Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2019  |  Volume : 15  |  Issue : 7  |  Page : 1581--1588

Correlations between maximum standardized uptake value measured via 18F-fluorodeoxyglucose positron emission tomography/computed tomography and clinical variables and biochemical indicators in adult lymphoma


Hongling Li1, Xiaohuan Wang2, Lingfang Zhang2, Xuemei Yi2, Yujie Qiao2, Qianqian Jin2,  
1 Lanzhou University; Department of Oncology, Gansu Provincial Hospital, Lanzhou, Gansu, China
2 Department of Oncology, Gansu Provincial Hospital, Lanzhou, Gansu, China

Correspondence Address:
Dr. Hongling Li
Lanzhou University, Lanzhou 730000, Gansu; Department of Oncology, Gansu Provincial Hospital, 204 West Donggang Road, Lanzhou 730000, Gansu
China

Abstract

Objectives: The aim of the current study was to investigate whether the maximum standardized uptake value (SUVmax) measured by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) could discriminate between aggressive and indolent non-Hodgkin lymphomas (NHLs) and correlations between the SUVmax and clinical variables and serum biochemical indicators in adult lymphoma. Methods: A total of 103 patients with lymphoma confirmed by biopsy, pretreatment 18F-FDG PET/CT scans, and a complete medical record were retrospectively enrolled in the study. Clinical variables that were evaluated included stage, pathological subtype, International Prognostic Index (IPI) score, and Ki-67 index, as well as serum biochemical indicators (e.g., lactate dehydrogenase [LDH] and erythrocyte sedimentation rate [ESR]) and metabolic parameters (e.g., SUVmax of the biopsy site on PET/CT). Correlations between SUVmax and clinical variables and serum biochemical indicators were investigated. Results: Of the 103 patients, 84 had NHL and 19 had Hodgkin lymphoma. The area under the receiver operating characteristic curve for examining the accuracy of SUVmax with regard to distinguishing between aggressive and indolent NHLs was 0.94 (95% confidence interval: 0.89–0.99), suggesting that SUVmax was a useful predictor of diagnosis. A cutoff value of 8.5 yielded a sensitivity of 76.3% and specificity of 92.0%. The SUVmax mean ± standard deviation of NHL (9.8 ± 6.0, range: 1.8–28.1) was higher than that of HL (7.5 ± 2.8, range: 3.5–13.9) (P = 0.016), but there was no statistically significant difference in SUVmax between NHL and HL (P > 0.05). SUVmax of the biopsy site was strongly positively correlated with Ki-67 index (r = 0.813, P < 0.001) and moderately positively correlated with IPI score (r = 0.332, P = 0.002), but it was not significantly correlated with clinical stage, LDH, or ESR (P > 0.05). Conclusions: 18F-FDG PET/CT may yield reliable measurements of tumor proliferation, and an SUVmax >8.5 may distinguish between aggressive and indolent NHLs. In adults with newly diagnosed lymphoma, SUVmax correlates with Ki-67 index and IPI score.



How to cite this article:
Li H, Wang X, Zhang L, Yi X, Qiao Y, Jin Q. Correlations between maximum standardized uptake value measured via 18F-fluorodeoxyglucose positron emission tomography/computed tomography and clinical variables and biochemical indicators in adult lymphoma.J Can Res Ther 2019;15:1581-1588


How to cite this URL:
Li H, Wang X, Zhang L, Yi X, Qiao Y, Jin Q. Correlations between maximum standardized uptake value measured via 18F-fluorodeoxyglucose positron emission tomography/computed tomography and clinical variables and biochemical indicators in adult lymphoma. J Can Res Ther [serial online] 2019 [cited 2020 Jul 7 ];15:1581-1588
Available from: http://www.cancerjournal.net/text.asp?2019/15/7/1581/275563


Full Text



 Introduction



Malignant lymphoma originates from cells of the lymphatic system and includes multiple inducing factors, diverse clinical manifestations, and immunohistochemical features.[1] Lymphomas vary in clinical evolution and response to treatment and are classified as Hodgkin lymphoma (HL) and non-HL (NHL). The prognostic factors of NHL have been classified into three major categories: patient related (age, performance status, and B symptoms), disease related (number of nodal and extranodal sites, tumor stage, and tumor size), and biologic measures including serum hemoglobin, β2-microglobulin, and lactate dehydrogenase (LDH).[2] The prognoses of different pathological subtypes are very different, and even the prognoses associated with different cases of the same pathological lymphoma type can vary markedly.

