Annals of Oncology Advance Access originally published online on April 11, 2007
Annals of Oncology 2007 18(7):1203-1208; doi:10.1093/annonc/mdm094
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© 2007 European Society for Medical Oncology
hematologic malignancies |
Clinicopathologic correlations of stage IE/IIE primary thyroid diffuse large B-cell lymphoma
1 Division of Hematology, Department of Internal Medicine, Saitama Medical University, Saitama, Japan
2 Adult Lymphoma Treatment Study Group (ALTSG), Nagoya, Japan
* Correspondence to: Dr N. Niitsu, Division of Hematology, Department of Internal Medicine, Saitama Medical University, 38 Morohongo, Moroyama, Iruma-Gun, Saitama, Japan. Tel: +81-49-276-1826; Fax: +81-49-276-1826; E-mail: nniitsu{at}saitama-med.ac.jp
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Background: We studied the clinicopathological characteristics and prognoses of localized stage thyroid diffuse large B-cell lymphoma (DLBCL).
Patients and methods: This study included 32 patients with stage I/IIE thyroid DLBCL. Their median age was 66 years, the male/female ratio was 10/22.
Results: As to the cellular immunophenotype, CD20 was positive in 31/32, CD5 in 0/32, CD10 in 4/32, CD23 in 1/32, BCL2 in 14/30, and BCL6 in 24/32. Twelve cases showed abnormal karyotypes: two cases with t(8;14)(q24;q32), four cases with 3q27, two cases with 17p11, and four cases with other abnormal karyotypes. As for treatment, eight cases were treated with chemotherapy alone and 24 cases were treated with chemotherapy followed by radiotherapy. Complete response was achieved in 94%. The 5-year progression-free survival was 84% and the 5-year overall survival was 90% with a median follow-up period of 62 months. The germinal center B-cell (GCB) type had a significantly better prognosis than the non-GCB type.
Conclusion: Localized stage thyroid DLBCL is a disease with a relatively good prognosis. It is, however, a heterogeneous disease with regard to histological type and pathological state. Localized stage thyroid DLBCL has a good prognosis and it is that there are more GCB-type DLBCL lymphomas.
Key words: BCL-6, germinal center B cell, Hashimoto's disease, nm23-H1, Thyroid lymphoma
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introduction |
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Primary thyroid lymphoma is a rare disease, accounting for
5% of all thyroid malignancies, 1%–2.5% of all lymphomas and 3%–7% of extranodal lymphomas [1]. Primary thyroid lymphoma is a heterogeneous disease, and the clinical course and histological features vary. There is a distinct female predominance, and this lymphoma usually develops between the ages of 50 and 80 years, with a peak incidence between 60 and 69 years [2]. Histopathological features of Hashimoto's disease are observed adjacent to a lymphomatous focus in 80%–90% of cases, even in patients with thyroid lymphoma who do not have symptoms of Hashimoto's disease. In addition, 60%–70% of patients with primary thyroid lymphoma are positive for antithyroid antibodies at the time of onset of the lymphoma [2]. As for the histological types of primary thyroid lymphoma, diffuse large B-cell lymphoma (DLBCL) accounts for 60%–85% and mucosa-associated lymphoid tissue (MALT) lymphoma accounts for 15%–40% [3]. Follicular lymphoma is very rare. As a component of MALT lymphoma is seen in 40% of primary thyroid DLBCLs, some cases of DLBCL are thought to have originated from MALT lymphoma [3]. For the treatment of primary thyroid DLBCL at the localized stage, radiotherapy alone, chemotherapy alone, and chemotherapy followed by radiotherapy [combined modality therapy (CMT)] have been used. There is, however, a high possibility of distant recurrence after treatment with radiotherapy alone, and at present CMT or chemotherapy alone is generally administered [4]. Thyroid DLBCL at the localized stage generally has a good prognosis, but it is heterogeneous with regard to the pathological state and histological type such that some cases have a poor prognosis. Therefore, it is necessary to evaluate the prognostic factors of thyroid DLBCL and establish stratified treatment plans.
We studied the clinical characteristics, cellular immunophenotypes, and chromosomal findings of 32 patients with localized stage primary thyroid DLBCL. In addition, the treatment results and prognostic factors were evaluated.
