Veterinary Pathology最新文献

The emergence of cell and gene therapies has transformed the therapeutic landscape, offering curative potential for a range of previously intractable diseases. However, their biological complexity and patient-specific mechanisms of action present significant challenges for preclinical evaluation, particularly in modeling human responses and predicting safety outcomes. Traditional animal models often lack translational fidelity, prompting the adoption of humanized immunodeficient mice, including those engrafted with human immune cells, as more predictive in vivo platforms. These models enable the assessment of pharmacodynamics, biodistribution, and immunotoxicity in a human-relevant context. This review critically explores the integration of humanized mice into regulatory submissions for cell and gene therapy products, highlighting their utility across proof-of-concept, pharmacokinetic, toxicology, and tumorigenicity studies. We also address key limitations of the different models, including variability in engraftment efficiency, immune reconstitution, and lifespan, as well as challenges in standardization and regulatory acceptance. Future directions include refining humanized mouse models to better mimic human physiology, incorporating pathological endpoints, and aligning with 3R principles and new methodological approaches. By enhancing the translational relevance of nonclinical data, humanized mice are poised to play an increasingly strategic role in early safety assessment and successful development of advanced therapies.

Companion animal cancer diagnostic reports are text-based documents containing essential information on tumor classification and diagnosis. Establishing an animal cancer registry requires integrating and extracting structured data from diverse report formats across multiple providers. This study presents the development of an object-oriented programming approach to standardize and automate cancer data collection for canine and feline patients, enabling the creation of the Australian Companion Animal Registry of Cancers (ACARCinom); Australia's first national registry of cat and dog cancers. An object-oriented programming approach was developed using the C# language for data processing, tested on sample data from 6 data providers. The initial programming phase focused on designing a parser that identified report sections using regular expressions based on standardized headings. The text was then cleaned to remove unnecessary formatting and HTML tags. Data dictionaries containing preferred terms and synonyms were used to extract key information such as diagnosis, topography, grade, and metastasis, improving consistency and accuracy. A coordinate map of extracted terms was generated to analyze spatial relationships within the report, allowing prioritization of diagnoses. The system also logged parsing decisions and potential issues for expert review. Markup using HTML tags enabled clear visualization of parsed content within the original reports. Extracted data and patient metadata were stored in an intermediary database table, allowing veterinary pathology experts to review and refine entries before final import. This automated solution streamlines data extraction and standardization from diverse sources, enabling the efficient analysis of cancer records and enhancing research and surveillance capacity in veterinary oncology.

Cutaneous malignant melanomas from 81 rabbits were retrospectively evaluated, and 51 cases were re-examined to elucidate their histopathological and immunohistochemical characteristics and to identify potential associated prognostic factors. The mean age of rabbits at tumor incidence was 6 years, 9 months (median age: 7 years; range: 2 years, 1 month to 12 years, 4 months). Netherland dwarfs and intact males were more prevalent in terms of breed and sex, respectively. The most common tumor location was the scrotum, followed by the head, including the eyelids and pinna, and trunk. The tumors were composed of 3 cell types: epithelioid, spindle, and mixed. Histopathological parameters examined included mitotic counts, nuclear atypia, multinucleated giant cells, degree of pigmentation, local invasion, tissue margins, presence of satellite nodules, vascular invasion, intralesional necrosis, and intralesional inflammation. In this study, most histopathological parameters were not associated with a shorter survival time. Maximum tumor diameter and mitotic counts were associated with a poor prognosis, with cutoffs of 2.0 cm and 10 mitoses per 2.37 mm², respectively. Immunohistochemically, 51 of 51 cases (100%), 50 of 51 cases (98%), and 49 of 51 cases (96%) were positive for PNL2, melan-A, and HMB-45, respectively. No apparent differences in positivity were observed among the cell types of the neoplasms. This study provides several new insights into malignant melanomas of rabbits, such as breed, anatomical site, and sex predilections, and detailed histopathology, including useful cutoff values of associated prognostic factors.

