Cases Of Intravascular Large B-cell Lymphoma Research Articles

Clinicopathological features of intravascular large B-cell lymphoma and collision tumors of five cases

Objective: To investigate the clinicopathological characteristics, diagnosis and differential diagnosis of intravascular large B-cell lymphoma (IVLBCL) and its collision tumors. Methods: Five cases of IVLBCL were collected, including 2 cases of collision tumors, and 1 case complicated with liver cirrhosis. The morphology and immunophenotype were analyzed. The related literature was reviewed. Results: There were 2 females and 3 males, aged from 53 to 73 years, with a median age of 65 years. The tumors were located in the lower extremities, right cerebellar hemisphere, left kidney, bilateral nasal cavity, and liver, respectively. Cases 2 and 3 were incidentally found in meningioma and renal cell carcinoma tissues, respectively. Case 5 had a background of liver cirrhosis. Morphologically, atypical large lymphoid cells were located in small blood vessels and capillary lumen, with little cytoplasm, hyperchromasia, prominent nucleoli, and obvious mitotic figures. Immunohistochemically, the IVLBCL tumor cells expressed CD20 and PAX5; 2 cases were CD5 positive. One of the 5 cases was GCB phenotype, and 4 cases were non-GCB phenotype. All cases expressed C-MYC (positive rate was 10%-40%). PD-L1 was positive in 4 cases (positive rate was 60%-90%). Ki-67 proliferation index was 70%-90%. CKpan, CD3, TDT, and CD34 were negative. In case 2, meningioma cells were positive for PR, EMA, and vimentin, but negative for CKpan and PD-L1. In case 3, renal carcinoma cells were positive for CKpan, PAX8, EMA, vimentin, CAⅨ and CD10, while PD-L1 was negative. No EBER expression (by in situ hybridization) or C-MYC gene translocation (FISH, break-apart probe) was detected in any of the 5 cases. Three patients were followed up, and all died within 1-13 months. Conclusions: IVLBCL is a highly aggressive lymphoma, with occult clinical manifestations and poor prognosis. Collision tumors of IVLBCL are extremely rare. A better understanding of IVLBCL would help pathologists avoid misdiagnoses.

Intravascular Large B-Cell Lymphoma Genomic Profile Is Characterized by Alterations in Genes Regulating NF-κB and Immune Checkpoints.

Intravascular large B-cell lymphoma (IVLBCL) is an uncommon lymphoma with an aggressive clinical course characterized by selective growth of tumor cells within the vessels. Its pathogenesis is still uncertain and there is little information on the underlying genomic alterations. In this study, we performed a clinicopathologic and next-generation sequencing analysis of 15 cases of IVLBCL using a custom panel for the detection of alterations in 68 recurrently mutated genes in B-cell lymphomagenesis. Six patients had evidence of hemophagocytic syndrome. Four patients presented concomitantly a solid malignancy. Tumor cells outside the vessels were observed in 7 cases, 2 with an overt diffuse large B-cell cell lymphoma. In 4 samples, tumor cells infiltrated lymphatic vessel in addition to blood capillaries. Programmed death-ligand 1 (PD-L1) was positive in tumor cells in 4 of 11 evaluable samples and in macrophages intermingled with tumor cells in 8. PD-L1 copy number gains were identified in a higher proportion of cases expressing PD-L1 than in negative tumors. The most frequently mutated gene was PIM1 (9/15, 60%), followed by MYD88L265P and CD79B (8/15, 53% each). In 6 cases, MYD88L265P and CD79B mutations were detected concomitantly. We also identified recurrent mutations in IRF4 , TMEM30A , BTG2 , and ETV6 loci (4/15, 27% each) and novel driver mutations in NOTCH2 , CCND3 , and GNA13 , and an IRF4 translocation in 1 case each. The mutational profile was similar in patients with and without evidence of hemophagocytic syndrome and in cases with or without dissemination of tumor cells outside the vessels. Our results confirm the relevance of mutations in B-cell receptor/nuclear factor-κB signaling and immune escape pathways in IVLBCL and identify novel driver alterations. The similar mutational profile in tumors with extravascular dissemination suggests that these cases may also be considered in the spectrum of IVLBCL.

