FORUM Spontaneous Neoplasms in Control Wistar Rats: A Comparison of Reviews

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1 TOHCOLOGICAL SCIENCES, - (99) ARTICLE NO. TX99 FORUM Spontaneous Neoplasms in Control Wistar Rats: A Comparison of Reviews James Poteracki and Kathleen M. Walsh Department of Pathology and Experimental Toxicology, Parke Davis Pharmaceutical Research, Division of Warner Lambert Company, 00 Plymouth Road, Ann Arbor, Michigan 0 Received January, 99; accepted May 9, 99 Spontaneous Neoplasms in Control Wistar Rats: A Comparison of Reviews. Poteracki, J., and Walsh, K. M. (99). Toxicol. Sci., -. Spontaneous neoplasms in 90 control Wistar rats from five carcinogenicity bioassays conducted between 990 and 99 were reviewed and compared with review findings in studies between 90 and 990. Mean survival at 0 weeks was % for males and 0% for females, similar to that of the previous review. A total of 99 neoplasms was diagnosed in (%) male and (9%) female rats; 9 (%) of these were benign and 0 (9%) were malignant (% with metastases). Sixty-eight percent of all neoplasms were in endocrine and integumentary systems, similar to % seen in the previous review. Most common neoplasms (affecting >% of either sex) were pituitary adenoma (% of males, 0% of females), benign adrenal pheochromocytoma (0% of males, % of females), thyroid C cell adenoma (% of males, % of females), mammary fibroadenoma (% of males, % of females), keratoacanthoma (% of males, 0.% of females), testicular interstitial cell tumor (% of males), uterine stromal polyp (% of females), pancreatic acinar cell adenoma (% of males, 0.% of females), and benign thymoma (% of males, % of females). Seventeen neoplasms affecting to.9% of either sex included adrenal cortical adenoma, thyroid follicular adenoma, pancreatic islet cell adenoma, pituitary carcinoma, mammary adenoma, mammary adenocarcinoma, fibroma, fibrosarcoma, dermal papilloma, uterine schwannoma, uterine granular cell tumor, pancreatic acinar cell carcinoma, hepatocellular adenoma, lymphoma, granular cell meningioma, renal mesenchymal tumor, and hemangiosarcoma. Remaining neoplasms occurred in fewer than % of animals. Mean tumor incidence did not differ significantly between our two reviews. Ratios of benign to malignant neoplasms were similar in both reviews and percentages of survival at 0 weeks were similar. Between the two reviews, greater than threefold increase in frequency of some neoplasms occurred only in males and included keratoacanthomas, pancreatic acinar cell adenomas/carcinomas, and astrocytomas. Frequencies of remaining neoplasms were within twofold or within 0% of previous frequencies. Some neoplasms diagnosed in this review but not in the previous review included cardiac schwannoma, pilomatrixoma, parathyroid adenoma, and prostatic adenoma but incidence was approximately % for any one tumor. Based on these reviews, Wistar rats appear to have a predilection to pituitary neoplasms and mammary fibroadenomas (females), c 99 Society of To Because rats are routinely used in carcinogenesis studies, historical data on spontaneous changes, strain sensitivities and susceptibilities, and background lesions in the strain used are essential for interpretation of carcinogenicity bioassay results. Historical control data are especially useful in assessment of increased incidence of uncommon neoplasms, when increase in frequency is marginal compared to concurrent controls, and in evaluation of genetic drift within a particular strain (Haseman et al, 9, 99; Hardisty, 9). As noted previously (Walsh and Poteracki, 99), spontaneous lesions have been extensively described and quantitated in commonly used Fischer (F) rats and in Sprague-Dawley rats but most reports in Wistar rats are restricted to specific organ systems or to a limited number of animals, were written before recent changes in histopathological criteria, or cover test periods longer than the years commonly used for carcinogenicity studies. The evaluation of spontaneously occurring neoplasms in 90 control Wistar rats from five carcinogenicity bioassays conducted over a -year period is presented and comparisons are made to findings from an earlier review (Walsh and Poteracki, 99) of 0 control Wistar rats over a 0-year period (90-990). METHODS Wistar (Crl:(WI)BR) rats from Charles River Laboratory in Kingston, NY, or Portage, MI were used in five carcinogenesis bioassays conducted between 990 and 99. Rats were to 9 weeks of age at initiation, housed individually, and fed Purina Laboratory Chow 00 (0-00 g/week ad libitum) and ad libitum water for 0 weeks. Animals were maintained on a h light/dark cycle at - F and 0 to % relative humidity. Complete necropsies were conducted on all animals and tissues were fixed in formalin, embedded in I 09-#)0/9 $.00 Copyright 99 by the Society of Toxicology. All rights of reproductionln any form reserved. Downloaded from on January 0

