Intravascular large B‐cell lymphoma cells in the bone marrow smear preparation

LR11 Is a Potential Serum and Histological Biomarker for Intravascular Large B-Cell Lymphoma

Dear Editor, Intravascular large B cell lymphoma (IVLBCL) is a rare subtype of diffuse large B cell lymphoma (DLBCL) characterized by the selective growth of lymphoma cells within the lumina of vessels [1]. Cytogenetically, the majority of IVLBCL cases demonstrated complex karyotypes with multiple numerical and structural changes, and the most frequent duplicated regions were shown to be the 11q13→qter region and all of chromosome 18 [2, 3]. On the other hand, triplications of chromosome segments other than 1q have been rarely found in hematological malignancies [4–8]. Here, we describe an unusual case of IVLBCL with a tandem triplication of the BCL2 gene at 18q21. An 82 year-old female was admitted because of fever. Computed tomography scans revealed hepatosplenomegaly without lymphadenopathy. Peripheral blood (PB) examination showed hemoglobin 105 g/L, platelets 52×10/L, and leukocytes 10.1× 10/Lwith 15% abnormal lymphocytes. Serum levels of lactate dehydrogenase (LDH) and soluble interleukin-2 receptor were 6,382 IU/L (normal range, 115~217) and 8,429 U/mL (124~ 466), respectively. Bone marrow (BM) was normocellular with 42.4 % abnormal lymphocytes positive for CD5, CD19, CD20, and HLA-DR (Fig. 1a). Pathological examination of the BM revealed a focal and sinusoidal growth pattern of large lymphoid cells, indicating a diagnosis of IVLBCL (Fig. 1b). Immunohistochemistry demonstrated that they were positive for CD5, CD20, BCL2, and MUM1, but negative for CD10 and BCL6 (Fig. 1c, d). The patient received R-CHOP therapy and achieved hematological complete remission. However, 12 months later, she relapsed and died of progressive disease. G banding and spectral karyotyping of BM cells showed 47,XX,del (2)(q?),+del(3)(p?),der(10)t(10;20)(q24;?), dup(17)(q21q23),dup(18)(q11.2q23) [20] (Fig. 1e). Unexpectedly, fluorescence in situ hybridization (FISH) detected three BCL2 signals on the dup(18)(q11.2q23), indicating a tandem triplication of BCL2 (Fig. 1f). Namely, the short 18q fragment containing BCL2 attached to the dup(18). FISH on interphase nuclei confirmed four BCL2 signals. According to the Mitelman Database, nine cases of hematological malignancies with duplication/triplication of 18q (duplication, eight; triplication, one) in the stem-lines have been described [4, 9, 10]. All cases were diagnosed with B lymphoid malignancies. The duplicated regions in two cases of acute lymphoblastic leukemia did not contain 18q21, whereas those in seven cases of B cell lymphomas (DLBCL, four; IVLBCL, one; Burkitt lymphoma, one; mantle cell lymphoma, one) retained 18q21. Thus, duplication/triplication of 18q including 18q21 seems to be specifically associated with B cell lymphomas and suggests the significance of BCL2 in their pathogenesis. Among these, one case with trp(18)(?q21q23) exhibited a tandem triplication of BCL2 [2]. This 62-year-old male was diagnosed as having IVLBCL with BM/PB involvement, thrombocytopenia (34×10/L), and high LDH (2,266 U/L). Lymphoma cells were positive for K. Yamamoto (*) :A. Okamura :K. Yakushijin :H. Matsuoka : H. Minami Division of Medical Oncology/Hematology, Department of Medicine, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan e-mail: kyamamo@med.kobe-u.ac.jp