Clinicopathological features and MYD88 L265P mutation status of intravascular large B cell lymphoma

Objective: To study the clinicopathologic features and MYD88 L265P mutation status of intravascular large B cell lymphoma (IVLBCL). Methods: Fourteen cases of IVLBCLs were diagnosed from March 2014 to December 2019 at the First Affiliated Hospital of Zhengzhou University. The clinicopathologic features and prognosis were analyzed. Epstein-Barr virus encoded RNAs and MYD88 L265P mutation status were detected using in situ hybridization and Sanger sequencing, respectively. The follow-up data were obtained by telephone interview. Results: There were 6 males and 8 females with a median age of 62 years (range: 48-73 years). The involved anatomic locations were demonstrated by positron emission tomography-computed tomography, including adrenal gland (7/14), bone (6/14), central nerve system (4/14), skin (3/14), female reproductive system (3/14), local lymph nodes (3/14), prostate (2/14), liver and spleen (2/14), sphenoid sinus (1/14), penis (1/14), bladder (1/14), and right lung (1/14). Fever was the most common symptom (7/14), followed by neurologic symptoms and lower abdominal pain (2/14 each). The reminder symptoms included rash with edema, legs weakness and numbness, or postmenopausal bleeding (1/14 each). Eleven cases were at Lugano stage Ⅳ. Four cases were associated with the hemophagocytic syndrome, while 6 cases with bone marrow involved. Microscopically, the tumor cells were generally concentrated within the small-to-medium vascular lumens or sinusoids; they had centroblast-like appearance and showed large round or oval nuclei with slightly irregularities, coarse chromatin and 1-3 distinct nucleoli. One exception was the one case with an embryoid nuclei, reminiscent of anaplastic large cell lymphoma. The mitosis was not uncommon. Extravascular neoplastic cells were seen in two cases. The neutrophils could be appreciable in most of the cases (10/14). Immunophenotyping showed that CD20 and CD79α were diffusely and strongly positive in 14 cases; 12 cases were classified as the non-GCB subtype; 6 out of the 11 cases were double expressor lymphoma; 7 out of the 12 cases were CD5-positive. Twelve cases were EBER negative. The MYD88 L265P mutation was detected in 1 case (1/10). The duration of the follow-up ranged from 0.5 to 24.0 months, and 11 patients survived and 3 died. Conclusions: IVLBCL is rare. The most common type of IVLBCL in China is Asian type with scant tumor cells. Combination of clinical and immunohistochemical features can avoid most, if not all, misdiagnoses and missed diagnoses. Some IVLBCL cases may harbor the MYD88 L265P mutation, but the prevalence of MYD88 L265P mutation in the population still warrants additional studies.

Diffuse large B-cell lymphoma (DLBCL) with significant intravascular invasion. Close resemblance of its clinicopathological features to intravascular large B-cell lymphoma, but not to DLBCL-not otherwise specified.

Intravascular large B-cell lymphoma (IVLBCL) is defined by the World Health Organization (WHO) Classification as one type of extranodal large B-cell lymphoma and it is characterized by the selective growth of lymphoma cells within blood vessels with minimal extravascular invasion. According to the criteria, however, several reported cases of IVLBCL with significant extravascular invasion cannot be classified as IVLBCL. The purpose of the present study was to assess the clinicopathological significance of the WHO criteria for IVLBCL. We characterized clinical, histopathological, and immunohistochemical features of 11 patients with extranodal diffuse large B-cell lymphoma (DLBCL) with significant intravascular invasion (DLBCL-IV), and statistically compared their features with those of 11 patients with IVLBCL and 15 patients with extranodal DLBCL with virtually no intravascular invasion (DLBCL-noIV). When compared with the DLBCL-noIV group, the DLBCL-IV group was characterized by significantly higher rates of splenomegaly, hemophagocytosis, advanced stage disease, and CD5 expression; higher average platelet count, serum lactate dehydrogenase level, and serum ferritin level. Progression-free survival was significantly shorter in the DLBCL-IV group than the DLBCL-noIV group. In contrast, there were no significant differences in clinicopathological features between the DLBCL-IV and the IVLBCL groups. Our study suggests that DLBCL-IV should be regarded as IVLBCL-related.

