Frequent genetic alterations in immune checkpoint-related genes in intravascular large B-cell lymphoma.

Intravascular large B-cell lymphoma (IVLBCL) is a unique type of extranodal lymphoma characterized by selective growth of tumor cells in small vessels without lymphadenopathy. Greater understanding of the molecular pathogenesis of IVLBCL is hampered by the paucity of lymphoma cells in biopsy specimens, creating a limitation in obtaining sufficient tumor materials. To uncover the genetic landscape of IVLBCL, we performed whole-exome sequencing (WES) of 21 patients with IVLBCL using plasma-derived cell-free DNA (cfDNA) (n = 18), patient-derived xenograft tumors (n = 4), and tumor DNA from bone marrow (BM) mononuclear cells (n = 2). The concentration of cfDNA in IVLBCL was significantly higher than that in diffuse large B-cell lymphoma (DLBCL) (P < .0001) and healthy donors (P = .0053), allowing us to perform WES; most mutations detected in BM tumor DNA were successfully captured in cfDNA and xenograft. IVLBCL showed a high frequency of genetic lesions characteristic of activated B-cell-type DLBCL, with the former showing conspicuously higher frequencies (compared with nodal DLBCL) of mutations in MYD88 (57%), CD79B (67%), SETD1B (57%), and HLA-B (57%). We also found that 8 IVLBCL (38%) harbored rearrangements of programmed cell death 1 ligand 1 and 2 (PD-L1/PD-L2) involving the 3' untranslated region; such rearrangements are implicated in immune evasion via PD-L1/PD-L2 overexpression. Our data demonstrate the utility of cfDNA and imply important roles for immune evasion in IVLBCL pathogenesis and PD-1/PD-L1/PD-L2 blockade in therapeutics for IVLBCL.

Pure intravascular recurrence of CD5-positive diffuse large B-cell lymphoma primarily arising from the nasal cavities.

BACKGROUND: CD5-positive diffuse large B-cell lymphoma (DLBCL) and intravascular large B-cell lymphoma (IVL) are recognized as rare subsets of large B-cell lymphoma with poor prognosis. These two categories have similar clinicopathological features suggesting that they might overlap. CASE PRESENTATION: We present a case of a 72-year-old man with submental tumors. Positron emission tomography/computed tomography (PET/CT) showed tumors in the nasal and paranasal region and multiple submental and jugular swollen lymph nodes with abnormal uptake of 18F-fluorodeoxyglucose (FDG). Histology of biopsy from nasal tumors showed diffuse infiltration of large lymphoid cells, which showed positive expressions for CD20, CD79a, CD5 and negative for CD3 on immunohistochemistry. Thus, a CD5-positive DLBCL was diagnosed. After administration of 8 cycles of R-THPCOP (rituximab, pirarubicin, cyclophosphamide, vincristine and prednisolone), complete remission was achieved. Eight months after the first chemotherapy dose, local recurrence occurred. After salvage chemotherapy, nasal and paranasal tumors and lymph node swelling disappeared on PET/CT images, although the patient suffered from respiratory disturbance. A random skin biopsy revealed IVL, which was consistent with intravascular recurrence of CD5-positive DLBCL. Bone marrow smears showed hemophagocytosis. CONCLUSION: We present a rare case of primary CD5-positive DLBCL that relapsed as pure IVL after chemotherapy. Our case suggests that CD5-positive DLBCL is closely related to IVL.

Cutaneous Involvement in a Case of Intravascular T-Cell Lymphoma With a γδ Phenotype.

Intravascular lymphomas (IVL) are uncommon variants of extranodal non-Hodgkin which are usually difficult to diagnose because of their lack of clinical uniformity. Most cases are of B-cell differentiation followed by natural killer/T-cell differentiation and underlying CD30 lymphoproliferative conditions. Epstein-Barr virus is pathogenically related in most of the natural killer/T-cell variants, and the skin is a common site of presentation noted in approximately 40% of cases. Recently, cases with uncommon phenotypes have been described, expanding our understanding of the pathogenesis of this condition. In this report, we describe a 67-year-old man with a 3-month history of constitutional symptoms associated with linear purpuric macules on the trunk, pancytopenia, and high levels of serum lactate dehydrogenase. He had been followed for longstanding adenopathy and hepatosplenomegaly. Skin biopsy demonstrated a intravascular lymphocytic proliferation with positivity for CD3, CD2, CD5, and γδ T-cell receptor marker; in situ hybridization Epstein-Barr virus RNA was negative. The patient was subsequently treated with chemotherapy and allogenic stem cell transplant. He remains in complete remission 6 months posttransplant. Although the presence of hepatosplenomegaly led to consideration of a hepatosplenic T-cell lymphoma, it was pre-existing for several years making the diagnosis doubtful. To our knowledge, this is the first case report of an IVL γδ T-cell lymphoma.

