Intravascular large B-cell lymphoma with a fulminant clinical course: a case report with definite diagnosis post mortem

M. Fiegl1,+, R. Greil1, C. Pechlaner2, J. Krugmann3 and S. Dirnhofer3

1 Department of Internal Medicine, Division of Hematology and Oncology; 2 Intensive Care Unit; 3 Institute of Pathology, University of Innsbruck, Innsbruck, Austria

Received 30 January 2002; accepted 19 February 2002

Abstract

A patient is described who presented with pancytopenia, splenomegaly and excessively elevated lactate dehydrogenase levels in concurrence with signs of extramedullary hematopoiesis. Although initially considered in the differential diagnostic spectrum, a highly aggressive lymphoma could not be identified before the patient died, 6 weeks after admission. Even an intensive diagnostic work-up including splenectomy and repeated bone marrow biopsies was inconclusive. Finally, the diagnosis of an intravascular large B-cell lymphoma, a highly aggressive clinical subtype of a diffuse large B-cell lymphoma, spreading within vascular structures of multiple organs was established by autopsy. Intravascular large B-cell lymphoma is often not diagnosed before death due to the exclusive intravascular growth pattern of the tumor cells and a fulminant clinical course. The heterogeneous clinical features of this lymphoma subtype are discussed.

Key words: angioendotheliomatosis, angiotropic lymphoma, intravascular lymphoma, splenomegaly

Introduction

Intravascular large B-cell lymphoma is a rare subtype of extranodal diffuse large B-cell lymphoma [1]. It is characterized by the presence of lymphoma cells only in the lumina of small vessels, particularly capillaries. Formerly, the disease was named malignant (systemic) angioendotheliomatosis, and, after the lymphoid origin of the infiltrating cells was recognized, intravascular malignant lymphomatosis [2, 3]. It corresponds to angiotropic large cell lymphoma in the Dukes–Collins classification and to angio-endotheliotropic (intravascular) lymphoma in the Kiel classification. In the recently published WHO classification, it is classified as a distinct clinico-pathological subtype of diffuse large B-cell lymphoma [1]. Herein, we report a patient presenting with splenomegaly, pancytopenia and high lactate dehydrogenase (LDH) levels in the absence of a detectable tumor in vivo.

Case report

A 62-year-old man with a short history of progressive impairment of general condition, intermittent fever and weight loss was admitted with thoracic pain, diarrhea, oliguria and signs of neuropsychological alteration. Fourteen years earlier, he had been treated for locally advanced laryngeal carcinoma by surgery, cisplatinum-based chemotherapy and irradiation. Alcohol abuse was the other remarkable condition in the medical history, and the manifest psychosyndrome was clinically attributed to encephalopathy and/or alcohol withdrawal.

X-ray examinations revealed right-sided pneumonia and both-sided pleural effusions. Sonography demonstrated splenomegaly with a maximum diameter of 22 cm, which, at least partly, was interpreted as a consequence of portal hypertension; the presence of cranial, thoracic or abdominal involvement by tumor or lymphadenopathy, however, was excluded by computed tomography (CT) scan. At admission, pronounced pancytopenia with leukocyte and platelet counts of 1.9 and 73 G/l, respectively, and a hemoglobin level of 10.7 g/dl was measured. In the first differential count, there were 58% segs, 24% lymphocytes, 17% monocytes, 1% eosinophils and 1% basophils; the reticulocyte count was within the upper normal limit (3.3%; 122 G/l). Leukemic blasts were not observed. The most striking laboratory features were massive elevations of LDH (4116 U/l; normal range 120–240 U/l) and of uric acid (12.48 mg/dl; normal range 2.4–7.5 mg/dl), indicating hyperproliferation. Bone marrow examination by both pelvic trephine biopsy and aspiration cytology revealed increased hematopoiesis with reactive atypia. A myelo- or lymphoproliferative disorder or non-medullary (ectopic) infiltration by tumor cells, however, was not detectable. Further differential diagnoses such as an autoimmune disease or a fulminant infection were excluded by clinical, laboratory and microbial examinations.