Prognosis of Intravascular Large B Cell Lymphoma (IVLBCL): Analysis of 182 Patients from Global Case Series.

PurposeThis study provides an overview of the prognosis of intravascular large B cell lymphoma (IVLBCL) over the past 10 years and analyzes the possible relevant factors.Patients and MethodsWe conducted a literature search of case reports, case series, and retrospective studies of IVLBCL published from January 2008 to July 2018. After excluding inappropriate data, 103 publications were selected for the analysis. Statistical analyses of different treatment modalities, the effect of blood–brain barrier (BBB)-penetrating drugs, and prognostic factors for outcomes were performed.ResultsIn total, 182 pathologically confirmed cases of IVLBCL were included in our study. The results revealed that the 1- and 3-year overall survival rates were 42.3 and 11.5%, respectively, whereas the median overall survival was 340 days. Overall survival (450 days vs 180 days) and progression-free survival (420 days vs 150 days) were significantly longer in patients who received rituximab-containing regimens than in those treated with other regimens. For IVLBCL involving the CNS, regimens containing BBB-penetrating drugs failed to provide an additional survival benefit. In addition, lactic dehydrogenase levels ≥700 U/L, CNS involvement, and hemophagocytic syndrome were identified as unfavorable risk factors in patients with IVLBCL, whereas skin involvement appeared to be a protective factor.ConclusionRituximab-containing chemotherapy can improve the outcomes of patients with IVLBCL, but the prognosis remains unsatisfactory. Treatment regimens containing BBB-penetrating drugs failed to improve outcomes in patients with CNS-involved IVLBCL. Several factors affect the prognosis of patients with IVLBCL, and further research on the underlying mechanisms is needed.

A study of PD-L1 expression in intravascular large B cell lymphoma: correlation with clinical and pathological features.

Intravascular large B cell lymphoma (IVLBCL) is a rare, aggressive, extranodal large B cell lymphoma characterised by growth of tumour cells within the lumen of vessels, particularly capillaries. Programmed cell death ligand 1 (PD-L1) is a cell surface glycoprotein that interacts with programmed death 1 (PD-1) on the T cell surface, leading to modulation of the immune response. PD-L1 is a targetable immune check-point molecule that is expressed on neoplastic cells in various cancers, including a subset of lymphomas. We correlated the expression of PD-L1 with clinical and pathological findings in this rare disease. Eleven cases of IVLBCL were identified in the archives of Laboratory of Pathology at the National Cancer Institute, NIH. A panel of immunostains (CD20, CD3, CD5, PD-L1) was performed. The cases were classified as the classic form or the variant associated with haemophagocytic syndrome (HPS) based on published 2017 WHO criteria. Three cases (27.3%) were HPS variant and eight cases (72.7%) were the classic form. Five (45.5%) of 11 cases were CD5-positive; two of three (66%) were HPS variants and three of eight (37.5%) were classic form. Overall, four of nine evaluable cases (44.4%) were positive for PD-L1, three of which were classic. Only one CD5-positive case was PD-L1-positive, a classic variant. In summary, a subset of IVLBCL express PD-L1. Although limited, these data suggest that PD-L1 is expressed in both the so-called classic form as well as the HPS variant. PD-L1 is expressed irrespective of CD5 expression. Finally, detection of PD-L1 expression in a subset of IVLBCL lymphoma cases may identify patients who might benefit from targeted immunotherapy.

