Application of 18F-fluorodeoxyglucose positron emission tomography/computerized tomography in mantle cell lymphoma
Shaoxi Yang, Lilan Fu, Meilinur AbuduRxiti, Jianhua Wu, Qiaoyu Wang, Yongde Qin, Xiaoguang Zou and Hongsheng Li
a Department of Nuclear Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang,
b PET Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong and
c Nuclear Medicine Center, The First people’s Hospital of Kashgar, Kashgar, Xinjiang, P.R. China
Abstract
Objective
The study is to investigate the application of 18F-fluorodeoxyglucose (18F-FDG) PET/computerized tomography (CT) for the evaluation of mantle cell lymphoma (MCL).
Methods
We retrospectively analyzed 39 patients who were pathologically diagnosed with MCL and underwent 18F-FDG PET/CT before treatment between August 2007 and August 2018. We compared the clinical information and PET/CT imaging characteristics in different groups based on bone marrow invasion, spleen invasion or International Prognostic Index (IPI) score. We also assessed the efficacy of PET/CT evaluation basing on the follow-up PET CT findings of 21 MCL patients and their biopsies.
Results
Thirty-five patients were stage IV according to the Revised Ann Arbor Staging System. Lymph nodeinvolvement was observed in all 39 cases. The maximum diameter of the affected lymph nodes (4.33 ± 3.09 cm) and maximum standardized uptake value (SUVmax) (8.38± 4.99) was positively correlated (r = 0.486, P = 0.002). Extranodal invasion was identified in 38 patients with MCL, and the SUVmax of extranodal invasion was 7.34 ±3.31. Extranodal invasion was most common in the spleen (25/38) and bone marrow (18/38). The group with bone marrow invasion was more prone to nasopharyngeal, lung and renal invasions (all P < 0.05). The groups with bone marrow invasion or spleen invasion were more likely to have decreased hemoglobin (Hgb) and platelets(all P < 0.01). The IPI high-risk group was more prone to lung involvement, elevated LDH and CRP, and decreased Hgb (all P < 0.05). Among the follow-up of 30 MCL patients, the 2-year progression-free survival and overall survival rates were 73.33 and 87.50%, respectively. PET/CT reexaminations of 21 MCL patients after treatment showed that the sensitivity, specificity, negative predictive value, positive predictive value and accuracy of the efficacy evaluation were 80, 90.91, 88.89, 83.33 and 85.71%, respectively.
Conclusion
18F-FDG PET/CT imaging has important application value in the diagnosis, staging, treatment efficacy assessment and prognosis monitoring of MCL, especially in the systemic assessment of advanced MCL. Nucl Med Commun 41: 477–484 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Introduction
Mantle cell lymphoma (MCL) is a rare B-cell derived non-Hodgkin’s lymphoma (NHL), accounting for 6–8% of NHL. MCL is more common among older males, and the median age of onset is approximately 65 years [1]. Translocation of t (11; 14) (q(13; q32) leads to high expres- sion of Cyclin D1, which is a characteristic marker of MCL [2]. The majority of MCL patients are in advanced stages (stage III or IV) at onset, which are clinically manifested by systemic lymphadenopathy and frequent extranodal involvement (with bone marrow, spleen and gastrointes- tinal tract involvement being the most common) [3,4]. MCL is a unique pathological type whose response to treatment indicates that it is an indolent lymphoma.
Additionally, MCL is highly invasive, progresses rapidly, responds poorly to chemotherapy and is prone to relapse [5,6]. MCL is characterized by both the high aggressive- ness of invasive lymphoma as well as the incurability of indolent lymphoma, and thus accurate MCL diagnosis, staging, monitoring of treatment efficacy and prognosis are extremely important.
Diagnosis of MCL mainly relies on the results of his- topathological and immunohistochemical analyses. Conventional imaging examination methods such as computerized tomography (CT) and MRI are widely used in the diagnosis, staging and treatment efficacy monitoring of MCL, but they have limitations in assess- ing lymph node lesions that are not obviously enlargedand the involvement status of extranodal sites such as the spleen, bone marrow and gastrointestinal tract [3,7]. In recent years, 18F-fluorodeoxyglucose (18F-FDG) PET/ CT has shown unique advantages in the diagnosis, differ- ential diagnosis, staging and evaluation of the prognosis of lymphoma (especially NHL) [8,9], which can make up for the limitations of CT and MRI. However, currently, evidence supporting the routine use of 18F-FDG PET/ CT to evaluate staging and therapeutic efficacy in MCL is insufficient. This study retrospectively analyzed clin- ical and 18F-FDG PET/CT data of 39 pathologically confirmed MCL patients with the aim of further investi- gating the PET/CT characteristics of MCL and its rele- vance to clinical manifestations.
