Intravascular large B-cell lymphoma
What every physician needs to know:
Intravascular large B-cell lymphoma (IVLBCL) is a rare form of an extranodal malignant non-Hodgkin lymphoma (NHL) that involves the growth of lymphoma cells within the lumina of capillaries, small arteries and small veins which plug these vessels. The diagnosis is characteristically established on extranodal tissue. There are two types of presentations: a Western form and an Asian variant, seen mainly in Japan.
Patients may be symptomatic or asymptomatic. Patients may present with fever of unknown origin, mental status, or personality changes. The presentation may be nonspecific and antemortem diagnosis has proven difficult. In a retrospective analysis of 740 cases, 88% were B-cell, 6% T-cell, and 2% were natural killer cell lymphoma.
The sites of involvement in the Western variant include the central nervous system (CNS), skin (nodules, plaques, macules, no cutaneous lesions but present on blind biopsy, purpura, vascular ectasias, petechia, senile hemangiomas [Campbell de Morgan sign] which may be present in up to one-third of patients), peripheral nerves, bone marrow, and lung (interstitial lung disease) followed by other organs, and essentially any organ can be involved. The four clinical neuropathic presentations include involvement with widespread disease, peripheral neuropathy as the only site of involvement at the time of initial presentation, as primary leptomeningeal involvement invading nerve roots with a progressive lumbosacral polyradiculoneuropathy or cauda equina lesion, or as a subsequent manifestation of relapse from IVLBCL.
The central nervous system is involved in up to two-thirds of patients with IVLBCL with an array of neurological symptoms that include mental status changes, pyramidal tract signs, encephalomyelitis, dementia, seizures, myelopathy, paresis, aphasia, hearing loss, transient visual loss, vertigo, ataxia, dysarthria, ascending paraparesis, sensory and motor deficits, neuropathies, paresthesias, altered consciousness, and cerebral hemorrhage not associated with or associated with disseminated intravascular coagulopathy. The plugging of cells results in ischemia to nerve fibers or demyelinization.
Patients typically present with symptoms relative to the organ involved, accompanied by the triad of an elevate erythrocyte sedimentation rate, an elevated lactate dehydrogenase (LDH), and normochromic normocytic anemia. Fever and weight loss may be a manifestation of this lymphoma. In an exhaustive literature review of 740 patients, 308/490 (63%) of newly diagnosed patients had CNS disease which included 151/250 (60%) patients diagnosed post mortem who had CNS disease. A variant of the Western presentation occurs in females who present with a cutaneous only presentation and who survive significantly longer than other IVLBCL patients. Most importantly, the diagnosis is still established in some cases postmortem.
Patients with the Asian variant characteristically present with multi-organ failure, hepatosplenomegaly, fever, pancytopenia, bone marrow involvement, and hematophagocytic syndrome. “B” symptoms are common. In one review, 38 (44%) Japanese patients and seven (19%) patients from other Asian countries had documented hemophagocytosis. CNS symptoms and cutaneous involvement are rare in the Asian variant. Stage IV disease has been reported in 76-82% of Asian cases.
Are you sure your patient has intravascular large B-cell lymphoma? What should you expect to find?
The diagnosis is established by a tissue biopsy incorporating immunohistochemical stains or flow cytometry. The biopsy demonstrates malignant cells in the lumens of small or intermediate blood vessel walls. There should be minimal extravascular involvement. In IVLBCL, the tumor cells express B-cell associated antigens (CD20, CD19) and may co-express CD5 and CD10. Peripheral nerve biopsies demonstrate infiltration of the nerve plexus or nerve roots.
Two rare variants have been reported, which the “WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues” considers to be different entities. T-cell VL and NK-cell intravascular lymphomatosis. These are even rarer than IVLBCL and are typically Epstein-Barr positive by in situ hybridization studies. Cutaneous manifestations are common.
