Distinct bone marrow findings in T-cell granular lymphocytic leukemia revealed by paraffin section immunoperoxidase stains for CD8, TIA-1, and granzyme B

Abstract

Unlike other leukemia types in which the bone marrow findings are diagnostic, the bone marrow pathology of T-cell granular lymphocytic leukemia (GLL) is subtle and ill-defined. In this study, bone marrow biopsy specimens from 36 patients with T-cell GLL and from 25 control patients with cytopenias and relative or absolute increases in blood large granular lymphocytes were studied by immunohistochemistry using antibodies to the cytolytic lymphocyte antigens CD8, CD56, CD57, TIA-1, and granzyme B. The goals were to clarify the bone marrow pathology of T-cell GLL and to refine the diagnostic criteria for T-cell GLL. Most bone marrow specimens from the T-cell GLL patients contained interstitially distributed clusters of at least 8 CD8 ؉ (83%) or TIA-1 ؉ (75%) lymphocytes or clusters of at least 6 granzyme B ؉ (50%) lymphocytes. Interstitial clusters of CD8 ؉ , TIA-1 ؉ , or granzyme B ؉ cells were present in 36%, 12%, and 0%, respectively, of the control bone marrows (all values significantly different, P < .001). An additional T-cell GLL disease-specific finding was the presence of linear arrays of intravascular CD8 ؉ , TIA-1 ؉ , or granzyme B ؉ lymphocytes, found in 67% of cases of T-cell GLL and in none of the 25 control samples (P < .001). Staining for CD56 and CD57 was noncontributory. These findings clarify the bone marrow histopathology of T-cell GLL and provide an additional tool by which the discrete, abnormal lymphocyte population required for a diagnosis of T-cell GLL can be identified. IntroductionGranular lymphocytic leukemia (GLL), also termed large granular lymphocyte leukemia, is a chronic, indolent lymphoproliferative disorder with distinctive clinical and laboratory manifestations. [1][2][3][4][5] The hallmark feature of GLL is expansion of a discrete, or clonal, population of cytolytic lymphocytes (CTLs) in the peripheral blood. These lymphocytes have characteristic morphologic features, including the presence of abundant cytoplasm containing a variable number of azurophilic granules and relatively small nuclei with inconspicuous nucleoli. In GLL the expansion of large granular lymphocytes (LGLs) often occurs in individuals with autoimmune disorders and is associated with variably severe neutropenia, anemia, and thrombocytopenia, which are responsible for most of the disease-associated morbidity and mortality. Most GLL cases can be subclassified into cytolytic T-cell type for the cases in which the neoplastic cells express CD3 and exhibit clonal T-cell antigen receptor gene rearrangements. 1,[6][7][8][9] This disorder is now referred to as T-cell granular lymphocytic leukemia in the current World Health Organization classification of diseases of the hematopoietic and lymphoid tissues. 10,11 The individual neoplastic cells in GLL have few, if any, cytologic features that distinguish them from benign granular lymphocytes. [12][13][14] This attribute makes a morphologic distinction between GLL and conditions associated with a reactive, polyclonal increase in granular lymphocytes almost impossible in ...

Diffuse large B-cell lymphoma with distinctive patterns of splenic and bone marrow involvement: clinicopathologic features of two cases

“…4 An intrasinusoidal pattern of marrow infiltration has been described in intravascular LBCL as well as in a number of other lymphoproliferative disorders including splenic marginal zone B-cell lymphoma, hepatosplenic T-cell lymphoma, and T-cell large granular lymphocytic leukemia. [21][22][23][24][25][26][27] These latter disorders share as a unifying feature prominent splenic involvement. It is recognized that morphologic detection of intrasinusoidal marrow involvement by these disorders is exceedingly difficult.…”

Refining the diagnosis of T-cell large granular lymphocytic leukemia by combining distinct patterns of antigen expression with T-cell clonality studies

“…10,18 Others have detailed specific bone marrow immunohistochemical criteria for defining cases of T-LGL leukemia with detailed statistical analyses. 8 However, a statistically powered study of cases of LGL expansions to determine the significance of variations in antigen expression by flow cytometry has not been performed to date.…”

“…14,15 In addition, the percentage of LGLs was significantly higher in cases of T-LGL leukemia compared with non-clonal LGL proliferations (26.5 vs 18%; P ¼ 0.01), again in agreement with prior studies. 8 Finally, morphologic features such as size, granularity or homogeneity of the LGL population were unable to stratify cases into clonal T-LGL leukemia vs reactive LGL proliferations ( Figure 1). …”

“…Therefore, predicting and defining patients with increased LGLs as a significant monoclonal, neoplastic proliferation remain difficult. Although prior studies have demonstrated distinct histologic features associated with T-LGL leukemia in the marrow 8 as well as novel TCR antibodies that can be used to define LGL leukemia, 9 relatively few studies have attempted to comprehensively and statistically define the specifics of non-TCR antigen expression by flow cytometry. 10,11 As such, we performed a detailed retrospective review of 85 patients, at Stanford University Medical Center, with LGL expansions in their peripheral blood in an attempt to determine distinct flow cytometry patterns that are associated with T-LGL leukemia.…”

T-cell large granular lymphocytic leukemia occurring after autologous peripheral blood stem cell transplantation

“…T-LGL leukemia was distinguished from conditions associated with a reactive polyclonal increase in granular lymphocytes based on the clinical course, aberrant coexpression of the natural killer cell-associated antigen CD57 as well as expression of cytolytic antigens TIA-1 and granzyme B, and demonstration of T-cell clonality. 1,9 There have been four cases of post transplant T-LGL leukemia in the literature, 10,11 which occurred in three renal transplant recipients and one liver transplant recipient. In those cases, the clinical courses were indolent and the presence of T-LGL leukemia did not affect prognosis.…”