Liquid Biopsy for the Identification of Intravascular Large B-Cell Lymphoma

A 71-year-old Caucasian man from the upper Midwest was transferred from an outside hospital for evaluation of new-onset mental status alterations, diaphoresis, and persistent hypoglycemia of 5 days duration in the setting of recurrent fevers and pancytopenia over the past 5 months. His past medical history was significant for coronary artery disease status post four-vessel coronary artery bypass grafting, hypertension, hyperlipidemia, restless legs syndrome, obstructive sleep apnea, and gastric banding for obesity. Of note, CBC was normal 1 year prior to presentation. Vital signs upon arrival include temperature 36.8°C, heart rate 100 beats per minute, blood pressure 135/78 mmHg, respiratory rate 30 breaths per minute, and oxygen saturation 97% on room air. He was oriented to place and person but not to time. Physical examination was remarkable for splenomegaly.1, 2 Lymphoma cells in bone marrow trephine biopsy touch prep, Wright-Giemsa, 400× magnification (A). Bone marrow trephine biopsy with intrasinusoidal infiltrate of large neoplastic lymphocytes, hematoxylin and eosin, 200× magnification (B). CD20 stains of neoplastic B-cells which fill intrasinusoidal lumina, L26 antibody to CD20; 200× magnification (C). Bone marrow trephine biopsy with extensive crush artifact, hematoxylin and eosin; 200× magnification (D). PET/CT scan [three-dimensional maximum-intensity projection imaging (A) and fusion images at the liver/spleen level (B)] showing profound glucose sequestration in liver, spleen, bone marrow, and brain. At this point, the differential remains broad. In the absence of any additional data, the most important differential to consider is infection, including bacterial, viral, fungal, or tick borne infection. The protracted time course of his illness makes bacterial etiologies less likely. The authors had to include noninfectious causes such as malignancies, primary bone marrow disorders, liver disease, rheumatologic, and autoimmune disorders in our differential. Initial work-up at our institution was notable for pancytopenia. Laboratory evaluation showed hemoglobin 11.8 g/dL, leucocyte count 1.9 × 109/L, and platelet count 26 × 109/L. Differential white count was remarkable for neutrophils 56%, lymphocytes 30%, monocytes 13%, metamyelocytes 1%, and few nucleated red blood cells. Absolute neutrophil count was 1,060/L. A peripheral smear showed dacrocytes (red blood cells shaped like teardrops; can be seen in myelofibrosis). He had mild coagulopathy with prothrombin time 16.6 sec, INR 1.4, and aPTT 33 sec. Serum chemistry was notable for direct hyperbilirubinemia (total bilirubin 2.1 mg/dL, direct bilirubin 1.6 mg/dL), elevated liver enzymes (alkaline phosphatase 508 U/L, AST 178 U/L, ALT 56 U/L), hypercalcemia (serum calcium 10.4 mg/dL, with albumin of 3.2 g/dL), hypophosphatemia (serum phosphorus 1.1 mg/dL), anion-gap metabolic acidosis (anion gap 20, bicarbonate 16 mmol/L) and elevated lactate (8.8 mmol/L). Creatinine was normal at 0.6 mg/dL. Blood glucose level at the outside hospital was very low at 26 mg/dL, and he received an intravenous bolus of dextrose 50% prior to transfer. Blood glucose on presentation to our hospital was 82 mg/dL. As the first step, this patient had to be resuscitated, ideally in an intensive care environment given the degree of lactic acidosis (LA). Infection still remains high on the differential. Further work-up had to include blood and urine cultures, chest X-ray, and possibly a computed tomography (CT) of chest, abdomen, and pelvis. Tick-borne illnesses such as anaplasmosis and ehrlichiosis can present similarly and, therefore, serology had to be obtained. A lumbar puncture with cerebrospinal fluid (CSF) cultures would be desirable, but its safety is questionable given the marked thrombocytopenia [1]. Bone marrow biopsy had to be strongly considered to evaluate pancytopenia. The patient had a bone marrow biopsy at the referring hospital. Per the outside interpretation, the diagnosis was myelofibrosis with normal trilineage hematopoiesis and complex cytogenetics, including monosomy 7, on cytogenetic analysis. Splenomegaly, pancytopenia, fevers, and night sweats are certainly features consistent with primary myelofibrosis. Dacrocytes in the peripheral blood smear are also a feature of bone marrow fibrosis. However, a diagnosis of myelofibrosis does not completely explain abnormalities in the liver function tests, unless the liver was involved with extramedullary hematopoiesis; notably, the degree of abnormalities in liver function tests is out of proportion to what is generally seen in extramedullary hematopoiesis involving the liver. In addition, it would also be unusual to see persistent hypoglycemia as well as LA with myelofibrosis. Given the unusual features of this case, I would seek a second opinion from a hematopathologist for an interpretation of the bone marrow biopsy. Monosomy 7 is the most frequent chromosomal abnormality in hematologic malignancies (about 80% of all isolated monosomies) according to analysis of a large unselected cohort of patients with suspected or confirmed hematological malignancies [2]. Monosomy 7 has been described in hematological disorders [3-8], including acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative neoplasms, CMML, and other nonmyeloid malignancies [2]. Shortly after admission to the general medicine floor, the