Beware of other conditions that can mimic intravascular large B-cell lymphoma:
This lymphoproliferative disorder is one of the real masqueraders in lymphoma. Other conditions in the differential diagnosis include multi-infarct dementia, vasculitis, primary angiitis of the central nervous system, occult neoplasm (glioblastoma multiforme), fever of undetermined etiology, acute disseminated intravascular coagulopathy, autoimmune encephalopathy, progressive multifocal leukoencephalopathy, acute hemorrhagic leukoencephalopathy, primary angiitis of the central nervous system, and infection.
The causes of CNS disorders with radiologic abnormalities, peripheral neuropathy, pulmonary infiltrates, and cutaneous disorders are legion. In addition, the clinical manifestations of IVLBCL are caused by the obliteration of blood vessels which can remit spontaneously or respond temporarily to empiric corticosteroid therapy approaches that are used to treat other disorders.
The peripheral neuropathies may be acute or more subacute polyradiculopathies. Patients may present with severe hypoxia or pulmonary hypertension which is potentially reversible.
Which individuals are most at risk for developing intravascular large B-cell lymphoma:
There are no known risk factors for the development of this particular lymphoma.
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
The diagnosis is established with a tissue biopsy, which demonstrates the malignant cells in the lumens of small or intermediate vessel walls. Immunohistochemical staining confirms the diagnosis. IVLBCL is CD20 positive and is accompanied by monoclonal kappa or lambda light chain restriction. There is obliteration of the blood vessels and parenchymal invasion is rare.
The biopsy technique employed in CNS lesions is a stereotactic biopsy which yields a very small tissue sample. Some biopsy samples may demonstrate only necrotic hemorrhage. A high degree of clinical suspicion is required. A repeat biopsy may be necessary.
Electromyography (EMG) studies demonstrate axonal neuropathy in the majority of cases presenting with manifestations of peripheral neuropathy. Slowed conduction studies or block have been described.
What imaging studies (if any) will be helpful in making or excluding the diagnosis of intravascular large B-cell lymphoma?
Contrasted whole-brain magnetic resonance imaging (MRI) of the head and contrasted total-body computed tomography (CT) of the chest, abdomen, and pelvis or FDG-positron emission tomography (PET) scanning with CT fusion are utilized recommended in the diagnosis and staging of this disorder. The neuroimaging presentations are variable, and they may fluctuate and change over time.
MRI scans of the brain demonstrate a hyperintense signal on T2-weighted signals, and the differential diagnosis includes primary CNS lymphoma, toxoplasmosis, glioblastoma multiforme, abscess, metastatic disease, and primary angiitis of the central nervous system. Brain masses are rare and present as iso-dense lesions on T1-weighted images. Peripheral nerves may be thickened. The lesions enhance with gadolinium.
If you decide the patient has intravascular large B-cell lymphoma, what therapies should you initiate immediately?
The therapy is dependent upon the histologic subtype of the lymphoma and the sites of involvement.
More definitive therapies?
The treatment of IVLBCL and outcomes are related to case reports or small retrospective multi-institutional series.
The most definitive therapies in aggressive B-cell lymphoproliferative disorders include immunochemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The addition of rituximab to chemotherapy has significantly influenced the natural history of IVLBCL.
The retrospective outcomes of 20 patients treated with chemotherapy alone with a CHOP-based regimen with a median follow-up of 71 months were compared with R-CHOP immunochemotherapy patients who had a median follow-up of 23 months in a report by the International Extranodal Lymphoma Study Group (IELSG).
Only 10 of the 20 patients in the planned chemotherapy group completed treatment, and 9 patients died from lymphoma progression.
In contrast, all patients in the rituximab chemotherapy group completed treatment. Five patients in each subset had CNS involvement. Six patients in the chemotherapy group and 1 patient in the rituximab group had cutaneous involvement. The addition of rituximab was associated with improved complete remission rate (90% versus 50%), 3 year event-free survival rate (89% versus 35%, P = 0.00003), and 3 year overall survival (OS) rate (89% versus 38%, P = 0.01). The one patient with CNS disease in the R-anthracycline group who failed treatment had massive CNS infiltration associated with extravascular dissemination and formation of perivascular cuffing.
