2017 NPA-07

This case was originally published in 2017. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

At age 20, the patient was diagnosed with aplastic anemia. He was subsequently treated with myeloablative therapy and allogeneic stem cell transplantation. Over the next five years, he experienced multiple flairs of chronic graft-versus-host disease (GVHD) that was treated by immunosuppression. Two years prior to this admission, an MRI depicted a confluent abnormal high T2-prolongation throughout the cerebral white matter, including the caudate, posterior limbs of the internal capsules, thalami, middle cerebral peduncle, and pons. At the current admission, he complained of a worsening headache, numbness and occasional pain in all of his extremities and intermittent dizziness. An MRI showed a new signal abnormality of uncertain nature in the left insula, in addition to the white matter abnormalities that had been present for years (Image A and Image B). His vital signs were normal, he was afebrile, but physical examination revealed decreased visual acuity and some leg weakness (R>L). A cerebral angiogram was interpreted as normal. The CSF was clear and colorless with a normal glucose and protein content and it contained 4 nucleated cells. Needle biopsies of left insula were obtained.

Tissue Site
Left insular cortex and white matter

The whole slide image provided is an H&E stain from a brain needle biopsy.

The best diagnosis is CNS angiitis associated with GVHD. This rare condition typically occurs years after an allogeneic bone marrow or stem cell transplantation. Patients may develop focal neurological deficits, seizures, cognitive abnormalities, and/or coma. MRI studies can show generalized brain atrophy, hyperintense cortical or subcortical lesions (Image A), leukoencephalopathy (Image B), and/or ischemic lesions. There is no single or pathognomonic alteration permitting diagnosis based on clinical presentation or imaging studies alone.

The histopathology usually shows a microangiitis; less frequently, medium sized vessels can be involved. Lymphocytes and mononuclear cells aggregate around and within the walls of small parenchymal vessels (Image C, Image D, Image E, and Image F). The lymphocytes are a mixture of CD4 and CD8 types (Image G and Image H) with a lesser population of CD68-positive mononuclear cells. The involved blood vessels may show necrosis and occlusion of the lumen (Image D, Image E, and Image F). Neutrophils, plasma cells, giant cells and atypical lymphocytic forms are absent. The infiltrating cells are negative for CD20 (a marker of B-cells) and EBV (Image I and Image J), in contrast to what is seen in post-transplant lymphoproliferative disorder (PTLD). There is little infiltration of the CNS parenchyma by leukocytes, although astrocytic and microglial activation may be extensive. The pathogenesis of the lesion is due to an attack by donor-derived lymphocytes on microglia and perivascular monocytic cells expressing the host’s MHC molecules.

The differential diagnoses of vasocentric, leukocytic infiltrates in the CNS parenchyma is very broad. It includes a spectrum of viral and other infections, neoplastic lymphocytic disorders, and various primary angiopathic processes. Viral diseases are typically rapidly progressive, associated with constitutional symptoms, and produce parenchymal damage and cytopathic effects. These features were absent in this case. Primary CNS lymphoma (PCNSL) exhibits the accumulation of morphologically atypical, enlarged B-lymphocytic forms which are most frequently CD20-positive. Both temporal arteritis/giant cell arteritis and polyarteritis nodosa involve medium to small muscular arteries, not non-muscular microscopic vessels. Moreover, these conditions are associated with giant cell formation in the former and extensive neutrophilic infiltration of the vessel wall in the latter.

Post-transplant lymphoproliferative disorder (PTLD) is a disease class that is critical in the differential diagnosis. PTLDs are infrequent neoplastic processes that may involve the CNS that can follow solid organ, bone marrow, or stem cell transplantation and chronic immunosuppression. The neoplastic elements are most frequently CD20-positive B-cells. EBV positivity of the infiltrating cells is found in over 70 percent of the cases. The lesion can be morphologically identical to PCNSL, or it can be a polymorphic infiltrate with an admixture of leukocyte types as well as the enlarged, atypical CD20-positive cells.

Recognizing the clinical setting is essential in reaching a diagnosis in such cases. The fact that the patient was known to have chronic GVHD was relevant. Key histopathological questions that help narrow the differential include the following:

• Are the perivascular lymphocytes of normal or atypical morphology?
• Are the infiltrating cells positive for CD20 or EBV?
• Are the infiltrating cells clonal or a heterogeneous mix of cell types?
• Are the leukocytic accumulations perivascular cuffs or vasodestructive mural collections?

• Numerous distinct diseases produce vasocentric leukocyte accumulations in the CNS.
• Clinical history is essential is establishing the correct diagnosis.
• Immunohistochemistry and in situ hybridization studies are often required to distinguish inflammatory from neoplastic disorders.
• Chronic GVHD can affect the CNS as an area of focal microangiitis.

1. Berlit P, M Kraemer. Cerebral vasculitis in adults: what are the steps in order to establish the diagnosis? Red flags and pitfalls. Clin Exp Immunol. 2014;175:419-424.
2. Campbell JN, Morris PP. Cerebral vasculitis in graft-versus-host disease: a case report. AJNR Am J Neuroradiol. 2005;26:654-656.
3. Gottschalk S, Rooney CM, Heslop HE. Post-transplant lymphoproliferative disorders. Annual Rev Med. 2005;56:29-44.
4. Hickey WF, Vass K, Lassmann H. Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. J Neuropathol Exp Neurol. 1992;51:246-256.
5. Kamble RT, Chang CC, Sanchez S, Carrum G. Central nervous system graft-versus-host disease: report of two cases and literature review. Bone Marrow Transplant. 2007;39:49-52.
6. Ma M, Barnes G, Pulliam J, Jezek D, Baumann RJ, Berger JR. CNS angiitis in graft vs host disease. Neurology. 2002;59:1994-1997.
7. Padovan CS, Bise K, Hahn J, et al. Angiitis of the central nervous system after allogeneic bone marrow transplantation? Stroke. 1999;30:1651-1656.
8. Powers WJ. Primary angiitis of the central nervous system: diagnostic criteria. Neurol Clin. 2015;33:515-26.
9. San-Juan R, Comoli P, Caillard S. Epstein-Barr virus-related post-transplant lymphoproliferative disorder in solid organ transplant recipients. Clin Microbiol Infect. 2014;20(Suppl 7):109-18.
10. Singavi AK, Harrington AM, Fenske TS. Post-transplant lymphoproliferative disorders. Cancer Treat Res. 2015;165:305-27.
11. Sostak P, Padovan CS, Eigenbrod S, et al. Cerebral angiitis in four patients with chronic GVHD. Bone Marrow Transplant. 2010; 45(7):1181-8.