Ki-67 expression is predictive of prognosis in patients with stage I/II extranodal NK/T-cell lymphoma, nasal type

Annals of Oncology, Aug 2007

Kim, SJ, Kim, BS, Choi, CW, Choi, J, Kim, I, Lee, Y-H, Kim, JS

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Ki-67 expression is predictive of prognosis in patients with stage I/II extranodal NK/T-cell lymphoma, nasal type

Ki-67 expression is predictive of prognosis in patients with stage I/II extranodal NK/T-cell lymphoma, nasal type S. J. Kim 2 B. S. Kim 2 C. W. Choi 2 J. Choi 1 I. Kim 1 Y.-H. Lee 0 J. S. Kim 2 0 Department of Diagnostic Radiology, Korea University Medical Center , Seoul , Korea 1 Department of Pathology 2 Department of Internal Medicine Background: Localized extranodal natural killer (NK)/T-cell lymphoma, nasal type, commonly has a low or low-intermediate risk of the international prognostic index (IPI), so the IPI has shown inconsistency in predicting prognosis. Thus, we analyzed Ki-67 expression and proposed a new prognostic model including Ki-67 expression for stage I/II extranodal NK/T-cell lymphoma. Patients and methods: We studied Ki-67 expression and its relationship with prognosis in 50 patients with extranodal NK/T-cell lymphoma. Results: The patients were dichotomized by the median value: low (<65%) versus high Ki-67 (‡65%). High Ki-67 was associated with a worse overall survival (OS; P = 0.021) and disease-free survival (DFS; P = 0.044). In multivariate analysis, Ki-67 expression and primary site of involvement were found to be an independent prognostic factor for OS and DFS (P < 0.05). Based on these results, we proposed a new clinico-pathological prognostic model with Ki-67 expression and the primary site of involvement. It showed a high degree of correlation with worse OS and DFS (P < 0.001). Conclusions: Ki-67 expression is predictive of prognosis, and our prognostic model may become a useful tool for predicting prognosis in patients with stage I/II extranodal NK/T-cell lymphoma, nasal type. - Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is a distinct subtype of non-Hodgkin’s lymphoma that is very rare in North America and Europe [ 1, 2 ]. However, it is rather common in Asia and South America [3]. Thus, it has been reported to account for 8.7% of all non-Hodgkin’s lymphomas and 74.1% of lymphomas that develop in the nasal cavity and paranasal sinuses in Korea [ 4 ]. Pathologically, extranodal NK/T-cell lymphoma has unique characteristics including the expression of cytoplasmic CD3, CD56 and cytotoxic molecules such as TIA-1, and is positive for Epstein–Barr virus (EBV) in situ hybridization [ 1, 5 ]. Clinically, it frequently occurs in middle-aged men, and usually presents as a localized disease involving the head and neck. Furthermore, most patients show good performance status, thus most patients have low international prognostic index (IPI) scores [ 6, 7 ]. However, the overall prognosis of this disease is poor because of frequent relapse or resistance to treatment [ 8, 9 ]. This discrepancy has led to conflicting results about the prognostic value of the IPI score in extranodal NK/T-cell lymphoma, nasal type. Thus, although a positive correlation of IPI with prognosis was reported in this rare subtype of non-Hodgkin’s lymphoma [10], other studies have not shown a correlation of IPI with prognosis in extranodal NK/T-cell lymphoma [ 11, 12 ]. Because the IPI mainly depends on the clinical characteristics, another prognostic indicator reflecting biological characteristics, such as a rapid growth of tumor cells, may help to predict differences in survival among patients with localized extranodal NK/T-cell lymphoma showing low IPI scores. Ki-67 is a nuclear antigen expressed by dividing cells. Thus, the percentage of Ki-67-positive cells reflects the proportion of actively proliferating tumor cells. Although the prognostic value of Ki-67 remains controversial in non-Hodgkin’s lymphoma, a recent study in peripheral T-cell lymphoma showed a positive correlation with poor prognosis [ 13 ]. However, the prognostic value of Ki-67 has never been studied in patients with extranodal NK/T-cell lymphoma. Therefore, we performed this study to determine the value of Ki-67 expression in predicting prognosis in patients with localized