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Background

Several synonyms have been used to describe this entity, such as malignant angioendotheliosis, neoplastic angioendotheliosis, malignant angioendotheliomatosis, hemangioendotheliosis, angioendotheliomatosis proliferans, angiotropic lympoma, and intravascular lymphomatosis. As one can observe by the previous names, many investigators favored a vascular origin for this tumor. However, there is conclusive evidence favoring a lymphoid phenotype of the tumor cells and therefore intravascular large cell lymphoma (IVL) is the most appropriate name for this disease.

IVL is an extensive proliferation of neoplastic mononuclear cells within the lumina of blood vessels. The disease is characterized by involvement of the skin and central nervous system, and disseminates rapidly with involvement of multiple organs. The prognosis is usually extremely poor, with rapid death despite chemotherapy. Most patients present with fever of unknown origin and nonspecific cutaneous and neurologic manifestations. Cutaneous lesions may be confused with mycosis fungoides, sarcoidosis, vascular neoplasms, or cutaneous involvement by lymphoma or leukemia. The typical appearance are erythematous or violaceous plaques mainly on the trunk and lower legs. IVL is a high-grade, non-Hodgkin's lymphoma and long-term survival may result in patients who are treated with aggressive combination chemotherapy. However, the overall prognosis is poor.

These intravascular cells in IVL were thought to be of endothelial origin. This observation was based on the presence of tumor cells attached to the endothelium of involved blood vessels. However, immunohistochemical stains have failed to demonstrate consistent staining for endothelial cell markers (Factor VIII and CD31). Instead, it is now clear that the neoplastic intraluminal cells are of lymphoid origin of B-cell lineage. The mechanisms that mediate the exclusive affinity of the lymphoma cells to certain types of blood vessels (capillaries, postcapillary venules) and prohibit the colonization of the organs most commonly linked to lymphoma, such as lymph nodes, spleen and bone marrow is still unknown.

Under the microscope, the diagnosis may be problematic and subtle. The small capillaries, venules and small arterioles are distended by noncohesive masses of large, pleomorphic lymphoid cells trapped by fibrin thrombi. These cells have irregular nuclear contours, coarse nuclear chromatin, with two or multiple nucleoli, and moderate amounts of basophilic cytoplasm. Some cells have vacuolated cytoplasm. Only rarely do the neoplastic cells extravasate into the neighboring tissues. In some cases there is evidence of vascular proliferation, presumably as a consequence of recanalization, and the endothelium may be thrown into complex folds, segmenting the vascular lumen. In the brain, areas of infarction may be present, but infarcts are infrequently encountered in other organs.

Immunohistochemistry shows strong immunopositivity for CD19, CD20, CD22, CD79alpha, and monotypic surface immunoglobulin. In addition, clonal rearrangement for the immunoglobulin genes may be demonstrated.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/
Other Diagnostic Testing
 
Gross Appearance
and Clinical Variants
 
Histopathological Features
and Variants
 
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

DISEASE ASSOCIATIONS CHARACTERIZATION
KAPOSI'S SARCOMA  

Epstein-Barr virus-associated intravascular lymphomatosis within Kaposi's sarcoma in an AIDS patient.

Hsiao CH, Su IJ, Hsieh SW, Huang SF, Tsai TF, Chen MY, How SW.

Department of Pathology, National Taiwan University Hospital, Taipei.

Am J Surg Pathol 1999 Apr;23(4):482-7 Abstract quote

Intravascular lymphomatosis (IL) is an unusual neoplasm characterized by multifocal proliferation of lymphoma cells exclusively within the blood vessels.

We report here a patient with acquired immunodeficiency syndrome (AIDS) and disseminated Kaposi's sarcoma. A 233-bp amplification product of HHV-8 was detected in the DNA extracted from specimens of Kaposi's sarcoma at different sites by polymerase chain reaction (PCR). At autopsy, the vessels within the Kaposi's sarcoma were dilated and filled with atypical large mononuclear cells. No such feature was seen in the vessels of non-Kaposi's sarcomatous regions. Immunohistochemically, the spindle cells of Kaposi's sarcoma were positive for CD31 (endothelial cell marker). The intravascular tumor cells were positive for CD45 (leukocyte common antigen) but negative for others, including chloroacetate esterase, CD45-RO (UCHL-1, Pan-T), CD3, CD43, CD20 (L26, Pan-B), CD30 (Ki-1), immunoglobulin heavy chains and light chains, CD56 (natural killer cell antigen), and CD31. Monoclonal rearrangement of immunoglobulin heavy chain gene was detected in the DNA extracts from fresh tissue of Kaposi's sarcoma by PCR, which indicated that the lymphoma cells within the Kaposi's sarcoma were of monoclonal B cell origin. In situ hybridization revealed that EBER-1 transcripts were present in the lymphoma cells of IL but not in the spindle cells of Kaposi's sarcoma.

To the authors' best knowledge, this is the first instance of IL in an AIDS patient with direct evidence of EBV association.

 

LABORATORY/
RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
RADIOLOGIC  

Intravascular lymphomatosis: contribution of cerebral MRI findings to diagnosis.

Liow K, Asmar P, Liow M, Spanaki M, Townsend JJ, Buys S, Baringer JR, Osborn A.

National Institute of Neurological Disorders and Stroke, University of Utah School of Medicine, Salt Lake City, USA.

J Neuroimaging 2000 Apr;10(2):116-8 Abstract quote

Intravascular lymphomatosis (IL) is a rare variant of non-Hodgkin's lymphoma with an unusual predilection for the central nervous system (CNS). Most cases are not diagnosed until postmortem because of variable clinical presentation and nonspecific laboratory findings. Neuroimaging findings vary widely and range from diffuse involvement of the deep white matter to infarct-like lesions.

Cerebral magnetic resonance imaging (MRI) may show parenchymal and meningeal gadolinium enhancement. The authors describe brain MRI findings of linear, punctate, and patchy enhancement suggestive of CNS IL in two patients confirmed by brain biopsy/histologic studies.

