A 72-year-old white man with a medical history significant for dilated cardiomyopathy and chronic atrial fibrillation, hypothyroidism, and osteoarthritis presented to his primary care physician with fatigue, weight loss, and polyuria. Additional review of systems revealed a history of mild hypertension for which he was taking antihypertension medications. Physical examination was unremarkable. Laboratory evaluation revealed proteinuria with hyaline casts in the urine sediment. He was referred to a nephrologist for further work-up of his proteinuria. A quantitative urinalysis revealed proteinuria near the nephrotic range, with 2.8 g protein/24 hours. Blood urea nitrogen was 25 mg/dL, and serum creatinine was 1.1 mg/dL. Additional laboratory analyses revealed a normochromic, normocytic anemia with hemoglobin concentration of 8.8 g/dL and a hematocrit of 26.3%. White blood cell count was 4.4 × 103/μL, with a differential of 69% polymorphonuclear leucocytes, 20% lymphocytes, 9% monocytes, 1% eosinophils, and 1% basophils. The platelet count was 230 × 103/μL. Serum and urine protein electrophoresis showed a small lambda light-chain immunoglobulin spike. Antinuclear antibody titer, iron, folate, and B12 levels were normal. Erythropoietin level was decreased relative to the degree of anemia.
A renal biopsy was performed, and 3 cores of tan, rubbery tissue 0.9 and 1.0 cm in length by 0.1 cm in diameter were obtained. These specimens were entirely submitted for light microscopic examination. Additional tissue was also submitted for immunofluorescence and electron microscopy. Twenty nonsclerotic glomeruli were available for examination. At low-power magnification, the glomeruli displayed variable mild to moderate hypercellularity. The tubules demonstrated no significant atrophy or tubulitis. Closer inspection revealed that the the hypercellularity in individual glomeruli was due to atypical intracapillary mononuclear cells (Figure 1). These atypical cells had irregularly shaped nuclei with finely stippled and focally coarse chromatin and small to moderate-size and occasional multiple nucleoli (Figure 2). Scattered mitotic figures (arrow, Figure 2) and apoptotic forms were also identified. No evidence of increased mesangial matrix or hyalinosis was seen with periodic acid–Schiff stain. Silver staining showed that the glomerular and tubular basement membranes were not appreciably thickened but clearly demonstrated the intracapillary mononuclear atypical cells. The atypical intracapillary cells were identified as B lymphocytes immunoreactive for CD20 (Figure 3, A) but not for CD3 (Figure 3, B), positive for Bcl-2 (Figure 3, C), and negative for CD68 (Figure 3, D), vimentin, and pancytokeratin (not shown). Immunofluorescence did not demonstrate immunoglobulin or complement deposition. Electron microscopic examination revealed focal foot process fusion (arrowheads, Figure 4) and microvillous transformation. Several atypical lymphocytes with large, irregular nuclei, multiple nucleoli, and abundant rough endoplasmic reticulum were visible (arrows, Figure 4), distending a glomerular capillary loop. No evidence of amyloidosis or other organized protein or immune complex deposition disorder was identified by electron microscopy.
What is your diagnosis?
Pathologic Diagnosis: Angiotropic (Intravascular) Large B-Cell Lymphoma
According to the World Health Organization classification, intravascular lymphoma is a rare subtype of extranodal diffuse large B-cell lymphoma characterized by the presence of lymphoma cells only in the lumina of small vessels, particularly capillaries. This condition usually presents as a disseminated intravascular proliferation of large lymphoid cells involving small blood vessels without an obvious extravascular tumor mass or leukemia. Since its first description as systemic angioendotheliomatosis by Pfleger and Tappeiner in 1959, approximately 200 cases have been reported worldwide, with only a few cases presenting with primary renal manifestations and subsequently diagnosed by kidney biopsy alone.1–4
Intravascular lymphoma is extremely rare and difficult to diagnose in the live patient because of its nonspecific clinical signs, and many reported cases have been diagnosed only at autopsy. Many clinical presentations are related to organ dysfunction secondary to transient or permanent vascular occlusion. The most common clinical scenario is fever of unknown origin, skin rash, and mental status change or rapidly progressive neurologic signs (eg, dementia). The organs most commonly involved are the central nervous system, skin, lungs, kidneys, and adrenal glands, but virtually any site may be involved. The lymphoma is usually extensively disseminated at presentation. The lymph nodes and spleen are frequently involved, but the bone marrow is rarely affected. The renal involvement usually manifests as a nephrotic syndrome and is usually accompanied by minimal glomerular changes.
Gross pathologic examination may show hemorrhage, thrombosis, and necrosis in different tissues, often postmortem. Microscopically, large neoplastic lymphoid cells with prominent nucleoli and frequent mitotic figures occlude small vessel lumina. Fibrin thrombi may also be present in some cases. The tumor cells are immunoreactive for B-cell–associated antigens (eg, CD19, CD20, CD22, and CD79a), and coexpression of CD5 was seen in some cases.5,6 A T-cell immunophenotype has been reported.7
The pathogenesis of intravascular lymphoma is unclear, but this condition may be related to lack of expression of lymphocyte-endothelium adhesion molecules. The consistent absence of CD29 (regarded as critical for lymphocyte trafficking and transvascular migration) and CD54 (also involved in transvascular lymphocyte migration) may contribute to the pattern of growth and distribution of this particularly aggressive type of lymphoma.8
Most of the cases involve immunoglobulin gene rearrangement, and few cases have been described with T-cell receptor gene rearrangements. Accumulations of karyotypic abnormalities on chromosomes 1, 6, and 18 have been reported, but the number of cases studied is very small.9
A timely pathologic diagnosis is essential, because death occurs in most cases within a short time after presentation. Combination chemotherapy10 with or without radiotherapy often is effective; many patients achieve complete remission, and long-term survival appears to be possible.
In this case of intravascular lymphoma, presentation was clinically limited to the kidneys. This patient subsequently received combination chemotherapy with ifosfamide, carboplatin, and etoposide and has demonstrated marked improvement in clinical signs and resolution of proteinuria. Early recognition and diagnosis of this particularly aggressive form of non-Hodgkin lymphoma is essential for effective treatment and positive outcome.
References
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