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CHAPTER 100 LARGE GRANULAR LYMPHOCYTIC LEUKEMIA

CHAPTER 100 LARGE GRANULAR LYMPHOCYTIC LEUKEMIA
Williams Hematology

CHAPTER 100 LARGE GRANULAR LYMPHOCYTIC LEUKEMIA

THOMAS P. LOUGHRAN
MARSHALL E. KADIN

Definition and History
Etiology and Pathogenesis
Clinical Features
Laboratory Features

Hematologic Findings

Immunophenotyping

Immune Abnormalities

Histopathologic Features
Differential Diagnosis
Therapy, Course, and Prognosis
Chapter References

Clonal diseases of larger granular lymphocytes (LGL) can arise from either T cells or natural killer (NK) cells. Although T-LGL and NK-LGL cells have a similar morphology, they have distinctive surface antigen phenotypes and represent two discrete diseases with different clinical features and clinical outcomes. Current treatment for either disease is not considered curative. This chapter describes these two disease entities and outlines current therapeutic approaches.

Acronyms and abbreviations that appear in this chapter include: CTL, cytotoxic T cells; LGL, large granular lymphocytes; NK, natural killer.

DEFINITION AND HISTORY
A clinical syndrome of chronic neutropenia associated with increased numbers of circulating LGL was described in 1977.1 Clonal cytogenetic abnormalities established its neoplastic nature, and the term LGL leukemia was introduced.2 Other terms used include Tg-lymphoproliferative disease3 and lymphoproliferative disease of granular lymphocytes.4
LGL comprise 10 to 15 percent of normal blood mononuclear cells and may be of either CD3– (NK cell) or CD3+ (T cell) lineage. LGL leukemia is classified into T-LGL leukemia and NK-LGL leukemia, reflecting different cellular origins.5,6 T-LGL leukemia is defined as a clonal proliferation of CD3+ LGL; NK-LGL leukemia as a clonal proliferation of CD3– LGL. T-cell receptor gene rearrangement studies are useful for confirming the clonality of T-LGL leukemia.7 NK-cell leukemia also is a clonal disease, as demonstrated by cytogenetics.8 However, NK cells, and NK-cell leukemia, lack convenient clonal markers, such as antigen receptor gene rearrangements.
ETIOLOGY AND PATHOGENESIS
The etiology of T-LGL leukemia is unknown. Infection with HTLV-II has been detected in two patients. However, most patients are not infected with either HTLV-I or HTLV-II.9 Nevertheless, serologic findings show frequent reactivity to the BA-21 epitope of the p21e env protein of HTLV-I, suggesting that a cellular or retroviral protein with homology to BA-21 may be important in pathogenesis.9 Epstein-Barr virus infection has been implicated in the pathogenesis of NK-LGL leukemia.10
Leukemic LGL show many characteristics of antigen-activated cytotoxic T cells (CTL), suggesting that an initial step in LGL expansion is an antigen-driven mechanism. Normal CTL are regulated through apoptosis. Dysregulated apoptosis is a characteristic finding in LGL leukemia and is thought to underlie the pathogenesis of the disease. Leukemic LGL constitutively express high levels of Fas, yet are resistant to Fas-mediated death.11 Defective apoptosis, therefore, may contribute to extended cell survival of leukemic LGL. Leukemic LGL also constitutively express Fas ligand, and patient sera contain high levels of this protein.12,13 It is conceivable that disease manifestations such as neutropenia and rheumatoid arthritis are related to circulating Fas ligand in these patients.
CLINICAL FEATURES
Clinical features of T-LGL leukemia are summarized in Table 100-1. Rheumatoid arthritis may be a prominent feature of LGL leukemia, sometimes resulting in a clinical picture resembling that of Felty syndrome.14 The clinical presentation of NK-LGL leukemia is different from that of T-LGL leukemia. Patients with NK-LGL leukemia usually are younger, more often have systemic B symptoms, and typically have more massive hepatosplenomegaly. Lymphadenopathy and gastrointestinal tract involvement are common.8

