Intravascular Large Cell Lymphoma Research Articles

A Puzzling Case of Rapidly Progressive Global CNS Deterioration From Intravascular Large-Cell Lymphoma

Intravascular large-cell lymphoma is a rare, aggressive subtype of B-cell lymphoma leading to microvascular organ dysfunction. It often presents nonspecifically and is difficult to diagnose, with a rapidly progressive course. It classically presents with “B” symptoms, although any organ system can be affected. Neurologic symptoms vary but can involve rapid neurologic deterioration. It lacks association with a primary tumor or malignant cells in the blood or bone marrow, so diagnosis is difficult, made only by biopsy of affected tissues. Because of its rarity and often aggressive course, increased clinician familiarity is key to facilitating early diagnosis and proper management.

Intravascular large cell lymphoma. 18F-FDG PET/CT and necropsy findings

Intravascular large cell lymphoma. 18F-FDG PET/CT and necropsy findings

Intravascular Cutaneous Disorders. A Clinicopathologic Review.

Intravascular proliferations of the skin are clinically heterogeneous and may present with a wide range of clinical features, including violaceous papules, nodules, plaques, or other unspecific cutaneous lesions. Histopathologically, these conditions are characterized by proliferation of different cell types within the lumina of dermal vessels and endothelial cell hyperplasia. Immunohistochemistry is the best tool to identify the nature of the intravascular proliferating cells and the type of involved vessel. In this review, we analyzed the clinicopathologic and immunohistochemical characteristics of intravascular large cell lymphoma, T-cell and natural killer-cell intravascular large cell lymphoma, intralymphatic variant of CD30+ cutaneous lymphoproliferative disorders, benign atypical intralymphatic CD30+ T-cell proliferation, reactive angioendotheliomatosis, intralymphatic histiocytosis, papillary intralymphatic angioendothelioma or Dabska tumor, glomeruloid hemangioma, papillary hemangioma, intravascular papillary endothelial hyperplasia or Masson phenomenon, and the intralymphatic involvement of Merkel cell carcinoma, cutaneous metastases, and cutaneous angiosarcoma.

Intravascular large cell lymphoma mimicking central nervous system vasculitis in a patient with rheumatoid arthritis (RCD code: VI-2C.2)

Increased incidence of lymphomas in patients with rheumatoid arthritis has been reported and may be associated with several factors, including genetic factors, chronic inflammation, and immunosuppressive treatment. Intravascular large cell lymphoma (ILCL) is a rare subtype of large cell lymphoma with undetectable lymphoma cells in peripheral blood and without any extravascular localisation. Diag- nosis is often delayed because bone marrow, spleen, and cerebrovascular fluid may not be involved and there are no specific laboratory studies for intravascular large cell lymphoma. We report the case of a 63-year-old woman with a 10-year history of seropositive rheumatoid arthritis and intravascular large cell lymphoma recognised at autopsy. The patient presented with progressive central nervous system-related symptoms mimicking vasculitis without lymphadenopathy or bone marrow involvement. Malignant lymphoproliferative disorders should be considered in RA patients with varying clinical presentation, even in the absence of lymphadenopathy and bone marrow involvement. JRCD 2018; 4 (1): 15-17.

