Ann Hematol DOI 10.1007/s00277-014-2289-4
ORIGINAL ARTICLE
Evaluation of bone marrow involvement in extranodal NK/T cell lymphoma by FDG-PET/CT Zhiyuan Zhou & Changying Chen & Xiang Li & Zhaoming Li & Xudong Zhang & Yu Chang & Lisha Lu & Yingying Cui & Yaozhen Ma & Mingzhi Zhang
Received: 24 October 2014 / Accepted: 18 December 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Evaluation of bone marrow involvement (BMI) by conventional bone marrow biopsy (BMB) can generate falsenegative results if marrow disease is focal. The sensitivity of 18F-2-fluoro-2-deoxy- D -glucose positron emission tomography/computed tomography (FDG-PET/CT) in assessing BMI in extranodal NK/T cell lymphoma (ENKL) has not been determined. We retrospectively collected clinical data from a series of 55 patients with newly diagnosed ENKL, who have received both FDG-PET/CT and BMB prior to treatment. BMB results were used as reference standard. Twelve patients (21.8 %) were considered positive lymphomatous infiltration by FDG-PET/CT (PET-CT/BM+), and five patients (9 %) were identified positive by BMB (BMB/BM+). There was a discordant result in seven patients who were PETCT/BM+ but BMB/BM−. The sensitivity and specificity of FDG-PET/CT for identifying BMI were 100 and 86 %, respectively. Then, we analyzed the overall survival (OS) and progression-free survival (PFS) of patients who were PET-CT/ BM+ and PET-CT/BM−. The median follow-up time was 16 months (range, 3 to 43 months). PET-CT/BM+ patients possessed worse 2-year OS than PET-CT/BM− patients (84.8 vs 67.9 %, P<0.05). The estimated 2-year PFS for PET-CT/ BM− and PET-CT/BM+ patients were 72.7 and 41.9 % (P<0.05), respectively. However, it was hard to conclude that patients who were PET-CT/BM+ had similar survivals to advanced-stage patients due to the low number of patients who were PET-CT/BM+. In conclusion, FDG-PET/CT can Z. Zhou : Z. Li : X. Zhang : Y. Chang : L. Lu : Y. Cui : Y. Ma : M. Zhang (*) Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450000, China e-mail:
[email protected] C. Chen : X. Li Outpatient Department, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450000, China
complementally detect positive BMI patients missed by BMB in ENKL. The utility of FDG-PET/CT for defining bone marrow status has important prognostic value. Keywords FDG-PET/CT . Bone marrow involvement . Extranodal NK/T cell lymphoma . Bone marrow biopsy
Introduction Extranodal NK/T cell lymphoma (ENKL) is one distinct lymphoid neoplasm characterized by an aggressive course and dismal outcomes. As an Epstein-Barr virus (EBV)-associated lymphoma, ENKL mainly affects Asian and South American populations [1]. Though bone marrow involvement (BMI) in stage I/II nasal ENKL is uncommon, the frequency is higher in disseminated nasal and non-nasal ENKL [2]. Evaluation of bone marrow status is one crucial procedure for initial staging, which directs different treatment strategies and prognoses. For early-stage patients, radiotherapy combined with chemotherapy is recommended. However, high-dose chemotherapy regimens incorporating L-asparaginase, gemcitabine, methotrexate, and ifosfamide are indicated for advanced-stage (stage III/ IV nasal and non-nasal) patients [3]. Moreover, patients with BMI predict high rate of relapse and poor survival [4]. Conventional assessment of bone marrow status is through bone marrow biopsy (BMB) at the iliac crest, which is an invasive operation. In addition, BMB may provide falsenegative results if samples are atypical or lesions are focal [5]. In recent years, 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) has been widely used for accurate staging prior to treatment in lymphoma. FDG-PET/CT not only can detect a focal
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malignant infiltration but also does not give rise to a painful experience [6]. Previous studies have reported the high sensitivity and accuracy of FDG-PET/CT in detecting BMI in Hodgkin lymphoma and non-Hodgkin lymphoma [7, 8]. However, the value of FDG-PET/CT for detecting lymphomatous involvement in the marrow is controversial. Other studies in diffuse large B cell lymphoma (DLBCL) argued that FDG-PET/CT could not substitute routine biopsy [9, 10]. In fact, NK/T cell lymphoma cells are FDG avid. Currently, the utility of FDG-PET/CT in evaluating BMI in ENKL has not been explored, and its prognostic impacts remain unknown. In the present study, we firstly investigated the performance of FDG-PET/CT in detecting BMI in newly diagnosed ENKL and then determined the prognostic value of FDG-PET/CT for bone marrow status stratification.