TABLE 100-1 CLINICAL FEATURES OF CD3+ LGL LEUKEMIA*

LABORATORY FEATURES
HEMATOLOGIC FINDINGS
Examination of the blood film is important to diagnose T-LGL leukemia, since approximately 25 percent of patients do not have an increased total lymphocyte count.6 LGL can be identified by morphology, although immunophenotyping is necessary to distinguish whether the LGL are of T-cell or NK-cell lineage (see below). The median LGL count of patients with T-LGL leukemia, however, is 4200/µl (4.2 × 109/liter). Patients with NK-LGL leukemia generally have much higher LGL counts, sometimes exceeding 50,000/µl (5.0 × 1010/liter).
Most patients (84 percent) with T-LGL leukemia have chronic neutropenia, and about half (48 percent) have neutrophil counts less than 500/µl (5 × 108/liter).6 In contrast, less than one-fifth (18 percent) of patients with NK-LGL have severe neutropenia.6 Anemia is observed in 50 percent and 100 percent of cases of T- and NK-LGL leukemia respectively. Pure red cell aplasia and Coombs’ positive hemolytic anemia are seen with T-LGL leukemia.2,6 Indeed, LGL leukemia is the most commonly associated disease in patients with pure red cell aplasia.15 Thrombocytopenia and coagulopathy are features of NK-LGL leukemia.6 Moderate thrombocytopenia occurring with T-LGL leukemia can resemble idiopathic thrombocytopenic purpura.2
IMMUNOPHENOTYPING
Immunophenotyping can distinguish T-LGL leukemia from NK-LGL leukemia. T-leukemic LGL usually are CD3+, CD4–, CD8+, CD16+, CD56–, CD57+, and often HLA-DR+. Cases of LGL leukemia expressing CD3 and CD56 may have a more aggressive clinical course.16 Leukemic T-LGL usually are T-cell receptor (TCR) ab+, although TCR gd+ cases with similar clinical features have been described.17 NK-leukemic LGL are usually CD3–, CD4–, CD8–, CD16+, CD56+, and CD57–.8
IMMUNE ABNORMALITIES
Patients with T-LGL leukemia frequently have humoral immune abnormalities, including positive tests for rheumatoid factor or antinuclear antibodies, polyclonal hypergammaglobulinemia, circulating immune complexes, and antineutrophil antibodies (Table 100-2). These patients also may have defects in cellular immunity, such as diminished NK activity.2 Immune function has not been evaluated in most patients with NK-LGL leukemia.

TABLE 100-2 SEROLOGIC FINDINGS IN CD3+ LGL LEUKEMIA

HISTOPATHOLOGIC FEATURES
T-LGL leukemia invariably affects the spleen, where the major findings are leukemic infiltration of the red pulp cords and sinuses, plasma cell hyperplasia, and prominent germinal centers.2,18 Liver sinusoids and portal areas are infiltrated by LGL. The marrow biopsy may contain nodules of B lymphocytes and scattered LGL, which are better seen in the aspirate. Granulocyte maturation arrest and pure red cell aplasia have been observed. Lymph nodes usually are not involved but can have expanded paracortical areas containing plasma cells and LGL.
DIFFERENTIAL DIAGNOSIS
The diagnosis of T-LGL leukemia should be considered in patients with chronic or cyclic neutropenia19 or in patients with pure red cell aplasia or rheumatoid arthritis who have increased concentrations of LGL cells. Cytomegalovirus or HIV infection can lead to a mild increase in the concentration of LGL cells. However, the LGL are not monoclonal.20 Some patients may have elevated numbers of CD3– LGL but lack the clinical features of NK-LGL leukemia and have a chronic clinical course.21 Molecular studies using X-linked probes indicate that these patients have polyclonal expansion of LGL.22 Of interest, sera from these patients with chronic NK lymphocytosis also have frequent reactivity to BA-21.23
THERAPY, COURSE, AND PROGNOSIS
Morbidity and mortality usually result as consequences of neutropenia.6 Optimum treatment for correction of neutropenia is not defined. Treatment with oral low-dose methotrexate, cyclosporine, or oral cyclophosphamide has been efficacious in small series.24,25 and 26 Clinical improvement may be associated with reductions in levels of circulating Fas ligand. Treatment with glucocorticoids has ameliorated the neutropenia of some patients. However, neutropenia generally recurs as the medication is tapered. Splenectomy is also of limited benefit. Experience with recombinant growth factors is limited.27,28 Single-agent chemotherapy with prednisone, cyclophosphamide, or chlorambucil is effective in correcting pure red cell aplasia associated with T-LGL leukemia.6 In contrast to the chronic course of T-LGL leukemia, NK-LGL leukemia has an acute presentation and poor clinical outcome. Most patients die within 2 months of diagnosis from disseminated disease with multiorgan failure, despite aggressive combination chemotherapy.8 Patients with chronic NK lymphocytosis do not usually require treatment.
To better define the natural history of LGL leukemia, a registry has been formed. Clinical trials are also being administered through the registry. For more information, the registry can be contacted at http://www.moffitt.usf.edu/lgl-leukemia, which can be accessed through the Williams Hematology, 6th edition, web page.
CHAPTER REFERENCES

1.
McKenna RW, Parkin J, Kersey JH, et al: Chronic lymphoproliferative disorder with unusual clinical, morphologic, ultrastructural and membrane surface marker characteristics. Am J Med 62:588, 1977.

2.
Loughran TP Jr, Kadin ME, Starkebaum G, et al: Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and auto-immune neutropenia, thrombocytopenia and hemolytic anemia. Ann Intern Med 102:169, 1985.

