or indirect damage from xenobiotic exposure; tissue anoxia.
Sometimes referred to as periacinar necrosis, it consists of irreversible cell death of centrilobular hepatocytes and is often seen after anoxia, or exposure to tannic acid, chloroform, or other hepatotoxic agents (Gopinath, Prentice, and Lewis 1987). This zone (Rappaport zone 3) is particularly vulnerable to ischemic damage because of its low oxygen gradient and generation of toxic metabolites due to high content of xenobiotic metabolizing enzymes (Comporti 1985; Walker, Racz, and McElligott 1985).
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; Satoh et al. 1996; Cheng 1956). The location is considered specific and has a metabolic basis.
Hepatic necrosis in the periportal zone is observed following a variety of agents (e.g., phosphorus, ferrous sulphate, allyl alcohol) (Kanel and Korula 2005; Atzori and Congiu 1996; Sasse and Maly 1991). Affected cells may encircle the portal tract (Popp and Cattley 1991) and may be associated with inflammatory and other changes (Ward, Anver, et al. 1994; Ward, Fox, et al. 1994; NTP Technical Report on the Toxicology and Carcinogenesis Studies of a Binary Mixture 2006; NTP Technical Report on the Toxicology and Carcinogenesis Studies of 2, 3, 7, 8-tetracholorodibenzo-p-dioxin 2006).
Synonym: Massive necrosis, panlobular necrosis.
Comment: Zonal necrosis is typically associated with exposure to xenobiotics that either directly damage hepatocytes or cause damage following metabolic activation by endogenous or induced enzymes. There is often a concentration gradient within the hepatic lobule with more extensive lobular involvement associated with higher doses of the toxic agent.
Hepatocellular necrosis can occur spontaneously in rodents or be induced by xenobiotics, toxins, or following treatment at high dosages with associated tissue anoxia, circulatory derangements, and biliary stasis. Necrosis (centrilobular, midzonal, periportal) might be accompanied by other histological changes (fatty change, congestion, hemorrhage, inflammation, bile stasis, fibrosis, etc.) to form a myriad of pathological changes. The distribution might also cross certain zones and may manifest as ‘‘bridging necrosis’’ showing confluence of the lesions (e.g., central to central veins, portal tract to portal tract, or portal tract to central zones). Bridging necrosis may ultimately give rise to bridging fibrosis.
A specific form of necrosis, ‘‘piecemeal necrosis’’, is characterized by necrosis of the limiting plate of the portal tract at the interface of hepatocytes and connective tissue of the portal tract, usually accompanied by inflammation, can be immune-mediated, and is seen in mice with resemblance to chronic active hepatitis in man (Kitamura et al. 1992; Nonomura et al. 1991; Kuriki et al. 1983).
Synonyms: Karyocytomegaly, multinucleated hepatocytes, binucleated hepatocytes, karyomegaly, nuclear hypertrophy, hepatocytomegaly, polyploidy, anisonucleosis, anisokaryosis.
Pathogenesis: Duplication of nuclear material in absence of cytokinesis. Variations in nuclear size and ploidy (karyomegaly and/or anisokaryosis) are common in aging rodents.
Comment: Karyocytomegaly is a reflection of hepatocyte polyploidy that occurs when there is duplication of nuclear material in the absence of cytokinesis. The result is an increase in the number of diploid nuclei per hepatocyte or an increase in the ploidy level of a single hepatocyte nucleus. Polyploidy increases with age in some strains of mice as well as following some treatment regimens resulting in hepatocytomegaly as well as karyomegaly (Harada et al. 1996). Variations in cell size as well as in nuclei and polyploidy are also common in aging rats of different strains. Karyomegaly and anisokaryosis are normal incidental findings, especially in older mice (Percy and Barthold 2001). Increase in cell size (cytomegaly) may accompany the increase in hepatocyte ploidy. Anisokaryosis (inequality in size of nuclei) is more common and dramatic in mice than in rats.
The development of polyploidy and its pattern vary among strains. C3H and DBA mice more commonly have octaploid cells with two tetraploid nuclei in adult liver while NZB and the out-bred strain NMRI at the corresponding age show a higher proportion of diploid cells with strikingly low proportions of tetraploid cells. Polyploidy has been observed in the early life (three weeks) in Ercc1 null mice. This premature polyploidy in Ercc1-deficient liver is most likely caused by increased levels of p21 in response to accumulating DNA damage (Chipchase, O’Neill, and Melton 2003). Toxic injury caused by chemicals such as phenobarbitone (Martin et al. 2001) and partial hepatectomy also induce an increase in ploidy, usually associated with extensive but transient hepatocyte proliferation (Gerlyng et al. 1993).
Although anisonucleosis (polyploidy) is known to occur as an age-related phenomenon, the nuclear and cellular changes can also be induced by xenobiotics (Schoental and Magee 1959; Jones and Butler 1975; Singh et al. 2007; Nyska et al. 2002; Guzman and Solter 2002; Lalwani et al. 1997; Travlos et al. 1996; Kari et al. 1995; Herman et al. 2002). In addition, multinucleated cells (formed by cell fusion rather than division) can be formed in rats after administration of 2, 3, 7, 8-tetrachloro-dibenzo-p-dioxin (Gopinath, Prentice, and Lewis 1987; Jones and Butler 1975). Eosinophilic cytoplasmic inclusions may be seen in affected hepatocyte nuclei because of cell membrane invaginations.
Pathogenesis: More common in aging animals occurs as a dilation of biliary structures.
Comment: Biliary cysts are commonly seen in older rats (Burek 1978; Greaves 2007; Harada et al. 1999). Solitary cysts can be observed without major adjacent morphology changes of the surrounding tissue. However, depending on the location, adjacent parenchyma may contain pressure atrophy of the hepatic cords of the liver, fibrosis, hemosiderin deposition, proliferation of bile ducts, or periportal lymphocytic infiltration. Single cysts are often caused by cystic dilatation of the intrahepatic bile ducts (Sato et al. 2005). Multiple cysts are observed also in hepatic polycystic disease, where they occur alone or in combination with polycystic kidney disease (Masyuk et al. 2004, 2007). They are often referred to as simple or multiloculated biliary cysts (Goodman et al. 1994). Polycystic liver can be observed in the rat (Muff et al. 2006; Sato et al. 2006) and hamster (Percy and Barthold 2001), resembling Caroli’s disease in humans (Clemens et al. 1980; Numan et al. 1986; Serra, Recalde, and Martellotto 1987). The cysts seen in polycystic disease are multiple and seen diffusely throughout the liver and are of variable size but generally large compared to the smaller biliary cysts.
A variety of focal, multifocal, and more generalized infiltrations of inflammatory cells are frequently present in liver tissue. Changes range from acute inflammatory cell infiltrate(s) or occasional aggregates of lymphocytes/lymphohistiocytic cells/foci of mononuclear cells without associated alterations of adjacent hepatocytes, to large panlobular patches of distinct hepatocyte necrosis accompanied by polymorphonuclear and mononuclear (lymphocytes, plasma cells, macrophages) cellular infiltrates. ‘‘Mononuclear cell’’ can be used when there is a mixture of cell types (lymphocytes; less often macrophages and plasma cells) or the cell type is mononuclear but cannot be unequivocally identified in H&E stain. If a cell type predominates, then the infiltrate should be classified as lymphocytic, plasmacytic, or histiocytic. While etiological agents (e.g., bacteria, virus, parasite) may be present, in most safety assessment studies the causes of significant inflammation are either cryptic or are attributed to a specific treatment regimen. Inflammatory reactions in the liver may be accompanied by oval cell and fibroblast proliferation and the propensity for hepatocellular proliferative responses to replace lost parenchyma.
