Immunohistochemical studies on cytokeratin 8 and 18 expressions in canine cutaneous adnexus and their tumors

The expressions of cytokeratin 8 and 18 (CK8 and CK18) in the normal canine skin (2 cases) and cutaneous adnexal tumors (127 cases) were investigated immunohistochemically. In the normal skin, co-expression of CK8/18 was found in the glandular epithelium of apocrine sweat glands, and single CK8-immunoreactivity was detected occasionally in the external root sheath at the isthmus and suprabulbar regions of the hair follicles. Neoplastic glandular epithelial cells in all apocrine gland tumors (21/21 cases, 100%) had co-expression of CK8/18. In trichoblastomas (27/28 cases, 96%), most neoplastic cells were diffusely positive for CK8, but those were negative for CK18. Single CK8-expression was also observed in basaloid neoplastic cells in several cases of trichoepitheliomas (7/19 cases, 37%) and pilomatricoma (1/7 cases, 14%). In several cases of trichoblastomas (4/28 cases, 14%) and trichoepitheliomas (2/19 cases, 11%), tumor cells forming glandular structures had co-expression of CK8/18. There were no positive reactions for both CK8 and 18 in infundibular keratinizing acanthomas, and sebaceous and hepatoid gland tumors. The present findings indicate that co-expression of CK8/18 is a specific feature of apocrine sweat glands and single CK8-expression represents the natures of external root sheath or pluripotential stem cells. Thus, the combination of CK8- and 18-immunostainings may have the utility to confirm the directions of differentiation in canine cutaneous adnexal tumors providing a reliable hallmark for histopathological diagnoses.     

Endometrial adenocarcinoma in two young queens

Endometrial adenocarcinoma is described in two young intact female Persian cats presented with haemorrhagic vaginal discharge. The discharge had been present for 3 and 15 days in each case, respectively. On the basis of signalment, history, clinical, laboratory and diagnostic imaging findings a tentative diagnosis of pyometra was made in each cat and ovariohysterectomy was subsequently performed. Histological examination revealed endometrial adenocarcinoma in both cats together with ovarian luteal cysts and pyometra in one case. Immunohistochemistry revealed a diffuse and strongly positive reaction for oestrogen receptors in the nuclei of glandular epithelium in well‐differentiated areas of the neoplastic tissue. Poorly differentiated areas of solid growth pattern had weak and focal expression of oestrogen receptors. Furthermore, the neoplastic cells within these areas displayed moderate to strong diffuse nuclear staining with Ki‐67 antibody suggestive of a high proliferative capacity. The owners reported that the cats were clinically healthy 23 and 21 months after the surgery. These cases highlight the importance of histological examination of surgically resected tissue even when clinical signs and laboratory findings suggest pyometra.     

Feline pulmonary Langerhans cell histiocytosis with multiorgan involvement

Histiocytic proliferative diseases are uncommon in cats, although recently a progressive histiocytosis of the skin with terminal involvement of internal organs has been described in cats. Here we describe 3 cats (2 males and 1 female) with pulmonary Langerhans cell histiocytosis (PLCH). The cats were euthanized due to progressive respiratory clinical symptoms and deterioration. Macroscopically, extensive, multifocal to confluent, pulmonary masses were evident. Infiltration of pancreas (2 cats), kidneys (1 cat), liver (1 cat), as well as tracheobronchial, hepatosplenic, or mesenteric lymph nodes (2 cats) was observed by gross or microscopic examination. The infiltrating cells had histiocytic morphology with cytologic atypia characterized by anisokaryosis and hyperchromasia regionally within infiltrated tissues. Lesional histiocytes expressed vimentin, CD18, and E-cadherin. Expression of E-cadherin was usually markedly reduced in extra-pulmonary lesions, which is consistent with possible down-regulation of E-cadherin associated with distant migration from the lung. Transmission electron microscopy demonstrated intracytoplasmic organelles consistent with Birbeck's granules of Langerhans cells in the lesional histiocytes in all cats, except in the pancreas of one cat. These findings were compatible PLCH with limited organ involvement of humans. It remains unproven whether feline PLCH represents a reactive or neoplastic cell proliferation.     