A rare cause of first seizure

A 52 year old man with no history of seizures presented following multiple generalized tonic-clonic seizures at home. He had a recent history of anorexia, weight loss and incoordination. Clinical examination revealed reduced level of consciousness, left-sided weakness and neglect. T2-weighted MRI (Fig. 1) and MRI SWAN (Fig. 2) are provided.Fig. 2MRI SWAN demonstrates widespread punctate hypodense foci.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A.Glioblastoma multiformeB.Acute Haemorrhagic EncephalomyelitisC.Intravascular lymphomaD.Primary CNS lymphomaE.Progressive multifocal leukoencephalopathy Answer: Intravascular lymphoma The MRI scan (Fig. 1) demonstrates T2 hyperintensity in right frontal lobe with central irregular enhancement and other foci of hyperintensity. MRI SWAN (Fig. 2) demonstrates multiple punctate hypointense foci consistent with microhemorrhages. Brain biopsy confirmed CD10+ Intravascular Lymphoma (IVL). IVL is a rare form of Non-Hodgkin lymphoma characterized by lymphocyte proliferation within blood vessels [[1]Ponzoni M. Ferreri A.J. Campo E. et al.Definition, diagnosis, and management of intravascular large B-cell lymphoma: proposals and perspectives from an international consensus meeting.J Clin Oncol. 2007; 25: 3168Crossref PubMed Scopus (345) Google Scholar]. Radiologic findings are largely nonspecific and brain biopsy is required for diagnosis. Although hemorrhagic infarcts are well described in the pathological literature, the potential for microhemorrhages on SWAN or T2 sequences has been rarely described [[2]Alexandrescu S. Orengo J.P. Toossi S. et al.CNS intravascular large cell lymphoma in a patient with autoimmune hemolytic anemia.Neuropathology. 2015; 35: 170-174Google Scholar]. This case well illustrates this finding, and adds to the differential diagnosis for multiple regional microhemorrhages. The patient in this case responded well to treatment with chemotherapy.

Abstract #119 Intravascular Large Cell Lymphoma Diagnosed from Bilateral Adrenal Involvement

Abstract #119 Intravascular Large Cell Lymphoma Diagnosed from Bilateral Adrenal Involvement

Surprising autopsy diagnosis in unclear initial situation. A case of intravascular B cell lymphoma

Intravascular large B cell lymphoma (IVLBCL) is a rare extranodal non-Hodgkin lymphoma characterized by proliferation of malignant cells within the lumen of small vessels, with a predilection for the central nervous system and the skin [1]. IVLBCL clinical course is highly aggressive, clinical signs and symptoms are not specific and may consist in neurological deficits, fever of unknown origin, cutaneous lesions, lacking of a typical neuroimaging pattern [1]. For all these reasons the diagnosis is frequently missed and the exitus is frequent, therefore post-mortem evaluation is necessary to clarify the clinical history. We present a case of IVLBCL in a 62-year-old female with unusual symptomatology, mimicking a vascular multinfarctual cerebropathy; post-mortem autopsy was diriment to define the nature of the disease. Immu- nohistochemical analysis for anti-CD20 revealed the ubiquitary presence of malignant lymphoid B-cells into the vessels of all organs analyzed, allowing the definitive diag- nosis. Although the diagnostic procedure for such pathology is still a matter for fur- ther studies, adequate interpretation of neuro-imaging and morphological findings, as well as of systemic symptoms can provide a right diagnostic hypothesis, suggest- ing focused biopsy in vivo .

Intralymphatic cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis: expanding the spectrum of CD30-positive lymphoproliferative disorders.

Intravascular large B-cell lymphomas and EBV NK/T-cell lymphomas commonly follow an aggressive clinical course. We recently reported an entirely intravascular anaplastic large cell lymphoma (ALCL) in the skin with a surprisingly indolent clinical course; interestingly, this lymphoma involved the lymphatic rather than the blood vasculature. We hypothesized that intravascular skin-limited ALCL is distinct from aggressive systemic intravascular lymphomas in its intralymphatic localization and clinical course. We now describe 18 cases of cutaneous intravascular large cell lymphoproliferations from 4 institutions. All 12 intravascular large T-cell lesions were intralymphatic; the majority (9) were CD30 T-cell lymphoproliferative disorders (TLPDs), 5 further classified as intravascular ALK ALCL. One ALK ALCL and 2 benign microscopic intravascular T-cell proliferations were also intralymphatic. A single case of otherwise typical cutaneous follicle center lymphoma contained intralymphatic centroblasts. The clinical and pathologic characteristics of the CD30 TLPDs were similar to those of their extravascular counterparts, including extralymphatic dermal involvement in a subset, DUSP22-IRF4 translocations in half of tested ALK ALCLs, and associated mycosis fungoides in 1; most were skin-limited at baseline and remained so at relapse. All 5 cases of intravascular large B-cell lymphoma involved the blood vasculature and behaved in a clinically aggressive manner; the ALK ALCL, although intralymphatic, was systemic and clinically aggressive. We propose that cutaneous ALK ALCL and related CD30 ALK TLPDs involving the lymphatics are part of an expanding spectrum of CD30 TLPDs. The identification of intralymphatic as distinct from blood vascular localization may provide critical prognostic and therapeutic information.