It is recommended that use of the diagnostic term ‘‘inflammation’’ for the liver should be used sparingly. Liver inflammation (hepatitis) is operationally defined as a constellation of changes that represent a severe and generalized liver reaction and would require multiple diagnostic terms to adequately characterize (Figure 70). This type of reaction is not typically encountered in conventional rodent toxicity studies.
Traditionally, hepatic inflammatory responses have been classified as acute, subacute, chronic, granulomatous, and so on. These terms are somewhat interpretative, lack precise definitions, vary depending upon study duration, usually do not consist of a singular cell type, and do not have exclusive pathognomic features. A more descriptive approach is recommended and can be qualified by lesion distribution or use of subclassification and discretionary qualifiers (Figure 71).
Pathogenesis: Infiltration of different inflammatory cells is typically a response to parenchymal cell death with causes ranging from infectious agents, exposure to toxicants, generation of toxic metabolites, and tissue anoxia.
Synonyms: Inflammation, acute; acute inflammatory cell infiltrate(s), focus/foci of acute inflammatory cells; aggregate(s) of acute inflammatory cells.
Comment: While neutrophilic infiltration in the liver is primarily a response to liver cell injury and necrosis, a few lymphocytes or macrophages may also be present. In addition, foci of neutrophils without apparent hepatocyte necrosis may be present, especially in situations of a transient effect on the liver. In florid reactions, areas of necrosis include degenerating neutrophils admixed with the necrotic hepatic parenchymal cells.
The extent of parenchymal cell death eliciting inflammatory cell infiltration varies from minimal microfocal lesions to large patches of coagulation necrosis encompassing multiple contiguous lobules. For xenobiotic-induced cell death and inflammation, the severity of the lesions is often a function of the dose of the hepatotoxicant. Apoptotic cell death may occur along with conventional necrosis. Depending upon etiology, acute inflammation can have a specific lobular distribution with the possibility of portal or centilobular bridging between adjacent lobules.
Synonyms: Inflammation, chronic; mononuclear cell aggregates; inflammation, granulomatous, focus/foci of mononuclear cells.
Pathogenesis: Persistent noxious stimuli associated with infection, toxic xenobiotics, continued low level parenchymal cell death, and immune mediated effects.
Specific subtypes may include: infiltration, lymphocytes; infiltration, histiocytes (monocytes); infiltration, plasma cells.
Comment: Mononuclear cell infiltration spans a wide spectrum of morphological features and severities depending upon the extent and duration of liver damage and any ongoing regenerative response. In distinction from acute inflammation, there are typically fewer neutrophils seen in chronic lesions and there is more involvement of portal areas with infiltrating mononuclear cells and disruption of limiting plates. Granulomatous inflammation with characteristic focal or multifocal nodular collections of mononuclear epitheloid cells and occasional giant cells associated with areas of hepatocyte necrosis can be considered a specific subtype of mononuclear cells infiltration and part of the spectrum comprising chronic inflammation of the liver (Figures 74–77). Some pathologists consider granulomatous inflammation of the liver to be a form of chronic inflammation when there is a prolonged duration with predominant presence of epitheloid cells/macrophages and prefer to address the fact that there may be areas containing mononuclear epitheloid cells and multinucleated giant cells in the chronic inflammatory process in an accompanying narrative. Fatty material and cholesterol deposits may accumulate in some granulomatous inflammatory reactions. Such localized accumulations of abundant cholesterol have been referred to as cholesterol granulomas (Figures 78 and 79).
When only few isolated collections of mononuclear cells are present, some pathologists may diagnose them as focal mononuclear cell aggregates. These focal accumulations are considered by some to be a background lesion, and for these aggregates using the cell type in the diagnosis, instead of inflammation or inflammatory cell infiltrate, may be preferable and less misleading. The frequency of these mononuclear cell aggregates may be exacerbated by treatment. Helicobacter sp. and murine norovirus infections in mice may cause these incidental lesions.
Synonym: Infiltration, purulent, and mononuclear; chronic active inflammation; mixed inflammatory cell focus/foci.
Comment: Some pathologists consider a combined neutrophilic and mononuclear inflammatory cell infiltration as chronic active inflammation. This type of response is suggestive that the adverse stimulus is still present and/or that the immune system is active. Others may consider chronic active inflammation simply as a form of chronic inflammation with areas of neutrophilic infiltration in the inflammatory process and prefer to address that in their accompanying pathology narrative. A combined neutrophilic and mononuclear infiltrate (chronic active inflammation) is a common response found in mice chronically infected with Helicobacter hepaticus.
Pathogenesis: Age associated change that may be exacerbated by treatment.
Comment: A minimal to moderate peribiliary inflammatory cell infiltration consisting primarily of mononuclear cells can occur commonly in the livers of rats and mice and increases in incidence with animal age. Persistent obstruction to biliary flow may also lead to bile duct inflammation in hepatic portal areas. Although this background lesion may be considered a subtype of mononuclear cell infiltration (see previous), it is frequently diagnosed separately when exacerbated by treatment.
Pathogenesis: A reaction to acute or prolonged hepatotoxicity.
Comment: The pattern of fibrotic response to chronic injury varies among the species. When hepatic fibrosis is accompanied by a nodular or non-nodular regenerative response in the liver, it may be considered by some to represent cirrhosis. Classical cirrhosis is rare in rodents in contrast to dogs and humans and cannot reliably or consistently separate from a robust fibrotic reaction with associated nodular regeneration, oval cell proliferation, and bile duct hyperplasia. Such a robust fibrosis can be induced in rodents with prolonged or repeated exposure to certain chemicals (carbon tetrachloride, alcohol, tetrachlorovinphos, diallylphthalate), dietary lipotrope deficiency, or chronic hepatitis secondary to persistent infection (Ward 1997). We see no advantage in calling severe hepatic reaction cirrhosis in contrast to a diagnosis of hepatic fibrosis with an appropriate severity grade. The specific morphological features of this response can easily be addressed in the pathology narrative. It should be noted that hepatocellular neoplasms might arise in severe hepatic fibrosis.
Infectious diseases of the mouse liver are an important group of conditions that may interfere with toxicology and carcinogenesis studies. The histological changes associated with the diseases described in the following may be recorded using the nomenclature described previously under inflammation and inflammatory cell infiltrates but they are also presented here as a separate category of disease diagnoses to help pathologists diagnose the infections, which can be confirmed by PCR, immunohistochemistry, and other diagnostic studies. Some major infectious diseases are mentioned in the following to separate these background lesions from xenobiotic induced lesions.
Pathogenesis: Infection by a number of different Helicobacter spp.