High index of clinical suspicion and careful interpretation of MRI (including gadolinium contrast studies) may contribute to premortem diagnosis and early intervention of this often-missed disease.

PCR  

Intravascular (angiotropic) large cell lymphoma: determination of monoclonality by polymerase chain reaction on paraffin-embedded tissues.

Sleater JP, Segal GH, Scott MD, Masih AS.

Department of Pathology and Laboratory Medicine, University of Florida, Gainesville.

Mod Pathol 1994 Jun;7(5):593-8 Abstract quote

Angiotropic lymphoma is a rare, aggressive, intravascular non-Hodgkin's lymphoma, usually of B-cell phenotype. Because lymphoma is often clinically unsuspected, the small skin or muscle biopsies typically obtained for evaluation make assessment of lymphoid clonality through cell surface markers or Southern blot hybridization analysis difficult or impossible. The recent development of polymerase chain reaction methodologies to detect chromosomal translocations and immunoglobulin heavy chain gene rearrangement on paraffin-embedded tissue offers an attractive alternative for ascertaining the clonality of lymphoproliferative processes.

We report a case of B-cell angiotropic lymphoma in which a monoclonal variable diversity joining region rearrangement of the immunoglobulin heavy chain locus was detected by polymerase chain reaction in both ante- and postmortem, formalin-fixed, paraffin-embedded skeletal muscle.

The use of polymerase chain reaction in assessing clonality in angiotropic lymphoma is enhanced by the general absence of a background of reactive B-lymphoid cells in angiotropic lymphoma, which can obscure the monoclonal band and/or compromise sensitivity. No amplification product was obtained for t(14;18) involving the bcl-2 major breakpoint region. It is interesting to note that this case exhibited rare circulating lymphoma cells and more extensive bone marrow involvement (more than 100 tumor cells/high magnification field) than has been previously described.

Molecular detection of bone marrow involvement in intravascular lymphomatosis.

DiGiuseppe JA, Hartmann DP, Freter C, Cossman J, Mann RB.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.

Mod Pathol 1997 Jan;10(1):33-7 Abstract quote

Intravascular lymphomatosis (IVL) is an extremely rare variant of aggressive non-Hodgkin's lymphoma characterized by confinement of neoplastic lymphocytes within vascular spaces. Although IVL is potentially curable with combination chemotherapy, diagnosis is often delayed, in part owing to the negative bone marrow biopsy specimens that are typical of this disorder.

We hypothesized that use of a more sensitive method of analysis might identify small clonal B-cell populations in histologically negative bone marrow biopsy specimens from patients with IVL. With use of a recently described assay for immunoglobulin heavy chain gene rearrangement based on the polymerase chain reaction, we demonstrated clonal B-cell populations in histologically negative marrow specimens from five (100%) of five patients with IVL. None of these specimens demonstrated molecular evidence of the t(14;18) associated with follicular lymphoma, providing no evidence for a common derivation of IVL and follicular lymphoma.

In summary, molecular analysis of routine bone marrow biopsy sepcimens from patients in whom the diagnosis of IVL is entertained may facilitate prompt recognition of a lympho-proliferative disorder and thereby permit timely therapeutic intervention. Moreover, these findings suggest that despite histologically negative staging bone marrow biopsy specimens, IVL typically disseminates early in its course, thus arguing against the use of localized therapy in this disorder.

LABORATORY CHEMISTRIES  
HYPOALBUMINEMIA  

Intravascular large cell lymphoma associated with hypoalbuminemia.

Suzumiya J, Ohshima K, Kanda M, Kato A, Shuuda K, Kimura N, Tamura K, Kikuchi M.

First Department of Pathology, School of Medicine, Fukuoka University, Japan.

Leuk Lymphoma 1998 Dec;32(1-2):179-82 Abstract quote

We report here a 71-yr-old Japanese woman who presented with severe anasarca and hypoalbuminemia. She had a postmortem diagnosis of intravascular large B-cell lymphoma, which is a rare type of lymphoma characterized by an intravascular proliferation of lymphoma cells.

Severe generalized edema was thought to be attributed to vascular and/or lymphatic obstruction due to proliferation of lymphoma cells within the lumina and/or an increase in catabolism induced by tumor proliferation.

PROSTATIC ACID PHOSPHATASE, SERUM  
Prostatic acid phosphatase: a possible diagnostic marker of intravascular large B-cell lymphoma.

Kishi Y, Kami M, Kusumi E, Mineyama T, Kato D, Hamaki T, Ueyama J, Miyakoshi S, Morinaga S, Muto Y, Taniguchi S.

Department of Hematology, Toranomon Hospital, Tokyo, Japan.

Haematologica. 2004 May 1;89(5):ECR13. Print 2004 May. Abstract quote  

BACKGROUND AND OBJECTIVE: Intravascular large B-cell lymphoma (IVL) has been treated as fever of unknown origin (FUO), and many patients have been treated inadequately based on incorrect diagnoses. We previously cares for a patient with IVL who tested positive for prostatic acid phosphatase (PAP), a marker of prostate cancer. Since then, we have regularly examined this mather when IVL was suspected to investigate the usefulness of PAP as a diagnostic marker for IVL. We retrospectively evaluated the usefulness of PAP as diagnostic marker of IVL.

DESIGN AND METHODS: We reviewed the clinical courses of 5 patients with IVL (3 males, 2 females) in comparison with 23 controls with hematologic malignancies other than IVL.

RESULTS: Serum levels of PAP were elevated in all 5 patients with IVL and 2 of the 23 controls. The difference was statistically significant using a chi-squared test (p=0.0002). The sensitivity and specificity of PAP were 100% and 91%, respectively, in the diagnosis of IVL. Its serum levels were closely associated with disease status.

INTERPRETATION AND CONCLUSIONS: This study suggests that PAP might be a useful marker for the screening and assessment of disease activity and responses to the treatment of IVL.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL  


Intravascular B-cell lymphoma.

