Intravascular large B-cell lymphoma: an elusive diagnosis with challenging management

Discussion

Clinical presentation

The clinical manifestation of this disease is highly variable, and virtually any organ can be involved. Besides causing constitutional symptoms, including fatigue, B symptoms, and decline in performance status, heterogeneity of the clinical presentation depends on the organ system involved. One of the exceptional features of this disease is the difference in clinical presentation based on the geographical origin of the patient.^2-4

Western-variant IVBCL has a higher frequency of CNS and skin involvement, whereas Asian-variant IVBCL shows preferential involvement of bone marrow with hemophagocytosis, hepatosplenomegaly, and thrombocytopenia. However, these 2 clinical variants have no difference in clinical outcome, except with the cutaneous-variant kind.²⁴ A retrospective case series of 38 Western-variant IVBCL cases showed that 55% of patients had B symptoms with poor performance status.³ Brain and skin were the organs that were most frequently involved, with 68% of patients having involvement of at least 1 of those organs. Ten patients in this case series had disease that was exclusively limited to the skin and described as a “cutaneous variant” of IVBCL.³

Similarly, a retrospective case series of 96 cases of Asian-variant IVBCL showed B symptoms in 76% of patients, with predominant bone marrow involvement in 75% of patients, accompanied by hemophagocytosis in 66% and hepatosplenomegaly and anemia/thrombocytopenia in 77% and 84% of the patients, respectively.⁴ This difference in clinical presentation might have existed as a result of ethnic difference associated with production of inflammatory cytokines, including interferon gamma, tumor necrosis factor-alpha, interlukin-1 beta, and soluble interlukin-2 receptor, with levels of soluble interlukin-2 receptor found to be significantly higher in Asian patients than non-Asian patients.²
 

Diagnosis

Involved organ biopsy is mandatory for establishing the diagnosis of IVBCL. Laboratory findings are nonspecific, with the most common abnormality being increased serum LDH and beta-2 microglobulin levels observed in 80% to 90% or more of patients. Despite its intravascular growth pattern, IVBCL was associated with peripheral blood involvement in only 5% to 9% of patients.¹

Staging

Clinical staging work-up suggested for IVBCL patients by International Extranodal lymphoma study group in 2005 included physical examination (with emphasis on nervous system and skin), routine blood studies, peripheral blood smear, total body CT scan with contrast or PET–CT scan, MRI brain with contrast, CSF cytology, and bone marrow or organ biopsy.¹ The role of fluorodeoxyglucose-PET scan is controversial but can be helpful to detect unexpected locations for biopsy and to assess treatment response.^5,6

Morphology and immunophenotyping

In general, IVBCL histopathology shows large neoplastic lymphoid cells with large nuclei along with one or more nucleoli and scant cytoplasm within blood vessel lumen. Immunophenotypically, IVBCL cells mostly express nongerminal B-cell–associated markers with CD79a (100%), CD20 (96%), MUM-IRF4 (95%), CD5 (38%), and CD10 (12%) expressions. IVBCL cells have been demonstrated to lack cell surface protein CD29 and CD54 critical to transvascular migration. Similarly, aberrant expression of proteins such as CD11a and CXCR3 allows lymphoma cells to be attracted to endothelial cells, which might explain their intravascular confinement.⁷