Comment: A number of different Helicobacter spp. have been identified that can affect the rodent liver spontaneously (Ward, Anver, et al. 1994; Ward, Fox, et al. 1994; Goto et al. 2000; Zenner 1999). Helicobacter spp. can cause an increase in hepatocellular tumors in certain strains of infected mice, but are also known to generate liver lesions (Ward, Fox, et al. 1994; Tian et al. 2005; Rogers and Fox 2004) and can promote experimental carcinogenesis of the liver (NTP Toxicology and Carcinogenesis Studies of Theophylline 1998; Zenner 1999; Diwan et al. 1997) in rodents. The pathogenicity of the bacteria can vary with strain of bacteria and mouse strain, stock or line.
Helicobacter hepaticus may cause acute to subchronic minimal to severe lesions in livers of susceptible mice such as A strain, C3H, and BALB/c (Ward, Anver, et al. 1994). Many mouse strains are resistant to liver infection but A strain mice are the most susceptible (Ward, Anver, et al. 1994; Ward, Fox, et al. 1994). Incidental findings of focal or multifocal necrosis in the liver with or without inflammatory cells such as macrophages, lymphocytes, and neutrophils can be seen. In severely affected livers, more severe chronic lesions can be observed. H. hepaticus hepatic lesions are more common in males than females and incidence is increased in mice six months of age or older (Percy and Barthold 2001). H. bilis may also cause mild hepatic lesions.
It is rare for H. hepaticus to cause liver lesions unless the facility and animal room are known to be infected. If susceptible mouse strains are used in research, the more severe diffuse lesions may occur. Mouse infection in two-year carcinogenesis bioassays has complicated interpretation of carcinogenesis studies (Hailey et al. 1998; Stout et al. 2008).
Pathogenesis: Infection by murine norovirus.
Comment: Murine norovirus (MNV) may cause severe hepatitis in some lines of immunodeficient mice but only minimal hepatitis or no lesions in most lines of infected immunocompetent mice (Ward et al. 2006). MNV infection is the most common viral infection in mouse colonies today. The implications for interfering in experimental results are not known. It can be assumed that chemicals or infectious agents involving the immune system or liver may be influenced by MNV infection.
Pathogenesis: Infection by mouse hepatitis virus affecting hepatocytes, endothelium, and macrophages (Kupffer cells).
Comment: Mouse hepatitis virus (MHV), a coronavirus, infects hepatocytes, endothelium, and macrophages. In mouse liver, virus strains may have different pathogenicities in the various mouse strains and in mice of different ages (Percy and Barthold 2007). Focal and multifocal necrosis is seen with multinucleated (syncytial) hepatocytes, endothelium, and macrophages. Immunodeficient mice may develop a chronic persistent infection with chronic lesions in liver (Ward, Collins, and Parker 1977).
Clinical MHV infection may be most commonly seen in young mice. Adult mice may have serum antibodies but no clinical signs and few, if any, histopathologic lesions. Some cases show lesions in liver only. MHV is one of the most prevalent murine viruses in the United States and Europe (Homberger 1996) but appears less common today.
Pathogenesis: Infection by Clostridium piliforme (Bacillus piliforme).
Comment: Named after Ernest Tyzzer who first described it in a colony of Japanese walzing mice (Fox et al. 2002). Clostridium piliforme (Bacillus piliformis) is a long, thin, spore forming (intracellular) bacterium. Rare lesion with sudden death, with or without diarrhea. Often infection of the colon with dissemination to the liver (focal hepatitis) and occasionally heart (myocarditis). Special stains (e.g., Giemsa or Warthin-Starry Silver stain) can reveal intracytoplasmic filamentous bacteria.
Tyzzer’s disease is rare in rodents. It is usually sporadic. The gerbil is known to be extremely susceptible to infection (Fox et al. 2002).
Gross lesions can include hepatomegaly, focal necrosis, single or multifocal, small or large lesions sometimes associated with lesions in other tissues, especially intestines (Percy and Barthold 2007). Multiple foci of necrosis (coagulative necrosis) and/or multifocal necrotizing hepatitis can be observed microscopically.
The liver has a dual blood supply consisting of a relatively major (about 75%) venous (portal) supply via the hepatic portal vein, which carries venous blood that is largely depleted of oxygen, and relatively minor (about 25%) arterial blood supply, via the hepatic artery. The portal blood contains toxic materials absorbed in the intestine, and therefore the liver is the first tissue to be exposed to toxic substances that have been absorbed through the gastro-intestinal tract.
Within the hepatic parenchyma, the hepatocytes are in intimate contact with the sinusoidal capillaries, which are carrying the mixture of blood originating from ramifications of the portal vein and hepatic artery to the central vein. The sinusoids are lined by modified endothelial cells containing fenestrations, which allow passage of lipoproteins and other large molecules but provide a barrier to blood cells. Kupffer cells reside in the lumen of the sinusoids and are anchored to their wall.
The morphological aspect of the hepatic pathology during circulatory disorders depends on the location of the vascular structure being affected (i.e., lobular sinusoids, the outflow hepatic vein, or the inflow portal vein).
Synonym: Chronic passive congestion.
Pathogenesis: Circulatory failure, typically right-sided heart failure.
Comment: Congestion may result from circulatory disturbance such as right-sided heart failure and is usually associated with necrosis of the centrilobular areas (Burt, Portmann, and MacSween 2002). Presence of blood in hepatic sinusoids seen in animals that die or in situations where there is incomplete exsanguination should not be diagnosed as congestion. If it is absolutely necessary to record such findings, it is important to qualify the blood stasis in the liver as passive congestion.
Synonyms: Peliosis hepatis, telangiectasis, sinusoidal dilation.
Pathogenesis: Perturbations in blood flow and/or drainage; weakening of sinusoidal walls.
Comment: Angiectasis is a cystic or cavernous widening of the liver sinusoids that can occur in a variety of pathological insults. In human, sinusoidal dilatation has been reported following hypoxia or hyperperfusion as a result of right-sided heart failure, thrombosis of hepatic veins, amyloid deposition, granulomatous, or neoplastic disease (Greaves and Faccini 1992; Bruguera et al. 1978). Although these lesions can also occur spontaneously in different rodents with different diseases or with certain neoplasms causing hemodynamic changes, it can also be induced by different compounds. Focal sinusoidal dilatation and peliosis hepatis have been observed in the rodent liver after treatment with nitrosamines, pyrrolizidine alkaloids or glucocorticoids (Greaves 2007; Ruebner, Watanabe, and Wand 1970; Ungar 1986; Wolstenholme and Gardner 1950). Altered hemodynamic and changes in the hepatic microcirculation have been proposed to be of importance in the pathogenesis of sinusoidal dilatation (Slehria et al. 2002). Subcapsular sinusoidal dilatation can also be found a postmortem finding in rats (Kimura and Abe 1994).
Angiectasis is defined by multiple blood-filled cystic spaces of different size and shape occurs after suspected loss or weakening of sinusoidal walls and/or supporting tissue. The two subtypes may occur in combination. The cystic spaces are devoid of endothelial lining in the cavernous subtype (‘‘parenchymal’’) although controversy still exists (Greaves 2007; Edwards, Colombo, and Greaves 2002). Angiectasis can be found in aged rats (Lee 1983). However, these lesions can also be induced in both rats and mice after viral infection (Bergs and Scotti 1967) or exposure to certain drugs or chemicals (Mendenhall and Chedid 1980; Husztik, Lazar, and Szabo 1984).