Intravascular NK-cell lymphoma: a case report and review of the literature.

BACKGROUND: Intravascular NK-cell lymphoma (IVNKL) is an extremely rare variant of non-Hodgkin lymphoma. To our knowledge, there are only a few cases reported in the English literature. Here, a case of a 29-year-old male with IVNKL involving the skin of the trunk and 4 extremities and liver is presented. A comprehensive literature review is undertaken to summarize the clinical and pathological features of this disorder. FINDINGS: In our case, large neoplastic lymphoid cells are restricted to the lumen of small vessels and exhibit the phenotype of a true NK cell. The morphology and immunophenotype, positivity of EBER and NK-cell origin are similar to other IVNKL cases. In addition, some cases including ours carry a poor prognosis as multiple systems or vital organs are involved. CONCLUSION: In summary, we report a case of an unusual intravascular lymphoma of NK-cell lineage that displays both clinical and pathological features and compare it with other differential diagnoses. It is important to recognize this rare entity to make an appropriate diagnosis and achieve a better understanding regarding the treatment and prognosis.

Intravascular large B-cell lymphoma secondary to lymphoplasmacytic lymphoma: a case report and review of literature with clonality analysis.

Intravascular large B-cell lymphoma (IVLBCL) can be a fatal malignancy mainly because of difficulty in early detection. Due to the lack of specific clinical manifestations, early detection of IVLBCL remains a challenge, especially in the presence of comorbidities. Lymphoplasmacytic lymphoma (LPL) is an indolent B-cell lymphoma accompanied by monoclonal immunoglobulin M protein in most patients, and known to be associated with high risk of secondary hematological malignancies. Here, we report a patient who developed IVLBCL during treatment for LPL that presented a diagnostic challenge. Rearrangement analysis of the immunoglobulin heavy chain revealed the different clonal origins of two lymphomas, implying a predisposition of LPL to develop unrelated secondary lymphoma. Secondary lymphoma including IVLBCL during the treatment for LPL deserves consideration in order to facilitate early diagnosis and intervention.

Unusual variants of intravascular malignant hematopoietic neoplasms: a report of 4 cases and review of the literature.

Intravascular lymphoma (IVL) is a rare and fatal disease, typically of B-cell origin. Most of the reported cases have been for primary IVL, and only a minority of cases are of recurrent IVL. In addition, recurrent IVL occurring after treatment of anaplastic large T-cell lymphoma (ALCL) by contrast is extraordinarily rare. In this article, we present 3 cases of recurrent cutaneous IVL (2 men and 1 woman) and compare these with 1 case of primary IVL. The patients ranged in age from 56 to 73 years and were encountered in the routine dermatopathology and consultative practices of one of the authors. In 2 of the cases, the patients had intravascular cutaneous ALCL. In regard to the remaining 2 patients, 1 patient had a recurrent intravascular cutaneous follicular lymphoma in the context of a history of diffuse large B-cell lymphoma. The fourth patient had a primary intravascular ALCL because there was no antecedent history. In all cases, the skin biopsies showed large aggregates of atypical cells within the blood vessels. Phenotypic studies revealed variable staining results with CD29 and CD54 in cases of recurrent IVL compared with those of primary IVL. Recurrent cutaneous IVL represents a somewhat heterogeneous group of lymphoproliferative disorders with a distinct variant being in the context of intravascular ALCL; the mechanisms of intravascular localization in recurrent IVL are likely different from those of primary IVL.

A rare case of intravascular large T-cell lymphoma with an unusual T helper phenotype.