Four days after admission, the patient was transferred to the intensive care unit because of progressive respiratory insufficiency, necessating ventilation support. Additionally, pancytopenia was aggravated, requiring frequent substitution of erythrocytes and thrombocytes. The appearence of numerous erythroblasts (leukoerythroblastic picture) pointed to a severe disturbance of the bone marrow–blood barrier and/or to extramedullary hematopoiesis. A hemato-oncologist was consulted, and, due to the differential diagnoses considered (Table 1), splenectomy and an additional bone marrow biopsy (day 31 after admission) were carried out. Pathohistological evaluation of the spleen, including immunohistochemistry, was diagnostic neither for lymphoma nor a chronic myeloproliferative disorder. The bone marrow showed reactive changes in a hyperproliferative hematopoiesis. Furthermore, there was a scattered infiltration of single atypical, CD20+ lymphoid cells, which, however, did not allow for a definitive diagnosis of lymphoma.


View this table:
[in this window]
[in a new window]
 
Table 1. Differential diagnosis and discussion of the combined presentation of pancytopenia, erythroblastosis, splenomegaly and excessively elevated LDH
 
In the period that followed, rapid deterioration with progressive encephalopathy (as determined by electroencephalography and evoked potentials) and multiorgan failure developed, and the patient died on day 35 after primary admission.

In the post mortem evaluation, the following pathological features were noted. Macroscopically, there was excentric cardiac hypertrophy, terminal lung edema and slight hepatomegaly without cirrhosis; there was neither gross lymphadenopathy nor signs of a mass lesion or recurrence of the former larynx carcinoma. Microscopically, the predominant finding was atypical blastoid cells with multiple mitoses, which exclusively proliferated within vascular and sinusoidal structures of lymph nodes, liver, lung or bone marrow (Figure 1A and B). Immunhistochemical staining revealed positivity for the B-cell markers CD20 and CD79a in the absence of staining for T-cell markers. Cytochemistry for myeloperoxidase and hemoglobin A1 was negative. Thus, the definitive diagnosis of a diffuse large cell B-cell lymphoma of the intravascular subtype was made. In a retrospective re-evaluation of the splenectomy and previous bone marrow specimens, a definitive lymphoma diagnosis at that time would not have been possible. At death, the proportion of lymphoma cells infiltrating the bone marrow sinusoids was 20% of all nucleated cells, indicating massive lymphoma expansion terminally (Figure 1C and D).



View larger version (132K):
[in this window]
[in a new window]
 
Figure 1. Post mortem histopathological work-up by which the definitive diagnosis could be established. (A) Hematoxylin–eosin (H&E) stain of soft tissue intravascular lymphoma infiltration. (B) CD20 immunostain of the neoplastic intravascular B lymphocytes. (C) H&E stain of the bone marrow. Note the presence of some interspersed atypical blasts, leading to suspicion of lymphoma infiltration. (D) CD20 immunostain highlights the neoplastic B lymphocytes in the bone marrow.

 
Discussion

The most remarkable feature of our case is the fact that, despite intense efforts, the definitive histopathological diagnosis of aggressive B-cell lymphoma could not be established before the patient died. Splenomegaly, pancytopenia, erythroblastosis and massive elevation of LDH levels urgently suggested the presence of a hematological neoplasia, in particular a myeloproliferative syndrome or aggressive lymphoma. Only autopsy revealed the presence of an intravascular large B-cell lymphoma, which obviously progressed rapidly in the final days.