Angiectasis has also been reported in animals or humans infected with Bartonella spp. (Wong et al. 2001; Breitschwerdt and Kordick 2000) and it has been associated with a number of diseases in humans as well as administration of anabolic steroids and oral contraceptives (Naeim, Cooper, and Semion 1973; Zimmerman 1998; Tsokos and Erbersdobler 2005).
Angiectasis may refer to a vascular lesion formed by dilatation of a group of small blood vessels. It can be observed in transgenic mouse models (Srinivasan et al. 2003; Bourdeau et al. 2001) or related to xenobiotic administration in rats and mice (Robison et al. 1984; Kim et al. 2004). It can be found as an incidental finding in aging mice and is sometimes associated with hepatocellular neoplasms (Harada et al. 1996, 1999). Angiectasis can be chemically induced (Bannasch, Wayss, and Zerban 1997) and has been suggested to be preneoplastic in some animal models.
Pathogenesis: Activation of the coagulation system associated with arteritis or phlebitis or secondary to atrial thrombosis.
Comment: There are several potential mechanisms leading to liver thrombosis. Activation of the coagulation system associated with fibrin deposits and hypoxia located in the centrilobular sinusoids was reported to occur in the livers of rats exposed to monocrotaline (MCT) (Copple et al. 2002). It was suggested that the fibrin thrombi were formed following chemical-induced hepatic endothelial cell damage. In studying an endotoxin-exposure model, it was suggested that the noted focal and random hepatocellular necrosis was caused by circulatory disturbances due to fibrin thrombi in clusters of adjacent sinusoids. Using a rat model of 2-butoxyethanol induced hemolytic anemia associated with systemic thrombosis, fibrin thrombi were noted in the central vein and sinusoids of the liver, in addition to the presence of thrombi seen in several other organs (Ramot et al. 2007).
Pathogenesis: Interruption of blood flow in a major vessel. Torsion of hepatic lobe.
Comment: Aside from torsion of liver lobes, which can occur spontaneously in rodents, infarction is a very rare lesion that can be induced only under very specific experimental conditions. The combined injection in mice of NG-monomethyl-L-arginine and aspirin after lipopolysaccharide exposure resulted in significant hepatocellular enzyme release, characterized histologically by intravascular thrombosis with diffuse infarction and necrosis (Harbrecht et al. 1994). Intraperitoneal injections in rats of vasoconstrictor xenobiotics such as phenylephrine produced infarcts of the spleen regularly and infarcts of the liver occasionally (Levine and Sowinski 1985). Isolated perfusion with 1.0 g/kg of the cytotoxic xenobiotic 5-FU or hyperthermia of 41 degrees C x 10 min resulted in 90% to 100% mortality in rats, with extensive, patchy necrosis, and infarction on histologic examination (Miyazaki et al. 1983).
Synonyms: Endothelial cell enlargement, cytomegaly.
3 The examples provided were confirmed with special stains (not shown).
However, based solely on H&E staining, a diagnosis of ‘‘sinusoidal cell hypertrophy/karyomegaly’’ is appropriate.
Introduction: This is a relatively new diagnostic entity. Because of the difficulty of identifying specific sinusoidal cell types from H&E-stained sections, definitive diagnosis of endothelial cell hypertrophy/karyomegaly requires confirmation using special stains.
Pathogenesis: Continued DNA synthesis and cell cycle arrest following exposure to certain xenobiotics.
Comment: In a study of monocrotaline (Wilson et al. 2000) it was suggested that the endothelial karyomegaly was the result of continued DNA synthesis and concentration-dependent cell cycle arrest. The exposed cells undergo a process of multiplication of chromosomal copies, defined as endopolyploidy, with nuclear and cytoplasmic gigantism. A direct correlation between cytoplasmic volume and nuclear DNA content was suggested.
A similar pathogenesis was suggested in the case of riddelliine-induced endothelial cytomegaly and karyomegaly (Nyska et al. 2002). Administration of riddelliine, a naturally occurring pyrrolizidine alkaloid, to rats results in cytomegaly and karyomegaly of hepatic endothelial cells as one of its pleotrophic responses to cell-specific cytotoxicity. A metabolite of this pyrrolizidine alkaloid is believed to directly interact with endothelial cell DNA.
Sometimes this change is interpreted as prominent Kupffer cells or Kupffer cell hypertrophy on H&E sections and warrants further characterization for confirmation of the endothelial cell origin. Immunohistochemical stains and electron microscopy can be used to identify the cell type involved.
Synonyms: Endothelial cell hyperplasia, angiomatous hyperplasia.
Pathogenesis: Proliferation of normally present sinusoidal lining endothelial cells without sinusoidal dilation.
Comment: Endothelial derivation and proliferation can be confirmed by dual immunostaining for CD31/KI-67 (Ohnishi et al. 2007). Comparative endothelial cell kinetic studies in human, mice, and rats indicated that the labeling index (LI) in the male and female B6C3F1 mouse liver was significantly higher (p < .01) compared to the LI in male and female rat 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 hemangiosarcoma formation in mice may be related to the increased proliferation rate of endothelial cells normally present in the B6C3F1 strain of mice compared to rats and humans (Ohnishi et al. 2007).
A variety of non-neoplastic proliferative lesions of different origin(s) occurs spontaneously in the liver of rodents and may also be induced by treatment with chemicals. Incidences and morphological characteristics vary considerably by animal species, strain, and sex. Some of these lesions might be regarded as pre-neoplastic alterations.
As a non-neoplastic proliferative response, increased hepatocyte mitoses (Figure 92) above normal background levels or increased above what is seen in control animals can occur in rodent livers. Causes vary from physiological responses such as during early growth, during pregnancy, and following partial hepatectomy to post-necrotic repair. This change may be diagnosed as cytologic alteration or mitotic alteration with a description in the pathology narrative. In some laboratories diagnosis of ‘‘increased mitoses’’ is used.
Introduction: Foci of cellular alteration are common in rodent studies greater than duration of twelve months and may be seen in short duration toxicity studies following exposure to certain xenobiotics. Foci of cellular alteration can be identified by special stains. In H&E-stained slides they may be subclassified based on the predominant cell type present. Diagnosis of the mixed cell subtype of altered hepatic focus varies among different laboratories. One viewpoint defines a mixed focus of cellular alteration as consisting of a combination 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 phenotypes of cells in approximately a 50%/50% proportion. Others regard a ‘‘true’’ mixed focus as one that contains clearly identified basophilic and eosinophilic cells regardless of the proportions of each. Because of this diverse set of diagnostic opinions regarding focus subtypes, the pathologist is encouraged to describe the morphological features of documented foci in detail, especially if they are altered by treatment.
Synonyms: Areas of cellular alteration; focus of altered hepatocytes; hyperplastic focus; preneoplastic focus; enzyme altered focus; phenotypically altered focus.
Pathogenesis: A localized proliferation of hepatocytes phenotypically different from surrounding hepatocyte parenchyma.
