Prognostic evaluation of feline mammary carcinomas: a review of the literature.

A large number of studies have investigated feline mammary tumors in an attempt to identify prognostic markers and generate comparative analyses with human breast cancer. Nevertheless, a retrospective base of assessments and the lack of standardization in methodology and study design have caused weakness in study results, making comparison difficult. We examined feline mammary tumor publications and evaluated postulated prognostic parameters according to the recently published "Recommended Guidelines for the Conduct and Evaluation of Prognostic Studies in Veterinary Oncology." Using these criteria, we determined with statistically significant reliability that prognostic parameters for feline mammary tumors are tumor grading and lymph node/lymphovascular invasion. Furthermore, tumor subtype, size, and staging are worthy of further standardized investigation. We present statistical significance for each studied parameter as well as its relevance to disease progression and survival. Our evaluation suggests that marker expression (ie, Ki67, HER2, ER) may provide relevant information applicable for therapeutic predictions; however, consensus efforts and protocol standardization are needed. We identify and discuss major points of concern--such as sample preservation and selection, standardization of immunohistochemical protocols, and evaluation of results--to provide support for subsequent reliable analyses.

Canine mammary tumors: a review and consensus of standard guidelines on epithelial and myoepithelial phenotype markers, HER2, and hormone receptor assessment using immunohistochemistry.

Although there have been several studies on the use of immunohistochemical biomarkers of canine mammary tumors (CMTs), the results are difficult to compare. This article provides guidelines on the most useful immunohistochemical markers to standardize their use and understand how outcomes are measured, thus ensuring reproducibility of results. We have reviewed the biomarkers of canine mammary epithelial and myoepithelial cells and identified those biomarkers that are most useful and those biomarkers for invasion and lymph node micrometastatic disease. A 10% threshold for positive reaction for most of these markers is recommended. Guidelines on immunolabeling for HER2, estrogen receptors (ERs), and progesterone receptors (PRs) are provided along with the specific recommendations for interpretation of the results for each of these biomarkers in CMTs. Only 3+ HER2-positive tumors should be considered positive, as found in human breast cancer. The lack of any known response to adjuvant endocrine therapy of ER- and PR-positive CMTs prevents the use of the biological positive/negative threshold used in human breast cancer. Immunohistochemistry results of ER and PR in CMTs should be reported as the sum of the percentage of positive cells and the intensity of immunolabeling (Allred score). Incorporation of these recommendations in future studies, either prospective or retrospective, will provide a mechanism for the direct comparison of studies and will help to determine whether these biomarkers have prognostic significance. Finally, these biomarkers may ascertain the most appropriate treatment(s) for canine malignant mammary neoplasms.

Evaluation of clinical and histopathologic prognostic factors for survival in canine osteosarcoma of the extracranial flat and irregular bones.

Osteosarcoma is the most common bone tumor in dogs. However, current literature focuses primarily on appendicular osteosarcoma. This study examined the prognostic value of histological and clinical factors in flat and irregular bone osteosarcomas and hypothesized that clinical factors would have a significant association with survival time while histological factors would not. All osteosarcoma biopsy samples of the vertebra, rib, sternum, scapula, or pelvis were reviewed while survival information and clinical data were obtained from medical records, veterinarians, and owners. Forty-six dogs were included in the analysis of histopathological variables and 27 dogs with complete clinical data were included in the analysis of clinical variables. In the histopathologic cox regression model, there was no significant association between any histologic feature of osteosarcoma, including grade, and survival time. In the clinical cox regression model, there was a significant association between the location of the tumor and survival time as well as between the percent elevation of alkaline phosphatase (ALP) above normal and survival time. Controlling for ALP elevation, dogs with osteosarcoma located in the scapula had a significantly greater hazard for death (2.8) compared to dogs with tumors in other locations. Controlling for tumor location, every 100% increase in ALP from normal increased the hazard for death by 1.7. For canine osteosarcomas of the flat and irregular bones, histopathological features, including grade do not appear to be rigorous predictors of survival. Clinical variables such as increased ALP levels and tumor location in the scapula were associated with decreased survival times.

