Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Thymomas in Fischer 344N Rats in The National Toxicology Program Database

398 views

Published on

Thymomas in Fischer 344N Rats in The National Toxicology Program Database

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

Thymomas in Fischer 344N Rats in The National Toxicology Program Database

  1. 1. Figure 7 Brandes, K., Fend, F., Monecke, S., Teifke, J.P., Breuer, W., and Hermanns, W. (2004). Comparative morphologic and immunohistochemical investigation of spontaneously occurring thymomas in a colony of European hamsters. Vet Pathol 41, 346-52. Frith, C.H., Ward, J.M., Harleman, J.H., Stromberg, P.C., Halm, S., Inoue, T., and Wright, J.A. (2001). Hematopoietic System. In International Classification of Rodent Tumors. The Mouse. (U. Mohr, ed.), pp 432-437. Springer-Verlag, New York, NY. Greaves, P. (2012). Histopathology of Preclinical Toxicity Studies, Fourth Edition. Elsevier, Academic Press, San Diego, CA, p 128. Hailey, J.R., Harleman, J.H., Stromberg, P., and Ward, J.M. (1993). 4. Hematopoietic System. In: International Classification of Rodent Tumours, Part I: The Rat, (U. Mohr, ed.), pp 17-21. International Agency for Research on Cancer, Lyon, France. Haseman, J.K., Hailey, J.R., and Morris, R.W. (1998). Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: a National Toxicology Program update. Toxicol Pathol 26, 428-441. Kupfer, C.F. and Beems, R.B., (1990). Thymoma, Epithelial, Rat, In. Hemopoietic System, Monographs on Pathology of Laboratory Animals, ed. T.C. Jones, J.M. Ward, U.M. Mohr and R.D. Hunt. Springer –Verlag, Berlin, Heidleberg, New York. pp. 280-286. Kupfer, C.F., Beems, R.B., and Hollanders, V.M.H. (1986). Spontaneous Pathology of the Thymus in Aging Wistar (Cpb:Wu) Rats. Vet Pathol 23, 270-277. Naylor, D.C., Krinke, G.J., and Ruefenacht, H.J. (1988). Primary Tumours of the Thymus in the Rat. J. Comp. Path. Vol 99, PP 187-203. Pearse, G. (2006). Histopathology of the Thymus. Toxicol Pathol 34, 515-547. Rao, G. N. (1996). New diet (NTP-2000) for rats in the National Toxicology Program toxicity and carcinogenicity studies. Fundam Appl Toxicol 32, 102-8. Rao, G. N. (2001). Beneficial effects of NTP-2000 diet on growth, survival, and heart and kidney diseases of Fischer 344 rats in chronic studies. Toxicol Sci 63, 245-55. Rosai, J., and Sobin, L. H., (1999). Histological typing of tumours of the thymus. In World Health Organisation, International Histological Classification of tumours, 2nd ed. pp 1-36. Springer, Berlin. Stefanski, S. A., Elwell, M.R., and Stromberg, P.C. (1990). Spleen, Lymph Nodes, and Thymus. In Pathology of the Fischer Rat: Reference and Atlas (Boorman G.A., Eustis, S. L., Elwell, M. R., Montgomery, C. A., MacKenzie, W. F., eds), pp. 369-93. Academic Press, San Diego, CA. Thymomas in Fischer 344/N Rats in the National Toxicology Program Database Gabrielle A Willson1, Rebecca R. Moore1, Hiroaki Nagai2, Rodney A. Miller1, Jerry F. Hardisty1, Neil Allison1, David E. Malarkey2 1Experimental Pathology Laboratories, Inc., Research Triangle Park, NC, USA 2Cellular and Molecular Pathology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA Figure 3 Thymoma is an uncommon tumor in most strains of rats and mice. Primary tumors of the thymus of Sprague-Dawley-derived rats (strain Tif:RAI) were reported from 7 different long-term studies (Naylor, et al., 1988). In that study, 192 primary thymic tumors were identified (out of 4281 animals), of which 171 appeared benign and 21 appeared malignant. In the F344/N rat spontaneously occurring thymomas are rare, and most of those have been reported to be benign (Stefanski, Elwell, and Stromberg, 1990; Haseman, Hailey, and Morris, 1998). The literature contains no reports of large studies of thymoma in F344/N rats. The purpose of this study is to describe the morphological features, incidence, and behavior of thymoma in F344/N rats in NTP studies. Two hundred seventy-seven thymomas recorded in chronic studies in the NTP archives database were reviewed. No thymomas were recorded in any of the subchronic studies. Thymomas