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patients
A total of 1592 patients with non-Hodgkin's lymphoma (NHL) were consecutively treated in the Adult Lymphoma Treatment Study Group (ALTSG) in Japan from 1998 to 2005. The ALTSG is a prospective study. Among the 1156 patients (72.6%) with B-cell lymphoma, 834 had DLBCL. There were 32 cases (2% of NHLs) of primary thyroid DLBCL. Primary thyroid lymphoma was defined as a lymphoma that arises from the thyroid gland and only swelling of a regional lymph node. Histological analysis of the materials from each patient was carried out independently by six pathologists from the ALTSG. The lymphomas were classified according to the new World Health Organization classification system [5] by the committee pathologists. All patients were newly presenting and were previously untreated. For DLBCLs, three courses of the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen followed by involved field radiotherapy (IFRT) were administered to patients with stage I, and six courses of CHOP regimen with or without IFRT were administered to patients with stage II. The decision as to whether to administer IFRT to patients with stage II was made at the discretion of physicians at each institution. CHOP plus rituximab was not administered to the patients because rituximab was not approved by the Japan Ministry of Health, Labour and Welfare until 2005.
The median follow-up period of the 37 patients was 62 months (range, 24–90 months).
Approval of the study protocol was obtained from the institutional review board of each participating institute. Informed consent was obtained from each patient according to the Declaration of Helsinki.
methods
immunohistochemistry.
Paraffin-embedded sections of each sample were immunostained with monoclonal antibodies against CD5 (Novocastra), CD10 (Novocastra), CD20 (Novocastra), CD23 (Novocastra), BCL2 (DAKO), BCL6 (Novocastra laboratories, Newcastle, UK), MUM-1 (DAKO), Mib-1 (Novocastra), and nm23-H1 (Novocastra). The percentages of positive cells were averaged to yield an immunohistological score of 10% increments. The following categories were defined: negative (<30% positively stained tumor cells) and positive (>30% positively stained tumor cells).
cytogenetic studies.
We used the standard technique for chromosome analysis [6]. Biopsied lymph nodes or other tumors were immediately disaggregated with a scalpel in RPMI-1640 medium, and single cells were suspended in RPMI-1640 supplemented with 20% fetal bovine serum at a concentration of 106 cells per ml. For the short-term unstimulated culture method, metaphase cells were arrested by exposing them to Colcemid at a final concentration of 0.02 g/ml for the last 2 h before harvesting. After hypotonic treatment with 0.075 M KCl at room temperature for 15 min, the cells were fixed with ethanol and acetic acid (3 : 1). Metaphase preparations were made by the steam-dry method. After the slides were incubated at 37°C for 4–7 days, the trypsin G-banding technique was used for analysis of karyotypes. Chromosome identification, karyotypic designation, and determination of clonality were carried out in accordance with the International System for Human Cytogenetic Nomenclature (1995) [7].
statistical analysis.
All statistical analyses were carried out with SAS software (version 9, SAS Institute, Cary, NC). Overall survival (OS) and progression-free survival (PFS) were analyzed according to the Kaplan–Meier method. The statistical significance of differences in survival was assessed by the log-rank and generalized Wilcoxon tests. Differences between groups were evaluated by the Mann–Whitney U-test (nonparametric analysis). Significance was set at P < 0.05.
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characteristics of patients with thyroid lymphoma
The median age of the 32 patients with DLBCL was 66 years (range, 18–60 years). There were 10 males and 22 females. An elevated lactate dehydrogenase (LDH) level was observed in 25%, and a bulky mass larger than 8 cm was present in 37.5% of the patients. Seven patients (21.9%) were at low-intermediate risk and the remaining 25 patients were at low risk according to the International Prognostic Index (IPI) [8]. Thyroid function was normal in 59% and antithyroid antibodies were detected in 41% of the patients.