A retrospective study of those histopathologic parameters predictive of invasion of the lymphatic system by canine mammary carcinomas.

The aim of the present study was to determine which histopathologic parameters of primary canine mammary carcinomas (CMCs) could predict metastatic spread via the lymphatic system. A modification of the World Health Organization classification was applied to 245 CMCs. In addition to tumor subtype, neoplastic infiltration of the surrounding mammary stroma, vasculogenic mimicry, and micropapillary pattern were evaluated, and 2 histologic grading systems were used for each sample. A statistical analysis was undertaken to determine the relationship between these histopathologic parameters and the detection of lymphatic vessels invasion (LVI) and regional lymph node metastases (RLM). To compare the predictive value for lymphatic spread of the 2 histologic grading systems, the Akaike information criterion was measured. The classification into tumor subtypes was significant (P < .01) in predicting the risk of LVI and RLM. Peripheral infiltration, vasculogenic mimicry, and micropapillary pattern were found in 170 of 245 (69.4%), 32 of 245 (13.1%), and 54 of 245 (22.0%) CMCs. The presence of peripheral infiltration was significantly associated (P < .001) with both LVI and RLM, and a similar relation (P < .05) was found for the micropapillary pattern. Vasculogenic mimicry was not predictive of invasion of the lymphatic system. Both histologic grading systems were significant predictors (P < .001) of the risk of LVI and RLM. The grading system that included a more rigorous evaluation of the neoplastic mitotic activity had the lower Akaike information criterion values, thus indicating a better predictive ability. The study confirms the significant prognostic role for the modified World Health Organization classification of CMCs and the prognostic value of additional histopathologic parameters.

Clinical and histologic features of 26 canine peripheral giant cell granulomas (formerly giant cell epulis).

Clinical and histologic features of 26 cases of canine peripheral giant cell granuloma (formerly giant cell epulis) are reported. Two main histologic categories were evident: (1) "classic" peripheral giant cell granuloma, characterized by variable numbers of multinucleated giant cells (MNGCs) admixed with densely cellular mononuclear spindle-shaped cells in variable amounts of collagenous matrix, and (2) the "collision" peripheral giant cell granuloma, with features of both a peripheral giant cell granuloma and a fibromatous epulis of periodontal ligament origin. In the 16 dogs for which the outcome was known, 2 peripheral giant cell granulomas recurred after excision. No age or sex predilection was evident; however, lesions were more common in maxillary than in mandibular gingiva. In contrast to cats, peripheral giant cell granulomas in dogs behave like fibromatous epulides of periodontal ligament origin and seldom recur after excision. Positive staining with TRAP (tartrate-resistant acid phosphatase) of the MNGCs and a fraction of the mononuclear cell population is consistent with osteoclastic origin.

Development, anatomy, histology, lymphatic drainage, clinical features, and cell differentiation markers of canine mammary gland neoplasms.

Mammary neoplasms are the most common neoplasm in female dogs. This article describes the embryologic development, normal anatomy, and histology of the canine mammary gland from the onset of first estrous and the changes that occur in the mammary gland during the estrus cycle. The clinical features of canine mammary gland tumors and their relation to prognosis are discussed, including age, hormones, breed, diet, and obesity. Additional clinical prognostic factors including clinical presentation, tumor size, and lymph node status at the time of presentation are discussed in relation to diagnosis and tumor staging. Immunohistochemical evaluation of the cell differentiation markers of the normal and neoplastic canine mammary gland is described and compared with similar studies in humans; the ways these markers may be used to assist with the prognosis of canine mammary neoplasms are discussed.

Recommended guidelines for submission, trimming, margin evaluation, and reporting of tumor biopsy specimens in veterinary surgical pathology.

