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Cutaneous angiogenesis in patient with intravascular lymphoma (IVL): A case report

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Cutaneous angiogenesis in patient with intravascular lymphoma (IVL): A case report
Andrzej Szuba MD PhD, Magdalena Koba MD, Marta Rzeszutko MD PhD, Wojciech Rzeszutko MD PhD, Piotr Dziegiel MD PhD, Agnieszka Loboda PhD, Jozef Dulak PhD, Ryszard Andrzejak MD PhD
Dermatology Online Journal 16 (8): 2

1. Department of Internal Medicine, Wroclaw Medical University, Wroclaw, Poland.
2. Department of Pathology, Wroclaw Medical University, Wroclaw, Poland
3. Department of Histology, Wroclaw Medical University, Wroclaw, Poland
4. Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland


We present a case of widespread cutaneous telangiectasias in a patient with a B-cell intravascular lymphoma most likely representing tumor-induced angiogenesis. The patient presented with a rapid onset of large cutaneous telangiectasias and skin edema, followed by the development of multiorgan failure. We describe difficulties with the ante-mortem diagnosis in the patient with predominant, clinically observed, skin lesions. The patient had disseminated disease involving many organs with a rapidly fatal outcome. The final diagnosis of intravascular malignant lymphoma (IVL) was established post-mortem after morphological and immunohistochemical studies of the autopsy material.


We present a patient with widespread cutaneous telangiectasias and peculiar pathological angiogenesis in the skin. To our knowledge this is one of the very few reports of intravascular lymphoma that has presented with such an uncommon manifestation [1, 2, 3].

Intravascular lymphoma (IVL) is an extremely rare subtype of cutaneous diffuse large B-cell lymphoma. In the more recent WHO-EORTC (World Health Organization and European Organization for Research and Treatment of Cancer) classification, the intravascular large B-cell lymphoma is classified under “primary cutaneous diffuse large B-cell lymphoma, other” [4, 5]. The most characteristic feature of this type of lymphoma is the presence of neoplastic cells in the lumina of capillaries in multiple organs. This entity was first described as a systemic angioendotheliomatosis by Pfleger and Tappeiner in 1959 [6]. It was initially thought that the tumor cells were of endothelial origin. Further immunohistological studies established the lymphoid origin of this unusual intravascular tumor [7, 8]. The lymphomatous nature of IVL has been confirmed by the presence of an immunoglobulin gene rearrangement as revealed by Southern blot analysis and polymerase chain reaction (PCR) analysis [9, 10]. Intravascular lymphoma is predominantly of B-cell lineage but occasionally T-cell origin occurs. There have not been any known distinctive epidemiological features of this lymphoma except that it affects only adults, usually over 60 years of age. However, one congenital case of intravascular lymphoma has been described. Men and women are equally affected. Usually IVL upon diagnosis is widely disseminated with the main presentation in skin, central nervous system (CNS), liver, spleen, bone marrow, kidneys, and lungs. Practically every organ can be affected and a great variety of clinically different presentations can be observed. Obliteration of capillaries, venules, and small arteries are thought to be responsible for the clinical symptoms. Only a limited number of cases of IVL have been reported in the literature [11-16]. The diagnostic difficulties are caused by the peculiar intravascular localization of lymphoma cells and the lack of evidence of focal disease. This multisystem neoplastic disease requires histological confirmation; early diagnosis is crucial for the early institution of suitable therapy [17, 18]. The case presented here emphasizes the need for repeated biopsies from affected organs, especially in cases of ambiguous morphological changes.

Case report

A 79-year-old woman was admitted to the hospital because of progressive weakness and diffuse edema involving the lower extremities and trunk. The disease had begun about 10 months prior with the appearance of unusual telangiectasias on her extremities. The skin lesions on the extremities subsided but were followed by the eruption of larger diffuse telangiectasias on her breasts and trunk. Prior to admission she had chest and abdomen computed tomography (CT) scans, mammography, and breast biopsy the results of which were unremarkable. Her past medical history was significant for hypothyroidism since 1984 treated with levothyroxine.

Figure 1Figure 2
Figure 1. Photograph of patients trunk: widespread cutaneous neovascularization on the patient’s chest and abdomen.

Figure 2. Closer view of dense network of newly formed blood vessels on the patient’s breast (view from the bottom of the right breast - marked area in Figure 1).

Physical examination on admission revealed a dense network of dilated skin blood vessels on her trunk (Figures 1 and 2) and diffuse pitting edema involving her legs and trunk. There was no palpable lymphadenopathy. Her abdomenal examination was benign without organomegaly. The results of the patient’s initial laboratory tests revealed moderate anemia (hemoglobin [Hb] 9.7 g/dl; red blood cell count [RBC] 2.86 x 1012/l; white blood cell count [WBC] 6.2 x 109/l with 54% neutrophils, 16% monocytes, and 29% lymphocytes), moderately elevated C-reactive protein (CRP) 28 mg/l, and fibrinogen degradation products (FDP) 2590 ng/l. Serum samples were sent also to an external laboratory for evaluation of angiogenic chemokines. Subsequent studies including bone marrow biopsy, chest X-ray, radiograph of the skeleton, and abdominal ultrasound were normal. There was no evidence of multiple myeloma. Skin biopsy revealed non-specific lymphocytic infiltrates surrounding cutaneous blood vessels. Low-titer anti-nuclear antibodies were detected and the patient was given a presumptive diagnosis of connective tissue disease. Therapy with oral corticosteroids (Prednisone 40 mg p.o. qD) was initiated. Three weeks after admission the patient developed acute bronchitis that was treated intravenously with cefuroxime. The patient was discharged in better condition after 5 weeks of hospitalization. One month later the woman was readmitted because of profound fatigue, shortness of breath, and persistent cough. Clinical examination revealed hepatosplenomegaly, diffuse edema, and cutaneous lesions that became hemorrhagic. Laboratory investigations were significant with a platelet count of 24,000/l; hemoglobin of 10.5 g/dl; hypoalbuminemia of 2.4 g/dl. Blood chemistry analysis also showed elevated levels of alkaline phosphatase (82 IU/l) and aspartate aminotransferase (119 IU/l). Examined serum angiogenic cytokines were significantly elevated: Vascular Endothelial Growth Factor A (VEGF-A) = 802.0 pg/ml; Platelet Derived Growth Factor (PDGF) = 1012.33 pg/ml; Interleukin-8 (IL-8) = 501.0 pg/ml.