Germany) was used to obtain PET-CT images. It was required that patients should fast for 6 h or more before he or she received intravenous injection with 18F-FDG (4.4 MBq/kg body weight). Sixty minutes later, CT scan was firstly performed without any contrast materials. Then, patients began to undergo whole-body scanning from the skull base to the foot in five to six bed positions with 2 min per bed position. Acquired PET images were attenuation corrected with lowdose CT data and reconstructed. Two experienced nuclear medicine physicians, who were blind to bone marrow biopsy and other clinical data, re-read the PET/CT images through visual and semiquantitative methods for evaluating marrow disease. Unifocal, multifocal, and diffuse FDG uptake within the skeleton higher than that in the liver was considered positive BMI (PET-CT/BM+). BMI was considered negative if the maximum standard uptake value (SUVmax) in the skeleton was equal to or lower than that in the liver.
Materials and methods BMB for identifying bone marrow involvement Patient population We searched the clinical database in our hospital for eligible patients and collected their clinical records. Between February 2011 and May 2014, 55 newly diagnosed ENKL patients, who received both FDG-PET/CT and BMB prior to therapy, were enrolled in this retrospective study. The diagnosis of ENKL should be pathologically confirmed. Physical examination, blood routine, and serum biochemical tests were all completed for initial staging and prognostic assessment. Patients who received any treatment before FDG-PET/CT or BMB examination were excluded. If the primary data from patients were insufficient, they should be excluded. Patients who underwent BMB beyond 2 weeks of FDG-PET/CT scan were also excluded. Patients with stage I/II nasal ENKL received combined radiotherapy and chemotherapy (DDGP regimen: gemcitabine, pegaspargase, cisplatin, and dexamethasone; VIPD regimen: etoposide, ifosfamide, cisplatin, and dexamethasone). For stage III/IV nasal ENKL and stage I–IV non-nasal ENKL patients, high-dose DDGP regimen or SMILE regimen (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) was given to them. However, four patients received anthracycline-based chemotherapy due to economic reasons. An informed consent was acquired from all patients, and clinical data were collected after approval obtained from the local ethics committee. FDG-PET/CT for identifying bone marrow involvement A high-resolution, high-speed FDG-PET/CT scanner (Biograph 64 True Point, True V, Siemens Healthcare,
Routine biopsy at the unilateral iliac crest was performed for pathological examination in all patients before treatment. If necessary, immunohistochemical stains and flow cytometry were added to define the final diagnosis. Assessment of bone marrow disease was mainly according to pathological reports. Bone marrow involvement was considered positive if lymphoma cells were found in the bone marrow. Statistical analysis The sensitivity and specificity of FDG-PET/CT for identifying BMI were calculated, and BMB results were used as reference standard. Overall survival (OS) was measured from initial treatment until death from any cause or the date of the last follow-up. Progression-free survival (PFS) was measured from initial treatment until the documentation of disease progression or death from any cause. Survival analysis was performed using the Kaplan-Meier method and the log-rank test.
Results Patient characteristics A total of 55 patients with newly diagnosed ENKL were enrolled. Their characteristics are shown in Table 1. The male and female ratio was 37:18, with a male predominance. The median age was 44 years, ranging from 18 to 72 years. Fortyseven patients had primary nasal ENKL disease, with 26 presenting stage I/II and 21 presenting stage III/IV. The other