Eros N, Karolyi Z, Kovacs A, Takacs I, Radvanyi G, Kelenyi G.

Departments of Dermatology, Pathology, and Hematology, Semmelweis Hospital, Miskolc, and the Department of Pathology, University Medical School, Pecs.

 

J Am Acad Dermatol 2002 Nov;47(5 Suppl):S260-2 Abstract quote

Intravascular (angiotropic) lymphoma is a unique and rare cutaneous lymphoma in which the malignant T or B lymphoid cells proliferate within the lumens of small blood vessels, primarily in the skin and central nervous system. Erythematous, tender nodules, tumors, and telangiectases are the most common skin symptoms in addition to various neurologic signs. Progression of the disease produces secondary organ involvement with variable symptoms and can be fatal.

We describe a case of a 74-year-old woman with edematous, infiltrated, orange-like skin with multiple telangiectases, generalized edema, severe weakness, and extremely high values of lactate dehydrogenase.

Skin biopsy specimens revealed atypical large cells filling up the lumens of dermal capillaries. Immunohistochemical investigation results identified them as B cells with CD20, CD45, CD79a, Ki-67, and HLA-DR positivity. After administration of diuretics, colchicine, and systemic PUVA therapy, the patient lost her edema, her skin became tender and free of telangiectases, and laboratory alterations normalized. Because of heavy neuralgia in her legs, oral monochemotherapy was introduced with chlorambucil, and now the patient is in remission.

VARIANTS  
BONE MARROW  

Intravascular large B-cell lymphoma with bone marrow involvement at presentation and haemophagocytic syndrome: two Western cases in favour of a specific variant.

Dufau JP, Le Tourneau A, Molina T, Le Houcq M, Claessens YE, Rio B, Delmer A, Diebold J.

Department of Pathology, Hopital d'Instruction des Armees Percy, Clamart, France

Histopathology 2000 Dec;37(6):509-12 Abstract quote

AIMS: To report two cases of an unusual form of intravascular lymphoma, characterized by bone marrow involvement at presentation with haemophagocytic syndrome.

METHODS AND RESULTS: We describe the clinicopathological features of two patients with intravascular lymphoma primarily involving bone marrow. Both patients complained only of fever with pancytopenia and reactive haemophagocytic syndrome. Diagnosis was made on bone marrow examination, which showed large tumour cells of B-cell lineage confined within the lumen of sinuses.

CONCLUSION: These two cases and five previous reports could represent a variant of intravascular lymphoma, characterized by early involvement of bone marrow without dissemination to other organs. This form of intravascular lymphoma, called IVL-HS, seems to be an 'Asian' variant with a high prevalence in Asian people and a very low prevalence in Western countries. At a practical level, bone marrow biopsy may be useful in the diagnosis of intravascular lymphoma when the clinical presentation is restricted to fever of unknown origin with a reactive haemophagocytic syndrome.

BREAST  
Intravascular large B-cell lymphoma of the breast.

Monteiro M, Duarte I, Cabecadas J, Orvalho ML.

Departamento de Imagiologia, Instituto Portugues de Oncologia de Francisco Gentil (I.P.O.F.G.), Centro de Lisboa, R. Prof. Lima Basto, 1099-023 Lisboa, Codex, Portugal.
Breast. 2005 Feb;14(1):75-8. Abstract quote  

The case of an 80-year-old woman with symmetrical breast engorgement and nonspecific systemic symptoms progressively developing over 3 months and confirmed on surgical biopsy to be due to an intravascular large B-cell lymphoma (ILBCL) is presented.

To our knowledge, ILBCL has never been reported in the breast before and its mammography and ultrasound appearances are described.
CNS  

Angiotropic intravascular large-cell lymphoma with massive cerebral extension.

Torenbeek R, Scheltens P, Strack van Schijindel RJ, Algra PR, Heimans JJ, van der Valk P.

Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.

J Neurol Neurosurg Psychiatry 1993 Aug;56(8):914-6 Abstract quote

Angiotropic intravascular large-cell lymphoma (AILL) is a rare, generally fatal disease characterised by a multifocal proliferation of neoplastic mononuclear cells within small blood vessels.

The diagnosis of a patient was made at necropsy. The malignant cells had infiltrated the periventricular areas of the brain

Angiotropic large B-cell lymphoma with clinical features resembling subacute combined degeneration of the cord.

Waring WS, Wharton SB, Grant R, McIntyre M.

Clinical Pharmacology Unit, University of Edinburgh, Western General Hospital, UK.

Clin Neurol Neurosurg 1999 Dec;101(4):275-9 Abstract quote

Angiotropic large cell lymphoma is a rare neoplastic disorder associated with a high mortality. The hallmark of the disease is lymphoid proliferation confined to the intravascular compartment without local tissue or vessel wall infiltration.. This feature is so striking that the disease was originally thought to arise from endothelial tissue and early cases were described as malignant angioendotheliomatosis. However, application of immunohistochemical methods for detection of lymphoid markers such as the CD45 and CD20 cell surface markers has confirmed its lymphoid origin, usually of B-cell lineage.

Clinical manifestations of the disease are protean and are due to multifocal medium and small vessel occlusion by tumour cells.. Characteristic sites of involvement are skin and central nervous system and although an ante-mortem diagnosis can be made from a biopsy specimen, it is often unsuspected.

We present a case of angiotropic large B-cell lymphoma in a 74-year-old man who presented with urinary symptoms and had a neurological picture resembling subacute combined degeneration of the cord.

KIDNEY  

Intravascular large cell lymphoma: diagnosis on renal biopsy.

Axelsen RA, Laird PP, Horn M.

Department of Pathology, Princess Alexandra Hospital, Brisbane, Queensland, Australia

Pathology 1991 Jul;23(3):241-3 Abstract quote

The case is reported of a woman aged 60 yrs who presented with systemic symptoms and who was found to have proteinuria of 3.5 g per day.