Despite intensive treatment, the patient developed fatal multiorgan failure and died on the sixth day after admission.

Post-mortem examination revealed multiple telangiectasias and ecchymoses on the skin of the trunk and forearms. Extensive edema of the soft tissues in the upper and lower extremities was seen. There was no lymphadenopathy and there were no macroscopically visible tumors in any organ. Provisional diagnosis established by gross examination included: advanced atherosclerosis of the aorta, coronary, renal, and cerebral arteries, dilation of cardiac chambers, and strong hyperemic reactions in all examined organs. Because of substantial discrepancies between clinical symptoms and scanty autopsy pathologic findings, specimens of each organ were collected for further histopathological examination.

The tissue samples were fixed in 10 percent buffered formalin. Paraffin wax embedded tissue blocks were processed for conventional histopathological analysis (hematoxylin and eosin) and for immunohistochemical staining. A standard avidin-biotin-peroxidase complex (ABC) technique was used according to the manufacturer’s protocols with 3′,3-diaminobenzidine tetrahydrochloride (DAB) as the chromogen (DakoCytomation). The following monoclonal antibodies were applied: CD45RO (UCHL-1), CD20 (L26), CD 79α, CD3, CD43, CD30, CD34, CD138, MPO, Ki67(MIB1), VEGF-A and a pan-keratin antibody cocktail (DakoCytomation).

Figure 3Figure 4
Figure 3. Skin: multiple foci of large lymphoid neoplastic cells (green arrows) are seen within cutaneous blood vessels (Postmortem specimen, H&E, x200)

Figure 4. Liver: multiple CD20 positive neoplastic cells (green arrows) are shown in a sinusoidal of the liver. The endothelial cells lining of normal sinusoids is not visualized (Postmortem specimen, Immunohistochemistry, CD20, x200).

Figure 5Figure 6
Figure 5. Liver: silver-impregnated reticulin fibers in a 4μm section of affected liver. The increased amount of coarse fibers closely adherent to the underlying hepatocytes. The liver sinusoids are clearly depicted with multiple neoplastic cells within the sinusoids’ lumen (Postomortem specimen, Silver staining, x200)

Figure 6. Heart: lymphoid cells within capillaries of the myocardium (H&E, x200). Higher magnification (right lower corner) shows invasion of veins by cords of neoplastic cells (green arrow) (Postmortem specimen, H&E, x600)

The histopathology of skin specimens revealed edematous dermis with very thickened collagen fibers. The perivascular and skin’s periappendicular lymphocytic infiltration has been seen. The blood stromal vessels were dilated and filled with large, atypical lymphoid cells with hyperchromatic nuclei and occasional mitotic figures; extravascular presence of neoplastic cells has not been noted (Figure 3). Examination of liver specimens revealed multiple lymphoid cells (CD20+) in the lumen of sinusoids (Figures 4 and 5). The brain samples revealed all thin-walled vessels within the white and grey matter filled with clusters of atypical neoplastic cells, with morphological features of cells seen in other organs. The lungs were also extensively involved with intravascular infiltrates that filled the microvasculature of the alveolar septa without involvement of the surrounding structures. Microscopic foci of vascular emboli were also identified in the heart (Figure 6). The presence of neoplastic mononuclear large cells was again confirmed by findings of luminal plugging of blood vessels in other examined organs including spleen and bone marrow (Figure 7). The secondary intravascular thrombi obliterating affected vessels were also seen.

Figure 7Figure 8
Figure 7. Hypocellular marrow of normal architecture with infiltration by lymphoma cells (green arrows). (Postmortem specimen, H&E x200)

Figure 8. Liver: extensive expression of VEGF in cytoplasm of hepatocytes

Figure 9
Figure 9. Control: no VEGF expression visible in the control liver (archive section) (B). (Postmortem specimen, Immunohistochemistry VEGF, x100)

In summary, a striking proliferation of large lymphoid cells with atypical features within the vascular lumina of small arterioles, capillaries, and venules with no adjacent parenchymal involvement was seen in all studied specimens. Cytological features of these cells were the large irregular nuclear shape, prominent nucleoli, and pale clear cytoplasm. There was no tissue infiltration. Of note was the occurrence of neoplastic large lymphoid cells in the lumen of liver sinusoids. They were well separated by a thick reticulin layer. This effect is clearly seen as the black line surrounding the sinusoids (Figure 5).

Immunohistochemical analysis showed the tumor cells to be reactive to CD20 and CD79α antibodies, thus revealing the B-cell lymphoid nature (Figure 4). The diagnosis of an intravascular lymphoma of the B-cell lineage was made. We have also analyzed tissue VEGF-A expression in affected organs with anti-VEGF-A antibodies. We have found strong VEGF-A expression in liver cells (Figures 8 and 9) but not in tumor cells. It suggests that the liver was the source of angiogenic cytokines.


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