9-year-old female spayed Pomeranian dog, (Canis familiars).This dog presented to the North Carolina State University College of Veterinary Medicine (NCSU-CVM) Neurology service in July 2010 for further evaluation of a two-week history of a head tilt.

Gross Description:  

In the subdural region of both cerebral hemispheres, the leptomeninges appear cloudy and multifocally contain a moderate hemorrhage in the form of petechiae and ecchymoses.

There are two sharp lines of demarcation, one that is noted at the beginning of the duodenum near the termination of the pylorus, and the other line is noted near the beginning of the jejunum. That area, which encompasses the duodenum, measures 15 cm in length, is diffusely dark red to black, and on cut surface, there is diffuse serial and mucosal hemorrhage. The jejunum, ileum, cecum, and colon contain multifocal dark red hemorrhagic areas on the serosa that measure 1.0 cm to 2.0 cm in diameter and contain a moderate amount of hemorrhagic luminal content.

Histopathologic Description:

Cerebrum: Multifocally, variably sized blood vessels within the parenchymal and meningeal layer contain neoplastic round cells. Neoplastic cells have large, round to oval nuclei, abundant coarsely clumped chromatin, sparse to moderate lightly basophilic cytoplasm, and 1-2 nucleoli. There is marked anisocytosis and ansiokaryosis and occasionally cells appear binucleated. Mitotic figures are occasionally seen. Multifocally, vessels that contain neoplastic cells also are partially occluded by fibrin thrombi that are composed of brightly eosinophilic, homogenous to beaded material and are admixed with scattered pyknotic and karyorrhectic cellular debris. Fibrin and necrotic cell debris multifocally expands and replaces the walls of scattered vessel profiles. Multifocally, expanding the meninges is a moderate cellular infiltrate that consists predominantly of lymphocytes, plasma cells, and macrophages. Multifocally, within the white matter, there are small aggregates of gitter cells. Multifocally, within the gray matter, there is a mild amount of vacuolation and a moderate amount of hemorrhage. Multifocally, admixed with the cellular infiltrate in the meninges is a moderate amount of hemosiderin laden macrophages and bright, yellow pigment consistent with hematoidin.

Additional findings (not included in slide set): The same neoplastic population of cells was seen within vascular lumens in the following organs: cervical and thoracic spinal cord, left and right bulla, liver, spleen, lung, lymph node, adrenal glands, and duodenum. Other histological findings in this animal included: moderate lymphoplasmacytic and neutrophilic cellular infiltrate within the epithelium of the middle ear of the left bulla; diffuse submucosal hemorrhage in the right bulla; diffuse hemorrhagic pancreatic necrosis; transmural duodenal hemorrhage, and multifocal mucosal hemorrhage in the remainder of the intestinal tract.

Morphologic Diagnosis:  

Brain with systemic organ involvement: intravascular lymphoma with multifocal vascular thrombosis.

Lab Results:  

CBC: mildly decreased hemoglobin (11.7 g/dl, reference range: 12.1-20.3 g/dl) and mild thrombocytopenia (99 x 103/UL, reference range 170-400 x103/UL).

Blood smear: unremarkable.

The neurological exam findings included the following: depressed, dull mental status; right sided head tilt and circling to the right; mild amount of pain elicited on palpation of cranial cervical region; no vestibulo-ocular response present; positional ventral strabismus OD; and anisocoria (L>R). Lesion localization was central vestibular disease (vestibular signs with altered mentation).

Tick panel, 4 DX (Ehrlichia, Anaplasma, Heartworm, Lyme), and Cryptococcus antibody: all negative.

MRI: multifocal regions of parenchymal T2 hyperintensity and increased meningeal enhancement with evidence of parenchymal hemorrhage consistent with a severe meningoencephalitis, and focal regions of compensatory hydrocephalus consistent with prior parenchymal necrosis, and left otitis media.

CSF analysis: mononuclear pleocytosis (NCC19). Otic cytology: septic suppurative inflammation. Otic culture: Staphylococcus pseudintermedius.

CD3 and CD79a immunohistochemical stains were applied to the tissue sections of cerebrum. The positive controls worked well and internal control lymphocytes were positive. CD3 immunostain revealed minimal to mild, occasional membrane staining of individual neoplastic cells within vessels. The CD79a immunostain was negative.

PARR (PCR for antigen receptor rearrangement) results for cerebrum: TCRγ PARR produced a crisp band in duplicate of the appropriate size that persisted upon heteroduplex analysis. BCR PARR was negative. PARR interpretation: These results should raise your suspicion of T cell neoplasia.


