Lymphosarcoma

* The expression of CDB, a restricted T cell antigen, on B cells in B chronic lymphocytic leukemia is rare, and its significance, if any, remains unknown. We report herein a patient with B chronic lymphocytic leukemia in whom CD8 was strongly expressed on all B cells, both in the bone marrow and peripheral blood. The patient required no therapy for 6 years after being diagnosed as having B chronic lymphocytic leukemia. Then, when the disease progressed, he was treated with conventional doses of fludarabine phosphate (25 mg/m2 daily for 5 days), but unlike other patients with B chronic lymphocytic leukemia he tolerated this therapy poorly. He received a total of only 4 series of fludarabine therapy, and following each course of treatment, he developed considerable myelosuppression. After the fourth course of therapy, his bone marrow failed to show any evidence of regeneration, and he died as a result of intercurrent respiratory tract infection 1 month after his last dose of fludarabine was given.

(Arch Pathol Lab Med. 2000;124:1361-1363)

The analysis of the expression of CD antigens on cells from peripheral blood, bone marrow, and lymph nodes of patients with leukemia and lymphoma (ie, im munophenotyping) has become routine and has been used to classify some of these hematologic malignant neoplasms. A few CD antigens are strictly lineage specific (eg, CD3 is normally expressed only on T cells) but "lineage promiscuity"1 and "lineage infidelity"2 have been proposed. The former refers to a normal period in the differentiation of hematopoietic cells in which they coexpress multiple lineage markers, whereas the latter pertains to malignant transformation (clonal expansion) that leads to aberrant gene expression.

Aberrant expressions of CD antigens have been found mainly in acute but also in chronic leukemias. Although these entities sometimes are called biphenotypic leukemias, their prognosis is often not different, although in a few cases it is worse than that of the "common" leukemias?*' The common B chronic lymphocytic leukemia (B-CLL) is characterized by an increased number of B lymphocytes that express CD19 and CD20 (so-called pan-B-cell markers), CD21, HLA-DR, and surface immunoglobulins. The latter are weakly expressed, giving a "dim fluorescence" when tested by flow cytometry. There is a restriction in the light chains of the surface immunoglobulins, which represents the clonal excess, a feature of malignancy. We describe a patient with B-CLL whose B cells expressed CD8, a predominantly T cell marker also expressed in natural killer cells, and we propose that patients with this uncommon feature of B-CLL might have an increased sensitivity to fludarabine phosphate, a substance recently often used to treat patients with CLL.

REPORT OF A CASE A 57-year-old white man was diagnosed as having stage 0 BCLL in December 1991, after a routine physical examination and laboratory tests. His laboratory tests revealed the following values: hemoglobin, 153 g/L; platelets, 150 x 10^sup 9^/L; white blood cells (WBC), 80 x 10^sup 9^ / L; and lymphocytes, 72 x 10^sup 9^ / L (more than 90% of the WBC were mature lymphocytes). Lymph nodes, liver, and spleen were not palpable. A flow cytometric analysis (2-color analysis, FACScan, Becton Dickinson Biosciences, San Jose, Calif) of peripheral blood cells showed that 95% of lymphocytes were CD5+ B cells with surface immunoglobulins of only lambda type (ie, evidence of clonal excess, consistent with a diagnosis of B-CLL). Surprisingly CD8 was expressed on virtually all B cells. The patient did not require any treatment and was followed up every 6 months in the clinic. In January 1997, he developed tiredness, recurrent respiratory tract infections, and cervical lymphadenopathy; both his spleen and liver were palpable 2 and 3 cm below the respective costal margin. A complete blood cell count showed the following values: hemoglobin, 120 g/L; platelets, 70 x 10^sup 9^/L; and WBC, 50 x 10^sup 9^/L. More than 90% of the WBC were lymphocytes. Bone marrow aspiration and biopsy (diffuse infiltration by mostly mature looking lymphocytes) also showed features consistent with the diagnosis of B-CLL. Immunophenotyping of peripheral blood and bone marrow aspirate (3color analysis, FACSCalibur, Becton Dickinson) showed that virtually all lymphocytes expressed CD19 and CD20 and also coexpressed CD5 and CD23 (Table 1). There was a dim surface fluorescence for immunoglobulin D, and immunoglobulin M was barely detected on a few cells. The lambda light chain restriction of the surface immunoglobulins was again noted, whereas B cells still showed aberrant expression of CDS (Figure). Genotypic studies performed on peripheral blood lymphocytes demonstrated (by polymerase chain reaction) rearrangement of the mu heavy chain gene.