Random Skin Biopsies Before Brain Biopsy for Intravascular Large B-Cell Lymphoma

To evaluate effectiveness of random skin biopsies for intravascular large B-cell lymphoma (IVLBCL) with or without central nervous system (CNS) involvement. Data from 21 patients with suspected IVLBCL (7 with CNS involvement and 14 without CNS involvement) who underwent single (4 patients), double (1 patient), and random (16 patients) skin biopsies were retrospectively analyzed. IVLBCL was diagnosed in 16 patients (including 6 with CNS involvement). Sensitivity, specificity, and positive predictive value of random skin biopsies were 75%, 100%, and 100%. Ratio of tumor-positive biopsy samples to plasma soluble interleukin-2 receptor (sIL-2R) values was significantly correlated in cases with data on both variables. sIL-2R values in the 6 tumor-negative skin samples (median, 1415 U/mL; range, 487-3200 U/mL) were significantly lower than in tumor-positive skin samples (median, 3550 U/mL; range, 595-8700 U/mL) with at least 1 skin specimen obtained. Mean ratio of tumor-positive biopsy samples in IVLBCL cases with low sIL-2R (<3000 U/mL) was only 45%, indicating a requirement for 3-site multiple sampling. No differences in median sIL-2 values between cases of IVLBCL with and without CNS involvement were found (2795 U/mL vs. 3550 U/mL). Steroids administered before diagnosis yielded false-negative results in 3 of 5 IVLBCL cases (all false-negative cases were IVLBCL with CNS involvement), whereas none of 11 IVLBCL cases without steroid administration yielded false-negative results. Random skin biopsies before brain biopsy are recommended in patients with suspected IVLBCL regardless of CNS involvement, but low sIL-2R values and steroids may yield false-negative results.

A Small Case Series of Intravascular Large B-Cell Lymphoma with Unexpected Findings: Subset of Cases with Concomitant Extravascular Central Nervous System (CNS) Involvement Mimicking Primary CNS Lymphoma.

BackgroundIntravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal lymphoma with growth mainly in the lumina of vessels. We studied a small series of IVLBCL and focused on its central nervous system (CNS) involvement. MethodsSearching the medical records of Northwestern Memorial Hospital, we identified five cases of IVLBCL from January 2007 to January 2015. Clinical information, hematoxylin and eosin stained histologic slides and immunohistochemistry studies were reviewed for all cases. Polymerase chain reaction (PCR) analysis for the immunoglobulin (Ig) heavy and light chain gene rearrangement was performed on all five cases.ResultsThree of the five cases of IVLBCL were autopsies. Patients’ age ranged from 56 to 84. CNS involvement was present in two cases—in both patients, the CNS involvement showed an extravascular pattern with confluent sheet-like formation. PCR analysis confirmed that in one case the systemic intravascular and CNS extravascular components were clonally identical. ConclusionsIn a small case series of IVLBCL, we observed that CNS involvement by IVLBCL often has an extravascular morphology, but is clonally identical to the intravascular counterpart by PCR analysis. As IVLBCL can have a rapidly progressing poor outcome, it should be kept in the differential diagnoses for patients presenting with lymphoma of the CNS. The presence of extravascular growth patterns in the CNS should not exclude IVLBCL as a diagnosis.

High Frequency of Bone Marrow Involvement in Intravascular Large B-Cell Lymphoma.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of diffuse large B-cell lymphoma. Thirteen cases of IVLBCL with a median age of 56 years were analyzed retrospectively. Nonspecific symptoms such as fever and hepatosplenomegaly were the most common manifestations, and the bone marrow was usually involved in 8/13 (61.5%) cases. All tumors expressed CD20, and 12/13 (92.3%) of the tumors exhibited a nongerminal center phenotype by Hans algorithm. CD5 was expressed in 3/12 (25%) of the tumors. MYC was negative in all cases, and BCL2 was positive in 10/12 (83.3%) cases. Cytogenetic analysis revealed 5 cases that did not have rearrangements in either the MYC or the BCL2 gene. No association with Epstein-Barr virus was found. Seven of 11 patients received chemotherapy. The median survival time was 6 months. Patients with hemophagocytic syndrome had poor prognoses. Our study demonstrates that IVLBCL has a poor clinical outcome with a high frequency of bone marrow involvement and that the MYC gene may not play an important role in the poor prognosis of IVLBCL.

