case 1 an 88-year - old woman presented with a history of frequent urinary tract infections along with relatively stable leukopenia and mild anemia that had been present for over 10  years . during the previous 6  years , the platelet count had become borderline low . at the time of this evaluation in june 2007 , the white blood count ( wbc ) was 2,500/l with 95% lymphocytes and 5% monocytes , hemoglobin 10.7  g / dl , mean corpuscular volume ( mcv ) 90.8  fl , and platelets 161,000/l . on physical exam the patient was treated with methotrexate ( 10  mg orally every week ) and the absolute neutrophil count ( anc ) had risen to 1,300/l 7  months later . she did have a klebsiella pneumoniae urinary tract infection in april 2008 when the anc was 1,000/l . case 2 a 69-year - old man with a 30-year history of rheumatoid arthritis was first noted to have neutropenia 2  years before this evaluation . the patient had no recurrent sinopulmonary infections , but for the previous 6  months he had a persistent staphylococcal infection of his left foot . at presentation in april 2007 , the wbc was 2,000/l with 3% bands , 12% segmented neutrophils , 1% eosinophils , 68% lymphocytes , and 16% monocytes . hemoglobin was 16.4  g / dl , mcv 87.1  fl , and platelets 204,000/l . there was no palpable organomegaly or lymphadenopathy , but ultrasound showed mild to moderate hepatosplenomegaly . the patient was treated with cyclophosphamide ( 50  mg orally every day , decreased to 25  mg after 2  months ) and the anc had risen to 2,300/l 3  months later . subsequent ancs for the next 6  months were highly variable ranging between 160 and 900/l . the biopsy had 50% cellularity with occasional small lymphoid aggregates and a subtle interstitial increase in small lymphocytes . immunohistochemical staining showed a significant increase in small cd3 + , cd8 + t cells mainly in an interstitial pattern . in the few small lymphoid aggregates , cd3 and cd20 each marked about half the lymphocytes with cd4 + cells exceeding cd8 + cells by roughly three to one . flow cytometry performed on the bone marrow aspirate showed 64% lymphocytes with over 90% t cells expressing cd2 , cd3 , cd5 , and cd7 without aberrancy . nearly half the t cells were cd4 , cd8 and the majority expressed tcr  along with cd57 ( fig . tcr gene rearrangement studies by polymerase chain reaction ( pcr ) were performed on a subsequent peripheral blood sample and showed clonal  and  patterns . b sixty - nine percent of cd3 + t cells expressed t cell receptor /. c thirty - one percent of cd3 + t cells expressed t cell receptor /. forty - seven percent of cd3 + t cells lacked both cd4 and cd8 ( not shown ) case 1flow cytometry performed on bone marrow aspirate . a sixty - one percent of cd3 + t cells coexpressed cd57 . b sixty - nine percent of cd3 + t cells expressed t cell receptor /. c thirty - one percent of cd3 + t cells expressed t cell receptor /. forty - seven percent of cd3 + t cells lacked both cd4 and cd8 ( not shown ) case 2 increased large granular lymphocytes were noted on the peripheral smear . the bone marrow aspirate showed 40% erythroid precursors with a low g / e ratio of 1.0:1.2 along with 20.0% lymphs and 3.4% mature plasma cells . the interstitial population was highlighted with cd3 . the large majority of these expressed cd8 and not cd4 ( fig .  2 ) . rare scattered b cells marked with cd20 . in the lymphoid aggregates , the majority of cells were cd3 + , but cd4 + cells exceeded cd8 + cells by roughly five to one with only occasional cd20 + b cells . flow cytometry on the aspirate showed about 40% of marrow nucleated cells in the lymphocyte region with about 95% t cells . cd16 and cd56 were negative while roughly a fourth of the t cells had loss of cd5 . a similar proportion of the lymphocytes ( presumably the same population ) expressed tcr . pcr studies showed clonal rearrangements of both tcr  and  ( fig . b predominantly cd4 + t cells in a lymphoid aggregate with relatively few interstitiallyfig . patient bone marrow sample in lane 3 ( from left ) shows a discrete clonal band . lanes 1 , 4 , and 5 have polyclonal patterns . lane 6 is a positive control . pcr primers described by mccarthy et al . [ 18 , 19 ] case 2immunohistochemistry performed on the bone marrow biopsy ( 10 ) . b predominantly cd4 + t cells in a lymphoid aggregate with relatively few interstitially case 2t cell receptor gamma pcr 6% polyacrylamide gel . patient bone marrow sample in lane 3 ( from left ) shows a discrete clonal band . lanes 1 , 4 , and 5 have polyclonal patterns . lane 6 is a positive control . case 1 an 88-year - old woman presented with a history of frequent urinary tract infections along with relatively stable leukopenia and mild anemia that had been present for over 10  years . during the previous 6  years , the platelet count had become borderline low . at the time of this evaluation in june 2007 , the white blood count ( wbc ) was 2,500/l with 95% lymphocytes and 5% monocytes , hemoglobin 10.7  g / dl , mean corpuscular