Morphologic manifestations of gene-specific molecular alterations ("genetic addictions") in mouse models of disease.

Neoplasia in both animals and humans results in part from lasting activation of tumor-promoting genes ("oncogenes") or diminished function of genes responsible for preventing neoplastic induction ("tumor suppressor genes"). The concept of "genetic addiction" has emerged to indicate that neoplastic cells cannot maintain a malignant phenotype without sustained genotypic abnormalities related to aberrant activity of oncogene(s) and/or inactivity of tumor suppressor gene(s). Interestingly, some genetic abnormalities reliably produce distinct morphologic patterns that can be used as structural signatures indicating the presence of a specific molecular alteration. Examples of such consistent genetic/microanatomic pairings have been identified for mutated oncogenes, such as rising mucin-producing capacity with RAS overexpression, and mutated tumor suppressor genes-including PTEN eliciting cell hypertrophy, RB1 dictating neuroendocrine differentiation, and TRP53 encouraging sarcomatous transformation. Familiarity with the concept of genetic addiction, as well as the ability to recognize such regular genomic-phenotypic relationships, are of paramount importance for comparative pathologists who are engaged in phenotyping genetically engineered mice to help unravel genomic intricacies in both health and disease.

The pathologist's slide reveals more than meets the eye: loss of heterozygosity and cancer biology.

In the postgenomic era, the accumulation of massive amounts of molecular and genetic data is quickly transforming the landscape of cancer research. A deeper understanding of cancer biology will allow pathologists studying genetically engineered mouse models and spontaneous tumors to ask novel questions and provide useful insights into disease mechanisms. Although tumor suppressor gene loss is known to be an essential step in the pathogenesis of many tumors, the variety of mechanisms that lead to such loss are poorly understood. This article provides an overview of loss of heterozygosity as an important mechanism of tumor suppressor gene loss; it also emphasizes the importance of loss of heterozygosity detection as a tool for tumor suppressor gene discovery. Understanding the applications of the array of molecular techniques currently available in cancer research will enable pathologists to further contribute to the advancement the field.

Necrotizing meningoencephalitis in five Chihuahua dogs.

An acute to chronic idiopathic necrotizing meningoencephalitis was diagnosed in 5 Chihuahua dogs aged between 1.5 and 10 years. Presenting neurologic signs included seizures, blindness, mentation changes, and postural deficits occurring from 5 days to 5.5 months prior to presentation. Cerebrospinal fluid analyses from 2 of 3 dogs sampled were consistent with an inflammatory disease. Magnetic resonance imaging of the brain of 2 dogs demonstrated multifocal loss or collapse of cortical gray/white matter demarcation hypointense on T1-weighted images, with T2-weighted hyperintensity and slight postcontrast enhancement. Multifocal asymmetrical areas of necrosis or collapse in both gray and white matter of the cerebral hemispheres was seen grossly in 4 brains. Microscopically in all dogs, there was a severe, asymmetrical, intensely cellular, nonsuppurative meningoencephalitis usually with cystic necrosis in subcortical white matter. There were no lesions in the mesencephalon or metencephalon except in 1 dog. Immunophenotyping defined populations of CD3, CD11d, CD18, CD20, CD45, CD45 RA, and CD79a immunoreactive inflammatory cells varying in density and location but common to acute and chronic lesions. In fresh frozen lesions, both CD1b,c and CD11c immunoreactive dendritic antigen-presenting cells were also identified. Immunoreactivity for canine distemper viral (CDV) antigen was negative in all dogs. The clinical signs, distribution pattern, and histologic type of lesions bear close similarities to necrotizing meningoencephalitis as described in series of both Pug and Maltese breed dogs and less commonly in other breeds.

Evaluation of P-glycoprotein expression in feline lymphoma and correlation with clinical outcome.

P-glycoprotein (Pgp) is a transmembrane protein pump involved in drug resistance in canine and human lymphoma. There are no published clinical studies evaluating Pgp expression in feline lymphoma. The purpose of this study is to evaluate the level of Pgp expression in feline lymphoma and correlate it with clinical outcome. Two human Pgp monoclonal antibodies, C219 and C494, were used to detect Pgp expression in tissue samples from 63 cats with lymphoma. Demographic results appear comparable to recently published feline lymphoma studies. The Kaplan-Meier median remission and survival times were 164 and 571 days, respectively. Fourteen cats had positive expression of Pgp using MAb C219, and 40 were positive with C494. Variables statistically associated with survival included bone marrow involvement, stage, substage, and use of radiation therapy as a part of treatment. Pgp expression as assessed by MAb C219 and C494 is not predictive of remission or survival time in cats with lymphoma.

Mycobacterium fortuitum pneumonia in a cat and the role of lipid in the pathogenesis of atypical mycobacterial infections.