Neoplastic diseases are typically diagnosed by biopsy and histopathological evaluation. The pathology report is key in determining prognosis, therapeutic decisions, and overall case management and therefore requires diagnostic accuracy, completeness, and clarity. Successful management relies on collaboration between clinical veterinarians, oncologists, and pathologists. To date there has been no standardized approach or guideline for the submission, trimming, margin evaluation, or reporting of neoplastic biopsy specimens in veterinary medicine. To address this issue, a committee consisting of veterinary pathologists and oncologists was established under the auspices of the American College of Veterinary Pathologists Oncology Committee. These consensus guidelines were subsequently reviewed and endorsed by a large international group of veterinary pathologists. These recommended guidelines are not mandated but rather exist to help clinicians and veterinary pathologists optimally handle neoplastic biopsy samples. Many of these guidelines represent the collective experience of the committee members and consensus group when assessing neoplastic lesions from veterinary patients but have not met the rigors of definitive scientific study and investigation. These questions of technique, analysis, and evaluation should be put through formal scrutiny in rigorous clinical studies in the near future so that more definitive guidelines can be derived.

Proposal of a 2-tier histologic grading system for canine cutaneous mast cell tumors to more accurately predict biological behavior.

Currently, prognostic and therapeutic determinations for canine cutaneous mast cell tumors (MCTs) are primarily based on histologic grade. However, the use of different grading systems by veterinary pathologists and institutional modifications make the prognostic value of histologic grading highly questionable. To evaluate the consistency of microscopic grading among veterinary pathologists and the prognostic significance of the Patnaik grading system, 95 cutaneous MCTs from 95 dogs were graded in a blinded study by 28 veterinary pathologists from 16 institutions. Concordance among veterinary pathologists was 75% for the diagnosis of grade 3 MCTs and less than 64% for the diagnosis of grade 1 and 2 MCTs. To improve concordance among pathologists and to provide better prognostic significance, a 2-tier histologic grading system was devised. The diagnosis of high-grade MCTs is based on the presence of any one of the following criteria: at least 7 mitotic figures in 10 high-power fields (hpf); at least 3 multinucleated (3 or more nuclei) cells in 10 hpf; at least 3 bizarre nuclei in 10 hpf; karyomegaly (ie, nuclear diameters of at least 10% of neoplastic cells vary by at least two-fold). Fields with the highest mitotic activity or with the highest degree of anisokaryosis were selected to assess the different parameters. According to the novel grading system, high-grade MCTs were significantly associated with shorter time to metastasis or new tumor development, and with shorter survival time. The median survival time was less than 4 months for high-grade MCTs but more than 2 years for low-grade MCTs.

Recommended guidelines for the conduct and evaluation of prognostic studies in veterinary oncology.

There is an increasing need for more accurate prognostic and predictive markers in veterinary oncology because of an increasing number of treatment options, the increased financial costs associated with treatment, and the emotional stress experienced by owners in association with the disease and its treatment. Numerous studies have evaluated potential prognostic and predictive markers for veterinary neoplastic diseases, but there are no established guidelines or standards for the conduct and reporting of prognostic studies in veterinary medicine. This lack of standardization has made the evaluation and comparison of studies difficult. Most important, translating these results to clinical applications is problematic. To address this issue, the American College of Veterinary Pathologists' Oncology Committee organized an initiative to establish guidelines for the conduct and reporting of prognostic studies in veterinary oncology. The goal of this initiative is to increase the quality and standardization of veterinary prognostic studies to facilitate independent evaluation, validation, comparison, and implementation of study results. This article represents a consensus statement on the conduct and reporting of prognostic studies in veterinary oncology from veterinary pathologists and oncologists from around the world. These guidelines should be considered a recommendation based on the current state of knowledge in the field, and they will need to be continually reevaluated and revised as the field of veterinary oncology continues to progress. As mentioned, these guidelines were developed through an initiative of the American College of Veterinary Pathologists' Oncology Committee, and they have been reviewed and endorsed by the World Small Animal Veterinary Association.

Postvaccinal sarcomas in the cat: epidemiology and electron probe microanalytical identification of aluminum.