Metabolic dysfunction-associated steatohepatitis (MASH) is a global health care burden. Appropriate large animal models mimicking the main MASH characteristics of steatosis, inflammation, and hepatocyte damage alongside progression of fibrosis are imperative for robust preclinical studies, especially in the field of hepatobiliary surgery. The present study aimed to characterize a novel model of steatohepatitis in fumarylacetoacetate hydroxylase-deficient (FAH^-/-) pigs. FAH^-/- pigs were generated using a CRISPR/Cas9 system. The animals received a choline-deficient, L-amino acid-defined high-fat diet and subtherapeutic doses of nitisinone and were followed for 3 months. Liver biopsies were obtained at baseline and every month during treatment. Steatosis, inflammation, and fibrosis were assessed by conventional histological scoring systems and by an artificial intelligence (AI) model. Serum liver parameters were analyzed every 2 weeks. Steatosis increased significantly throughout the study, with severe steatosis observed as early as 2 months into treatment. The inflammation score was increased in all animals after 3 months of treatment, whereas the AI-based CD45+ cell count showed region-specific trends in the portal and lobular areas. Collagen content and the corresponding fibrosis stage showed an increase over the 3-month period; however, the difference was not significant. Serum liver parameters did not show any relevant elevations during the study. In summary, we successfully developed and characterized a novel model of steatohepatitis in the FAH^-/- pig within 3 months. Further studies with prolonged observation time and/or cycling of nitisinone administration are needed to evaluate whether progressive fibrosis and cirrhosis could be achieved with this model.

Diagnosis and classification of ovarian epithelial neoplasms in guinea pigs (Cavia porcellus) are challenging due to inconsistent terminology and few available diagnostic criteria. This study evaluated 23 ovarian epithelial neoplasms in 15 guinea pigs with the objectives of (1) differentiating ovarian surface epithelial (OSE) neoplasms from rete ovarii neoplasms using immunohistochemistry, (2) describing salient histologic features, and (3) classifying neoplasms according to canine, human, and rodent classification schemes. PAX-8 immunohistochemistry separated immunoreactive rete neoplasms from nonreactive OSE neoplasms. OSE neoplasms (n = 12) were well-differentiated and arose directly from the ovarian surface, rather than the primarily cortical location of OSE neoplasms in other species. Focal OSE neoplasms with papillary projections on a fibrous core or tubules within a fibrous stroma were classified as surface papilloma and surface adenoma, respectively. Generalized OSE neoplasms with tubules, papillae, and fibrous stroma were classified as surface borderline tumors. Neoplasms with invasion, 2-4 mitotic figures per 2.37 mm², and/or peritoneal implantation were classified as surface carcinoma. The only carcinoma with follow-up had resolution of clinical signs and no radiologic evidence of recurrence 6 months after ovariohysterectomy. Rete neoplasms (n = 11) included rete cystadenomas and rete adenomas, and consisted of epithelial cells arranged in papillae and tubules within a rete tubule, with or without cysts, respectively. Further investigation is needed to correlate diagnoses with neoplasms' biologic behavior. We propose using "surface" and "rete" in the diagnosis to denote location, rather than "papillary," "cystic," or "serous," which are variably used in other ovarian neoplasia classification schemes, to standardize terminology.