家畜的消化系统增生性病变与癌前病变的研究

增生性病变与癌前病变的研究对于肿瘤的早期诊断、早期防治以及认识肿瘤在形态学上的发生发展过程均有重要意义。国内外医学对这一方面的研究日益重视,但在兽医科学领域中,尚未引起注意。本文作者应用病理组织学方法,对家畜和一部分野生动物的食管、胃和大小肠等消化系统组织共1,037例进行了研究,检出了一批增生性病变和癌前病变,它们是:上皮的单纯性增生、上皮的乳头状增生、粘膜白斑、慢性溃疡、上皮的不典型增生、乳头状瘤和腺瘤性息肉。研究中并发现上皮的异型性增生、乳头状瘤癌变为原位癌与浸润癌,以及腺瘤性息肉恶变为腺癌等移行现象。 本文重点描述检出的各种增生性病变与癌前病变的形态学特征,并对某些病变向癌转变的移行现象进行了分析讨论。     

The morphology and behavior of feline cutaneous mastocytomas

Correlation of histopathology with the behavior of cutaneous mastocytomas in 85 cats revealed two distinct histologic subtypes which were predictive of biologic behavior. The first subtype comprised 65 cats of various breeds which had solitary, discrete, dermal tumors composed of slightly atypical mast cells. Most tumors in this group were histologically and behaviorally benign. However, seven solitary tumors with marked anisocytosis and mitotic activity recurred or spread to other sites within 2 to 3 months. The second subtype occurred in 18 cats which had discrete subcutaneous nodules composed primarily of histiocyte-like cells with equivocal cytoplasmic granularity after staining with toluidine blue. They were identified as mast cells by electron microscopy. Seventeen of the 18 affected cats were Siamese. The histiocytic mastocytomas occurred predominantly in young cats (less than 4 years) and were usually multiple. In the four cats of this group for which we have prolonged follow-up data, the tumors underwent apparently spontaneous regression within 2 years of initial tumor detection. Two other cats had tumors which contained mixtures of mast cell and histiocytic morphologies.     

Uterine neoplasia in 13 cats.

Thirteen uterine tumors were diagnosed in 13 cats and accounted for 0.29% of all feline neoplasms received during a 9.6-year period. Age at diagnosis ranged from 3 to 16 years; median 9 years. Six were Domestic Shorthair cats, and 7 were purebred cats of 5 different breeds. Eight adenocarcinomas and 1 mixed Müllerian tumor (adenosarcoma) comprised the endometrial tumors. Myometrial tumors included 3 leiomyomas and 1 leiomyosarcoma. One of the adenocarcinomas developed in the uterine stump of an ovariohysterectomized cat; the other cats were sexually intact. Concurrent mammary adenocarcinoma was diagnosed in 1 cat with uterine adenocarcinoma and in another with uterine leiomyoma. Tumors were discovered during elective ovariohysterectomy in 2 cats, but at least 3 others had experienced reproductive problems (infertility or pyometra). Five cats presented for abdominal or pelvic masses. Endometrial adenocarcinomas were positive immunohistochemically for cytokeratins and negative for smooth muscle actin (SMA): 1 of 6 cats was positive for vimentin and 4 of 8 were positive for estrogen receptor-alpha (ER alpha). Adenosarcoma stromal cells were positive for vimentin and ER alpha but negative for cytokeratins and SMA. Smooth muscle tumors were positive for vimentin and SMA and negative for cytokeratins. Leiomyomas, but not the leiomyosarcomas, were positive for ER alpha. Adenocarcinomas in 4 cats had metastasized by the time of ovariohysterectomy. Two other cats were euthanized 5 months after ovariohysterectomy; at least one of these cats had developed an abdominal mass that was not examined histologically. Only 2 cats with endometrial adenocarcinoma had disease-free intervals longer than 5 months after surgery. Metastasis was not detected in any mesenchymal tumor; however, these cats were either euthanized on discovery of the tumor or the tumor was first detected at necropsy.     

Endometrial stromal sarcoma with smooth muscle and glandular differentiation of the feline uterus

The intra-abdominal tumor developing in the uterus and lung of a domestic Shorthair cat was examined histopathologically and immunohistochemically. The tumor showed a proliferation of both endometrial stromal and smooth muscle cells accompanied by prominent vasculature. There were well-differentiated endometrial glands, and tubuli made up a monolayer of eosinophilic cuboidal epithelium. Immunohistochemically, the spindle-shaped cells and half of the stromal-like cells reacted to caldesmon and desmin antibodies. The neoplastic epithelium expressed AE1/AE3 cytokeratin. Feline endometrial stromal tumor has, to the best of our knowledge, not been reported previously and has smooth muscle and glandular components that are a unique variant to the human counterpart.     