Concurrent thymic squamous cell carcinoma and disseminated intravascular large B-cell lymphoma. A previously unreported association

Abstract The incidence of extrathymic malignancies in patients with thymoma is significantly higher than in the general population. Non-Hodgkin lymphoma represents the most commonly associated tumor type. We report the concurrence of primary thymic squamous cell carcinoma and disseminated intravascular large B-cell lymphoma (IVL) in a 78-year-old man characterized by a rapidly fatal clinical course. To our knowledge, this is the first time that such an association is reported. Due to its rarity and the multiplicity of presentations, it is very difficult to diagnose this type of extranodal lymphoma antemortem. The intravascular lymphoma should be included in the differential diagnosis when a patient presents signs of a systemic disease and marked elevation of serum LDH. In this case the lymphoma may have been developed as a result of defective immunologic surveillance or impaired immunoregulation caused by the thymic carcinoma. In our case as in some other cases of IVL, diagnosis could only be conclusively confirmed on autopsy.

Intravascular large B-cell lymphoma with diffuse FDG uptake in the lung by 18FDG-PET/CT without chest CT findings

We report a rare case of intravascular large B-cell lymphoma (IVLBCL) with diffuse fluorodeoxyglucose (FDG) uptake in the lung by 18FDG-positron emission tomography/computed tomography (PET/CT). CT showed nodular shadow, whereas diffuse FDG uptake in PET/CT suggested IVLBCL in the lung. A random skin biopsy provided histological evidence of IVLBCL. The patient responded well to combination chemotherapy. Only two cases of IVLBCL in which diffuse pulmonary FDG uptake was demonstrated have been reported previously. FDG-PET/CT plus random skin biopsy may be useful for the early diagnosis of IVLBCL with pulmonary involvement even without convincing radiological findings in the lung.

Intravascular Large B-Cell Lymphoma (IVLBCL): A Study of 12 Cases with Special Emphasis on High Density Lipoprotein Cholesterol (HDL-C) Preceding Diagnosis

