INTRAVASCULAR LARGE B CELL LYMPHOMA, CD20-POSITIVE
The World Health Organization defines intravascular large B-cell lymphoma as a distinctive lymphoma characterized by intravascular (luminal) growth1, with a predilection for capillaries and post-capillary venules. The underlying mechanism for this growth pattern is not well understood, though the lack of surface integrins and adhesion molecules (e.g. CD29, ICAM-1) may restrict extravasation of lymphoma cells from the intravascular space2.
Intravascular lymphoma can involve any organ, but the skin and central nervous system (CNS) are most commonly affected3. The CNS is involved in the majority of cases (over 75%), while fewer (25%) show only cutaneous involvement. Bone marrow, spleen and liver are frequently involved (25-30% of cases)3. The organs typically involved differ by geography: CNS and cutaneous involvement predominate in Western countries3, while hemophagocytic syndrome, bone marrow involvement, and hepatosplenomegaly are the more frequent manifestations in Asian countries, especially Japan4.
Patients are frequently older (median 60-70 years) and present with a myriad of symptoms attributed to occlusion of small vessels. B symptoms (e.g. fever, night sweats, weight loss) are a common presentation3. Patients have variable but often rapidly progressive neurologic signs including dementia, myelopathy, progressive cerebral vascular accident and peripheral neuropathy5. Symptoms can mimic cerebral infarction, vasculitis, or subacute encephalopathy. The leading differential diagnoses include primary CNS angiitis, paraneoplastic syndromes, and neuromyelitis optica. Rarely, intravascular lymphoma can form a mass lesion in the CNS, with biopsies confirming intravascular lymphoma in sites outside the CNS6. Skin lesions are variable and can appear as maculopapular eruptions, nodules, plaques, and ulcers. Biopsies are diagnostic in most cases7. Remarkably, multiple studies have shown the sensitivity of random biopsies of normal appearing skin in diagnosing suspected intravascular lymphoma 8,9.
A clinical diagnosis is very challenging in the absence of a tissue biopsy as circulating lymphoma cells are very rare in peripheral blood and CSF. Histologically, intravascular lymphoma involving the CNS can appear as infarcts of varying ages, necrosis and/or hemorrhage. On closer inspection, the vessels contain large atypical intraluminal B cells with vesicular chromatin and prominent nucleoli. Mitoses and a high Ki-67 proliferation index are common. Most cases are positive for CD19/CD20/CD22/CD79a consistent with a mature B cell immunophenotype. Very rare cases are of T cell or NK cell origin10. Interestingly, EBV infection as assessed by in situ hybridization is not detectable in most cases of intravascular B cell lymphoma11, but has been reported in several cases of intravascular T cell lymphoma 12-14.
Intravascular lymphoma is aggressive, often with a fatal course. In the past, the diagnosis was typically discovered at autopsy. With early detection and treatment with R-CHOP, many patients achieve a complete response and improved two year survival15,16. CNS directed therapies including intrathecal chemotherapy, systemic high dose methotrexate, and radiation are also frequently given.
Diana Thomas, MD, PhD and Ronald Hamilton, MD