Methods
Patients
This study was approved by the Institutional Review Broad of our hospital. This study recruited 39 patients who were pathologically diagnosed with MCL and underwent 18F-FDG PET/CT examination before treat- ment between August 2007 and August 2018. Their clini- cal information [including age, sex, blood routine, lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), C-reactive protein (CRP) and clinical symptoms], PET/ CT imaging manifestations [including the maximum standardized uptake value (SUVmax) and maximum diameter of the involved lymph nodes, the distribution of invaded extranodal sites and the SUVmax of extran- odal lesions] and the pathological results were collected. Furthermore, the efficacy of PET/CT evaluation is assessed based on the follow-up PET CT findings of 21 MCL patients and their biopsies.
18F-FDG PET/CT imaging and image analysis
A total of seven patients underwent PET/CT scanning using a Discovery LS PET/CT scanner (GE Healthcare, Milwaukee, Wisconsin, USA), and 32 patients under- went scanning using a BiographmCTx scanner (Siemens Medical Systems, Knoxville, Tennessee, USA). 18F-FDG was automatically synthesized by a PETtrace cyclotron (GE) and the 18F-FDG chemical synthesis module (GE) with a radiochemical purity of >95%. Patients in a calm state who had fasted for more than 6 h were intravenously injected with 18F-FDG 270–410 MBq (5.55 MBq·kg−1) through a port according to body weight. After lying down for approximately 1 h in a dark room, the patient under- went PET/CT scanning after urination. PET/CT imaging included CT plain scanning and PET emission scanning from the middle of the thigh to the vertex; the lower limbs were also scanned when necessary. The acquisition parameters of the Discovery LS were as follows: for CT, the voltage was 140 kV, the current was 160 mA, the pitch was 0.75, the tube rotation time was 0.8 s and the layer thickness was 5 mm. PET scanning used two-dimen- sional acquisition for 3 min/bed. The acquisition param- eters of the BiographmCTx were as follows: for CT, thevoltage was 120 kV, the current was automatic mA, the pitch was 0.55, the tube rotation time was 1.0 s, and the layer thickness was 3 mm. PET scanning used 3-dimen- sional acquisition for 2 min/bed. PET reconstruction used the ordered subset expectation maximization method and image attenuation correction using CT scan data. CT images were reconstructed using the standard method with a layer thickness of 4.25 mm for Discovery LS and2.0 mm for BiographmCTx. The PET and CT images were uploaded to the Xeleries and Syngo MMWP work- stations for frame-to-frame image alignment.
After frame-to-frame alignment analysis of the images, the lesions were confirmed by two senior physicians who were highly experienced in PET/CT diagnosis and were combined with the findings of the same CT scanner for comprehensive judgement after excluding physiological18F-FDG uptake. The lesion was positive if the 18F-FDGaccumulation was significantly higher than that of normal liver. A region of interest was outlined along the edge of the lesion with accumulation, and the SUVmax was auto- matically calculated by the workstations.
Statistical analysis
Data were analyzed with the statistical software SPSS
20.0. Quantitative data were described by the mean ± SD for normally distributed data and by the median and inter- quartile range for nonnormally distributed data. Counting data and categorical data were described by the rate or composition ratio. The sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and accuracy of PET/CT evaluation were calculated, all with 95% confidence interval. The independent sample t-test was used for comparisons between two groups that followed a normal distribution, and the Wilcoxon Rank- Sum test was used for comparisons between two groups that did not follow a normal distribution. The χ2 test was used for comparisons of sample rates. The Kaplan–Meier method was used for survival analysis, and the log-rank test was used for univariate survival analysis. Differences with P < 0.05 were considered statistically significant.
