Aggressive natural killer-cell leukemia (ANKL) is a rare form of large granular lymphocyte leukemia, which is characterized by a systemic proliferation of NK cells. The clinical features of 22 ANKL cases were analyzed. Hepatomegaly (64%), splenomegaly (55%) and lymphadenopathy (41%) were also frequently observed. Leukemic cells were identified as CD1−, CD2+, surface CD3−, CD4−, CD5−, CD7+, CD8+/−, CD10−, CD11b+/−, CD13−, CD16+, CD19−, CD20−, CD25−, CD33−, CD34−, CD38+, CD56+, CD122+, HLA-DR+ and TCR−. Two of the 16 cases examined for CD57 were positive and three of the seven cases examined for cytoplasmic CD3. Epstein–Barr virus was detected in the tumor cells of 11 of the 13 cases examined. No common cytogenetic abnormalities were identified and 6q anomaly was detected in only one. Three of 13 patients treated with chemotherapy containing anthracycline/anthraquinone attained complete remission, in contrast to none of the eight who were treated with regimens without anthracycline. Although the overall prognosis was poor with a median survival of 58 days, those who attained remission showed better prognosis (P=0.005). These findings suggest that ANKL is an entity of mature cytotoxic NK-cell neoplasms with distinct phenotype and disease presentations. Intensive treatment for ANKL may result in a better prognosis.
Aggressive natural killer-cell leukemia (ANKL) is a neoplasm characterized by a systemic proliferation of NK cells with an aggressive clinical course.1, 2, 3, 4, 5 It was originally recognized in the mid-1980s as a non-T-cell type of aggressive large granular lymphocyte (LGL) leukemia.6, 7, 8 Owing to its rarity and unique presentations, there have been many reports of small series of cases9, 10, 11, 12, 13, 14, 15, 16, 17 or individual case reports.18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 Patients present with fever, circulating leukemic LGLs with CD2+ CD16+ CD56+ HLA-DR+ phenotype, anemia and thrombocytopenia. Leukemic cells do not have any characteristics of T cells; they are negative for surface CD3 and show a germline configuration of T-cell receptor genes β, γ and δ. ANKL is further characterized by frequent hepatosplenic involvement,2, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 32, 33, 34, 35, 36, 37, 38 expression of multidrug-resistant P-glycoprotein39, 40 and presence of the Epstein–Barr virus (EBV).6, 9, 13, 14, 15, 17, 25, 28, 32, 33, 34, 37, 38 Although Song et al41 recently described a series of 11 patients, detailed clinical features from a large number of cases have not yet been reported. Therefore, the optimal therapeutic strategy remains unclear. The NK-cell Tumor Study Group conducted an analysis of a series of patients who were diagnosed as having ANKL in Japan with the aim of better characterizing this leukemia.
Materials and methods
From 1994 to 1998, 22 patients were diagnosed with ANKL in 19 collaborating institutions. This study was conducted by the NK-cell Tumor Study Group and approved by the institutional review board of participating institutions. Initial diagnosis was carried out at each institution and was revised when the original histologic material was available. Specimens were reviewed by two expert hematopathologists (SN and JS) and clinical data were reviewed by the Diagnostic Committee (RS, KK and KO). Only the cases diagnosed with ‘de novo’ ANKL were included and those transformed from chronic NK-cell proliferative disorder were excluded. The patients' follow-up data were reviewed in January 2002.
The diagnosis of ANKL was based on the published criteria.1,42 Briefly, patients were diagnosed with aggressive NK-cell leukemia when proliferation of LGLs of NK-cell type was found in peripheral blood (PB) and/or bone marrow (BM). Flow-cytometric analyses were performed as described previously.43 To exclude T-cell-type LGL leukemia and leukemic infiltration of other T-cell lymphomas, the tumor cells were required to be negative for surface CD3 as determined by flow-cytometry or in germline configurations of T-cell receptor genes. For cases presenting with extramedullary involvement accompanied by PB and/or BM disease, those with PB/BM involvement of more than 30% of the nucleated cells were included. The presence of EBV was determined with either in situ hybridization with the Epstein—Barr-encoded RNA probe44 or with Southern blotting,45 but was not required for the diagnosis.