2 POTERACKI AND WALSH TABLE Summary of Neoplastic Incidence in Control Wistar Rats Population Rats with neoplasm(s) (TBA 0 ) Rats with benign neoplasm(s) Rats widi malignant neoplasm(s) Neoplasms Benign neoplasms Malignant neoplasms Metastatic neoplasms Rats with neoplasm Rats with > neoplasm Mean % survival at 0 weeks Week first neoplasm diagnosed " Tumor-bearing animals. b Percentage of malignant neoplasms. c Percentage of population (male or female). d Percentage of TBA (male or female). % 0 0 " ' " ' " 0 9 % 9 0 " ' " sr " paraffin, sectioned (- fim), and stained with hematoxylin and eosin. Tissues routinely examined microscopically included brain (four sections), spinal cord, sciatic nerve, pituitary, thyroid, parathyroid, adrenal, pancreas, liver, submandibular salivary gland, esophagus, stomach, small and large intestine, trachea, larynx, lung, heart, thymus, spleen, mesenteric lymph node, tongue, skeletal muscle, eye, Harderian gland, kidney, urinary bladder, mammary gland, skin, bone, marrow, testis, ovary, seminal vesicle, prostate, epididymis, uterus, and vagina. Special stains, immunohistochemistry, and/or electron microscopy were used as needed to aid in diagnosis. Because of variation in nomenclature, synonyms for several neoplasms had been used. If available, nomenclature and criteria suggested by the Committee for Standardized System of Nomenclature and Diagnostic Criteria were used to equate synonyms (Streett et al., 990). For example, Leydig cell tumor was equated with interstitia] cell tumor of testis. Pathology data from all studies were subjected to peer review. Briefly, all slides from a random 0% sample of animals, all target organs, and all tumors were examined by a review pathologist. Any discrepancies between study pathologist's and review pathologist's diagnoses were submitted to a peerreview group composed of study and review pathologists, a senior director of pathology, and a minimum of three additional pathologists that may have included any combination of staff pathologists, contract pathologists, and consultant pathologists. Final tables and narratives were then prepared by a study pathologist. RESULTS Table summarizes data on control rats ( males, females). Survival at 0 weeks ranged from to % among males and to % among females with combined mean of.% ±.% (.% ±.% males; 0.% ±.% females). Deaths were seen from Week in males and Week 9 in females but neoplasms were first diagnosed in males dying in Week 0 and in females in Week. Among males, (%) had neoplasms, (%) had benign tumors, and (%) had malignant neoplasms. Incidence was higher among females, (9%) of which had neoplasms ( (%) with benign, (0%) with malignant). A total of 99 neoplasms was diagnosed, in males and in females. Of those in males, 9 (0%) were benign, (0%) were malignant; (%) of the malignancies had metastases. Of neoplasms in females, 0 (%) were benign, 9 (%) were malignant, and (%) had metastases. Three hundred three rats ( males, females) had single neoplasms; (0 males, females) had or more neoplasms. Lethality data were available for all animals. One hundred thirty-nine rats (0 males, 9 females) had tumors that were considered to be the cause of death. Among these animals were single incidences of several tumors (pheochromocytoma, adrenal cortical carcinoma, pancreatic acinar cell carcinoma, cardiac sarcoma, cardiac schwannoma, spinal cord schwannoma, small intestine leiomyoma, abdominal cavity schwannoma, oral squamous cell carcinoma, medulloblastoma, Harderian gland adenocarcinoma, hemangioma, uterine leiomyosarcoma, uterine stromal polyp, ovarian sertoli cell tumor, transitional cell carcinoma, and histiocytic sarcoma) but the majority (%) died or were euthanatized moribund due to pituitary adenoma/carcinoma ( males, females). Tumors identified as cause of death in to rats included thymoma (), astrocytoma (), oligodendroglioma (), granular cell meningioma (), small intestine adenocarcinoma (), renal mesenchymal tumor (), dermal fibrosarcoma (), lymphoma (), uterine schwannoma (), and leukemia (). Mean body weight at study initiation was g (range to g) for males and g (range to 0 g) for females. Mean weight at study termination was 99 g (range to g) for males and g (range to 9 g) for females. Rats gained weight over the length of the studies except for males in two studies in which the terminal mean weights were -% lower than the highest weight achieved. Table summarizes tumor incidence by system and Table lists by system and sex the number and frequency of spontaneous neoplasms found in three or more control rats. Percentage ranges are included as indicators of variability between studies. Table lists neoplasms occurring in one (or two as indicated) rat of each sex. The endocrine system had the highest incidence of tumors ( tumors,.% of all tumors) in both males (9 tumors in 9 males) and females ( tumors in 9 females) due mainly to pituitary adenomas in.% (range. to.%) of males and 0.% (range. to.%) of females. Pituitary carcinomas were found in females only (.%) in this review. Benign adrenal pheochromocytomas were seen in 9.% of males but only.% of females; malignant pheochromocytomas were seen in.% of males and % of females. Incidences of adrenal cortical adenomas were similar in males (.%) and females (.%); cortical carcinomas were uncommon (<%). Pancreatic islet cell adenomas occurred three times more often in males (.%) than Downloaded from on January 0

3 NEOPLASMS IN CONTROL WISTAR RATS TABLE Neoplastic Incidence in Control Wistar Rats by System Combined sexes System % Tumors in males % s % Tumors in females % s % Tumors % Rats Endocrine Integumentary Reproductive Gastrointestinal Hematopoietic/lymphatic Cardiovascular Nervous Urinary Musculoskeletal Respiratory females (.%); islet carcinomas were twice as common in males (.%) as females (0.%). Incidence of thyroid C cell adenoma was slightly higher in females (.%) than in males (.%) while follicular cell adenomas were seen more often in males (.9%) than in females (.%). Parathyroid adenomas were seen only in males (.9%). Neoplasms in integument/soft tissue were common also, accounting for.9% of all tumors, (% of all tumors in males) in males and 9 (0% of all tumors in females) in females. Tumors of mammary origin were most common: 0 of neoplasms of integumentary origin were from mammary tissue and 9 of these were in females. Fibroadenomas were the most common mammary tumor, occurring in.% of females and.% of males; adenocarcinoma occurred in.% of females and adenomas in.9%. Keratoacanthomas were the most common tumor in males (.%) but were seen in only 0.% of females. Dermal fibromas occurred in.% of males and.0% of females; fibrosarcomas were in.% of males and no females. Papillomas were diagnosed in.% of males and % of females;.% of males and.% of females had squamous cell carcinoma. Other tumors were seen in fewer than % of either sex. There were neoplasms (% of all tumors) in reproductive system, (.% of tumors in males) in males and 0 (.9% of tumors in females) in 0 females. Testicular interstitial cell tumors accounted for most of the neoplasms in males, occurring in 9 (0.%), and uterine stromal polyps were the most common tumor in females, occurring in (.%). Uterine granular cell tumor and schwannoma were seen in. and.% of females, respectively. Remaining neoplasms of the reproductive system were seen in <% of either sex. Gastrointestinal (GI) neoplasms were diagnosed in males and females and accounted for.% of all tumors ( tumors). Sixty-two (.%) pancreatic acinar cell adenoma and (.%) of acinar cell carcinomas in males accounted for most of GI neoplasms. Acinar cell tumors were uncommon in females with adenomas, occurring in only 0.% of females. Incidence of hepatocellular adenoma was similar in males (.%) and females (.%). Remaining GI tumors were present in <% of either sex. Eighty-nine (.% of all tumors) tumors of hematopoietic/ lymphoid (HL) system were found in rats, males and females. Thymomas (.% of males: benign, malignant;.% of females: benign, malignant) accounted for the majority of HL tumors occurring in twice as many females as males. Lymphomas were also slightly more frequent in females (.%) than males (.