decision was made to transfer the patient to a higher level of care (medical intensive care unit), where he was started on broad-spectrum antibiotics after blood and urine cultures were obtained. Continuous glucose infusion was administered for persistent symptomatic hypoglycemia. A chest X-ray showed mild scattered fibrosis of the left lower lobe with otherwise clear lungs. CT of head and abdomen/pelvis was normal except for splenomegaly. A CT scan of the chest was available from the outside hospital showing small bilateral pleural effusions and atelectasis in the lung bases. Further laboratory evaluation revealed a reticulocyte percentage of 1.19, absolute reticulocyte count of 46.4 × 109/L, lactate dehydrogenase (LDH) of 1,485 U/L and uric acid of 15.1 mg/dL. Vitamin B12 and folate levels were normal. Iron panel showed total iron binding capacity of 222 mcg/dL and ferritin of 883 mcg/L. Creatinine kinase level was normal. The combination of LA, persistent hypoglycemia, elevated LDH, and uric acid levels make me wonder about high cell turnover and an increase in metabolic rate; as could be observed in leukemia and lymphoma. Myelofibrosis has a significant potential of transformation into an acute, aggressive leukemia [9]. Review of the bone marrow biopsy slides became available on hospital day #5 and revealed significant extensive crush artifact and insufficient sample for analysis, and the hematopathologist recommended a repeat biopsy which was performed on hospital day #6. Results of the repeat bone marrow biopsy became available on hospital day #8 (see image 1) and were diagnostic for intravascular large B-cell lymphoma (IVLBCL) involving 40% of the marrow cellularity. Flow cytometry revealed B cells positive for CD19, CD20, CD 22, and CD5. No expression of CD10 and CD23 was noted. About 60% of nuclei had an unbalanced BCL6 gene rearrangement and a 14q deletion. Nineteen out of 20 metaphases were found to have a complex clone with multiple numeric and structural abnormalities, including monosomy 7. The diagnosis of IVLBCL provides a unifying explanation for the patient's severe LA and LDH elevation (high cell turnover) as well as hypoglycemia (utilization by lymphoma cells). The next step in management should include staging with a PET/CT scan. Since the central nervous system is involved in 27–39% IVLBCL cases at diagnosis, this patient should also have CSF analysis as a part of the staging workup [10, 11]. Involvement of the CNS will significantly alter therapy as well as prognosis. IVLBCL is usually treated with anthracycline-containing regimen. Since the lymphoma cells are CD20+, rituximab had to be a part of the treatment regimen [12]. Serology for infectious hepatitis had to be obtained prior to therapy with rituximab. The very high LDH and elevated uric acid are worrisome for spontaneous tumor lysis. I would treat with rasburicase and aggressive intravenous fluid therapy prior to chemotherapy initiation to reduce the risk of end-organ damage [13]. A PET/CT scan on hospital day #8 showed profound glucose sequestration in the liver, spleen, and bone marrow with dramatically decreased cerebral glucose metabolism (see image 2). Spleen was enlarged at 16.7 cm, and there was no lymphadenopathy. CSF analysis was negative for lymphoma cells. Serology was negative for hepatitis. I would treat this patient with an anthracycline-based regimen, such as CHOP [14]. As mentioned earlier, rituximab had to be added to the regimen due to improved clinical outcomes in patients treated with rituximab [12]. Unfortunately, his liver dysfunction precludes use of standard-dose CHOP chemotherapy. Mechloramine (nitrogen mustard), high dose corticosteroids, and rituximab are not metabolized by the liver and have been shown to improve outcomes when used as a bridge to conventional chemotherapy in patients with lymphoma and significant liver dysfunction [15]. Treatment was started with intravenous methylprednisolone (1,000 mg on hospital day #9, #10, and #11) and rituximab (800 mg on hospital day #9). Mechloramine was not included due to the nation-wide shortage of this drug. After the third dose of methylprednisolone, the patient's mental status significantly improved and the LA and hypoglycemia resolved. Liver function tests were normalized, and, therefore, he was able to receive treatment with standard-dose cyclophosphamide, vincristine, and doxorubicin on hospital day #12. Because IVLBCL has a significant risk of CNS relapse, the authors decided to include prophylactic high-dose intravenous methotrexate as part of the chemotherapy regimen, which may have better efficacy than intrathecal methotrexate therapy in preventing CNS relapse in patients with aggressive lymphoma, although data is limited [16]. After further clinical improvement, the patient was discharged to a rehabilitation facility. The initial presentation of this gentleman steered the investigations toward an infectious etiology. An added difficulty was the misleading bone marrow biopsy report of myelofibrosis. The patient's first bone marrow biopsy showed extensive crush artifact involving approximately half of the trephine core. Additionally, the finding of a complex karyotype with monosomy 7 was erroneously used to provide further evidence of a myeloid-lineage neoplasm. A second biopsy clearly showed neoplastic B-cells with an intravascular distribution pattern. Flow cytometric and paraffin immunohistochemical immunophenotyping