Basophilic, diffuse (Figures 93 and 94).
Basophilic, tigroid (Figure 95).
Basophilic, NOS (Figure 96).
Basophilic (no further classification in mice) (Figure 97).
Synonyms: Acidophilic, ground glass.
Synonyms: Basophilic/eosinophilic mixed.
Heterogeneous focus consisting of a combination of cell types (see Introduction above).
Comments: Foci of cellular alteration represent a localized proliferation of hepatocytes that are phenotypically different from surrounding hepatocyte parenchyma. They are subclassified based upon phenotypic and tinctorial features. Foci of cellular alteration can occur spontaneously in aged rats and other rodents and can be induced by chemical treatment. The incidence, size, and/or multiplicity of foci are usually increased and time to development usually decreased after administration of hepatocarcinogens (Hanigan, Winkler, and Drinkwater 1993; Frith, Ward, and Turusov 1994; Bannasch and Zerban 1990; Moore, Thamavit, and Bannasch 1996). Foci of cellular alteration are not necessarily preneoplastic. Foci of cellular alteration may have prominent fat deposition and characteristic features of cystic degeneration and angiectasis (See B-focus with spongiosis; Figure 96).
Foci can be subclassified based on the predominant cell type. If no single cell type comprises at least 80% of a given focus, it should be classified as mixed. Mostly these mixed foci consist of both basophilic and eosinophilic/clear type cells. In these foci, it is not clear what is the predominant phenotype and are therefore indicated as ‘‘mixed.’’
Species and strain differences occur in the prevalence of these foci. It is not uncommon for a focus predominantly of one cell type, however, to have a small number of a different type.
Mixture of eosinophilic and clear cells can be classified into either eosinophilic or clear cell focus in accordance with proportion of clear cells. Mixture of amphophilic and other phenotypes has never been observed in rodents.
Usually, amphophilic foci are less frequently observed in rats and mice compared to other foci.
A number of models have linked specific types of foci of cellular alteration with carcinogenesis (Mahon 1989). The nitrosomorpholine model is linked with eosinophilic and clear cell foci as precursors. Aflatoxin is linked with basophilic foci as a tumor precursor (Bannasch, Zerban, and Hacker 1985). It was also reported that hepatocarcinogenesis was associated with increase of basophilic or amphophilic foci (Goodman et al. 1994). Although age-related eosinophilic or tigroid basophilic foci were not associated with exposure to hepatocarcinogens, in hamsters, treatment with nitrosamines or other carcinogens caused a variety of foci including basophilic foci (Frith, Ward, and Turusov 1994; Moore, Thamavit, and Bannasch 1996). As some foci may be potential precursors of neoplastic formation, careful identification of altered foci is warranted (Maronpot et al. 1989). Although induced by carcinogens, foci of cellular alteration can be found as non-neoplastic end stage lesions and not all foci can be related to carcinogens (Peraino et al. 1984; Harada, Maronpot, Morris, Stitzel, et al. 1989; Harada, Maronpot, Morris, and Boorman, 1989; Squire 1989; Schulte-Hermann et al. 1989). Most importantly, types of foci in controls should be compared to those found in treated animals. Some pathologists regard vacuolated foci as focal fatty change and do not consider them a subtype of focus of cellular alteration.
Synonyms: Hyperplasia, hepatocellular, focal hepatocellular hyperplasia.
Pathogenesis: A spontaneous or treatment-associated proliferative collection of hepatocytes spanning several lobules and without evidence of prior hepatic damage.
Comment: Non-regenerative hepatocellular hyperplasia is rare in rodents. It may occur spontaneously or be treatment-associated and consists of a proliferative collection of hepatocytes spanning several lobules and without evidence of prior hepatic damage. This lesion is not associated with any evidence of existing or prior hepatocellular injury. Diagnostic difficulties occur when preneoplastic foci and hepatocellular adenomas occur in the same liver sections of older rodents. This lesion may be similar to that of hepatic nodular hyperplasia in dogs.
There are basically two variations of non-regenerative hepatocellular hyperplasia. One is relatively smaller and is accompanied by angiectasis and/or spongiosis hepatis and the other tends to be larger than several lobules. The former occurs in both sexes and the latter predominantly in untreated female control F344 rats but occasionally reported in treated rats (Tasaki et al. 2008; Hailey et al. 2005; Bach et al. 2010). When present near the capsular surface, this type of nodular hyperplasia may be evident grossly as a raised area. The proliferating cell nuclear antigen (PCNA) labeling index in these nodules is increased in comparison with surrounding parenchyma and the lesion is glutathione S-transferase placental form (GSTP) immunonegative.
Very early non-regenerative hyperplasia may be the size of small foci of cellular alteration and are identified by their altered growth pattern and tinctorial similarity to surrounding parenchyma (see Figure 109).
Synonyms: Hyperplasia, hepatocellular; hyperplasia, regenerative; hyperplasia, nodular; regeneration, nodular.
Pathogenesis: A nodular regenerative response to prior or continuous hepatocellular damage.
Comment: These lesions are considered to represent a regenerative response to prior or continuous hepatocellular damage. A history of exposure to a hepatotoxicant and the presence of multiple nodules of regeneration that maintain a lobular but usually distorted architecture makes diagnosis more convincing. Diagnostic difficulties occur when preneoplastic foci and hepatocellular adenomas occur in the same liver sections of older rodents or in livers with many induced foci and tumors.
In livers with partial hepatectomy (PH), the pattern of hyperplasia at twenty-four to seventy-two hours post-surgery is diffuse hepatocyte hyperplasia with many mitotic figures and no evidence of liver toxicity. Although this response is also hyperplasia (hepatocellular, regenerative), it is not to be confused with the nodular hepatic response to toxic damage to hepatocytes. After ninety-six hours, the liver may be almost normal histologically. In mice however, chronic biliary lesions may be seen in the liver after PH.
Synonyms: Kupffer cell proliferation; histiocytosis, focal or diffuse.
Pathogenesis: Following phagocytosis of foreign material, estrogen treatment, inflammatory conditions, and response to cytokines. A rare spontaneous finding.
Comment: Rare as a spontaneous finding, hyperplasia of Kupffer cells may be seen following phagocytosis of foreign material and as a consequence of estrogen treatment and in inflammatory conditions. It can be induced by cytokines. Hypertrophy and hyperplasia often accompany each other. The hypertrophy of normal Kupffer cells gives the impression of presence of more Kupffer cells since they are difficult to visualize in normal livers.
Synonyms: Stellate cell; perisinusoidal cell; fat-storing perisinusoidal cell.
Pathogenesis: Proliferation of fat-storing perisinusoidal cells.
Comment: Ito cell hyperplasia is extremely rare and occurs predominantly in mice. It arises from fat-storing perisinusoidal cells, better known as Ito cells (Dixon et al. 1994; Enzan 1985; Tillmann et al. 1997). The biological behavior of the lesion is not well established. There appears to be a continuum with Ito cell tumor (see the following), which may be just an exaggerated and sometimes more localized form of Ito cell hyperplasia.
Pathogenesis: A spontaneous change in portal areas of older animals; may be induced or exacerbated by treatment.
