Intravascular Lymphoma

Definition

• A rare subtype of diffuse large cell lymphoma characterized by the presence of lymphoma cells in the lumina of small vessels

Alternate/Historical Names

• Angioendotheliomatosis proliferans systemisata
• Angio-endotheliotropic lymphoma (Kiel)
• Diffuse large B cell lymphoma (REAL)
• Intravascular lymphomatosis
• Malignant angioendotheliomatosis
• Intravascular histiocytosis (variant)

Diagnostic Criteria

• Predominantly Intravascular Involvement
  • Brain and skin most common sites of involvement
  • Capillaries to medium sized vessels
  • Occasional features
    • Endothelial proliferation
    • Thrombosis with recanalization
    • Regional infarction
    • Minor extravascular involvement
  • Infiltrate may be free floating or subendothelial
  • Atypical cells may appear to be adherent to wall
  • Cells may be trapped in clots
• Large Noncohesive Cells
  • Cytologically malignant nuclei
  • Scant to moderate cytoplasm
  • Erythrophagocytosis in Asian Variant and Histiocytic Variant
• Predominantly B Lineage
  • Originally thought to be a neoplasm of endothelial cells, now clearly shown to be a lymphoma
  • Leukocyte common antigen (LCA) positive
  • Most cases B lineage, occasionally T
  • Rare reports of true histiocytic lineage cases
• Occasionally Associated with Conventional Lymphomas

Yasodha Natkunam MD PhD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting:: May 6, 2006

Asian Variant

• Presents with reactive hemophagocytic syndrome with anemia, thrombocytopenia, hepato-splenomegaly, absence of peripheral lymphadenopathy or mass formation
• Rare CNS and skin involvement
  • Frequently involves liver, marrow, lung, kidney
• Immunophenotype same as conventional intravascular lymphoma
• Nearly all cases reported to date in Asians
  • Rare non-Asian cases reported
• Poor prognosis, same as conventional intravascular lymphoma
• Alternate names in literature
  • Malignant histiocytosis-like B-cell lymphoma
  • Diffuse large B-cell lymphoma with haemophagocytic syndrome
  • Intravascular lymphoma with haemophagocytic syndrome
• The precise classification of this disorder or variant is not clear as apparently not all cases of Asian diffuse large B-cell lymphoma with haemophagocytic syndrome exhibit intravascular features

Intravascular Histiocytosis Variant

• Very rare cases are described with a true histiocytic phenotype
• Clinical
  • One case restricted to skin, remained localized but recurred following electron beam therapy
  • One case generalized including skin, responded to chemotherapy
• Histology
  • Intravascular with few extravascular atypical cells
  • Granular foamy cytoplasm with occasional phagocytosis of erythrocytes and neutrophils
  • Nuclei oval, no grooves, minimal pleomorphism
• Immunohistology
  • Histiocytic markers positive
    • CD68, Mac387 in paraffin sections
    • CD11b, CD14, HLADR in frozen tissue
  • Other markers negative
    • CD20, MB1, kappa, lambda, heavy chains
    • CD3, CD45RO, CD43
    • CD15, CD30, S100, CD34, elastase, FactorVIIIRA
• Genotypic studies negative for B and T receptor rearrangement
• Lacks high grade nuclear pleomorphism of true histiocytic lymphoma

Association with Conventional Lymphomas

• Intravascular lymphoma may occasionally be associated with conventional, non-intravascular lymphoma
• Incidence unknown
• Types of lymphoma reported
  • Follicular
  • Diffuse large B-cell lymphoma
  • Extranodal marginal zone B cell lymphoma
• Evidence that this represents transformation is limited, but has been suggested by some authors

Supplemental studies

Immunohistology

• Leukocyte common antigen (LCA) positive
• Predominantly B lineage
  • Probably at least 95% B
  • CD5 co-expression reported 22-75%
  • BCL2 expression reported in 98% (no bcl2 rearrangement)
  • BCL6 expression reported in 22%
  • CD10 expression reported in 22%
  • No CD43 co-expression reported
• Infrequent T lineage cases
• Single case with NK phenotype
• Very rare cases with true histiocytic phenotype
• Endothelial markers negative
• Lack expression of adhesion molecules CD29 (beta-1 integrin) and CD54 (ICAM-1), may explain intravascular growth
• Prostatic acid phosphatase positive
  • Reported in 5/5 autopsy cases
  • Also present in serum
  • Prostate specific antigen negative

Genetic Study

• PCR may detect marrow or peripheral blood involvement in cases negative by light microscopy
• Immunoglobulin gene rearrangements detectable in most cases
• T receptor gene rearrangements detectable in T lineage cases
• bcl2 gene rearrangements not detectable
• EBV detectable by PCR in 7/9 cases but fewer by in situ hybridization

Differential Diagnosis

Reactive angioendotheliomatosis vs Intravascular Large Cell Lymphoma

	ReactiveAngioendotheliomatosis	Intravascular LargeCell Lymphoma
Cytology	Benign	Malignant
Lymphoid antigens	Negative	Positive
Endothelial antigens(CD31, CD34, Factor VIIIRa, Smooth muscle actin)	Positive	NegativeWeak Factor VIIIRa may be adsorbed from clots
Associated bacterial endocarditis	Frequent	Negative