in F344/N rats in this survey were rare occurrences (<0.2% incidence). No occurrences of this tumor were found to be associated with treatment. Thymomas occurred more commonly in male rats (156/277 [56.3%]) than in female rats (121/277 [43.7%]). Benign thymomas comprised 84.8% (235/277) of the thymomas reviewed, and the remaining 15.2% (42/277) were diagnosed as malignant thymomas based upon metastasis, unequivocal tissue invasion, or cytological malignant features (Table 1). In male rats 27/156 (17.3%) thymomas were malignant, and in female rats 15/121 (12.4%) were malignant. Metastases were observed in 14 of the 42 animals with malignant thymomas, and in all 14 cases metastatic lesions were observed in the lung. Metastases also were present in the lymph node of 1 animal and in the liver of another animal. All of the malignant thymomas that metastasized had features of the main tumor mass and no malignant epithelial neoplasms were present in other organs. Seventeen of the remaining 28 malignant thymomas that exhibited no metastases were diagnosed due to their unequivocal tissue invasion, and 11 cases were diagnosed based upon cytological features, such as pleomorphism, cellular atypia, karyomegaly, anisokaryosis, prominent nucleoli, and increased mitoses. These cytologic features typically associated with malignancy seemed to have little to no relationship to a propensity for invasion or metastasis. Thymomas in Fischer 344/N rats were morphologically heterogeneous but could be divided into 6 general categories according to morphologic features (Table 2). Most tumors displayed a mixture of more than one morphologic pattern, and these were grouped according to the predominant pattern. The most common morphologic pattern consisted of epithelial cells arranged in cords and tubules and was present in 155/277 (56.0%) of the tumors in this review (Figure 1). This was followed by thymomas with a predominantly spindloid pattern, which occurred with a frequency of 79/277 (28.5%) (Figures 2 and 3). A papillary pattern was observed in 17/277 (6.1%) of the tumors and was frequently associated with cystic features (Figure 4). A squamous epithelial pattern was present in 12/277 (4.3%) of the tumors (Figure 5). A myoid pattern was present in 11/277 (4.0%) of the tumors (Figure 6A). The myoid cell is a striated muscle cell which exhibits expression of desmin (Figures 6B and 6C). While it is possible that myoid cells within the thymomas in this series represented invasion of pre-existing muscle, myoid differentiation of neoplastic cells could not be ruled out. A neuroendocrine pattern was observed in only 3/277 (1.1%) of the tumors (Figure 7). No particular pattern was unequivocally correlated with a metastatic or invasive propensity. Four benign thymomas (4/228; 1.8%), 11 malignant thymomas without metastasis (11/28; 39.3%), and 11 malignant thymomas with metastasis (11/14; 78.6 %) were considered to be the cause of death. The survival days of animals with malignant thymomas were less than those of animals with benign thymomas (Table 3). Figure 2 Results Thymoma is defined as the neoplastic proliferation of thymic epithelial cells. By virtue of the cellular composition of the thymus, thymomas contain varying numbers of non-neoplastic lymphocytes. Various classification schemes have been described in veterinary medicine, and most are based upon histomorphological features. One such scheme creates divisions based upon the relative proportions of lymphocytes and epithelial cells, thus specifying tumor types as either epithelial type, mixed epithelial and lymphoid cell type, or “pure” lymphoid type (containing scattered epithelial cells to distinguish it from well-differentiated lymphoma) (Greaves, 2012). Others suggest that thymomas are divided into two types, consisting of tumors with and without medullary differentiation (Kuper, Beems, and Hollanders, 1986; Kuper and Beems, 1990). Tumors exhibiting lobular, medullary differentiation have pale staining areas containing fewer lymphocytes, fibrous trabeculae, and may contain epithelial cells forming cords, tubules, and