Immunohistochemistry of ultimobranchial thyroid carcinomas in seven slaughtered cows and one bull.

Eight thyroid gland epithelial tumors were found in 7 cows and 1 bull in a retrospective study of thyroid gland lesions in slaughtered cattle. All tumors were classified as ultimobranchial thyroid carcinomas based on morphology and immunohistochemistry. All tumors consisted of solid sheets and nests of polygonal to oval epithelial cells, with more sparsely dispersed colloid-filled follicles. Connective tissue separating nests of epithelial cells varied from delicate fibrovascular stroma to dense collagenous stroma. Fusiform epithelial cells with rare neural fibers and ganglion cells were present in 1 tumor. Cells within solid areas of these tumors were immunoreactive for calcitonin, calcitonin gene-related peptide, neuron-specific enolase, and synaptophysin. Colloid and follicle cells were immunoreactive for thyroglobulin. Few follicle cells also were reactive for calcitonin gene-related peptide. Neoplastic cells invaded the fibrous capsules in all 8 cattle. These tumors represented proliferation of a mixed population of undifferentiated cells, C cells, and thyroid follicular epithelial cells, presumably derived from the thyroid ultimobranchial bodies. These ultimobranchial carcinomas in slaughtered cattle are comparable to ultimobranchial tumors described in dairy bulls and the intermediate type of thyroid gland carcinomas (mixed thyroid medullary carcinomas) described in human beings.     

Two Cases of Metastatic Parathyroid Carcinoma in Male C3H Mice Following Irradiation

White nodules were observed in the thyroid in two male C3H mice (at 99 and 122 weeks of age) exposed to fast neutrons at the age of 8 weeks. Histopathologically, in both cases, tumors were developed in the region corresponding to the parathyroid gland, and the tumor cells were arranged in a solid sheet or nest-like structures. Necrosis, cell debris and/or hemorrhage were sometimes seen in the center of the tumor structures. Tumor cells were small and uniform with scanty cytoplasm, cell margins were indistinct, and basally located tumor cells were aligned along the vascular stroma. Mitotic figures were frequently observed. Metastasis to the renal cortex was observed in both cases. These cases were diagnosed as parathyroid carcinoma. A parathyroid tumor is an extremely rare endocrine tumor in mice, regardless of whether the tumor is spontaneous or experimentally induced. These cases may have been induced by neutron-exposure; however, how radiation induces parathyroid carcinoma in mice is not clear.     

Computer-assisted image analysis of neovascularization in thyroid neoplasms from dogs

OBJECTIVE: To develop a computer-assisted image analysis procedure for quantitation of neovascularization in formalin-fixed paraffin-embedded specimens of thyroid gland tissue from dogs with and without thyroid gland neoplasia. SAMPLE POPULATION: 47 thyroid gland carcinomas, 8 thyroid gland adenomas, and 8 specimens of thyroid tissue from dogs without thyroid gland abnormalities (normal). PROCEDURE: Serial tissue sections were prepared and stained with antibodies against human CD31 or factor VIII-related antigen (factor VIII-rag). The areas of highest vascularity were identified in CD31-stained sections, and corresponding areas were then identified in factor VIII-rag-stained sections. Image analysis was used to calculate the total vascular density in each section, and neovascularization, expressed as a percentage, was determined as the absolute value of the total vascular density derived from factor VIII-rag-stained sections minus the vascular density derived from CD31-stained sections. RESULTS: Mean vascular density of thyroid gland carcinomas derived from CD31-stained sections was significantly greater than density derived from factor VII I-rag-stained sections. This incremental difference was presumed to represent degree of neovascularization. However, significant differences were not detected between vascular densities derived from CD31 and factor VIII-rag-stained sections for either normal thyroid gland tissue or thyroid gland adenomas. No significant correlations were found between vascular density in thyroid gland carcinomas and survival time following surgery. CONCLUSION AND CLINICAL RELEVANCE: A computer-assisted image analysis method was developed for quantifying neovascularization in thyroid gland tumors of dogs. This method may allow identification of dogs with tumors that are most likely to respond to treatment with novel antiangiogenesis agents.     

E-cadherin immunoreactivity in canine mammary tumors.