Thus far,18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and the maximum standardized uptake value (SUVmax) have been widely used for the diagnosis and initial staging of various malignant diseases,[3],[4],[5],[6] as well as for the evaluation of therapeutic responses.[7] Fortunately,18F-FDG PET/CT is gaining popularity for evaluating patients with lymphoma [8],[9],[10],[11] and has proven to be more sensitive and specific than contrast-enhanced CT [12] and magnetic resonance imaging [13] for evaluating nodal and extranodal lymphomatous involvement (e.g., bone marrow malignant infiltration). The SUVmax, which is a semi-quantitative index of 18F-FDG concentration in tissue, has been used for the diagnosis and evaluation of treatment effectiveness in lymphoma. High 18F-FDG uptake indicates aggressive NHL, and lower 18F-FDG uptake is a sign of tumor response to therapy.[14] In addition, SUVmax correlates with histological grade in follicular lymphoma (FL)/high-grade B-cell lymphoma, Ki-67 index, and LDH.[15] Moreover, Ki-67 index correlates with histological grade and clinical aggressiveness.

Several studies have reported that SUVmax was significantly correlated with risk as determined by the International Prognostic Index (IPI), tumor burden, and the presence of extranodal involvement in FL and/or diffuse large B-cell lymphoma (DLBCL).[16],[17] In one study, SUVmax and LDH were significantly higher in the DLBCL group than in the FL group (P = 0.004 and 0.007, respectively).[18] However, in another study investigating the diagnostic role of 18F-FDG PET/CT for FL with gastrointestinal involvement, there were no significant differences in Ann Arbor stage (P > 0.05), LDH (P > 0.05), or IPI risk (P > 0.05) between 18F-FDG-negative and 18F-FDG-positive groups,[19] and this is in accordance with results reported by Akkas and Vural.[16] Most of the previous studies have focused on the utilization of SUVmax and/or clinical variables or serum indicators in a single lymphoma, where some SUVs did not match the site of biopsy, and conclusions have not been consistent. The potential usefulness of SUVmax in lymphoma and the significance of correlations between SUVmax and various indicators are currently unknown. The current study investigated these aspects of SUVmax of the biopsy site in adult lymphoma patients, including cases of HL and various pathological subtypes of NHL, and analyzed direct relationships between SUVmax of the biopsy site and several important parameters.

The primary aim of the study was to investigate whether SUVmax measured via 18F-FDG PET/CT facilitated discrimination between aggressive NHL and indolent NHL. An additional aim was to investigate correlations between SUVmax of the biopsy site and clinical variables and serum biochemical indicators in adult lymphoma.

 Materials and Methods



Patients

We retrospectively analyzed the medical records of patients with malignant lymphoma treated at Gansu Provincial Hospital in Western China. One hundred and three lymphoma patients who underwent pretreatment 18F-FDG PET/CT examinations from January 2011 to December 2016 were included in the study. Patients were eligible for inclusion if they had (1) been newly diagnosed with lymphoma by biopsy but were not receiving therapy; (2) received a whole-body 18F-FDG PET/CT for pretreatment staging; (3) received complete pretreatment evaluation including history, physical examination, and the standard laboratory tests for erythrocyte sedimentation rate (ESR) and LDH; and (4) had had biopsy samples evaluated via immunohistochemical staining to determine Ki-67 expression. Patients were excluded if they (1) were aged <18 years; (2) had incomplete clinical data; or (3) had yielded negative pathology results. Patients were staged in accordance with the Ann Arbor staging criteria. Pathology results were reviewed by expert pathologists and classified in accordance with the WHO/Revised European-American Lymphoma classification of lymphoid neoplasms. All patients provided written informed consent to undergo biopsy before the invasive examination. In addition, the committee of Gansu Provincial Hospital approved the study, and all patients gave written informed consent to be included in the study.