The tumor-immune microenvironment (TIME) plays a pivotal role in cancer progression, yet its characterization in veterinary oncology remains limited. Eighty-five soft tissue sarcomas (STSs), comprising fibrosarcomas, leiomyosarcomas, liposarcomas, myxosarcomas, and perivascular wall tumors (PWTs), were immunohistochemically assessed for IBA-1 (total tumor-associated macrophages) and CD204 (M2-like macrophages) expression, scored by image analysis, and correlated with histological parameters. IBA-1 was higher in grade 3 STSs compared with grade 1 (W = 3.40, P = .043) and in PWTs compared with myxosarcomas (W = 6.037, P < .001). CD204 was lower in PWTs compared with fibrosarcomas (W = 5.152, P = .003), leiomyosarcomas (W = 4.394, P = .016), and myxosarcomas (W = 4.812, P = .006). Stratifying by STS type, IBA-1 was higher in grade 2 myxosarcomas compared with grade 1 (Mann U = 4, P = .018). IBA-1 and CD204 were higher in myxosarcomas with necrosis compared with those without (Mann U = 5, P = .026, and Mann U = 0, P = .001, respectively). In PWTs, the mitotic count was higher in cases with higher IBA-1 (Spearman's rho = 0.438, P = .041) and cases with lower CD204 (Spearman's rho = -0.459, P = .035). Considering all STSs, IBA-1 correlated with total tumor-infiltrating lymphocytes (TILs), T-cells, and regulatory T-cells (Tregs). In fibrosarcomas, IBA-1 and CD204 directly correlated with total TILs, T-cells, and Tregs. In myxosarcomas, CD204 correlated with Tregs. In leiomyosarcomas, IBA-1 scores correlated with Tregs and CD204 with T-cells and Tregs. In PWTs, B-cells correlated with IBA-1 and inversely correlated with CD204. These findings suggest the presence of a TIME favoring anti-tumor immunity in PWTs and a pro-tumoral TIME in myxosarcomas, reinforcing the concept that canine STS histotypes elicit distinct immune responses.

ΔNp63 is an isoform of p63 that plays an essential role in the development and growth of some epithelial tissues. In this study, we investigated the expression of ΔNp63 in normal and neoplastic tissues of cats and compared the results with the expression of pan-p63. Immunohistochemistry for ΔNp63 and pan-p63 was performed in normal tissues from 2 adult cats and in 10 cases each of 22 different types of feline neoplasms. In normal tissues, there was nuclear ΔNp63 immunolabeling in basal cells of stratified squamous, transitional, and pseudostratified columnar epithelia; basal cells of sebaceous glands; trophoblasts; and myoepithelial cells. Of the neoplasms, 10/10 apocrine ductal adenomas, 10/10 mammary ductal carcinomas, 10/10 pulmonary adenosquamous carcinomas, 10/10 squamous cell carcinomas, 10/10 trichoblastomas, and 10/10 urothelial carcinomas immunolabeled for ΔNp63. The ΔNp63 immunolabeling was diffuse in almost all neoplastic cells with squamous, basal, and urothelial origins. In the neoplasms with ductal differentiation, only the neoplastic suprabasal myoepithelial cells immunolabeled. Application of pan-p63 to the same set of neoplasms revealed positivity not only in the same neoplasms, but also in several unexpected tumor types (3/10 exocrine pancreatic carcinomas, 3/10 fibrosarcomas, 3/10 pulmonary adenocarcinomas, 2/10 lymphomas, 1/10 cholangiocarcinomas, 1/10 hemangiosarcomas, 1/10 mast cell tumors, and 1/10 meningiomas). Both ΔNp63 and pan-p63 antibodies demonstrated 100% diagnostic sensitivity and negative predictive value for diagnosing feline neoplasms with squamous, basal, and urothelial epithelia or myoepithelial cells. However, ΔNp63 showed higher diagnostic specificity (100% vs. 90.6%), positive predictive value (100% vs. 80%), and overall accuracy (100% vs. 93.1%) compared with pan-p63.

