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Lymphohistiocytic tumors

Intravascular large B cell lymphoma

Authors: Jusmita Saifullan, M.D., Aisha Cato, M.H.S., PA (ASCP), Sergio Pina-Oviedo, M.D.

Editorial Board Member: Matthew J. Cecchini, M.D., Ph.D.

Last author update: 8 October 2024

Last staff update: 8 October 2024

Copyright: 2020-2024, PathologyOutlines.com, Inc.

PubMed Search: Intravascular large B cell lymphoma

Table of Contents

Cite this page: Saifullan J, Cato A, Pina-Oviedo S. Intravascular large B cell lymphoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungtumorintravascularLBCL.html. Accessed December 25th, 2024.

Definition / general

Rare and aggressive subtype of large B cell lymphoma with a predilection for intravascular spaces, absence of mass forming lesions and few to no circulating lymphoma cells
3 subtypes: cutaneous, classic and hemophagocytic; lung involvement is seen in the classic and hemophagocytic subtypes

Essential features

Lung involvement is seen in the classic and hemophagocytic subtypes
On histology, large lymphoid cells with a B cell immunophenotype mostly present in alveolar capillaries; a minimal extravascular component is acceptable
Diagnosis is often delayed and made at autopsy
If detected in a timely manner, chemotherapy with rituximab (R-CHOP) may result in improved survival (Mol Clin Oncol 2016;5:689)

Terminology

Lung intravascular large B cell lymphoma (IVLBCL)
Not recommended: angiotrophic lymphoma, angiotropic large cell lymphoma, angioendotheliotrophic lymphoma, intravascular lymphomatosis, malignant angioendotheliomatosis

ICD coding

ICD-O: 9712/3 - intravascular large B cell lymphoma
ICD-10: C83.8 - other nonfollicular lymphoma: intravascular large B cell lymphoma
ICD-11: 2A81.1 & XH50S7 - intravascular large B cell lymphoma

Epidemiology

Rare; incidence of IVLBCL is 0.095 per million (Blood 2018;132:1561)
Skin and central nervous system are the most affected sites (30 - 40% of cases) (Br J Haematol 2019;186:255)
Specific incidence of IVLBCL involvement at other sites (i.e., lung, kidney, endocrine organs) is not well established
Lung involvement is seen in the classic and hemophagocytic subtypes, with most examples documented as case reports or as case series
Classic subtype
- Adults; median age of 70 years
- No sex predilection
- Most cases reported in North America and Western countries
Hemophagocytic subtype
- Same age and sex distribution as classic subtype
- Most cases reported in Asia

Sites

Intravascular spaces of the lung parenchyma, particularly alveolar capillaries

Pathophysiology

Intravascular proliferation of lymphoma cells, leading to occlusion of small and medium sized blood vessels, leading to pulmonary dysfunction
Lymphoma cells lack adhesion molecules required for proper migration across the endothelium
- CD29 (integrin beta 1)
- CD54 (ICAM1) (Hum Pathol 2000;31:220)
Chemokine receptors needed for tumor migration beyond vascular lumen are decreased or absent
- CCR6, CCR7, CXCR5

Etiology

Currently unknown

Clinical features

Chest pain, dyspnea, hypoxia, cough, pulmonary embolism, pulmonary hypertension (Oncol Lett 2023;25:234)
B symptoms (systemic symptoms): fever of unknown origin (50 - 70%), weight loss, night sweats
Lung involvement is seen in the classic and hemophagocytic subtypes
Involvement of more common organs: skin with cutaneous lesions and central nervous system with altered mental status and strokes (Br J Haematol 2019;186:255)
Hemophagocytic subtype presents with hemophagocytic syndrome, hepatosplenomegaly and cytopenia(s) (Blood 2018;132:1561)
Few to rare lymphoma cells found in peripheral blood in 5 - 10% of cases

Diagnosis

Transbronchial biopsy, lung wedge biopsy, lung cryobiopsy or lung tissue obtained at autopsy (Am J Med 2021;134:926, Sarcoidosis Vasc Diffuse Lung Dis 2015;31:354)
WHO classification of hematolymphoid tumors (5th edition) criteria
- Essential: large lymphoid cells restricted to intravascular spaces, especially capillaries (a minimal extravascular component is acceptable); pan-B cell markers positive
- Desirable: negative immunohistochemistry for human herpesvirus 8 (HHV8) latency associated nuclear antigen (LANA); negative in situ hybridization for Epstein-Barr virus (EBV) encoded small RNA (EBER)

Laboratory

Hypoxemia, pulmonary hypertension (J Clin Oncol 2007;25:2137, Intern Med 2010;49:51)
Anemia, leukopenia or thrombocytopenia
Decreased albumin, elevated LDH, elevated erythrocyte sedimentation rate and C reactive protein (Oncol Lett 2023;25:234)
Markers of disseminated intravascular coagulation (increased D dimer, prothrombin time [PT], partial thromboplastin time [PTT]) in the hemophagocytic subtype

Radiology description

Chest Xray and computed tomography (CT) scan may be normal in a substantial number of cases, leading to a delayed diagnosis
CT scan findings (if present): ground glass opacities, multiple small pulmonary nodules, interlobular septal thickening (Blood 2018;132:1561, Intern Med 2024;63:559, Oncol Lett 2023;25:234)
Positron emission tomography (PET) / CT scan may or may not demonstrate increased radiotracer uptake
Variable detection of defects in pulmonary blood flow scintigraphy secondary to embolisms
Usually no mediastinal adenopathy

Radiology description

Contributed by Sergio Pina-Oviedo, M.D.

