Spectrum of Posttransplant Lymphoproliferations in NSG Mice and Their Association With EBV Infection After Engraftment of Pediatric Solid Tumors.

Pediatric patients receiving solid organ transplants may develop lymphoproliferative diseases, including graft-versus-host disease (GvHD) and posttransplant lymphoproliferative diseases (PTLDs). We characterized lesions in 11 clinically ill NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice that received pediatric-patient-derived solid tumors (PDXs) and developed immunodeficiency-associated lymphoproliferations comparable to GvHD and PTLDs over a period of 46 to 283 days after implantation. Lymphoproliferations were diffusely positive for human-specific biomarkers, including NUMA1, CD45, and CD43, but lacked immunoreactivity for murine CD45. Human immune cells were CD3-positive, with subsets having immunoreactivity for CD4 and CD8 as well as PAX5, CD79a, and IRF4, resulting from populations of human T and B cells present within the xenotransplants. Tissues and organs infiltrated included mucocutaneous zones (oral cavity and perigenital and perianal regions), haired skin, tongue, esophagus, forestomach, thyroid, salivary glands, lungs, liver, kidneys, spleen, lymph nodes, bone marrow, and brain. In 4 of 5 mice with PTLD, Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) were detected by in situ hybridization in PAX5+ human B cells associated with the PDX (n = 1/4) or with engrafted human immune cells at other anatomic locations (n = 4/11). One of the 4 mice had an EBV-associated human large B-cell lymphoma. NSG mice receiving xenotransplants can develop combinations of GvHD, EBV-driven PTLD, and B-cell lymphoma similar to those occurring in human pediatric patients. Therefore, pediatric xenotransplants should undergo histopathologic and immunohistochemical assessment upon collection to ensure that the specimen is not a lymphoma and does not contain lymphoma cells because these neoplasms can morphologically mimic small round blue cell pediatric solid tumors.

Spontaneous uterine leiomyosarcoma in a rhesus macaque.

A 12-year-old female Rhesus macaque (Macaca mulatta) presented with a uterine enlargement during physical exam. Exploratory celiotomy revealed an intrauterine mass that extended into the cervix. A cystic lesion surrounded and enveloped the left ovary. Because of numerous adhesions and the size of the mass, the animal was euthanized. Microscopically, the neoplasia showed small to medium-sized spindle-shaped cells which formed bundles. The cells resembled smooth muscle, with elongated nuclei, indistinct nucleoli, and scant to moderate quantities of eosinophilic cytoplasm. Mitotic activity was low (0 to 2 mitotic figures/high-power field). Immunohistochemistry revealed that the cells stained for smooth muscle actin. In light of the biological activity (locally invasive) and immunohistochemical findings, a diagnosis of leiomyosarcoma of the myometrium was made. Grossly and histologically, uterine leiomyosarcoma can resemble uterine leiomyoma. Although uterine leiomyosarcoma represents a small percentage of uterine tumors, it should always be considered as a rule out for uterine leiomyoma (fibroids).

Chronic restraint via tail immobilization of mice: effects on corticosterone levels and other physiologic indices of stress.

Chronic venous cannulation in mice is an acceptable and useful technique for repeated blood sampling or continuous intravenous administration of substances, for which mild restraint of the animal may be necessary. Because chronic restraint has drawn considerable attention in the animal welfare community, the purpose of this study was to evaluate physiologic indices of stress in mice restrained by using an established tail restraint method. Serum corticosterone levels and body, thymus, adrenal, and spleen weights on days 2, 5, 8, and 12 were compared between tail-restrained and unrestrained mice. There were no significant differences between the two groups at the time points evaluated. Corticosterone levels were highest on day 8 for both groups and were significantly different from those on days 2 (P<0.009) and 5 (P<0.04) for restrained mice and on day 2 (P<0.02) for unrestrained mice. Levels in both groups declined by day 12, suggesting habitation. Weight loss was observed in all mice whether restrained or unrestrained. Significant differences in body, thymus, adrenal, and spleen weights were not evident between restrained and unrestrained mice. This study provides important information for balancing issues of prolonged restraint, animal well-being, and research goals.