%). Remaining tumors of HL were seen in <% of either sex. Individual tumors in remaining systems were fewer than % for any system for either sex (cardiovascular > nervous > urinary > musculoskeletal > respiratory); overall tumors in these systems accounted for.% of all tumors. Hemangiomas and hemangiosarcoma were placed in cardiovascular system even though they occurred in multiple tissues. This was done to remove the effect of varying site of tumor from assessment of overall incidence. Hemangiosarcomas were seen in.% of males and 0.% of females while incidence of hemangiomas was similar in males (.%) and females (.%). Granular cell meningiomas were slightly more frequent in males (.%) than females (.%) and were the most common neoplasm in the nervous system. Renal mesenchymal tumors were seen more in females (.%) than males (%). Tumors of musculoskeletal and respiratory systems were rare, accounting for 0. and 0.% of all tumors, respectively. Table summarizes incidence of connective tissue and vascular neoplasms that may involve multiple sites and/or systems; these tumors were combined to assess total body burden versus organ burden for comparison purposes. The majority of fibromas and all fibrosarcomas were in integumentary system. Fibromas were slightly more common in males (.%) than females (.0%); fibrosarcomas were not diagnosed in females. Hemangiomas and hemangiosarcomas were commonly present in lymph node, spleen, and skin. Vascular Downloaded from on January 0

4 POTERACKI AND WALSH TABLE Spontaneous Neoplasms Occurring in Three or More Control Wistar Rats Neoplasm % % Range %" % Range Endocrine Pituitary adenoma Carcinoma Adrenal pheochromocytoma benign Pheochromocytoma malignant Cortical adenoma Cortical carcinoma Thyroid C cell adenoma C cell carcinoma Follicular adenoma Follicular carcinoma Pancreatic islet cell adenoma Islet cell carcinoma Parathyroid adenoma Integumentary Mammary fibroadenoma Adenoma Adenocarcinoma Keratoacanthoma Fibroma Fibrosarcoma Papilloma Squamous cell carcinoma Lipoma Liposarcoma Trichofolliculoma Pilomatrixoma Schwannoma Basal cell tumor Histiocytic sarcoma Zymbal's gland carcinoma Reproductive Testicular interstitial cell tumor Prostatic adenoma Uterine/vaginal stromal polyp Stromal sarcoma Schwannoma Granular cell tumor Endometrial adenoma Granulosa cell tumor Gastrointestinal Pancreatic acinar cell adenoma Acinar cell carcinoma Hepatocellular adenoma Carcinoma Cholangioma Intestinal adenocarcinoma Intestinal leiomyoma Hematopoietic/lymphatic Thymoma benign Thymoma malignant Lymphoma Granular cell leukemia Histiocytic sarcoma Nervous Granular cell meningioma Astrocytoma O ^ O Downloaded from on January 0

5 NEOPLASMS IN CONTROL WISTAR RATS TABLE Continued Neoplasm % Range % Range Oligodendroglioma Urinary Renal cell adenoma Renal cell carcinoma Renal mesenchymal tumor Cardiovascular Cardiac schwannoma Hemangioma Hemangiosarcoma Musculoskeletal Osteosarcoma ' Percentage of population (male or female). tumors were four times more common in males (.%) than in females (.%). Tumors of smooth muscle occurred mostly in gastrointestinal tract; only of the 0 leiomyomas and leiomyosarcomas were in uterus. One of 9 lipoma/liposarcoma was in kidney; the rest were in skin. Schwannomas were found in multiple sites in uterus, in heart, in skin, and each in prostate, skeletal muscle, spinal cord, and abdominal cavity. Because of the number of schwannoma in uterus, the incidence of schwannoma was three times higher in females (.%) than in males (.%). Two of osteosarcomas were in skin; the rest were in bone. Several tumors were rare and seen in >0.% of either sex. These included melanoma, basosquamous tumor, mammary adenolipoma, pilomatrixoma, Zymbal's gland adenoma, Harderian gland adenoma/adenocarcinoma, sebaceous gland adenoma, clitoral adenocarcinoma, thecoma, ovarian Sertoli TABLE Spontaneous Neoplasms Occurring in One (or Two) Control Wistar Rats System Endocrine Integumentary Reproductive Gastrointestinal Hematopoietic/lymphatic Nervous Urinary Cardiovascular Musculoskeletal Respiratory Ganglioneuroma, adrenal Basosquamous tumor Sebaceous gland adenoma () Harderian gland carcinoma Mesothelioma, testis () Schwannoma, prostate Melanoma, penis Squamous cell carcinoma, oral PapiUoma, tongue Leiomyoma, stomach Fibroma, intestine Ependymoma Meningioma Schwannoma, cord Sarcoma, heart Rhabdomyosarcoma () Schwannoma, muscle Neurofibrosarcoma, muscle Carcinoma, mediastinum Ganglioneuroma, adrenal Mammary adenolipoma Osteosarcoma () Zymbal's gland adenoma Harderian gland adenoma Sertoli cell tumor, ovary () Thecoma () Squamous cell carcinoma, clitoris Adenocarcinoma, clitoris Leiomyoma, uterus Leiomyosarcoma, uterus Squamous cell carcinoma, oral Leiomyosarcoma, intestine Schwannoma, abdominal cavity Carcinoma, lymph node Medulloblastoma Lipoma, kidney Transitional cell carcinoma, bladder Mesothelioma, heart Carcinoma, lung Downloaded from on January 0

