Intravascular lymphomatosis (IVL) is a rare disease characterized by neoplastic cells within small to medium blood vessels. When it was originally described in 1959, it was thought to be an endothelial neoplasm1. However, studies have shown that it is lymphocytic, most commonly B-cell. The WHO recognizes this entity as a subtype of extranodal large B-cell lymphoma. Although rare cases of T-cell and NK-cell phenotypes have been described, it is suggested that they are separate entities2. IVL usually presents as a rapidly progressive disseminated disease and is difficult to diagnose, so that approximately 50% of cases are diagnosed only at autopsy3.
Two variants of intravascular diffuse large B-cell lymphoma (IVLBCL) have been described, based on the clinical and histopathologic characteristics of patients diagnosed in Asian and Western countries. The Western variant has been described as the cutaneous variant or classical form4 and is characterized by involvement of the skin and central nervous system leading to neurologic impairment. Fever is the most common general symptom and other clinical manifestations relate to the primary organs of involvement, usually the lungs, kidney and liver5.
THE ASIAN VARIANT
The first case of what is commonly referred to the Asian variant (AIVL) was reported by Kuratsune et al in 1988 and described as “B-cell lymphoma showing clinicopathologic features mimicking MH”1. This terminology was used to describe the clinical symptoms of fever, wasting, pancytopenia, hepatosplenomegaly and hemophagocytosis accompanied by a B-cell lymphoma. Other names have been used to describe cases with similar presentations, including malignant histiocytosis-like B-cell lymphoma and diffuse large B-cell lymphoma associated with hemophagocytic syndrome1,6. Most of the cases proposed to belong to this variant share several characteristics, most importantly hemophagocytosis, which may be mild, but is usually seen in the bone marrow, spleen and liver1. Other clinical features include fever, fatigue, hepatosplenomegaly, jaundice or hyperbilirubinemia, respiratory disturbance, anemia and an elevated LDH4. Unlike the Western variant, these patients usually do not have skin involvement and rarely have neurologic impairment. Common sites of involvement include the bone marrow, liver, spleen, lymph nodes, kidney, lung, central nervous system, adrenal gland and gastrointestinal tract. Bone marrow involvement, while common in AIVL, may be minimal or undiagnosed while the patient is alive, since it seems to have a higher incidence as the disease progresses1.
Murase et al have proposed diagnostic criteria for AIVL: criteria 1 and 2 are required for diagnosis6.
While it is rare, a few cases of AIVL have been reported in western countries6.
MORPHOLOGY AND PHENOTYPE
Morphologically, the malignant cells are found in the lumens of small to medium vessels throughout the body. Extravascular spread of the neoplastic cells is uncommon, but may be seen. The cells are usually large with prominent nucleoli but rare cases with smaller cells or anaplastic morphology have been reported. Mitoses are usually frequent2. Oddly, neoplastic cells are not usually detected in the blood and the lymph nodes are often spared. The tumor cells are positive for B-cell markers, including CD20 and CD79a. Varying expression of CD5 has been reported, but the clinical characteristics of CD5-negative cases are not different from CD5-positive cases, so these do not seem to represent separate entities6.
Why is it found intravascularly? Based on the findings of frequent mitoses and rare extravascular spread, it has been suggested that vessels are the site of replication of the neoplastic cells. It has been proposed that defects in the surface receptor molecules of either the endothelium or the neoplastic cells are responsible for the intravascular location of this neoplasm. Studies using immunohistochemistry have shown a loss of CD29 (beta-1 integrin) and CD45 (ICAM-1) on the neoplastic cells. These molecules are involved in the movement of neoplastic cells out of the endothelium. The absence of CD29 and CD45 on the neoplastic cells, as well as the lack of the endothelial counter-receptors, could prevent the extravasation of the neoplastic cells3
Unfortunately, IVL is a diagnosis often missed because it is not picked up by normal screening methods that detect mass lesions and it is not usually present in the peripheral blood. Approximately 50% of cases are not diagnosed until autopsy3. A high clinical suspicion of IVL in a patient with fever of unknown origin is needed for diagnosis. For patients with the Western variant, diagnosis is usually made on skin biopsy. In one case, the diagnosis was made following a renal biopsy for proteinuria, 10 months after the patient’s initial presentation of fever5. If AIVL is suspected, a bone marrow biopsy is suggested, as well as a liver biopsy. However, it should be noted that a diagnosis on a needle biopsy is difficult if malignant cells are sparse or the diagnosis is not considered. Murase also suggests that a splenectomy with a wedge biopsy of the liver should be considered if AIVL is suspected7.
The best treatment regiment for IVLBCL has not been clearly established, mainly because many cases go undiagnosed until autopsy. In the larger studies reported, incomplete therapeutic data and minimal follow-up have made firm conclusions difficult. Anthracyline-based chemotherapy has been used and associated with complete remission in 53% of cases in one series. The addition of rituximab to chemotherapy has also been used and resulted in complete remission in most patients4. It seems that this would be a reasonable treatment in patients with CD-20 positive disease. It has also been proposed that autologous or allogenic bone marrow transplant should be considered in younger patients4,6. Despite chemotherapy, prognosis is poor for both types of IVL.
Contributed by Anna Woodard, MD and Larry Nichols, MD