The reduction or loss of E-cadherin (E-cad), a calcium-dependent epithelial cell adhesion molecule, has been associated with tumor dedifferentiation and invasiveness. The immunohistochemical pattern of E-cad expression was evaluated in formalin-fixed and paraffin-embedded sections of 6 normal mammary glands, 3 dysplasias, 12 benign tumors (8 benign mixed tumors, 4 adenomas), and 60 malignant tumors (12 stage 0, 29 stage I, 19 stage II) of the canine mammary gland. E-cadherin expression was classified as membranous, when on cell-cell boundaries, or as cytoplasmic, when in the form of a diffuse cytoplasmic staining. In addition, the percentage of E-cad-positive epithelial neoplastic cells was graded by a semiquantitative method, categorizing cases into a reduced (or -) type group, when showing less than 25% positivity, a reduced (or +/-) type group, when showing 25-75% positivity, and a preserved (or +) type group, when more than 75% positive cells were present. In the normal mammary gland, E-cad expression was evident in epithelial luminal cells. A stronger positivity was revealed in ductular than in alveolar luminal cells. The myoepithelial cells showed inconsistent, weak cytoplasmic positivity in the normal gland as well as in mammary tumors. In normal glands and benign and malignant noninvasive tumors, E-cad expression was mainly membranous and preserved in most of the epithelial cells. In stage I tumors, both membranous (38%) and cytoplasmic (62%) positivity were well represented, as well as preserved type (55%) and reduced type (45%) tumors. All stage II malignant tumors showed the highest frequency of cytoplasmic positivity (79%) and reduced type (62%) tumors.     

Magnetic resonance imaging of the normal canine thyroid gland.

The magnetic resonance (MR) imaging features of the normal canine thyroid gland were retrospectively compiled from images acquired in 44 dogs presented for a variety of diseases unrelated to the thyroid gland. The appearance of the thyroid gland on different sequences, including pre- and postcontrast T1-weighted, T2-weighted, two-dimensional gradient echo, three-dimensional T2*-weighted gradient echo and proton density weighted images, were described in different image planes. The characteristic shape, location, and intensity of thyroid lobes compared with surrounding structures made them easily detectable in all dogs. The most common location of the thyroid lobes was dorsolateral to the trachea with the maximal cross-sectional area of the lobes located ventral to C2/3 or C3 in more than 85% of the dogs. The majority of the lobes were ovoid on transverse images. An isthmus was seen in one large dog and parathyroid glands could not be seen. The mean maximal thyroid lobe diameter on transverse images was 8.1 mm, being twice the mean diameter of the common carotid artery. Considering the excellent conspicuity and characteristic appearance of the canine thyroid gland, MR imaging can be beneficial in the diagnosis of diffuse thyroid diseases, in differentiating thyroid vs. nonthyroid neck masses and in staging and treatment planning of thyroid tumors in this species.     

王不留行增乳活性单体对奶牛乳腺上皮细胞增殖及泌乳性能的影响

应用CASY细胞分析仪及HPLC分别检测王不留行邻苯二甲酸二丁酯对乳腺上皮细胞增殖、细胞活力及乳腺上皮细胞分泌β-酪蛋白、乳糖的影响,研究王不留行增乳活性单体邻苯二甲酸二丁酯对奶牛泌乳中期乳腺上皮细胞增殖和泌乳性能的影响。试验结果表明,王不留行增乳活性单体成份邻苯二甲酸二丁酯对奶牛乳腺上皮细胞的增殖和细胞活力提高均显著(P0.05);能显著提高乳腺上皮细胞β-酪蛋白的表达(P0.05),也能提高乳糖的分泌(P0.05,P0.05)。因此,王不留行增乳活性单体邻苯二甲酸二丁酯可显著提高乳腺上皮细胞的增殖和泌乳能力。     

Alveolar type II cells expressing jaagsiekte sheep retrovirus capsid protein and surfactant proteins are the predominant neoplastic cell type in ovine pulmonary adenocarcinoma

