Final Diagnosis -- Intravascular Large B-cell Lymphoma

FINAL DIAGNOSIS

INTRAVASCULAR LARGE B CELL LYMPHOMA, CD20-POSITIVE

DISCUSSION

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.

REFERENCES

  1. WHO Classification of Tumours of the Central Nervous System. 4th edn, (2016).
  2. Ponzoni, M. et al. Lack of CD 29 (beta1 integrin) and CD 54 (ICAM-1) adhesion molecules in intravascular lymphomatosis. Human pathology 31, 220-226 (2000).
  3. Ferreri, A. J. et al. Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the 'cutaneous variant'. British journal of haematology 127, 173-183, doi:10.1111/j.1365-2141.2004.05177.x (2004).
  4. Murase, T. et al. An Asian variant of intravascular large B-cell lymphoma: clinical, pathological and cytogenetic approaches to diffuse large B-cell lymphoma associated with haemophagocytic syndrome. British journal of haematology 111, 826-834 (2000).
  5. Tahsili-Fahadan, P., Rashidi, A., Cimino, P. J., Bucelli, R. C. & Keyrouz, S. G. Neurologic manifestations of intravascular large B-cell lymphoma. Neurology. Clinical practice 6, 55-60, doi:10.1212/CPJ.0000000000000185 (2016).
  6. Imai, H. et al. Intravascular large B-cell lymphoma presenting with mass lesions in the central nervous system: a report of five cases. Pathology international 54, 231-236, doi:10.1111/j.1440-1827.2004.01613.x (2004).
  7. Zuckerman, D., Seliem, R. & Hochberg, E. Intravascular lymphoma: the oncologist's "great imitator". The oncologist 11, 496-502, doi:10.1634/theoncologist.11-5-496 (2006).
  8. Asada, N. et al. Use of random skin biopsy for diagnosis of intravascular large B-cell lymphoma. Mayo Clinic proceedings 82, 1525-1527 (2007).
  9. Yunoki, M., Suzuki, K., Uneda, A. & Yoshino, K. A case of intravascular lymphoma presenting as myelopathy diagnosed with a skin biopsy. Surgical neurology international 6, S367-370, doi:10.4103/2152-7806.163316 (2015).
  10. Wu, H. et al. First reported cases of intravascular large cell lymphoma of the NK cell type: clinical, histologic, immunophenotypic, and molecular features. American journal of clinical pathology 123, 603-611, doi:10.1309/X597-G3QM-XAFB-CM5V (2005).
  11. Murase, T. et al. Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5. Blood 109, 478-485, doi:10.1182/blood-2006-01-021253 (2007).
  12. Au, W. Y. et al. T-cell intravascular lymphomatosis (angiotropic large cell lymphoma): association with Epstein-Barr viral infection. Histopathology 31, 563-567 (1997).
  13. Merchant, S. H., Viswanatha, D. S., Zumwalt, R. E. & Foucar, K. Epstein-Barr virus-associated intravascular large T-cell lymphoma presenting as acute renal failure in a patient with acquired immune deficiency syndrome. Human pathology 34, 950-954 (2003).
  14. Cerroni, L. et al. Intravascular large T-cell or NK-cell lymphoma: a rare variant of intravascular large cell lymphoma with frequent cytotoxic phenotype and association with Epstein-Barr virus infection. The American journal of surgical pathology 32, 891-898, doi:10.1097/PAS.0b013e31815d29c9 (2008).

Diana Thomas, MD, PhD and Ronald Hamilton, MD



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