Ann Hematol Table 1
Patient characteristics (n=55)
Characteristics Sex Male Female Age (years) Median Range Stage I/II nasal ENKL III/IV nasal ENKL I–IV non-nasal ENKL LDH Normal Elevated B symptom Negative Positive IPI 0 1 2 3 4 First-line therapy Combined chemoradiotherapy High-dose chemotherapy Anthracycline-based regimen
Table 2
Number
Percentage
37 18
67.3 32.7 44 18–72
26 21 8
47.3 38.2 14.5
26 29
47.3 52.7
35 20
63.6 36.4
8 13 13 15 6
14.5 23.6 23.6 27.3 10.9
25 26 4
45.5 47.3 7.3
ENKL extranodal NK/T cell lymphoma, LDH lactate dehydrogenase, IPI International Prognostic Index
eight patients had primary lesions in the lung, skin, testis, and intestinal tube. The level of lactate dehydrogenase (LDH) was elevated in 29 cases. B system was observed in 20 patients. The IPI score was 0~2 in 34 patients and 3~4 in 21 patients. Twenty-five patients with stage I/II nasal ENKL received sequential chemotherapy and radiotherapy as first-line therapy. For advanced-stage nasal disease and non-nasal ENKL patients (n=26), four to six cycles of DDGP or SMILE regimens were given to them. However, four patients received anthracycline-based chemotherapy due to economic reasons. Since bone marrow biopsy was used as reference standard for assessing bone marrow status and initial staging, treatment planing was not altered in any patient if there was a discordant result between PET-CT and bone marrow biopsy. PET/CT for detecting bone marrow involvement Bone marrow status was evaluated by both PET-CT and routine biopsy in all patients. The results are summarized in Table 2. Twelve patients were considered PET-CT/BM+, who
Bone marrow status detected by PET-CT and BMB
BMB
BMB/BM+ BMB/BM−
PET-CT PET-CT/BM+
PET-CT/BM−
5 7
0 43
BMB bone marrow involvement, PET-CT/BM+ positive bone marrow involvement detected by PET-CT, PET-CT/BM− negative bone marrow involvement detected by PET/CT, BMB/BM+ positive bone marrow involvement detected by bone marrow biopsy, BMB/BM− negative bone marrow involvement detected by bone marrow biopsy
presented focal or diffuse FDG uptake within the skeleton higher than that in the liver. The SUVmax ranged from 4.2 to 11.9. Among them, five patients were also positive BMI by BMB. Seven patients were BMB/BM− but PET-CT/BM+. The sensitivity and specificity of PET-CT for identifying BMI were 100 and 86 %, respectively.
Prognostic impacts of bone marrow status stratification by PET/CT To investigate the prognostic impacts of bone marrow status defined by PET/CT, we compared the survival curves of patients who were PET-CT/BM+ and PET-CT/BM−. No significant difference was observed for baseline clinical characteristics between group PET-CT/BM− and group PET-CT/ BM+ (Table 3). The median follow-up time was 16 months (range, 3 to 43 months). Patients who were PET-CT/BM+ possessed worse 2-year OS than PET-CT/BM− patients (67.9 vs 84.8 %, P < 0.05; Fig. 1a). Similar results were also Table 3 Comparison of clinical characteristics between PET-CT/BM− and PET-CT/BM+ patients Characteristics
Male:female Median age (years) Elevated LDH Positive B symptom Advanced stagea IPI>2 First-line therapy Combined chemoradiotherapy High-dose chemotherapy Anthracycline-based regimen
PET-CT PET-CT/BM+ (n, %)
PET-CT/BM− (n, %)
8:4 45 7 (58.3 4 (33.3 6 (50.0 5 (41.7
29:14 44 22 (51.2 16 (37.2 23 (53.5 16 (37.2
%) %) %) %)
6 (50 %) 5 (41.7 %) 1 (8.3 %)
%) %) %) %)
19 (44.2 %) 21 (48.8 %) 3 (7.0 %)
LDH lactate dehydrogenase, IPI International Prognostic Index, PET-CT/ BM+ positive bone marrow involvement detected by PET-CT a
Advanced stage: stage III/IV nasal ENKL and non-nasal ENKL
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observed regarding PFS. The estimated 2-year PFS was 41.9 % in PET-CT/BM+ patients, which was significantly lower than that in PET-CT/BM− patients with 72.7 % (Fig. 1b).