An increase in fibrosarcomas in a biopsy population of cats in the Pennsylvania area appears to be related to the increased vaccination of cats following enactment of a mandatory rabies vaccination law. The majority of fibrosarcomas arose in sites routinely used by veterinarians for vaccination, and 42 of 198 tumors were surrounded by lymphocytes and macrophages containing foreign material identical to that previously described in postvaccinal inflammatory injection site reactions. Some of the vaccines used have aluminum-based adjuvants, and macrophages surrounding three tumors contained aluminum oxide identified by electron probe microanalysis and imaged by energy-filtered electron microscopy. Persistence of inflammatory and immunological reactions associated with aluminum may predispose the cat to a derangement of its fibrous connective tissue repair response, leading to neoplasia.

Glutaraldehyde-induced esophageal injury. Histologic study of laboratory rats.

RATIONALE AND OBJECTIVES: A patient was encountered with a long esophageal stricture that may have been caused by glutaraldehyde-contaminated endoscopic equipment. An in vivo study of laboratory rats was performed to determine the effect of glutaraldehyde exposure on the esophagus. METHODS: Ten laboratory rats were divided into five groups that received daily gavage of the esophagus with either 3.2% glutaraldehyde solution (treated rats) or 1 mL of normal saline (control rats) for varying durations. After the rats were killed, histologic sections from the esophagus were reviewed in a blind fashion. The degree of inflammatory infiltrate at the gastroesophageal junction was quantified as mild, moderate, or marked. RESULTS: Histologic examination revealed greater neutrophilic infiltration in the submucosa of the gastroesophageal junction in three of four glutaraldehyde-treated rats compared with controls. Treated rats also had evidence of segmental esophageal vasculitis not seen in any of the controls. Both controls and treated rats had areas of myositis and myonecrosis within the esophagus. CONCLUSION: Exposure to glutaraldehyde has a toxic effect on the rat esophagus. Glutaraldehyde-induced esophageal injury should therefore be considered in patients who develop esophagitis or esophageal strictures after upper endoscopy.

Factors associated with Army obstetricians-gynecologists' practice of HIV prevention education during routine gynecologic care.

The authors evaluate obstetricians-gynecologists' (OB-GYNs') anxiety about clinical uncertainty and patient, physician, and organizational factors associated with their selection of HIV-related educational activities for high-risk and low-risk written case simulations. A total of 117 U.S. Army OB-GYNs completed a mailed, anonymous questionnaire. Overall, informants were much less likely to educate in response to the low-risk simulation; however, more informants who were anxious about uncertainty were more likely to do so in a model that included supportive institutional policies, willingness to educate despite patient barriers, and comfort with the topic. OB-GYNs were more likely to educate in response to the high-risk simulation given greater willingness to discuss HIV despite organizational barriers, supportive policies, and comfort. Findings suggest a need to better understand the role that anxiety about uncertainty plays in HIV prevention and the need to promote organizational policies that support and remove barriers to clinically based education.

Effect of spaying and timing of spaying on survival of dogs with mammary carcinoma.

The risk of developing mammary gland tumors in dogs is significantly decreased by ovariohysterectomy at an early age. However, previous studies have not found a benefit to ovariohysterectomy concurrent with tumor removal in dogs with established mammary gland tumors, suggesting that the progression of these tumors is independent of continued estrogen stimulation. The purpose of this study was to evaluate the effect of spaying and of the timing of spaying on survival in dogs with mammary gland carcinoma. Signalment, spay status and spay age, tumor characteristics, treatment. survival, and cause of death of 137 dogs with mammary gland carcinoma were analyzed. The dogs were classified into 3 groups according to spay status and spay time: intact dogs, dogs spayed less than 2 years before tumor surgery (SPAY 1), and dogs spayed more than 2 years before their tumor surgery (SPAY 2). Dogs in the SPAY 1 group lived significantly longer than dogs in SPAY 2 and intact dogs (median survival of 755 days, versus 301 and 286 days, respectively, P = .02 and .03). After adjusting for differences between the spay groups with regard to age, histologic differentiation, and vascular invasion, SPAY 1 dogs survived 45% longer compared to dogs that were either intact or in the SPAY 2 group (RR = .55; 95% CI .32-.93; P = .03). This study reveals ovariohysterectomy to be an effective adjunct to tumor removal in dogs with mammary gland carcinoma and that the timing of ovariohysterectomy is important in influencing survival.