One Patient, Two Uncommon B-Cell Neoplasms: Solitary Plasmacytoma following Complete Remission from Intravascular Large B-Cell Lymphoma Involving Central Nervous System

Second lymphoid neoplasms are an uncommon but recognized feature of non-Hodgkin's lymphomas, putatively arising secondary to common genetic or environmental risk factors. Previous limited evaluations of clonal relatedness between successive mature B-cell malignancies have yielded mixed results. We describe the case of a man with intravascular large B-cell lymphoma involving the central nervous system who went into clinical remission following immunochemotherapy and brain radiation, only to relapse 2 years later with a plasmacytoma of bone causing cauda equina syndrome. The plasmacytoma stained strongly for the cell cycle regulator cyclin D1 on immunohistochemistry, while the original intravascular large cell lymphoma was negative, a disparity providing no support for clonal identity between the 2 neoplasms. Continued efforts atcataloging and evaluating unique associations of B-cell malignancies are critical to improving understanding of overarching disease biology in B-cell malignancies.

Intravascular ALK-negative Anaplastic Large Cell Lymphoma With Localized Cutaneous Involvement and an Indolent Clinical Course

Intravascular large T-cell or NK-cell lymphomas rarely present with cutaneous involvement. Intravascular cytotoxic T or NK lymphomas presenting in the skin (cIT/NKL) are often EBV, and reported cases follow a highly aggressive clinical course. Intravascular anaplastic large cell lymphoma (ALCL) by contrast is extraordinarily rare and, when it presents in the skin, raises the question of aggressive clinical behavior in the manner of cIT/NKL versus indolent clinical behavior in the manner of primary cutaneous ALCL. Here we describe a case of localized cutaneous intravascular anaplastic lymphoma kinase-negative ALCL (cIALCL) with a very indolent clinical course. The patient experienced a single cutaneous relapse and remains alive without disease 4 years after diagnosis. Review of the literature reveals multiple clinicopathologic differences between cIALCL and cIT/NKL: distribution (cIALCL, single skin region, P=0.021, Fisher exact test); histology (cIALCL, cohesive with necrosis, P=0.005); immunophenotype (cIALCL, strongly CD30, P=0.021; cIT/NKL, CD56 and/or EBV, P=0.003); and indolent clinical behavior with a trend toward better overall survival (P=0.067, Kaplan-Meier survival analysis). Our index case of cIALCL and 1 other tested case were immunohistochemically confirmed to be intralymphatic (contained within D2-40+vessels) as compared with the blood vessel localization of cIT/NKL. Recognition of cIALCLs as a distinct clinicopathologic entity, and in particular their distinction from aggressive, usually EBV cIT/NKLs, may be possible on the basis of a combination of clinicopathologic criteria, allowing for localized therapy in a subset of patients.

Cutaneous Intravascular Anaplastic Large T-Cell Lymphoma

Intravascular lymphoma (IVL) is a rare subtype of extranodal lymphoma. In the 2008 WHO classification of tumors of the hematopoietic and lymphoid tissues intravascular large B-cell lymphoma is included as a distinct entity. IVL of T-cell type is not included as a diagnostic category and is only mentioned in passing by Nakamura et al. as "a different entity" in their discussion of intravascular large B-cell lymphoma. T-cell IVL is rare, the majority of cases being of natural killer/T-cell phenotype. Exceptionally rare is primary cutaneous intravascular anaplastic large T-cell lymphoma. We present such a case in an otherwise well 39-year-old female having disease limited to the skin established after detailed staging investigations. This is only the third such case described in the literature. We report the clinicopathological features of this case and also review previously documented cases of cutaneous intravascular anaplastic large cell lymphoma.