Intravascular lymphoma (malignant angioendotheliomatosis)

Contributor Comment:  

The histological findings and special testing in this case are most consistent with intravascular lymphoma (IVL), also known as malignant angioendotheliomatosis, intravascular lymphomatosis, and angiotropic large-cell lymphoma.(3) This neoplasm is defined by a proliferation of neoplastic lymphocytes within vessels of organs with a lack of a primary extravascular neoplasm or circulating neoplastic cells or leukemia.(3) The location of the neoplastic cells causes secondary occlusion of the vessel, which then can lead to thrombosis, hemorrhage, and infarction,(2) as in this case. In order to distinguish IVL from disseminated lymphoma and leukemia, one publication suggests that the following criteria can be used: inability to locate neoplastic cells in blood smears, lack of a primary extravascular mass, and absence of bone marrow involvement,4 which were all consistent findings in this case. The neoplasm is predominantly of Tlymphocyte origin in dogs.(3)

Although this neoplasm is rare, the disease in dogs has been reported to have a predilection for CNS, lung, and less commonly skin.(3,4) One retrospective review of cases of canine IVL found that the most common clinical presentation in dogs included spinal cord ataxia, seizures, vestibular disease, and posterior paralysis.(4) The laboratory findings (CBC, chemistry panel) in the dogs in this study, as well as the dog in this case, were non-specific. Intravascular lymphoma appeared to affect mostly large breed dogs with an average age of six years.(4) The diagnosis of IVL is predominantly a postmortem diagnosis; however, there is one report of an antemortem diagnosis achieved by CT-guided biopsy of a brain lesion.(2) Intravascular lymphoma is typically rapidly progressive; death is reported to occur from 20 days to six months after the first reported clinical signs.(2)

Although the reason for the tendency of neoplastic cells to remain within vessels has not been definitively proven in dogs, several human studies have demonstrated an absence of leukocyte adhesion molecules such as CD11a/CD185,7 and CD29,6 in neoplastic cells. Based on the findings, it was hypothesized that due to the lack of adhesion molecules, the neoplastic cells could not extravasate.

JPC Diagnosis:  

1. Cerebrum: Intravascular lymphoma.
2. Midbrain, gray matter and meninges: Vascular necrosis and thrombosis, multifocal, severe with infarction.

Conference Comment:  

In human intravascular lymphoma, which is usually of B-cell origin, several studies have demonstrated β 1 (CD29) or β2-integrin (CD18) deficiencies.(4,5) β-integrins are important in the leukocyte adhesion cascade, enabling leukocytes to exit blood vessels and migrate through tissue in order to participate in inflammation. Once activated, all stages of the leukocyte adhesion cascade (i.e., margination, rolling, stable adhesion, locomotion and transmigration) occur concurrently. Initial vasodilation leads to decreased hydrostatic pressure and a slowing of blood flow. Leukocytes exit laminar flow due to decreased vessel wall shear stress, and move toward the endothelial cell surface (margination). Initial rolling is mediated by selectins; low affinity binding between selectins and their receptors allows leukocytes to roll along the endothelium. Leukocytes in some species express L-selectin, which binds to GlyCam-1/CD34 and MadCAM-1on endothelial cells; P-selectin glycoprotein ligand-1 (PSGL-1) which is a sLe-X glycoprotein that binds to Pselectin released from endothelial Weibel-Palade bodies; and a sLe-X type protein receptor which binds E-selectin expressed by endothelial cells (Table 1). Expression of adhesion molecules is enhanced by inflammatory mediators released from mast cells, endothelial cells and macrophages in response to infection or injury. For instance, TNF and IL-1 induce endothelial cells of post-capillary venules to express Eselectin and ligands for L-selectin, while histamine, thrombin and platelet activating factor stimulate the release of P-selectin from storage within the Weibel-Palade bodies of endothelial cells.(1)

Integrins mediate stable adhesion, which must be preceded by activation, margination and rolling. Leukocytes that normally express integrins in low affinity state are activated by chemokines, while L-selectins are cleaved from the neutrophil surface by A Disintegrin and Metalloproteinase 17 (ADAM17). This results in the conversion of β1integrins, such as VLA-4 (α4β1, CD49d/CD29), and β 2integrins, such as LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18, CR3), gp150, 95 (CD11c/CD18, CR4) and αdβ2 (CD11d/CD18) to a high affinity state. Inflammatory mediators also induce endothelial expression of ligands for β1/β2-integrins. These ligands generally belong to the immunoglobulin superfamily. Most β2-integrins on appropriately stimulated leukocytes firmly adhere to ICAM-1 (CD-54) on endothelial cell; αdβ2, on the other hand, binds ICAM-3. Alternatively, β 1integrins on lymphocytes, monocytes and high endothelial venules (HEVs) bind VCAM-1 on endothelial cells (Table 1).(1)