General information

The retrospectively collected data included sex, age at lymphoma diagnosis, Ki-67 index, LDH, ESR, clinical stage, pathological subtype, IPI score, and SUVmax of the biopsy site on initial PET/CT. Elevated LDH was defined as >245 U/L (our institution's upper normal threshold), and elevated ESR was defined as >20 mm/h (our institution's upper normal threshold). Ki-67 staining was performed to estimate the expression rate. After staining a 10% neutral formaldehyde-fixed paraffin-embedded section of a biopsy specimen with a mouse anti-Ki-67 antibody (bsm-33070M; Bioss, Beijing, China), hematoxylin and eosin (Bioss, Beijing, China) were used for immunohistochemical staining in accordance with the manufacturer's instructions. 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 high-power magnification fields. Specimens were reviewed by two pathologists with extensive experience who were blinded to the 18F-FDG PET/CT results and clinical presentation data. All authors had no access to information that could identify individual participants during or after data collection.

18F-fluorodeoxyglucose positron emission tomography/computed tomography image acquisition

18F-FDG PET/CT (Discovery STE 16, General Electric Healthcare, Fairfield, CT, USA) scans were performed to further assess the nature of liver abnormalities and to detect other abnormal abdominal lesions. All patients were asked to fast for 6 h prior to the study, and their blood glucose levels were confirmed to be <8.0 mmol/L. The standard studies were performed 1 h following intravenous administration of 3.7–5.55 MBq/kg of 18F-FDG; during that 1-h period, patients were asked to rest quietly to avoid muscular tracer accumulation and to drink water (800–1000 mL) to dilate the gastrointestinal tract. A CT scan without injection of iodinated contrast agent was performed from the top level of the skull to the upper thighs, with the following technical parameters: 140 kV, 110 mA, 0.8 s/rotation, pitch of 1.75:1, FOV 50 cm, and slice thickness of 3.75 mm. This was followed immediately by acquisition of PET data in the same anatomic locations acquired in three-dimensional mode with 1.5–2 min/bed position. The acquired data were reconstructed using an iterative reconstruction and CT-based attenuation correction method. The parameter of SUVmax was recorded. In order to more accurately study the relationships among Ki-67 index of biopsy samples, pathological subtype, and SUVmax, we defined the SUVmax as the maximum SUV value at the biopsy site within the target volume of lymphoma; this ensured that the FDG uptake measurement matched the site of biopsy. All images were interpreted independently by two nuclear physicians with extensive experience with PET/CT. Any discrepancies in diagnosis among the readers were resolved by consensus.

Statistical analysis

Statistical analyses were performed using SPSS 18.0 (SPSS Inc., Chicago, IL, USA) software. Continuous data were expressed as mean ± standard deviation (SD), and quantitative values were expressed as numbers, ranges, and/or percentages. Receiver operating characteristic (ROC) curves of SUVmax and Ki-67 index were used for estimating the accuracy of predicting aggressive histological subtype. Student's t-test was used to analyze differences between two groups, and one-way analysis of variance was used to analyze data derived from multiple groups. Correlations between SUVmax and clinical stage, IPI index, Ki-67, LDH, and ESR were calculated using the Spearman's rank correlation test. Correlations were considered relevant when r > 0 and statistically significant when P < 0.05.

 Results



Patient characteristics

There were 103 patients enrolled in the study: 54 men (52.4%) and 49 women (47.6%), with a mean age of 51.9 ± 15.6 years (range: 18–96 years). Among these patients, 19 (18.4%) were diagnosed with HL and the other 84 (81.6%) were diagnosed with NHL. Subtypes of HL were mixed cellularity HL (n = 14, 73.6%), nodular sclerosis HL (n = 3, 15.8%), lymphocyte-rich HL (n = 1, 5.3%), and lymphocyte-depleted HL (n = 1, 5.3%). NHL included DLBCL (n = 38, 36.9%), natural killer-T-cell lymphoma (NK-TL; n = 12, 11.8%), anaplastic large-cell lymphoma (ALCL; n = 6, 5.8%), small lymphocytic lymphoma (SLL; n = 6, 5.8%), FL (n = 6, 5.8%), peripheral T-cell lymphoma (PTCL; n = 8, 7.8%), T-cell lymphoblastic lymphoma (T-LBL; n = 3, 2.9%), marginal zone lymphoma (MZL; n = 3, 2.9%), and mantle cell lymphoma (MCL; n = 2, 1.9%). [Table 1] shows that 52 (50.5%) of the 103 patients were at clinical Stage I–II and 51 (49.5%) were at Stage III–IV. With respect to IPI scoring of 84 NHL patients, 17 (20.2%) were high risk, 30 (35.7%) were intermediate risk, and the remaining 37 (44.1%) were low risk. Forty-seven patients (45.6%) had elevated LDH and 66 (64.1%) had abnormal ESR. With regard to the Ki-67 index of the biopsy, 50 patients (48.5%) were ≥60% and the remaining 53 (51.5%) were <60%.{Table 1}