Although most cases of intravascular large cell lymphoma exhibit a B-cell phenotype, less than 50 cases in the literature describe a T-cell or natural killer cell phenotype and, of these, the majority are CD3+, CD4-, CD5-, CD30-, CD56+, TIA-1+, and EBER+. We present a case of a rare intravascular large T-cell lymphoma in a 59-year-old man with an unusual CD3+, CD4+, CD5-, CD30+, CD56-, TIA-1-negative and EBER-negative phenotype. This T helper or CD30 phenotype is particularly uncommon. To our knowledge, it has only been described once before and never in the absence of the cytotoxic marker TIA-1. This case exemplifies the particular diagnostic challenges raised by intravascular large cell lymphomas generally and should encourage the use of endothelial immunohistochemical staining in questionable cases. While evaluating skin punch biopsies, it is critical to keep this rare entity on the differential diagnosis along with the relatively more common intravascular large B-cell lymphoma and epithelial malignancies. Additionally, our understanding of intravascular large natural killer/T-cell lymphoma as a heterogeneous phenotypic entity continues to evolve. This case demonstrates that the degree of this phenotypic heterogeneity may be even greater than previously thought.

Intravascular large B cell lymphoma in Taiwan: an Asian variant of non-germinal-center origin.

BACKGROUND/PURPOSE: 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. METHODS: Clinical data were reviewed and immunoperoxidase stains were performed with antibodies against CD20, CD10, Bcl-6, MUM1, and CD5. RESULTS: 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. CONCLUSION: 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.

Analysis of CXCL9 and CXCR3 expression in a case of intravascular large B-cell lymphoma.

Intravascular large B-cell lymphoma is a rare disease with multiorgan involvement that also affects the skin. Skin manifestations include purpuric to red macules, plaques, or nodules with occasional edema and tenderness. We report a 68-year-old woman with bilateral leg edema and occasional high fever. A biopsy specimen from a subcutaneous nodule showed that the blood vessels in the dermis and subcutaneous tissue were filled with irregularly shaped chromatin-rich large atypical lymphocytes positive for CD20 and bcl-2, consistent with the diagnosis of intravascular large B-cell lymphoma. In addition, immunohistochemical analysis showed expression of CXCR3 in the atypical lymphocytes; its ligand, CXCL9, was detected in blood vessels. Although limited to a single case, our study could provide a possible new clue to the pathogenesis of intravascular large B-cell lymphoma by virtue of the characteristic expression of CXCL9-CXCR3.

[Asian variant of intravascular large B-cell lymphoma diagnosed by bone marrow biopsy].

A 63-year-old male presented with fever and general malaise in June 2004. On admission hepatosplenomegaly was apparent, but without lymphadenopathy. The laboratory examination revealed pancytopenia and increased levels of lactate dehydrogenase, direct bilirubin and soluble interleukin-2 receptor. Histological analysis of the bone marrow biopsy specimen demonstrated proliferation of atypical lymphoid cells positive for CD20 in the small capillaries, leading to the diagnosis of the Asian variant of intravascular large B-cell lymphoma (AIVL). The presence of rearrangement of the immunoglobulin gene confirmed the diagnosis. The patient responded well to CHOP therapy followed by seven courses of rituximab-combined CHOP therapy and has remained in complete remission up to the present. This case implies that bone marrow biopsy could be a useful examination for diagnosing AIVL and that rituximab-combinedchemotherapy could improve survival in patients with the disease.

Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5.

Intravascular large B-cell lymphoma (IVLBCL) is pathologically distinct with a broad clinical spectrum and immunophenotypic heterogeneity. A series of 96 patients with IVLBCL (median age, 67 years; range, 41-85 years; 50 men) was reviewed. Anemia/thrombocytopenia (84%), hepatosplenomegaly (77%), B symptoms (76%), bone marrow involvement (75%), and hemophagocytosis (61%) were frequently observed. The International Prognostic Index score was high or high-intermediate in 92%. For 62 patients receiving anthracycline-based chemotherapies, median survival was 13 months. CD5, CD10, Bcl-6, MUM1, and Bcl-2 were positive in 38%, 13%, 26%, 95%, and 91% of tumors, respectively. All 59 CD10- IVLBCL cases examined were nongerminal center B-cell type because they lacked the Bcl-6+MUM1- immunophenotype. CD5 positivity was associated with a higher prevalence of marrow/blood involvement and thrombocytopenia and a lower frequency of neurologic abnormalities among patients with CD10-IVLBCL. Compared with 97 cases of de novo CD5+CD10-diffuse LBCL, 31 cases of CD5+CD10-IVLBCL exhibited higher frequencies of poor prognostic parameters, except age. Multivariate analysis in IVLBCL revealed that a lack of anthracycline-based chemotherapies (P<.001, hazard ratio [HR]: 9.256), age older than 60 years (P=.012, HR: 2.459), and thrombocytopenia less than 100x10(9)/L (P=.012, HR: 2.427) were independently unfavorable prognostic factors; CD5 positivity was not. Beyond immunophenotypic diversity, IVLBCL constitutes a unique group with aggressive behavior.