volume ( mcv ) 90.8  fl , and platelets 161,000/l . on physical exam the patient was treated with methotrexate ( 10  mg orally every week ) and the absolute neutrophil count ( anc ) had risen to 1,300/l 7  months later . she did have a klebsiella pneumoniae urinary tract infection in april 2008 when the anc was 1,000/l . case 2 a 69-year - old man with a 30-year history of rheumatoid arthritis was first noted to have neutropenia 2  years before this evaluation . the patient had no recurrent sinopulmonary infections , but for the previous 6  months he had a persistent staphylococcal infection of his left foot . at presentation in april 2007 , the wbc was 2,000/l with 3% bands , 12% segmented neutrophils , 1% eosinophils , 68% lymphocytes , and 16% monocytes . hemoglobin was 16.4  g / dl , mcv 87.1  fl , and platelets 204,000/l . there was no palpable organomegaly or lymphadenopathy , but ultrasound showed mild to moderate hepatosplenomegaly . the patient was treated with cyclophosphamide ( 50  mg orally every day , decreased to 25  mg after 2  months ) and the anc had risen to 2,300/l 3  months later . subsequent ancs for the next 6  months were highly variable ranging between 160 and 900/l . the biopsy had 50% cellularity with occasional small lymphoid aggregates and a subtle interstitial increase in small lymphocytes . immunohistochemical staining showed a significant increase in small cd3 + , cd8 + t cells mainly in an interstitial pattern . in the few small lymphoid aggregates , cd3 and cd20 each marked about half the lymphocytes with cd4 + cells exceeding cd8 + cells by roughly three to one . flow cytometry performed on the bone marrow aspirate showed 64% lymphocytes with over 90% t cells expressing cd2 , cd3 , cd5 , and cd7 without aberrancy . nearly half the t cells were cd4 , cd8 and the majority expressed tcr  along with cd57 ( fig . tcr gene rearrangement studies by polymerase chain reaction ( pcr ) were performed on a subsequent peripheral blood sample and showed clonal  and  patterns . b sixty - nine percent of cd3 + t cells expressed t cell receptor /. c thirty - one percent of cd3 + t cells expressed t cell receptor /. forty - seven percent of cd3 + t cells lacked both cd4 and cd8 ( not shown ) case 1flow cytometry performed on bone marrow aspirate . a sixty - one percent of cd3 + t cells coexpressed cd57 . b sixty - nine percent of cd3 + t cells expressed t cell receptor /. c thirty - one percent of cd3 + t cells expressed t cell receptor /. forty - seven percent of cd3 + t cells lacked both cd4 and cd8 ( not shown ) case 2 increased large granular lymphocytes were noted on the peripheral smear . the bone marrow aspirate showed 40% erythroid precursors with a low g / e ratio of 1.0:1.2 along with 20.0% lymphs and 3.4% mature plasma cells . the interstitial population was highlighted with cd3 . the large majority of these expressed cd8 and not cd4 ( fig . rare scattered b cells marked with cd20 . in the lymphoid aggregates , the majority of cells were cd3 + , but cd4 + cells exceeded cd8 + cells by roughly five to one with only occasional cd20 + b cells . flow cytometry on the aspirate showed about 40% of marrow nucleated cells in the lymphocyte region with about 95% t cells . cd16 and cd56 were negative while roughly a fourth of the t cells had loss of cd5 . a similar proportion of the lymphocytes ( presumably the same population ) expressed tcr . pcr studies showed clonal rearrangements of both tcr  and  ( fig . b predominantly cd4 + t cells in a lymphoid aggregate with relatively few interstitiallyfig . patient bone marrow sample in lane 3 ( from left ) shows a discrete clonal band . pcr primers described by mccarthy et al . [ 18 , 19 ] case 2immunohistochemistry performed on the bone marrow biopsy ( 10 ) . a increased interstitial cd8 + t cells . b predominantly cd4 + t cells in a lymphoid aggregate with relatively few interstitially case 2t cell receptor gamma pcr 6% polyacrylamide gel . patient bone marrow sample in lane 3 ( from left ) shows a discrete clonal band . lanes 1 , 4 , and 5 have polyclonal patterns . lane 6 is a positive control . however , they are highly prevalent in certain peripheral tissues such as the skin , intestinal tract , and mammary ducts where they play a central role in the early response to infections . expansions of  t cells have been described with epstein similar to their representation in the peripheral blood , the  variant of t - lgl leukemia probably accounts for less than 5% of t - lgl leukemia cases . most investigators report that the vast majority of circulating and bone marrow  lymphocytes are cd4 and cd8 , but at least one study found that nearly half are cd4 , cd8 + . both patients in this report were cd4 , cd8 , cd57 + , cd16 , and cd56. about 35% to 40% of  t - lgl leukemia cases are cd4 , cd8 [ 7 , 9 ] . note , however , that the cd4,cd8 immunophenotype is not entirely specific for  lymphoid proliferations . rare cases of  t - lgl leukemia being cd4 , cd8 have been reported [ 10 , 11 ] . similar to  t - lgl