Intravascular Large B-cell Lymphoma

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Primary Author(s)*

Kate Berry, MBBS, BBus (Hons), Pathology Queensland

Cancer Category/Type

Mature B-cell neoplasms

Cancer Sub-Classification / Subtype

Intravascular large B-cell lymphoma

Definition / Description of Disease

Intravascular large B-cell lymphoma (IVLBCL) is a rare, extranodal B-cell lymphoma in which there is selective growth of lymphoma cells within the lumina of small blood vessels, especially capillaries. Larger arteries and veins are not affected. [1]

Synonyms / Terminology

Obsolete: malignant angioendotheliomatosis; angioendotheliomatosis proliferans syndrome; intravascular lymphomatosis; angioendotheliotropic lymphoma.

Epidemiology / Prevalence

  • IVLBCL is an extremely rare disease, with incidence estimated at 0.095 per million per year[2]
  • The median age at diagnosis is 63-67 years[1][3]
  • Incidence is not affected by sex

Clinical Features

The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues[1] describes three patterns of clinical presentation observed in patients with IVLBCL. In the classic variant symptoms are related to the organ system primarily involved, usually cutaneous or neurological. Cutaneous manifestations are highly variable and include ecchymoses, blanchable erythematous macules and patches with telangiectasia[4] as well as tumours and ulcerated nodules. Approximately one third of patients show isolated cutaneous lesions and a similarly sized second group of patients presents with multi-organ involvement[5] including neurological symptoms, observed in 23.5-41% of cases[3][4] , which include impaired level of consciousness and heterogenous focal neurological deficits[6]. Patients tend to experience a rapid deterioration in performance status due to the aggressive nature of the disease[5].

The haemophagocytic syndrome-associated variant, initially described by Murase et al[7], and occurring primarily in Asian countries, presents with bone marrow involvement, fever, hepatosplenomegaly and thrombocytopoenia in the majority of patients[5]. Often, non-neoplastic haemophagocytic histiocytes can be identified in the bone marrow or peripheral blood[5]. Bone marrow haemophagocytosis is statistically associated with B symptoms, splenomegaly, higher CRP levels, lower albumin concentration, lower creatinine levels, and an absence of tumour cells in the peripheral blood[7]. Disease progression tends to be rapid and aggressive, with a median survival time of 2 to 8 months[5]. Fever of unknown origin is common in both variants, occurring in the majority of patients[1][3][4][6], as are night sweats and weight loss[8]. There is generally no tumour mass or lymphadenopathy suitable for biopsy or detectable using imaging[1], causing diagnostic challenges and frequent false negatives during conventional staging. Radiological findings are often non-specific, but frequently include abnormalities if the central nervous system is imaged using MRI, including hyperintense lesions in the pons, non-specific white matter lesions, infarct-like lesions and meningeal enhancement[6]. Other findings include pleural effusion, ground glass appearance of lung parenchymal tissue on CT, splenomegaly, and abnormal FDG uptake in the adrenal glands and bone marrow on PET-CT[6].

Other clinical features include:

·        Eastern Cooperative Oncology Group (ECOG) performance score ≥2 at diagnosis[1][6]

·        Median International Prognostic Index score of 4 at diagnosis[3]

·        Ann Arbor stage IV at diagnosis (86%)[3]

·        Hepatomegaly or splenomegaly[4][7]

·        Dyspnoea and hypoxaemia[4][6]

·        Anaemia[3][4][6][7]

·        Thrombocytopenia[3][4][6][7]

·        Leukopoenia or leukocytosis[4]

·        Increased serum LDH[3][4][6]

·        Hypoalbuminaemia[3][6]

·        Low level monoclonal immunoglobulin (approximately 14%)[7]

Additionally, an isolated cutaneous variant occurs almost exclusively in females. These individuals are of younger age than patients with other IVLBCL variants, and display a significantly better prognosis with less aggressive disease progression[1][9]. These cutaneous lesions exhibit identical histological features to the classic variant, without involvement of other organ systems, and normal peripheral blood leukocyte and platelet counts[5].