Comment: Often associated with evidence of hepatic injury and repair and obstruction of bile flow. Dilation of intrahepatic bile ducts is a spontaneous, age-associated lesion that is more common in rats than in mice.
Synonyms: Bile duct adenomatosis; intestinal cell metaplasia; adenofibrosis.
Pathogenesis: Originates from an initial oval cell hyperplasia in response to pronounced hepatic parenchymal necrosis.
Comment: This lesion is an inflammatory, proliferative, and metaplastic reaction involving bile duct epithelium and is seen with hepatocellular toxicity caused by xenobiotics such as dioxins, furans, and related chemicals in rats (Bannasch and Zerban 1990; Deschl et al. 1997; Eustis et al. 1990; Kimbrough et al. 1973; Kimbrough and Linder 1974; Sirica 1992; Hailey et al. 2005). The initial reaction following pronounced hepatic parenchymal necrosis is oval cell hyperplasia (Engelhardt 1997).
Cholangiofibrosis is a controversial lesion that has been diagnosed as cholangiocarcinoma especially when there is extensive involvement of the liver. Cholangiofibrosis is not seen as a spontaneous lesion but occurs primarily in rats treated with a variety of xenobiotic agents that are hepatotoxic at high dose. The intestinal cell metaplasia in cholangiofibrosis includes goblet and Paneth cells and columnar cells similar to chief cells identified in H&E-stained paraffin sections and enterochromaffin cells identified by special staining. The metaplastic cells have been confirmed by electron microscopy in some cases. While cholangiofibrosis has been reported to progress to cholangiocarcinoma with malignant features (Bannasch and Zerban, 1990; Sirica 1992), unequivocal metastases have not been confirmed in most cases. This lesion is not observed in humans.
Synonyms: Oval cell proliferation; bile ductule cell hyperplasia.
Pathogenesis: Arises from terminal ductule epithelial cells (canal of Hering cells) spontaneously, following liver infections, and secondary to hepatotoxic injury.
Comment: Oval cell proliferation is considered to arise from terminal ductule epithelial cells (canal of Hering cells). It is a rare spontaneous lesion in rats. Oval cell hyperplasia can be observed following severe hepatotoxic injury and treatment with hepatocarcinogens. There is often a close relation to the portal tract, although more scattered groups of proliferating oval cells can be seen diffusely throughout the liver following xenobiotic-induced hepatic injury (Engelhardt 1997).
In mice oval cell hyperplasia is a feature of chronic active hepatitis caused by H. hepaticus and H. bilis and is seen following treatment with various hepatocarcinogens. Hyperplastic oval cells occur in association with a high incidence of hepatocellular neoplasms and may play an important role in hepatocarcinogenesis. Some authors support the concept that oval cells may participate in the lineage of hepatocellular and cholangiocellular carcinomas and may serve as hepatic stem cells. Oval cell hyperplasia diagnosis including grade is recommended, even when it is part of a complex set of hepatic changes.
The rodent liver is the most common target site of chemical carcinogens (Maronpot et al. 1986; Evans and Lake 1998), perhaps due to its major function as a metabolizing and detoxifying organ for xenobiotics. Rodent hepatocarcinogens are usually hepatotoxins. The chronic toxicity of these toxins may contribute to hepatocarcinogenesis although genotoxic liver carcinogens are often also hepatotoxins. There is over a thirty-year history of experimental induction (Frith and Wiley 1982; Malarkey et al. 1995; Evans et al. 1992; Ward et al. 1983, 1986; Ward, Lynch, and Riggs 1988; Popp 1984) and classification of preneoplastic and neoplastic lesions of the rat and mouse liver in book chapters (Bannasch and Zerban 1990; Brooks and Roe 1985; Greaves and Faccini 1984; Jones and Butler 1978; Ward 1981; Harada et al. 1999; Eustis et al. 1990) and by committee (ILAR 1980) or toxicologic pathology societies (Standardized System of Nomenclature and Diagnostic Criteria [SSNDC] Guides, http://www.toxpath.org/ssndc.asp). Terminology has evolved to the present nomenclature that is also based on many publications on liver carcinogenesis.
There is evidence from experimental studies documenting the regression of proliferative hepatocellular lesions including foci of cellular alteration, hepatocellular adenomas, and hepatocellular carcinomas following cessation of treatment (Maronpot 2009). A dramatic example was reported in mice following cessation of chronic chlordane exposure (Malarkey et al. 1995). Similar experience has been reported in rats and mice in other studies (Lipsky et al. 1984; Greaves, Irisarri, and Monro 1986; Marsman and Popp 1994) as well as in humans (Frémond et al. 1987; McCaughan, Bilous, and Gallagher 1985; Emerson et al. 1980; Steinbrecher et al. 1981). Agents that require continual administration for the stable presence and growth of preneoplastic and neoplastic rodent liver lesions can be categorized as conditional hepatocarcinogens (Maronpot 2009).
Synonyms: Adenoma, hepatic; adenoma, liver parenchymal cell; hepatoma, benign; tumor, liver cell, benign; hepatoma, benign; type A nodule.
Pathogenesis: Spontaneous and following treatment with hepatotoxins that are carcinogenic xenobiotics; with gene alterations in genetically engineered mice.
Comment: Hepatocellular adenomas occur spontaneously with increased incidence in older rodents and following treatment with hepatotoxins that are carcinogenic xenobiotics (Harada et al. 1999; Eustis et al. 1990; Stinson, Hoover, and Ward 1981). In mice, hepatocellular carcinomas can be seen histologically arising within adenomas of both spontaneous and induced adenomas (Jang et al. 1992). This process is less common in rats. Occasionally large proliferative hepatocellular lesions are observed that are difficult to diagnose. These lesions can compress adjacent parenchyma and/or bulge from the surface. They also have, at least in some areas, normal to slightly distorted lobular architecture with central veins and portal triads. The biologic nature of these lesions is unknown but because of their size and distinct compression, they are sometimes included in the category of hepatocellular adenoma. It is recommended that large lesions of this type with some evidence of lobular architecture and the presence of central veins and portal areas be diagnosed as non-regenerative hepatocellular hyperplasia (described previously in this document).
Synonyms: Adenocarcinoma, liver cell; carcinoma, hepatic cell; carcinoma, hepatocellular; carcinoma, liver cell; hepatoma, malignant; hepatocarcinoma; nodule, type B.
Pathogenesis: Spontaneous and following treatment with hepatotoxins that are carcinogenic xenobiotics; with gene alterations in genetically engineered mice.
Acinar (synonym: glandular):
Comment: Occur spontaneously with increased incidence in older rodents and following treatment with carcinogenic and hepatotoxic xenobiotics (Bannasch and Zerban 1990; Brooks and Roe 1985; Greaves and Faccini 1984; Jones and Butler 1978; Ward 1981; Harada et al. 1999; Eustis et al. 1990; Popp 1984, 1985; Vesselinovitch, Mihailovich, and Rao 1978). Diagnosis may be modified based on growth pattern (Frith and Wiley 1982).