Ovine pulmonary adenocarcinoma is caused by jaagsiekte sheep retrovirus. To gain insight into the histogenesis and viral pathogenesis of this neoplasm, the tumor cell phenotypes and differentiation state were correlated with the distribution of jaagsiekte sheep retrovirus capsid protein in neoplastic and normal cells of the lung in nine naturally occurring and 12 experimentally induced cases of ovine pulmonary adenocarcinoma. Overall, 82% of tumor cells had ultrastructural features consistent with alveolar type II cells, 7% of tumor cells had features of Clara cells, and 11% of tumor cells were insufficiently differentiated to classify. The proportion of the neoplastic cell phenotypes varied within tumors, and no tumor consisted of a morphologically uniform cell population. To further characterize the neoplastic cell population, sections of tumors were immunostained with antibodies to surfactant protein A, surfactant protein C, and Clara cell 10-kd protein. Overall, surfactant proteins A and C were expressed in 70% and 80% of tumor cells, respectively, whereas Clara cell 10-kd protein was expressed in 17% of tumor cells. Jaagsiekte sheep retrovirus capsid protein was detected in 71% of tumor cells and in macrophages (5/21 tumors examined) and in nonneoplastic alveolar and bronchiolar cells (6/14 tumors). Expression of this viral protein in neoplastic cells, classified morphologically and by immunophenotyping primarily as of the alveolar type II lineage, implies an important role for specific virus-cell interactions in the pathogenesis of ovine pulmonary adenocarcinoma.     

Hyperplastic and neoplastic changes in ultimobranchial remnants and in parafollicular (C) cells in bulls: a histologic and immunohistochemical study

Thyroid glands from 64 bulls with hyperplastic and/or neoplastic changes in ultimobranchial remnants and in the parafollicular (C) cell system were studied structurally and with immunohistochemical methods. Antibodies against thyroglobulin, calcitonin, somatostatin, and neurotensin were used to detect these substances. Two different types of changes were observed. One change was hyperplasia and neoplasia of the ultimobranchial remnants that affected all their epithelial constituents. These included ultimobranchial follicles, cysts and tubules, as well as solid nests formed by basophilic immature cells which were functionally undifferentiated and unreactive with all the antisera used. Differentiated follicular cells that formed thyroid follicles and cribriform structures with immunohistochemical evidence of thyroglobulin production were also found. In addition, differentiated light and cytoplasm-rich cells were scattered in the walls of the thyroid follicles, ultimobranchial follicles, cysts and tubules as well as in the solid component. They were argyrophilic and reacted with antibodies against calcitonin and somatostatin. The other change was a diffuse or multifocal hyperplasia of the parafollicular (C) cells that was present in other parts of the thyroid parenchyma--sometimes with gradual development of sclerotic tumors that had been exclusively formed by these cells. They corresponded to light cytoplasm-rich cells seen in the ultimobranchial lesions that were argyrophilic and harbored material reactive with antibodies against calcitonin and/or somatostatin. The changes observed in the parafollicular cell system resembled lesions seen in human thyroid glands with the familial variant of medullary carcinoma as well as those reported in thyroid glands of patients with longstanding hypercalcemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carcinogen-induced Thyroid Proliferative Lesions in Wistar Hannover GALAS Rats with Thyroid Dysplasia

Incidences and morphological features of thyroid proliferative lesions induced by carcinogens in Wistar Hannover GALAS rats (GALAS rats) showing normal growth with or without thyroid dysplasia were examined. All thyroid tissue samples were obtained from our recently conducted study using male GALAS rats treated with 5 carcinogens according to the medium-term multiorgan carcinogenicity bioassay protocol (called DMBDD treatment). In the DMBDD-treated rats, thyroid dysplasia was found in 9 out of 114 rats. Follicular cell adenomas were found in 5 out of 9 rats with thyroid dysplasia and in 7 out of 105 rats without thyroid dysplasia. The incidence of adenoma was significantly increased in rats with thyroid dysplasia (55.6%) compared with that in rats without thyroid dysplasia (6.7%). Adenomas in rats with thyroid dysplasia were observed as single or multiple nodules, well demarcated and composed of variously sized vacuolated cells or unvacuolated cells. These histopathological features and staining profiles of luminal colloid for PAS and thyroglobulin, together with PCNA-positive cells, were fundamentally similar to those of rats without thyroid dysplasia. On the other hand, the luminal colloid in adenomas of rats with thyroid dysplasia had a tendency to be poorly stained for T(4) compared with that of rats without thyroid dysplasia. From these findings, it appears that dysplastic thyroids of rats showing normal growth are more sensitive to carcinogens than normal thyroids. In addition, the morphological features of carcinogen-induced thyroid proliferative lesions in GALAS rats with thyroid dysplasia were fundamentally similar to those of rats without thyroid dysplasia, except for the vacuoles and T(4) staining profile.     