During transmigration, leukocytes emigrate between endothelial cells, primarily at intercellular junctions in post-capillary venues. This is mediated by adhesion molecules, which vary slightly depending on the leukocyte and tissue type. PECAM-1 (CD31) and CD99 on leukocytes bind homotypically to PECAM-1 and CD99, respectively on endothelial cells. Additionally, leukocyte junctional adhesion molecules JAM-A and JAM-B can bind to JAMA and JAM-C at endothelial cell junctions. Leukocyte integrins also play a role in transmigration. Leukocytes extend pseudopodia between endothelial cells to interact with basement membrane laminins and collagen as well as extracellular matrix proteins such as proteoglycans, fibronectin and vitronectin. Leukocyte binding to these proteins, primarily via β1-integrins, enables leukocytes to transmigrate into perivascular tissue, from which they can migrate along chemotactic gradients toward the area of injury. Whether endogenous (e.g., cytokines, C5a, arachidonic acid metabolites) or exogenous (e.g., bacterial) substances, chemotactic agents bind to specific G-protein coupled receptors and activate second messengers, which induces actin polymerization and allows filopodia to pull the cell into the area of inflammation. In connective tissue, leukocytes can adhere to the extracellular matrix and advance via β1-integrins (Table 2).(1)

Deficiencies in β1 (CD29) or β2-integrins (CD18) have been reported in the neoplastic cells in human intravascular lymphoma. Although other defects are likely involved as well, this lack of leukocyte adhesion molecules may render neoplastic lymphocytes unable to successfully exit the blood vessel, resulting in the intravascular cellular accumulation characteristically noted in this neoplasm. A similar leukocyte adhesion deficiency has not yet been demonstrated in canine intravascular lymphoma, and its molecular basis remains unknown.(4,5,6)

Table 1: Select endothelial cell and leukocyte adhesion molecules1
Endothelial MoleculeLeukocyte ReceptorMajor Role
P-selectinPSGL-1 (a Sialyl-Lewis-X glycoprotein)Rolling (neutrophils,monocytes, lymphocytes)
E-selectinESL-1 (a Sialyl-Lewis-X glycoprotein); Sialyl-Lewis A glycoproteinSlow rolling, adhesion to active endothelium (neutrophils, monocytes, Tcells)
Important in homing of effector & memory T-cells, especially to skin
ICAM-1β2-integrins: LFA-1 (CD11a/CD18), Mac-1 (CR3; CD11b/CD18); gp150,95 (CR4; CD11c/CD18)Adhesion, stable adhesion, transmigration (all leukocytes)
VCAM-1β1-integrins: VLA-4 (α4β1; CD49d/CD29), LPAM-1 (α4β7)Adhesion (eosinophils, monocytes, lymphocytes) VLA-4 mediates homing of lymphocytes to endothelium at peripheral sites of inflammation
L-selectinRolling; lymphocyte homing to high endothelial venules (HEV)
Also serves to bind neutrophils to activated endothelium
PECAM (CD31)Transmigration; Leukocyte migration through endothelium
JAM-AJAM-A, LFA-1Transmigration
JAM-CJAM-B, Mac-1Transmigration

Table 2: Select leukocyte integrins and extracellular matrix components involved in leukocyte chemotaxis1
Leukocyte IntegrinECM Component
VLA-1, 2Collagen
VLA-3, 5Fibronectin


1. Ackermann MR. Inflammation and healing. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO: Elsevier; 2012:96-98.

2. Bush WW, Throop JL, McManus PM, et al. Intravascular lymphoma involving the central and peripheral nervous systems in a dog. J Am Anim Hosp Assoc. 2003;39(1):90-96.

3. Ginn PE, Mansell JEKL, Rakich PM. Skin and appendages. In: Maxie, MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. 5th ed. Vol. 1. Philadelphia, PA: Elsevier; 2007:775.

4. McDonough SP, Van Winkle TJ, Valentine BA, et al . Clinicopathological and immunophenotypical features of canine intravascular lymphoma (Malignant Angioendotheliomastosis). J Comp Pathol. 2002;126(4):277-288.

5. Ossege LM, Postler E, Pleger B, et al. Neoplastic cells in the cerebrospinal fluid in intravascular lymphomatosis. J Neurol. 2000;48 (8):656-658.

6. Ponzoni M, Ferreri AJM. Intravascular lymphoma: a neoplasm of homeless lymphocytes? Hematol Oncol. 2006;24(3): 105-112.

7. Valli VEO. Hematopoietic system. In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. 5th ed. Vol. 3. Philadelphia, PA: Elsevier;2007:183.

Click the slide to view.

2-1. Cerebrum at level of hippocampus

2-2. Cerebrum at level of hippocampus

2-3. Cerebrum at level of hippocampus

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