Sites of Involvement

Almost any organ can be affected by IVLBCL including the thyroid, liver, pancreas, prostate and central nervous system[6]. Bone marrow involvement is observed in 33-67% of patients[3][6][10][8], but this number increases to 93% in patients that present with organomegaly. Within the bone marrow the malignant cells are often limited to the sinusoids and merge with the surrounding haematopoietic elements, making histological recognition difficult. Peripheral blood involvement occurs in 5-12% of cases[6][9] and the lymph nodes are generally not involved[1]. Tumour cells are often observed in the subcutaneous tissues, even in the absence of macroscopic skin lesions[11][3]. Extravascular lymphoma infiltration is rare, but may be observed, and can be extensive in the absence of treatment, such as in cases diagnosed at autopsy[6].

Morphologic Features

IVLBCL can show variable cytomorphology. Most commonly the lymphoma cells are large with vesicular nuclei, prominent nucleoli and plentiful mitotic figures[1][9][7]. Less commonly, they may show coarse chromatin and irregular or indented nuclei[9]. By definition, the lymphoma involves the lumina of small to intermediate sized blood vessels[1], and this occurs within many organs, including the central nervous system. Sinusoidal involvement (of the liver, spleen and bone marrow) and focal extravasation of tumour cells into surrounding tissues may be seen[1][9]. Haemophagocytosis by benign-appearing histiocytes occurs in the haemophagocytic syndrome-associated variant[9], in approximately 12% of IVLBCL patients overall[3].


Intravascular large B cell lymphoma is overwhelmingly a neoplasm of activated B-cell (ABC) type, rather than germinal centre (GCB) type, when classified by immunohistochemistry using the Hans algorithm[3][12][13][10]. Pan B-cell markers are almost universally expressed by IVLBCL, and MUM1 and IgM expression can be seen in up to 95% and 91% of cases, respectively[7][8]. In up to 50% of cases there is aberrant expression of CD5[1][3][6][7]. The tumour cells are usually negative for CD23, CD10 and BCL6, and EBER-ISH is negative.

Finding Marker
Positive (universal) CD20, CD79a
Positive (usually) CD5 (38-50%)[3][1][6][7], MYC (63-68%)[3][8], BCL2 (80-96%)[3][7][8], CD19(85%)[7], MUM1(75-95%)[8][7], Igκ, IgM(91%)[8]
Negative (universal) EBER-ISH, Cyclin D1, CD30
Negative (usually) CD23(96%)[7], CD10(92%)[1][8][7], BCL-6(42-74%)[8][7]

Chromosomal Rearrangements (Gene Fusions)

Due to limited data, the prevalence of chromosomal rearrangements in IVLBCL are incompletely described. However, multiple case reports and small series exist describing an array of gene fusions, many of which include the IgH gene, located at 14q32[14][15][16][17][18][19], rearrangements of which constitute a very common cytogenetic abnormality in DLBCL[20]. The t(14;19)(q32;q13) translocation, involving the BCL3 gene at 19q13, is a recurrent translocation in chronic lymphocytic leukaemia (CLL) and confers an adverse prognosis with a higher probability of requiring therapy and shorter overall survival[21]. However, in CLL the translocation is associated with over-expression of BCL3, which is involved in the regulation of the NF-κβ signalling pathway and is a suggested proto-oncogene. In one confirmed[14] and one possible [22] IVLBCL case with t(14;19)(q32;q13) in the literature, BCL3 overexpression was not identified by immunohistochemistry and Southern blot analysis, respectively, suggesting the role of a second oncogene at 19q13 in these tumours. In a karyotypic analysis of three cases of IVLBCL and a literature review, Khoury et al[17] described case reports of breakpoints involving BCL6, CMYC, PAX5, BCL1, BCL2 and BCL3, all gene loci which have been implicated in other haematological diseases, but more data is required to determine if IVLBCL harbours the same recurrent translocations as other B-cell malignancies.

There is insufficient data to comment on the prevalence of high-grade B-cell lymphoma (in which there are concurrent translocations of MYC as well as BCL2 and/or BCL6) amongst IVLBCL cases, but given that the vast majority of high-grade B-cell lymphomas are of germinal centre B-cell type[23][24], and small series have failed to identify MYC rearrangements by break-apart FISH[8] ,it can be assumed to be low.