A renal biopsy revealed numerous neoplastic cells filling many of the glomerular capillary lumina. Immunoperoxidase stains revealed that the phenotype of the malignant cells was LCA+, L26+, MB2+, UCHL1-, CD43-, CAM5.2- and S100-, indicating that they were of lymphoid origin and B-cell lineage. The diagnosis of intravascular large cell lymphoma was therefore made. Remission was induced by chemotherapy with CAVP (cyclophosphamide, adriamycin, vincristine and prednisone). A subsequent relapse was treated with cyclophosphamide, VP16 and prednisone, and again remission occurred.

This is the first case known to the authors in which the diagnosis of intravascular large cell lymphoma was made on renal biopsy. We confirm the experience of others that chemotherapy with regimens utilized in other varieties of large cell lymphoma may also be appropriate for this unusual neoplasm.

SKIN  
Cutaneous Intravascular NK-cell Lymphoma: Report of a Rare Variant Associated With Epstein-Barr Virus.

Departments of *Pathology daggerDermatology double daggerHematology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kwei San, Taoyuan, Taiwan.

 

Am J Surg Pathol. 2006 Sep;30(9):1197-1201 Abstract quote

Intravascular lymphoma (IVL) is a rare variant of non-Hodgkin lymphoma with a predilection for skin and brain. Except a few cases of T-cell lineage, most of the reported cases were large B-cell lymphomas.

We encountered a case of cutaneous IVL in a 71-year-old woman presenting with multiple erythematous patches and nodules on her trunk and extremities. The intravascular large cells showed an immunophenotype of CD3ϵ, CD5, CD20, CD30, CD56, and TIA-1. The lymphoma cells were also positive for Epstein-Barr virus by Epstein-Barr virus-encoded RNA in situ hybridization test and the T-cell receptor gene was germline. This IVL differs from nasal type NK/T-cell lymphoma only by its intravascular nature. Only 3 cases of intravascular NK-cell lymphoma have been reported before.

Because this variant is extremely rare, our case is documented and compared with the 3 previously reported cases.

Intravascular large cell lymphoma: a patient with asymptomatic purpuric patches and a chronic clinical course.

Chang A, Zic JA, Boyd AS.

Department of Dermatology, Vanderbilt University, Nashville, Tennessee, USA.

J Am Acad Dermatol 1998 Aug;39(2 Pt 2):318-21 Abstract quote

Intravascular large cell lymphoma (malignant angioendotheliomatosis) is a rare, multifocal, intravascular neoplasm of lymphoid cells that preferentially involves the vasculature of the skin and central nervous system.

We describe a 54-year-old man with asymptomatic purpuric patches on the lower extremities for 10 years duration and a more recent lesion on the right arm. A biopsy specimen showed intravascular collections of tumor cells with irregular nuclear contours and prominent nucleoli. These cells were leukocyte common antigen (CD45), CD20, and CDW75 positive, but CD3, CD43, CD45RO, and cytokeratin negative. Polymerase chain reaction analysis of the skin for immunoglobulin heavy chain gene rearrangement detected a clonal population of B cells, supporting the diagnosis of a B-cell lymphoma. Peripheral blood showed no abnormal circulating cells.

This case of malignant angioendotheliomatosis is unusual for its prolonged clinical course and presence of purpuric patches.


A case of intravascular large B-cell lymphoma mimicking erythema nodosum: the importance of multiple skin biopsies.

Kiyohara T, Kumakiri M, Kobayashi H, Shimizu T, Ohkawara A, Ohnuki M.

Department of Dermatology, Fukui Medical University, Japan.

J Cutan Pathol 2000 Sep;27(8):413-8 Abstract quote

BACKGROUND: Intravascular lymphoma is a rare disease characterized by the proliferation of neoplastic monuclear cells within the lumens of small blood vessels. The neoplastic cells are usually of B-cell origin, and rarely of T-cell or histiocytic origin. Although this clinicopathological entity of lymphoma has not been listed in general pathological classifications such as REAL classification or the Working Formulation, it is recently in the WHO classification scheme, which is essentially an updated REAL scheme, and the EORTC classification scheme.

METHODS: In this report, a 62-year-old woman with intravascular large B-cell lymphoma was observed by clinical, histopathological, immunohistochemical and molecular methods.

RESULTS: A 62-year-old woman presented with large erythematous macules on the bilateral thighs and lower legs. The lesions were accompanied with hard, tender, intradermal or subcutaneous nodules mimicking erythema nodosum. Histopathological examination in the first biopsy revealed non-specific panniculitis compatible with erythema nodosum. The second biopsy revealed emboli of atypical lymphocytes within many of the dilated and proliferated vessels in the deep dermis and subcutaneous tissue. These cells were positive for L-26 and kappa light chain, and negative for lambda light chain, factor VIII-related antigen, CD30, CD34, CD68 and UCHL-1. These findings confirmed the diagnosis of intravascular large B-cell lymphoma. A laboratory examination showed a high level of LDH and abnormal cells in the bone marrow. An MRI of the brain and computed tomographic (CT) scans of the chest and abdomen revealed no evidence of malignancy. Before the treatment, the size of the nodules decreased spontaneously by about 50% in one month and significantly in two months. Although combination chemotherapy, which consisted of CHOP, brought her partial remission, she experienced neurological symptoms 6 months after the initial treatment and died of brain metastasis 9 months after the treatment.

CONCLUSIONS: This is a unique case for two following reasons: 1) the first biopsy revealed non-specific findings compatible with erythema nodosum; and 2) before the treatment, the nodules regressed spontaneously. Dermatologists should take multiple skin biopsies for EN lesions with the non-specific histopathological findings not to refute the existence of this disease.

TESTIS  

Intravascular large B-cell lymphoma or intravascular lymphomatosis: report of a case diagnosed by testicle biopsy.

Van Droogenbroeck J, Altintas S, Pollefliet C, Schroyens W, Berneman Z.

Department of Hematology, University Hospital Antwerp, Edegem, Belgium.

