Proliferative and Nonproliferative Lesions of the Rat and Mouse Central and Peripheral Nervous Systems: New and Revised INHAND Terms.

Harmonization of diagnostic terminology used during the histopathologic analysis of rodent tissue sections from nonclinical toxicity studies will improve the consistency of data sets produced by laboratories located around the world. The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a cooperative enterprise of 4 major societies of toxicologic pathology to develop a globally accepted standard vocabulary for proliferative and nonproliferative lesions in rodents. A prior manuscript (Toxicol Pathol 2012;40[4 Suppl]:87S-157S) defined multiple diagnostic terms for toxicant-induced lesions, common spontaneous and age-related changes, and principal confounding artifacts in the rat and mouse central nervous system (CNS) and peripheral nervous system (PNS). The current article defines 9 new diagnostic terms and updates 2 previous terms for findings in the rodent CNS and PNS, the need for which has become evident in the years since the publication of the initial INHAND nomenclature for findings in rodent neural tissues. The nomenclature presented in this document is also available electronically on the Internet at the goRENI website (http://www.goreni.org/).

Effect of combined dyslipidemia and hyperglycemia on diabetic peripheral neuropathy in alloxan-induced diabetic WBN/Kob rats.

Clinical and experimental research have suggested that dyslipidemia aggravates diabetic peripheral neuropathy (DPN). However, whether dyslipidemia is a risk factor for DPN remains unclear. To investigate the effect of dyslipidemia on DPN, morphological features of peripheral nerves were analyzed in diabetic rats treated with a high-fat diet (HFD). Male rats were divided into four groups: nondiabetic rats (N), alloxan-induced diabetic rats (AL), diabetic rats treated with an HFD (AH), and nondiabetic rats treated with an HFD (HF). Combined hyperglycemia and dyslipidemia (AH group) induced a significant increase in plasma triglyceride and cholesterol levels. In addition, the combined effects contributed to a reduction in myelin size and a reduction in myelin thickness as indicated on sensory sural nerve histograms. There was also a reduction in the size of motor nerve axons when compared with the effects of hyperglycemia or dyslipidemia alone. However, the sensory nerve conduction velocity in the AH group was slightly but not significantly lower than those in the HF and AL groups. These results suggest that combined hyperglycemia and dyslipidemia induced mild peripheral motor and sensory nerve lesions, without significantly affecting sensory nerve conduction velocity.

Effect of deoxycorticosterone acetate-salt-induced hypertension on diabetic peripheral neuropathy in alloxan-induced diabetic WBN/Kob rats.

The relationship between hypertension and diabetic peripheral neuropathy (DPN) has recently been reported in clinical research, but it remains unclear whether hypertension is a risk factor for DPN. To investigate the effects of hypertension on DPN, we analyzed morphological features of peripheral nerves in diabetic rats with hypertension. Male WBN/Kob rats were divided into 2 groups: alloxan-induced diabetic rats with deoxycorticosterone acetate-salt (DOCA-salt) treatment (ADN group) and nondiabetic rats with DOCA-salt treatment (DN group). Sciatic, tibial (motor) and sural (sensory) nerves were subjected to qualitative and quantitative histomorphological analysis. Systolic blood pressure in the two groups exhibited a higher value (>140 mmHg), but there was no significant difference between the two groups. Endoneurial blood vessels in both groups presented endothelial hypertrophy and narrowing of the vascular lumen. Electron microscopically, duplication of basal lamina surrounding the endothelium and pericyte of the endoneurial vessels was observed, and this lesion appeared to be more frequent and severe in the ADN group than the DN group. Many nerve fibers of the ADN and DN groups showed an almost normal appearance, whereas morphometrical analysis of the tibial nerve showed a significant shift to smaller fiber and myelin sizes in the ADN group compared with DN group. In sural nerve, the fiber and axon-size significantly shifted to a smaller size in ADN group compared with the DN group. These results suggest that combined diabetes and hypertension could induce mild peripheral nerve lesions with vascular changes.

Hepatic Lesions Caused by Large Granular Lymphocyte Leukemia in Fischer 344 Rats: Similar Morphologic Features and Morphogenesis to Those of Nodular Regenerative Hyperplasia (NRH) in the Human Liver.

