Pure red cell aplasia

A 41-year-old Chinese man was admitted to the hospital because of exertional dyspnea and dizziness in December 1996. His medical history was significant for recent weight loss from 69 to 65 kg in 1 month. Physical examination revealed pale conjunctiva. His hemogram was remarkable for macrocytic normochromic anemia (hemoglobin, 5.8 g/dL; mean corpuscular volume, 111.5 fL; mean corpuscular hemoglobin concentration, 34 g/dL) and reduced reticulocyte count (0.1% after correction). The leukocyte and platelet counts were normal (5200/(mu)L and 388000/(mu)L, respectively), but relative lymphocytosis (71%; reference, 20% to 45%) was noted. The results of renal function tests were normal. Bone marrow aspirate smears showed normocellularity but markedly decreased erythroid series, with a myeloid-erythroid ratio of 32:1 (Figure 1; Giemsa stain, original magnification x200), consistent with pure red cell aplasia (PRCA). No dyspoiesis or increased blast cells were observed. He was treated with oral steroids and transfusion and then discharged.

During the subsequent 5-year follow-up period at the clinic, his anemia fluctuated and required transfusion and steroid therapy occasionally. The leukocyte counts were never found to be elevated. The results of one chest x-ray examination performed a year after initial presentation were normal. A bone marrow aspirate smear taken in November 1999 revealed normocellularity, a myeloid-erythroid ratio of 6:1, and a slightly increased lymphocyte count, whereas the concurrent hemogram was normal except for lymphocytosis (58%). In January 2001, 4 years ofter the initial presentation, his regular complete blood cell count showed leukocytosis (22600/(mu)L; lymphocytes, 95%) and macrocytic anemia (hemoglobin, 6.5 g/dL; mean corpuscular volume, 116 fL). The blood smears showed many large lymphocytes with round nuclei, condensed chromatin, a moderate amount of cytoplasm, and a few azurophilic granules in the cytoplasm (Figure 2; Giemsa stain, original magnification x 1000, oil). Immunophenotyping by flow cytometry and immunocytochemical analysis showed that these lymphocytes were CD3+/CD16+/ CD56- and belonged exclusively to the CD8+ subset (data not shown). Gene rearrangement studies of the gamma chain of the T-cell receptor gene by polymerase chain reaction demonstrated a monoclonal band (Figure 3).

What is your diagnosis?

Pathologic Diagnosis: T-Cell Large Granular Lymphocyte Leukemia

Large granular lymphocyte (LGL) lymphoproliferative disorder is a heterogeneous group of diseases that can be divided into those arising from CD3+ T-cell lineage (T-- LGL) or from a CD3- natural killer cell lineage (NK-LGL). The T-LGL leukemia is the most common form of LGL leukemia and usually follows a long-term course. Among the NK cell disorders, a very aggressive NK-LGL leukemia and an indolent NK cell chronic lymphocytosis have been recognized.1

Most patients with T-LGL leukemia are older adults (mean age at diagnosis, 55 years). Approximately 60% of patients with T-LGL leukemia have clinical manifestations attributed to neutropenia, anemia, or immune dysregulation, such as recurrent infection, pallor or weakness, or rheumatoid arthritis (RA), respectively.1 Although neutropenia and RA are the most common presentations, acquired PRCA may occur at some stage of the disease.2-4 In a study on a limited number of Chinese patients with T-- LGL leukemia, PRCA occurred in all 5 patients, whereas none of them had recurrent infections or RA, which is commonly seen in patients from Western countries.3 Other important causes of acquired PRCA include thymoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma, and parvovirus B19 infection.5,6

Both normal and neoplastic T-LGLs are antigen-activated cytotoxic T lymphocytes that constitutively express high levels of CD95 (Fas) and CD95L (Fas ligand).7 The CD95/CD95L pathway is an important mechanism to induce apoptosis. High levels of circulating CD95L have been detected in serum of patients with T-LGL leukemia. Such serum can trigger apoptosis of normal neutrophils in vitro. The serum CD95L levels also correlate with patients' neutropenia. Therefore, this pathway is thought to be important in the pathophysiology of T-LGL leukemia.7 The etiology of T-LGL leukemia is unknown. Serologic reactivity to epitopes on the p21 envelope protein of human T-lymphotropic virus type 1 is frequently seen, suggesting that a cellular or retroviral protein with homology to such protein may be important in pathogenesis.1,8

The T-LGL leukemia is frequently underdiagnosed because leukocytosis may not be evident initially, such as in this case, or not present.3 However, the association of relative neutropenia and lymphocytosis regardless of the leukocyte count should raise suspicion. Typical LGLs have moderate amounts of cytoplasm and azurophilic granules (Figure 2). They are composed of NK cells and a subset of cytotoxic T cells and may increase significantly during active viral infection. The most common phenotype of T-- LGL leukemia is CD3+/CD4-/CD8+/CD16+/CD56-/ CD57+.1 In cases where the numbers of the LGL are not high, T-cell receptor gene rearrangement studies help establish the diagnosis.

The clinical course of T-LGL leukemia is usually indolent. Patients may require transfusion or antibiotics when severe anemia or infections occur, respectively. Immunosuppression with steroids, cyclosporine, cyclophosphamide, or low-dose oral methotrexate can alleviate the neutropenia and anemia in 50% to 60% of the patients, whereas others remain transfusion-dependent despite immunotherapy.2,3 Late complications include treatment-related myelodysplasia and cyclosporine-induced renal failure.2

References

1. Lamy T, Loughran TP Jr. Current concepts: large granular lymphocyte leukemia. Blood Rev. 1999;13:230-240.

2. Go RS, Li CY, Tefferi A, Phyliky RL. Acquired pure red cell aplasia associated with lymphoproliferative disease of granular T lymphocytes. Blood. 2001;98:483-- 485.

3. Kwong YL, Wong KF. Association of pure red cell aplasia with T large granular lymphocyte leukemia. J Clin Pathol. 1998;51:672-675.

4. Masuda M, Arai Y, Nishina H, Fuchinoue S, Mizoguchi H. Large granular lymphocyte leukemia with pure red cell aplasia in a renal transplant recipient. Am J Hematol. 1998;57:72-76.

5. Lacy MQ, Kurtin PJ, Tefferi A. Pure red cell aplasia: association with large granular lymphocyte leukemia and the prognostic value of cytogenetic abnormalities. Blood. 1996;87:3000-3006.

6. Ahsan N, Holman MJ, Gocke CD, Groff JA, Yang HC. Pure red cell aplasia due to parvovirus B19 infection in solid organ transplantation. Clin Transplant. 1997;11:265-270.

7. Liu JH, Wei S, Lamy T, et al. Chronic neutropenia mediated by fas ligand. Blood. 2000;95:3219-3222.

8. Loughran TP Jr, Hadlock KG, Perzova R, et al. Epitope mapping of HTLV envelope seroreactivity in LGL leukaemia. Br Haematol. 1998;101:318-324.

Po-Shing Lee, MD; Wei-Shou Hwang, MD

Accepted for publication December 11, 2001.

From the Departments of Pathology (Dr Lee) and Internal Medicine (Dr Hwang), Chi Mei Foundation Medical Center, Yungkang City, Tainan, Taiwan.

Reprints not available from the author.

Copyright College of American Pathologists Dec 2002
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