The following clinical information was collected: age, sex, PB cell count at diagnosis, sites of disease, presence of B symptoms, serum lactate dehydrogenase (LDH) level, performance status, outcome and therapies administered (chemotherapeutic regimens and hematopoietic stem cell transplant). The LDH index was defined as the patients' serum LDH level divided by the upper limit of serum LDH established in each institutes. The B symptoms were defined as recurrent fever exceeding 38°C, night sweats or the loss of more than 10% of body weight. The International Prognostic Index (IPI) score for malignant lymphoma was determined according to the published criteria.46
Correlation between two groups was examined with the χ2 test, Fisher's exact test and the Mann–Whitney U-test. Patient survival data were analyzed with the method of Kaplan and Meier and compared by using the log-rank test. Univariate and multivariate analyses were performed using the Cox's proportional-hazard regression model and variables were selected with the step-wise method. Data were analyzed with STATA statistical software (Stata Cooperation, College Station, TX, USA).
Patient characteristics of 22 cases from 19 institutes are listed in Table 1. Two cases have also been reported elsewhere.16,17,36 There were seven males and 15 females with an age range from 12 to 80 (median 42) years. Nine patients showed leukocytosis exceeding 10 × 109/l and seven leukopenia at less than 3 × 109/l. Anemia (less than 10 g/dl hemoglobin) was predominant in nine patients and thrombocytopenia (platelet count <100 × 109/l) in 13. All 19 patients who had a marrow examination showed varying degrees of BM infiltration of LGLs. Four cases showed no or little circulating neoplastic LGLs. Five cases showed BM involvement less than one-third of that of PB. Extramedullary involvements at initial presentation were identified in all but one patient (case no. 1). Hepatomegaly, splenomegaly and lymphadenopathy were detected in 14, 12 and nine patients, respectively. Skin lesions were less common and recognized in only three cases. In 18 patients presenting with B symptoms, all but one showed an LDH index greater than one. In contrast, three of four patients without B symptom showed the IPI score of low-intermediate category. These three parameters showed a high degree of correlation and might represent tumor burdens.
Results of flow-cytometric immunophenotyping and EBV examination are summarized in Table 2. All cases examined were positive for CD2 (n=22), CD56 (n=21) and HLA-DR (n=16). The NK-cell marker CD16 was positive for 15 of the 20 cases (75%) and CD57 for two of the 16 cases (13%). Although T-lineage-specific markers, such as CD1 (n=12), CD3 (n=22), CD5 (n=17) and T-cell receptors (n=11), were negative for all cases examined, those shared by T and NK cells were expressed in a part of the cases. CD7, CD8 and cytoplasmic CD3 were positive for 74% (14 of 19), 29% (six of 21) and 43% (three of seven) of the cases, respectively. B-lineage markers (CD10 (n=14), CD19 (n=17), CD20 (n=15) and surface immunoglobulins (n=5)) and myelomonocytic markers (CD13 (n=17), CD14 (n=8), CD15 (n=5) and CD33 (n=14)) were uniformly negative. CD34 was also negative in 15 cases examined, whereas CD38 was expressed in eight of the 10 cases (80%). Although all 15 cases examined were negative for interleukin-2 receptor (IL-2R) α chain (CD25), IL-2R β chain (CD122) was expressed in five of the seven cases (71%). EBV was detected in 11 of the 13 cases (85%).
Cytogenetic characteristics are listed in Table 3. The karyotype of leukemic cells could not be determined in three cases and was normal diploid in nine cases. In the 10 cases with an abnormal karyogram, no specific recurrent cytogenetic abnormalities were recognized. Five patients presented with chromosome 7 abnormalities, but only one (no. 2) with isochromosome 7. Although 6p abnormality was found in three cases (nos. 8, 9 and 14), no deletion of 6q was detected.
