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Liver; lipomatous lesion in a B6C3F1 mouse. Fig. 6a. Hepatocytes contain single large and/or multiple small vacuoles. Also note finely vacuolated spindle-shaped cell with cytoplasmic extension (arrow). Vacuoles (V) of signet-ringshaped cells. Fig. 66. Note three cells morphologically similar to hepatocytes shown in Fig. 6a. The cells are undergoing fusion. Vacuoles (V) of signet-ring-shaped cells. Toluidine blue. Bar = 15 pm.
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The gross, microscopic, and ultrastructural features of lipomatous lesions in the liver of B6C3F1 mice are described. The cases were selected from a database of 45,406 male and 45,674 female mice used as treated, control, or vehicle-control animals in the National Cancer Institute's Bioassays or the National Toxicology Program's 2-year carcinogenic...
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Context 1
... hepatocytes, and cap- illaries. The majority of the signet-ring-shaped cells had a thin rim of compressed cytoplasm and periph- erally located crescent-shaped nuclei (Fig. 5). Occa- sionally, these cells were adjacent to individualized hepatocytes that had extremely vacuolated cytoplasm, or clusters of vacuolated hepatocytes that appeared to fuse (Fig. 6). Identifiable spindle-shaped cells had elon- gated centrally located nuclei and cytoplasmic exten- sions (Fig. 7), and they were finely vacuolated. Pleo- morphic cells with round to oval centrally located nuclei and finely vacuolated cytoplasm were observed adja- cent to spindle-shaped ...
Citations
... Facing the condition's rarity, a definitive causal explanation would be too speculative because the causes could reasonably range from purely genetic to toxicopathic. Although the latter aetiology is unlikely, it cannot be discarded in view of the sampling location, i.e., when knowing that liver lipomatous lesions resembling human hepatic lipomas evolved in rats from carcinogenic assays [46]. ...
A lipoma is a benign tumour of mature adipocytes which may appear in various species, including marine and freshwater fish. It usually occurs in isolated locations, such as a superficial or deep mass, mainly in the skin and seldom in other organs. In non-mammalian vertebrates, there is no agreed minimal size for the mass to be considered a lipoma. This study histologically describes a case proposed to be a microlipoma in the liver of Barbus balcanicus. The structure was an oval-shaped mass of well-differentiated adipocytes, surrounded by hepatic parenchyma. The adipocyte cluster did not contact with major vascular or biliary tracts, the liver capsule, or the hilum. The cell mass reached a maximal linear length and width of ~0.5 mm and ~0.4 mm. A three-dimensional and software-assisted reconstruction of the adipocytic mass showed that it had the shape of a flattened prolate spheroid (~0.01 mm3). Given the histological criteria currently used in the literature, we consider the mass as a lipoma, or, better, a microlipoma because it was tiny. We interpret this structure as an early growing lipoma. This work is the second description of a liver lipoma in a fish to the best of our knowledge.
... Incidental solitary and/or multiple lipomas with or without bone, and or bone marrow components have frequently been described in a variety of avian and mammalian species, including humans (Young 1951, Lombard et al. 1968, Stroud et al. 1982, Dixon et al. 1994, Latimer & Rakich 1995, Zhuo et al. 1995, Klopfleisch et al. 2009, Suzuki et al. 2010, Kleinschmidt et al. 2015. Lipomatous masses include myelolipomas, lipomas, angio myelolipomas, and ma-ture teratomas; we found no histopathologic evidence of the latter 2 types of lesions in the examined case material. ...
... Lipomatous masses include myelolipomas, lipomas, angio myelolipomas, and ma-ture teratomas; we found no histopathologic evidence of the latter 2 types of lesions in the examined case material. Various etiological hypotheses have been proposed, including endocrine−metabolic disturbance (lipomas), extra-medullary hematopoiesis (myelolipomas), embolization and ectopic tissue, and chronic environmental stimulus resulting in metaplasia of stem cells (Stroud et al. 1982, Dixon et al. 1994, Martin-Benitez et al. 2012. The pathogenesis and exact cell origin of these benign fatty tumors in bowhead whales is undetermined. ...