To characterize the hepatic lesions in Fischer 344 (F344) rats afflicted with large granular lymphocyte (LGL) leukemia, the livers of rats with LGL leukemia at various stages were examined histopathologically and immunohistochemically. The morphologic features in the livers of rats afflicted with LGL leukemia were diffuse, uniform-sized, granular, or micronodular lesions consisting of hepatocytes showing centrilobular atrophy and perilobular hypertrophy (CAPH) without fibrosis. With progression in the stage of the LGL leukemia, the severity of the CAPH of hepatocytes increased resulting in fatty change and/or single-cell necrosis, along with compensatory hyperplasia of the hepatocytes, finally resulting in lesions similar to those seen in nodular regenerative hyperplasia (NRH) in the human liver. The CAPH of hepatocytes was a nonspecific tissue adaptation against ischemia or hypoxemia and/or imbalance in blood supply due to disturbance in the portal circulation and hemolytic anemia induced by the leukemia cells. In addition, direct and/or indirect hepatocellular injuries by leukemia cells were considered to be necessary for the formation of human NRH-like lesions. Morphogenetic investigation of the livers of rats afflicted with LGL leukemia may be helpful to clarify the pathogenesis of NRH in the human liver.

Iridal coloboma induces dyscoria during miosis in FLS mice.

OBJECTIVE: Fatty liver Shionogi (FLS) mice exhibit characteristic retinochoroidal coloboma because of a failure in fusion of the embryonic optic fissure. However, the same pathogenesis should result in iridal coloboma that has not been reported in this strain. The purpose of this study was to describe the physiologic and morphometric changes in iridal tissue involved in ocular coloboma in FLS mice. PROCEDURES: The miotic response after light exposure was evaluated in three strains of live mice, and the shape and location of the pupil were judged macroscopically. Subsequently, macroscopic abnormalities in the anterior segment and fundus were observed postmortem in all mice. During miotic and mydriatic responses in the eyes of live male FLS mice with dyscoric and normal pupils, each iris was measured in four radial directions. The enucleated eyes were examined morphometrically and histologically in both sexes of FLS mice. RESULTS: Inferior corectopia upon light-induced miosis was clearly detected in live FLS mice. The deviated pupils were not round but oval-shaped. Clinical and postmortem examination revealed that all dyscoric eyes had hypoplastic and dysfunctional irides inferiorly in FLS mice. Histopathological examination confirmed that both the dilator and sphincter muscles and iris stroma were quantitatively diminished in the affected inferior iris. Meanwhile, the rate of fundus (retinochoroidal) coloboma in eyes exhibiting dyscoria was remarkably high, although some dyscoric eyes had no fundus coloboma. CONCLUSIONS: Fatty liver Shionogi mice had iridal coloboma, resulting in inferior corectopia upon light-induced miosis as an indicator of ocular coloboma.

Organogenesis of mild ocular coloboma in FLS mice: failure of basement membrane disintegration at optic fissure margins.

Fatty Liver Shionogi (FLS) mice have been shown to develop a hereditary disorder characterized by localized retinochoroidal defects of the ventral fundus very similar to human typical ocular coloboma without microphthalmia. The objective of this study was to determine when and how the failure of the optic fissure closure occurs, and to clarify the disturbed mechanism of basement membrane disintegration during embryonal stage in FLS mice. Fetuses at day 11.5-15.5 of gestation were obtained from dams of FLS and BALB/c strain of mice. Coronal serial sections through the eye were examined by light and electron microscopy. The sections were followed by observation of the basement membrane using reaction with periodic acid-Schiff (PAS) reagent and immunohistochemical staining with anti-Laminin and anti-Type IV collagen antibodies. Both optic fissure margins closely approached each other up to GD 11.5 in all FLS and BALB/c embryos. The inner and outer layers of the optic cup did not normally fuse at midlenticular levels of the optic fissure in almost 70% of FLS fetuses by GD 15.5, whereas both margins were completely fused in all BALB/c fetuses of the same gestational day. In the FLS fetuses at GD 12.5, rolling on one side of fissure margins and consequent asymmetry were observed at the ventral optic fissure. The basement membrane persisted after the close contact of both sides of the fissure margins during GD 11.5 and 15.5. Ultrastructurally, the basal lamina was not disintegrated and mesenchymal cells intervened between the two neuroepithelial layers, resulting in complete separation of both fissure margins at GD 13.0. It is highly probable that the disturbed basement membrane disintegration right before optic fissure closure causes mild ocular coloboma without microphthalmia in FLS mice.

Antimicrobial agent, tetracycline, enhanced upper alimentary tract Candida albicans infection and its related mucosal proliferation in alloxan-induced diabetic rats.