Discussion In the present study, we firstly investigated the role of FDGPET/CT in detecting BMI in ENKL. Twelve patients were defined positive marrow involvement by PET/CT. There was a discordant result in seven patients who were PET-CT/BM+ but BMB/BM−. The sensitivity and specificity of FDG-PET/ CT for evaluating bone marrow involvement were 100 and 86 %, respectively. Assessment of bone marrow status is one important procedure of initial staging in ENKL, which directs different treatment strategies. Combined chemotherapy-radiotherapy was recommended for early-stage patients, and high-dose chemotherapy such as SMILE or AspaMetDex regimens is indicated for advanced-stage cases [3, 11]. BMB at the iliac crest is recommended as the standard method for detecting bone marrow disease in the past decades. However, it may provide false-negative results if patients present bone marrow disease in other sites. Patients usually have a painful experience and adverse reactions from this invasive operation [5]. FDG-PET/CT has become a valuable instrument for initial staging in lymphoma as it can detect involved extranodal organs [12]. A series of studies in Hodgkin lymphoma and B cell lymphoma have demonstrated the superiority of PET/ CT to conventional BMB in detecting lymphomatous infiltration. Berthet L [13] reported a higher sensitivity (94 %) and accuracy (98 %) of FDG-PET/CT in detecting BMI in DLBCL in comparison with BMB, which were 24 and 81 %. A meta-analysis on the diagnostic value of PET/CT in evaluating bone marrow involvement in newly diagnosed DLBCL was conducted, which resulted in a pooled sensitivity of 88.7 % and specificity of 99.8 % [14]. Pooled sensitivity
Fig. 1 Overall survival and progression-free survival of patients who were PET-CT/BM− and PET-CT/BM+. The estimated 2-year OS for PET-CT/BM− and PET-CT/BM+ patients were 84.8 and 67.9 %, respectively (a). The estimated 2-year PFS for PET-CT/BM− and PETCT/BM+ patients were 72.7 and 41.9 %, respectively (b)
and specificity of FDG-PET/CT in assessing bone marrow disease in Hodgkin lymphoma were also performed, which were 96.9 and 99.7 %, respectively [15]. However, whether FDG-PET/CT can take the place of BMB in evaluating bone marrow involvement is controversial. Some studies argued that the role of PET/CT in assessing bone marrow involvement was limited [10, 16], and PET/CT can also miss truepositive patients. A workshop at the latest International Conference on Malignant Lymphoma in Lugano agreed to revise criteria for Ann Arbor staging. FDG-PET/CT can replace bone marrow biopsy in newly diagnosed Hodgkin lymphoma. A bone marrow biopsy is no longer indicated if he or she were positive for bone marrow involvement by PET-CT. For patients with DLBCL, routine biopsy should be conducted to exclude mild marrow involvement unless he or she were definitely demonstrated positive by PET/CT. As to other lymphomas including ENKL, bone marrow biopsy is still recommended as a standard method since PET-CT is not sufficient to define bone marrow status. In clinical practice, we are frequently confronted with one problem in ENKL patients: the BMB result is negative but FDG-PET/CT showed higher FDG uptake in the marrow. How do we define the bone marrow status? Currently, there is rare study to determine the diagnostic performance of PET/ CT for detecting BMI in ENKL. Our research shows that PET/ CT can detect true-positive patients missed by BMB, and PET/CT has a complemental value to BMB in identifying bone marrow involvement in ENKL. In recent years, the utility of FDG-PET/CT for accurate staging in ENKL has been recommended [17, 18]. Compared with conventional staging methods, PET/CT reveals more extranodal lesions with high sensitivity [19, 20]. Moreover, PET/CT for staging is of great help to treatment planning. However, the prognostic influences of PET/CT in ENKL have not been well explored. PET parameters such as whole-body metabolic tumor volume (WBMTV) and SUVmax seem to be better predictive factors [21]. Here, we determined the prognostic value of bone marrow status identified by FDG-PET/CT in ENKL. Both estimated
Fig. 2 Overall survival and progression-free survival of patients who were PET-CT/BM+ and advanced-stage patients. The estimated 2-year OS for PET-CT/BM+ and advanced-stage patients were 67.9 and 80.0 %, respectively (a). The estimated 2-year PFS for PET-CT/BM+ and advanced-stage patients were 41.9 and 59.3 %, respectively (b)
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that the 2-year OS and PFS of PET-CT/BM+ patients were lower than those of PET-CT/BM− patients. These data indicated that positive BMI by PET/CT was associated with worse OS and PFS. In addition, we compared the survival curves of PET-CT/BM+ patients with advanced-stage patients. There was no difference in either OS or PFS between these two groups (Fig. 2a, b). These data were in accordance with researches in DLBCL, which demonstrated that bone marrow status evaluated by PET/CT was a better prognostic stratification [22]. This phenomenon could be explained by that some true-positive BMI patients missed by biopsy received lowdose chemotherapy. However, due to the low number of patients who were PET-CT/BM+, it was hard to conclude that PET-CT/BM+ patients had similar survivals to advancedstage patients. What we want to emphasize is that inflammatory activation or myeloid hyperplasia can also lead to higher FDG uptake in the bone marrow [23]. Guided bone marrow biopsy after FDG-PET/CT scan will increase the diagnostic accuracy of malignant infiltration in ENKL. Due to the rarity of ENKL patients and the low frequency of BMI, a large-scale prospective study is expected to define the role of FDG-PET/CT for evaluating bone marrow involvement in ENKL. Acknowledgments This work was supported by the National Natural Science Foundation of China (grant number 81172118). Conflict of interest The authors declare that they have no conflict of interest.
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