We describe a case series of benign hepatic fatty tumors in 10 subsistence-harvested bowhead whales. Microscopic features included lipomatous and myelolipomatous masses. Extensive atrophy and/or destruction of hepatic parenchyma was not observed. No other significant disease was present except in an animal with unrelated chronic pleuritis. Based on our longitudinal case series (1980-2016) which identified 1-2 hepatic lipomas and myelolipomas in landed whales annually at Barrow, Alaska (USA), since 2012, hepatic lipomas and myelolipomas are occasionally seen in hunter-harvested bowhead whales. A conservative estimate for the percentage of bowhead whales with hepatic fatty tumors in landed whales in Barrow from 2012 to 2016 was 6% (7/111). The pathogenesis and exact cell origin of these benign fatty tumors in bowhead whales is undetermined. Assessment of further cases is warranted to better define the tissue distribution and pathogenesis of these tumors in bowhead whale liver.
... 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 30S THOOLEN ET AL. ...
... Tumor, Ito Cell, Benign (Figures 153 and 154 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). ...
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.
... Detailed histopathological examination suggested that the origin of the present tumor might be Ito cells. To our knowledge, only ''benign'' Ito cell tumors have been reported in aging mice (Dixon et al. 1994;Tillmann et al. 1999), whereas there have been no reports of ''malignant'' Ito cell tumors in mice. Reports of benign Ito cell tumors described two types of components in proliferative areas (Dixon et al. 1994;Kotani et al. 2007;Tillmann et al. 1999). ...
... To our knowledge, only ''benign'' Ito cell tumors have been reported in aging mice (Dixon et al. 1994;Tillmann et al. 1999), whereas there have been no reports of ''malignant'' Ito cell tumors in mice. Reports of benign Ito cell tumors described two types of components in proliferative areas (Dixon et al. 1994;Kotani et al. 2007;Tillmann et al. 1999). One type is a lipomatous lesion composed of signet-ring-shaped cells, and the other type consists of spindle-shaped cells proliferating among disrupted hepatic plates with a stromal matrix closely resembling the tumor morphology seen in the present case. ...
We found a malignant mesenchymal tumor with myofibrogenic differentiation in the liver of a 110-week-old female B6C3F1 mouse used for a carcinogenicity study. Sclerous white patches (maximum size: 20 x 14 mm) were observed mainly in the median lobe of the liver at necropsy. Histologically, the tumor was composed of interlacing fascicles of spindle-shaped cells with oval or elongated nuclei and lightly eosinophilic cytoplasm. Tumor cells metastasized to the lung, parapancreatic lymph node, and spleen. Special staining revealed individual tumor cells surrounded by reticulin fibers and an abundant collagenous matrix. Immunohistochemically, the tumor cells were positive for vimentin, alpha-smooth muscle actin, and desmin, but were negative for von Willebrand factor, Mac-2, S-100, and cytokeratin. Electron microscopic examination revealed that the tumor cells contained prominent rough endoplasmic reticulum and thin filaments in the cytoplasm, although they lacked basal lamina, focal densities, or lipid droplets. Collagenous fibers were observed in the intercellular matrix. Thus, detailed histopathological examination suggested the origin of the present tumor to possibly be Ito cells within the fibrous stroma. This report provides additional histopathological evidence of malignant hepatic nonepithelial tumors in mice.
... These crystals occur both in macrophages, where they have been diagnosed as eosinophilic macrophage pneumonia, and free in the alveolar spaces. Another type of poorly understood lesion involves the fatty cells in the liver (Dixon et al., 1994). The function of these cells is unclear, and the morphologic appearance often becomes clouded when there is significant deposition of lipid in the liver. ...