The trabecular type of hepatocellular carcinoma is the most common form in rats and to a lesser extent in mice. Hepatocellular carcinomas may appear to arise within preexisting adenomas, especially in mice (Figures 139 and 140). While some authors refer to these lesions as focus of carcinoma in adenoma, such lesions should be diagnosed as hepatocellular carcinoma. These carcinomas exhibit the same morphological appearance as the carcinomas described earlier and hint toward a progression of adenoma into carcinoma. Attention should be paid to hemorrhagic areas, where proliferation of endothelial cells or formation of large sinusoidal-like spaces may lead to the erroneous diagnosis of a vascular tumor.
Synonyms: Tumor, mixed, poorly differentiated.
Pathogenesis: Unknown but origin from liver blastema cells, neoplastic hepatocytes, oval cells, and biliary epithelial cells proposed.
Comment: Hepatoblastomas consist of organoid structures often oriented around vascular spaces (Harada et al. 1999; Nonoyama et al. 1986, 1988; Turusov, Day, et al. 1973; Turusov, Deringer, et al. 1973). The cells are primitive in appearance of scant, pale basophilic cytoplasm and ovoid hyperchromatic nuclei. They are usually seen with other types of hepatocellular tumors, especially within hepatocellular adenomas. Rare reports of this lesion in rats appear in literature. They are seen in certain strains of mice and have also been induced by certain hepatocarcinogens (Diwan, Ward, and Rice 1989).
Hepatoblastoma is generally seen within or adjacent to hepatocellular neoplasms. In these cases, some preference has been expressed for a single diagnosis of hepatoblastoma, rather than two diagnoses (the hepatoblastoma and the hepatocellular neoplasm). If this preferred convention of using the single diagnosis of hepatoblastoma is not used, then the alternative convention will need to be defined by the pathologist. Hepatoblastomas can have high rates of lung metastases in some experiments.
Synonyms: Adenoma, bile duct; adenoma, biliary; adenoma, cholangiocellular; cholangioma, benign.
Pathogenesis: Proliferation of biliary cells.
Comment: Cholangioma is rare in control and treated rodents (Bannasch and Zerban 1990; Brooks and Roe 1985; Frith and Ward 1979; Greaves and Faccini 1984; Harada et al. 1999; Jones and Butler 1978; Lewis 1984; Maronpot et al. 1986).
Synonyms: Adenocarcinoma, bile duct; adenocarcinoma, cholangiocellular; carcinoma, bile duct; carcinoma, cholangiocellular; cholangioma, malignant.
Pathogenesis: Arise from proliferating cholangial cells.
Comment: Cholangiomas and cholangiocarcinomas are rarely seen as spontaneous neoplasms in rats and mice but may occur following exposure to hepatotoxic xenobiotics (Eustis et al. 1990; Frith and Ward 1979; Harada et al. 1999; Jones and Butler 1978; Lewis 1984; Narama et al. 2003). A specific phenotype of cholangiocarcinoma with features of cholangiofibrosis consisting of dilated biliary glands, mucus production, intestinal metaplasia, inflammatory cell infiltrates, and fibrosis has been diagnosed in rats treated with a variety of hepatotoxic xenobiotics (Bannasch and Zerban 1990; Bannasch, Brenner, and Zerban 1985; Sirica 1992; Kimbrough and Linder 1974; Maronpot et al. 1986). The distinction between cholangiofibrosis and this phenotype of cholangiocarcinoma is difficult and controversial and is primarily based on extent of liver involvement since unequivocal metastasis is rare.
These rare lesions of cholangiocarcinoma can contain parameters of cholangiofibrosis but show less inflammation and less mucus cyst(s) but with atypical ductular structures and can metastasize. It has been proposed to diagnose this specific form of cholangiocarcinoma as ‘‘cholangiocarcinoma, intestinal type’’ (Greaves 2007), but that nomenclature as a separate (sub-) diagnosis was not favorably encouraged at a recent scientific workshop (NTP Satellite Symposium 2010).
Pathogenesis: Proliferation of admixture of hepatocytes and intrahepatic bile duct epithelium. Stem cell origin speculated.
Comment: Rare spontaneous lesion. A proliferative mixture of hepatocytes and intrahepatic bile duct epithelium with neither component being malignant comprise to this tumor type (Deschl et al. 2001; Frith and Ward 1979; Harada et al. 1999; Narama et al. 2003).
Pathogenesis: Proliferation of admixture of hepatocytes and intrahepatic bile duct epithelium. Stem cell origin speculated.
Comment: Rare spontaneous lesion. This neoplasm contains neoplastic elements of both hepatocytes and bile duct epithelium (Deschl et al. 2001; Frith and Ward 1979; Harada et al. 1999; Narama et al. 2003; Teredesai, Wohrmann, and Schlage 2002). A diagnosis of malignancy may be based on just one of the components being malignant.
Synonyms: Fat-storing cell tumor; stellate cell tumor, lipoma.
Pathogenesis: Arises from fat-storing perisinusoidal cells, so-called Ito cells.
Comment: Ito cell neoplasms are extremely rare. As a consequence, the histogenesis and the biological behavior of these tumors are not well established (Dixon et al. 1994; Enzan 1985; Tillmann et al. 1997).
Synonym: Kupffer cell sarcoma.
Pathogenesis: May arise from fixed macrophages (Kupffer cells) attached to the sinusoidal endothelial cells or from circulating macrophages, unless metastasized from other organs (e.g., skin, uterus).
Comment: Histiocytic sarcomas occur at a low frequency in rats and mice (Harada et al. 1999; Eustis et al. 1990). The tumor can be part of a systemic lesion involving various tissues (spleen, lung, and uterus); when involving only the liver it is sometimes referred to as Kupffer cell sarcoma (Deschl et al. 2001; Carlton et al. 1992).
Synonym: Hemangioendothelioma, benign.
Pathogenesis: Arises from endothelial cells lining vascular spaces, most commonly of the hepatic sinusoids.
Comment: The occurrence of hemangiomas in rodents has been well documented (Booth and Sundberg 1996; Carter 1973; Faccini, Abbott, and Paulus 1990; Frith and Ward 1988; Frith and Wiley 1982; Heider and Eustis 1994; Jones and Butler 1975; Maita et al. 1988; Greaves and Barsoum 1990; Greaves and Faccini 1984; Mitsumori 1990; Peckham and Heider 1999; Stewart 1979; Stewart et al. 1980; Squire and Levitt 1975; Ward et al. 1979; Yamate et al. 1988; Zwicker et al. 1995). The cavernous type of hemangioma is considered by some authors to be a congenital malformation rather than a neoplasm.
Synonym: Hemangioendothelioma, malignant.
Pathogenesis: Arises from pluripotential mesenchymal stem cells; endothelial cells of blood vessels or hepatic sinusoids.
Comment: As in the case of hemangiomas, the occurrence of hemangiosarcomas in rodents has been well described in the published literature (Binhazim, Coghlan, and Walker 1994; Booth and Sundberg 1996; Faccini, Abbott, and Paulus 1990; Frith and Ward 1988; Frith and Wiley 1982; Giddens and Renne 1985; Greaves and Barsoum 1990; Greaves and Faccini 1984; Heider and Eustis 1994; Jones and Butler 1975; Maita et al. 1988; Mitsumori 1990; Morgan et al. 1984; Peckham and Heider 1999; Popper, Maltoni, and Selikoff 1981; Pozharisski and Turusov 1991; Sakamoto, Takayama, and Hosoda 1989; Solleveld et al. 1988; Stewart 1979; Yamate et al. 1988).