microscopic features and immunohistochemical analysis of DLBCL
The pathological features of the DLBCL specimens were as follows. Marginal zone/monocytoid B-cell differentiation was seen in 10 (31%) of 32 cases, plasmacytoid differentiation was seen in one case, and a ‘starry sky’ pattern was seen in two cases. The clinical, pathological, phenotypic, and genetic features of the 11 cases of thyroid DLBCL with MALT component are shown in Table 1. The B-cell immunophenotype of the lymphomas was confirmed by immunoreactivity with antibodies to CD20 in 31 cases and with antibodies to CD79a in one case with extensive plasmacytoid differentiation (Table 2). Among the 32 cases, CD5 was negative in all cases, CD10 was positive in four cases (12.5%), and CD23 was positive in one case (3.1%). BCL-2 was positive in 14 (46.7%) of 30 cases that did not show a starry sky pattern as well as in the two cases that showed a starry sky pattern. BCL-6 was positive in 24 (75%) of 32 cases while nm23-H1 was positive in eight (25%) of 32 cases. Mib-1 was 
80% (0%–80%) in all cases. MUM-1 was positive in 12 (37.5%) of 32 cases (Table 3). The 32 cases were assigned to the germinal center B-cell-like (GCB) group or the non-GCB group according to the classification method of Hans et al. [9]. If CD10 alone was positive or if both BCL-6 and CD10 were positive, the case was assigned to the GCB group. If both BCL-6 and CD10 were negative, the case was assigned to the non-GCB group. If BCL-6 was positive and CD10 was negative, the expression of MUM1 determined the group: if MUM1 was negative, the case was assigned to the GCB group, and if MUM1 was positive, the case was assigned to the non-GCB group. When the DLBCL cases were divided into the GCB group and the non-GCB group, the GCB group consisted of 20 cases (62.5%) and the non-GCB group consisted of 12 cases (37.5%).
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chromosomal analysis of DLBCL
Chromosomal analysis was carried out in 16 of 32 DLBCL cases, and 12 cases showed abnormal karyotypes. t(8;14)(q24;q32) was seen in two cases [10]. These two cases were also positive for c-myc/IgH on FISH, but they were negative for CD10. BCL-2 was positive in one of two cases. We experienced two cases of DLBCL having t(8;14)(q24;q32). The immunophenotype and karyotype of case 1 and case 2 (70-year-old female) were as follows: CD10–, CD20+, BCL-2+/add(13)(q34),t(8;14)(q24;q32) and CD10–, CD20–, CD79a+, BCL-2-/t(8;14)(q24;q32), respectively. Case 1 was not observed starry sky appearance. Histopathological examination of the thyroid biopsy specimen showed diffuse proliferation of large lymphoid cells with distinctive nucleoli and plasmacytoid cells accompanied by a starry sky appearance of case 2. Among the four patients with DLBCL with 3q27 translocation, an IG-type translocation t(3;14)(q27;q32) was seen in two patients. The other two patients with a non-IG-type translocation had der(3)(q27). All four cases with 3q27 translocation showed positive immunostaining for BCL-6. 17p11 was found in two cases. Both of these cases showed an additional chromosomal abnormality of t(3;14)(q27;q32). No case had both the 3q27 translocation and t(8;14)(q24;q32). There were no cases with t(14;18)(q32;q21.3) or t(11;18)(q21;q21). In the 16 cases in whom chromosomal analysis was not carried out, FISH for c-myc/IgH, BCL-2/IgH, and MALT1/IgH was carried out; 2, 0, and 0 cases were positive for c-myc/IgH, BCL-2/IgH, and MALT1/IgH, respectively.
