History
A 15-week-old 14.1-kg (31-lb) male yellow Labrador Retriever was referred to the Neurology and Neurosurgery service at The Ohio State University because of dullness, lethargy, and a right-sided head tilt that progressively worsened over a period of several weeks.
Clinical and Gross Findings
Results of the clinical neurologic examination were consistent with a central vestibular lesion. Abnormalities included dull mentation, intermittent opisthotonic posture and lateral recumbency, absent menace response in both eyes, decreased oculocephalic reflex in both eyes, bilateral decreased nasal sensation, and spontaneous vertical nystagmus in both eyes. Magnetic resonance imaging of the brain revealed a large, well-demarcated, hetero-geneously hyperintense mass that appeared to be originating from the mesencephalon (midbrain) but extended caudally to the rostral portion of the medulla. This mass caused marked compression and displacement of the cerebellum caudally and the brainstem ventrally, leading to obstructive hydrocephalus and cerebellar herniation through the foramen magnum. The mass had minimal contrast enhancement on T1-weighted images (obtained after administration of contrast medium) and minimal edema on T2-weighted images. The dog's clinical signs did not improve with palliative corticosteroid treatment. Euthanasia by means of an IV pentobarbital overdose was elected by the owners, and a complete necropsy was performed immediately thereafter.
Gross postmortem lesions were confined to the brain. On removal of the dorsal portion of the calvarium, coning and protrusion of the caudal cerebellar vermis through the foramen magnum were observed, consistent with acute cerebellar herniation. On incision of the left parietal cerebral cortex, a large volume of CSF was expelled, revealing a thinned cerebral cortex that measured 5 to 7 mm in thickness from the lateral ventricle to the leptomeninges, interpreted as chronic hydrocephalus with cerebral cortical atrophy. The mesencephalon was markedly enlarged with disruption and effacement of the rostral and caudal colliculi. The dorsal surface of the mesencephalon was smooth and slightly discolored blue. The brain was fixed whole in neutral-buffered 10% formalin, then dissected into serial coronal sections 72 hours later. A large, tan to gray, multinodular mass was found originating from the mesencephalon slightly left of midline and extending through the mesencephalic aqueduct into the fourth ventricle, displacing and compressing the cerebellum and rostral portion of the medulla (Figure 1). Several large, confluent, slightly depressed areas of hemorrhage and necrosis were observed centrally within the mass.
Photograph of a large, well-demarcated, pale pink to gray, multinodular mass that is displacing and compressing the cerebellum and brainstem of a 15-week-old Labrador Retriever that was evaluated because of dullness, lethargy, and a right-sided head tilt that progressively worsened over a period of several weeks. The dog was euthanized and underwent necropsy. Notice the large, confluent areas of hemorrhage and coagulation necrosis within the mass. Scale = 1 cm.
Citation: Journal of the American Veterinary Medical Association 250, 1; 10.2460/javma.250.1.55
Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page →
Histopathologic Findings
Brain tissues were processed routinely, and sections were stained with H&E stain. The mesencephalic mass was consistent with a neoplasm that was densely cellular, expansile, unencapsulated, and well demarcated despite the presence of foci of invasiveness. There were multiple large, confluent areas of central coagulation necrosis, hemorrhage, and mineralization. The mass was comprised of a biphasic population of large, round to polygonal, undifferentiated cells arranged in solid sheets that were admixed with streams and bundles of palisading spindle-shaped cells (Figure 2). Round cells had distinct cytoplasmic margins; large, eccentric, round nuclei; and a small amount of eosinophilic cytoplasm. The spindle-shaped cells had indistinct cell borders, oblong to teardrop-shaped nuclei, and ample, streaming eosinophilic cytoplasm. Tumor cells compressed the fourth ventricle and focally disrupted the ependyma. Intraventricular growth of the neoplasm was observed caudal to the main body of the mass in discrete, subependymal foci, which was interpreted as intraventricular metastasis. No rosettes or tubules were observed. The mitotic index was high throughout the mass, with 91 mitotic figures/10 hpf (400X). Separately from the tumor, a focus of pan-necrosis of white matter was identified within the hippocampus. Immunohistochemical staining of the mass revealed expression of neuron-specific enolase, nestin, and β III tubulin in both the round and spindle-shaped cells (Figure 3). Vimentin expression was predominant in the spindle-shaped cell population. Throughout the neoplasm, there was low-level expression of S100 (Figure 3) and synaptophysin and no expression of glial fibrillary acidic protein (not shown).
Photomicrographs of sections of the mass (at the level of the mesencephalon) from the dog in Figure 1. A—The mass is multinodular, expansile, and invasive with central coagulation necrosis, hemorrhage, and mineralization. H&E stain; bar = 500 um. B—The neoplasm consists of a biphasic population of undifferentiated, round to polygonal cells intermixed with spindle-shaped cells. H&E stain; bar = 50 um. C—High-magnification view of the round to polygonal cells within the mass. H&E stain; bar = 20 um. D—High-magnification view of the spindle-shaped cells within the mass. H&E stain; bar = 20 um.