In a retrospective review of 740 patients, patients who were treated with rituximab had an improved median time from treatment to death (P < 0.0001). The combination of age and LDH significantly influenced the time from treatment to death (p = 0.0345) with an optimal cutoff age of 71 years and a LDH of 577 mg/dL). Rituximab and doxorubicin regimens improved the outcomes.
CNS disease is usually confined to the vessels. However, four cases of IVLrevealed a brain mass postmortem and five cases have been reported to demonstrate a brain mass. In one series, six patients were treated with methotrexate chemotherapy alone or in combination with CHOP, and three patients were in complete remission 9-20 months after the initial diagnosis. In a literature review of 740 cases, 88% (14/16) of patients with CNS IVL relapsed in the CNS. In a large retrospective review, no difference was observed when methotrexate was compared to non-methotrexate-based regimens. Although R-CHOP is the standard of care and this approach has significantly improved the outcomes, treatment with MR-CHOP is an alternative approach in patients with a brain mass. In the ILESG report, 2 patients were treated with R-CHOP and high-dose methotrexate.
Rituximab toxicities in patients with the Western variant IVLBCL were as anticipated. In a retrospective multi-institutional analysis of Japanese patients with IVLBCL in Japan, 49 patients were treated with immunochemotherapy that included rituximab and 57 patients were treated with chemotherapy alone. The progression-free survival was 56% versus 27% (P = .001) and OS was 66% versus 46% (P = 0.01).
29% of Japanese patients with the hemophagocytosis-related form of IVLBCL experienced significant rituximab toxicities, characterized by a cytokine release syndrome and severe systemic inflammatory response symptoms, including very significant respiratory symptoms. The IELSG recommends delaying rituximab for 3 to 4 days following standard concomitant chemotherapy administration.
The utilization of high-dose chemotherapy followed by autologous stem cell transplantation has been reported in a very limited number of patients in both first and second-line treatment strategies.
The most definitive therapy in T-cell IVL disorders is CHOP chemotherapy although the outcomes are very poor. If a patient enters complete remission, then consideration should be given for autologous stem cell transplantation. Alternatively, investigational clinical trials should be considered.
Other reported therapies include high-dose methotrexate and high-dose cytarabine. Patients primarily relapse in the central nervous system (88%), with same organ relapse in skin (23%), bone marrow and spleen (50%), and lung (20%).
What other therapies are helpful for reducing complications?
Allopurinol is indicated at the onset of treatment for 10 days’ duration, to reduce the risk of hyperuricemia with subsequent renal injury. The routine use of growth factors is not recommended in the initial management of these disorders. The American Society of Clinical Oncology (ASCO) guidelines should be followed.
What should you tell the patient and the family about prognosis?
The prognosis is dependent on the histology, the organs involved, and the degree of involvement of the organ.
In IVLBCL, the outcomes are very encouraging with rituximab anthracycline-based regimens, which have significantly changed the natural history of the disease. In the IELSG data set, 9/10 patients were alive and relapse-free. Patients with a CNS presentation can have dramatic improvements. It is important to stress to patients that the literature is complicated by very small series, including patients who died before a diagnosis was established, and the inclusion of patients before rituximab was incorporated into treatment regimens.
Patients with the cutaneous only involvement variant of Western IVLBCL have been reported to have a more favorable outcome.
With treatment, the improvement in symptoms and signs can be quite significant and occur within days to weeks in many patients.
What if scenarios.
The most common what if scenario is relapse following initial therapy. Patients who relapse are potential candidates for rituximab/ifosfamide/carboplatin/etoposide (R-ICE) or rituximab/dexamethasone/cytarabine/cisplatin (R-DHAP), and if the disease responds to high dose therapy, autologous stem cell transplantation (ASCT). Isolated case reports have reported significant long-term outcomes. If the relapse is in the central nervous system, then high-dose methotrexate should be utilized prior to ASCT.