Ureterocolonic anastomosis in clinically normal dogs.

Ureterocolonic anastomosis was evaluated in 13 clinically normal dogs. Urinary continence was maintained after surgery, and the procedure was completed without technique errors in all but 2 dogs. Three dogs died within 5 weeks (2 of undetermined causes and 1 of aspiration pneumonia and neurologic disease), and 1 dog was euthanatized 4 months after surgery because of neurologic signs. Two healthy dogs were euthanatized 3 months after surgery for light microscopic evaluation of their kidneys. Five dogs were euthanatized 6 months after surgery for light microscopic evaluation of their kidneys. Gastrointestinal and neurologic disturbances developed in 4 dogs at various postoperative intervals. Plasma ammonia concentration measured in 2 dogs with neurologic signs was increased. Plasma ammonia concentration measured in 5 dogs without neurologic signs was within normal limits. All 5 dogs, in which metabolic acidosis was diagnosed, had high normal or above normal serum chloride concentration. Serum urea nitrogen values were increased after surgery because of colonic absorption of urea. Serum creatinine concentration was increased in 1 dog 6 months after surgery. Individual kidney glomerular filtration rate was reduced in 38% (3/8) of the kidneys from 4 other dogs at 6 months after surgery. Of 5 dogs euthanatized at 3 to 4 months after surgery, 4 had bilateral pyelitis, and 1 had unilateral pyelonephritis. Six months after surgery, pyelonephritis was diagnosed in 40% (4/10) of the kidneys from 5 dogs. The ureterocolonic anastomosis procedure is a salvage procedure that should allow complete cystectomy. However, variable degrees of metabolic acidosis, hyperammonemia, and neurologic disease may result.

Systemic paecilomycosis in a dog.

Disseminated paecilomycosis was diagnosed in an adult dog without underlying immunosuppressive disease. During the 3-month illness (before euthanasia), the dog had ulcerative granulomatous inguinal lymphadenitis, fever, anorexia, dyspnea, generalized lymphadenopathy, retinochoroiditis, and seizures. Fungal organisms isolated from inguinal and prescapular lymph nodes before the dog was euthanatized were identified histologically. Paecilomyces variotii was isolated from the prescapular lymph node specimen. Paecilomyces variotii may be more pathogenic (once it has gained bodily entry) than previously thought.

Vitamin A-responsive dermatosis in the dog.

In 3 dogs, focal, well-circumscribed skin lesions compatible clinically with seborrheic dermatitis responded to oral treatment with vitamin A. Skin biopsy findings were compatible with phrynoderma in man, a disease thought to be associated with vitamin A deficiency. The dogs had been fed commercial dog food and were otherwise healthy. The skin lesions resolved rapidly and completely with vitamin A therapy. Seven other dogs with similar lesions but with histopathologic findings not compatible with phrynoderma or follicular keratosis did not respond to vitamin A therapy.

Epidemiologic, clinical, pathologic, and prognostic characteristics of splenic hemangiosarcoma and splenic hematoma in dogs: 217 cases (1985).

Data on age, sex, and breed were obtained from surgical pathologic records of 92 dogs with splenic hemangiosarcoma (SHS) and for 125 dogs with splenic hematoma (SHA) diagnosed in 1985 at the University of Pennsylvania School of Veterinary Medicine. Further information on body weight, clinical and surgical findings, and survival time was obtained for 59 dogs (64.1%) with SHS and 91 dogs (72.8%) with SHA. Splenic hemangiosarcoma was markedly more common in dogs 8 to 13 years old, and SHA was appreciably more common in dogs greater than or equal to 8 years old, compared with dogs 1 to 7 years old. Compared with sexually intact females, only spayed females were at significantly (odds ratio [or], 2.2; 95% confidence interval [CI], 1.2 to 4.1) increased risk for developing SHS; sex predisposition was not found for dogs with SHA. The German Shepherd Dog was the only breed with increased risk for development of either SHS (OR, 4.7; 95% CI, 2.7 to 7.8) or SHA (OR, 2.8; 95% CI, 1.7 to 4.9), compared with all other purebred dogs. Association of tumor type for 7 commonly reported clinical signs with observance of hemoperitoneum at surgery was determined; anorexia (P = 0.01), collapse (P = 0.01), and hemoperitoneum (P less than 0.001) were significantly more common in dogs with SHS. The median survival time for dogs with SHS was 19 days, compared with 338 days for dogs with SHA (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin F2 alpha treatment of canine pyometra.