Intravascular large B-cell lymphoma, a subtype of diffuse large B-cell lymphoma in the WHO classification, is a very rare non-Hodgkin’s lymphoma with an estimated frequency of <1% of all lymphomas. Single cases of aggressive lymphoma of T-cell or histiocytic origin with an angiotropic growth pattern have also been reported [2, 4]. Intravascular lymphoma is characterized by nearly exclusive intravascular neoplastic proliferation of B lymphocytes, usually without involvement of lymphoid tissues and peripheral blood. A variant may be primary large cell lymphoma of the splenic sinuses [5]. Intravascular lymphoma usually shows rapid progression and short survival, with at best transient remissions. The very poor prognosis in these patients reflects in part frequent delays in diagnosis and initiation of therapy due to their extraordinary presentation. Exceptions are rare cases diagnosed in an early stage of disease [68]. Common symptoms derive from skin or CNS involvement, of which at least one is observed in two-thirds of cases [6]. Treatment-resistant fever of unknown origin and pain syndromes are recurrent findings leading to diagnostic procedures [7, 9]. Since vessels of all organs may be affected, many different signs can be observed [5, 8]. For example, ‘catastrophic’ cases of intravascular lymphoma have been reported, manifesting as adrenal insufficiency, thrombotic microangiopathy, progressive dementia, interstitial pneumonia or multiple organ failure [1015].

Little is known about the etiology and pathophysiology of intravascular lymphoma. In the case presented here, radio-chemotherapy 14 years before lymphoma manifestation may have had an initiating or promoting effect. Interestingly, a similar case of intravascular lymphoma, treated by radiation for carcinoma of the cervix uteri 14 years earlier, was reported recently [15]. Furthermore, intravascular lymphoma is observed repeatedly in patients with transplantation- or HIV-associated immunosuppression [16, 17], and a relationship with Epstein–Barr virus infection was suggested [18]. Low-grade follicular lymphoma with intravascular growth has also been described [19]. Intravascular lymphoma is characterized by an acquired affinity to vascular structures. This may occur by: (i) a specific interaction of adhesion molecules of lymphoma and endothelial cells favoring intravascular proliferation [20]; and (ii) a lack of homing receptors on the neoplastic cells normally trafficking transvascular lymphocyte migration [21].

In conclusion, a highly elevated LDH and pancytopenia without lymphadenopathy, associated with a leukoerythroblastic picture in, peripheral blood should prompt the clinician to consider intravascular lymphoma as a possible differential diagnosis (Table 1). The initiation of an intensive diagnostic work-up in that direction is of paramount importance since a potentially curative therapeutic option is available, but only at an early stage of the disease [7, 22].

Acknowledgements

The publication of this work was kindly supported by Novartis Pharma GmbH, Vienna, Austria.

Footnotes

+ Correspondence to: Dr M. Fiegl, Department of Internal Medicine, Division of Clinical Hematology and Oncology, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. Tel: +43-512-504-4003; Fax: +43-512-504-4006; E-mail: Michael.fiegl{at}uibk.ac.at Back

References

1. Gatter KC, Warnke RA. Intravascular large B-cell lymphoma. In Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer (IARC): Lyon. IARC Press 2001; 177–178.

2. Sepp N, Schuler G, Romani N et al. ‘Intravascular lymphomatosis’ (angioendotheliomatosis): evidence for a T-cell origin in two cases. Hum Pathol 1990; 21: 1051–1058.[ISI][Medline]

3. Sheibani K, Battifora H, Winberg CD et al. Further evidence that ‘malignant angioendotheliomatosis’ is an angiotropic large-cell lymphoma. N Engl J Med 1986; 314: 943–948.[Abstract]

4. Snowden JA, Angel CA, Winfield DA et al. Angiotropic lymphoma: report of a case with histiocytic features. J Clin Pathol 1997; 50: 67–70.[Abstract]

5. Kobrich U, Falk S, Karhoff M et al. Primary large cell lymphoma of the splenic sinuses: a variant of angiotropic B-cell lymphoma (neoplastic angioendotheliomatosis)? Hum Pathol 1992; 23: 1184–1187.[ISI][Medline]

6. Levin KH, Lutz G. Angiotropic large-cell lymphoma with peripheral nerve and skeletal muscle involvement: early diagnosis and treatment. Neurology 1996; 47: 1009–1011.[Abstract]

7. Sanna P, Bertoni F, Roggero E et al. Angiotropic (intravascular) large cell lymphoma: case report and short discussion of the literature. Tumori 1997; 83: 772–775.[ISI][Medline]