6 POTERACKI AND WALSH TABLE Neoplasms Occurring in Varied Sites and/or Systems in Control Wistar Rats Neoplasm Fibroma Fibrosarcoma Hemangioma Hemangiosarcoma Histiocytic sarcoma Leiomyoma Leiomyosarcoma Schwannoma Rhabdomyosarcoma Osteosarcoma Lipoma Liposarcoma ' Percentage of population. % %" cell tumor, ganglioneuroma, medulloblastoma, ependymoma, neurofibrosarcoma, oligodendroglioma, pulmonary carcinoma, renal cell carcinoma, and transitional cell carcinoma. DISCUSSION To develop a useful historical control data base, it is necessary to periodically add and assess new data which become available and delete or alter data which may be misleading. Variation based on genetic drift within the rodent strain, atypically high or low incidence of a specific tumor in one study, and modification of diagnostic criteria can have major impacts on reliability of the data when used for comparison purposes. Wistar rats are used less often as the rat strain for testing drug candidates than are other strains such as Fischer so there are less published data available concerning neoplastic incidence. In the following discussion, results from this review are compared with results of a previous evaluation of tumors in control Wistar rats in 0 carcinogenicity studies run between 90 and 990 (Walsh and Poteracki, 99) and, when appropriate, to other published reports, particularly a review of 0 Wistar BOR:WISW (SPF Cpb) rats (Bomhard and Rinke, 99). This review covers results from studies conducted between 990 and 99 and was done to assess genetic drift and further develop historical control data. Among 90 control Wistar rats ( male, female), 99 neoplasms affecting (%) animals were diagnosed. The percentage of rats affected is higher than the % recently reported in BOR:WISW and is minimally higher than the incidence in our previous review (%). The majority of neoplasms (%) was found in two organ systems, endocrine (%) and integumentary (%). An additional % was found in reproductive (%), GI (.%), and hematopoietic/lymphatic (.%) systems; the remaining % were in other systems. This is similar to the % of neoplasms in endocrine, % in integumentary, 9% in reproductive, and % in hematopoietic/lymphatic systems in our previous review. Fewer neoplasms affected the GI system previously (%) compared to the percentage of GI tumors in this review (9%). Previously, benign neoplasms occurred in % of control rats and malignant tumors in %. In this review, incidence of benign neoplasia was minimally increased (%) while malignancies decreased minimally (9%) and metastastic incidence remained the same. The number of benign neoplasms was higher in females (0) compared to males (9) due mainly to high incidence of mammary fibroadenomas. Mean combined sex survival at 0 weeks was similar to that reported previously (%). The malignancy rate is similar to the mean of % in B0R:WISW. Pituitary adenomas were common in our five most recent bioassays accounting for % of all neoplasms in males and % of all neoplasms in females. Although the incidence of pituitary adenomas was decreased -% compared to our previous findings, they were similarly common in our previous review and in BOR:WISW rats. In this review, females had ^ times more pituitary adenomas than males. This sex predilection was similar to the two-fold difference we found previously but was not seen in BOR:WISW rats nor in TNO/W0 rats, the parent strain of BOR:WISW (Bomhard et al., 9). Pituitary carcinomas were rare and only in females; however, the incidence was higher in this review (.%) than previously (0.0%) but still much lower than the % in Wistar SPF Tox rats (Kroes et al, 9). Adrenal cortical adenomas were diagnosed in.% of males and.% of females, less than half the incidence in our first review (.% males, 9.% females). In the previous review, the incidence of cortical adenomas was skewed by one study. When that study was removed from analysis, incidence range was similar in both reviews (0-9%) and overall incidences were similar. Incidence of cortical adenomas was slightly higher than the to.