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Myeloperoxidase-Positive Intravascular Large B-Cell Lymphoma.

Intravascular large B-cell lymphoma (IVLBL) is an uncommon form of non-Hodgkin lymphoma that is also known as malignant angioendotheliosis, intravascular lymphomatosis, and angiotropic large-cell lymphoma. Clinically, the disease presentation may be diverse, and the diagnosis is often not suspected until a postmortem examination is performed. Histologically, the disease is characterized by a bizarre population of neoplastic cells that are found systemically within the vascular lumina. The differential diagnosis often includes leukemias, carcinomas, and other poorly differentiated malignant neoplasms.

Traditionally, immunohistochemical markers have been used to characterize leukemias and lymphomas in formalin-fixed tissues. A wide variety of B-cell and T-cell markers have been used effectively to determine the lineage of lymphoid neoplasms. Alternatively, myeloperoxidase positivity in analyzed cell populations is indicative of myeloid derivation. Although biphenotypic leukemias are a notable exception, most hematopoietic neoplasms usually demonstrate either myeloid or lymphoid differentiation.

Herein, we describe a patient with a history of a myelodysplastic syndrome who subsequently developed IVLBL. Interestingly, this case of IVLBL demonstrated not only the expected B-cell immunophenotype by immunohistochemistry but also expression of myeloperoxidase. To our knowledge, this represents the first case of a malignant lymphoma to demonstrate positivity for both lineages and underscores the difficulty in distinguishing myeloid from lymphoid neoplasms on the basis of immunohistochemical findings alone.


A 55-year-old white woman with a history of myelodysplastic syndrome-refractory anemia type presented to the emergency department with a 2-day history of shortness of breath, fever, and abdominal pain. Chest x-ray examination at admission demonstrated bilateral pleural effusions, with bilateral pulmonary consolidations and cardiomegaly. Serum chemistry analyses were remarkable for elevated blood urea nitrogen and creatinine levels. Complete blood cell counts done at that time showed anemia and thrombocytopenia with no other significant findings. No blast cells were identified in the peripheral smear. The patient continued to decline and subsequently died.


Tissues obtained at autopsy were formalin-fixed and paraffin-embedded and examined with routine hematoxylin-eosin stains. Immunohistochemical stains were performed using the Ventana NexES automated immunostainer (Ventana Medical Sytems Inc, Tucson, Ariz). The immunohistochemical panel included antibodies against CD45, MB1, MB2, CD20, [Kappa] and [Lambda] light chains, CD3, UCHL-1, epithelial membrane antigen, S100, and cytokeratin. Two separate antibodies from different manufacturers against myeloperoxidase (Cell Marque Corp, Austin, Tex, and Novocastra Corp, Newcastle upon Tyne, England) were also tested.


Postmortem examination demonstrated bilateral pulmonary consolidations and bilateral pleural effusions. In addition, 1500 mL of ascitic fluid was present. The urinary bladder had multiple small purplish lesions of the mucosa. The liver and spleen were mildly enlarged, and there was para-aortic lymphadenopathy. Microscopic examination demonstrated a population of large cells with atypical nuclei and amphophilic cytoplasm within the vasculature of many organs, including the urinary bladder, liver, spleen, heart, lymph nodes, adrenal glands, and brain. Occasional mitoses were identified in the cells of interest (Figure 1, a). Immunohistochemical studies performed on the cells of interest in the vascular lumina demonstrated positivity for CD45 (Figure 1, b) and B-cell markers, including CD20 (Figure 1, c), MB1, and MB2. CD3, UCHL-1, [Kappa] and [Lambda] light chains, cytokeratin, S100, and epithelial membrane antigen were all negative. Interestingly, the lymphoid cells showed strong positivity by immunohistochemistry for both antimyeloperoxidase antibodies tested (Figure 1, d). Heavy chain gene rearrangement studies by polymerase chain reaction were performed on the cells of interest in tissue sections and demonstrated clonality. Sections of the bone marrow demonstrated areas of erythroid hyperplasia; however, there was no evidence of malignant lymphoid infiltrates or a significant increase in blast cells.



Intravascular large B-cell lymphoma is an uncommon lymphoid neoplasm, which has been alternatively designated as angiotropic large cell lymphoma, intravascular lymphomatosis, or malignant angioendotheliosis. Originally described in 1959 by Pfleger and Tappeiner,[1] IVLBL was thought initially to be a malignancy of the endothelial cells. With the advent of molecular techniques and immunohistochemistry, it was eventually demonstrated that IVLBL is a lymphoid neoplasm.[2]

Usually, IVLBL presents in middle-aged to elderly patients, although congenital cases have been reported.[3] Patients often present with varied neurologic abnormalities or fever of unknown origin. Because of the systemic involvement of the disease, other presentations of the disease are diverse and common. The disease has a poor prognosis and is usually fatal.

