Immunohistochemical characterization of spontaneous and acrylonitrile-induced brain tumors in the rat.

Twenty-eight spontaneously occurring glial tumors (previously diagnosed as astrocytomas, oligodendrogliomas, and gliomas) and eleven granular cell tumors (GCTs) were selected for evaluation using a panel of immunohistochemistry (IHC) stains (Ricinus communis agglutinin type 1 [RCA-1], ionized calcium-binding adapter molecule 1 [Iba-1], OX-6/major immunohistocompatibility complex class II, oligodendrocytes transcription factor 2 [Olig2], glial fibrillary acidic protein [GFAP], S100 beta, glutamine synthetase, neurofilament, proliferating cell nuclear antigen). In addition, nine brain tumors from a 2-year drinking water study for acrylonitrile were obtained from the Acrylonitrile Group, Inc. Based on IHC staining characteristics, Olig2+ oligodendrogliomas were the most commonly diagnosed spontaneous tumor in these animals. Many of the spontaneous tumors previously diagnosed as astrocytomas were RCA-1+, Iba-1+ and negative for GFAP, S100beta, and glutamine synthetase; the diagnosis of malignant microglial tumor is proposed for these neoplasms. Three mixed tumors were identified with Olig2+ (oligodendrocytes) and Iba-1+ (macrophage/microglia) cell populations. The term mixed glioma is not recommended for these tumors, as it is generally used to refer to oligoastrocytomas, which were not observed in this study. GCT were positive for RCA-1 and Iba-1. All acrylonitrile tumors were identified as malignant microglial tumors. These results may indicate that oligodendrogliomas are more common as spontaneous tumors, while acrylonitrile-induced neoplasms are microglial/histiocytic in origin. No astrocytomas (GFAP, S100 beta, and/or glutamine synthetase-positive neoplasms) were observed.

Immunohistochemical investigation of F344/N rat islet cell tumors from national toxicology program studies.

In this study, we have investigated the immunoexpression of peptide hormones and mediators associated with human islet cell tumors in a group of proliferative islet cell lesions in F344 rats including islet cell hyperplasias, adenomas, and carcinomas, as defined by conventional histopathologic criteria. All proliferative islets expressed synaptophysin, although decreased expression intensity was observed in hyperplasias and adenomas. Most of the proliferative lesions expressed insulin, which generally decreased as lesions progressed toward malignancy. The distribution of glucagon, somatostatin, and gastrin-expressing cells was altered in proliferative islet lesions but did not comprise a large proportion of cells. Islet cell tumors were associated with increased nuclear expression of cyclin-dependent kinase 4 as well as increased proliferating cell nuclear antigen and decreased ß-catenin expression. c-Myelocytomatosis oncogene expression was variable. This is the first study to describe the immunophenotype of islet cell tumors in the F344 rat and to show that islet cell tumors in the F344 rat exhibit similarities in protein expression to the human counterpart.

Proceedings of the 2011 National Toxicology Program Satellite Symposium.

The 2011 annual National Toxicology Program (NTP) Satellite Symposium, entitled "Pathology Potpourri," was held in Denver, Colorado in advance of the Society of Toxicologic Pathology's 30th Annual Meeting. The goal of the NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for audience voting or discussion. Some lesions and topics covered during the symposium include: proliferative lesions from various fish species including ameloblastoma, gas gland hyperplasia, nodular regenerative hepatocellular hyperplasia, and malignant granulosa cell tumor; spontaneous cystic hyperplasia in the stomach of CD1 mice and histiocytic aggregates in the duodenal villous tips of treated mice; an olfactory neuroblastoma in a cynomolgus monkey; various rodent skin lesions, including follicular parakeratotic hyperkeratosis, adnexal degeneration, and epithelial intracytoplasmic accumulations; oligodendroglioma and microgliomas in rats; a diagnostically challenging microcytic, hypochromic, responsive anemia in rats; a review of microcytes and microcytosis; nasal lesions associated with green tea extract and Ginkgo biloba in rats; corneal dystrophy in Dutch belted rabbits; valvulopathy in rats; and lymphoproliferative disease in a cynomolgus monkey.

Histopathology of the urinary bladders of cynomolgus monkeys treated with PPAR agonists.

Peroxisome proliferator-activated receptors (PPAR) are involved in the pathogenesis of insulin resistance, diabetes, hyperlipidemias, and related complications. Consequently, a mechanistic understanding of PPAR subtypes and their activation provides promising therapeutic targets for the management of type 2 diabetes mellitus and the metabolic syndrome. Available data from rodent carcinogenicity studies, however, demonstrate that PPAR agonists can be tumorigenic in one or more species of rodents at multiple sites. Sufficient data are not yet available to explain the mode(s) of action for most of these tumor types. There has been information presented by FDA that indicates there are urothelial changes in the monkey (and possibly the dog) in addition to the rat. Outstanding questions exist regarding potency, species differences, safety margins, and other issues. In 2005, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) PPAR Agonist Project Committee was established to advance research on the modes of action and potential human relevance of emerging rodent tumor data. Additionally, the HESI PPAR Agonist Project Committee authorized a Pathology Working Group (PWG) to examine the urinary bladder from cynomolgus monkeys. The focus of this PWG was to establish consistent diagnostic criteria for urothelial changes and to assess the potential relationship of these changes to treatment. Specific diagnostic criteria and nomenclature were recommended for the diagnosis of urothelial granules, vacuolation, hypertrophy, and hyperplasia in studies conducted with PPARgamma and dual alpha/gamma agonists in cynomolgus monkeys, which will assist investigators performing toxicity studies to provide data in a consistent manner between studies and laboratories. In this review of selected tissues, treatment with PPAR agonists was not associated with urothelial hypertrophy or hyperplasia, but there was an increased incidence in the size and frequency of vacuoles within the superficial urothelial and adjacent intermediate cell layers.

Histopathology of hemangiosarcomas in mice and hamsters and liposarcomas/fibrosarcomas in rats associated with PPAR agonists.

Peroxisome proliferator-activated receptors (PPAR) are involved in the pathogenesis of insulin resistance, diabetes, and related complications. Consequently, the identification of PPAR subtypes and the potential for their activation provides promising therapeutic targets for the management of type 2 diabetes mellitus. Available data from rodent carcinogenicity studies, however, demonstrate that PPAR agonists can be tumorigenic in one or more species of rodents at multiple sites. In 2005, the Health and Environmental Sciences Institute (HESI) PPAR Agonist Project Committee was established by a group of pharmaceutical companies to advance research on and to understand the modes of action and human relevance of this emerging rodent tumor data for PPAR agonists. Since the most commonly observed tumor types reported in rodents are hemangiosarcomas, fibrosarcomas and liposarcomas, the PPAR Agonist Project Committee approved a Pathology Working Group (PWG) to develop consensus of morphologic criteria for tumor diagnoses and consistency of diagnoses across multiple studies for hemangiosarcomas in mice and hamsters and liposarcomas/fibrosarcomas in rats. Therefore, the focus of the PWG review was to establish consistent tumor diagnostic criteria, to assess evidence of potentially preneoplastic changes and to identify distinguishing morphologic differences which may exist between spontaneous changes present in control animals with similar changes from treated animals. Specific diagnostic criteria and nomenclature are recommended for the classification of proliferative vascular lesions which may be present in mice or hamsters and for proliferative mesenchymal changes in rats in studies that are conducted with PPAR agonists.