Toxicopathology, also referred to as toxicologic pathology, can be defined as the study of structural and functional changes in cells, tissues, and organs that are induced by toxicants (such as drugs, industrial and agricultural chemicals), toxins (chemicals of biological origin such as mycotoxins and phycotoxins), and physical agents (such as heat and radiation); the investigation of the mechanisms by which these changes are induced; and the development of risk assessment and risk management policies based on such information. Toxicologic pathology primarily deals with the morphologic or structural effects of the toxicant and the mechanism by which this structural effect is induced. This article highlights some of the problems that toxicologic pathologists may encounter in obtaining and interpreting pathology lesions. By alerting toxicologists to some of these issues, it is hoped that a better understanding of the use and limitations of toxicologic pathology data will occur.
... Paraffin sections of tissues collected from all time points studied were stained for Bandeiraea simplicifolia lectin binding in order to identify endothelial cells, using a method modified from that described in the literature (Thurston et al., 1996). Frozen sections on the other hand, were used for Oil Red O staining of triglyceride in both lipoblasts and adipocytes (Dixon et al., 1994). Transmission electron microscopy was performed on ultrathin sections of tissues fixed with Karnovsky's fixative and 2% osmium tetroxide, and embedded in Spur's epoxy resin. ...
In mammals, wound healing is thought to result in the formation of scar tissue, with the exception of bony healing after fractures. Here we describe a previously unknown pattern of wound healing in which adipose rather than scar tissue is formed. Adipogenesis is normally confined to the embryo, although there are several experimental models for adipogenesis with highly specific dietary, cytokine, matrix, sex, or age requirements. The adipogenic healing described in this work provides a simple and reproducible experimental mouse model for adipogenesis without these limitations. Mice received intramuscular implants of nylon mesh material. Fibrinous material impregnated implants and within 4 weeks was replaced with highly vascular granulation tissue, typical of wound healing. Also consistent with wound healing was a reduction in vascularity of the newly formed tissue over time (P < 0.05). Lipoblasts were prevalent in granulation tissue, reaching a maximum in week 2 (P < 0.001) but falling to very low levels by week 9. These cells matured to adipocytes, with intermediate forms being seen. The identity of lipoblasts and adipocytes was confirmed by Oil Red O staining and electron microscopy. Control experiments confirmed that adipogenesis was independent of the materials used as well as of the sex and age of the animals. Rather, adipogenesis appeared to be due to replacement of fibrinous material in a space created within muscle. It is possible that adipogenic healing represents an adaptation for limiting the formation of restrictive scar tissues within muscle, and that this is the basis for the formation of traumatic lipomas in humans. Also, muscle tissue is replaced by adipose cells, seemingly derived from pluripotential satellite cells, in several degenerative muscle conditions, suggesting a role for adipogenic healing in these conditions.
... Thirteen cases were selected and re-evaluated from more than 90,000 B6C3F1 mice in the NTP database. Although the gross, microscopic, and ultrastructural features of these rare lipomatous lesions have published (4), the authors could not conclusively determine the origin of the pro-liferated cells and hence prove their Ito cell origin beyond doubt. In a recently published reference (10) on the pathobiology of the aging mouse liver, the authors were not able to define the origin of the lesions under consideration. ...
... Based on light microscopy, an Ito cell origin for these tumors in the liver of the F344 rats (5) and mice (8) has been suggested. Dixon et al have analyzed similar lesions in the liver of B6C3F, mice by electron microscopy (4). Signet-ringshaped cells with thin rims of compressed cytoplasm and peripherally located nuclei were observed in addition to spindle-shaped cells with cytoplasmic extensions and centrally located nuclei. ...
... By light microscopy, proliferating cells with 2 different histologic appearances were observed in our investigation using CBA/J mice. Similar cell types were seen in B6C3F1 mice (4). During the proliferating process, Ito cells lose their fat droplets and vitamin A content and produce increasing amounts of extracellular matrix (6,11). ...
