Spontaneous Acute Tumor Lysis Syndrome in a DBA/1J Mouse: A Case Report and Review

Abstract

Spontaneous acute tumor lysis syndrome (ATLS) was diagnosed in a 10-month-old female DBA/1J sentinel mouse with leukemic lymphoma. The mouse was unable to maintain balance and died shortly after being observed rolling around in its cage. Disseminated neoplastic disease, including a large cranial mediastinal mass, enlarged lymph nodes and splenomegaly, was present at necropsy. Histopathologic examination revealed widespread massive necrosis of lymphoblastic tumor cells, and widely disseminated microemboli composed of nuclear and cytoplasmic cell debris. Although ATLS is widely recognized as an oncologic emergency in humans, acute lesions of ATLS have not been described. The mechanical obstruction of capillary beds by microemboli originating from disintegrating necrotic tumor cells was the likely cause of clinical signs and death in this mouse. We propose that similar microemboli may contribute to the pathogenesis of the acute renal failure and other clinical signs associated with ATLS in humans. Recognition of spontaneous ATLS in laboratory animals is especially important in studies that assess the efficacy and/or toxicity of anticancer treatments, where early deaths due to ATLS might mistakenly be attributed to a direct test article effect.

Case Series

“…Lovelace et al suggested that microthrombi in organs such as the lung or brain may be reflected clinically by the increased respiratory rate or neurological signs they observed in their mouse (Lovelace et al 2003). Consistent with this hypothesis, we observed parenchymal damage associated with vascular microthromboemboli within the brain, liver, lung, and kidney (Figure 2).…”

“…Acute tumor lysis syndrome cases were identified by the presence of microthromboemboli, lesions similar to those described previously in single case reports (Lovelace et al 2003;Radaelli et al 2009). All cases in our series were found in mutator mice with disseminated lymphoblastic lymphoma, primarily of T-cell origin.…”

“…Most cohorts exhibited a high susceptibility to cancer and accelerated mortality compared to wild-type animals. During these survival studies, we noted a high incidence of spontaneous death in mice with disseminated lymphoblastic lymphoma and histopathologic lesions consistent with ATLS (Lovelace et al 2003). To define the overall incidence of ATLS and further characterize the associated pathologic lesions, we analyzed necropsy and histology data from seventeen cohorts of mutator mice that were at increased risk of developing lymphoblastic lymphoma.…”

“…Acute tumor lysis syndrome was defined histologically as the presence of microthromboemboli composed of neoplastic cells admixed with abundant dark, basophilic acellular material (Lovelace et al 2003). These lesions were observed in diverse tissues, including the lung (94%), kidney (61%), liver (23%), brain (16%), and spleen (16%) of affected mice (Supplemental Table 1).…”

“…A single series of three canine ATLS cases revealed generalized microthrombi in the necropsy specimens of two dogs (Laing and Carter 1988). Additionally, Lovelace et al describe a single DBA mouse with lymphoblastic lymphoma that exhibited neurologic symptoms associated with multifocal vascular thrombi throughout all tissues; special stains and electron microscopy suggested the microthrombi were composed of DNA and fragmented cellular components, consistent with debris from tumor cell lysis (Lovelace et al 2003). The authors proposed that symptoms in this mouse may have been secondary to ischemia from mechanical obstruction of the vasculature by thromboemboli.…”