The pathophysiology of the unique localization to the blood vessel walls has been related to a defect in homing receptors. The malignant cells lack CD29 and CD64.
What other clinical manifestations may help me to diagnose intravascular large B-cell lymphoma?
Key questions in the history include: fevers, night sweats, and weight loss, which are the classic “B” symptoms of lymphoma. Fatigue may be a manifestation of anemia. CNS symptoms include: memory changes, manifestations of dementia, gait disturbances, balance problems, changes in hearing, and new onset of seizures. Peripheral nerve involvement is characterized by numbness in the fingers and toes. Patients may note new skin lesions. In pulmonary IVLBCL, dyspnea may be a presentation.
The findings on physical examination are a manifestation of the organ involved. In contrast to other lymphomas, the majority of patients do not have pathologic lymphadenopathy. CNS involvement manifestations include dementia, mental status changes, pyramidal tract signs, ataxia, paresis, ascending paraparesis, and cerebral hemorrhage. The physical examination findings consistent with peripheral neuropathy may be present. Patients with skin involvement may present with erythyematous telangiectatic plaques or a livedoid macular rash.
What other additional laboratory studies may be ordered?
The LDH is more characteristically elevated in IVLBCL.
Routine chemistries are important to evaluate renal, liver, and thyroid function prior to therapeutic intervention, since these may be abnormal in 15% to 20% of patients.
Bone marrow aspiration and biopsy are recommended.
Cerebral spinal fluid total protein and fluid cytology should be considered in the appropriate clinical situations.
What’s the Evidence?
Fonkem, E, Lok, E, Robison, D. “The natural history of intravascular lymphomatosis”. Cancer Medicine.. vol. 3. 2014. pp. 1010-1024. (This is a retrospective analysis of 704 cases reported in the literature from 1959-2011. The authors analyzed outcomes according to the 1960-1980s, 1990s, and 2000s because of advancements in the pathologic diagnosis in the 1980s, utilization of doxorubicin-based cytotoxic therapy in the 1990s, and the addition of rituximab in the 2000s. Six-hundred and fifty one (88%) patients had B-cell lymphoma, 45 (6%) T-cell lymphoma, and 12 (2%) NK cell lymphoma. Favorable prognostic factors included age <70 years (p = 0.0073), non-CNS site at the time of initial diagnosis (P=0.0014), lactate dehydrogenase (LDH) <700 (P = 0.0112), and rituximab treatment (P<0.0001). Patients presenting with skin involvement had a more favorable prognosis.)
Ponzoni, M, Ferreri, AJM, Campo, E. “Definition, diagnosis, and management of intravascular large B-cell lymphoma: proposals and perspectives from the International Consensus Meeting”. J Clin Oncol.. vol. 25. 2007. pp. 3168-3173. (This is a summary of a consensus meeting proposing practical systemic guidelines for IVLBCL and T-cell IV disorders. Half of the patients treated with anthracycline-based chemotherapy alone relapsed and died within 18 months from diagnosis. One third of the relapses occurred in the central nervous system.)
Ferreri, AJM, Dognini, GP, Bairey, O. “The addition of rituximab to anthracycline-based chemotherapy significantly improves outcome in “Western” patients with intravascular large B-cell lymphoma”. British Journal of Haematology.. vol. 143. 2008. pp. 253-257. (This retrospective series reports on the improved outcome for patients treated with the addition of rituximab to anthracycline chemotherapy. After initially reporting that anthracycline-based chemotherapy was the cornerstone in the treatment of IVL, the ILESG recommended including rituximab in the regimen. This paper is a retrospective follow-up to that recommendation.)
