Correlation of PET/CT Maximal Standardized Uptake Values with Clinicopathologic Parameters of Aggressive Non-Hodgkin’s Lymphoma

Introduction

Non-Hodgkin’s lymphoma (NHL) is the most common hematological malignancy in clinical practice, with numerous biological and clinical heterogeneity subtypes.¹ According to the World Health Organization (WHO) and International Agency for Research on Cancer (ICC) classification, it contains many biological and clinical heterogeneous subtypes, mainly divided into B-cell lymphoma and T-cell lymphoma.^2,3 Although NHL usually manifests as aggressive spreading disease or rapidly growing mass, with the characteristics of multicentric origin and long-distance spread, not all patients have a poor prognosis.⁴ Taking diffuse large B-cell lymphoma (DLBCL) treated with CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) as an example, about 60% of patients can be cured by first-line treatment. However, there are still some patients who have resistance to radiotherapy, chemotherapy and immunotherapy, which affects their lives and health.⁵ Hematopoietic stem cell transplantation is one of the standard treatments for patients with relapsed or refractory disease after chemotherapy. However, due to potential comorbidities and chemotherapy-resistant diseases, about 40% of patients may not be suitable for hematopoietic stem cell transplantation, and about 50% of patients who receive this treatment may relapse.⁶ Therefore, early and accurate diagnosis and appropriate treatment are very important to improve the prognosis of patients with NHL.

Positron emission tomography (PET) / Computed tomography (CT) scanning imaging combines both PET and CT techniques. Imaging that combines metabolic abnormalities and tumor morphological changes plays an important role in the diagnosis, staging, efficacy monitoring, and outcome prediction of various cancers.⁷ Standardized uptake value Maximum (SUV_max) is the most widely analyzed semi quantitative parameter in PET/CT. Research has found that SUV can reflect changes in glucose metabolism and proliferation activity of tumor cells.⁸ However, due to differences in individual patient situations, different variables may have an impact on the standardization of measurements.⁹

In this study, 128 patients with NHL treated in our hospital were selected as study subjects. We investigated the correlation between PET/ CT SUV_max with the clinicopathologic parameters of NHL and the diagnostic value of PET/CT SUV_max, aiming to provide reference for accurately assessing the invasiveness of NHL and evaluating the prognosis.

Materials and Methods

General Materials

A total of 128 patients with NHL treated in our hospital from June 2021 to May 2024 were retrospectively selected as the research objects. In order to reduce research bias, only patients with DLBCL and follicular lymphoma (FL) were included in this study. No patients with FL transformed to DLBCL were screened. The inclusion process was shown in Figure 1. Inclusion criteria: (1) All patients met the guidelines for the diagnosis and treatment of lymphoma,¹⁰ and had been diagnosed through pathological testing. (2) All patients had complete clinical data. (3) All patients underwent PET/CT SUV_max examination. Exclusion criteria: (1) Patients with Hodgkin’s lymphoma; (2) Patients with hepatitis B, hepatitis C, cirrhosis or liver injury; (3) Patients who had received previous relevant treatment for NHL in the past. This study was ratified by the Ethics Committee of our hospital.

Figure 1 Process diagram for patient inclusion.

PET/CT Detection

The PET/CT examination was conducted using the Discovery 710 Clarity scanner (GE Healthcare, USA). 18F-FDG was synthesized by PETtrace cyclotron and Siemens Explora FDG4 chemical synthesis module, with a radiochemical purity of not less than 95%. The patients should fast for at least 6 hours before the examination. If blood glucose was lower than 6.1 mmol/L (non-diabetes patients) or 11.1 mmol/L (diabetes patients), the injection dose should be set to 3.7 MBq/kg. After 1 hour of intravenous injection, CT (parameter settings were listed as follows: voltage 120 kV, current intensity 40 mA, layer thickness 5 mm, interval 5 mm) and PET (parameter settings were listed as follows: 3D mode, 2 minutes/bed, layer thickness 4 mm. The brain scanning ranged from the top of the skull to the plane of the mandible, and the body scanning ranged from the base of the skull to the proximal femur) scanning were performed. Data analysis was conducted by two or more experienced diagnostic physicians who were capable of independently reading images. Visual and semi quantitative analysis methods were used to analyze and interpret images. A circular Region of interest (ROI) was drawn on PET-CT slices registered in the axial, coronal, or sagittal planes. SUV_max was calculated using the following standard formula and could be adjusted according to body weight: SUV_max =average ROI activity (MBq/mL) / [injection dose (MBq)/body weight (kg)].