Histologically, IVLBL demonstrates an intravascular proliferation of large atypical cells with bizarre nuclear features. The neoplastic cells are usually limited to the lumen of capillaries, small veins, and small arteries, but the additional finding of neoplastic cells outside the vasculature does not exclude the diagnosis. Entities included in the differential diagnosis include leukemias, metastatic melanoma, metastatic carcinoma, and other poorly differentiated malignant neoplasms. Distinction between these neoplasms is often made with the help of immunohistochemistry.

Immunohistochemical analysis of the neoplastic cells of IVLBL demonstrates positivity for CD45 as well as for B-cell markers including CD20. CD5 positivity has also been recently reported in IVLBL.[4] Less commonly, T-cell variants may be identified by their expression of CD3.[5] Epithelial membrane antigen, S100, and antibodies against various cytokeratins are negative.

Our major differential diagnosis in this patient with a history of myelodysplastic syndrome was transformation into acute myelogenous leukemia. Myeloperoxidase is an enzyme expressed in neutrophilic granules and is therefore thought to be indicative of myeloid differentiation. Myeloperoxidase expression in hematopoietic neoplasia is often used to distinguish myeloid infiltrates from lymphoid infiltrates. Because of this characteristic, one would expect that the distinction between acute myelogenous leukemia and IVLBL may be made based on the presence or absence of myeloperoxidase positivity by immunohistochemistry. However, in this case a clear distinction could not be made based on this finding alone. Myeloperoxidase positivity by immunohistochemistry is occasionally identified in acute lymphoblastic leukemia, but to our knowledge has never before been identified in a malignant lymphoma.[6]

The association of IVLBL occurring in association with a myelodysplastic syndrome has only once been previously reported in the literature.[7] In our particular case, the finding of myeloperoxidase immunopositivity in an otherwise B-cell lymphoma and the patient's history of myelodysplasia may suggest that both processes may have originated from a neoplastic multipotential stem cell. Such an assumption, however, would require further investigational studies.

In summary, we present a case of IVLBL with aberrant expression of myeloperoxidase by immunohistochemistry in a patient with a history of a myelodysplastic syndrome. Although myeloperoxidase has been often used to distinguish myeloid from lymphoid proliferations, our findings demonstrate that lymphoid neoplasms might also manifest myeloperoxidase positivity and should be considered in the differential diagnosis even when myeloperoxidase studies are positive. In such situations, additional immunohistochemical studies, including B-cell or T-cell lineage-related antigens and gene rearrangement studies, may be helpful in delineating the true nature of the process.


[1.] Pfleger VL, Tappeiner J. Zur Kenntnis der systemiserten Endotheliomatose der cutanen Blutgefasse (Reticulendotheliose?). Hautarzt. 1959;10:359-363.

[2.] Otrakjh CL, Voigt W, Amador A, Nadji M, Gregorios JB. Malignant angioendotheliomatosis--a true lymphoma: a case of intravascular malignant lymphomatosis studied by Southern blot hybridization analysis. Hum Pathol. 1988;19: 475-478.

[3.] Warnke RA, Weiss LM, Chan JKC, Cleary ML, Dorfman RF. Tumors of the Lymph Nodes and Spleen. Washington, DC: Armed Forces Institute of Pathology; 1995:184-187. Atlas of Tumor Pathology, 3rd series, fascicle 14.

[4.] Khalidi HS, Brynes RK, Browne P, Koo CH, Battifora H, Medeiros LJ. Intravascular large B-cell lymphoma: the CD5 antigen is expressed by a subset of cases. Mod Pathol. 1998;10:983-988.

[5.] Au WY, Shek WH, Nicholls J, Tse KN, Todd D, Kwong YL. T-cell intravascular lymphomatosis (angiotropic large cell lymphoma): association with Epstein-Barr viral infection. Histopathology. 1997;31:563-567.

[6.] Hu ZB, MA W, Uphoff CC, Metge K, Gignac SM, Drexler HG. Myeloperoxidase: expression and modulation in a large panel of human leukemia-lymphoma cell lines. Blood. 1993;82:1599-1607.

[7.] Ozaki S, Kawachi Y, Igaki T, Ogasawara N, Mori M, Setsu S. Myelodysplastic syndrome with neoplastic angioendotheliosis: report of a case. Rinsho Ketsueki. 1991;11:509-514.

Accepted for publication January 31, 2001.

From the Department of Pathology, Texas Tech University Medical Center, Lubbock, Tex. Dr Orden is now with the Department of Family Practice, University of Oklahoma Southwest, Lawton, Okla.

Reprints: Phillip A. Conlin, MD, Department of Pathology, Texas Tech University Medical Center, 3601 Fourth St, Lubbock, TX 794430 (e-mail:
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Author:Conlin, Phillip A.; Orden, Mageline B.; Hough, Tiffany R.; Morgan, David L.
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Jul 1, 2001
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