demonstrated a mature, B-lineage immunophenotype. Given the lack of evaluable morphology in the initial biopsy, the repeat biopsy was crucial to establish the proper diagnosis. This case highlights the importance of avoiding premature closure, which can be triggered by over-interpretation of inadequate sample specimens. The initial crush artifact was likely read as myelofibrosis due to the “supporting evidence” of splenomegaly and monosomy 7 on cytogenetics. IVLBCL belongs to the more aggressive subtypes of Non-Hodgkin lymphomas and usually has a poor prognosis related to a significant delay in diagnosis of most cases. It is characterized by massive proliferation of lymphoma cells within the lumina of small blood vessels (predominantly capillaries). According to the most recent WHO classification, IVLBCL attained the status of an independent disease entity [17] after initially being classified as a rare form of extranodal diffuse large B-cell lymphoma [18]. A series of 96 IVLBCL patients reported the following clinicopathologic features at diagnosis: anemia/thrombocytopenia (84%), hepatosplenomegaly (77%), B symptoms (76%), bone marrow involvement (75%), and hemophagocytosis (61%) [11]. Most patients have an intermediate-high or high score on the International Prognostic Index [11]. Treatment outcomes have significantly improved with the addition of rituximab to standard anthracycline based chemotherapy. Shimada et al. [12] compared treatment outcomes for IVLBCL in Asian patients using chemotherapy with and without rituximab and noted a significantly higher complete response rate (82% rituximab group versus 51% nonrituximab group) and progression-free/overall survival at 2 years (56%/66% rituximab group; 27%/46% nonrituximab group). Similar results were achieved in a report from Ferreri et al. [19] using immunochemotherapy in Western patients. Addition of rituximab to conventional chemotherapy improved complete remission (90% vs. 50%), event-free survival at 3 years (89% vs. 35%), and overall survival at three years (89% vs. 38%). The CNS is not infrequently involved (from 27% [11] to 39% [10]), either during the initial presentation or in relapse. Some groups have treated patients with high-dose chemotherapy followed by autologous stem-cell transplantation either in first remission [20] or in the relapsed setting [21], which may lead to long-term remission [22], although widespread use of this approach is often limited by patient's performance status. Since chemotherapeutic agents commonly used for IVLCBL have insufficient CNS penetration, some groups recommended the addition of methotrexate or cytarabine [23-25]. This is a controversial area, particularly in light of a recent analysis of CNS relapse in DLBCL patients that did not show a benefit from prophylactic intrathecal methotrexate [16]. There is limited evidence to support the use of high-dose intravenous methotrexate in those considered to be at high risk of CNS relapse, and this is an area that requires prospective evaluation. LA is a rare complication of hematologic malignancies and even less commonly encountered in conjunction with hypoglycemia. A helpful conceptual framework makes a distinction between type A LA, related to tissue hypoxia/ischemia, and type B LA secondary to underlying disease (B1), drugs or toxins (B2), or inborn errors of metabolism (B3) [26]. Sepsis is one of the most common causes for type A LA while hematologic malignancies, as seen in this case, produce a type B1 LA, presumably by increased glycolysis in tumor cells and decreased lactate clearance secondary to impaired organ function (mainly liver and kidney which account for 90% and 10% of lactate clearance, respectively) [27]. In a case series of 53 patients with LA and underlying hematologic malignancies, 43 had neoplastic involvement of the liver. Hypoglycemia was present in 20 of the 53 patients [28]. Both LA and hypoglycemia can be attributed to a high rate of glycolysis in tumor cells. The intense glucose uptake in the liver, spleen, and bone marrow on the PET scan of our patient can very well be explained by high rate of glucose utilization by neoplastic cells in these tissues. Decreased availability of glucose to vital organs such as the brain led to a correspondingly low uptake in the brain. Production of lactate results in anion-gap metabolic acidosis, thereby triggering a respiratory compensation that manifests as tachypnea. This can be easily misinterpreted as respiratory distress from a more ominous process such as sepsis or adult respiratory distress syndrome. Both hypoglycemia and uncompensated metabolic acidosis can lead to mental status changes, as seen in our patient. Although sodium bicarbonate can be using as a temporizing measure for LA, early cytoreduction with initiation of chemotherapy is crucial [29]. Presence of LA with hematologic malignancies heralds a poor prognosis, especially for patients who do not receive or do not respond to chemotherapy [28]. This case highlights the importance of time-sensitive diagnosis of IVLBCL but also shows that many of the life-threatening metabolic derangements can be directly related to lymphoma burden and may respond to treatment of the underlying disease. The discovery of unexplained refractory hypoglycemia and/or LA without signs of sepsis or cardiorespiratory dysfunction in a patient with constitutional symptoms should prompt consideration of a hematological malignancy.