Ferreri, AJM, Dognini, GP, Campo, E. “Variations in clinical presentation, frequency of hemophagocytosis and clinical behavior of intravascular lymphoma diagnosed in different geographical regions”. Haematologica.. vol. 92. 2007. pp. 486-492. (This study contrasts differences in Western and Japanese IVLBCL pointing out the significantly increased incidence of hemophagocytosis, fever, incidence of stage IV disease, anemia, hepato-splenic involvement, dyspnea, and thrombocytopenia. Lymph node and peripheral blood involvement were uncommon in each subgroup.)
Shimada, K, Matsue, K, Yamamoto, K. “Retrospective analysis of intravascular large B-cell lymphoma treated with rituximab-containing chemotherapy as reported by the IVL study group in Japan”. Haematologica.. vol. 92. 2007. pp. 486-492. (Retrospective analysis of intravascular large B-cell lymphoma treated with rituximab-containing chemotherapy as reported by the IVL study group in Japan. This is the largest retrospective report of IVLBCL by the IVL study group in Japan which analyzed the outcomes of 49 patients who were treated with R-chemotherapy and 577 who were treated with chemotherapy alone. This study brings to light the differences in Western and Japanese IVLBCL.)
Nakamichi, N, Fukuhara, S, Aozasa, K. “NK-cell intravascular lymphomatosis – a mini-review”. European J Haem.. vol. 81. 2008. pp. 1-7. (This is a summary of six cases of NK-cell intravascular lymphomatosis. The most recent WHO classification does not include this pathologic classification.)
Ferreri, AJM, Campo, E, Seymour, JF. “Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the ‘cutaneous variant.’”. Br J Haematol.. vol. 127. 2004. pp. 173-183. (This study reported that patients with skin only IVLBCL were females with a normal platelet count and had significantly better outcomes than other patients with IVLBCL.)
Wahie, S, Dayala, S, Husain, A. “Cutaneous features of intravascular lymphoma”. Clinical and Experimental Dermatology.. vol. 36. 2010. pp. 288-291. (This is a case report of the classical indurated telangectatic plaques of IVLBCL.)
Baehring, JM, Longtine, J, Hochberg, FH.. “A new approach to the diagnosis and treatment of intravascular lymphoma”. Journal of Neuro-Oncology.. vol. 61. 2003. pp. 237-248. (Six patients were treated with methotrexate chemotherapy alone or in combination with CHOP and three were in complete remission 9-20 months after the time of initial diagnosis.)
Fonkem, E, Lok, E, Robinson, D. “The natural history of intravascular lymphomatosis”. Cancer Medicine. 2014. pp. 1010-1024. (This is a comprehensive literature search from 1959-2011 of 740 patients from 431 publications, 270 diagnosed in the 2000s. Eighty-eight percent (651) had a diagnosis of B-cell lymphoma. Postmortem diagnosis was highest in CNS disease, 250 (60%) compared with other presentations. Favorable prognostic factors included age < 70, non-CNS site of initial diagnosis, LDH < 700, and rituximab treatment.)
Oomura, M, Sakakibara, N, Suzuki, S. “Intravascular lymphomatosis mimicking primary CNS lymphoma. A case report and literature review”. Case Reports in Neurology.. vol. 6. 2014. pp. 101-108. (In a review of the literature, there were four reported cases with a brain mass and five cases have been reported with a brain mass with tissue-proven IVL at postmortem examination.)
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- Intravascular large B-cell lymphoma
- What every physician needs to know:
- Are you sure your patient has intravascular large B-cell lymphoma? What should you expect to find?
- Beware of other conditions that can mimic intravascular large B-cell lymphoma:
- Which individuals are most at risk for developing intravascular large B-cell lymphoma:
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What imaging studies (if any) will be helpful in making or excluding the diagnosis of intravascular large B-cell lymphoma?
- If you decide the patient has intravascular large B-cell lymphoma, what therapies should you initiate immediately?
- More definitive therapies?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- What if scenarios.
- What other clinical manifestations may help me to diagnose intravascular large B-cell lymphoma?
- What other additional laboratory studies may be ordered?