Feline progressive histiocytosis

Histiocytic proliferative diseases include reactive and neoplastic proliferations of dendritic cells (DC) or macrophages. Various forms of DC proliferations have been documented in humans and dogs; their etiology is largely unknown. With the exception of a few case reports, histiocytic proliferations have not been characterized in cats. This study summarizes clinical, morphologic, and immunophenotypic features of a feline progressive histiocytosis (FPH) in 30 cats. There was no breed or age predilection. Females were more often affected than males. Solitary or multiple nonpruritic firm papules, nodules, and plaques had a predilection for feet, legs, and face. Lesions consisted of poorly circumscribed epitheliotropic (13/30) and nonepitheliotropic (17/30) histiocytic infiltrates of the superficial and deep dermis, with variable extension into the subcutis. The histiocytic population was relatively monomorphous early in the clinical course. With disease progression, cellular pleomorphism was more frequently encountered. Histiocytes expressed CD1a, CD1c, CD18, and major histocompatibility complex class II molecules. This immunophenotype suggests a DC origin of these lesions. Coexpression of E-cadherin, a feature of cutaneous Langerhans cells, was only observed in 3 cats. FPH followed a progressive clinical course; the lesions, however, were limited to the skin for an extended period of time. Terminal involvement of internal organs was documented in 7 cases. Treatment with chemotherapeutics or immunosuppressive and immunomodulatory drugs was not successful. The etiology of FPH remains unknown. FPH is best considered an initially indolent cutaneous neoplasm, which is mostly slowly progressive and may spread beyond the skin in the terminal stage.     

Clinical and histological evaluation of immediate and delayed flea antigen intradermal skin test and flea bite sites in normal and flea-allergic cats

Seven cats diagnosed as flea allergic by specific criteria and seven normal control cats were exposed to flea bites in a controlled manner and were given intradermal injections of 1:1000 w/v flea antigen. Subjective evaluation of gross lesions and documentation of histological changes at flea antigen intradermal skin test (IDST) and flea bite sites were performed at 15 min, 24 h and 48 h after IDST or flea exposure. Control cats did not develop an immediate gross reaction to either flea bites or the intradermal injection of flea antigen. All seven flea-allergic cats had an immediate gross reaction at the site of IDST with flea antigen; five of these cats also developed immediate gross reactions to flea bites. Three of seven flea-allergic cats developed a gross 24 h and/or 48 h delayed reaction at the flea antigen IDST sites. These three and one other cat had both an immediate and delayed gross reaction to flea bites. Histological examination of 15 min skin specimens from IDST and flea bite sites of flea-allergic cats were similar with a mild lymphocytic, histiocytic and mastocytic superficial perivascular dermatitis. Histological examination of 24 h and 48 h skin specimens from IDST and flea bite sites of flea-allergic cats showed that they were often indistinguishable. Histological features of IDST and flea bite sites of flea-allergic cats at 24 h consisted of a perivascular to diffuse predominately eosinophilic dermatitis and mural folliculitis with variable epidermal necrosis and ulceration.     

Chronic gastroenterocolitis in nine cats.

Lesions of a chronic gastroenterocolitis were found in 9 cats of the Persian breed that were euthanized after a prolonged period of bloody diarrhea. Gross lesions consisted of gastrointestinal edema with prominent Payer's patches, multiple grayish nodules, and a few irregular erosions within the colonic mucosa. Microscopically, the changes were composed of degeneration, necrosis, and proliferation of gastric glandular epithelium, dilated intestinal crypts with lymphoplasmacytic cell infiltration of the lamina propria, and in 1 cat, severe transmural necrosis of the colon. With the Giemsa stain, spiral-shaped organisms in the gastrointestinal lumen and intracellularly in the gastric and the colonic epithelium were observed. These organisms could not be cultured. Although the role of these spiral-shaped organisms was not determined, other agents that could explain the disorder were not found.     