Ann Hematol 2001 May;80(5):316-8 Abstract quote

Intravascular large B-cell lymphoma or intravascular lymphomatosis (IVL) is an extremely rare form of non-Hodgkin's lymphoma. The most common clinical sign is fever of unknown origin (FUO). Histologically, there is proliferation of malignant lymphoid cells within vascular lumina. Cytologically, the cells have features similar to those found in classical large cell lymphoma. Examination of pulmonary artery blood showed the presence of this abnormal population in our patient; to the best of our knowledge there are only four other. reports of detection of circulating tumor cells in IVL. The outcome is very poor. The diagnosis is most frequently made after biopsy of skin or brain but is often established post mortem.

We present what is--to our knowledge--the first reported case of IVL diagnosed after biopsy of a testicle. In the event of FUO and suspicion of a malignancy, IVL--although very rare--should be one of the differential diagnoses.

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL  

Angiotropic Lymphoma: An Immunophenotypically and Clinically Heterogeneous Lymphoma

Subramanian Yegappan, M.D., Robert Coupland, M.D., Daniel A. Arber, M.D., Nancy Wang, M.D., Ranko Miocinovic, B.S., Raymond R. Tubbs, D.O. and Eric D. Hsi, M.D.

Department of Clinical Pathology (SY, NW, RM, RRT, EDH), Cleveland Clinic Foundation, Cleveland, Ohio; Department of Pathology (RC), Cross Cancer Center, Edmonton, Alberta, Canada; and Department of Pathology (DAA), City of Hope National Medical Center, Duarte, California

Mod Pathol 2001;14:1147-1156 Abstract quote

Angiotropic lymphoma (AL) is an uncommon lymphoma often presenting with nonspecific clinical features and having a high mortality rate. Although not specifically recognized by the Revised European-American Classification of Lymphoid Neoplasms, it likely will appear as a subtype of diffuse large B-cell lymphoma in the upcoming WHO classification. Some authors may also consider it to be a subtype of cutaneous lymphomas. Recent studies have reported an immunophenotypic heterogeneity of AL, and in rare instances, an association with other NHL.

To further characterize AL, we studied the immunophenotype by immunohistochemistry for CD5, CD10, CD20, bcl-2, and bcl-6 in 18 cases of B-cell AL identified at three medical centers in North America. Bcl-2 gene rearrangement status by polymerase chain reaction and Epstein Barr virus status by in situ hybridization also were evaluated. Eight men and 10 women were identified with AL (median age 71 years). Eleven patients were diagnosed in life and seven were diagnosed at autopsy. Neurologic symptoms were the most common presentation, seen in six patients. Skin was the most commonly biopsied site. All showed classic intravascular localization; in two cases, there was also a minor diffuse large cell lymphoma component observed in some organs. Most (89%) of the cases expressed bcl-2 protein; CD10, bcl-6 and CD5 were each expressed in 22% of cases. Based on CD5 and CD10 expression, three major groups were evident: CD5-, CD10- (11 cases); CD5+, CD10- (3 cases), and CD5-, CD10+ (3 cases). Even though a follicle center lymphoma preceded the AL in one patient, we did not detect bcl-2 gene rearrangement in any of these cases. All cases were negative for Epstein Barr virus.

Of the five treated with chemotherapy, two achieved a complete remission.

Based on these findings, we conclude that ALs are clinically and immunophenotypically heterogeneous and may represent more than one pathogenetic entity. In some instances AL may be preceded by another lymphoproliferative disorder, raising the possibility that some cases of AL may represent a transformation from another type of lymphoma. Cutaneous manifestations of AL are common; however, it appears to be a systemic lymphoma. Although often fatal, patients with AL who are diagnosed early and treated with chemotherapy may achieve remission.

VARIANTS  
HISTIOCYTIC  

Angiotropic lymphoma: report of a case with histiocytic features.

Snowden JA, Angel CA, Winfield DA, Pringle JH, West KP.

Department of Haematology, Royal Hallamshire Hospital, Central Sheffield University Hospitals Trust.

J Clin Pathol 1997 Jan;50(1):67-70 Abstract quote

Angiotropic lymphoma, also known as intravascular lymphomatosis, is characterised by widespread intravascular proliferation of malignant lymphoid cells, usually without evidence of focal disease.

A case of a 52 year old man referred for investigation of a two year history of pyrexia of unknown origin, skin rash and multiple organ failure is described. Angiotropic lymphoma was seen in gastric, colonic and skin biopsy specimens, and review of an earlier skin biopsy specimen showed similar morphological features. In contrast to previous cases which showed B or T cell differentiation, immunohistochemical examination was positive for histiocyte markers. Molecular studies showed no evidence of immunoglobulin heavy chain gene or T cell receptor gene rearrangement. The patient responded to combination chemotherapy, comprising cyclophosphamide, doxorubicin, etoposide, and prednisolone.

This case highlights the fact that advanced lymphoma may be present without evidence of focal disease and that the diagnosis may be missed easily both clinically and histologically.

NK CELL  
First Reported Cases of Intravascular Large Cell Lymphoma of the NK Cell Type
Clinical, Histologic, Immunophenotypic, and Molecular Features

Huiqing Wu, MD, etal.
Am J Clin Pathol 2005;123:603-611 Abstract quote

Most cases of intravascular large cell lymphoma are of B-cell phenotype, with a few cases of T-cell lineage and rare cases with histiocytic features described. A definitive natural killer (NK) cell variant has not been recognized.

This report is the first to describe the clinical, histologic, immunophenotypic, and molecular features of 2 cases of intravascular lymphoma with an NK cell phenotype (CD3e+, CD2+, CD7+, CD56+, T-cell intracytoplasmic antigen-1+ (TIA-1), perforin+, granzyme B+, CD20–, CD4–, CD5–, CD8–, T-cell receptor [TCR] bF1–). Molecular studies for TCR gene rearrangements revealed a germline configuration. A 41-year-old man had erythematous plaque-like subcutaneous lesions of the lower extremities in which biopsy revealed Epstein-Barr virus–positive intravascular lymphoma. Following chemotherapy and stem cell transplantation, he was alive with no evidence of disease at 1 year. A 47-year-old woman had myalgias, arthralgias, weakness, fever, altered mental status, and pancytopenia. Bone marrow biopsy demonstrated intravascular lymphoma. Therapy was initiated; however, her condition deteriorated rapidly, and she died. Autopsy revealed involvement of multiple organs, including brain, kidneys, ovaries, and bone marrow. These cases represent the first documented examples of an NK cell variant of intravascular lymphoma.
T-CELL  
Intravascular cytotoxic T-cell lymphoma: A case report and review of the literature.