extranodal NK/T-cell lymphoma. materials and methods patients Fifty patients diagnosed with localized extranodal NK/T-cell lymphoma at the Korea University Medical Center were included from January 2000 to October 2006. They were consecutively diagnosed from 2000, and had paraffin-embedded blocks available for Ki-67 immunohistochemical staining. Patients were diagnosed based on the following criteria: the presence of a tumor mass with histological features and immunophenotypes compatible with NK/T-cell lymphoma (cCD3+, CD20–, CD56+, cytotoxic molecules +, EBV in situ hybridization +). All patients had undergone staging investigations including: complete blood counts, serum biochemistry, serum lactate dehydrogenase (LDH), serum b2 microglobulin, bone marrow aspiration and trephine biopsy, endoscopic examination of the nasal and oral cavity, computed tomographic (CT) or magnetic resonance imaging (MRI) of the involved organs of the head and neck and CT of the chest and abdomen-pelvis. The Ann Arbor staging system was used; however, the size of the primary lesion was calculated by the sum of products of the longest diameters and greatest perpendicular diameters to define the bulk of the lesion (‡10 cm2). The reason why the sum of products was used instead of diameter, e.g. mass with >10 cm diameter, was that most cases occurred in the head and neck, such as paranasal sinuses, thus the size of the primary lesion was commonly smaller than other types of non-Hodgkin’s lymphoma. Treatment modalities that patients received were as follows: chemotherapy followed by involved-field radiotherapy (19 patients) and chemotherapy alone (31 patients). CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisolone)-like chemotherapy regimens were used including CEOP-B (cyclophosphamide, epirubicin, vincristine, prednisolone and bleomycin), and CEOP-E (cyclophosphamide, epirubicin, vincristine, prednisolone and etoposide). Involved-field radiotherapy of 44–60 Gy was delivered in daily fractions of 1.8–2.0 Gy by a conventional fractionation schedule (five fractions per week). immunohistochemistry for Ki-67. For the detection of Ki-67, we used the anti-Ki-67 mouse monoclonal antibody (clone MIB-1, DakoCytomation, Carpinteria, CA, USA). First, tissue sections were dewaxed and rehydrated. After endogenous peroxidase was quenched with methanol and 3% hydrogen peroxide for 5 min, antigen retrieval was done with citrate buffer (pH 6.0) in a pressure cooker for 2 min. After blocking with 10% donkey serum, the slides were incubated with the primary antibody (dilution 1:100) for 30 min at room temperature, and washed with Tris-buffered saline (TBS). The secondary antibody (ChemMate Dako Envision, DakoCytomation) was applied for 30 min. Slides were again washed with TBS and color was developed by 5-min incubation in diaminobezidine (DAB) solution. Slides were counterstained with hematoxylin. Tumor cells were considered positive for the Ki-67 antigen if there was intranuclear DAB staining. After the slides were scanned at low magnification (·40), the cells with positively stained nuclei were counted at high magnification (·400). The percentage of Ki-67 expression was quantified by determining the number of positive cells expressing nuclear Ki-67 among the total number of tumor cells in the high-power field. The median percentage (65%) of Ki-67 expression was designated as a cutoff, thus cases higher than the median value (‡65%) was defined as high Ki-67 expression, and less than the median value (<65%) was designated as low Ki-67 expression for the survival analysis. Slides were reviewed by pathologists (J.C. and I.K), and all interpretations of immunohistochemistry were performed without knowledge of clinical outcome. statistical analysis. The relationship of Ki-67 expression with clinical variables was evaluated using the chi-squared test. The period of overall survival (OS) was measured from the date of diagnosis to the date of death or the last follow-up visit. The disease-free survival (DFS) was measured from the date treatment began to the date when disease progression was recognized or the date of the last follow-up visit. The Kaplan–Meier method was used to calculate OS and DFS, and survival curves were compared by the log-rank test. The Cox