Radiographic and Scintigraphic Evidence of Focal Pulmonary Neoplasia in Three Cats With Hyperthyroidism: Diagnostic and Therapeutic Considerations

Three cats were diagnosed as hyperthyroid based on clinical signs, historical findings, laboratory abnormalities, and basal serum thyroxine (T₄) concentrations, and/or nuclear thyroid scans. Additionally, a presumptive diagnosis of thyroid carcinoma with pulmonary metastasis was made in each cat based on radiographic or scintigraphic evaluation. All three cats had solitary pulmonary nodules 1.5 to 2 cm in diameter on survey thoracic radiographs; one cat also had chylous pleural effusion and pulmonary lobar consolidation. Focal pulmonary accumulation of sodium pertechnetate (^99mTcO₄ -) and/or radioiodine (¹³¹I) corresponding to radiographic lesions were seen in all cats. Two cats were treated with single ablative doses (1111 to 1480 MBq) of¹³¹I; the remaining cat was euthanatized.
One of the treated cats died 8 days later; the other cat was euthanatized 22 weeks following treatment. Histopathologic examination of tissue obtained at necropsy confirmed metastatic thyroid carcinoma in one cat and bronchogenic adenocarcinoma in two cats. Our findings indicate that increased radionuclide uptake in focal pulmonary lesions and cytologic evaluation of tissue obtained by fine-needle aspiration are not specific for thyroid tissue. (Journal of Veterinary Internal Medicine 1993; 7:303–308. Copyright © 1993 by the American College of Veterinary Internal Medicine.)     

Surgical versus non-surgical treatment of feline small intestinal adenocarcinoma and the influence of metastasis on long-term survival in 18 cats (2000-2007)

This study retrospectively evaluated long-term outcomes of 18 cats diagnosed with small intestinal adenocarcinoma, based on surgical versus non-surgical treatment and the presence or absence of metastasis at the time of surgery. Ten cats had surgery and histopathologic confirmation of adenocarcinoma and 8 cats did not have surgery but had cytologic diagnosis of adenocarcinoma. Median survival of cats with adenocarcinoma that underwent surgical excision was 365 days and 22 days for those with suspected adenocarcinoma that did not undergo surgery (P = 0.019). Median survival of cats was 843 days for those without evidence of metastatic disease at the time of surgery and 358 days for those that had (P = 0.25). In conclusion, surgical excision is beneficial in the treatment of small intestinal adenocarcinoma in the cat, including those patients with metastasis, and may result in a significantly longer survival time compared with patients which do not have their mass surgically excised.     

Dermatophytic pseudomycetomas in four cats

The aim of this retrospective study was to describe the clinical characteristics and treatment of four cats with dermatophytic pseudomycetoma. Four Persian cats, one female and three males, with age ranging from 1.4 to 5 years, were diagnosed with dermatophytic pseudomycetoma by histological examination and fungal culture. Wood's lamp examination revealed positive fluorescence of hairs in all four cats. Characteristic skin lesions consisted of multifocal, raised, firm and nodular to dome-shaped lesions varying in size from 1 to 8 cm in diameter, with ulcers or fistulas in some of the lesions. One cat was treated and cured with 3 months of oral itraconazole; lesions completely regressed, and at the time of writing there has been no recurrence. One cat was treated with surgical excision alone, and recurrence of lesions occurred after a disease-free interval of 15 months. Two cats were treated with surgical excision and systemic itraconazole therapy. Itraconazole therapy was started 1-2 months before surgery and continued for 3 months after surgery. Surgical margins were wide in both cats, and underlying adipose tissue and/or deeper fascia was removed. One cat relapsed, but had a disease-free interval of 18 months. The other cat has been disease free for 32 months. This case series suggests that aggressive, wide surgical excision and concurrent oral itraconazole are highly beneficial in treating dermatophytic pseudomycetoma in cats.     

Changing cytokeratin expression patterns in diethylstilbestrol dipropionate-induced metaplastic lesions of the goat prostate.