% reported in BOR:WISW rats. Adrenal pheochromocytomas were increased more than twofold in males in this review (.%) compared to our previous review (.%). Although one study in our current investigation had numerous pheochromocytomas (.%), ranges were similar between reviews (-% versus 0-%). The incidences among females were similar (.% versus.%). The incidence in males and the sex difference were similar in Bomhard's review (Bomhard and Rinke, 99). Frequencies of pancreatic islet cell adenomas were similar between our reviews, however, an extremely high incidence (%) occurred in one study in this review. Except for this single study, incidence ranges for males were similar in both of our reviews (0-.% versus 0-.%). This study also had a higher incidence (.%) of islet cell carcinomas than the other four studies (0-.%). As seen previously there was a fre- Downloaded from on January 0

7 NEOPLASMS IN CONTROL WISTAR RATS quency difference based on sex for acinar cell tumors although it was less marked in this review (three times more pancreatic acinar cell tumors in males than females versus eight times more in previous review). Although the same sex difference was found in BOR:WISW rats, the incidence of pancreatic acinar cell tumors was only %. Mammary tumors accounted for % of neoplasms in the integument; 9% of these were in females. The overall incidence of mammary tumors (%) was slightly lower than that in our first review (%) but was higher than that reported by in BOR:WISW rats ( %). Fibroadenomas were again the most common mammary tumor (% of all integumentary tumors, % of all mammary tumors) as was seen in BOR: WISW rats in which % of mammary tumors were fibroadenomas. Other than mammary tumors, integumentary tumors were diagnosed more often in males (%) than females (9%). Keratoacanthomas were the most common tumor in males (% of males, % of nonmammary integumentary tumors). Keratoacanthomas were rare in females (0.%). This sex predilection was not noted in our previous review as keratoacanthomas were diagnosed in only % of males and 0.% of females. Although incidences of fibroma between males and females were similar, fibrosarcomas were diagnosed only in males. Papillomas were seven times more common in males than females. Occurrence of testicular interstitial cell tumors was increased in this review (%) compared to the previous review (%). This was less than the high incidence in F rats (Solleveld et al, 9; Goodman et al, 99) but was higher than % found in BOR:WISW rats. All interstitial cell tumors were considered benign. Most (0%) of uterine neoplasms were benign stromal polyps and were in % of females. The incidence in this review is higher than the 0% we saw previously. Unlike our first review in which one uterine granular cell tumor was diagnosed and uterine schwannomas were not diagnosed, this review had granular cell tumors in.% of females and schwannomas in.%. Excluding stromal polyps, overall tumor incidence in uterus was.% and was similar to that reported in BOR:WISW rats (.%). Tumors of GI tract accounted for.% of all tumors. Pancreatic acinar cell adenomas and carcinomas were the most common GI tumor and had a marked sex predilection occurring in.% of males and 0.% of females. This sex predilection has been reported in F rats (Goodman et al, 99; Solleveld et al, 9) and, although the overall incidence was much lower (%), also was seen in BOR:WISW rats. It was more obvious in this review because of the increased incidence from our previous review (.% of males, 0.% of females). One study in this review had an unusually high occurrence of acinar adenomas (%) and carcinomas (%) in males; this study also had an atypically high incidence of islet cell tumors (noted above). An explanation for this high incidence of pancreatic tumors is not known at this time. When this study is removed from analysis, ranges of adenoma and carcinoma incidences were similar to our previous review. Although hepatocellular tumors have been reported to occur frequently in Lobund Wistar rats (Pollard and Luckert, 99) and Han:Wistar rats (Deerberg et al., 9), in our review these neoplasms were not common and were seen in.9% of males and.