Metastatic carcinoma and melanoma:

• Occasionally may be intravascular
• Can be identified with stains for keratin, S100 and other markers

Clinical

• Rare, no incidence figures available
• Age
  • Predominantly 7th and 8th decade
  • Cases reported in 12 and 13 year olds
  • One congential case reported but inconclusive phenotype (only CD43 positive with focal LCA reactivity)
• Geographic distribution
  • Most cases reported from North America and Europe
  • Asian variant primarity reported from Asia
• Sites of involvement
  • Central nervous system and skin are the most commonly reported sites
    • Brain lesions may present as dementia or as focal mass lesions
    • Skin lesions may be nodules or plaques
  • Disease limited to skin reported in 26%
    • All females
    • Better prognosis
  • Wide range of other sites reported
    • Liver and spleen in 26%
    • Lymph nodes only in 11%
  • Peripheral blood and marrow
    • Older literature rarely reported involvement
    • Recent reports using immunologic or genotypic means have found involvement
      • Marrow in 32%
    • Marrow frequently involved in Asian variant
• May be associated with autoimmune disorders
• Originally considered nearly uniformly fatal (most cases diagnosed at autopsy)
  • Antemortem diagnosis with aggressive treatment may yield good results

Grading

Not applicable

Staging

Ann Arbor Staging System

• (Intravascular lymphoma is typically Stage IV at presentation)
• Stage I
  • I if involvement of a single lymph node region
  • IE if involvement of a single extralymphatic organ or site
• Stage II
  • II if two or more lymph node regions on same side of diaphragm
  • IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm
• Stage III
  • III if Involvement of lymph node regions on both sides of the diphragm
  • IIIS if spleen involved
  • IIIE if extralymphatic site involved
• Stage IV
  • Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement
• Systemic Symptoms in 6 months preceding admission
  • Fever, night sweats, 10% weight loss
  • A = absent
  • B = present
• Extranodal sites are also designated
  • M+ = marrow
  • L+ = lung
  • H+ = liver
  • P+ = pleura
  • O+ = bone
  • D+ = skin and subcutaneous tissue
• Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas

Report

The surgical pathology report should contain or address the following:

• Diagnosis in the World Health Organization (WHO) classification
  • Equivalent diagnosis in other classifications used by relevant clinicians
• Results of supplementary studies if performed
• Relationship to other specimens from the same patient
• Information relevant to staging if available

Lists

Types and variants of large B cell lymphoma

• Diffuse large B cell lymphoma (DLBCL)
  • ALK positive large B cell lymphoma
  • Anaplastic variant of DLBCL
  • Immunoblastic variant of DLBCL
  • Microvillous large B cell lymphoma
  • T cell / histiocyte rich B cell lymphoma
• Follicular lymphoma grade 3
• Intravascular large B cell lymphoma
• Lymphomatoid granulomatosis variant of DLBCL
• Plasmablastic lymphoma
• Primary effusion lymphoma
• Primary mediastinal (thymic) B cell lymphoma
• Pyothorax associated lymphoma

Bibliography

• Warnke RA, Weiss LM, Chan JKC, Cleary ML, Dorfman RF . Tumors of the Lymph Nodes and Spleen, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 14, 1995
• Jaffe ES, Harris NL Stein H, Vardiman JW . Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2001
• 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). Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the 'cutaneous variant'. Br J Haematol. 2004 Oct;127(2):173-83.
• Seki K, Miyakoshi S, Lee GH, Matsushita H, Mutoh Y, Nakase K, Ida M, Taniguchi H. Prostatic acid phosphatase is a possible tumor marker for intravascular large B-cell lymphoma. Am J Surg Pathol. 2004 Oct;28(10):1384-8.
• Imai H, Kajimoto K, Taniwaki M, Miura I, Hatta Y, Hashizume Y, Watanabe M, Shiraishi T, Nakamura S. Intravascular large B-cell lymphoma presenting with mass lesions in the central nervous system: a report of five cases. Pathol Int. 2004 Apr;54(4):231-6.
• Bazhenova L, Higginbottom P, Mason J. Intravascular lymphoma: a role for single-agent rituximab. Leuk Lymphoma. 2006 Feb;47(2):337-41.
• Takahashi E, Kajimoto K, Fukatsu T, Yoshida M, Eimoto T, Nakamura S. Intravascular large T-cell lymphoma: a case report of CD30-positive and ALK-negative anaplastic type with cytotoxic molecule expression. Virchows Arch. 2005 Dec;447(6):1000-6.
• Wu H, Said JW, Ames ED, Chen C, McWhorter V, Chen P, Ghali V, Pinkus GS. First reported cases of intravascular large cell lymphoma of the NK cell type: clinical, histologic, immunophenotypic, and molecular features. Am J Clin Pathol. 2005 Apr;123(4):603-11.