Five-month-old male goats were treated with 25 mg diethylstilbestrol dipropionate (DES-DP) by a single intramuscular injection, causing characteristic histological alterations in the peripheral glandular epithelium of the prostate, resulting in squamous metaplasia. Using a panel of monoclonal and polyclonal cytokeratin antibodies on frozen tissue sections of control prostates, we were able to immunohistochemically distinguish between the normal secretory cells, which are positive for cytokeratin 18 as detected with the antibody RGE 53, and the scattered basal cells, which could be specifically stained by the antibody RCK 103. Cytokeratins indicating squamous differentiation, i.e., nos 4 and 13, recognised by the antibodies 6B10 and 1C7, respectively, were found in sporadic cells throughout the normal goat prostate. Profound changes in cytokeratin expression were observed in the metaplastic lesions as compared to control peripheral glandular tissue. In this respect three monoclonal antibodies are of special interest. RCK 103 is immunoreactive with resting and all stages of differentiating basal cells. Antibodies 1C7 and 6B10 strongly stain the squamous cells in the metaplastic lesions, with 1C7 staining all the squamous cells in the lesions except the basal cell layer, and 6B10 being immunoreactive with the same suprabasal cells or the more differentiated cells in the upper strata. As a result the number of cytokeratin 18-positive cells is drastically reduced upon metaplasia. The results indicate that the goat system can be used as a suitable model system to further test the applicability of immunohistochemical methods in meat inspection and toxicological pathology.     

Multiple endocrine neoplasia type-I-like syndrome in two cats

Multiple endocrine neoplasia (MEN) embodies a group of diseases in human patients and domestic animals that are characterized by hyperplasia or neoplasia, or both, of two or more endocrine tissues. The MEN-1 syndrome is associated with menin gene mutations that induce various combinations of parathyroid, pituitary, and pancreatic endocrine tumors in humans. Two male, Domestic Shorthair cats developed symmetric alopecia, insulin-resistant diabetes mellitus, and pituitary-dependent hyperadrenocorticism at 12 and 13 years of age. Examination of skin biopsy specimens revealed atrophic dermatosis associated with hyperadrenocorticism. In one cat, cutaneous lesions consistent with paraneoplastic alopecia associated with pancreatic adenocarcinoma also were evident. Multiple invasive pancreatic beta cell carcinomas, pituitary corticotroph adenomas, and thyroid C-cell and parathyroid chief cell hyperplasia were diagnosed on the basis of results of gross, histologic, and immunohistochemical findings in both cats. Pancreatic exocrine adenocarcinoma was diagnosed in both cats. One cat also had hepatocellular carcinoma. Exons 1-8 of the feline menin gene were sequenced and were found to bear 93% homology with the human gene sequence, and the corresponding amino acid sequences shared 98% homology. Purification of total RNA and amplification of cDNA from lesional tissues to document mutations in the feline menin gene sequence were unsuccessful. The combination of lesions observed was consistent with the diagnosis of MEN-1-like syndrome in both cats.     

Seasonal morphology and immunoreactivity of cytokeratin and atrial natriuretic peptide in dromedary camel poll glands

Poll glands are characteristic feature of dromedary camels; although they yield a yellowish offensive secretion, especially during rutting (breeding) season, their function is not yet exactly specified. The present study shows the seasonal morphology and immunoreactivity of cytokeratin (CK) and atrial natriuretic peptide (ANP) in the camel poll gland; the result could clearly specify the role of the gland in camel reproduction. Poll glands are compound tubulo-alveolar in structure. During rutting season, the secretory units showed wide lumina and simple squamous epithelium surrounded by myoepithelial cells; the lumina became narrower and the epithelium changed to simple cuboidal during non-rutting season. Many glandular lobules showed abundant interlobular connective tissue with fewer and smaller secretory units during non-rutting season compared to rutting season. Positive CK and ANP immunoreactivity was detected in the cytoplasm of epithelial cells of secretory units and ducts together with the myoepithelial cells and blood vessels. Although CK immunoreactivity was more intense during rutting season in comparison to non-rutting season, there was no seasonal variation in ANP immunoreactivity. During both seasons, while the glandular capsule, connective tissue septa, interstitium showed negative CK immunoreactions, they reacted moderately to ANP. In conclusion, the poll gland undergoes annual structural and functional changes which are suggested to correlate with the male seasonal sexual behaviour. Further, the biological role of CK and ANP proteins together with their immunohistochemical expression in the camel poll gland suggests a stimulatory effect in the glandular secretory cells, and hence, they might modify camel sexual activity.     