Alloxan-induced diabetic rats showed proliferative changes in the forestomach, accompanied by chronic inflammation, and one lesion progress to squamous cell carcinoma (SCC) without distant metastasis. The authors demonstrated that these lesions might be caused by Candida albicans infection. Antimicrobial therapy, particularly tetracycline treatment, has been blamed for a reduction in the number of competing bacterial organisms, which is frequently mentioned as a cause of candidiasis. The objective of this study is to ascertain whether or not tetracycline treatment can accelerate early-onset of C. albicans infection and the proliferative changes in this diabetic model. Alloxan-induced diabetic rats were given chlorinated water (AL group) and tetracycline solution (0.1% during week 1 and 0.01% thereafter) as drinking water (AT group). They were sacrificed after 25 weeks of drinking the treated water. The infection rate with C. albicans in the AT group was significantly higher than in the AL group. The incidence and severity of the squamous cell hyperplasia were enhanced in the AT group compared to the AL group. The proliferative lesions were consistently accompanied by inflammation and C. albicans infection in both groups. SCC was detected in one case in the AT group. These findings demonstrate that tetracycline induces C. albicans infection and enhances forestomach proliferative lesions in alloxan-induced diabetic rats.

Proliferative and nonproliferative lesions of the rat and mouse central and peripheral nervous systems.

Harmonization of diagnostic nomenclature used in the pathology analysis of tissues from rodent toxicity studies will enhance the comparability and consistency of data sets from different laboratories worldwide. The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of four major societies of toxicologic pathology to develop a globally recognized nomenclature for proliferative and nonproliferative lesions in rodents. This article recommends standardized terms for classifying changes observed in tissues of the mouse and rat central (CNS) and peripheral (PNS) nervous systems. Sources of material include academic, government, and industrial histopathology databases from around the world. Covered lesions include frequent, spontaneous, and aging-related changes as well as principal toxicant-induced findings. Common artifacts that might be confused with genuine lesions are also illustrated. The neural nomenclature presented in this document is also available electronically on the Internet at the goRENI website (http://www.goreni.org/).

Carnitine is necessary to maintain the phenotype and function of brown adipose tissue.

The juvenile visceral steatosis (JVS) mouse is a mutant strain with an inherited systemic carnitine deficiency. Mice of this strain show clinical signs attributable to impaired heat production and disturbed energy production. Brown adipose tissue (BAT) is the primary site of non-shivering thermogenesis in the presence of uncoupling protein-1 (UCP-1) in rodents and humans, especially in infants. To investigate the possible cause of impaired heat production in BAT, we studied the morphological features, carnitine concentration, and UCP-1 production of BAT in JVS mice. The effect of carnitine administration on these parameters was also examined. JVS mice aged 5 or 10 days (60 each) and age-matched control mice were used in this study, along with 10-day-old JVS mice treated subcutaneously with L-carnitine once a day between postpartum days 5 and 10. JVS mice showed lower body temperatures and lower concentrations of carnitine in BAT. Morphologically, BAT cells in JVS mice contained large lipid vacuoles and small mitochondria, similar to those present in white adipose tissue cells. In addition, UCP-1 mRNA and protein expression levels were significantly reduced in JVS as compared with control mice. Carnitine treatment resulted in significant increases in body temperature and carnitine concentrations in BAT, together with the recovery of normal morphological features. UCP-1 mRNA and protein expression levels were also significantly increased. These findings strongly suggest that carnitine is essential for maintaining the function and morphology of BAT.

A rapid and easy method for the qualitative detection of intracellular deposition of inhaled nanoparticles.

In recent years, nanoparticle exposure risk has drawn increasing attention from the research community and the general public. However, analysis of nanoparticles is hindered by their small size, which prevents the development of methods for their detection in cells and tissues. For risk assessment of nanoparticle exposure, it is important to measure the exact amount of deposited material in pulmonary tissue. Using a nanoparticle exposure device, A/JJmsSlc mice were chronically exposed transtracheally to anatase-type titanium dioxide particles. A microscope-integrated laser Raman spectrometer was used to detect differentially stained macrophages in a pulmonary wash obtained from the mice exposed to the particles. This detection method allowed rapid and easy sample collection and qualitative analysis, and the method may be useful for conducting large-scale evaluations in workers exposed to environments heavily contaminated with nanoparticles. FROM THE CLINICAL EDITOR: This paper discusses a microscope-integrated laser Raman spectrometer method to measure the exact amount of nanoparticles deposited in pulmonary tissue. This method allows rapid sample collection, qualitative analysis, and may be useful for large-scale evaluations.