Development and Analysis of Novel Intravascular Large B-Cell Lymphoma NOD/Shi-Scid IL2Rγnull Mouse Xenograft Model

Use of Random Skin Biopsy for Diagnosis of Intravascular Large B-Cell Lymphoma

Intravascular Lymphoma: Case Series and Review of the Literature.

Elevated FDG Uptake in the Lung Is a Characteristic Finding of Intravascular Large B-Cell Lymphoma

Detection of Recurrent Genetic Mutations in Intravascular Large B-Cell Lymphoma By Comprehensive Genetic Analyses Using Peripheral Blood Circulating Cell-Free DNA

Intravascular large B cell lymphoma (IVLBCL) is a rare type of non-Hodgkin lymphoma characterized by a disseminated intravascular proliferation of tumor cells in the lumina of small vessels. Although the kidney is one of the target organs of IVLBCL, it is extremely rare that lymphoma cells are localized only in the kidney. We report here a Japanese patient with kidney-limited IVLBCL. The patient presented with mild proteinuria and a good performance status without B symptoms at presentation. A renal biopsy showed large B cell neoplastic lymphocytes in the glomerular capillary lumina. Extensive systemic examinations showed no other organ involvement. The patient responded well to rituximab and anthracycline-based chemotherapy. A follow-up renal biopsy showed the disappearance of intraglomerular lymphoma cells with restoration of glomerular architecture. Within 20 months past the discontinuation of chemotherapy, no evidence of recurrence was observed. Although IVLBCL is commonly a fatal disease, favorable clinical courses were reported in some cases of IVLBCL, such as the cutaneous variant. To our knowledge, there are 8 reported cases of kidney-limited IVLBCL in the English literature. All 4 patients treated with intensive chemotherapy responded well to the treatment as our patient. We suggest that kidney-limited IVLBCL might be a distinct variant of IVLBCL.

Intravascular lymphoma (IVL) is a rare type of extranodal lymphoma in which the lymphoma cells proliferate exclusively in the lumina of small vessels. The diagnosis of IVL requires histological confirmation. Although random skin biopsy from healthy-appearing skin in patients with suspected IVL appeared to be useful, the sensitivity of this method for the diagnosis of IVL remains unknown. We performed a random skin biopsy from 12 consecutive cases of IVL diagnosed at our institution over the past 4years and evaluate its relevance of clinical and laboratory characteristics, presence or absence of skin lesions, and bone marrow involvement. All 12 patients were diagnosed antemortem by either random skin biopsy or bone marrow biopsy and treated with rituximab-containing chemotherapy. Random skin biopsy was performed in all 12 patients, and the results were positive in ten patients (83.3%). Erythematous skin lesions were seen in 3 of 12 patients, but biopsy was positive for lymphoma lesion in two patients. Bone marrow invasion was seen in 11 of the 12 patients (91.6%) by bone marrow smear and/or flow cytometric analysis, but was detected in only half of the patients by trephine biopsy. We concluded that random skin biopsy from normal-appearing skin is highly sensitive in the diagnosis of IVL comparable to bone marrow trephine biopsy. It should be performed irrespective of the presence or absence of skin lesions in patients who were suspicious of IVL.