univariate analysis of OS and PFS in patients with thyroid DLBCL
Among the 32 patients with thyroid DLBCL, 30 patients (94%) achieved complete response. The 5-year OS was 90% and the 5-year PFS was 84% with a median follow-up period of 62 months (Figure 1). OS and PFS were analyzed in each of the following groups: age (60 years old versus 
61 years old), Ann Arbor stage (IE versus IIE), serum LDH level (normal versus elevated), bulky mass (yes versus no), IPI (low versus low-intermediate risk), and soluble interleukin 2 receptor (sIL-2R) (<1000 U/ml versus >1000 U/ml). There were no significant differences in either the OS or PFS when the patients were divided according to age, stage, LDH level, or presence of bulky mass. As to the IPI, the low-intermediate risk cases showed significantly poorer prognosis than the low-risk cases in terms of both OS and PFS. The patients with sIL-2R >1000 U/ml showed significantly poorer prognosis than those with sIL-2R <1000 U/ml in both OS and PFS (Table 3). OS and PFS were then analyzed in each of the following categories: BCL-2, positive versus negative; BCL-6, positive versus negative; nm23-H1, positive versus negative; and MALT lesion, positive versus negative. The 5-year PFS of the BCL-2-positive group (n = 14) was 85.7% and that of the BCL-2-negative group (n = 16) was 83.3%, showing no significant difference. The OS of the BCL-2-positive group was 82.5% and that of the BCL-2-negative group was 100%, showing no significant difference. There was no significant difference in OS between the BCL-6-positive group (n = 24) and the BCL-6-negative group (n = 8). The 4-year PFS of the BCL-6 negative group, however, was 50% and that of the BCL-6-positive group was 95.8%, showing a significant difference (P = 0.001) (Figures 2A and B). As for nm23-H1 expression in thyroid DLBCL in the present study, the 5-year PFS of the nm23-H1-positive group (n = 8) was 37.5% and that of the nm23-H1-negative group (n = 24) was 100%, indicating that the nm23-H1-positive group showed significantly poorer prognosis (Wilcoxon, P = 0.0004; log-rank, P = 0.0007) (Figure 3C). Similarly, the 5-year OS of the nm23-H1-positive group was 60% and that of the nm23-H1-negative group was 100%, showing that the nm23-H1-positive group had significantly poorer prognosis (Wilcoxon, P = 0.0024; log-rank, P = 0.0016) (Figure 2D). The GCB group (n = 20) and non-GCB group (n = 12) were also compared (Figure 3A). The 5-year OS of the GCB group was 94.7% and that of the non-GCB group was 72.9%, showing a significant difference (Wilcoxon, P = 0.039; log-rank, P = 0.047) (Figure 3B). The 5-year PFS of the GCB group was 89.9% and the 4-year PFS of the non-GCB group was 66.6%, and the GCB group showed significantly better prognosis (Wilcoxon, P = 0.049; log-rank, P = 0.026) (Figure 3C). Among the DLBCL patients, the presence or absence of MALT lesions were analyzed in a similar manner, and there was no significant difference in either the OS or PFS.
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The patients with localized stage primary thyroid DLBCL in this study showed a median age of 66 years, female predominance (69%), and a performance status of zero in all cases. The LDH level was within the normal range in the majority of cases (75%), and 78% of the patients were at low risk according to the IPI. Primary thyroid lymphoma is frequently detected by thyroid gland enlargement. Therefore, the rate of detection during a relatively localized stage is high. Among our patients, 25% had a past history of Hashimoto's disease and 41% were positive for antithyroid antibodies. It was reported that the concordance rate of Hashimoto's disease and thyroid lymphoma is 25%–75% and MALT lymphoma has an especially high rate of concordance [2, 11].
Although it has been postulated that lymphomatous change may be a result of prolonged antigenic stimulation in autoimmune thyroiditis, the majority of patients with Hashimoto's thyroiditis do not develop lymphoma of the thyroid gland. Williams [12] compared the situation in the thyroid gland with that in other organs in which there is an association between primary lymphoma and prolonged immune stimulation, and concluded that there is a causal relationship between Hashimoto's thyroiditis and the later development of lymphoma. Other studies do not support the theory that lymphoma develops from Hashimoto's thyroiditis. Long-term follow-up of patients with Hashimoto's thyroiditis appears to be necessary in the future. In 60%–85% of thyroid lymphomas, the histological type is DLBCL. Some DLBCLs, however, include a component of marginal zone/monocytoid B-cell differentiation or plasmacytoid differentiation. In the present study, marginal zone/monocytoid B-cell differentiation was seen in 31% of the DLBCL cases. There was no significant difference in prognosis between DLBCL patients with or without marginal zone/monocytoid B-cell differentiation.