Genomic Gain/Loss/LOH

IVLBCL cases in the literature with available cytogenetic information have invariably complex karyotypes, comprising both numerical and structural changes with a median of 10 aberrations per case [17][18][25]. The most commonly detected cytogenetic abnormalities are 6q deletions, rearrangements of 8p, chromosome 1 aberrations and deletions or duplication of chromosome 18[25][17][7]. Recurrent cytogenetic abnormalities involving chromosomes 1, 6q and 18 occur in more than 50% of cases[18] .The majority of chromosome 6 deletions involve the long arm, in particular 6q21-q23[17][18], a region which has been implicated in a number of other mature B-cell neoplasms, including diffuse large b-cell lymphoma(DLBCL)[26]. Gains of chromosome 18 are common in DLBCL, mantle zone lymphoma and follicular lymphoma and, frequently, the amplified region involves the BCL2 oncogene at 18q21.3[17]. Whether 18q gain is associated with BCL2 protein overexpression in IVLBCL requires further analysis. Furthermore, loss of chromosome 18 has been shown to be associated with inactivation of the DCC tumour suppressor gene, located at 18q21[27]. One of the most frequently involved chromosome 1 loci, 1p13, contains the NOTCH2 gene[18], a gene essential for the transition of B-cells towards marginal zone maturation[28], mutations in which have been implicated in a number of mature B-cell lymphomas.

Structural variations or copy-number gains in the PD-L1 and PD-L2 encoding genes (CD274 and PDCD1LG2) occur in up to 48% of cases, primarily involving truncation of the 3'UTR sequence which leads to increased expression of PD-L1 transcripts, facilitating immune invasion[13].Small series have confirmed an association between PD-L1 overexpression on IHC and tumours with 9p mutations including amplifications and structural variations[13]. Deish et al[25] postulated that amplification of the MLL or KMTD2 gene, seen in AML and myelodysplastic disorders, may also be a recurrent abnormality in IVLBCL, based on a case they identified with tandem triplication of 11q21-23 leading to three copies of the gene, and three other reported cases in the literature, one with a segmental 11q23 duplication[15] and two with a gain of chromosome 11[29][15].

Chromosome Number Gain/Loss/Amp/LOH Region
1[17] Loss whole chromosome
3[17][16] Loss q21-qter
6[13][17] Loss q21-q23; q11-qter
8[17] Loss p21-qter
9[17] Loss p21-pter; p22-qter
15[17] Loss whole chromosome
18[17][13] Gain whole chromosome, 11q13→qter region
18[17] Loss q23
21 Amp q
22[17] Loss q21-q23

Gene Mutations (SNV/INDEL)

Due to the rarity of IVLBCL, only small series describing recurrent gene mutations are currently available. However, several studies have identified recurrent mutations in multiple genes with known aberrations in both nodal DLBCL and other extranodal lymphomas. These include driver mutations in genes involved in the B-cell receptor/NF-κβ signalling pathways (CD79B, MYD88, IRF4, ITPKB, NFKBIE and TNFAIP3), genes targeted by Activation Induced Deaminase (PIM1 and IGLL5), genes affecting B-cell development (PRDM1 and TOX) and histone modification factors (SETD1B, KMT2D and EP300)[13]. Although the mutational landscape of IVLBCL tends to be similar to that of ABC type nodal DLBCL, there is a higher frequency of mutations in several genes including MYD88, CD79B, TBL1XR1 and SETD1B[13].

Collated, comprehensive gene mutation prevalence data is not currently available, however the table below summarises the most common gene mutations identified from a number of recent studies[8][30][13][10]:

Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
IGLL5 Not fully characterised 90% (19/21)
PIM1 Oncogene GOF 83% (25/30)
SET1B Not fully characterised 57% (12/21)
CD79B Oncogene GOF; Driver 49% (26/53)
MYD88 L265P Oncogene GOF; Driver 45% (29/65)
PRDM1 Tumour suppressor LOF 43% (13/30)
IRF4 Oncogene GOF 38% (8/21)
TOX3 Not fully characterised 33% (7/21)
TNFAIP3 Tumour suppressor LOF 24% (5/21)
KMT2D Tumour suppressor LOF 24% (5/21)
BTG2 Tumour suppressor LOF 22% (2/9)
ITPKB Tumour suppressor LOF 14% (3/21)
NFKBIE Tumour suppressor LOF 14% (3/21)
EP300 Oncogene GOF 14% (3/21)

Epigenomics (Methylation)

Although the role of epigenomics in IVLBCL specifically has been incompletely described, several of the genes most frequently mutated in IVLBCL have been shown to be epigenetic determinants in DLBCL, including KMT2D and EP300.