cysts. Thymomas without medullary differentiation consist of a mixture of small lymphocytes and epithelial cells without a lobular architecture. While epithelial cell morphology can be quite variable, cellular atypia has been found to be rare (Kuper and Beems, 1990). Epithelial cells of thymomas can form several morphological patterns, which have been described by one author as epidermoid (non-keratinizing squamous epithelium); squamoid (with keratinization); papillary; ribbons, cords, or tubules; spindloid; endocrine-like; neuroendocrine; and myoid (Pearse, 2006). Thymoma is an uncommon tumor in most strains of rats and mice. Primary tumors of the thymus of Sprague-Dawley-derived rats (strain: Tif:RAI) were reported from 7 different long-term or lifespan studies (Naylor, et al., 1988). In that study, 192 primary thymic tumors were identified (out of 4281 thymuses), of which 171 were classified as benign and 21 were called malignant. In the F344/N rat spontaneously occurring thymomas are rare, and most of those have been reported to be benign (Stefanski, Elwell, and Stromberg, 1990; Haseman, Hailey, and Morris, 1998). The purpose of this study is to describe the morphological features, incidences, and behavior of thymoma in Fischer 344/N rats in NTP studies. Introduction Figure 1 Figure 4 Thymomas are neoplasms of thymic epithelial cell origin which may contain variable numbers of non-neoplastic lymphocytes. Thymomas appear grossly as a firm, smooth mass in the anterior mediastinum, and compression of the surrounding tissues may or may not be present. These tumors are rare in humans and most lab animals. In the Fischer 344/N rat, thymomas are rare and are said to occur with no apparent sex difference (Stefanski, Elwell, and Stromberg, 1990), although in this review more thymomas were observed in male rats. There is no meaningful established classification system of thymomas in veterinary medicine, whereas in human medicine there is the widely used classification system established by the World Health Organization (WHO) (Rosai and Sobin, 1999). Nevertheless, the WHO system has been adapted for use in one of the largest hamster thymoma papers to date (Brandes et al., 2004). Diagnostic paradigms have been described for rat thymomas, including those dividing them according to the proportions of epithelial and lymphoid cells (Greaves, 2012), as well as divisions based upon thymomas with and without medullary differentiation (Kuper and Beems, 1990; Kuper, Beems, and Hollanders, 1986). While understandable and useable, these paradigms do not seem to add significantly to our ability to interpret the rat thymoma in relation to toxicologic or biological significance. The thymomas in this review were variable in microscopic appearance and were separated into 6 categories based upon morphological patterns. Although this could be done with some consistency, there was no apparent difference in biological behavior between the categories. Since separating thymomas into several sub-classifications appears to have limited, if any, scientific relevance in terms of biological behavior, it seems adequate to designate them only as benign or malignant until new information is obtained. Classifying thymomas as benign or malignant traditionally has been based upon cytologic features and biological behavior such as invasion and metastasis as discussed in two volumes of International Classification of Rodent Tumors (Hailey et al., 1993; Frith et al., 2001). In this review there was little evidence that cytologic features typically associated with malignancy were necessarily correlated with invasion or metastasis Discussion References The NTP studies evaluated for this review ended at 104 to 105 weeks for chronic studies and 13 weeks for subchronic studies. Complete necropsies were performed on all animals. All gross lesions and approximately 43 tissues were collected, fixed in 10% neutral buffered formalin, stained with H&E, and examined. Thymic tissue and/or thymic masses were collected from all rats on each study. The NTP historical databases were reviewed for the diagnosis