The patient was then given a course of fludarabine phosphate therapy (25 mg / m^sup2^ daily for 5 days). He responded well to this regimen; the WBC count decreased to 10 X 10^sup 9^/L (>90% lymphocytes), the spleen and liver were not palpable, and the lymphadenopathy disappeared. However, throughout the ensuing days, his blood cell count continued to decrease, and he became severely pancytopenic (hemoglobin, 80 g/L; WBC, 2.0 x 10^sup 9^/L, mostly lymphocytes; and platelets, 31 x 10^sup 9^/L). Because of the fear of further myelosuppression, he was not administered any additional fludarabine until 6 months later, when his complete blood cell count returned to normal. He was then given 2 more courses of fludarabine at 3- and 5-month intervals. Following each course, he became rapidly pancytopenic, and further treatment with fludarabine was withheld for some time. He received his fourth and last course of fludarabine in November 1998, after which he again became pancytopenic (hemoglobin, 90 g / L; WBC, 2.9 x 10^sup 9^/L, mostly lymphocytes; absolute neutrophil count,

COMMENT B chronic lymphocytic leukemia is the most common form of leukemia in western countries, typically afflicting persons older than 50 years. B chronic lymphocytic leukemia has a characteristic immunophenotype, with expression of pan-B-cell antigens (CD19, CD20), HLA-DR, low-intensity expression of a monoclonal surface immunoglobulin together with expression of CDS, an antigen expressed on T cells and also on a small subset of normal B cells (B^sub 1^ lymphocytes). The expression of at least one T cell antigen (in addition to CD5) in B-CLL cells was observed in 28% of the patients described by Kurec et al.5 However, CDB, a glycoprotein typically expressed on the surface of thymocytes, cytotoxic and suppressor T cells, and natural killer cells, was found on B cells only in 1 of their 61 patients with B-CLL. Another retrospective analysis of 72 patients with B-CLL showed only 1 patient with CDS expression on B cells, suggesting that this is a distinctly rare event.6 Indeed, only a small number of patients with B-CLL whose B cells expressed CDS have been described, mostly as individual case reports (Table 2). CD8 expression on B cells has also been reported in lymphosarcoma cell leukemia and lymphoma.7-9 In a recent study, Mulligan et al10 concluded that CDS expression in B-CLL is perhaps more common than generally recognized. They found that this occurred in 0.5% of their 2000 cases of BCLL. Of their 10 cases, 8 had stable stage A disease, mostly stage A(0), and 2 had progressive disease. All had moderate to high-intensity CD8 expression on the B-CLL cells, weak expression of CD22, and very weak expression of FMC-7, whereas CD23 was strongly expressed. The percentage of B cells that expressed CD8 was not given. An increased expression of CD25 and a higher-than-expected frequency of lambda light chain was found. They speculated that the aberrant expression of CD8 may have resulted from alterations of the regulatory mechanisms when the C^sub kappa^ locus was deleted.

In our laboratory's experience of more than 100 cases of B-CLL, we had never before noticed the presence of CD8 on B cells. As in most reported cases of CDS+ B-CLL cells, our patient showed only lambda light chains (dim) on the surface of B cells. This selectivity of lambda light chains in this rare type of B-CLL, in contrast to the typical B-CLL, is unexplained. Our patient did not show expression of CD25 on his B cells, in contrast to most of the published cases.10-12 In one report of B-CLL, CD8 expression on B cells was suggested as a marker of aggressive disease6; however, other reports did not show any difference in presentation or survival of these patients when compared with patients with classic B-CLL, strongly suggesting that CD8 antigen is not a marker of aggressive disease.

Our patient showed increased sensitivity to fludarabine therapy. According to the drug's manufacturer, myelosuppression manifested as neutropenia (neutrophils,

The generous grant from the John R. Oishei Foundation is gratefully acknowledged.

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Anwarul Islam, MD, PhD; Adrian O. Vladutiu, MD, PhD; Theresa Donahue, MT(ASCP); Selina Akhter, MD, MS; Amy M. Sands, MD; Julian L. Ambrus, MD, PhD

Accepted for publication January 11, 2000.

From the Division of Hematology/Oncology, Departments of Medicine (Drs Islam, Akhter, and Ambrus) and Pathology (Drs Vladutiu and Sands), State University of New York at Buffalo, School of Medicine and Biomedical Sciences, and Kaleida Health/Buffalo General Hospital (Drs Islam, Vladutiu, Akhter, Sands, and Ambrus and Ms Donahue), Buffalo, NY.

Reprints: Anwarul Islam, MD, PhD, FRCPath, Division of Hematology/Oncology, Department of Medicine, Buffalo General Hospital/Kaleida Health, 100 High St, Buffalo, NY 14203 (e-mail: aislam@acsu. buffalo.edu).

Arch Pathol Lab Med-Vol 124, September 2000

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