Department Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

J Am Acad Dermatol. 2008 Feb;58(2):290-4. Abstract quote

Intravascular lymphoma (IVL) is a rare subtype of extranodal diffuse large B-cell lymphoma in the World Health Organization classification. Although the majority of cases are of B-cell lineage, cases of IVL with a T-cell phenotype and, rarely, histiocytic and natural killer (NK)-cell phenotypes have been reported.

We report a case of T-cell IVL with a cytotoxic phenotype. A 62-year-old male presented with erythematous patches and plaques on the lower extremities, and a biopsy revealed IVL with an activated cytotoxic phenotype (CD56(+), perforin+, granzyme B+, TIA-1+, CD3epsilon(+), CD20(-), CD4(-), CD8(-), CD5(-), and T-cell receptor [TCR] betaF1(-)), consistent with either NK-cell or T-cell origin. TCR gene analysis showed a monoclonal T-cell population, supporting the diagnosis of a T-cell IVL.

Although the patient's skin lesions were refractory to combination chemotherapy and salvage chemotherapy regimens, there has been no evidence of disease progression in 24 months of follow-up.

T-cell intravascular lymphomatosis (angiotropic large cell lymphoma): association with Epstein-Barr viral infection.

Au WY, Shek WH, Nicholls J, Tse KM, Todd D, Kwong YL.

University Department of Medicine, Queen Mary Hospital, Hong Kong.

Histopathology 1997 Dec;31(6):563-7 Abstract quote

AIMS: Intravascular lymphomatosis (IVL) is a very rare non-Hodgkin's lymphoma characterized by proliferation of lymphoma cells in the vascular lumina without involvement of adjacent parenchymal tissue. IVL is predominantly of B-cell lineage, but occasional cases of T lineage IVL involving almost exclusively the skin have been described. A case of IVL that occurred initially in the epididymis of a patient with an antecedent nasopharyngeal carcinoma was studied to define the clinicopathological features associated with this unique presentation.

METHODS AND RESULTS: This lymphoma was studied by standard histological and immunophenotyping methods. The results showed lymphoma cells confined within the blood vessels, which expressed leucocyte common antigen, and T-cell markers CD3 and UCHL-1. The T-cell origin of the IVL prompted investigations for an association with Epstein-Barr virus infection (EBV). In-situ hybridization with digoxigenin-labelled anti-sense RNA probes to EBV encoded RNA (EBER) showed strong signals in the nuclei of virtually all of the lymphoma cells.

CONCLUSIONS: EBV infection of the malignant cells was demonstrated by in-situ hybridization. This case suggests that T-cell IVL may be another EBV related human neoplasm. This observation will need to be validated by further studies.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
SPECIAL STAINS  
IMMUNOPEROXIDASE  

Intravascular large B-cell lymphoma: the CD5 antigen is expressed by a subset of cases.

Khalidi HS, Brynes RK, Browne P, Koo CH, Battifora H, Medeiros LJ.

Division of Pathology, City of Hope National Medical Center, Duarte, California, USA.

Mod Pathol 1998 Oct;11(10):983-8 Abstract quote

The CD5 antigen is a T-cell associated marker that is also usually expressed by two B-cell neoplasms, chronic lymphocytic leukemia/small lymphocytic lymphoma and mantle cell lymphoma.

We observed CD5 antigen expression in a subset of cases of intravascular large B-cell lymphoma (IVLBL), and we report here five cases. The patients, two men and three women, ranged in age from 59 to 81 years. Biopsy specimens were obtained from kidney, lung, bone marrow, abdominal wall, and neck, the latter involving a lymphangioma. All of the cases had histologic features typical of IVLBL, with large and atypical lymphoid cells located predominantly within blood vessels. Immunohistochemical studies performed using routinely fixed, paraffin-embedded tissue sections showed that the neoplastic cells were B cells, positive for the CD20 antigen and negative for the CD3 or CD43 antigens. All cases were also positive for the CD5 antigen. One case had an immunoglobulin heavy chain gene rearrangement shown by using a polymerase chain reaction method. The finding of CD5 antigen expression in a subset of IVLBL cases adds to other evidence in the literature suggesting that IVLBL is a heterogeneous entity. We considered the possibility that these cases were related to or represented unusual histologic forms of transformation from either chronic lymphocytic leukemia/small lymphocytic lymphoma or mantle cell lymphoma. All of the cases, however, were negative for the CD23 antigen and cyclin D1 (bcl-1) protein, which is evidence against this interpretation.

The biologic significance of CD5 antigen expression in cases of IVLBL is uncertain. These neoplasms might arise from a separate lineage of CD5-positive B cells or from a specific, early stage of B-cell differentiation. Alternatively, some investigators have suggested that CD5 antigen expression by B cells is a marker of activation.

Intravascular large cell lymphoma: clinicopathological, immuno-histochemical and molecular genetic studies.

Kanda M, Suzumiya J, Ohshima K, Tamura K, Kikuchi M.

First Department of Pathology, School of Medicine, Fukuoka University, Japan.

Leuk Lymphoma 1999 Aug;34(5-6):569-80 Abstract quote

Intravascular large cell lymphoma (IVLL) is a rare neoplasm characterized by a proliferation of lymphoma cells within the blood vessels. Its cell origin and clinicopathological characteristics have not been well understood.