Citation: Journal of the American Veterinary Medical Association 250, 1; 10.2460/javma.250.1.55
Photomicrographs of sections of the mass after immunohistochemical staining. Neoplastic cells are positive for neuron-specific enolase (A), SI00 (B), nestin (C), and β III tubulin (D). Immunohistochemical stains specific for neuron-specific enolase, SI00, nestin, and β III tubulin in panels A, B, C, and D, respectively; bar in each panel = 20 μm.
Citation: Journal of the American Veterinary Medical Association 250, 1; 10.2460/javma.250.1.55
Morphologic Diagnosis and Case Summary
Morphologic diagnosis and case summary: primitive neuroectodermal tumor (PNET) of the mesencephalon and obstructive hydrocephalus in a juvenile dog.
Comments
Primitive neuroectodermal tumors are rare among domestic veterinary species, but young dogs and cattle appear to be the most frequently affected.1–4 Other veterinary species for which PNETs have been reported include nonhuman primates,5–7 cats,8 pigs,1 rats,1 horses,9 and some exotic species such as wild deer,10 a kowari,11 an umbrella cockatoo,12 a striped dolphin,13 and fish.14 When age is not a consideration, the most common primary intracalvarial, intra-axial tumors of dogs are astrocytomas, oligodendrogliomas, choroid plexus tumors, and lymphosar-comas.15 However, the incidence of all these tumors changes with age and in a dog 15 weeks of age (as was the dog of the present report), a PNET becomes a more likely differential diagnosis for primary intracranial neoplasia. Primitive neuroectodermal tumors can be most broadly defined as a heterogeneous group of tumors of embryonal neuroectodermal origin.16 Typically, PNETs develop in young adult (2- to 8-year-old) dogs.17 Other differential diagnoses for a focal, intracranial, space-occupying mass in young dogs include an abscess or granuloma, hematoma, or possibly congenital malformations (ie, cyst of the Rathke pouch or arachnoid cyst). Subclassifications of PNETs with a definitive anatomic location and his-togenesis include neuroblastoma, medulloblastoma, and thoracolumbar spinal cord tumors of young dogs.18 Primitive neuroectodermal tumors of the peripheral nervous system, bones, and soft tissues are also documented.18,19 In human and veterinary cases of medulloblastoma, obstructive hydrocephalus as a result of occlusion of the fourth ventricle has been reported.3,8 In the dog of the present report, blockage of the mesencephalic aqueduct and fourth ventricle by the tumor led to obstructed flow of CSF with subsequent enlargement of the lateral and third ventricles.
Primitive neuroectodermal tumors are thought to arise from primitive, multipotent neuroectodermal cells that may differentiate toward neuronal, glial, or ependymal lineages.18,20,21 Classic but inconsistently observed histologic features of PNETs include carrot-shaped cells with oblong nuclei that palisade and form rosettes and pseudorosettes.20 Immunohistochemical markers for canine PNETs include glial fibrillary acidic protein, neuron-specific enolase, neurofilament protein M, doublecortin, synaptophysin, neuronal nuclear antigen, nestin, vimentin, β III tubulin, and c-kit.15,22 Reactivity with these markers differs among dogs and may be variable within a single PNET, depending on the tumor cells’ lineage and degree of differentiation.1,19,22 Tumors with early neuronal differentiation are more likely to express doublecortin and β III tubulin markers, whereas in later stages of differentiation they gain neurofilament reactivity; tumors with differentiation toward glial precursors can be detected immunohistochemically with anti-nestin antibody.22 In the tumor of the dog of the present report, S100 reactivity was used to confirm its neural crest origin. Positive immuno-reactivity for neuron-specific enolase, nestin, and β III tubulin supported the presence of 2 lineages of cell differentiation, both neuronal and glial, with multiple stages of differentiation from each lineage within the PNET. Vimentin staining of the spindle-shaped cells in the dog's tumor was likely multifactorial, both representing areas of glial or ependymal differentiation among bundles of palisading tumor cells and separate foci of reactive changes (gliosis, angiogenesis, and fibrosis) at the margins of the tumor near areas of invasiveness or necrosis. The pathogenesis of PNETs is not completely understood. In the human medical literature, molecular diagnostic techniques have elucidated several subclassifications of embryonal tumors of the CNS, which have chromosomal mutations or dys-regulation of the v-myc avian myelo-cytomatosis viral oncogene homolog (MYC) or wingless signaling (WNT) pathways and are associated with different prognoses.23,24 Chromosomal genomic assays were not performed for the dog of the present report. Recent research into canine PNETs suggests that the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt (a serine-threonine kinase also known as protein kinase B) pathways may be involved in the development of these tumors.22 Further studies are needed to determine which similarities, if any, exist in the pathogenesis and prognostic indicators of human and canine PNETs. Taken together, the signalment of the dog of the present report, the gross appearance of the tumor, the histologic features of the neoplastic cells, and the immunohistochemical staining profile supported the diagnosis of a PNET.
Acknowledgments
The authors received no financial support for the research, authorship, or publication of this article. The authors declare there were no conflicts of interest with respect to the research, authorship, or publication of this article.
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