Intravascular lymphoma: a role for single-agent rituximab.

Intravascular lymphoma is a rare aggressive systemic neoplasm with neurological and cutaneous presentation, which commonly eludes the diagnosis ante mortem. We document a case of intravascular lymphoma in a 65-year-old man who presented with altered mental status, fevers and weight loss. The diagnosis was made by random skin biopsies demonstrating an intravascular, CD20 positive cellular infiltrate. Initial treatment consisted of cyclophosphamide, vincristine, doxorubicin, prednisone and rituximab. Because of disease progression, the therapy was switched to weekly rituximab after the first cycle. A complete response was observed with resolution of symptoms and laboratory abnormalities. The patient remains in remission 3 years after completion of therapy. This is the first case report to describe a sustained remission following single-agent rituximab in the patient with neurologic involvement of intravascular lymphoma who failed antracycline-based therapy. Single-agent rituximab has activity in this disease and may be considered as a treatment option.

Intravascular lymphoma: magnetic resonance imaging correlates of disease dynamics within the central nervous system.

BACKGROUND: Intravascular lymphoma (IVL) is a rare non-Hodgkin's lymphoma with relative predilection for the central nervous system. In the absence of extraneural manifestations, the disease is not recognised until autopsy in the majority of cases underlining the need for new clinical markers. METHODS: This is a retrospective series of five patients with IVL seen at a single institution over three years. An advanced magnetic resonance imaging (MRI) protocol was performed at various time points prior to diagnosis and during treatment. RESULTS: MRI revealed multiple lesions scattered throughout the cerebral hemispheres; the brainstem, cerebellum, and spinal cord were less frequently involved. On initial presentation, hyperintense lesions were seen on diffusion weighted images suggestive of ischaemia in three of four patients in whom the images were obtained at that time point. In four patients lesions were also identifiable as hyperintense areas on fluid attenuated inversion recovery (FLAIR) sequences. Initial contrast enhancement was encountered in three cases. Diffusion weighted imaging lesions either vanished or followed the typical pattern of an ischaemic small vessel stroke with evolution of abnormal FLAIR signal followed by enhancement with gadolinium in the subacute stage and tissue loss in the chronic stage. Diffusion weighted imaging and FLAIR abnormalities proved to be partially reversible, correlating with the response to chemotherapy. CONCLUSION: We provide the first detailed description of the dynamic pattern of diffusion weighted MRI in IVL. These patterns in combination with systemic findings may facilitate early diagnosis and serve as a new tool to monitor treatment response.

Diffuse neurodeficits in intravascular lymphomatosis with ADAMTS13 inhibitor.

Inhibitory antibody to von Willebrand factor (vWF)-cleaving protease (ADAMTS13) was detected in a patient with intravascular lymphomatosis. The increased serum level of the antibody paralleled an increase in the expression of uncleaved vWF, which might cause microvascular thrombosis and platelet consumption. Malignant cell proliferations with superimposed thrombosis within the lumina throughout the entire vasculature account for diffuse neurodeficits observed in the patient.

Testicular ischemia due to intravascular large B-cell lymphoma: a novel presentation in an immunosuppressed individual.

A 56-year-old man presented with fever, disorientation, and testicular pain. He was receiving azathioprine immunosuppression for autoimmune hepatitis. Orchiectomy identified occlusion of spermatic cord vessels by intravascular large B-cell lymphoma (IVLBL) and ischemic changes in the testis. Tumor cells were positive for CD 10, CD 20, CD 30, and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) and early region RNA (EBER). He was treated with the cessation of azathioprine, chemotherapy, anti-CD 20 immunotherapy, and radiotherapy. Twenty months after diagnosis, he is alive with no evidence of lymphoma or hepatitis. This is the first report of IVLBL presenting with testicular ischemia. It highlights the importance of prompt diagnosis and intervention to achieve durable response. That this lymphoma arose in the setting of immunosuppressive therapy introduces additional complexity relating to pathogenesis, clinical behavior, and treatment.

Angiolymphoid hyperplasia with eosinophilia: a rare artery lesion.