Mycobacterium fortuitum is a saprophytic, fast-growing, nontuberculous, and nonlepromatous mycobacterium that can cause infections in animals and humans. In dogs and cats, it is one of the most common agents of ulcerative dermatitides and panniculitides caused by atypical mycobacteria. In humans, it is frequently found in lipoid pneumonias or contaminated surgical sites. We report a cat with granulomatous pneumonia caused by M fortuitum resembling lipoid pneumonia in humans. The similarity between the histopathology of the lung and skin lesions caused by this organism in dogs and cats is emphasized. We discuss the role of lipids in the pathogenesis of mycobacterioses and suggest an association between atypical mycobacteria and lipid-rich environments. We conclude that M fortuitum should be included as a differential in cases of lipid-rich pneumonias that do not respond to common antibiotics.

Feline vaccine-associated fibrosarcoma: morphologic distinctions.

Forty-four primary feline vaccine-associated fibrosarcomas and 16 recurrences were examined histologically for detailed morphologic characterization with emphasis on tumor grade, presence of neoplastic multinucleated giant cells, presence and proportion of T and B lymphocytes within the tumor, and thin and intermediate filament contents of neoplastic and stromal cells. The microvascularity and proliferation rates of central and peripheral areas of the tumors were also quantified by computerized image analysis. For primary fibrosarcomas, 11 of 44 (25%) were grade I, 21 of 44 (47.7%) were grade II, and 12 of 44 (27.3%) were grade III. The recurrences followed a similar pattern: 4 of 16 (25%) were grade I, 8 of 16 (50%) were grade II, and 4 of 16 (25%) were grade III. A positive correlation was found between the presence of neoplastic multinucleated giant cells and tumor grade. These cells were present in 9 of 12 (75%) of grade III and none of the grade I tumors. Prominent peritumoral lymphoid aggregates or follicles were present in 59% of the tumors, and many contained high proportions of T lymphocytes, varying from 19 to 87%. All fibrosarcomas were immunoreactive for vimentin and 28 of 44 (64%) were reactive for alpha-smooth muscle actin. The actin-positive cells were either part of the tumor or formed a capsule around tumor nodules. The peripheral vascularity was significantly higher than the central vascular density but no difference was found in tumor cell proliferation rates between the two areas. Centrally located, fluid-filled micro- or macrocavitations were frequently observed in the large vaccine sarcomas and probably formed secondary to rapid tumor growth and central necrosis.

Marsupialization and iodine sclerotherapy of a branchial cyst in a horse.

A 6-month-old Morgan colt was evaluated because of a 10-cm right-sided retropharyngeal swelling. The swelling was soft and moveable on examination, and palpation did not elicit signs of pain. Radiography revealed a large space-occupying mass ventral to the second cervical vertebra; ultrasonography revealed an anechoic fluid-filled structure with a well-defined hyperechoic capsule. Fine-needle aspiration yielded a viscous amber fluid. Cytologic evaluation indicated that the fluid was an exudate; anaerobic and aerobic bacterial culture did not yield any growth. Histologic examination of a portion of the cyst capsule revealed a connective tissue wall lined by pseudostratified columnar to cuboidal epithelium, consistent with a branchial cyst. The cyst wall was marsupialized to the skin, and iodine sclerotherapy was performed twice daily for 14 days, at which time forceps were introduced into the cyst and the cyst lining was removed. The site was allowed to heal by second intention, but 10 days later, the swelling recurred. An incision was made over the previous marsupialization site, and residual remnants of the cauterized cyst lining were removed with a forceps. The foal did not have any other complications during the subsequent 2 years. Branchial arch cysts are uncommon embryonic anomalies of horses, mice, cats, dogs, and cattle. Results suggest that marsupialization and iodine sclerotherapy may be a viable alternative to surgical excision in horses with branchial cysts; however, the entire cyst lining must be removed at the completion of sclerotherapy to prevent recurrence and abscess formation.

Pyogranulomatous meningoencephalitis due to Actinomyces sp. in a dog.

Actinomyces sp. are commensal, filamentous, gram-positive, acid-fast-negative bacteria that can cause pyogranulomatous inflammation in animals and humans. Central nervous system (CNS) disease is a rare presentation of actinomycosis and is usually due to extension from infected wounds or seeding from distant sites. A dog with progressive, poorly localized neurologic signs had primary CNS actinomycosis without history or evidence of previous trauma or other organ involvement. Histologically, there was a severe pyogranulomatous meningoencephalitis with intralesional filamentous bacteria that were also visible on cytology of the cerebral spinal fluid (CSF) postmortem. Actinomyces sp. was cultured postmortem from the CSF, confirming the diagnosis. This case demonstrates that Actinomyces sp. can be a causative agent of primary CNS disease in dogs.