3.
Reynolds CW, Foon KA: Tg Lymphoproliferative disease and related disorders in humans and experimental animals. A review of the clinical, cellular, and functional characteristics. Blood 64:1146, 1984.

4.
Semenzato G, Pandolfi F, Chisesi T, et al: The lymphoproliferative disease of granular lymphocytes. A heterogeneous disorder ranging from indolent to aggressive conditions. Cancer 60:2971, 1987.

5.
Loughran TP Jr: Clonal diseases of large granular lymphocytes. Blood 82:1, 1993.

6.
Lamy T, Loughran TP Jr: Large granular lymphocyte leukemia. Cancer Control 5:25, 1998.

7.
Rambaldi A, Pelicci P-G, Allavena P, et al: T cell receptor b chain gene rearrangements in lymphoproliferative disorders of large granular lymphocytes/natural killer cells. J Exp Med 162:2156, 1985.

8.
Taniwaki M, Tagawa S, Nishigaki H, et al: Chromosomal abnormalities define clonal proliferation in CD3- large granular lymphocyte leukemia. Am J Hematol 33:32, 1990.

9.
Loughran TP Jr, Hadlock KG, Perzova R, et al: Epitope mapping of HTLV envelope seroreactivity in LGL leukemia. Br J Haematol 101:318, 1998.

10.
Kawa-Ha K, Ishihara S, Ninomiya T, et al: CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA. J Clin Invest 84:51, 1989.

11.
Lamy T, Liu JH, Landowski TH, et al: Dysregulation of CD95/CD95 ligand-apoptotic pathway in CD95+ LGL leukemia. Blood (in press).

12.
Tanaka M, Suda T, Haze K, et al: Fas ligand in human serum. Nat Med 2:317, 1996.

13.
Perzova R, Loughran TP Jr: Constitutive expression of Fas ligand in LGL leukemia. Br J Haematol 97:123, 1997.

14.
Loughran TP Jr, Starkebaum G, Kidd P, Neiman P: Clonal proliferation of large granular lymphocytes in rheumatoid arthritis. Arthritis Rheum 31:31, 1988.

15.
Lacy MQ, Kurtin PJ, Tefferi A, et al: Pure red cell aplasia: association with large granular lymphocyte leukemia and the prognostic value of cytogenetic abnormalities. Blood 87:3000, 1996.

16.
Gentile TC, Uner AH, Hutchison RE, et al: CD3+, CD56+ aggressive variant of large granular lymphocyte leukemia. Blood 84:2315, 1994.

17.
Foroni L, Matutes E, Foldi J, et al: T-cell leukemias with rearrangement of the g but not b T-cell receptor genes. Blood 71:356, 1988.

18.
Agnarsson BA, Loughran TP Jr, Starkebaum G, Kadin ME: The pathology of large granular lymphocyte leukemia. Hum Pathol 20:643, 1989.

19.
Loughran TP Jr, Hammond WP: Adult onset cyclic neutropenia is a “benign” neoplasm associated with clonal proliferation of large granular lymphocytes. J Exp Med 164:2089, 1986.

20.
Zambello R, Trentin L, Agostini C, et al: Persistent polyclonal lymphocytosis in HIV-1 infected patients. Blood 81:3015, 1993.

21.
Tefferi A, Li CY, Witzig TE, et al: Chronic natural killer cell lymphocytosis: a descriptive clinical study. Blood 84:2721, 1994.

22.
Nash R, McSweeney P, Zambello R, et al: Clonal studies of CD3-negative lymphoproliferative disease of granular lymphocytes. Blood 81:2363, 1993.

23.
Loughran TP Jr, Hadlock KG, Yang Q, et al: Seroreactivity to an envelope protein of human T-cell leukemia/lymphoma virus in patients with CD3-(NK) lymphoproliferative disease of granular lymphocytes. Blood 90:1977, 1997.

24.
Loughran TP Jr, Kidd PG, Starkebaum G: Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate. Blood 84:2164, 1994.

25.
Sood R, Stewart CC, Aplan PD, et al: Neutropenia associated with T-cell large granular lymphocyte leukemia: long-term response to cyclosporine therapy despite persistence of abnormal cells. Blood 91:3372, 1998.

26.
Dhodapkar MU, Li CY, Lust JA, et al: Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance? Blood 84:1620, 1994.

27.
Thomssen C, Nissen C, Gratwohl A, et al: Agranulocytosis associated with T-gamma-lymphocytosis: no improvement of peripheral blood granulocyte count with human-recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF). Br J Haematol 71:157, 1989.

28.
Kaneko T, Ogawa Y, Hirata Y, et al: Agranulocytosis associated with granular lymphocyte leukaemia: improvement of peripheral blood granulocyte count with human recombinant granulocyte colony-stimulating factor (G-CSF). Br J Haematol 74:121, 1990.
Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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