proportional hazards regression model was used for the multivariate analysis to compare the factors proven significant in the univariate analysis. A two-sided P-value of less than 0.05 was considered statistically significant. results characteristics of patients The clinical characteristics of the 50 patients are presented in Table 1. Thirty patients (60.0%) initially presented as stage I and 20 patients as stage II. In 11 patients, their primary lesion was bulky (‡10 cm2). The number of patients with extranodal NK/T-cell lymphoma originating from the nasal cavity and nasopharynx was 33 (66.0%). Seventeen patients (34.0%) presented with lymphomas from the upper aerodigestive tract: tonsil (n = 10), oropharynx (n = 5), hypopharynx (n = 1), palate (n = 1). response to treatment and outcomes. The median OS was 42.43 months (95% confidence interval (CI), 13.45–71.42) and the estimated 5-year OS rate was 43.9%. Twenty-three patients (46.0%) and 16 patients achieved complete remission (CR) and partial response (PR), respectively, thus the overall response rate was 78.0%. Among them, 28 patients showed evidence of relapse or disease progression after achieving CR or PR. The median DFS was 19.03 months (95% CI, 5.89–32.17). When the survival difference was analyzed based on the type of treatment, chemotherapy followed by radiotherapy failed to show a significant benefit over chemotherapy alone in terms of OS and DFS (P = 0.653, and 0.467, respectively). This is the same as the results of our previous report [ 14 ]. Ki-67 expression. The nuclear staining pattern of Ki-67 expression was evaluated and the quantified Ki-67 expression (the percentage of Ki-67-positive cells to tumor cells) was noted to have a wide range of distribution from 5% to 95% (Figure 1). When the patients were separated into two groups based on the median value (65%), high Ki-67 (‡65%) and low Ki-67 (<65%), its relationship with clinical features is summarized in Table 2. Bulky primary lesions was significantly associated with high Ki-67 expression (P = 0.006), suggesting that bulky tumors may have a high proliferation of tumor cells. However, there was no association of Ki-67 expression with other clinical features such as stage, IPI, B symptoms and so forth except for Eastern Cooperative Oncology Group (ECOG) performance status. The group with high Ki-67 showed increased cases with elevated serum LDH and b2 microglobulin compared with the low Ki-67 group; however, it failed to show a statistical significance (P = 0.112 and 0.098, respectively). The status of Ki-67 expression was not different between the chemotherapy and chemotherapy plus radiotherapy groups (P = 0.773). The response to chemotherapy was not significantly associated with the status of Ki-67 expression (P > 0.05). The mean percentage of Ki-67 expression in patients responding to chemotherapy was not significantly different from non-responders (54.74 6 26.82 vs. 58.63 6 27.84). survival analysis. In the univariate analysis, the group with high Ki-67 expression had a shorter OS (P = 0.021, Figure 2A) and DFS (P = 0.044, Figure 2B). The results of the univariate analysis are summarized in Table 3. The primary site of involvement was significantly associated with a poor OS (P = 0.022), and this was consistent with our previous report [ 14 ]. Thus, NK/T-cell lymphomas in the nasal cavity/ nasopharynx were associated with worse OS. Bulky tumors (‡10 cm2) showed a marginal significance with OS (P = 0.052). However, the IPI failed to show prognostic significance for OS (P = 0.296). The association of DFS with IPI, bulky tumors, B symptoms and primary site of involvement did not reach statistical significance (P > 0.05). Serum LDH was found to be significantly associated with DFS (P = 0.045). Ann Arbor stage failed to discriminate a survival difference between stages I and II (P > 0.05). In the multivariate analysis with the parameters used in the univariate analysis, Ki-67 expression was found to be an independent prognostic factor for OS (response rates (RR) = 4.330; 95% CI, 1.108– 16.918; P = 0.035) and DFS (RR = 3.230, 95% CI 1.073-9.720, P = 0.036). The primary site of involvement was also an independent prognostic factor for OS (RR = 6.105; 95% CI, 1.530–24.363; P = 0.010) and DFS (RR = 