8. Stroup RM, Sheibani K, Moncada A et al. Angiotropic (intravascular) large cell lymphoma. A clinicopathologic study of seven cases with unique clinical presentations. Cancer 1990; 66: 1781–1788.[ISI][Medline]

9. Kuvliev E, Glamour T, Shekar R, West BC. Angiotropic large cell lymphoma presenting as fever of unknown origin. Am J Med Sci 1999; 317: 266–268.[ISI][Medline]

10. Yousem SA, Colby TV. Intravascular lymphomatosis presenting in the lung. Cancer 1990; 65: 349–353.[ISI][Medline]

11. Hayashi T, Watanabe E, Ogawa M et al. Angiotropic B-cell lymphoma presenting with progressive dementia: an autopsy case and review of the literature in Japan. Intern Med 1995; 34: 1134–1139.[ISI][Medline]

12. Sill H, Hofler G, Kaufmann P et al. Angiotropic large cell lymphoma presenting as thrombotic microangiopathy (thrombotic thrombocytopenic purpura). Cancer 1995; 75: 1167–1170.[ISI][Medline]

13. Chu P, Costa J, Lachman MF. Angiotropic large cell lymphoma presenting as primary adrenal insufficiency. Hum Pathol 1996; 27: 209–211.[ISI][Medline]

14. Kuwahara K, Fukuta J, Kamio M et al. Angiotropic large cell lymphoma which infiltrated to the adrenal glands presenting as reversible adrenal insufficiency. Intern Med 1998; 37: 73–76.[ISI][Medline]

15. Deusch E, Mayr A, Hobisch-Hagen P et al. Angiotropic large B-cell lymphoma misdiagnosed as urosepsis with multiple organ dysfunction syndrome. Acta Anaesth Scand 1999; 43: 100–103.[ISI][Medline]

16. Ghorbani RP, Shokouh-Amiri H, Gaber LW. Intragraft angiotropic large-cell lymphoma of T-cell-type in a long-term renal allograft recipient. Mod Pathol 1996; 9: 671–676.[ISI][Medline]

17. Malicki DM, Suh YK, Fuller GN, Shin SS. Angiotropic (intravascular) large cell lymphoma of T-cell phenotype presenting as acute appendicitis in a patient with acquired immunodeficiency syndrome. Arch Pathol Lab Med 1999; 123: 335–337.[ISI][Medline]

18. Au WY, Shek WH, Nicholls J et al. T-cell intravascular lymphomatosis (angiotropic large cell lymphoma): association with Ebstein–Barr viral infection. Histopathology 1997; 31: 563–567.[ISI][Medline]

19. Carter DK, Batts KP, de Groen PC, Kurtin PJ. Angiotropic large cell lymphoma (intravascular lymphomatosis) occurring after follicular small cleaved cell lymphoma. Mayo Clin Proc 1996; 71: 869–873.[ISI][Medline]

20. Kanda M, Suzumiya J, Ohshima K et al. Intravascular large cell lymphoma: clinicopathological, immunohistochemical and molecular genetic studies. Leuk Lymphoma 1999; 34: 569–580.[ISI][Medline]

21. Ponzoni M, Arrigoni G, Gould VE et al. Lack of CD 29 (beta1 integrin) and CD 54 (ICAM-1) adhesion molecules in intravascular lymphomatosis. Hum Pathol 2000; 31: 220–226.[ISI][Medline]

22. Koizumi M, Nishimura M, Yokota A et al. Successful treatment of intravascular malignant lymphomatosis with high-dose chemotherapy and autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 2001; 27: 1101–1103.[ISI][Medline]





This Article
Abstract
Full Text (PDF)
E-letters: Submit a response
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Disclaimer
Request Permissions
Google Scholar
Articles by Fiegl, M.
Articles by Dirnhofer, S.
PubMed
PubMed Citation
Articles by Fiegl, M.
Articles by Dirnhofer, S.