Preparation and in vitro/in vivo evaluations of dimpled poly(L-lactic acid) fibers mixed/coated with hydroxyapatite nanocrystals.

A novel hydroxyapatite (HAp)/poly(L-lactic acid) (PLLA) nanocomposite nonwoven fabric, which was coated and mixed with calcined HAp nanocrystals, and has submicron-sized dimples on its surface, was fabricated. First, HAp-mixed PLLA fabric was prepared by electrospinning a HAp nanocrystal dispersion in dichloromethane (DCM)-dissolved PLLA. It was found that most of the HAp nanocrystals were not exposed on the HAp-mixed PLLA fiber surface but covered with the PLLA matrix. A HAp-nanocrystal coating was applied onto the surface of the HAp-mixed PLLA fabric after corona discharge treatment followed by ethanol washing. The submicron-sized dimples were enlarged after the ethanol washing. After the HAp-nanocrystal coating, the HAp-mixed PLLA fabric surface was uniformly coated with the HAp nanocrystals. In vitro cell spread tests showed that the rat osteoblasts spread more on HAp-nanocrystal-coated fabrics than on non-HAp-coated fabrics. Upon covering calvarial defects, the in vivo hard tissue responses suggested earlier restoration of the defects with HAp-nanocrystal-coated fabrics than those with non-HAp-coated fabrics.

Enhanced tumorigenesis of forestomach tumors induced by N-Methyl-N'-nitro-N-nitrosoguanidine in rats with hypoinsulinemic diabetes.

Hyperinsulinemia and hyperglycemia in prediabetic and diabetic patients are thought to increase the risk of developing neoplasms because insulin is a growth factor with pre-eminent metabolic but also mitogenic effects. To determine the effect of hypoinsulinemic diabetic conditions on carcinogenesis, we examined N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced forestomach carcinogenesis in hypoinsulinemic diabetic WBN/Kob rats aged about 45 weeks (DM) compared with non-diabetic younger WBN/Kob rats (C1), non-diabetic Wistar rats age-matched to DM (C2), and non-diabetic Wistar rats age-matched to C1 (C3). All rats were treated with MNNG by gavage and were killed at 40 weeks after dosing. Various-sized tumors were disseminated throughout the forestomach of all rats, and the ratio of the area of tumors to the whole forestomach area was 23.3% in the DM group and was higher than in the C1-3 (4.2-14.3%) groups. The incidence of carcinoma was much higher in the DM group (36.8%) than in the C1-3 (7.1-16.7%) groups, and the incidence of papilloma was also significantly higher in the DM group (84.2%) than in the C1-3 (28.5-50.0%) groups. The average thickness of the squamous epithelium in the non-neoplastic mucosa was significantly greater in the DM group (50.8 mum) than in the C1-3 (29.6-37.9 microm) groups. Immunohistochemically, the Ki-67-positive index in the non-tumorous mucosa of the DM group (42.0%) was significantly higher than that of the C1-3 groups (18.8-33.3%). These results suggest that prolonged hyperglycemic conditions without hyperinsulinemia enhance tumorigenesis of MNNG-induced tumors by enhanced proliferative activity of the squamous epithelium in the rat forestomach.

Giant mitochondria in pancreatic acinar cells of alloxan-induced diabetic rats.

This was a study of the microscopic, ultrastructural, immunohistochemical, and enzyme cytochemical features of giant eosinophilic granules encountered in pancreatic acinar cells of alloxan-induced diabetic rats. Seven male F344 rats with diabetes induced by a single i.v. dose of alloxan were sacrificed after twenty-five weeks of treatment. Histologically, the pancreatic acini were diffusely atrophied, and the islets showed marked atrophy or had disappeared, and giant eosinophilic granules and small vacuoles were observed in almost all acinar cells. The eosinophilic granules showed negative reactions for periodic acid-Schiff (PAS) and acid phosphatase, as well as fat stains such as Nile blue, Oil red O, and Sudan III. Ultrastructurally, the giant eosinophilic granules were huge structures surrounded by a double membrane containing many irregular cristae. A large amount of small lipid droplets was also apparent in the basal area of the acinar cells. Immunohistochemical analysis of prohibitin, a kind of protein located in the mitochondrial inner membrane, was partially positive in the marginal area of some giant eosinophilic granules, but negative for the central area. The enzyme activity for succinic dehydrogenase (SDH), one of the mitochondrial enzymes, showed a localizing pattern similar to that of prohibitin. These findings confirmed that the giant eosinophilic granules in the exocrine pancreas of alloxan-induced diabetic rats were giant mitochondria.