Immunohistochemical features of canine ovarian papillary adenocarcinoma and utility of cell block technique for detecting neoplastic cells in body cavity effusions

Dogs with ovarian papillary adenocarcinoma occasionally present with ascites and/or pleural effusion. These aspirated fluids often contain a large number of cells, and distinction between neoplastic cells and activated mesothelial cells can be difficult. In this study, 7 cases of canine ovarian papillary adenocarcinoma, including 3 with ascites and pleural effusion, were immunohistochemically examined. Ovarian tumor cells were positive for cytokeratin CAM5.2 (CAM5.2), Wilms’ tumor 1 (WT-1) and progesterone receptor (PR) in all 7 cases. A metastatic lesion of the mediastinum in one case was also positive for CAM5.2, WT-1 and PR. Immunohistochemistry on cell blocks obtained from ascites and/or pleural effusion of 2 cases revealed the presence of PR-positive epithelial cells. Whereas, activated mesothelial cells in ascites or pleural effusion collected from dogs without neoplastic lesions were negative for PR. In addition, surface epithelium and subsurface epithelial structures (SES) of normal canine ovaries, that are considered to be the cell of origin for ovarian papillary adenocarcinoma, were also positive for CAM5.2, WT-1 and PR. These results indicate that, together with CAM5.2, WT-1 and PR is a useful diagnostic marker for canine ovarian papillary adenocarcinoma. Expression of PR may be associated with progesterone-dependent nature of canine ovarian papillary adenocarcinoma.     

Small intestinal adenocarcinoma in cats: 32 cases (1978-1985)

The medical records of 32 cats with small intestinal adenocarcinoma were reviewed. Common clinical signs included vomiting, dehydration, weight loss, cachexia, anorexia, and lethargy. In 50% of the cats, an abdominal mass was palpated, and in 38%, a mass was seen on radiographs. Biopsy of the tumor without resection was performed in 9 cats; 8 cats were euthanatized at the time of surgery, 7 because of metastases, and 1 cat died 1 day after surgery. In 23 cats, resection was performed. Eleven of these died within 2 weeks after surgery (mean survival time, 2.6 days); 8 had lymph node metastasis. Twelve cats survived greater than 2 weeks after surgery. The mean survival of 11 of these cats was 15 months. Six cats were euthanatized because of recurrent signs; 5 of the 6 had a recurrent abdominal mass. One cat was alive 2 years after surgery. Results of this study indicated that cats with adenocarcinoma, even those cats with advanced disease, can have long-term survival after surgery.     

Hepatoblastoma in a cat

Hepatoblastomas are neoplasms that originate from putative pluripotential stem cells of the liver. A hepatic mass from an 8-year-old Abyssinian cat was composed of cords and sheets of neoplastic cells, with scattered rosettes and small ductal structures. Most neoplastic cells had a pale eosinophilic cytoplasm and a round to ovoid nucleus. The tumor also had short spindle cells with an oval nucleus. Immunohistochemically, neoplastic cells were weakly positive for embryonic hepatocellular markers, such as alpha-fetoprotein and cytokeratin (CK) 8/18, but negative for the hepatocellular marker Hepatocyte Paraffin 1. The cells were also positive for CD56/neural cell adhesion molecule and for the biliary epithelial markers CK 7, CK 8/18, CK CAM5.2, and vimentin, but negative for CK 20. Some neoplastic cells expressed neuroectodermal or neuroendocrine markers, such as protein gene product 9.5 and synaptophysin, but were negative for chromogranin A and not argyrophilic by the Grimelius technique. The cat died soon after the biopsy without clinical improvement.     

Overexpression of c-Ras in hyperplasia and adenomas of the feline thyroid gland: an immunohistochemical analysis of 34 cases

Formalin-fixed, paraffin-embedded thyroid glands from 18 cats diagnosed with hyperthyroidism were evaluated immunohistochemically for overexpression of the products of oncogenes c-ras and bcl2 and the tumor suppressor gene p53. Fourteen thyroid glands from euthyroid cats without histologically detectable thyroid lesions were examined similarly as controls. Results from these investigations showed that all cases of nodular follicular hyperplasia/adenomas stained positively for overexpression of c-Ras protein using a mouse monoclonal anti-human pan-Ras antibody. The most intensely positively staining regions were in luminal cells surrounding abortive follicles. Subjacent thyroid and parathyroid glands from euthyroid cats did not stain immunohistochemically for pan-Ras. There was no detectable staining for either Bc12 or p53 in any of the cats. These results indicated that overexpression of c-ras was highly associated with areas of nodular follicular hyperplasia/adenomas of feline thyroid glands, and mutations in this oncogene may play a role in the etiopathogenesis of hyperthyroidism in cats.