KMT2D mutants promote lymphomagenesis in part by impeding H3K4 methylation, driving enhanced proliferation in germinal centres, and impeding terminal differentiation of B-cells[31]. The extent to which KMT2D inactivation promotes lymphomagenesis appears to be affected by dysregulation of the expression of a number of other genes, including BCL2 and AICDA. KMT2D loss, in combination with increased BCL2 expression, has been shown in mouse models to increase lymphoma incidence from that of mice with wild type KMT2D, and the effect is greater for those with homozygous deletions[31][32]. AICDA encodes activation-induced cytidine deaminase (AID), an enzyme involved in somatic hypermutation, class switch recombination and gene conversion in the process of immunoglobulin diversification. Overexpression of AICDA has been shown in mice models, in combination with KMT2D inactivation, to be associated with increased lymphoma incidence and also with more aggressive phenotypes than tumours with KMT2D deletion alone[31].

In DLBCL, mutations in EP300, a histone acetyltransferase, have been shown to inhibit H3K27 acetylation and activate the NOTCH signalling pathway, possibly through inhibition of FBXW7 expression, which acts as a NOTCH suppressor[33]. The NOTCH pathway plays a critical role in normal B-cell development and dysregulation of NOTCH signalling has been implicated in a wide array of mature B-cell malignancies, including DLBCL[34]. Additionally, mutations in EP300 have been shown to promote tumour-associated macrophage (TAM) activation, as evidenced by increased macrophages in the tumour microenvironment, which promote tumour progression by inhibiting T-cell immunity[33]. Notably, patients with mutations in EP300 and CREBBP, a closely related chromatin-modifying gene, have been shown to have significantly lower 3-year progression-free and overall survival rates than patients with wild-type EP300/CREBBP[33]

Genes and Main Pathways Involved

One of the most widely studied genes in IVLBCL is MYD88 with 45% of patients found to have a somatic MYD88 mutation, 86% of these being L265P mutations. This mutation is commonly associated with lymphoplasmacytic lymphoma and Waldenstrom macroglobulinaemia (WM), being present in >90% of WM cases and 54% of IgM MGUS patients[35]. MYD L265P mutations have also been found in 29% of activated B-cell (ABC) type DLBCL[36], and can be seen in primary cutaneous DLBCL, testicular and primary CNS DLBCL and DLBCL of leg type[37]. Overall, the mutational profile of IVLBCL is more similar to these entities than to DLBCL, NOS[13]. Ngo et al[36] demonstrated that in ABC-type DLBCL L265P functions as a gain-of-function driver mutation which promotes cell survival through the promotion of NF-κβ and JAK-STAT3 signalling. Given that IVLBCL is overwhelmingly of ABC type, the role of MYD L265P as a driver mutation in IVLBCL should be considered. Some studies have also shown that TNFAIP3 loss (observed in approximately 24% of IVLBCL) acts synergistically with MYD88 L265P to drive upregulation of anti-apoptotic signalling in DLBCL[38]. Loss of TNFAIP3 occurs in around 55% of DLBCL and also contributes to higher baseline phosphorylation of NF-κβ and STAT3 as well as p38 which, in association with NF-κβ, causes upregulation of BCL2 and MYC[38]. IGLL5 located at 22q11, which is mutated in around 90% of IVLBCL, is a recurrently mutated gene in DLBCL and multiple myeloma, in which mutations confer an increased risk of disease progression[39].