Prevention of proliferative changes of forestomach mucosa by blood glucose control with insulin in alloxan-induced diabetic rats.

Diabetes mellitus is one of the risk factors for carcinogenesis. Recently we reported that alloxan induces squamous cell carcinoma (SCC) with coincidental inflammation, bacteria/fungal infections, and a severe diabetic condition. The present study was conducted to examine the effects of blood glucose control with insulin on the proliferative changes of the forestomach in alloxan-induced diabetic rats. Male 15-week-old WBN/Kob rats were divided into a control group of non-treated rats with naturally occurring diabetes after 40 weeks of age (non-treated group), alloxan-induced diabetic rats (AL group), and alloxan-induced diabetic rats given insulin implant treatment (AL + In group). The animals were sacrificed at 90 weeks of age for histopathologic examination. The blood glucose and urinary glucose level of the AL + In group fluctuated variously from high to normal levels compared with a constantly high level of AL (for 75 weeks) as well as in the non-treated group (for 50 weeks). The mucosal hyperplasia in the forestomach developed in 88.2% of the AL group and 37.5% of the non-treated group, but in only 10.0% of the AL + In group. SCC was only detected in 23.5% of the AL group. Hyperplastic changes were constantly accompanied by inflammation and fungal/bacterial infections in the AL and non-treated groups, whereas inflammation and fungal infection were completely suppressed in the AL + In group. These findings demonstrate that blood glucose control suppressed neoplastic changes in alloxan-induced diabetic rats. We postulate that inflammation together with bacterial/fungal infections under prolonged severe diabetic conditions play a pivotal role in carcinogenesis.

Nephrotic syndrome induced by dibasic sodium phosphate injections for twenty-eight days in rats.

Sprague-Dawley rats received once daily tail-vein injections of 360 mM dibasic sodium phosphate solution at 8 mL/kg for fourteen or twenty-eight days. Clinical examination revealed persistent proteinuria from three days after the first dosing and thereafter severe proteinuria from eight days or later in the phosphate-treated groups. Proteinuria developed without remission even after fourteen-day withdrawal in the fourteen-day dosed group. Phosphate-treated animals developed lipemia, hypercholesterolemia, anemia, higher serum fibrinogen levels, and lower serum albumin/globulin ratios on day 29. Renal weight increased significantly compared with control animals, and the kidneys appeared pale and enlarged with a rough surface. Histopathologically, glomerular changes consisted of mineralization in whole glomeruli, glomerular capillary dilatation, partial adhesion of glomerular tufts to Bowman's capsule, and mesangiolysis. Ultrastructural lesions such as an increased number of microvilli, effacement of foot processes, and thickening of the glomerular basement membrane, and immunocytochemical changes in podocytes, mainly decreased podoplanin-positive cells and increased desmin expression, were also conspicuous in the phosphate-treated rats for twenty-eight days. Marked tubulointerstitial lesions were tubular regeneration and dilatation, protein casts, mineralization in the basement membrane, focal interstitial inflammation, and fibrosis in the cortex. These clinical and morphological changes were similar to features of human nephrotic syndrome.

Effects of the antifungal agent itraconazole on proliferative changes of the forestomach mucosa in alloxan-induced diabetic rats.

Alloxan-induced diabetic rats frequently exhibit proliferative lesions of squamous hyperplasia accompanied by chronic inflammation and Candida albicans infection in the forestomach, and some lesions progress to squamous cell carcinoma (SCC). Candida infection causes not only hyperplastic changes with inflammation but might also lead to SCC in human oral mucosa. Thus, the present study was conducted to examine the effects of the antifungal agent itraconazole (ITCZ) on proliferative and inflammatory changes of the forestomach in alloxan-induced diabetic WBN/Kob rats. Diabetes was induced by alloxan at fifteen weeks of age. Rats were allocated to three groups at forty-five weeks of age and were given ITCZ by gavage 0 (vehicle control), 5, and 10 mg/kg/day for four weeks, and they were sacrificed at the sixty-fifth week of age. Mucosal hyperplastic changes were consistently accompanied by inflammation and Candida infections in the 0 mg/kg group. These lesions were reduced by ITCZ (0 mg/kg; 100%, 5 mg/kg; 53.5%, 10 mg/kg; 61.5%). Squamous cell carcinoma was detected in three rats from the 0 mg/kg, but only one rat from the 10 mg/kg dose groups in this study. Itraconazole reduced the degree of mucosal hyperplasia, inflammatory changes, and Candida infection. Therefore, C. albicans infection was an important factor in pathogenesis of mucosal proliferation and inflammation.