The study uses 5 male and 4 female patients who were diagnosed as having IVLL from 1978 to 1996. We examined cell lineage and adhesion molecules using immunohistochemical staining and performed a molecular analysis by using polymerase chain reaction (PCR) on the IgH gene, on T-cell receptor chain genes, and the Epstein-Barr virus (EBV) and in situ hybridization on EBV.

The immunohistochemical and PCR results disclosed 8 cases of B- cell and one of T-cell lymphoma. Three of four cases whose frozen specimens were available expressed CD5. PCR showed EBV in 7 of 9 cases, although EBV was found by in situ hybridization in only 3 cases. Lymphoma cells express CD11a and CD49d (VLA-4), while endothelial cells expressed CD54 (CD11a ligand) and CD106 (CD49d ligand). Such interaction of these adhesion molecules might contribute to the intravascular proliferation of lymphoma cells. Furthermore, the CD5 expression of lymphoma cells suggests that IVLL most likely originates from a unique subtype of B cells, although their normal counterpart remains uncertain.

PROSTATIC ACID PHOSPHATASE  
Prostatic Acid Phosphatase Is a Possible Tumor Marker for Intravascular Large B-Cell Lymphoma.

Seki K, Miyakoshi S, Lee GH, Matsushita H, Mutoh Y, Nakase K, Ida M, Taniguchi H.

Departments of *Pathology, daggerHematology, and double daggerNeurology, Toranomon Hospital; and section signGenome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
Am J Surg Pathol. 2004 Oct;28(10):1384-1388. Abstract quote  

Intravascular large B-cell lymphoma (LBCL) is a rare and aggressive subtype of diffuse LBCL characterized by disseminated intravascular proliferation of neoplastic lymphocytes. Obstruction of blood flow by tumor cells in a variety of organs can cause an array of clinical changes, including alteration of the neural and spinal system and the respiratory system, as well as skin lesions. It is usually very difficult to diagnose intravascular LBCL in a patient simply from clinical symptoms or laboratory examinations.

We here document our findings that serum prostatic acid phosphatase levels in both males and a female (2.2–24.0 microg/L) reflect the presence of intravascular LBCL, changing synchronously in response to chemotherapy. To determine whether prostatic acid phosphatase (PAP) might be a useful tumor marker for early diagnosis, we reviewed five intravascular LBCLs.

Immunohistochemically, tumor cells in all cases were positive for anti-PAP antibody. The results were further confirmed in one case by Western-blot analysis and in another by the detection of amplified messenger RNA for PAP in microdissected tumor cells, respectively. PAP has not been detected in 17 lymphomas (diffuse LBCL, 8 cases; follicular lymphoma, 3 cases; T-cell lymphoma, 3 cases; Hodgkin lymphoma, 3 cases) by Western blot analyses.

We conclude that serum PAP is a useful tumor marker for intravascular LBCL and that it deserves further investigation in this context.

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
DIFFUSE Large B-cell lymphoma  
HEMANGIOMAS  
Intravascular large B-cell lymphoma involving hemangiomas: an unusual presentation of a rare neoplasm.

Nixon BK, Kussick SJ, Carlon MJ, Rubin BP.

1Department of Anatomic Pathology, University of Washington Medical Center, Seattle, WA, USA.
Mod Pathol. 2005 Aug;18(8):1121-6. Abstract quote  

We report the clinicopathological features of two cases of intravascular large B-cell lymphoma involving cutaneous hemangiomas. The cases were identified from the consultation files of two of the authors.

Both patients were women, 64 and 55 years of age, who presented with long-standing cutaneous hemangiomas of the posterior scalp and left shoulder, respectively. The lesions were brought to medical attention by an increase in size and change in color.

Biopsies and immunohistochemical evaluation of the hemangiomas revealed extensive involvement by intravascular large B-cell lymphoma. The neoplastic cells were diffusely positive for CD20 in both cases and negative for CD3, pan-cytokeratin (AE1/AE3), epithelial membrane antigen, S-100, Factor VIII-related antigen, CD34 and CD31. Disease was limited to the hemangiomas in both patients.

Treatment consisted of chemotherapy (both patients) and adjuvant radiation therapy (one patient). One patient had a recurrence of disease 33 months after initial diagnosis, leading to an autologous stem cell transplant. The other patient is without evidence of disease 27 months after initial diagnosis. Although this is a rare neoplasm, it is important to consider intravascular large B-cell lymphoma in the differential diagnosis of vascular lesions containing intravascular neoplastic cells.
Intravascular large B-cell lymphoma colonizing cutaneous hemangiomas.

Cerroni L, Zalaudek I, Kerl H.

Department of Dermatology, University of Graz Medical School, Graz, Austria.
Dermatology. 2004;209(2):132-4. Abstract quote  

Intravascular large B-cell lymphoma is a malignant neoplasm characterized by the proliferation of large B cells (rarely of T lymphocytes) confined within the blood vessels.

Although the disease can be limited to the skin, involvement of other organs is common.

We report a case of intravascular large B-cell lymphoma colonizing the vessels of preexisting cutaneous cherry hemangiomas.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSTIC FACTORS  
Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the 'cutaneous variant'.

Ferreri AJ, Campo E, Seymour JF, Willemze R, Ilariucci F, Ambrosetti A, Zucca E, Rossi G, Lopez-Guillermo A, Pavlovsky MA, Geerts ML, Candoni A, Lestani M, Asioli S, Milani M, Piris MA, Pileri S, Facchetti F, Cavalli F, Ponzoni M; International Extranodal Lymphoma Study Group (IELSG).

Department of Radiochemotherapy, San Raffaele H Scientific Institute, Milan, Italy.
Br J Haematol. 2004 Oct;127(2):173-83. Abstract quote  

Despite its recognition as a distinct, extremely rare entity, no large studies of intravascular lymphoma (IVL) have been reported. The clinico-pathological characteristics of 38 human immunodeficiency virus-negative patients with IVL diagnosed in Western countries were reviewed to better delineate clinical presentation, clinical variants, natural history and optimal therapy. The IVL is an aggressive and usually disseminated disease (Ann Arbor stage IV in 68% of cases) that predominantly affects elderly patients (median age 70 years, range: 34-90; male:female ratio 0.9), resulting in poor Eastern Cooperative Oncology Group Performance Status (ECOG-PS >1 in 61%), B symptoms (55%), anaemia (63%) and high serum lactate dehydrogenase level (86%).