Abstract 5221 Background:Intravascular large B-cell lymphoma (IVLBCL) is a rare entity characterized by growth of neoplastic lymphocytes in the lumina of small blood vessels. Hallmarks of the disease include poor performance status, elevated lactate dehydrogenase levels, anemia, B symptoms and variable clinical presentation. In this study, we conducted a retrospective analysis of all identified cases of intravascular lymphoma that presented within a large integrated healthcare delivery system, reviewing clinical presentation, laboratory findings, pathological features and outcomes. Methods:Kaiser Permanente Northern California (KPNC) provides care to approximately 3.2 million members and maintains centralized database of all hospital and ambulatory visits, laboratory, pathology, radiology, and pharmacy records. We utilized electronic pathology record databases to identify all cases of intravascular lymphoma, defined by the World Health Organization from January 1995 - July 2010 using the following search terms: intravascular lymphoma, intravascular B-cell lymphoma, intravascular T-cell lymphoma, intra vascular lymphoma, malignant angioendotheliomatosis, and angiotropic large-cell lymphoma. Results:Twelve cases of IVLBCL were identified. Median age was 70 years, female to male ratio of 2 to 1. 50% were diagnosed in vivo. The median time of diagnosis from onset of symptoms was 1.5 months. Four patients underwent multiple biopsies prior to diagnosis. Of the six patients with in vivo diagnosis, three were made by bone marrow biopsy, one by small bowel resection, one by muscle biopsy, and one by abdominal fat pad biopsy.At the time of diagnosis, ten (83%) patients had B symptoms and seven (58%) patients had ECOG≥4. Other common organ systems involved on presentation included neurological (58%) and gastrointestinal symptoms or hepatic involvement (58%).Increased serum lactate dehydrogenase was seen in 92% of patients, anemia in 92% of patients and thrombocytopenia in 75% of patients. Elevated erythrocyte sedimentation rate seen in 67% of patients and elevated C-reactive protein in 58% of patients.Extremely low subnormal high density lipoprotein cholesterol level (HDL-C) was present in 10 of 11 patients with measured lipoprotein profiles. The median HDL-C was 22 mg/dl (range <4–56 mg/dl). Levels of low density lipoprotein cholesterol, total cholesterol and triglyceride levels were all within the normal range (median 61 mg/dl, 117 mg/dl and 230 mg/dl respectively).All patients had biopsy proven involvement of at least one organ. Four patients had complete autopsy. The sites of disease involvement included bone (4), gastrointestinal tract (4), renal (4), lymph node (3), spleen (3), central nervous system (2), liver (2), peripheral blood (1), hemophagocytosis syndrome (1).Four patients received chemotherapy. CHOP (1), R-CHOP (3). Overall survival was 8 days (CHOP); 38 days to >5 years (R-CHOP). The one patient in our cohort who achieved complete remission had localized bowel IVLBCL, treated with resection and three cycles of R-CHOP. Conclusions:Our cases represent a population-based ascertainment of IVLBCL within a large unselected clinic population. The clinical presentation and organ system involvement is variable. The disease is aggressive with poor outcomes. The unique finding in our series was the low HDL-C prior to diagnosis of IVLBCL. HDL-C may represent a possible preclinical indicator of this rare lymphoma. Disclosures:No relevant conflicts of interest to declare.

Intravascular Large B cell Lymphoma in Taiwan: An Asian Variant of Non-germinal-center Origin

Intravascular large B cell lymphoma (IVLBCL) is a rare variant of diffuse large B cell lymphoma. We reported the clinical and immunohistochemical characteristics of 10 cases of IVLBCL from Taiwan between 1995 and 2008. Clinical data were reviewed and immunoperoxidase stains were performed with antibodies against CD20, CD10, Bcl-6, MUM1, and CD5. There were eight males and two females with a median age of 59 years. Patients presented with dyspnea (5/10), fever (7/10), splenomegaly (5/10), and bone marrow involvement (8/10). Anemia (9/10), thrombocytopenia (6/10), and elevated serum lactate dehydrogenase or ferritin levels (8/10) were also common. Nine cases were CD20+CD10(-)Bcl-6(-), similar to non-germinal center B cells. Six out of seven patients survived after chemotherapy, but three cases with thrombocytopenia that precluded chemotherapy died within 2 months. Our cases of IVLBCL had a non-germinal center B origin and belonged to the Asian variant of this disease. The liver, spleen, and bone marrow, but rarely the skin or brain, were involved. Thrombocytopenia is a major risk factor for mortality in these cases.

Intravascular large B‐cell lymphoma with cutaneous manifestations: a clinicopathologic, immunophenotypic and molecular study of three cases

Intravascular large B-cell lymphoma (IVLBCL) is an extremely rare type of malignant lymphoma characterized by exclusive or predominant growth of neoplastic cells within the lumen of blood vessels. Cases in the literature predominantly involve the skin and central nervous system, with special emphasis on the 'cutaneous variant'. Three cases of IVLBCL with cutaneous manifestations, including two systemic IVLBCL and one cutaneous variant, were described in this study. In all cases, clinical presentation and follow-up data were meticulously evaluated and immunophenotypic and molecular studies were performed. All three cases displayed the B-cell phenotype and showed monoclonality with immunoglobulin heavy chain gene rearrangement. Bcl2 was expressed in the two systemic IVLBCL cases with fatal outcomes. The third patient with the 'cutaneous variant' achieved complete remission and a longer survival time of 15 months after chemotherapy. Skin manifestations and neurological findings, although to different degrees, are important clues to the diagnosis of IVLBCL. As most IVLBCL are grouped into the post-germinal center B-cell subtype of diffuse large B-cell lymphoma, Bcl2 expression may be correlated with a worse prognosis in IVLBCL. The cutaneous variant of IVLBCL has a significantly better outcome than that of systemic IVLBCL.