Merkel cell carcinoma in a cat.

A 17-year-old spayed female Japanese domestic cat presented with a solitary cutaneous mass in the right thoracic area. Histopathologically, the mass consisted mainly of round tumor cells that had infiltrated throughout the dermis and deep subcutaneous tissue. The proliferating pattern of tumor cells was solid but also trabecular or cord-like in some areas, and lined with small cells resembling mature lymphocytes or basal cells. The tumor cells were positive for cytokeratin 20 and synaptophysin. The positive reaction for cytokeratin 20 showed localized to diffuse pattern. This is the first report describing now cytokeratin 20 was clearly beneficial for the differential diagnosis of feline Merkel cell carcinoma.

Morphological study on dental caries induced in WBN/KobSlc rats (Rattus norvegicus) fed a standard laboratory diet.

In our previous studies, WBN/KobSlc was characterized as a rat strain in which only males began to develop pancreatitis, and then presented with diabetic symptoms. In the course of studying their pancreatic inflammation, we detected molar caries in prediabetic males feeding on a standard diet (CRF-1) widely used for experimental animals. The purpose of this study is to confirm whether the WBN/KobSlc strain is caries-susceptible to the diet reported to be non-cariogenic, and to examine the effect of a prediabetic condition on their dental caries. For a morphological study, 25 male WBN/KobSlc rats aged 3.2-7.8 months and 24 females of the same strain aged 3.3-6.6 months were used, along with 10 males and 10 females of 8.2-month-old F344 rats. Marked dental caries were detected in the mandibular molars of male and female WBN/KobSlc rats regardless of pancreatitis, although no similar changes were observed in any teeth of the F344 strain fed the same diet. Soft X-ray examination revealed that the caries began in the crown and progressed horizontally and vertically, and that a severe radiolucent lesion extensively expanded to the entire crown, corresponding to a macroscopically deleted molar. The caries had gradually developed mainly in the second mandibular molar from more than 3.5 months of age, while none were seen in any rats before that time. The WBN/KobSlc rats were caries-susceptible even to the standard laboratory diet, and pancreatitis was not directly associated with the onset of dental caries in this strain.

Malignant Lymphoma with Severe Infiltrative Growth into Skeletal Muscles in WBN/Kob Rats.

Although spontaneously occurring neoplasms have been reported repeatedly in F344, SD and Wistar rats, which are commonly used strains for routine toxicologic and carcinogenicity studies, there are only a few reports of malignant lymphoma or lymphatic leukemia except for large granular lymphocytic leukemia (LGL) in F344 rats. Malignant lymphoma (lymphosarcoma) is thought to be uncommon in F344 rats. The authors encountered malignant lymphomas of the non-LGL leukemia type with characteristic pathologic features in WBN/Kob rats. The mean age at onset of the disease in all 13 affected rats (8 males and 5 females) was about 60 weeks. Common and characteristic clinical signs were abnormal gait with hind limb paralysis. Macroscopically, the enlargement of the lymph nodes, spleen and liver was slight to moderate. Scattered multiple white-to-gray nodules encompassed the aorta and assumed a bead-like appearance near the thoracic and lumbar vertebrae. Histopathologically, neoplastic proliferative changes were predominant in the bone marrow tissue of the entire body, and many tumor cells infiltrated the spleen and several lymph nodes. The most striking histological features were constant and severe infiltration of tumor cells in the adipose tissue and skeletal muscle adjacent the thoracic and lumber vertebrae. Immunohistochemically, all tumor cells were positive for B-cell markers (PAX-5, CD79a and CD45) and negative for CD3. From the results of immunohistochemistry and morphological examination, these tumors were diagnosed as malignant B-cell lymphomas.

Polypoid eosinophilic cystitis with pseudosarcomatous proliferative tissue in a dog.

A dog presented with hematuria, and two small polypoid masses were detected in the urinary bladder. Histopathologically, the masses were located in the mucosal or submucosal layer. That tissue consisted of a random proliferation of spindle-shaped, round and pleomorphic cells with single or multiple large atypical nuclei and abundant cytoplasm, and eosinophil infiltration. These large cells were confirmed by immunohistochemical staining as fibroblasts, myofibroblasts and macrophages. Mitotic figure was rarely seen. These masses were diagnosed as eosinophilic polypoid cystitis with pseudosarcomatous proliferative tissue, since they consisted of a wide variety of cells and showed low growth activity.