Drug Development Targeting Microenvironment for Malignant Lymphoma

Abstract 1661Most cancer drug developments are focusing either in vitro target-based screening or cell-based phenotypic screening to identify potential compounds. The target-based screenings are powerful screening methods if the cancer relay on a single driver mutation. On the other hand, cell-based phenotypic screenings measure cell phenotypes such as growth inhibitory effect on established cancer cell lines. However, these established cell lines do not recapitulate human cancer in some aspects. For instance, most cell lines have the microenvironment-independent growth ability, while primary cancer cells can not survive in ex vivo culture. In this study, we established a new drug screening system targeting microenvironment-dependent primary lymphoma cells.First of all, we established primary lymphoma xenograft models, including three diffuse large B cell lymphoma (DLBCL), one follicular lymphoma, one intravascular large cell lymphoma (IVL), and one mantle cell lymphoma. Interestingly, lymphoma cells from the patient with severe extranodal invasion invaded extranodal organ also in mice. And pattern of invasion in tissue such as intravascular tumor invasion of IVL was maintained in the xenograft models. In addition, mRNA expression profiles were similar between primary lymphoma cells and the lymphoma cells obtained from NOG mice. Furthermore, the heterogeneity of primary tumor such as heterogenous expression of CD20 was maintained in the xenograft models. These data suggested that the lymphoma cells propagated in NOG mice kept the original patient's phenotype.Next, we investigated the microenvironment of lymphoma in primary lymphoma xenograft models. Fibroblastic reticular cell (FRC) and follicular dendritic cell (FDC) are reported to be important to support the survival of lymphoma cells in their microenvironment. In the spleen of DLBCL model mice, lymphoma cells colocalized with FRC, but FDC was not detected in NOG mouse. FRC is known to produce reticular fiber and forms fibroblastic reticular network (FRN). Lymphoma induced reticular fiber production and tumor formation on FRN were also observed in our system. Furthermore, co-culture with FRC cell line, BLS4, significantly enhanced viability of 2 out of 3 DLBCL cells obtained from primary lymphoma xenograft mice and enabled more than three weeks long-term ex vivo culture of them. These results indicated that FRC played an important role for lymphoma cell survival.Finally, we established a new drug screening system using this co-culture system. Primary DLBCL cells transplanted to NOG mice were collected and seeded on pre-seeded BLS4 in 96-well plates (lymphoma cell co-culture). Monoculture of BLS4 in 96-well plates was also prepared. Both lymphoma co-cultured cell and BLS4 monoculture cell were treated by 2613 kinds of pharmacologically active compounds for 72 h. DAPI-stained dead cells of lymphoma cells were counted by image analyzer, and the proliferation of BLS4 was measured by MTT assay. We calculated Drug Effect Index (DEI) by multiplication of dead cell number of lymphoma cells and MTT value of BLS4 and compared. The compound with the highest DEI was pyrvinium pamoate, oxyuricide. Pyrvinium pamoate aborogated the survival of lymphoma cells co-cultured with BLS4 dose-dependently. And subcutaneous tumor of primary lymphoma cells and BLS4 were diminished by single intratumoral injection of 20 mg/kg pyrvinium pamoate. These results indicated that our screening system could be performed in large scale and select drugs with anti-tumor activity to primary lymphoma cells. Screening against primary lymphoma cells sheds new light on lymphoma drug development. Disclosures:Sugimoto:Otsuka Pharmaceutical co ltd: Employment.

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.

