Patient presented with a 2 week history of inappropriate mentation that became progressively worse in the last few days. Owners described episodes where dog would stand in a corner and seemed mentally unaware. It was noted the dog would often pace and pant excessively and was sleeping more than usual. The patient had a poor appetite and was losing weight over the past weeks.
Physical Exam: The dog’s body condition score was 2.5/5. TPR was normal except for panting. The dog was ambulatory with a mild pelvic limb ataxia. A slight decrease in conscious proprioception was detected in both pelvic limbs and the left thoracic limb. Mentation was dull. Spinal reflexes were normal. No other neurologic deficits were present. Neuroanatomical localization was judged to be right-sided supratentorial.
Diagnostics: Abnormalities on CBC/Serum Chemistry included decrease in lymphocytes at 0.83 x 103/ul (0.9-4.0 x 103/ul normal range), RBC at 5.18 x 106/ul (5.2-8.4 x 106/ul normal range), hemoglobin at 11.7 g/dL (12-20 g/dL normal range), PCV at 34% (36-56% normal range), platelets at 104 x 103 (160-500 x 103 normal range), total protein at 4.5 mg/dL (5.5-7.5 mg/dL normal range) and albumin at 2.0 mg/dL (2.9-3.8 mg/dL normal range). Urinalysis was within normal range. Thoracic radiography 3 weeks prior was normal.
MRI of the brain and cervical spine was performed (see images).
Brain and Cervical Spine MRI: Multiplanar images of the brain pre and post-contrast administration (5 cc Magnevist intravenous bolus) as well as multiplanar images of the cervical spine pre-contrast are available for review.
Brain: An ill-defined area of FLAIR hyperintensity is present in the right dorsal caudal cerebral cortex in the parietal lobe. On the proton density sequence there is a subtle loss of distinction between the grey and white matter in this region. A small linear focus of T1 hypointensity and T2 hyperintensity, that remains hyperintense on the FLAIR sequence, is present in the region within the right side of the thalamus/interthalamic adhesion. The initial T1w post-contrast enhancement scan was acquired approximately 5 minutes following bolus gadolinium administration with the phase encoding direction in the left-to-right direction. There was no appreciable abnormal enhancement, however there was heterogeneous signal superimposed over the region of the brain stem. Consequently, a second T1w post-contrast enhancement scan was obtained 25 minutes post gadolinium administration with the frequency and phase encoding directions flipped. On the delayed T1w images a small triangular area of abnormal contrast enhancement is present. There is meningeal enhancement along the dorsal aspect of the right olfactory lobe also evident. There were the incidental findings of slight thickening of the falx cerebri and mild asymmetry of the medial retropharyngeal lymph nodes.
Cervical Spine: There is protrusion of the degenerative intervertebral disc at C5-6 with mild extradural compression of the ventral spinal cord however the dorsal subarachnoid space is maintained. Mild protrusions of the discs between C2-3, C3-4, and C4-5 are present with no significant compression of the spinal cord in these locations. The signal within the spinal cord parenchyma is normal. T2 hypointense proliferation is present on the ventral aspect of the caudal border of C5 and the cranial border of C6, consistent with spondylosis. The nucleus pulposus of the intervertebral discs throughout the cervical spine have varying degrees of T2 hypointensity features, consistent with degeneration and dessication. Linear hyperintensity was present in the right longus colli muscle adjacent to C2-3.
Brain: Based on the multifocal, delayed-enhancing lesions within the brain in this older patient, possible etiologies considered were infectious/inflammatory, neoplastic, or vascular in nature. CSF collection and analysis was advised.
Cervical Spine: Disc protrusion with mild ventral spinal cord compression and spondylosis deformans at C5-6, with multiple sites of degenerative discs without spinal cord compromise. Focal unilateral longus colli muscle inflammation of unknown etiology.