leukemia where over 95% of cases express cd57 , the vast majority of  cases express cd57 ( 86% in the series by sandberg ) . also , like the common  variant , cd16 and cd56 expression is more variable . based on sandberg s series and other case reports , cd16 and cd56 are each expressed in nearly half of the  t - lgl leukemia cases . perhaps 20% and 60% of t - lgl leukemia cases express cd56 and cd16 , respectively ; rarely are all three nk markers coexpressed . the bone marrow findings in our two cases conformed to the general pattern described by osuji et al . for the common  variant . that group described the bone marrow histology in 38 cases of t - lgl leukemia . ninety - seven percent of cases had an interstitial infiltration of cd3 + cells that were cd8 + in all but one instance . nonparatrabecular lymphoid nodules were seen in 55% of cases and were predominantly cd4 + t cells surrounding cd20 + collections of b cells . a reliable distinction between reactive lymphoid infiltrates and t - lgl leukemia in bone marrow biopsies is difficult . interstitial clusters of six or more t cells expressing cd8 , tia-1 , or granzyme b reportedly favor an lgl leukemia ( either t cell or nk cell ) . interestingly , in both our cases , interstitial cd8 + t cells were slightly increased even though the neoplastic  t cells were cd8 by flow cytometry on the marrow aspirate . since  t cells often weakly express cd8 , perhaps this observation reflects the different monoclonal antibodies used in flow cytometry ( sk1 ; bd biosciences ) versus immunohistochemistry ( c8/144b ; dako ) in our laboratory or different sensitivities by the two techniques . alternatively , the interstitial cd8 + t cells could be an immune epiphenomenon and not part of the neoplastic population as has been described by morice for nk - lgl leukemia . both cases had severe neutropenia with the anc 300/l or less . like the common  variant , neutropenia is commonly associated with  t - lgl leukemia with an anc below 1,500/l in 50% to 70% of cases [ 7 , 9 ] . pure red cell aplasia has been described in about 5% of cases similar to the common  t - lgl leukemia [ 5 , 7 , 9 ] . a history of rheumatoid arthritis has been described in about 20% of  t - lgl leukemia cases [ 7 , 9 , 10 ] compared with about 25% of  cases . whether the type of tcr (  versus  ) should be a pivotal diagnostic criterion for t cell lymphoproliferative disorders is unclear . hepatosplenic t cell lymphoma was originally restricted to  cases , but subsequent reports described an essentially indistinguishable  subtype . in contrast , the  subtype of subcutaneous panniculitis - like t cell lymphoma is purported to have a significantly worse prognosis than its  counterpart , thus generating a separate provisional entity . saito et al . reported an aggressive clinical course for 10 of 11  t cell neoplasms , but interestingly the one indolent case was a t - lgl leukemia that was cd4 , cd8 and after 4  years of follow - up , the patient had no progression of disease without treatment . recent reviews are reluctant to place the  subtype of t - lgl leukemia in the general t - lgl leukemia diagnostic category largely based on concerns regarding the aggressive clinical behavior of many  t cell lymphoproliferative disorders [ 1 , 3 , 4 ] . however , our two cases and a review of the literature on this topic suggest that  t - lgl leukemia is usually indolent and rarely may even spontaneously regress . in summary , it is proposed that the  variant of t - lgl leukemia be included in the general diagnostic category of t - lgl leukemia . other than often being cd4 and cd8  double negative  ( in 35% to 40% of cases ) , it is essentially indistinguishable from the common  variant in terms of cytology , immunophenotype , bone marrow morphology , clinical presentation , and prognosis . as a cautionary note , however , when a  lymphoproliferative disorder is encountered , it is crucial to exclude more aggressive disorders ( e.g. , hepatosplenic t cell lymphoma and peripheral t cell lymphoma ) and also transient reactive  expansions ( e.g. , infection - related ) . this requires full evaluation of the morphology , immunophenotype , genetic data , and clinical presentation .
the vast majority of cases of t cell large granular lymphocyte ( t - lgl ) leukemia have a cd3 + , cd4 , cd8 + phenotype and express the  t cell receptor . whether the rare  variant should be included in the same diagnostic category 
 is currently unclear . 
 two well - characterized cases of  t - lgl leukemia were identified by our laboratory in 2007 . 
 these two cases and other reports of  t - lgl leukemia were compared with the common  variant . 
 other than more often being negative for both cd4 and cd8 ( in about 35% to 40% of cases ) , the  variant of t - lgl leukemia is similar to the common  type in virtually all respects and should be included in the general category of t - lgl leukemia . 
 however , it is important to exclude other more aggressive  t cell lymphoproliferative disorders .