Maximum standardized uptake value in aggressive and indolent non-Hodgkin lymphomas

SUVmax data were available from all 103 patients, and the SUVmax mean ± SD was 9.4 ± 5.6 (range: 1.8–28.1). The SUVmax mean ± SD of NHL (9.8 ± 6.0, range: 1.8–28.1) was higher than that of HL (7.5 ± 2.8, range: 3.5–13.9) (P = 0.016), whereas there was no correlation between NHL and HL in terms of SUVmax (r = 0.134, P = 0.178) [Table 2]. Box plotting of SUVmax by histology subtypes of NHL was performed [Figure 1]. Within the histological NHL subtypes, the collective SUVmax mean ± SD of DLBCL, NK-TL, ALCL, and T-LBL (12.0 ± 5.7) was higher than that of SLL, FL, PTCL, MZL, and MCL (4.6 ± 2.1) (P < 0.001).{Table 2}{Figure 1}

ROC curve analysis was used to examine the accuracy of SUVmax for distinguishing between aggressive NHL and indolent NHL. The estimated area under the ROC curve was 0.94 (95% confidence interval: 0.89–0.99), suggesting that SUVmax was a useful predictor of diagnosis. We used various cutoff values for SUVmax to obtain a reasonable balance of sensitivity and specificity; an SUVmax of 8.5 yielded a sensitivity of 76.3% and specificity of 92.0% [Figure 2].{Figure 2}

Correlations between maximum standardized uptake value and clinical features

Correlations between SUVmax and clinical stage and IPI score are shown in [Table 2]. There was no significant correlation between SUVmax and stage (r = 0.182, P = 0.066), but there was a moderate correlation between SUVmax and the IPI score (r = 0.332, P = 0.002). The high-risk group differed significantly from the intermediate-risk group (P = 0.004) and the low-risk group (P < 0.001), but there was no significant difference between the intermediate-risk group and the low-risk group (P = 0.485).

Correlations between maximum standardized uptake value and Ki-67 and serum biochemical indicators

The Ki-67 index values of tissues taken by biopsy ranged from 8% to 95%, mean ± SD = 57% ± 25%. The area under the ROC curve was 0.93 (95% confidence interval: 0.88–0.99, P < 0.001) [Figure 3]; the sensitivity and specificity of a Ki-67 index of 42.5% were 93.2% and 76.0%, respectively. There was a strong correlation between SUVmax and Ki-67 index. Correlations between SUVmax of the biopsy site and Ki-67 index that reached statistical significance are shown in [Table 2] and [Figure 4]. SUVmax of the biopsy site was significantly positively correlated with Ki-67 index (r = 0.813, P < 0.001) [Table 2] and [Figure 4]a, [Figure 4]b but not with LDH (r = 0.091, P = 0.362) [Table 2] or ESR (r = −0.069, P = 0.488) [Table 2].{Figure 3}{Figure 4}