Collection of Clinical Pathological Parameters

Clinical and pathological parameters of patients were collected, including the age (≤ 55 years, >55 years), gender, tumor size (≤ 2 cm, >2 cm), bone marrow infiltration, clinical staging (Stage I + Stage II, Stage III + Stage IV), International Prognostic Index (IPI) (≤ 3 points, >3 points), B symptoms, globulin (≤ 19 g/L, >19 g/L), albumin (≤ 40 g/L, >40 g/L), ferritin (≤ 390 ng/mL, >390 ng/mL), β2-microglobulin (β2-MG) (≤ 2.6 mg/L,>2.6 mg/L), lactate dehydrogenase (LDH) (≤ 245 U/L, >245 U/L), cell proliferation nuclear antigen-67 (the Ki-67) (≤ 30%, >30%), etc.

Detection Method

The levels of β2-MG and LDH were detected by enzyme-linked immunosorbent assay (ELISA), and the level of Ki-67 was detected by immunohistochemistry. The specific operation was carried out according to the relevant kit instructions.

Malignant Diagnosis

Given the aggressive course of mantle-cell lymphoma, the different treatment options for T-cell NHL and the highly variable disease course, only 74 cases of DLBCL representing aggressive NHL, and 54 cases of follicular NHL, were included in this study to reduce study bias. According to the results of pathological examination, the patients were divided into aggressive group (DLBCL cases) and indolent group (follicular NHL cases).

Correlation Analysis

The correlation between PET/CT SUV_max and clinical pathological parameters was analyzed through Pearson correlation test. The clinical pathological parameters taken for analysis were the indicators with significant differences in Table 1.

Table 1 The Relationship Between PET/CT SUVmax and Clinical Data ()

Diagnostic Value Analysis

Establish ROC curves were established to analyze the diagnostic value of PET/CT SUV_max, β2-MG, LDH and Ki-67 alone and in combination for invasive NHL.

Statistical Analysis

Statistical analysis was conducted using SPSS 23.0. The measurement data that conformed to the normal distribution were presented as mean ± standard deviation, and independent sample t-test was used for inter group comparison. The correlation between PET/CT SUV_max and clinical pathological parameters was analyzed using Pearson correlation test. The diagnostic value of combined detection by PET/CT SUV_max, β2-MG, LDH, and Ki-67 for invasive NHL was analyzed using ROC curve analysis. The statistical test level was set at P<0.05.

Results

The Relationship between PET/CT SUV_max and Clinical Data

PET/CT SUV_max levels were not associated with gender, age, clinical stage, albumin, ferritin, globulin, IPI score, and B symptoms (P>0.05). PET/CT SUV_max levels increased significantly in aggressive NHL patients with the increase of β2-MG (t=7.479), LDH (t=5.625), Ki-67 (t=14.056), tumor size (t=14.113) and bone marrow infiltration (t=6.659) (P<0.05, Table 1).

The Correlation between PET/CT SUV_max and Clinical Pathological Parameters

Pearson correlation analysis revealed that PET/CT SUV_max levels were significantly positively correlated with tumor size (r=0.416), bone marrow infiltration (r=0.308), and the levels of β2-MG (r=0.314), LDH (r=0.552), and Ki-67 (r=0.468) (P<0.05, Table 2 and Figure 2).

Table 2 The Correlation Between PET/CT SUVmax and Clinical Pathological Parameters

Figure 2 The correlation between PET/CT SUVmax and clinical pathological parameters. (A) The correlation between PET/CT SUVmax and tumor size; (B) The correlation between PET/CT SUVmax and bone marrow infiltration; (C) The correlation between PET/CT SUVmax and β2-MG; (D) The correlation between PET/CT SUVmax and LDH; (E) The correlation between PET/CT SUVmax and Ki-67.