ALK-negative systemic intravascular anaplastic large cell lymphoma presenting in the skin

Systemic cases of the CD30-positive T-cell neoplasm, anaplastic large cell lymphoma (ALCL), are typically anaplastic lymphoma kinase (ALK)-positive. The failure to express ALK protein has been shown to portend a worse prognosis. We describe a case of ALK-negative systemic ALCL that presented as a violaceous plaque on the scalp of a 79-year-old man. Interestingly, the neoplastic cells were confined largely within vascular spaces, a configuration that is exceedingly rare in the skin and is more typically seen with intravascular large B-cell lymphoma. In addition, bcl-2 immunohistochemical staining was strongly positive in this case, which may portend a more aggressive clinical course. To our knowledge, this report represents the first case of an ALK-negative ALCL to present intravascularly in the skin. Therefore, the recognition of systemic anaplastic T-cell lymphoma present within the intravascular spaces is important to avoid misdiagnosis.

Cutaneous intravascular anaplastic large cell lymphoma

Intravascular lymphoma (IL) is a rare variant of non-Hodgkin lymphoma with a predilection for skin. Most reported cases are large B cell lymphomas. Intravascular anaplastic large cell lymphoma (IALCL) is extremely rare. Retrospective analysis of a case of cutaneous IALCL was performed. Hematoxylin and eosin stained sections and immunohistochemical staining results were analyzed. The patient was a 47-year-old woman who had developed multiple erythematous patches and plaques on her back. The lesions responded well to CHOP (cyclophosphamide, hydroxydoxorubicin, oncovin, prednisone) chemotherapy, but relapsed shortly after therapy. The patient was surviving with the disease for eight years but was ultimately lost to follow up. Histopathologically, the neoplasm evolved from IL to extravascular lymphoma. This was showed in biopsies obtained at different stages of the disease. The lymphoma cells stained positively for CD30, CD45, CD3, CD4, CD5 and Ki67, and lacked expression of anaplastic lymphoma kinase (ALK), CD8, CD45RA, CD45RO, CD20, CD79, CD56, perforin and granzyme B. Our results suggest that IALCL represents a distinct subtype of IL and is histopathologically and biologically different from IL with B, NK or T cell phenotype.

Disseminated intravascular large‐cell lymphoma with initial presentation mimicking Guillain–Barré syndrome

We report a patient with intravascular large B-cell lymphoma who initially presented with acute ascending weakness and sensory changes. Electrodiagnostic testing and cerebral spinal fluid (CSF) studies were initially suggestive of a demyelinating polyneuropathy. Further clinical evaluation and testing were consistent with mononeuropathy multiplex. Autopsy revealed disseminated intravascular large-cell lymphoma. Intravascular large-cell lymphoma should be considered in the differential diagnosis of a rapidly evolving neuropathy associated with other organ involvement.

Intravascular Lymphoma with Conus Medullaris Syndrome Followed by Encephalopathy

Intravascular large cell lymphoma (ILCL) is a diagnostic challenge, with neurological, cutaneous and constitutional symptoms. The natural history is usually an evolution to a comatose state. As invasive procedures are usually required for diagnosis, recognizing the typical clinical pattern is critical since an effective treatment is available. After an extensive literature review of the subject, we report a case of ILCL, analyzing clinical, laboratory, radiological and pathological data. We will also give a special attention to the clinical picture of a conus medullaris (CM) lesion with subsequent encephalopathy in the same patient, We report here a 61-year-old woman with a paraplegia caused by a CM lesion, evolving about one year latter to encephalopathy and eventual coma, with the diagnosis of ILCL confirmed by autopsy. The present case is similar to eight other cases in literature who had CM lesion associated with ILCL, knowing that 80-90% of these patients will eventually evolve to encephalopathy without treatment. ILCL is a recognized but rare cause of coma. Diagnosing it is tremendously important since it is fatal if left untreated. We propose that this specific picture (conus medullaris lesion, eventually evolving to encephalopathy) is quite characteristic and will directly result in better outcome if recognized.