 Discussion



18F-FDG PET/CT is now the imaging modality of choice for staging, evaluating treatment response, and follow-up in HL and NHL. Strong evidence from a growing number of studies suggests that SUVmax is highly positively correlated with tumor aggressiveness and a worse prognosis.[2],[20],[21] In a number of previous studies, aggressive NHL has exhibited higher 18F-FDG uptake than indolent lymphoma.[22],[23] This is consistent with the results of the current study, in which within the subtypes of NHL histology, the collective mean SUVmax of DLBCL, NK-TL, ALCL, and T-LBL was higher than that of SLL, FL, PTCL, MZL, and MCL (P < 0.001) [Figure 1]. In ROC curve analysis investigating the accuracy of SUVmax for distinguishing between aggressive NHL and indolent NHL, the area under the curve was 0.94 (95% confidence interval: 0.89–0.99), and an SUVmax cutoff value of 8.5 yielded a sensitivity of 76.3% and specificity of 92.0% [Figure 2]. Thus, SUVmax >8.5 may indicate aggressive NHL histology. The cutoff value of SUVmax was lower than that of previous studies such as Ngeow et al.,[22] who reported that an SUVmax cutoff value of >10 provided a sensitivity of 91% and specificity of 62%, and Schöder et al.,[23] who reported that an SUVmax cutoff value of 10 yielded a sensitivity of 71% and specificity of 81% with regard to distinguishing between indolent NHL and aggressive NHL. To the best of our knowledge, SUVmax is dependent on body composition, blood glucose level, and 18F-FDG uptake time (e.g., postinjection delay) and is influenced by partial volume effects and the recovery coefficient.[24] Notably, however, the aforementioned previous studies were published approximately 10 years ago; medical technology has improved significantly, and more research is available regarding lymphoma. In our collective opinion, the above reasons may lead to a little difference in a cutoff value of SUVmax.

18F-FDG is a glucose analog that is differentially taken up by malignant cells, due to their increased glucose metabolism.[25] The sensitivity of malignant tumor detection by 18F-FDG PET/CT depends on the avidity of the tumor cells for FDG; this avidity is strongly linked to tumor aggressiveness and cellularity.[26] However, FDG is not a specific tracer, and uptake may vary based on the patient, the reference background, and the PET/CT system employed.[27] According to a report by Weiler-Sagie et al., DLBCL, FL, NK-TL, ALCL, and Burkitt lymphoma have high 18F-FDG avidity, while SLL and MZL do not.[28] In addition,18F-FDG avidity has a close relationship with the histopathologic subtype of NHL. For example, FL is an indolent NHL but is also an 18F-FDG-avid lymphoma. High 18F-FDG avidity in potentially curable lymphoma subtypes warrants further investigations of the utility of 18F-FDG PET/CT in these diseases at presentation.[28]

Reports suggest that FL has been the most common low-grade lymphoma during the past 10 years worldwide [15] and that it now constitutes approximately 10%–20% of all lymphomas,[29] which are characterized by a variable clinical course. FL, while an indolent NHL, is divided into three histological grades. Grade 3 FL is often treated differently from Grade 1 or Grade 2, as it is believed to be biologically more aggressive. Ngeow et al. suggested that 18F-FDG PET/CT can be reliably used in aggressive B-cell NHL, T-cell NHL, and HL for staging; notably, they showed that high SUVmax (>10) may predict more aggressive B-cell NHL (sensitivity and specificity were 91% and 62%, respectively) and may be used to detect histological transformation of low-grade lymphoma.[22] The observation in the current study that SUVmax >8.5 was predictive of a more aggressive histological component has potential diagnostic implications in clinical settings. In a patient with an indolent lymphoma, sites with SUVmax of >8.5 may suggest the possibility of transformation. In the present study, all six FL patients exhibited low 18F-FDG uptake (mean SUVmax: 3.7 ± 1.4, range: 1.8–5.8), and none had Grade 3 FL or aggressive transformed FL.