Chest CT scan

Prognostic factors

Poor prognosis (Oncol Lett 2023;25:234)
- Most rapid and aggressive course with hemophagocytic subtype
Diagnosis often delayed and made at autopsy

Case reports

41 year old man with normal chest Xray, multiple ground glass opacities and recurrent strokes (Cureus 2024;16:e66112)
56 year old man with respiratory failure treated with prednisolone and R-CHOP chemotherapy (Respir Med Case Rep 2022;37:101625)
68 year old man with fever of unknown origin, multiple nodules and ground glass opacities on imaging, diagnosed by transbronchial cryobiopsy (Transl Cancer Res 2021;10:4571)
73 year old man with pneumonia, bilateral ground glass opacities and adenocarcinoma (J Clin Exp Hematop 2019;59:140)
75 year old woman with severe respiratory failure, high lactase dehydrogenase (LDH) and normal imaging studies (Am J Case Rep 2019;20:1199)

Treatment

Chemotherapy with rituximab may result in improved survival, if diagnosed in a timely manner (Mol Clin Oncol 2016;5:689)

Gross description

Lung may be normal or may show focal or diffuse congestion with no mass forming lesions

Microscopic (histologic) description

Large lymphoid cells identified within the lumina of pulmonary alveolar capillaries
- Lymphoma cells may or may not be admixed with intravascular fibrin or a thrombus
- Minimal extravascular tumor cells are accepted
- Lymphoma cells may distend alveolar septa producing septal thickening
- Challenging diagnosis when scant intravascular lymphoma cells are present
Tumor cells have centroblastic or immunoblastic morphology (multiple nucleoli or a central prominent nucleolus, vesicular chromatin and moderate amount of basophilic cytoplasm) (Arch Pathol Lab Med 2022;146:1160, J Clin Oncol 2007;25:3168)
- Lymphoma cells rarely show anaplastic morphology
- Intravascular mitotic figures may be seen
4 different patterns of vascular involvement (single or combined)
- Noncohesive: lymphoma cells float freely in the vascular lumen
- Cohesive: lymphoma cells fill the entire vascular lumen
- Marginated: lymphoma cells attached to vascular endothelium without fibrin or thrombus
- Tumor associated: intravascular lymphoma cells seen within a solid tumor (i.e., adenocarcinoma) but not in the adjacent normal tissue

Microscopic (histologic) images

Contributed by Sergio Pina-Oviedo, M.D.

Multifocal intravascular infiltrates

Intravascular lymphoid infiltrate

Intravascular lymphoma cells

Alveolar septal thickening

CD3 / CD20 double immunostain

CD79a

CD3

CD31

Pancytokeratin

Ki67

Positive stains

CD45 / LCA
Pan-B cell markers: CD20, CD79a, CD19, PAX5
BCL2 (Blood 2018;132:1561)
MUM1 / IRF4 in 75 - 80% of cases with a nongerminal center / activated B cell-like immunophenotype (Arch Pathol Lab Med 2012;136:333)
Ki67 proliferation index: high (> 60%)

Negative stains

T cell markers
Cyclin D1, CD30 (Blood 2018;132:1561)
Cytokeratins and melanoma markers
HHV8 LANA: rare positive cases have been described; desirable negative marker in the WHO classification of hematolymphoid tumors (5th edition)
EBV by EBV encoded small RNA (EBER) in situ hybridization: rare cases have been described; desirable negative marker in the WHO classification of hematolymphoid tumors (5th edition)
CD5 (positive in 20 - 40% of cases) (Mod Pathol 1998;11:983, Blood 2007;109:478)
CD10 and BCL6 (positive in 10 - 15% of cases) (Arch Pathol Lab Med 2012;136:333)
PDL1 (positive in up to 40% of cases) (Histopathology 2019;75:282)

Molecular / cytogenetics description

In general, IVLBCL exhibits a range of reported cytogenetic alterations but they are not diagnostic or specific for this type of lymphoma
Reported mutations in MYD88 L265P (40 - 60%), CD79B Y196 (30 - 70%), HLA-B (~60%), SETD1B (~60%) and rearrangements in PDL1 (CD274) / PDL2 (PDCD1LG2) (~40%) (Blood 2018;131:2086, Blood 2021;137:1491)

Sample pathology report

Lung, left, wedge biopsy:
- Intravascular large B cell lymphoma (see comment)
- Comment: The lung parenchyma contains a variable number of large, atypical lymphoid cells confined to the lumen of alveolar septal capillaries. In some areas, the alveolar septa are mildly expanded. The atypical lymphoid cells are positive for CD45, CD20, CD5 and MUM1 / IRF4 and are negative for pancytokeratin, S100, CD3, CD10, HHV8 and EBER in situ hybridization. These findings support the diagnosis of IVLBCL.