Lectin histochemistry on squamous metaplasia in different epithelial tumors of dogs.

Biotinylated lectins and avidin-biotin-peroxidase complex were used to study the correlation between cellular glycoconjugates' expression and squamous maturation in normal canine skin and in various epithelial neoplasms. Normal skin tissue was obtained from five, male, random-source dogs, 5 to 7 years old. The tumors tested, selected from the files of our Department, were fifteen squamous cell carcinomas from different tissue origin, five hepatoid perianal gland adenocarcinomas with squamous metaplasia, and fourteen solid mammary carcinomas with and without histologic evidence of squamous metaplasia. Except for mammary gland carcinomas, all tumors had been surgically excised from male dogs. Intermediate filament aggregation of twelve solid mammary gland carcinomas were studied electron microscopically. The basal and the lower spinous cells in normal skin and the less differentiated cells in squamous cell carcinomas stained moderately with Griffonia simplicifolia agglutinin-I. Spinous and granular cell layers stained strongly with Phytolacca americana mitogen and Arachis hypogaea agglutinin. Both lectins stained well-differentiated cells in squamous cell carcinomas. The electron microscopic study carried out in solid carcinomas of mammary glands revealed some relationship between the presence of intracytoplasmic tonofibrils and the binding of Griffonia simplicifolia agglutinin-I and Phytolacca americana mitogen to the tumors tested. Our results suggest that the glycosylation pattern occurring during normal keratinocyte differentiation is conserved in squamous cell carcinomas and that Griffonia simplicifolia agglutinin-I and Phytolacca americana mitogen may represent useful tools in distinguishing poorly differentiated squamous cell carcinomas from other poorly differentiated mammary epithelial tumors.     

Simultaneous occurrence of multiple neoplasms and hyperplasias in the adrenal and thyroid gland of the horse resembling multiple endocrine neoplasia syndrome: case report and retrospective identification of additional cases

Neoplastic and hyperplastic disorders that affect multiple endocrine tissues in a single individual are well described in humans but less so in domestic animals. Multiple endocrine neoplasia (MEN) in humans is a genetically determined syndrome characterized by the appearance of benign or malignant proliferations within two or more endocrine glands. The primary endocrine tumors that are characteristic of MEN arise from cells that share the capacity for amine precursor uptake and decarboxylation. Here we describe the case of a 22-year-old Thoroughbred mare that died during an unattended parturition and subsequently was presented for necropsy at the University of California, Davis, Veterinary Medical Teaching Hospital. A C-cell (medullary) thyroid adenoma, pheochromocytoma, and multicentric bilateral nodular hyperplasia of the adrenal medulla were present, findings that are remarkably similar to those of human MEN syndrome. Mortality during pregnancy in women with undiagnosed pheochromocytoma is high (approximately 50%), typically because of hypertension and/or hemorrhage associated with catecholamine release from the tumor. Similarly, the mare in this report died of hemorrhage subsequent to parturition. A retrospective evaluation of endocrine tumors in horses that underwent necropsy at the Veterinary Medical Teaching Hospital from 1987 to 1997 was undertaken to identify additional possible cases of MEN in horses. Data from this retrospective evaluation suggest that coexistence of hyperplasias and neoplasias of the thyroid and adrenal glands, similar to MEN syndrome of humans, also occurs with some frequency in the horse.     

Morphology of thyroid follicular cells of methimazole-treated rats

Thyroids of rats treated with methimazole (MMI) were analysed histologically, immunohistochemically and electron microscopically. Thyroids of MMI-treated rats displayed greater hypertrophy and were heavier than those of control rats. Thyroids of MMI-treated rats were composed of variant or small follicles and contained more columnar cells than those of control rats. Strong staining of thyroid granules by azocarmine G was evident in the apical regions of follicular cells from MMI-treated rats. Anti-thyroglobulin positivity was detected in the apical regions of follicular epithelial cells, especially those of MMI-treated rats. After application of a post-embedding method to detect thyroglobulin, colloidal gold particles were often observed in apical vesicles of MMI-treated rats. Our study suggests that apical vesicles may serve as markers of hyperthyroidism. When the functional state of the thyroid gland is known from histological analysis, use of the Azan stain could provide useful additional information.     