of benign thymoma, malignant thymoma, and thymoma. The databases contained data on ~190,000 Fischer 344/N rats (~175,000 rats from chronic studies and ~15,000 rats used in subchronic studies). All sections of thymomas were evaluated for unique morphologic features, patterns of growth, and the presence or absence of invasion and/or metastasis that could be used to categorize them as benign or malignant. Tabulation of data was designed to determine thymoma occurrences in male and female rats, classification of tumors as benign or malignant, and to characterize general morphologic patterns that may relate to determining malignancy. The classification of the neoplasms as benign or malignant was based upon tumor expansion and invasion of surrounding tissues, as well as presence of metastatic lesions. Thymomas were classified as benign when they were confined to the mediastinal space, discrete, exhibited an expansile non-invasive growth pattern, and there was no evidence of metastasis. Extension into the mediastinal fat was considered a benign feature as long as there was connection to the main tumor mass and as long as the other benign tumor criteria were met. Malignant thymomas were characterized by implantation on serosal surfaces, metastasis to other organs, invasion of adjacent tissues (body wall, diaphragm, or thoracic organs), and/or infiltration of mediastinal fat with nests of neoplastic cells but no apparent connection with the main tumor mass. Methods Abstract Figure 6 Figure 5 Figure 1A. Benign thymoma from a male F344/N rat from a 2-year NTP study. (H&E) Figure 1B. Higher magnification of 1A, the neoplastic epithelial cells form cords and tubules. (H&E) Figure 2. Spindloid pattern in a malignant thymoma from a female F344/N rat from a two-year NTP study. (H&E) Figure 3. Lung metastasis from a malignant thymoma in a male F344/N rat from a 2-year study. Sheets of elongated neoplastic cells form a spindloid pattern. (H&E) Figure 4. Benign thymoma is from a male F344/N rat from a 2-year study. Neoplastic epithelial cells form papillary projections, which protrude into cystic spaces. There are small clusters of non-neoplastic lymphocytes interspersed with the neoplastic cells. (H&E) Figure 5. Malignant thymoma is from a male F344/N rat from a 2-year study. The neoplastic epithelial cells form a squamous pattern. (H&E) Figure 6A. Malignant thymoma is from a female F344/N rat from a 2-year study. The neoplastic epithelial cells form a myoid pattern. (H&E) Figure 6B. Immunohistochemical staining of neoplasm from 6A showing expression of desmin in myoid cells. (Desmin) Figure 6C. Immunohistochemical staining of neoplasm from 6A showing expression of desmin with prominent cross striations in myoid cells. (Desmin) Figure 7. Benign thymoma is from a female F344/N rat from a 2-year study. Packets of elongated neoplastic cells form a neuroendocrine pattern. (H&E) Benign Malignant without metastasis with metastasis Number of animals 228 a 28 14 Mean survival days b 713 ± 4 609 ± 27 506 ± 42 Cause of death: thymoma 4 11 11 Sacrifice type Natural death 16 8 8 Moribund sacrifice 48 9 6 Terminal sacrifice 164 11 0 a Seven animals were not included in this table because there were 2 accidental deaths and 5 animals were sacrificed for interim necropsy. b Study days on which animals were sacrificed. Value shown is group mean ± S.E. Morphologic pattern Benign Malignant Total Cords/Tubules 139 16 155 Spindloid 66 13 79 Papillary 17 0 17 Squamous 5 7 12 Myoid 6 5 11 Neuroendocrine 2 1 3 Table 2. The morphologic patterns of thymomas Benign Malignant Total Male 129 27 (10*) 156 Female 106 15 (4*) 121 Total 235 42 (14*) 277 Table 1. The incidence of thymomas in male and female Fischer 344/N Rats Table 3. Correlation of the malignancy of thymoma with survival days, cause of death and sacrifice type *The number within parentheses denotes the number of malignant thymomas with metastasis. A B C A B Grateful thanks for assistance with this poster to Karen Cimon, Kim Pernicka, Maureen Puccini and Emily Singletary, of EPL and Lois Wyrick of Image Associates. Acknowledgments

×