Immediate and long-term outcomes of prostaglandin F2 alpha treatment for canine pyometra were studied in 10 bitches. Examination of pretreatment uterine biopsy specimens, taken for histopathologic diagnosis and classification of disease severity, revealed either type III or IV pyometra. Dinoprost tromethamine (0.25 or 0.5 mg/kg of body weight, SC) was given once daily for 3 days. Bitches were bred at the first posttreatment estrus and monitored for a minimum of one year. When pure cultures of Escherichia coli (n = 3) or Staphylococcus aureus (n = 1) were obtained from the vagina, these bacteria also were found in the uterus. Pretreatment WBC counts often did not reflect the severity of histopathologic findings in the uterus, but posttreatment WBC counts were useful in monitoring response to treatment. Four bitches produced a litter within one year of treatment. Four bitches (40%) had recurrence of pyometra within one year of treatment, and these same bitches had another recurrence after an additional prostaglandin treatment. Three additional bitches had a recurrence by 27 months after therapy, establishing a total recurrence rate of 77% (7/9). Results suggested that subclinical disease may persist after treatment, with clinical recurrence during diestrus. Despite the high recurrence rate, it was concluded that this treatment is a practical treatment for canine pyometra when reproduction is desired.

Anemia, splenomegaly, and increased osmotic fragility of erythrocytes in Abyssinian and Somali cats.

OBJECTIVE: To determine clinical and clinicopathologic features of a chronic intermittent severe hemolytic anemia characterized by erythrocyte osmotic fragility in Abyssinian and Somali cats. DESIGN: Case series. ANIMALS: 13 Abyssinian and 5 Somali cats. PROCEDURES: History, pedigree information, and results of routine laboratory tests, special erythrocyte studies, and histologic evaluation of splenic and hepatic specimens were analyzed. RESULTS: Age at which clinical signs of anemia were first apparent ranged from 6 months to 5 years. Ten cats had splenomegaly. Most often, the PCV was between 15 and 25%, but it was as low as 5% at some times. The anemia was characterized by macrocytosis and mild to moderate reticulocytosis, but no poikilocytosis. Hyperglobulinemia, lymphocytosis, mild hyperbilirubinemia, and high hepatic enzyme activities were common findings. Results of Coombs tests and tests for infectious diseases were negative. The erythrocytic osmotic fragility was high in affected cats (mean osmotic fragility, 0.66 to 0.78%), compared with healthy cats (0.48 to 0.58). No specific membrane protein abnormality, erythrocyte enzyme deficiency, or hemoglobinopathy was identified. Histologic evaluation of splenic and hepatic specimens revealed extramedullary hematopoiesis and hemosiderosis. Four of the 5 Somali cats were closely related. CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of results of pedigree analyses, the apparent breed predilection, and the exclusion of other known causes of anemia in cats, we believe that the hemolytic anemia in these cats was likely a result of a novel hereditary erythrocyte defect. A genetic predisposition to immune-mediated destruction of erythrocytes could not be ruled out.

Cutaneous lymphosarcoma and leukemia in a cat.

A cat with cutaneous lymphosarcoma and leukemia, similar to Sézary syndrome in human beings, had initial clinical signs that included pruritus and exfoliative dermatosis, associated with weight loss and lymphadenopathy. Dermatopathologic findings and ultrastructural morphologic features of the circulating cells and cellular infiltrate were consistent with Sézary cells. Cutaneous lymphosarcoma and leukemia should be considered in cats with chronic pruritic exfoliative dermatoses.