BACKGROUND: Angiolymphoid hyperplasia with eosinophilia (AHE) is a rare skin condition of unknown aetiology. The lesion seems neoplastic in nature, or at least an abnormal vasoproliferative reaction. CASE REPORT: A 40-year-old man presented with an 18-month history of erythematous papula over the right temporal area without a history of trauma. The patient reported a history of Hodgkin lymphoma at the age of 20, treated by radiochemotherapy. A subcutaneous nodule was found on the superior branch of the right temporal artery. An echocolordoppler revealed a normal temporal artery flow with pariental thickness. An excisional biopsy was performed and the patient remained asymptomatic at 24 months. The histological diagnosis was angiolymphoid hyperplasia with eosinophilia of the temporal artery. CONCLUSION: More appropriate studies are necessary to assess whether AHE is a manifestation of an unknown immunological disorder. If a correlation could be found between an altered immunological system and AHE, an intensive follow-up could be applied to patients. We report this case to encourage further studies to highlight potential challenges in the diagnosis and management of variants of vascular processes, such as AHE.

Prevalence of intravascular large B-cell lymphoma with bone marrow involvement at initial presentation.

We used immunohistochemical analysis to investigate 146 bone marrow (BM) clot specimens from patients with fever of unknown origin (FUO) (n = 124) or hemophagocytic syndrome (HPS) (n = 22). Intravascular lymphoma (IVL) primarily involving BM was detected in 12 (8.2%) of the 146 patients. Diagnosis was based on the presence of CD20+ and CD79a+ tumor cells confined within the lumina of sinuses and surrounded by CD34+ endothelial cells. Of the 12 IVL cases, 6 were CD5+; of these 6 CD5+ cases, 5 were positive for vimentin. The finding of a considerably high prevalence of IVL tumor cells in BM from patients with FUO or HPS suggests that immunohistochemical examination of BM may be helpful in the diagnosis of IVL in these patients. Vimentin coexpression in CD5+ IVL might be evidence of origin from a subset of prefollicular B-cells.

Fatal tumor thrombosis due to an inferior vena cava leiomyosarcoma in a patient with antiphospholipid antibody syndrome.

We describe a patient with antiphospholipid antibody syndrome (APS) who died because of relentless inferior vena cava (IVC) tumor thrombosis due to an unsuspected leiomyosarcoma. Laboratory confirmation for APS was provided by functional identification of a lupus anticoagulant and anticardiolipin IgG and anti-beta2-glycoprotein I IgM antibodies. Although sensitive for detecting vascular obstruction, radiocontrast venography and magnetic resonance imaging and angiography detected the IVC thrombosis but failed to distinguish its malignant nature. Concomitant refractory thrombocytopenia prevented further invasive diagnostic and therapeutic maneuvers for progressive, severe IVC thrombosis unresponsive to aggressive treatment of APS. Deep venous thrombosis refractory to anticoagulant and immunomodulatory therapies in a patient with APS may be due to a concomitant underlying malignancy, such as a leiomyosarcoma, causing vascular obstruction.

Human endothelial cells expressing polyoma middle T induce tumors.

The middle T oncogene of murine polyomavirus (PymT) rapidly transforms and immortalizes murine embryonic endothelial cells (EC), leading to the formation of vascular tumors in newborn mice, by recruitment of host, non-transformed EC. These tumors are reminiscent of human vascular tumors like cavernous hemangioma, Kaposi's sarcoma or those characterizing Kasabach-Merrit syndrome. Here we investigate the in vitro and in vivo behavior of human primary umbilical cord vein EC expressing PymT. While PymT has been unable to transform human fibroblasts in earlier experiments or controls done here, mT expressing EC (PymT-EC) derived by infection with pLX-PymT retrovirus induce hemangiomas in nu/nu mice. These tumors contain not only human cells but also recruited mouse EC as shown by the presence of human and murine CD31 positive EC. In vitro analysis shows that PymT-EC retain endothelial specific markers like CD31, Von Willebrand factor, and VE-cadherin, and reach the confluence without signs of overgrowth. They are also responsive to vascular endothelial growth factor-A. However, their proliferation rate is increased. The balance between urokinase-type plasminogen activator and plasminogen activator inhibitor-1 is modified; RNA and catalytic activity for the former are elevated while PAI-1 RNA is reduced. In contrast with murine model, where the PymT EC cells become immortal, the effects induced by PymT in human EC are transient. After 12-15 passages, human PymT EC stop proliferating, assume a senescent phenotype, and lose the ability to induce hemangiomas. At the same time both the amount of middle T protein and the level of activation of pp60c-src lower.