Ki-67, a nuclear protein expressed in all active phases of the cell cycle, is associated with cell proliferation and can be used as a cellular marker to investigate cell proliferation activity. It has been shown that Ki-67 index is correlated with clinical presentation in patients with different kinds of cancers, including breast cancer,[30],[31],[32] lung cancer,[33] and lymphoma.[34] A number of studies have demonstrated that Ki-67 proliferation index correlates with SUVmax at the biopsy site and may help to differentiate indolent lymphoma from aggressive lymphoma.[2],[35] In a study of 268 patients with newly diagnosed NHL, Broyde et al.[35] reported that a Ki-67 index cutoff of 70% facilitated discrimination between patients with good and bad prognoses in DLBCL (area under the curve = 0.65, P = 0.004) and a cutoff value of 45% facilitated differentiation between indolent lymphoma and aggressive lymphoma (area under the curve = 0.877, P < 0.001). Watanabe et al.[36] reported a significant correlation between Ki-67 index and SUVmax at the biopsy site in NHL. Concordant with the findings in the current study, there was a significant correlation between Ki-67 index and SUVmax (r = 0.813, P < 0.001). In addition, the present study suggests that a Ki-67 index cutoff of 42.5% can differentiate indolent NHL from aggressive NHL (P < 0.001) with a sensitivity of 93.2% and specificity of 76.0%, and the area under the ROC curve was 0.93 (95% confidence interval: 0.88–0.99) [Figure 3]. Albano et al. recently demonstrated that the SUVmax of a region of interest was correlated with the Ki-67 index in gastric mucosa-associated lymphoid tissue (MALT) lymphoma,[37] whereas it was not correlated with Ki-67 index in extragastric MALT lymphoma [38] or splenic MZL (SMZL).[39] However, Ki-67 index has been correlated with 18F-FDG avidity of gastric MALT lymphoma,[37] extragastric MALT lymphoma,[38] and SMZL.[39] Furthermore, Eryilmaz et al. showed that Ki-67 was not correlated with SUVmax in patients diagnosed with laryngeal cancer.[40] These studies have suggested that the relationship between SUVmax and Ki-67 index may be influenced by lesion location and pathological subtype. Although 18F-FDG has not been characterized as a specific tracer of cellular proliferation, it has recently been reported that 18F-fluorothymidine accumulates in proliferating tissues and malignant tumors and that it may be a selective biomarker of tumor proliferation.[41] In addition, many factors may influence the reliability of SUVmax, such as patient weight and body habits. Therefore, an in-depth study of the relationships between Ki-67 index and SUVmax values is needed.

The IPI, a strong predictor of survival in aggressive NHL, is based on five factors such as age, tumor stage, serum LDH concentration, performance status, and number of sites of extranodal involvement. The FL IPI was introduced in 2004,[42] and several retrospective analyses have confirmed its accuracy as a standard prognostic index for FL.[43],[44] Three risk groups were defined, low, intermediate, and high. In the current study, there was a moderate correlation between the SUVmax and IPI score in NHL (r = 0.332, P = 0.002). This was consistent with the findings of Akkas and Vural, as well as those of Jung. Serum LDH, which represents a quantitative measure of tumor burden and aggressiveness in NHL, is one of the components of the IPI score. However, there was no correlation between serum LDH and SUVmax of the biopsy site in the current study, and ESR was not significantly correlated with SUVmax either.

The limitations of the present study include its retrospective design and the lack of follow-up data. Some of the subgroups were also very small: notably, there were only six FL, three T-LBL, three MZL, and two MCL patients. This may be because some potentially eligible patients were excluded in accordance with the strict inclusion criteria; it may also be related to the relatively rare incidences of some lymphoma subtypes. In addition, our FDG uptake metrics may vary from those obtained in other institutions because of differences in technical and patient-related factors. Larger prospective studies investigating the utilization of SUVmax in combination with Ki-67 index and IPI score in lymphoma and information about progression-free survival and/or overall survival are warranted to confirm our observations.

 Conclusion



The findings of this study highlight the potential usefulness of SUVmax of the biopsy site in pretreatment PET/CT. The results suggest that in adults with newly diagnosed NHL, high SUVmax may facilitate distinguishing between aggressive NHL and indolent NHL in clinical settings and may be used to detect histological transformation of low-grade lymphoma. SUVmax was also significantly correlated with IPI score and Ki-67 index. Further, prospective studies should be performed to ensure the efficient use of SUVmax of the biopsy site in combination with Ki-67 index and IPI score in adults with lymphoma.

Acknowledgment

We would like to thank two pathologists Fenghui Zhao and Yamei Dang in the Department of Pathology of Gansu Provincial Hospital (Lanzhou, China), for their support and help. We would like to thank Editage (www.editage.cn) for English language editing.

Financial support and sponsorship

This study was financed by the Project of Gansu Natural Science Fund (No. 17JR5RA037) and the Project of Gansu Provincial Hospital Research Fund (No. 16GSSY2-7). Professor HL is currently the Chairholder of the projects.

Conflicts of interest

There are no conflicts of interest.

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