Contributed by Wen-Wei Chung, M.D., Ph.D., A. Julio Martinez, M.D., Susanne M. Gollin, Ph.D., Sofia Shekhter-Levin, M.D., Ph.D., Lydia Contis, M.D.FINAL DIAGNOSIS:
CONTRIBUTORS' NOTE:
First described as angioendotheliomatosis proliferans systemisata by Pfleger and Tappeiner (1) in 1959, intravascular (angiotropic) lymphoma (IVL) is a rare variant of large cell lymphoma characterized by proliferation of neoplastic lymphoid cells within small blood vessels. Only recently has this disease been included in the updated Kiel Classification and in the Revised European-American Classification of Lymphoid Neoplasms (REAL) (15, 16). Well over 100 cases have been reported in the literature (17). The origin of the intravascular neoplastic cells was once controversial and thought to be of endothelial origin or metastatic carcinoma from occult sites; it was also regarded as lymphoid malignancy. However, immunohistochemical stains and molecular studies have demonstrated the intravascular cells in IVL to be neoplastic lymphoid cells. The IVLs are predominantly of B-cell lineage; only a small number are of the T-cell phenotype (9) and rare cases have been reported with histiocytic features (18). While most cases of IVL arise de novo, a small proportion of patients develop a similar picture following, or concurrently with, a solid lesion of typical non-Hodgkin's lymphoma.
IVL may present over a wide age range with a predilection for patients in the seventh decade. No clear-cut gender difference has yet been demonstrated. Many cases of IVL are found at autopsy. The clinical presentations are varied and frequently simulate vasculitis with bizarre neurologic symptoms and/or non-specific skin lesions. Cutaneous lesions include partly hemorrhagic nodules or firm, deeply adherent, infiltrative plaques which may ulcerate and often with overlying telangiectasia. The neurological manifestations are often clinically confounding. Patients may present with mental confusion, aphasia, progressive muscle weakness, and a range of focal signs including hemianopsia and blindness. A more unusual presentation for IVL is disseminated intravascular coagulation (7). Many investigators (4, 5, 6, 7) have noted a thrombotic tendency in IVL. Some patients have identifiable 'B' symptoms such as fever, night sweats, malaise, and weight loss (8). While IVL can involve all organs of the body (9, 13), the liver, spleen, lymph nodes and bone marrow are relatively spared until late in the disease. A recent study by Estalilla et al. demonstrated that B-cell IVL can be detected by morphologic examination and immunohistochemical studies of peripheral blood and bone marrow, and involvement of these sites may be more common than is reported in the literature (17).
Histopathologically, capillaries, venules and small arterioles are distended by noncohesive masses of large, pleomorphic lymphoid cells trapped by fibrin thrombi. These cells have irregular nuclear contours, coarse nuclear chromatin, with two or multiple nucleoli, and moderate amounts of basophilic cytoplasm. Some cells have vacuolated cytoplasm. Only rarely do the neoplastic cells extravasate into the neighboring tissues. In some cases there is evidence of vascular proliferation, presumably as a consequence of recanalization, and the endothelium may be thrown into complex folds, segmenting the vascular lumen. In the brain, areas of infarction may be present, but infarcts are infrequently encountered in other organs (8).
Common laboratory abnormalities include a mild anemia, elevated erythrocyte sedimentation rate, and markedly elevated serum lactate dehydrogenase levels (11). Some of the findings, such as anemia and leukopenia, may be associated with a myelosuppressive serum factor (12), which is a cytokine produced by the lymphoma cells.
The pathogenesis of IVL remains largely obscure. Multiple karyotypic abnormalities have been described in one case of IVL, including trisomies involving chromosomes 5, 7, 12, and 18, t(1;3) and 6q- (10). It has been postulated that the IVL may be related to abnormal cell adhesion molecules, although attempts to demonstrate this have proved elusive (14).
In summary, this patient presented with fever of unknown origin, nonspecific neurological symptoms and signs, without cutaneous lesions or lymphadenopathy. Pathologic examination demonstrated the presence of intravascular B-cell lymphoma in the peripheral blood, bone marrow, skeletal muscle and sural nerve. The clinical data also suggested involvement of intravascular lymphoma in other sites such as kidney and central nervous system. The cytogenetic studies demonstrated a mosaic abnormal male bone marrow chromosome analysis. He underwent systemic and intrathecal chemotherapy with a good response and was transferred to a nursing home.
In conclusion, IVL is a rare entity with a polymorphic clinical presentation, generally fatal if diagnosed at late stage. Untreated IVL has a 1-year mortality rate approaching 80% from the time of diagnosis and an average survival rate of about 13 months (19). Early diagnosis is very important since it may be curable with an appropriate chemotherapeutic regimen (2). With aggressive combination chemotherapy and early diagnosis, the prognosis of IVL is similar to other lymphomas of conventional presentation, with a complete remission rate approaching 42% that can allow for long term survival (3, 13).
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Contributed by Wen-Wei Chung, M.D., Ph.D., A. Julio Martinez, M.D., Susanne M. Gollin, Ph.D., Sofia Shekhter-Levin, M.D., Ph.D., Lydia Contis, M.D.
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