The histologic diagnosis of some cases of bovine dermatitis can be challenging. We investigated the predominant histologic patterns of dermatitis in cattle, to propose histologic pattern analysis as a diagnostic approach. Sixty-two cases of bovine dermatitis with confirmed etiologic diagnoses were selected in a 20-year retrospective study. The cases included 13 different primary and secondary diseases, ranging from infectious (48/62, 77%) to toxic/irritant-associated diseases (14/62, 23%). The cutaneous lesions were histologically classified into 11 dermatitis patterns, adapted from those described for small animals. Nodular to diffuse dermatitis (22/62, 34%), perivascular dermatitis (14/62, 23%), necrotizing dermatitis (11/62, 18%), and intraepidermal pustular dermatitis (10/62, 16%) were the most common patterns, followed by panniculitis (3/62, 5%); vasculitis (1/62, 2%); and perifolliculitis, folliculitis, or furunculosis (1/62, 2%). The nodular to diffuse, perivascular, necrotizing, and intraepidermal pustular dermatitis patterns included diseases with different etiologies, while the remaining patterns covered a smaller number of distinct cutaneous diseases in each classification. Our results highlighted the histologic analysis as an efficient tool for directing diagnoses, representing a starting point for the application of this technique in large animal dermatology.

Immunodeficient mice, particularly the NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ (NSG) strain and other non-obese diabetic (NOD)-derived lines are widely used in biomedical research due to their profound immunosuppression, which enables stable engraftment of human cells and tissues with minimal rejection. Despite their broad utility, these models exhibit unique immunologic and anatomic features and are predisposed to infectious and noninfectious diseases that may confound experimental outcomes and limit translational relevance. This review summarizes current knowledge on spontaneous, infectious, and experimentally induced lesions in NSG and related strains. These mice characteristically display hypoplastic lymphoid organs, including the spleen, thymus, and lymph nodes, due to a near-complete absence of lymphocytes. Spontaneous background lesions include splenic osseous metaplasia, neurodegeneration, pancreatic mastocytosis, cochlear degeneration, intervertebral disk disease, skull hyperostosis, and pancreatic duct cysts, among others. Common spontaneous neoplasms include lymphomas, osteosarcomas, and mammary gland tumors. Due to their immunodeficient status, NSG and NOD-derived mice are also highly susceptible to opportunistic infections, such as Corynebacterium bovis, Chlamydia muridarum, Clostridioides difficile, and mouse kidney parvovirus. In humanized models, engraftment of human immune cells can result in distinctive syndromes, including xenogeneic graft-versus-host disease, post-transplant lymphoproliferative disorders, and chimeric myeloid cell hyperactivation syndrome, which can impact study outcomes and lead to mortality and morbidity. This review is intended as a resource for comparative pathologists to become familiar with these widely used immunodeficient mice, so they can interpret strain-specific lesions and recognize experimental confounders in these mouse models.

Porcine circovirus 3 (PCV3) is a recently identified pathogen in swine populations. It is considered a ubiquitous virus and is frequently associated with subclinical infections throughout various stages of production. PCV3 is detectable in diverse tissues, blood, and secretions, indicating systemic dissemination and potential for both vertical and horizontal transmission. PCV3 has been implicated in reproductive and postnatal diseases collectively named as PCV3-associated diseases (PCV3-AD). Clinically, PCV3-AD encompasses reproductive disorders such as mummified fetuses, stillbirths, and weak neonates, alongside postnatal manifestations including anorexia, weight loss, and progressive wasting. Histopathologically, PCV3-AD is primarily defined by systemic nonsuppurative periarteritis and arteritis that are observed across multiple tissues, particularly within the heart, mesenteric arterial plexus, and kidneys. Despite the broad tissue tropism and frequent detection of viral nucleic acids within affected vascular and parenchymal structures, the precise mechanisms underpinning PCV3 pathogenesis remain poorly understood. Diagnosis of PCV3-AD relies on the confluence of characteristic clinical signs, compatible histopathological findings, and the in situ detection of the virus within lesions. However, the true prevalence of PCV3-AD under field conditions is likely underestimated due to the limited availability and high costs associated with laboratory techniques for definitive viral detection. This review seeks to consolidate and interpret clinical and pathological evidence indicative of PCV3-AD while addressing the critical diagnostic challenges faced by veterinary pathologists. Enhanced understanding of the disease's clinical-pathological correlations and diagnostic approaches is essential to accurately assess its impact on swine health and production.