Following the MR examination, CSF was collected via AO puncture. CSF analysis yielded a nucleated cell count of 27 cells/uL (<5 cells/uL normal), 0 RBCs/uL, microprotein of 19.8 mg/dL (<25 mg/dL normal). Cytospin preparation resulted in a nucleated cell count of 52% unclassified cells and 48% large mononuclear cells (macrophages/CNS lining cells). Rare erythrocytes were noted and no infectious agents were apparent. The unclassified cells had basophilic cytoplasm and their nuclei were irregular with smooth to very fine stippled chromatin pattern containing 0-2 nucleoli.
The CSF interpretation was mild mononuclear pleocytosis characterized by predominantly unclassified cells, which exhibited features most consistent with lymphoid cells. Causes for a mononuclear or lymphoid pleocytosis include infection (viral, bacterial, fungal, protozoal, parasitic or rickettsial), necrotizing encephalitis, GME or neoplasia. A PCR for antigen receptor rearrangement (PARR) test of the CSF and peripheral blood for clonality for confirmation of lymphoma was advised.
Toxoplasma and Neospora titers were negative. Bacteriology using aerobic and anaerobic cultures were both negative. PCR for antigen receptor on the peripheral blood was negative; however PARR on the CSF sample was positive for T-cell lymphoma. Repeated testing of another CSF sample one week later was also positive showing clear evidence of the T-cell lymphoma, considered 94% specific for lymphoma. There was no evidence of this clonal population in the peripheral blood, leading to the diagnosis of intravascular lymphoma.
Intravascular lymphoma (IVL) is a rare form of neoplasia. The literature has limited reports in dogs (1-5) and a single report in a cat.(6) In veterinary medicine the condition has been previously termed malignant angioendotheliomatosis, angiotrophic lymphoma or intravascular lymphoma.(5) In humans, historical names for intravascular lymphoma have included angioendotheliomatosis proliferans systemica, malignant angioendotheliomatosis, intravascular lymphomatosis, angio-endotheliotrphic (intravascular) lymphoma, angiotrophic large cell lymphoma and diffuse large B-cell lymphoma. The B-cell immunophenotype is the most common form in humans, although cases with T-cell receptor rearrangements have been reported.(7) First described in humans in 1959, it was not until the 1980’s that immunophenotyping demonstrated the neoplastic cell origin is the lymphocyte and not the vascular endothelial cell.(8) The unique presentation is characterized by the proliferation of clonal lymphocytes within small vessels with relative sparing of the surrounding tissue. The clinical symptoms of the disease are dependent on the specific organ involvement, which most often includes the central nervous system and skin. Beyond these presentations, there are single case reports of IVL presenting in almost every organ system. It is uncommon to find significant adenopathy, hepatosplenomeagly or circulating cells in the peripheral blood. This absence of IVL in the traditional sites of manifestations of lymphoma makes accurate and timely diagnosis difficult.(7)
In humans computed tomography imaging has been normal or shown cortical atrophy and areas of low attenuation,(9) and MR imaging, combined with immunoglobulin heavy chain rearrangement analysis is considered more sensitive.(10) Characteristic MRI findings in humans include 1) multifocal lesions on DWI in association with T2 abnormalities, confirming the diagnosis of ischemia or infarction; 2) a dynamic pattern of MR lesions with resolution of some DWI or T2 lesions and the emergence of others; and 3) gadolinium enhancement appearing in proximity to the T2 or DWI changes, persisting or enlarging over weeks to months.(10) In dogs, MR is the preferred modality for ante mortem diagnosis, with lesions most conspicuous on FLAIR imaging.(5)
The imaging features in this case are similar to a case report in a dog by Kent, et al, (2001), with the exception that the lesions were not hyperintense on the T1w pre-contrast sequence. The reported T1w pre-contrast hyperintensity may be related to increased protein content from neuronal necrosis. Notably, the contrast enhancement of the lesions in this case were not evident on the initial acquisition 5 minutes after gadolinium bolus administration, but became apparent after 10-25 minutes had passed. The benefits of time delayed gadolinium-enhanced imaging of the meninges and normal brain in dogs has recently been reported.(11,12) The heterogeneous ill-defined signal detected over the brainstem on the initial T1w post-contrast sequence (Seq. 1401), was confirmed to be flow artifact by flipping the phase and frequency-encoding directions on the repeated acquisition (Seq. 1701).