Therapy and clinical course
Table 4 summarizes the treatments and clinical courses of the patients, 13 of whom were treated with chemotherapy containing anthracycline/anthraquinone and three of them attained complete remission (CR). Two patients who attained CR further received allogeneic BM transplantation (no. 19) and autologous PB cell transplantation (no. 22). Another patient who did not respond to CHOP attained CR after allogeneic BM transplantation. Eight patients were treated with chemotherapy without anthracyclines for various reasons, for example, poor performance status, advanced age, complications or the physician's preference for palliative therapy. A total of four patients attained CR and three partial remission (PR), but relapse occurred in all but one. Although no recurrence was seen in patient no.19, she died of graft-versus-host disease and infection 39 months after diagnosis. The other six patients all experienced recurrence of the disease. Except for case no. 19, all 21 patients died of leukemia.
The median survival of all patients was 58 days (range: 1–1163 days) and the overall survival curve is shown in Figure 1. The presence of B symptom (P=0.03), the IPI category (P=0.04) and therapeutic response (P=0.005) were significant prognostic factors (Figure 2). LDH index (P=0.07) and chemotherapeutic regimen (with or without anthracycline, P=0.07) showed marginal significance. Age, performance status, number of extranodal involvement sites and presence of EBV had no prognostic significance.
Although the first recognition of ANKL as a specific disease was approximately 20 years ago, this leukemia has not yet been satisfactorily characterized. This may be the result of its rarity and the fact that still the ontogeny of NK cells is not clarified enough. As compared with T or B cells, the absence of specific receptor gene rearrangement also inhibited the recognition and characterization of NK-lineage malignancies. ANKL is also featured by its ethnic predisposition for Oriental countries, but cases occurring in Western populations have been reported.7,18,25,31,34,35,38 Here, we have characterized the clinical presentation and courses of 22 cases, the largest series in the literature. Clinicopathologic similarities between ANKL and nasal-type NK-cell lymphoma that these two diseases are derived from the same NK-lineage cells may raise a possible notion that the former represents the leukemic phase of the latter.47 However, several clinical and morphologic features distinguish these two diseases. ANKL occurs in a younger population (median: 42 years old) and more frequently shows lymphadenopathy and hepatosplenic involvement than does nasal-type NK-cell lymphoma.48
The exclusive expression of CD2 and CD56 and the absence of CD3 and TCRs in ANKL reflect its NK-cell origin. A high expression rate of CD16 (75%) is also characteristic of ANKL. CD16 is usually not expressed in other hematolymphoid malignancies, including nasal-type NK-cell lymphoma, suggesting that CD16 is a specific marker for ANKL. Although the expression of CD16 was reported to be downregulated by activation49 or administration of IL-2,50 it is now recognized to represent functional NK-cell subsets. CD16+ CD56dim NK cells were first regarded as more mature form of NK cells, as compared with CD16neg/dim CD56bright NK cells.51 However, recent subset analysis has shown that the former produce less amount of immunoregulatory cytokines (interferon-γ, tumor necrosis factor-β, granulocyte–macrophage colony-stimulating factor, IL-10 and IL-13) than the latter,52 suggesting that the CD16+ CD56dim NK cells are cytotoxic NK cells.53 Intermediate-affinity IL-2 receptor (IL-2Rβγ) is expressed on both subsets of NK cells, but high-affinity receptor (IL-2Rαβγ) is only expressed on the immunoregulatory CD16dim/neg NK cells.54 The hypothesis that ANKL is derived from the cytotoxic NK cells is further supported by the lack of CD25 and relatively high frequency (71%) of CD122 expression of the present series of cases.