In 2 lifespan transgeneration experiments using a total of 4,682 CBA/J mice, we observed uncommon lipomatous lesions in the livers of 8 mice independent of the treatment. Macroscopically, the lesions were described as pale white areas (2) or nodules (6) during necropsy. The lesions ranged from 1 to 15 mm in diameter. Microscopically, the lesions consisted of nodular aggregations of round to spindle-shaped cells that partly caused distinct compression of the adjacent hepatic parenchyma. The tumor cells were smaller than hepatocytes and had dark oval nuclei. Many of the more spherical cells contained clear vacuoles of various sizes, which were shown to be lipid droplets by oil red O staining. In addition to Gomori's silver and Masson's trichrome staining, several immunohistochemical stains were used to characterize the origin of the proliferating cells. Tumor cells were labeled by vimentin, actin, desmin, and proliferating cell nuclear antigen. The 2 cell phenotypes showed similar staining characteristics. Increased amounts of laminin and tenascin, 2 extracellular matrix proteins of the liver, were detected within these neoplasms. Summarizing, we suggest that these tumors are of Ito cell origin.
... A lesion that has generated some interest in small fish carcinogenesis studies is spongiosis hepatis, or cystic degeneration. In rodents, spongiosis hepatis is a pathological process believed to involve the perisinusoidal (Ito) cell of the liver (1,2,11,32). Those studies suggested that the characteristic multilocular cystlike complexes result from a carcinogen-induced metabolic disturbance of the perisinusoidal cells. ...
... Also, because some spongiotic lesions in rats examined after long periods following exposure to a carcinogen demonstrated elevated cell proliferation, it was suggested that the spongiotic lesion might transform into pericytoma, a malignant mesenchymal tumor (2). However, there is uncertainty as to whether spongiosis hepatis should be considered a preneoplastic or neoplastic liver lesion in mice (11). In fish, spongiosis hepatis was first reported from ...
Diagnostic criteria are presented for degenerative, inflammatory, nonneoplastic proliferative, and neoplastic lesions in the liver of medaka (Oryzias latipes), a small fish species frequently used in carcinogenesis studies. The criteria are the consensus of a Pathology Working Group (PWG) convened by the National Toxicology Program. The material examined by the PWG was from Medaka exposed to N-nitrosodiethylamine for 28 days, removed to clean water, and sacrificed 4, 6, or 9 mo after initiation of exposure. Degenerative lesions included hepatocellular intracytoplasmic vacuolation, hepatocellular necrosis, spongiosis hepatis, hepatic cysts, and hepatocellular hyalinization. Inflammatory lesions consisted of granulomas, chronic inflammation, macrophage aggregates, and focal lymphocytic infiltration. Nonneoplastic proliferative lesions comprised foci of cellular alteration (basophilic focus, eosinophilic focus, vacuolated focus, and clear cell focus) and bile duct hyperplasia. Neoplastic lesions included hepatocellular adenoma, hepatocellular carcinoma, cholangioma, and cholangiocarcinoma. Two lesions composed mainly of spindle cells were noted, hemangiopericytoma and spindle cell proliferation. Rather than being an exhaustive treatment of medaka liver lesions, this report draws from the published literature on carcinogen-induced liver lesions in medaka and other fish species and attempts to consolidate lesion criteria into a simplified scheme that might be useful to pathologists and other researchers using medaka lesions for risk assessment or regulatory purposes.
This chapter provides a basic overview of the multiple aspects and considerations that impact the proper conduct of regulatory toxicologic pathology studies. The chapter introduces the novice toxicologic pathologist to topics that include, but are not limited to, Good Laboratory Practices, animal welfare issues, necropsy processes, clinical chemistry data, organ weight data, tissue fixation, histology procedures, and Cause of Death documentation. The goal of the chapter is to enhance awareness of factors that influence study protocol development and interpretation of in-life, gross, and histomorphologic data. Regulatory topics are also briefly discussed.