The Linear-Regression Analysis

Linear regression analysis was performed with tumor size, bone marrow infiltration (yes = 1, no = 0), β2-MG, LDH and Ki-67 levels as independent variables and PET/CTSUV_max as dependent variable. The results showed that the regression equation between tumor size and PET/CTSUV_max was Y=2.15X1+5.2 (X1 was tumor size, Y was the predicted value of PET/CTSUV_max), and the regression coefficient of 2.15 was statistically significant (P<0.05). The regression equation between bone marrow infiltration and PET/CTSUV_max was Y= 3.5 X2+10.5 (X2 was bone marrow infiltration), and the regression coefficient 3.5 was statistically significant (P<0.05). The regression equation between β2-MG and PET/CTSUV_max was Y=1.8X3+8.3 (X3 was the level of β2-MG), and the regression coefficient 1.8 was statistically significant (P<0.05). The regression equation between LDH and PET/CTSUV_max was Y=2.5X4+12.2 (X4 was LDH level), and the regression coefficient 2.5 was statistically significant (P<0.05). The regression equation between Ki-67 and PET/CTSUV_max was Y=2.3X5+9.5 (X5 was the level of Ki-67), and the regression coefficient 2.3 was statistically significant (P<0.05).

Analysis of PET/CT SUV_max, β2-MG, LDH, and Ki-67 Levels in Patients with Different Degrees of Malignancy

Compared with the inert group, the invasive group had much higher levels of PET/CT SUV _max (t=15.334) and serum β2-MG (t=8.352), LDH (t=13.278), and Ki-67 (t=22.559) (P<0.05) (Table 3).

Table 3 Analysis of PET/CT SUVmax, β2-MG, LDH and Ki-67 Levels in Patients with Different Degrees of Malignancy ()

ROC Curve Analysis

ROC curve analysis confirmed that the AUCs of PET/CT SUV _max, β2-MG, LDH, and Ki-67 for the diagnosis of invasive NHL were 0.786, 0.805, 0.851 and 0.830, respectively. The combined detection of the four indicators had an AUC of 0.920, specificity of 82.43%, sensitivity of 96.30%, and Jordan index of 0.787. The combined detection had higher diagnostic value for invasive NHL (Table 4 and Figure 3).

Table 4 Diagnostic Value of PET/CT SUVmax, β2-MG, LDH and Ki-67 for Invasive NHL

Figure 3 ROC curve analysis of PET/CT SUVmax, β2-MG, LDH, and Ki-67 in the diagnosis of invasive NHL.

Discussion

NHL is a malignant tumor originating from the lymphatic system. Radiochemotherapy and immunotherapy are typical treatment methods. However, approximately 20% to 30% of patients may develop resistance to the aforementioned treatments, affecting their life and health.¹ NHL typically appears in an invasive or inert form, with invasive patients having a lower 5-year survival rate and a poorer prognosis.¹¹ Therefore, early diagnosis and selection of appropriate treatment options are of great significance for improving the prognosis of NHL patients.