As to treatment of localized stage thyroid DLBCL, surgical resection alone was carried out in the past. Complications of surgery, however, include recurrent laryngeal nerve injuries or hypoparathyroidism, and there is a high possibility of distant recurrence. Therefore, surgical resection has not been carried out recently. According to a study that compared the treatment results of IFRT to the thyroid bed and cervical lymph nodes and extended field radiotherapy (EFRT) covering the thyroid bed, cervical, and mediastinal lymph nodes, the 5-year OS for stage I was 40% in the IFRT group and 88% in the EFRT group, and for stage II it was 25% in the IFRT group and 36% in the EFRT group [13]. Therefore, it was indicated that a complete cure should not be expected by IFRT alone for patients with stage I and stage II, and combination with chemotherapy was necessary. As a result, a combination of chemotherapy and radiotherapy (CMT) or chemotherapy alone has recently been used for the treatment of primary thyroid DLBCL. Doria et al. [14] reported that the incidence of distant recurrence was high at 31% following surgical resection of the thyroid gland alone or radiotherapy alone, and that the incidence of distant recurrence decreased to 5% by administering a combination of chemotherapy and radiotherapy. Therefore, the combination of radiotherapy and chemotherapy (CMT) is effective as a treatment of thyroid DLBCL. DiBiase et al. [15] treated 19 of 27 cases of stage IE and IIE thyroid lymphoma with radiotherapy alone and eight cases with CMT. Among the 19 patients who were treated with radiotherapy alone, the 5-year OS was 56% and nine patients (47%) showed distant recurrences; on the other hand, only one of eight patients in the CMT group showed distant recurrence. The results indicate that CMT could be a standard treatment of thyroid lymphoma. In this study, we administered CMT to patients with stage I DLBCL and six courses of CHOP regimen to patients with stage II DLBCL. The results showed that among the 32 patients with DLBCL, the 5-year OS was 90.3% and the 5-year PFS was 84.3%. Univariate analysis showed that low-intermediate risk IPI, sIL-2R >1000 IU/l, non-GCB type, and positive nm23-H1 were significant poor prognostic factors for OS. For PFS, low-intermediate risk IPI, sIL-2R >1000 IU/l, negative BCL-6, non-GCB type, and positive nm23-H1 were significant poor prognostic factors. We previously established an enzyme-linked immunosorbent assay technique for determination of the serum level of nm23-H1 protein [16, 17]. nm23-H1 was originally identified as a protein that was expressed at a lower level in metastatic cancer cells. Since then, low expression or mutation of nm23-H1 and nm23-H2 has been implicated in cancer prognosis or metastasis in a variety of tumors and malignant transformations. We previously reported that the serum level of nm23-H1 in patients with aggressive NHL was significantly higher than that in healthy controls, and that a high nm23-H1 level was associated with poor prognosis in aggressive NHL [17]. In our previous study on cytoplasmic nm23-H1 expression in DLBCL by immunohistochemical staining, we found that patients with positive cytoplasmic staining had significantly poorer prognosis than patients with negative staining [18]. In the present study, patients with nm23-H1-positive specimens had significantly poorer prognosis. Derringer et al. [3] reported that stage greater than IE, rapid clinical growth, high mitotic rate, perithyroidal extension, and compressive clinical symptoms were poor prognostic factors. Hans et al. [9] reported that non-GCB-type DLBCL had a significantly poorer prognosis than GCB-type DLBCL. In this study, the GCB type accounted for 62.5% of the DLBCL cases, and the GCB type had a significantly better prognosis. In a previous study that included 33 gastric DLBCLs, high BCL-6 expression was a good prognostic factor. In addition, they reported that the GCB type was a better prognostic factor than the non-GCB type [19]. Therefore, it is indicated that one reason why localized stage thyroid DLBCL has a good prognosis is that there are more GCB-type DLBCL lymphomas. Also, our results indicated that nm23-H1 was a poor prognostic factor for thyroid DLBCL.
Our results indicate that localized stage thyroid gland lymphoma of non-GCB type with high nm23-H1 expression has a poor prognosis. Studies on the prognostic factors of other types of thyroid gland lymphoma are necessary in the future.
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The authors thank the following institutions for providing patient data and specimens: Kitasato University School of Medicine, Fujita Health University School of Medicine, Kanazawa University School of Medicine, Yokohama City University, Niigata University School of Medicine, Kanagawa Cancer Center. The authors thank for having had S Nakamura, Oshima, Tamaru, and Yoshino carrying out pathological diagnosis. Supported in part by a grant from the Ministry of Health and Welfare, and Grants-in-Aid for Scientific Research (C) and Cancer Research, from The Ministry of Education, Culture, Sports, Science, and Technology (MEXT) Japan.
Received for publication January 4, 2007. Revision received February 8, 2007. Accepted for publication February 16, 2007.
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