5.028; 95% CI, 1.514–16.698; P = 0.008). prognostic model with Ki-67 expression and primary site of involvement. According to the results of our univariate and multivariate analyses, we proposed a new prognostic model with two poor prognostic factors: Ki-67 expression and primary site of involvement. Thus, we designated a high-risk group as the presence of two factors including high Ki-67 expression and nasal cavity/nasopharynx-originated NK/T-cell lymphomas and a low-risk group as the presence of one factor or none. This new prognostic model showed a high degree of correlation with survival outcomes in terms of OS and DFS (P < 0.001; Figure 3A, B). discussion Since the IPI was proposed by the International Non-Hodgkin’s Lymphoma Prognostic Factors Project, the IPI has been used for both predicting prognosis and selecting therapeutic options in patients with aggressive non-Hodgkin’s lymphoma. However, its value has been challenged by extranodal NK/T-cell lymphoma because it has failed to predict prognosis in retrospective analyses [ 11, 12 ]. Thus, newer prognostic models have been suggested to supplement the IPI for extranodal NK/T-cell lymphoma [ 6, 7 ]. However, these prognostic models are based primarily on pre-treatment clinical Volume 18 | No. 8 | August 2007 characteristics; the molecular factors that may predict the aggressiveness and malignant potential of extranodal NK/T-cell lymphoma have not yet been defined. The status of cellular proliferation and cell-cycle regulation have been studied for possible molecular prognostic markers in non-Hodgkin’s lymphoma including cell-cycle regulatory molecules TP53, p27kip1 and cyclin D [ 15, 16 ]. The uptake of fluorodeoxyglucose (FDG) in positron emission tomography (PET) is known to be related to cellular proliferation and has been reported to predict prognosis in patients with non-Hodgkin’s lymphoma [17]. Recently, Ki-67 proliferation rate was also reported to be correlated with increased angiogenesis in the canine non-Hodgkin’s lymphoma spontaneous model, suggesting its relationship with aggressive behavior of lymphomas [ 18 ]. Therefore, measurement of the proliferation status before commencement of treatment may improve the overall prognostic assessment of patients with non-Hodgkin’s lymphoma allowing therapy to be tailored to patients. The measurement of Ki-67 expression using immunohistochemistry techniques is one of the methods available to measure cellular proliferation. Ki-67 is a protein synthesized as a cell begins proliferation; thus it is present in the proliferation-associated phase of the cell cycle including S, G2 and M [ 19 ]. Immunohistochemical staining of cells with Ki-67 monoclonal antibody (clone MIB-1) is a commonly used technique that can be more easily applied to formalin-fixed, paraffin-embedded tissue sections compared with other methods such as mitotic figure counting and measurement of proliferating cell nuclear antigen (PCNA) [ 20 ]. This technique allows for the differentiation of proliferating cells from quiescent cells. Thus, the proliferation index, which is the percentage of Ki-67-positive cells among the total tumor cells in a selected area, has been used to assess the proliferative activity of tumors. Ki-67 expression has been reported to be associated with tumor aggressiveness and poor prognosis in a variety of malignancies [ 21 ]. The prognostic significance of Ki-67 has been studied in several subtypes of non-Hodgkin’s lymphoma. Previous retrospective analyses of diffuse large B-cell lymphoma, have reported that the proportion of proliferating cells, marked by Ki-67 expression, correlated with poor treatment outcome and survival [ 22, 23 ]. A recent retrospective analysis of peripheral T-cell lymphoma has shown the prognostic significance of Ki-67 expression; the results of this study suggested Low Ki-67 a prognostic model based on age (>60 years), high LDH, poor performance status and high Ki-67 expression [13]. However, a study by the Nordic Lymphoma Group showed that the expression of Ki-67 was not associated with survival difference in patients with diffuse large B-cell lymphoma [ 24 ]. Although the reason for these inconsistent results regarding the prognostic significance of Ki-67 expression in non-Hodgkin’s lymphoma