Final Diagnosis

Intravascular Large B-cell Lymphoma

Patient Follow-up

The patient underwent chemotherapy for the lymphoma. He received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and methotrexate (MTX) with marked improvement. He was discharged to subacute rehab after 3 months of hospitalization. After another 3 months, he was discharged home. He was disease-free with negative whole body fludeoxyglucose-positron emission tomography (FDG-PET) scan. He had mild residual bilateral hip flexor and knee extensor weakness. He still had sensory ataxia and needed a walker for ambulation.

Discussion

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of lymphoma with an incidence of 0.095 cases/1,000,000 according to a population-based study in the United States [1]. It is characterized by almost exclusive growth of lymphoma cells within the lumens of blood vessels [2]. Almost all blood vessels can be involved [3]. The most commonly affected sites include central nervous system, skin, and hematopoietic system [4–6]. There are three variants according to the clinical features: classical variant, cutaneous variant, and hemophagocytic syndrome-associated variant [2, 7]. The classical variant has a wide spectrum of clinical presentation depending on the organ involvement. The median age is 70 years with no sex prevalence. Patients may present with systemic symptoms and organ-specific symptoms. The most common systemic symptom is fever of unknown origin. Weight loss without fever is present in 10% of patients. The cutaneous variant predominantly manifests skin lesions, and it is more frequently seen in Western Countries. The hemophagocytic syndrome-associated variant predominantly manifests bone marrow abnormalities and hepatosplenomegaly with rapid onset and progression; it is mostly seen in Asians.

Neurological symptoms are present in 35% of IVLBCL patients, which include encephalopathy, aphasia, visual loss, vertigo, sensorimotor deficits, seizures, and others. Central nervous system (CNS) is much more frequently affected than peripheral nervous system (PNS). CNS involvement is present in about 25% of patients with IVLBCL at the time of diagnosis [8]. Neurologically, our patient had PNS involvement and presented with progressive cauda equina syndrome with gadolinium enhancement of cauda equine nerve roots but no MRI abnormalities in the spinal cord or brain, which is very rare [9, 10].

Tissue biopsy is essential for the diagnosis of IVLBCL, as no discrete tumor masses can be appreciated on radiographic studies, blood and CSF usually do not show malignant lymphocytes, symptoms are non-specific, and cutaneous lesions, when present, display a variety of gross morphologies [7]. As IVLBCL is aggressive, rare, and lacks a characteristic clinical presentation, it has been stated that diagnosis is often made at autopsy; however, recent studies reveal antemortem ascertainment in up to 80% of patients [11]. Muscle, skin and nerve biopsies constitute important diagnostic modalities; even in the absence of macroscopic lesions, skin biopsies may achieve upwards of 75% sensitivity for definitive diagnosis [12]. The peripheral tissue biopsy is less invasive than brain or internal organ biopsy.

Histologically, tumor cells reflect the morphology of large B-cell lymphoma , with large nuclei, prominent nucleoli, and scant cytoplasm. The cells often crowd and distend the lumens of small caliber blood vessels; importantly, they do not invade the vascular wall, and there is no evidence of an angiodestructive process (as might be seen with lymphomatoid granulomatosis, infection, or vasculitis) [7]. The aggregation of tumor cells within vascular lumens is thought to reflect expression of cell surface molecules promoting endothelial adhesion; the lack of tumor cell infiltration into parenchymal structures is thought to reflect an absence of cell surface molecules enabling vascular extravasation, such as the b1 integrin CD29 [11]. When vascular lumens are distended by monomorphous tumor cells, IVLBCL can be easily recognized on routine light microscopy, but when admixed with other blood elements, care must be taken to distinguish atypical tumor morphology from benign but immature circulating blood elements. Immunohistochemical analysis of lymphocyte markers is therefore a critical part of the diagnostic work-up. The vast majority of IVLBCL express pan B cell markers such as CD79a and CD20; MUM1/IRF4, Bcl-2, and CD19 are also extremely frequent; but there is known variation in immunophenotypes, with some tumors displaying germinal center (20%) and others non-germinal center (80%) surface marker patterns [7]. Through immunohistochemical analysis , rare T cell intravascular lymphomas have been recognized [11].

Due to the rarity of IVLBCL, there have been no prospective therapy trials for the disease. Since IVLBCL is a rapidly progressive disseminated disease except for the cutaneous variant, it requires aggressive treatment . The R-CHOP regimen has been shown to achieve an 88% complete remission rate, a 91% overall response rate, and a 60% two year survival rate [13–15]. Our patient also responded very well to this regimen. MTX is recommended to use for CNS prophylaxis and treatment in IVLBCL patients given its better CNS bioavailability [3]. The outcomes depend largely on the early diagnosis and treatment of the disease.

Pearls