Intravascular Large T-cell or NK-cell Lymphoma

Most cases of intravascular large cell lymphoma have a B-cell phenotype, but rare T-cell and natural killer (NK)-cell variants have been reported. We describe the clinicopathologic features of 4 patients (M:F=3:1; age range: 63 to 87; median age: 65) with intravascular large NK/T-cell lymphoma. The skin was the site of presentation in all patients (leg: 1 case; trunk: 1 case; trunk and extremities: 2 cases). Two patients had lesions confined to the skin; in 1 case concomitant involvement of the brain was detected and in 1 case no further studies were carried out. Immunohistology showed positivity for cytotoxic markers in 3/4 cases. One case had an NK phenotype similar to NK/T-cell lymphoma, nasal-type, whereas the other cases could not be precisely classified into specific categories (peripheral T-cell lymphoma, NOS). One of these cases was negative for cytotoxic markers and was positive only for CD2 and CD3 epsilon. Association with Epstein-Barr virus (EBV) was demonstrated in 2 cases by in situ hybridization, whereas 1 case was negative. All our patients had aggressive disease and died between 2 weeks and 7 months from presentation. Analysis of our cases and of those published in the literature shows that intravascular large NK/T-cell lymphoma is a rare, aggressive lymphoma with variable phenotypic features, frequent expression of cytotoxic proteins, true NK-cell phenotype and association with Epstein-Barr virus infection, and common presentation in the skin. Homogeneous studies on larger number of patients and reevaluation of cases published with incomplete phenotypic data would be necessary to gather more information on this extremely rare type of lymphoma.

Intravascular large cell lymphoma

A 19‐year‐old female presented at our hospital with a 1‐year history of a 5‐cm indurated nontender lesion on the left shoulder. Two months later, a similar lesion appeared in the left mammary region, accompanied by necrosis and fever.At admission to our department, she presented disseminated lesions in the left submandibular region, the sternal area and the posterior part of the upper and lower extremities.The lesions were indurated erythematous‐violaceous plaques affecting the adipose tissue, some with ulcerations and necrotic crusting (Fig. 1). The first histopathological report was thrombosis of the capillary vessels and focal vasculitis (Fig. 2).Ulceration and necrotic crusting lesion in the left mammary regionimageHistopathology showing dilation of thrombosed vessels with fibrin deposits (hematoxylin and eosin, magnification ×244)imageA biopsy from a lesion on the left thigh showed dilated vessels with large atypical intravascular cells with hyperchromatic nuclei and numerous atypical mytoses in the dermis and subcutaneous tissue. Some of these cells were immersed in fibrin thrombi or in the perivascular connective tissue (Fig. 3). An immunohistochemical study was positive for the common leukocytic antigen and for the B‐cell phenotype. The diagnosis was large B‐cell lymphoma. The patient persisted with a high fever, dry cough, pericardial effusion complicated by an abscess and left pleural effusion. She died before systemic workings for lymphoma could be carried out, and before chemotherapy could be attempted.Histopathology showing atypical intravascular lymphocytes (hematoxylin and eosin, magnification ×366)image

Myocardial infarction as an uncommon clinical manifestation of intravascular large cell lymphoma

Intravascular large cell lymphoma (IVL) is a very rare variant of non-Hodgkin`s lymphoma presenting with puzzling clinical manifestations.There is a predilection for the central nervous system, but the tumour often affects also skin, lung, and kidneys while lymphadenopathy and hepatosplenomegaly are usually absent. Myocardial infarction due to IVL has not been reported so far.We here report on a 56-year-old patient who was admitted to our hospital with fever and clinical signs of erysipelas. He had a 6-month history of “collagen vasculitic disease” treated with prednisolon and azathioprin. He received antibiotic treatment, but after transient improvement fever recurred with generalized seizures and myocardial infarction, which required transfer to the intensive care unit where the patient died with signs of an acute cardiogenic shock. Autopsy revealed a generalized highgrade B cell lymphoma of IVL type affecting and obstructing small vessels of a variety of tissues including heart, brain and lungs.The tumorous obliteration of small intramyocardial vessels had led to an acute ischaemia with infarction and subsequent signs of myocardial insufficiency.To the best of the authors’ knowledge myocardial infarction as a leading symptom of IVL has not been described.