Chromosomal abnormality for isochromosome 7q, which is the most frequent and specific anomaly for hepatosplenic γδ and αβ T-cell lymphoma,55,56 was recognized in one (no. 2) of our series. However, the patient did not show hepatosplenomegaly and the tumor cells did not show any evidence of T-cell origin: they were negative for surface CD3 and their T-cell receptor β gene demonstrated a germline configuration. Since the presence of isochromosome 7q has also been reported in NK-cell malignancies,26 our case no. 2 is different from hepatosplenic T-cell lymphoma. The most frequently altered chromosome was chromosome 6 (four cases), but three of them (nos. 8, 9 and 14) showed 6p abnormalities. In the literature, the most frequent cytogenetic aberration for NK-cell malignancies is reportedly the deletion of chromosome 6q.15,57 Although 6p abnormality was found in three of our cases, deletion of 6q was not detected and an undetermined additional 6q anomaly was identified in only one case (no. 7). ANKL may cytogenetically be different from nasal-type NK-cell lymphoma, but this has not been proven. Half of the cases showed normal diploid karyotype, but this does not directly reflect the karyotype of tumor cells, since two NK-cell leukemia cell lines established from cases presenting with normal karyotype are found to show abnormal karyotype.27,31 The original leukemic NK cells may not be capable of producing metaphase, which is also probably the case in our series. Therefore, conventional cytogenetic analysis is not sufficient for the identification of chromosomal/genetic abnormalities responsible for the leukemogenesis of ANKL. Molecular examinations, such as comparative genomic hybridization or microarray analyses, are thus warranted.58,59,60,61
Most of the reports concerning ANKL in the literature emphasize poor prognosis and resistance to chemotherapeutic agents. The latter has been ascribed to the presence of P-glycoprotein, which mediates multidrug resistance.37,38 However, our study suggests that the use of anthracycline-containing chemotherapy tends to result in a better response and prognosis. Recently, Trambas et al62 demonstrated that the P-glycoproteins expressed on NK cells have molecular weights of 70 and 80 kDa, which do not allow them to transport doxorubicin and make them functionally different from those with the conventional weight of 170 kDa. These observations warrant the re-evaluation of anthracycline-containing regimens for ANKL. Another promising agent is L-asparaginase. Although one patient who attained PR was treated with L-asparaginase, several recent reports emphasizing this agent have been published.63,64
Patients attaining CR or PR showed significantly longer survival, but the remission did not translate into cure of the disease. One pediatric case (no. 19) who did not experience relapse received allogeneic BM transplantation, but died of graft-versus-host disease and infection. The use of allogeneic stem cell transplantation has also been reported in the literature.32,33 The younger age onset of ANKL points to the possible usefulness of a hematopoietic stem cell transplantation for those who have attained remission. The results for our ANKL cases and those reported in the literature indicate that many of them were not treated with powerful chemotherapy. Although the presence of B symptoms or poor performance status may in part have contributed to the poor prognosis, intensive anthracycline-containing chemotherapy followed by stem cell transplantation31,32 should be attempted in prospective clinical trials.
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This work was supported in part by a grant-in-aid for the second-term comprehensive 10-year strategy for cancer control from the Ministry of Health and Welfare, a grant-in-aid for science on primary areas (Cancer Research), from the Ministry of Education, Science and Culture, Japan. We thank the collaborators from the following institutions for providing the patients' data and specimens: Saiseikai Maebashi Hospital; Mie University; Japanese Red Cross Nagoya First Hospital; Kitano Hospital; Dokkyo University School of Medicine; Fujita Health University School of Medicine; Hiroshima University School of Medicine; Kansai Medical University; Toride Kyodo Hospital; Tokyo Medical and Dental University; Kyushu University and a grant-in-aid for Encouragement of Young Scientists from the Ministry of Education, Science and Culture, Japan.
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Suzuki, R., Suzumiya, J., Nakamura, S. et al. Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells. Leukemia 18, 763–770 (2004) doi:10.1038/sj.leu.2403262
- natural killer cell
- interleukin-2 receptor
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