remains unclear, the following might be possible explanations. First, a different definition for high Ki-67 expression might be related to different results. The arbitrarily defined various cut-offs from 20% to 80% were used for high Ki-67 expression to dichotomize their study populations into high and low Ki-67 expression [ 13, 22–25 ]. Second, lymphoma cells having high proliferative activity, represented by Ki-67 expression, may be more sensitive to chemotherapy than cells with low Ki-67 expression. However, our study used the median value to define high Ki-67 expression so that we could avoid the first problem. Furthermore, the response to treatment was no different depending on the status of Ki-67 expression, thus the second problem may not be applicable to our results. In this study, high Ki-67 expression defined by the median value (65%) was significantly associated with a shorter OS and DFS (P < 0.05), while Ann Arbor stage and IPI failed to predict prognosis of the patients with extranodal NK/T-cell lymphoma. We also found a relationship between high Ki-67 expression and bulky tumors (‡10 cm2). These findings suggest that the extent of Ki-67 expression may reflect the proliferative activity of NK/T-cell lymphoma. In our study, a new definition of bulky tumors was used with the sum of products of the longest diameters and greatest perpendicular diameters (‡10 cm2). Considering that most cases of extranodal NK/T-cell lymphoma occurred in the head and neck, such as in the paranasal sinuses, a previous definition of bulky disease (a lesion with >10 cm diameter) can rarely be applied to this disease entity. In fact, there were no cases having a lesion of >10 cm diameter in our study. Because the patient population of this study was confined to localized disease (stage I and II) with low or low–intermediate IPI risk, our results support the idea that cellular proliferation, represented by Ki-67 expression, can identify patients with extranodal NK/T-cell lymphoma that may show aggressive clinical course and poor treatment outcome. Thus, pre-treatment evaluation of Ki-67 expression may become a marker for predicting prognosis and rendering a more tailored treatment strategy in patients with extranodal NK/T-cell lymphoma. Based on our results, we propose a new prognostic model with high Ki-67 expression and the primary site of involvement. Because high Ki-67 expression showed a significant relationship with the size of primary tumors, this model including Ki-67 expression can reflect the aggressive biological characteristics of extranodal NK/T-cell lymphoma. Furthermore, its prognostic significance can be augmented by the fact that nasal cavity/nasopharynx-originated A 1.0 .8 l a v i rv .6 u S ll rae .4 v O .2 0.0 Low Risk High Risk 0 20 40 Months NK/T-cell lymphomas showed inferior survival outcome compared with upper aerodigestive tract lymphomas. Thus, this new prognostic model may be a useful prognostic index for localized extranodal NK/T-cell lymphoma, nasal type. In conclusion, this study demonstrated the prognostic significance of Ki-67 expression in extranodal NK/T-cell lymphoma, especially localized disease with low and low–intermediate IPI risk. Considering the limited role of the Ann Arbor stage and IPI in extranodal NK/T-cell lymphoma, the assessment of Ki-67 expression and our new prognostic model may become a useful tool for predicting prognosis and deciding upon a therapeutic strategy in patients with localized extranodal NK/T-cell lymphoma, nasal type. acknowledgement The Brain Korea 21 project supported this work. references 1. Jaffe ES , Chan JK , Su IJ et al. Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas . Definitions, differential diagnosis, and epidemiology . Am J Surg Pathol 1996 ; 20 : 103 - 111 . 2. Harris NL , Jaffe ES , Diebold J et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House , Virginia November 1997 . J Clin Oncol 1999 ; 17 : 3835 - 3849 . 3. Aozasa K , Ohsawa M , Tajima K et al. 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Kim, SJ, Kim, BS, Choi, CW, Choi, J, Kim, I, Lee, Y-H, Kim, JS. Ki-67 expression is predictive of prognosis in patients with stage I/II extranodal NK/T-cell lymphoma, nasal type, Annals of Oncology, 2007, 1382-1387, DOI: 10.1093/annonc/mdm183