Differential diagnosis for the MR findings would include neoplasia, vascular compromise and infection/inflammation. The utility of PCR for antigen receptor rearrangement (PARR) in diagnosing, staging and predicting prognosis in canine lymphoma has been reported.(13,14) Random skin biopsies have been helpful in the ante mortem diagnosis in human cases,(7) but the usefulness of this technique is unknown in veterinary patients. The definitive diagnosis of IVL may require post mortem histology with immunophenotyping. Most cases of IVL are associated with a poor prognosis and should be treated systemically with anthracycline-based regimen for aggressive non-Hodgkin’s lymphoma. Intrathecal or high dose systemic methotrexate has been advised if there is evidence of the disease within the CSF.(7)
- Summers BA, deLahunta A. Cerebral angioendothelialiomatosis in a dog. Acta Neuropathol (Berl) 1985;68:10-14.
- Dargent FJ, Fox LE, Anderson WI. Neoplastic angioendothelialiomatosis in a dog; an angiotrophic lymphoma. Cornell Vet 1988;78:253-262.
- Kilrain CG, Saik JE, Jeglum KA. Malignant angioendoentheliomatosis with retinal detachments in a dog. J Am Vet Med Assoc 1994;204:918-921.
- McDonough S, Summers B, VanWinkle T, et al. Immunophenotypic Hetereogeneity of canine intravascular lymphoma (Malignant Angioendotheliomatosis). Vet Pathol 1998;35:438.
- Kent M, deLahunta A, Tidwell AS. MR imaging findings in a dog with intravascular lymphoma in the brain. Vet Radiol Ultrasound 2001;42:504-510.
- Lapointe JM, Higgins RJ, Kortz GD, et al. Intravascular malignant T-cell lymphoma (malignant angioendotheliomatosis) in a cat. Vet Pathol 1997;34:247-250.
- Zuckerman D, Saliem R, Hochberg E. Intravascular lymphoma: the oncologist’s “great imitator” The Oncol 2006;11:496-502.
- Sheibani K, Battifora H, Winberg CD, et al. Further evidence that “malignant angioendotheliomatosis” is an angiotrophic large-cell lymphoma. N Engl J Med 1986;314:943-948.
- Knight RS, Anslow P, Theaker JM. Neoplastic angioendotheliomatosis: a case of subacute dementia with unusual cerebral CT appearances and a review of the literature. J Neurol Neurosurg Psychiatry 1987;50:1022-1028.
- Baehring JM, Longtine J, Hochberg FH. New approach to the diagnosis and treatment of intravascular lymphoma. J Neurooncol 2003;61:237-248.
- D’Anjou M-A, Carmel EN, Blond L, et al. Effect of acquisition time and chemical fat suppression on meningeal enhancement on MR imaging in dogs. Vet Radiol Ultrasound 2011;53:11-20.
- Joslyn S, Sullivan M, Novellas R, et al. Effect of delayed acquisition times on gadolinium-enhanced magnetic resonance imaging of the presumably normal canine brain. Vet Radiol Ultrasound 2011;52:611-618.
- Lana SE, Jackson TL, Burnett RC, et al. The utility of PCR for antigen receptor rearrangement (PARR) in staging and predicting prognosis in canine lymphoma. Vet Comp Onco 2005;3:40-41.
- Lana SE, Jackson RC, Burnett RC, et al. Utility of polymerase chain reaction for analysis of antigen receptor rearrangement in staging and predicting prognosis in dogs with lymphoma. JAVMA 2006;20:329-334.