Evaluation of techniques to demonstrate foot-and-mouth disease virus in bovine tongue epithelium: comparison of the sensitivity of cattle, mice, primary cell cultures, cryopreserved cell cultures and established cell lines

Tongue epithelia infected with each of the 7 serotypes of foot-and-mouth disease virus (FMDV) were used to evaluate in vivo and in vitro systems for the detection of FMDV. Cattle inoculated by the intradermal route in the tongue (IDL) and suckling mice inoculated intraperitoneally were compared for susceptibility to FMDV with freshly prepared bovine thyroid cell cultures; cultures from cryopreserved bovine thyroid, bone marrow, mammary gland, myocardium, tongue, ovary and kidney cells; cultures from cryopreserved embryonic ovine kidney, newborn ovine kidney, ovine testicle, bone marrow, and chloroid plexus cells; and the continuous porcine kidney cell lines MVPK-1 and S6. The mean titers determined for each serotype in each system were statistically compared. The FMDV titers obtained in freshly prepared bovine thyroid cell cultures and by cattle IDL inoculation were the highest and were statistically indistinguishable. The titers obtained by suckling mouse inoculation were significantly lower than the titers obtained in thyroid cultures for serotypes A, C, Asia 1, and SAT 3. The cattle IDL assay was significantly more sensitive than the mouse assay for serotype A. The cell cultures from the cryopreserved newborn ovine kidney and embryonic ovine kidney were significantly less susceptible to serotype Asia 1 when compared with the fresh bovine thyroid cultures, but not significantly different when compared with the cattle assay for all serotypes. Cryopreservation of bovine thyroid cells directly after trypsinization resulted in the loss of susceptibility to FMDV serotype SAT 2. The other cryopreserved cell culture systems exhibited no or minimal susceptibility to all 7 serotypes, or exhibited considerable inconsistency. The established cell lines MVPK-1 and S6 were not susceptible to serotype A, and were less sensitive to serotype C than other culture systems. Quality control of cell cultures used to evaluate field specimens for FMDV was critical. The cell cultures of cryopreserved ovine kidney cells provided the most practical diagnostic system.     

Neoplasia and hyperplasia of pancreatic endocrine tissue in the rat: an immunocytochemical study

Spontaneously occurring neoplasms and non-neoplastic proliferative changes of the pancreatic cells in aging Sprague-Dawley and Long-Evans rats were examined for the presence and distribution of pancreatic hormones using immunocytochemical techniques. Islet cell tumors were indistinguishable in the two rat strains. They were composed principally of insulin-containing beta cells, but had additional and variable small proportions of cells that stained for somatostatin, glucagon, or rarely, pancreatic polypeptide. The heterogeneity in these spontaneous islet cell neoplasms was similar to that reported in humans as well as those induced in rats by streptozotocin. Hyperplasia of the islet cells also mainly affected the beta cells, but the overall pattern of immunocytochemical staining usually remained similar to that of normal islets, a point of distinction from islet cell neoplasms. In addition, rats with exocrine atrophy and fibrosis were found to have considerable disruption and focal proliferation of the islets.     

Immunoreactivity of A103, an antibody to Melan A, in canine steroid-producing tissues and their tumors.

The monoclonal antibody A103 to the melanocytic differentiation antigen Melan A stains human steroid-producing cells and their tumors. A total of 200 formalin-fixed, paraffin-embedded canine normal tissues and hyperplastic and neoplastic lesions of the adrenal gland, testis, and ovary were immunohistochemically tested for Melan A with antibody A103. Leydig cell tumors (23/23, 100%), Sertoli cell tumors (14/15, 93%), and adrenocortical adenomas (12/13, 92%) were consistently positive. Adrenocortical carcinomas (23/35, 65%) and granulosa cell tumors (10/17, 59%) were less frequently positive. All pheochromocytomas, seminomas, and dysgerminomas were negative. The pattern of staining was cytoplasmic, but nuclear staining was also frequently seen in normal Leydig cells and their tumors. As in human tumors, immunohistochemistry for Melan A stains many canine steroid-producing tumors and can be used to distinguish these tumors from those of nonstereidogenic cells.     