At present, PET/CT imaging has become the mainstream clinical imaging tool for staging, treatment evaluation, and follow-up evaluation of lymphoma patients. PET/CT imaging not only provides high-resolution anatomical information, but also information about the metabolic activity of lesions.¹² PET/CT SUV_max is the ratio of the radioactive activity of the imaging agent taken up by the local lesion to the total injected dose of radioactive activity. In recent years, there has been some controversy over the factors related to PET/CT SUV_max in lymphoma. Patients with FL in different stages had different SUV_max, and high SUV_max may be associated with more advanced diseases.¹³ There are also studies suggesting that high SUV_max are often associated with poorer prognosis. For example, patients with high SUV_max of inert lymphoma are commonly accompanied by shorter progression free survival (PFS) and overall survival (OS), leading to shorter and higher mortality rates.¹⁴ A study has found that PET/CT SUV_max is significantly correlated with the prognosis of NHL patients. The higher the SUV_max is, the greater the possibility of invasion is, and the poorer the prognosis of the patient is.¹⁵ In this study, it was found that PET/CT SUV_max levels were significantly positively correlated with tumor size and bone marrow infiltration. Previous studies have found that high levels of circulating tumor cells and large volume lesions may be independent risk factors for B-cell malignancy.¹⁶ Larger tumor volume accompanied by more neovascularization and abundant blood supply can promote the development of tumor malignancy and enhanced metabolism of lesion tissue, leading to an increase in PET/CT SUV_max levels.¹⁷ Bone marrow is the most common site of extranodal involvement in lymphoma patients. Thus, the bone marrow status is a key step in evaluating the initial examination of lymphoma patients and can provide key information for treatment decision-making. PET/CT detection confirmed that patients with bone marrow infiltration had significantly lower survival time than those without bone marrow infiltration. Therefore, PET/CT can be used to evaluate the prognosis of patients with bone marrow infiltration.¹³ According to reports, the sensitivity and specificity of PET/CT in diagnosing bone marrow infiltration in invasive NHL are much higher than those in inert NHL.¹⁸ In the study of follicular lymphoma, it was found that PET/CT SUV_max levels were markedly higher in patients with bone marrow involvement than in unaffected patients,¹⁹ which was similar to the results of this study. In summary, understanding the relationship between PET/CT SUV_max with tumor size and bone marrow infiltration is beneficial for improving lesion detection rate.

In addition, our present study found that PET/CT SUV_max was closely related to levels of β 2-MG, LDH, and Ki-67. The combined detection could effectively evaluate the invasiveness of patients with invasive NHL. A study has found that higher levels of β2-MG may indeed be related to MHC-I. MHC-I deficiency is more common in cancer cells, which may help cancer cells evade immune responses and progress to metastasis. It can be seen that β2-MG levels may be one of the indicators reflecting tumor cell proliferation activity.²⁰ LDH has become an important prognostic biomarker for tumor diseases, and serum LDH levels are significantly negatively correlated with the survival rate of lymphoma patients. The diagnostic value of PET/CT SUV_max combined with LDH in NHL invasiveness is higher than that of LDH alone, with an AUC of 0.831, sensitivity and specificity of 63.10% and 80.00%, respectively.²¹ In this study, the combined detection of multiple indicators including PET/CT SUV_max, β2-MG, LDH, and Ki-67 showed a diagnostic AUC of 0.920, specificity of 82.43%, and sensitivity of 96.30%, which was higher than the combined diagnosis of PET/CT SUV_max and LDH, further demonstrating the accuracy of the combination of various indicators in this study. Ki-67 is a nuclear protein related to the cell cycle, expressed in all the stages except the resting phase of cell division. Ki-67 reflects the rate of tumor cell proliferation, which is closely related to the ability of tumor cell infiltration, metastasis, and implantation.²² Previous studies have found that hepatocellular carcinoma patients with Ki-67 positive lesions have stronger FDG uptake ability.²³ The stronger the ability of tumor tissue to uptake FDG is, the larger the SUV is, and the stronger the diagnostic ability for NHL invasiveness is. Combined detection using ET/CT SUV_max, β2-MG, LDH, and Ki-67 levels is beneficial for clarifying the patient’s condition and conducting timely intervention and treatment.

Conclusion

In general, this study confirmed that PET/CT SUV_max was significantly correlated with tumor size, bone marrow infiltration, β2-MG, LDH, Ki-67 and other clinicopathological parameters. The combined detection of these indicators had high value in the diagnosis of aggressive NHL, which provided a strong basis for clinical diagnosis. In this study, patients with DLBCL and FL were selected as the study subjects, which reduced the research bias caused by the diversity of histological types and made the results more reliable. However, NHL also includes other histological types. Follow-up studies can further expand the sample coverage to explore the relationship between PET/CT SUV_max and clinicopathological parameters in different histological types and its diagnostic value.

However, this study has some limitations due to its small sample size and single-center study. Further studies with larger sample size and multicenter studies are needed to further verify the results of this study, so as to evaluate aggressive NHL more accurately and provide more reliable guidance for the treatment and prognosis of patients.