Kidney-limited intravascular large B cell lymphoma: a distinct variant of IVLBCL?

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.

A Cumulative Series from 14 Western Countries Suggests That Rituximab Significantly Changed the Dismal Natural History of Intravascular Large B-Cell Lymphoma (IVL) .

Background: IVL is a typically disseminated and aggressive malignancy that results in severe multi-organ failure and poor survival. There are two well-recognized clinical forms of IVL (“classical” and “hemophagocytosis-related”) that exhibit significant clinical, biological and prognostic differences, with substantial variability between Japanese and Western patients (pts). Treatment with anthracycline-based chemotherapy is associated with disappointing results in both groups of pts (3-yr OS ~35%), but encouraging results of the addition of rituximab in a retrospective Japanese series were recently reported. Conversely, nothing is known on the efficacy and tolerability of rituximab in IVL pts diagnosed in Western countries since available information is limited to a few single case reports and a small retrospective series.Methods: To investigate the role of rituximab as upfront treatment for IVL in Western countries, we contacted all the authors of previous pertinent reports, asking for updated follow-up of their published and unpublished cases of IVL, treated with or without rituximab at their Institutions, from August 2002 to June 2008. Three-fourth of investigators replied, providing complete information and updated follow-up of 41 pts. Seven pts were excluded due to death before treatment initiation (n=2) and rituximab administration only after relapse/progression (n=5). The remaining 34 pts treated with rituximab, either alone (n=3) or in combination with anthracycline-based chemotherapy (n=31), constituted the study population.Results: Median age of the 34 pts was 65 yrs (range 20–86; 18 males), with ECOG-PS 3–4 in 32% of pts, elevated LDH levels in 86%, B-symptoms in 70%, and stage-IV disease in 73%, with bone marrow (35%), skin (32%) and CNS (26%; n=9) being the most commonly involved organs. Rituximab (375 mg/m2) was administered concurrently with the 1st course of chemotherapy (within the same day) in all pts except 2 (administered from the 2nd course); this information was not available in 2 cases. None of the patients received rituximab maintenance. Chemotherapy regimens included CHOP21 (n=29), CEOP21 (n=1) and CHOP14 (n=1). Upfront treatment included high-dose methotrexate in 1 of the 9 pts with CNS involvement; 4 of the 25 pts without CNS involvement at diagnosis received CNS prophylaxis (HD-MTX in 1; intrathecal chemo in 3). Twenty-nine pts (85%) completed the planned program; 2 pts died of infectious complications, 1 pt experienced disease progression, 1 pt interrupted chemotherapy for toxicity and proceeded with rituximab alone, 1 pt is still receiving treatment. Rituximab was generally well tolerated, with mild side effects in 4 pts (12%); it was discontinued due to severe toxicity only in 2 (6%) pts (pulmonary failure and coma after the first course). After treatment (n=33), 29 (88%) pts achieved a complete remission, with an ORR of 91%. At a median follow-up of 2 years, 6 pts experienced relapse, with CNS involvement in 5; only 1 of these pts had CNS disease at diagnosis. Twenty-eight pts are alive, with a 3-yr OS of 81%; 2 pts died of toxicity, 1 died of unrelated causes and only 3 pts died of lymphoma, all of them after CNS relapse.Conclusions: This is the largest cumulative experience with upfront rituximab in IVL pts diagnosed in Western countries. The addition of rituximab was safe in 94% of cases and significantly improved the dismal prognosis of IVL. CNS was the principal failure site after R-CHOP therapy. To reduce rituximab side effects, perhaps by administration delay of 3–4 days at the 1st course in pts with high tumour burden, and to improve CNS disease control by using drugs with a better CNS bioavailability are two advisable strategies to further improve therapeutic efficacy in pts with IVL.