Endothelial cell-derived hemangiosarcomas can be induced in rats and mice by a wide range of industrial, natural, and pharmaceutical compounds. There are numerous examples documenting the progress that is being made in recent years in suggesting the genesis and potential relevance for human risk assessment of these tumors (Klaunig and Kamendulis 2005; Laifenfeld et al. 2010; Ohnishi et al. 2007).
Synonym: Hematopoietic cell proliferation; myelopoiesis; erythropoiesis.
Pathogenesis: In adult rodent, a response to increased hematopoietic demand.
Comment: Extramedullary hematopoiesis (EMH) can be observed in rodent liver occasionally in response to an increased hematopoietic demand. Hematopoiesis is normally found in the embryonic liver where embryonic hematopoiesis dramatically expands at mid-gestation but decreases after birth. Hepatic EMH is seen more common in rodents than in man, more common in mice than rats, and more often observed in females as compared to males as a general rule (Eustis et al. 1990; Harada et al. 1996, 1999). Precipitating factors for the occurrence are: anemia, stress, xenobiotic toxicity, infection, neoplasia (e.g., histiocytic sarcoma), and pregnancy. When the erythroid precursors predominate, often the term extramedullary erythropoiesis is used.
Synonyms: Emperipolesis, cytoplasmic inclusions; hepatic erythrophagocytosis.
Comment: The intracytoplasmic inclusion of large numbers of erythrocytes in hepatocytes has been seen exclusively in mice (Harada et al. 1999). It has occurred in at least nine separate cancer bioassays and one fourteen-day study in B6C3F1 mice. In two of these studies, it appears to have been exacerbated or possibly caused by treatment. Attempts to demonstrate active erythrophagocytosis by electron microscopy have been unsuccessful. A potential mechanism is emperiopolesis. Internalization of erythrocytes in hepatocytes has been reported in hibernating frogs (Barni and Bernocchi 1991).
Pathogenesis: Islands of pancreatic tissue localized within the hepatic parenchyma are rare spontaneous occurrences in rats but have been reported following prolonged exposures to polychlorinated biphenyls (Kimbrough 1973; Eustis et al. 1990; Greaves 2007).
Comment: In spontaneous cases, a distinction between metaplasia and ectopic pancreas may not be possible. Since both pancreas and liver are embryologically related, there is a definite potential for metaplasia.
Pathogenesis: Proliferation of hepatocytes to form glandular structures.
Comment: Partial replacement of hepatic parenchyma by glandular structures with features resembling hepatocytes has been observed in chronic studies of 3, 3’, 4, 4’, 5-pentachlorobiphenyl and 2, 3’, 4, 4’, 5-pentachlorobiphenyl (NTP Toxicology and Carcinogenesis Studies 2006). It is speculated that the glandular structures represent abnormal differentiation of hepatic precursor cells (NTP Toxicology and Carcinogenesis Studies 2006).
Synonyms: Vascular pseudoinvasion; vascular infiltration of hepatocytes.
Pathogenesis: Unknown. Sporadic occurrence.
Comment: Intravascular infiltration of hepatocytes is rarely seen in control and treated mice. A similar change was reported in diethylnitrosamine treated mice as part of a basophilic focus of cellular alteration response (Goldfarb et al. 1983; Koen, Pugh, and Goldfarb 1983). The significance of this change is unknown.
Pathogenesis: Developmental anomaly; postnatal transdifferentiation.
Pathogenesis: Developmental abnormality; postnatal transdifferentiation.
Synonyms: Hyalinosis, cytoplasmic inclusions, crystals.
Pathogenesis: A change in the gallbladder epithelium that can be induced by inflammation and unknown factors.
Comment: The hyaline protein in the cells has been shown to be Ym1/Ym2 (now Chi313), a chitinase-like protein, with unknown functions. In sickle cell mice, it is associated with gallstones. Hyalinosis is rare in most lines of mice (Harada et al. 1999; Hsu et al. 2006; Yang and Campbell 1964) but may occur in high incidence in 129 and B6;129 mice (Ward et al. 2001) and in some genetically engineered mouse lines. Hyalinosis is reported to occur in increased incidence in B6C3F1 female mice exposed to penicillin.
Synonym: Adenomatoid change.
Pathogenesis: Spontaneous and associated with inflammatory and proliferative changes in gallbladder.
Comment: Glandular metaplasia has been observed at low prevalence in the gall bladder and intra-hepatic bile ducts (all associated with cholelithiasis), cholecystitis, cholangitis, papillomatous hyperplasia, papilloma, intra-mural cysts, and focal epithelial ulceration of aged mice from life span carcinogenicity studies. The lesions are found predominantly in female mice (Lewis 1984) and can occur spontaneously in some strains of mice. Other metaplastic changes have also been described in the human gallbladder, including goblet cells, paneth cells, and/or enterochromaffin cells in the mucosa (Hruban, Argani, and Ali 2006).
Synonyms: Stones, gallstones, choleliths.
Pathogenesis: Excess dietary factors and altered metabolism.
Comment: Gallstones are rare spontaneously in mice but may be experimentally induced by various methods (Chang, Suh, and Kwon 1999; Hsu et al. 2006; Ichikawa et al. 2009; Lee and Scott 1982; Lewis 1984; Rege and Prystowsky 1998; Tepperman, Caldwell, and Tepperman 1964; Trotman et al. 1983; Xie et al. 2009).
Synonym: Inflammation, gallbladder.
Pathogenesis: Toxicant exposure and bacterial and viral infections (Greaves 2007; Harada et al. 1999).
Pathogenesis: Irritation of gallbladder mucosa and after xenobiotic exposure.
Comment: Details related to gallbladder hyperplasia can be found in several references (Deschl et al. 2001; Harada et al. 1996, 1999; Yoshitomi, Alison, and Boorman 1986; Yoshitomi and Boorman 1994).
Synonym: Adenoma, papillary.
Pathogenesis: Arises from epithelium of gallbladder.
Comment: Benign and malignant epithelial neoplasms of the gallbladder are described in several published references (Deschl et al. 2001; Harada et al. 1996, 1999; Lewis 1984; Yoshitomi, Alison, and Boorman 1986; Yoshitomi and Boorman 1994).
Pathogenesis: Arises from epithelium of the gallbladder.
Comment: Benign and malignant epithelial neoplasms of the gallbladder are described in several published references (Deschl et al. 2001; Harada et al. 1996, 1999; Lewis 1984; Yoshitomi, Alison, and Boorman 1986; Yoshitomi and Boorman 1994).
The authors wish to express their thanks for the excellent editorial support and suggestions provided by John Vahle, Bob Greenhill, John Foster, Chirukandath Gopinath, Rupert Kellner, Beth Mahler, Stuart Levin, Ken Schafer, Gordon Hard, Ian Pyrah, Charlotte Keenan, Maria-Luisa Phan Lung Whu, and Suzy Tirtodikromo. Special thanks to Beth Mahler and Emily Singletary for photography support. The majority of the photomicrographs used in this document were provided courtesy of the National Toxicology Program Archives, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
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