Differential diagnosis

Lymphangitic carcinomatosis or lymphangitic spread by other solid tumors:
- Lymphangitic carcinoma:
  - Most common: carcinomas from lung, breast and gastric origin (Postgrad Med 2019;131:309)
  - Positive cytokeratins and lineage specific markers depending on primary site (TTF1, GATA3, CDX2, others)
  - Negative for CD45 and pan-B cell markers
- Lymphangitic spread of melanoma:
  - Very rare
  - Positive for S100, HMB45, MelanA, SOX10
  - Negative for CD45 and pan-B cell markers
Intravascular leukemic infiltrates seen in hyperleukocytosis or leukostasis:
- Severe leukocytosis in the CBC and blasts / left shifted myeloid cells in peripheral blood smear
- In tissue sections, intravascular acute myeloid leukemia may be morphologically indistinguishable from lymphoma cells
  - Positive for CD34, CD117 and MPO
  - Negative for pan-B cell markers
- Intravascular infiltrates in chronic myeloid leukemias composed of a spectrum of immature and maturing myeloid cells
  - Positive for myeloid markers CD33, CD11c, MPO
  - Negative for CD34 and pan-B cell markers
  - CD117 variable
Other intravascular lymphomas:
- Rarely, NK / T cell lymphomas may present with an intravascular component (Cancers (Basel) 2022;14:5458)
- Positive for CD3, CD8, CD56 and EBER by in situ hybridization
- Negative for pan-B cell markers
Alveolar capillary angiomatosis:
- Vascular proliferation of alveolar capillaries with congestion without atypical intravascular cells
- Positive for CD34, CD31 and ERG
- Negative for CD45 and pan-B cell markers
Interstitial organizing pneumonia:
- At low magnification, secondary to alveolar septal expansion
- At high magnification, the interstitial alveolar fibrosis lacks atypical intravascular cells
- Negative for CD45 and pan-B cell markers
Lymphomatoid granulomatosis:
- Clinical and imaging presentation with multiple pulmonary nodules
- Angiodestructive and angiocentric; no intravascular proliferation
- Positive for pan-B cell markers and EBER in situ hybridization

Additional references

WHO Classification of Tumours Editorial Board: Haematolymphoid Tumours, 5th Edition, 2024, Cancers (Basel) 2021;13:415, Diagnostics (Basel) 2023;13:3321, Pathol Int 2019;69:148

Board review style question #1

A 62 year old woman with multiple comorbidities presents to the emergency department with sepsis and multiorgan system failure. After a difficult hospital course and despite aggressive measures, the patient died and an autopsy is performed. The above is seen on histologic evaluation of the lungs. Which of the following is true about this entity?

Neoplastic cells are positive for T cell markers, such as CD3, CD5 and CD7
Neoplastic cells confined to intravascular spaces are a diagnostic requirement
Prognosis for this entity is excellent
This entity has a very characteristic clinical and radiographic presentation

Board review style answer #1

B. Neoplastic cells confined to intravascular spaces are a diagnostic requirement. As the entity's name intravascular large B cell lymphoma (IVLBCL) indicates, it is a diagnostic requirement that the neoplastic cells be confined to intravascular spaces. Answer A is incorrect because by immunohistochemistry, the lymphoma cells are positive for pan-B cell markers, such as CD20, CD79a and PAX5 and are negative for T cell markers. Answer C is incorrect because in terms of prognosis, this is a very aggressive entity with largely poor outcomes. Answer D is incorrect because this entity may affect any organ / organ system and presents with nonspecific findings. Chest Xrays or CT scans are not uncommonly normal; therefore, the diagnosis is often delayed and sometimes not established until after death, when / if an autopsy is performed.

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Reference: Intravascular large B cell lymphoma

Board review style question #2

Which of the following immunophenotypes is diagnostic of intravascular large B cell lymphoma (IVLBCL)?

CD20-, CD3+, CD56+, EBER+
CD20+, CD3-, MUM1+, EBER-
CD34-, CD13+, CD33+, CD11c+
CD34+, CD117+, MPO+, CD11c+

Board review style answer #2

B. CD20+, CD3-, MUM1+, EBER-. IVLBCL is a subtype of large B cell lymphoma that is positive for pan-B cell markers with a nongerminal center phenotype (MUM1+), negative for T cell and myeloid markers and negative for EBER. Answer A is incorrect because CD20-, CD3+, CD56+, EBER+ is the immunophenotype of NK / T cell lymphoma, which rarely presents with an intravascular component. Answer C is incorrect because the immunophenotype CD34-, CD13+, CD33+, CD11c+ indicates that the intravascular tumor cells are of myeloid origin. This result is expected in leukemic infiltrates in chronic myeloid leukemia with hyperleukocytosis or leukostasis. Answer D is incorrect because CD34, CD117, MPO and CD11c are positive in intravascular infiltrates of acute myeloid leukemia.

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Reference: Intravascular large B cell lymphoma

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