BACKGROUNDIntravascular lymphoma (IVL) is a rare subtype of lymphoma involving the growth of lymphoma cells within the vessel lumina without lymphadenopathy. Because of various modes of presentation and its rarity, IVL is often diagnosed postmortem. Herein, we report a case of intravascular B-cell lymphoma with hypopituitarism, an extremely rare complication, that was successfully treated with chemotherapy.CASE SUMMARYAn 80-year-old Japanese woman presented with a 7-mo history of a tingling sensation in the lower limbs. She also presented with various other symptoms such as pancytopenia, high fever daily, and unconsciousness with hypoglycemia. Although the doctor who previously treated her diagnosed hypoglycemia as being due to hypopituitarism, the cause of the other symptoms remained uncertain despite a 7-mo evaluation period. We performed bone marrow aspiration to evaluate pancytopenia and found that she had hemophagocytic lymphohistiocytosis (HLH). On the basis of a random skin biopsy for assessing the cause of HLH, she was diagnosed with intravascular B-cell lymphoma. HLH and hypopituitarism were considered secondary to IVL. All her clinical findings matched the presentations of IVL. She was immediately treated with chemotherapy and achieved complete response. She was relapse free two years after treatment.CONCLUSIONIVL should be included in the differential diagnosis of hypopituitarism, which although life-threatening, is treatable through prompt diagnosis and appropriate chemotherapy.

Retrospective Study of Intravascular Lymphoma Cases Diagnosed in Quebec

Intravascular large B-cell lymphoma (IVLBCL) is a rare distinct disease entity of the extranodal large B-cell lymphoma type, characterized by the selective growth of tumor cells in the lumina of small vessels of various organs. Lack of remarkable lymphadenopathy and non-specific clinical abnormalities including fever of unknown origin and lactate dehydrogenase elevation generally make timely and accurate diagnosis difficult. Recent diagnostic advances in the detection of this disease using FDG-PET/CT and random skin biopsies are expected to increase the diagnostic yield. Regarding the therapeutic aspects of this disease, improvement of clinical outcomes by the application of anti-CD20 monoclonal antibody, rituximab, and a high risk of CNS recurrence have been indicated. Thus, a prospective phase II trial of immunochemotherapy combined with CNS prophylaxis is now ongoing. Previously, the difficulty of obtaining sufficient tumor samples hampered biological investigations but the novel technique developing xenograft models is opening the door to uncovering the underlying mechanisms by focusing on the fundamental biological question: "Why do tumor cells become lodged in the lumina of vessels?" This review describes the current understanding of research on IVLBCL and discusses the future prospects for this disease entity.

We report 5 cases of intravascular lymphoma (IVL) initially diagnosed by bone marrow aspiration and biopsy. Each patient had generalized symptoms; 1 also had neurologic deficits. CBC counts revealed anemia (4 patients), thrombocytopenia (4 patients), or mild leukopenia (1 patient). The bone marrow biopsy specimen was diagnostic in each case. Lymphoma cells were present in small groups or single file in sinusoids (in 1 patient, sinusoids were distended markedly by IVL) and were detected in bone marrow aspirate smears (4 patients) and peripheral blood smears (all patients). Immunohistochemical studies demonstrated that every neoplasm was of B-cell lineage, CD20+, positive for other B-cell antigens, and CD3- or CD43-. Immunophenotypic studies revealed at least 2, and possibly 3, distinct immunophenotypic groups of B-cell IVL: CD20+ CD5+ (3 neoplasms), CD20+ CD5- CD10+ (1 neoplasm), and CD20+ CD5- CD10 unknown (1 neoplasm). B-cell IVL may be detected by morphologic examination of peripheral blood and bone marrow, and involvement of these sites may be more common than is reported in the literature. Immunophenotypic studies are helpful in establishing the diagnosis and suggest that B-cell IVL is a heterogeneous group of neoplasms that may arise from more than 1 normal B-cell precursor.