Intravascular large B-cell lymphoma: report of two autopsy cases with literature review

To study the clinicopathologic features of intravascular large B-cell lymphoma (IVLBCL). Two autopsy cases of IVLBCL were retrieved from the archival file. The clinicopathologic features, immunohistochemistry and molecular findings were studied. The deceased were 70-year-old and 50-year-old males. Both of them had complained of a sudden onset of weakness and numbness of lower extremities. The clinical course deteriorated rapidly, with multi-organ failure. They died 85 days and 44 days after the presentation, respectively. Post-mortem examination did not reveal any mass lesion, except the presence of multiple skin and epicardium nodules, ranging from 0.5 cm to 2.5 cm in diameter, in the first patient. Pericardial effusion, ascites and pleural effusion were also observed. Histologically, neoplastic lymphoid cells filled up the small vessel lumina in many organs, including brain, hypophysis, spinal cord, spinal nerve roots, heart, lungs, kidneys, liver, spleen, digestive tract, pancreas, adrenal, thyroid, testes and lymph nodes. The tumor cells were relatively monotonous and of medium to large in size with round vesicular nuclei and 1 to 3 small basophilic nucleoli. Immunohistochemical study showed that the lymphoma cells expressed B-cell markers CD20 and CD79a, occasionally positive for CD5 and bcl-2 but negative for CD3, bcl-6, CD10, CD30, myeloperoxidase and cytokeratin. In-situ hybridization for Epstein-Barr virus-encoded RNA was negative. The proliferative index, as demonstrated by Ki-67 staining, was about 80%. Molecular study showed the presence of immunoglobulin heavy chain gene rearrangement in both cases, T-cell receptor-gamma gene rearrangement was not found. IVLBCL may present as neurological disturbance and carries distinctive morphologic characteristics, immunophenotype and molecular findings. The prognosis of this disease is often dismal.

Intravascular Lymphomatosis: A Study of 20 Cases in Thailand and a Review of the Literature

BackgroundAccording to the World Health Organization classification (2001), intravascular large B-cell lymphoma (IVLBCL) is characterized by the presence of lymphoma cells only in the lumina of small vessels. It has not been proven whether IVLBCL is a specific clinicopathologic entity. Intravascular large B-cell lymphoma and other intravascular lymphomatoses (IVLs), including IVL with B-cell phenotype and extravascular growth (B-IVL) and IVL with T-cell phenotype (T-IVL), were compared in a series of cases diagnosed at a single institution and in cases reported in the literature. Patients and MethodsTwenty cases of IVL diagnosed among 1826 consecutive cases of non-Hodgkin's lymphoma (NHL,1.1%) at Siriraj Hospital included 3 cases of IVLBCL, 14 cases of B-IVL, and 3 cases of T-IVL. In the literature, 102 cases of IVLBCL, 88 cases of B-IVL, and 18 cases of T-IVL were described in sufficient detail to be analyzed. ResultsAll 3 groups were quite similar in clinical manifestations and outcome. Contrary to the previous review of 79 cases of IVL in 1989, blood, marrow, and nodal involvement could be detected in approximately 30% of cases. Patients who received chemotherapy had better survival than patients without treatment—statistically significant in IVLBCL and B-IVL (P < 0.05). Cases with skin involvement had better survival than cases without skin involvement—statistically significantly in T-IVL (P < 0.05). ConclusionThese results indicate that IVLBCL is not different from B-IVL or T-IVL in a biologic sense, and IVL seems to be better terminology than IVLBCL because it includes the T-cell phenotype that constitutes approximately 9% of cases. Early diagnosis is very important because chemotherapy significantly prolongs survival.