Diagnostic Testing Methods

Due to its non-specific clinical presentation and frequent lack of characteristic radiological findings, such as lymphadenopathy, IVLBCL often poses a diagnostic challenge. When IVLBCL is suspected clinically, random skin biopsy is easy to perform and frequently diagnostic[10], with tumour cells often observed in subcutaneous tissues, even in the absence of macroscopic lesions[11]. However, as the lymphoma cells are most commonly found within the subcutaneous adipose tissues, rather than the dermis, inadequate hypodermic sampling may lead to false negative results[6]. Although intrasinusoidal infiltration of the bone marrow is considered to be characteristic of IVLBCL, nodular and interstitial infiltration are often also seen, making it difficult on bone marrow biopsy alone to distinguish it from splenic and primary bone marrow DLBCL which show many common clinical features and immunohistochemical findings[6].

The use of plasma- and serum-derived cell-free DNA (cfDNA) is emerging as a potential non-invasive means of obtaining tumour material for both diagnosis and genetic testing. A 2021 study by Shimada et al[13] showed the yield of cfDNA to be ten times higher in patients with IVLBCL than diffuse large B-cell lymphoma, and significantly higher than that from healthy controls. Furthermore, cfDNA levels were significantly correlated with serum lactate dehydrogenase level and the status of bone marrow invasion, and rapidly decreased after commencing chemotherapy, whilst being elevated in the refractory phase. This not only suggests that cfDNA is mainly derived from lymphoma cells, but that lactate dehydrogenase level is a reliable surrogate marker for monitoring disease progression and response to treatment. When using whole-exome sequencing to compare mutations detected in plasma-derived cf-DNA to those in bone marrow samples, not only did the mutations observed in cf-DNA have substantially higher variant allele frequencies (a marker of intratumoural heterogeneity), suggesting that tumour-derived DNA is significantly enriched in cfDNA, but many mutations detected in cfDNA were not found in the corresponding bone marrow samples, suggesting improved sensitivity with the use of cf-DNA over bone marrow samples[13]. Variant allele frequency has also been shown to be significantly higher in cfDNA than tissue-derived DNA samples, with increased sensitivity[10]. In patients with an L265P MYD88 mutation, monitoring of cfDNA has been shown in small-scale longitudinal analysis to be of potential diagnostic utility, with detectable L265P MYD88 in cfDNA from one patient 117 days prior to definitive diagnosis, at a time in which bone marrow biopsy was negative, and in three patients prior to a definite diagnosis of disease relapse[10].

In a study in 1997, DiGiuseppe et al.[40] detected monoclonal B-cell populations by IgH gene rearrangement studies in the bone marrow of 5/5 cases of IVLBCL studied, all of whom had histologically non-involved marrow, suggesting both that marrow involvement may be under-recognised in IVLBCL, and that bone marrow biopsy may be a useful diagnostic tool to provide material for genetic testing, even when disease cannot be visualised histologically within the bone marrow.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Intravascular large B cell lymphoma is an aggressive disease, with median overall survival of 105 months and a 5 year survival rate of 46-84%[6][41][13]. Commonly used treatment regimens include R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) +/- high dose methotrexate, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), R-CODOX-M (rituximab, cyclophosphamide, cytarabine, doxorubicin, vincristine, methotrexate) and R-IVAC (rituximab, ifosfamide, cytarabine, etoposide)[3].Patients with the cutaneous variant have significantly longer overall survival, independent of their International Prognostic Index[9][8]. The effect of molecular aberrations on overall survival is difficult to define, both because of the limited data available and since a significant percentage of IVLBCL cases are diagnosed at a very advanced stage, or at autopsy. However in a small series of cases mutational status of MYD88 and CD79B did not significantly influence disease-specific overall survival, and were detected in patients with both the systemic and isolated cutaneous variants of the disease[8]. Several possible therapeutic targets exist amongst identified recurrent mutations. The high prevalence of PD-L2 and PD-L2 aberrations suggests a possible therapeutic role for immune checkpoint inhibitors [13] and the presence of MYD88 and CD79B mutations suggests that there may be a role for drugs targeting NFκβ signalling, such as ibrutinib[8]. TNFAIP3 loss has been shown to be associated with ibrutinib resistance in ABC-type DLBCL[38] and the implications of this mutation on treatment in IVLBCL requires further research. Finally, the most commonly detected MYD88 mutant, L265P, can form a stable protein signalling complex containing IRAK1, a serine/threonine protein kinase, providing a possible therapeutic target in the form of IRAK4 inhibitors[36].

Familial Forms

No known familial association exists.

Other Information

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