% of females. This incidence in males is almost two times higher than that in our first review and two to three times higher than that in BOR:WISW rats. Neoplasms in hematopoietic/lymphatic system were.% of all tumors, an incidence similar to % of our first review. Thymomas were the most common tumor affecting.% of males and.% of females. The twofold higher incidence in females was less than the eightfold difference seen previously but this sex difference has been reported in Wistar Cpb:WU rats (Kuper et al., 9) and suggested by data in the review of BOR:WISW rats. Lymphoma and leukemia accounted for % of neoplasms, slightly less than the incidence of % noted in our first review and much less than the high frequency of large granular cell leukemia in F rats (Solleveld et al, 9). Neoplasms of nervous system are uncommon in Wistar rats (Dagle et al., 99; Sumi et al., 9; Al Zubaidy and Malinowski, 9; Maekawa et al., 9) and in this review accounted for.% of tumors in.% of all rats. Unlike our previous review in which astrocytomas were the most common neural neoplasm, granular cell meningiomas were the most common neoplasm in this review. The incidence of astrocytoma was three times lower in this review (.%) than that in the first review (.%) and of granular cell meningioma was six times higher (.9%) than previously (%). Other tumors of neural tissue were seen in fewer than % of either sex. The incidence of urinary tumors (.%) was higher than that in the previous evaluation (.%) due mainly to an increase in frequency of renal mesenchymal tumors and of renal cell adenomas. Neoplasms of the urinary tract are uncommon in Wistar rats; only % of 0 BOR:WISW rats had tumors in this system. When hemangiomas and hemangiosarcomas are considered as part of the cardiovascular (CV) system the incidence of CV tumors (.%) was slightly less than half that in the previous review (.%). Other tumors of CV are rare except for endocardial schwannomas that occurred in.% of all rats, an incidence 0 times greater than our previous review in which only one cardiac schwannoma was identified and 0 times greater than incidence reported in BOR:WISW rats (Bomhard and Rinke, 99). Musculoskeletal and respiratory systems of Wistar rats are rarely affected by spontaneous neoplasms (Bomhard et al., 9; Kroes et al., 9; Feron et al., 990; Novilla et al, 99). In this review, 0.% of all neoplasms were in these tissues, an incidence lower than the.9% of our previous review but comparable to the 0.% reported in BOR:WISW rats. Diagnostic bias based on pathologist's experience and con- Downloaded from on January 0

8 POTERACKI AND WALSH sistency is difficult to evaluate. These studies and those in the previous review were all read or reviewed by a group of pathologists within one company in which turnover during this time was minimal. The peer-review process was partially designed to ensure that the STP criteria were followed and that consistency was maintained over time as much as possible. Because of this attempt at stability, the increase of pancreatic acinar cell tumors and keratoacanthomas are probably accurate but need further data to confirm. Mean tumor incidence did not differ significantly between our two reviews but was higher than that seen in the Wistar BOR:WISW strain used in Germany. Susceptibility of endocrine organs as reflected by high incidence of neoplasms was seen in both of our reviews; pituitary adenomas were the most common tumor diagnosed. Sex predilections were supported by both reviews for pituitary tumors (female), pheochromocytoma (male), pancreatic acinar cell tumors (male), mammary fibroadenoma (female), and thymoma (female). Sex predilection for keratoacanthoma (male) was seen only in our second review. Ratios of benign to malignant neoplasms were similar in both reviews. Percentage of survival at 0 weeks were similar. REFERENCES AJ Zubaidy, A. J., and Malinowski, W. (9). Spontaneous pineal body tumours (pinealomas) in Wistar rats: A histological and ultrastructural study. Lab. Anim., -9. Barsoum, N. J., Gough, A. W., Sturgess, J. M., and de la Iglesia, F. A. (9). Morphologic features and incidence of spontaneous hyperplastic and neoplastic mammary gland lesions in Wistar rats. Toxicol. Pathol., -. Barsoum, N. J., Moore, J. D., Gough, A. W., Sturgess, J. M., and de la Iglesia, F. A. (9). Morphofunctional investigations on spontaneous pituitary tumors in Wistar rats. Toxicol. Pathol, Berkvens, J. 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