The brain and skin are the most common sites of disease. In contrast to previous reports, hepatosplenic involvement (26%) and bone marrow infiltration (32%) were found to be common features in IVL, while nodal disease was confirmed as rare (11% of cases). Patients with disease limited to the skin ('cutaneous variant'; 26% of cases) were invariably females with a normal platelet count, and exhibited a significantly better outcome than the remaining patients, which deserves further investigation.

Overall survival was usually poor; however, the early use of intensive therapies could improve outcome in young patients with unfavourable features. ECOG-PS >1, 'cutaneous variant', stage I and chemotherapy use were independently associated with improved survival.
TREATMENT  
Intravascular Large B-Cell Lymphoma with Bone Marrow Involvement and Superior Sagittal Sinus Thrombosis: Report of a Case Successfully Treated with a CHOP/Rituximab Combination Regimen.

Jardin F, Callonnec F, Contentin N, Picquenot JM, Gueit I, Heron F, Bastard C, Tilly H.

Department of Hematology, Centre Henri Becquerel, Rouen, France
Clin Lymphoma. 2005 Jun;6(1):46-9. Abstract quote  

Intravascular large B-cell lymphoma (ILBCL) is a rare subtype of diffuse large B-cell lymphoma (as currently recognized by the World Health Organization classification) and is characterized by proliferation of mature B-cells within the lumina of small and medium vessels.

We report on a 66-year-old man who presented with a fever of undetermined origin, a splenomegaly, and an elevated lactate dehydrogenase level. The diagnosis of ILBCL was established by a bone marrow biopsy that showed CD20+ tumor cells confined within the lumina of sinuses. A karyotypic analysis obtained from the bone marrow aspirate showed a hypotetraploid clone. Magnetic resonance imaging of the brain revealed multiple high-signal areas in the periventricular white matter above the tentorium. Focal dural enhancement (pachymeningitis) close to the medium third of the superior sagittal sinus was also observed and was related to a partial superior sagittal sinus thrombosis as confirmed by venous magnetic resonance angiography.

After 8 courses of a CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) plus rituximab regimen, normalization of the superior sagittal sinus and of the bone marrow was obtained. With a follow-up of 15 months, the patient is still considered in complete remission.

This observation highlights an unusual vascular aspect of ILBCL and the efficacy of the current standard treatment for this age group (CHOP/rituximab) in this particularly aggressive lymphoma subtype.

Diagnosis and treatment of intravascular lymphomatosis.

Baumann TP, Hurwitz N, Karamitopolou-Diamantis E, Probst A, Herrmann R, Steck AJ.

Department of Neurology, University Hospital, Basel, Switzerland.

Arch Neurol 2000 Mar;57(3):374-7 Abstract quote

OBJECTIVE: To describe a patient with unusually good outcome of a rare, high-grade lymphoma that often involves the nervous system.

DESIGN: Case report.

SETTING: University hospital. CASE: A 70-year-old pharmacist first presented with meningoencephalitislike symptoms and 6 months later with acute confusional state followed by complex partial status epilepticus. Diagnosis of intravascular lymphomatosis was made using detection and biopsy of a bilateral adrenal tumor.

MAIN OUTCOME AND RESULTS: Polychemotherapy consisting of CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) led to complete remission. The patient's survival time currently exceeds 21/2 years.

CONCLUSIONS: The possibility of intravascular lymphomatosis should be considered in adult patients with unclear meningoencephalitic syndrome, acute confusional state, dementia, or other unexplained neurologic conditions with signs of a systemic disease. In intravascular lymphomatosis, as in other high-grade non-Hodgkin lymphomas, CHOP polychemotherapy should be the standard treatment.

Cerebral angiotropic large cell lymphoma (neoplastic angioendotheliosis): therapeutic considerations.

Williams DB, Lyons MK, Yanagihara T, Colgan JP, Banks PM.

Department of Neurology, Mayo Clinic, Rochester, MN 55905.

J Neurol Sci 1991 May;103(1):16-21 Abstract quote

Cerebral angiotropic large cell lymphoma (neoplastic angioendotheliosis) is a rare disease with a particular propensity to affect the central nervous system by vascular occlusion. Because the disease is rare and there are no specific diagnostic procedures apart from cerebral biopsy, it is difficult to diagnose in life. Accordingly, chemotherapy or radiotherapy has only rarely been attempted and their effectiveness is uncertain. We established the diagnosis in a 62-year-old patient by cerebral biopsy and observed remission following institution of combination chemotherapy. Unfortunately, neurologic deterioration recurred during maintenance chemotherapy.

We identified 30 patients in the literature who initially presented with definite central nervous system manifestations and whose clinical conditions were described sufficiently enough for comparison with our case. Eleven patients had the diagnosis made in life, but only 5 received chemotherapy other than corticosteroid hormones. Our patient's survival for 16 months exceeded that in the majority of the 30 reported cases.

Intense anti-lymphoma chemotherapy, and possibly radiotherapy, may be beneficial and should be studied in this otherwise rapidly fatal disease. It seems certain that early diagnosis is essential if therapeutic intervention is to be successful.

Angiotropic B-cell lymphoma (malignant angioendotheliomatosis): failure of systemic chemotherapy.

Williams RE, Seywright MM, Lever R, Lucie NP.

Department of Dermatology, Western Infirmary, Glasgow, U.K.

Br J Dermatol 1990 Dec;123(6):807-10 Abstract quote

A 65-year-old female with angiotropic B-cell lymphoma is reported. Despite the absence of systemic involvement on formal staging and the favourable response of the cutaneous lesions to triple systemic chemotherapy with prednisolone, vincristine and cyclophosphamide, postmortem findings showed that death was due to widespread disease dissemination.

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