COMPARISON BETWEEN CLINICAL,ULTRASOUND, CT,MRI, AND PATHOLOGY FINDINGS IN DOGS PRESENTED FOR SUSPECTED THYROID CARCINOMA

This study compares clinical, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and pathology findings in 16 prospectively, and seven retrospectively recruited dogs presented for suspected thyroid carcinoma. Of these, 17 were confirmed thyroid carcinoma, while six were initially misdiagnosed. These included four carotid body tumors, one para‐esophageal abscess, and one undifferentiated squamous cell carcinoma. Thyroid carcinomas occurred in older dogs without evidence of sex predilection, and were more often unilateral. All were large, heterogeneous, moderately to strongly vascularized, and most commonly contained areas of dystrophic mineralization and/or fluid accumulations. On MRI, thyroid carcinomas appeared hyperintense compared to surrounding musculature in all imaging sequences used, while on CT they had a lower attenuation value than normal thyroid gland tissue. Histologically confirmed tumor capsule disruption with invasion of the surrounding structures was most commonly detected with MRI. Palpation was not an accurate predictor of locally invasive vs. well‐encapsulated masses. Computed tomography had the highest specificity (100%) and MRI had the highest sensitivity (93%) in diagnosing thyroid carcinoma, while ultrasound had considerably lower results. We conclude that ultrasound is adequate for use as a screening tool for dogs with suspected thyroid carcinoma, but recommend either CT or MRI for preoperative diagnosis and staging.     

乳腺上皮细胞体外培养的研究进展

乳腺上皮细胞体外培养的成功对研究乳腺的生长发育、泌乳机制、乳腺肿瘤和癌变的发生及乳腺生物反应器的应用等方面的研究都有重要的意义。具体来说．体外培养建立的乳腺上皮细胞系可为克隆和转基因动物生产提供良好的核供体;分泌功能的乳腺上皮细胞系的建立为乳腺发育学、乳腺病理学、泌乳生物学研究提供细胞模型。本文综述了国内外在此领域的研究进展,对乳腺上皮细胞的体外培养技术进行了总结为相关领域的研究提供参考。     

24例20种犬肿瘤的病理组织学观察

对犬的皮脂腺瘤、肛周腺腺瘤、肛周腺癌、毛基质瘤、间叶性软骨肉瘤、腺样型基底细胞上皮瘤、囊样型基底细胞上皮瘤、水母样型基底细胞上皮瘤、混合型基底细胞上皮瘤、基底鳞状细胞上皮瘤、甲状腺腺瘤、肥大细胞瘤、组织细胞瘤、乳腺良性混合瘤(软骨腺瘤)、乳腺良性混合瘤(肌上皮腺瘤)、恶性肌上皮细胞瘤、乳腺恶性混合瘤(癌肉瘤)、汗腺囊性增生、汗腺腺瘤、汗腺癌等20种24例肿瘤(良性肿瘤14种,恶性肿瘤6种)作了详细的病理组织学描述。     

Granular cell lesions in the distal female reproductive tract of aged Sprague-Dawley rats

During the review of a rat carcinogenicity study, a spectrum of granular cell lesions was recognized in the distal female reproductive tract. To verify the diagnoses, cell populations of nine granular cell alterations of the cervix or vagina were characterized immunohistochemically and four were evaluated ultrastructurally. Immunoreactivity was demonstrated in 8/9 cases with S100 protein, 6/9 cases with neuron-specific enolase, and 7/9 cases with Leu-7. Granular cells were negative for smooth muscle-specific actin and calretinin. The immunohistochemical profile of these lesions was similar to that previously reported in other species, including humans. Ultrastructurally, as expected many lysosomal bodies were present in the cytoplasm of granular cells in all specimens evaluated. Based on the detailed evaluation of a series of lesions, we adopted the following diagnostic criteria and nomenclature for the granular cell changes of the female reproductive tract of rats. Granular cell aggregates were non-space-occupying lesions composed of clusters of typical granular cells. Benign granular cell tumors were space occupying lesions that typically contained prominent interstitial collagen and were either discrete masses or were difficult to discern from the surrounding tissues. Some benign tumors also contained foci of spindle cells with decreased granularity. Malignant tumors exhibited pleomorphism and an increased nucleus: cytoplasm ratio morphologically but had the same biologic behavior as the benign tumors. We applied these diagnostic criteria during the review of controls from 9 carcinogenicity studies. Up to 23% of control females in those carcinogenicity studies had granular cell lesions that could be classified into one of the three categories. Granular cell lesions appear to be common in the cervix/vagina of the Sprague-Dawley rat, and tumors may develop from granular cell aggregates.