Results
Clinical and pathological characteristics of mantle cell lymphoma
Among the 39 MCL patients, 30 were male and nine werefemale, with an average age of 58.5 years (ranging from 42–81 years) and an average disease course of approxi- mately 1 year (1 month to 3 years). For approximately 51.28% of the patients (20/39), the initial symptom was painless progressively enlarging surface masses, followed by gastrointestinal symptoms such as abdominal discom- fort and changes in stool characteristics in approximately 35.90% of the patients (14/39). Three patients had diz- ziness and fatigue, three patients had significant weight loss and two patients had fever. All 39 MCL patients were confirmed by histopathology, the CyclinD1-positiverate was 84.62% (33/39) and the CD20-positive rate was 97.37% (37/38). A total of 38 MCL patients were sub- jected to Ki-67 counting, including 16 patients with Ki-67 of >30% and 22 patients with Ki-67 of ≤30%.
All 39 patients underwent the blood routine examination, in which hemoglobin (Hgb) and platelets (Plt) were all decreased or normal, and patients with decreased Hgb and Plt levels accounted for 74.36% (29/39) and 17.95% (7/39), respectively. White blood cell was elevated in 38.46% (15/39) of patients, reduced in 15.38% (6/39) of patients, and normal in the remaining patients. Prognosis-related indicators (LDH and β2-MG) were examined in 35 and 29 patients, respectively, among whom 42.86% (15/35) had elevated LDH and 96.55% (28/29) had elevated β2-MG. Additionally, inflammatory indicators (CRP, ESR and Ferr) were examined in some patients, among whom 52.00% (13/25) had elevated CRP, 70% (7/10) had elevated ESR and 41.94% (13/31) had elevated ferritin level.
Based on the Revised Ann Arbor Staging System which is a combination of PET/CT, MRI, biopsy, bone mar- row examination, etc, as per Lugano Classification, all 39 MCL patients were stage II or above, including three cases in stage II, one case in stage III and 35 cases in stageIV. A total of 33 patients underwent bone marrow biopsy, and 18 patients were pathologically confirmed with bonemarrow invasion. Our analysis showed that compared to the non-bone marrow invasion group, the bone marrow invasion group was more likely to have reduced Hgb (Z= −2.012, P = 0.000), reduced Plt (Z = −3.180, P = 0.001)and elevated β2-MG (Z = −3.109, P = 0.002). According to the International Prognostic Index (IPI) score, among the 39 MCL patients, 17 patients were in the low-risk group (0–2 points) and 22 patients were in the high-risk group (3–5 points). Compared to the IPI low-risk group, patients in the high-risk group were more likely to have reduced Hgb (Z = −2.399, P = 0.016) and elevated LDH (Z = −2.874, P = 0.04), β2-MG (Z = −2.879, P = 0.04) and CRP (Z = −2.045, P = 0.041).
PET/CT findings
A lesion was positive if the 18F-FDG accumulation was higher than that of the liver. The involved lesions in all 39 MCL patients were 18F-FDG PET/CT positive, with a positive rate of 100%. Multiple lymph nodes were involved in all 39 patients (Fig. 1), and the maximum diameter of involved lymph nodes was 4.33 ± 3.09 cm (ranging from 1.7–14.1 cm). The SUVmax of the involved lymph nodes was 8.38 ± 4.99 (3.3–24.1). Cervical lymph nodes (92.31%, 36/39) were most frequently involved, followed by abdominal lymph nodes (84.62%, 33/39), axillary lymph nodes (82.05%, 32/39), pelvic and inguinal lymph nodes (74.36%, 29/39), mediastinal lymph nodes (71.79%, 28/39) and hilar lymph nodes (38.46%, 15/39). Our analysis showed that the SUVmax of involved lymph nodes was positively correlated with their maxi- mum diameter (r = 0.486, P = 0.002 < 0.01). Among all MCL patients, 13 patients had conglomerate lymph nodes, and two patients showed invasion of adjacent tis- sue by involved lymph nodes. Analysis of patients with and without conglomerate lymph nodes showed that the SUVmax of the involved lymph nodes did not differsignificantly between the two groups (t = −1.079, P = 0.288). Additionally, there were no significant correlations of the SUVmax of involved lymph nodes with the IPI score and bone marrow invasion status (P > 0.05).
A total of 97.43% of MCL patients (38/39) had extran- odal invasion (Fig. 2), and the SUVmax of the extranodal lesions was 7.34 ± 3.31 (2.4–14.3). The spleen (25/38), bone marrow (18/38), parotid gland (17/38) and gastro- intestinal tract (10/38) were among the most common organs with extranodal invasion, followed by the tonsil(8/38), liver (6/38), nasopharynx (5/38), lung (5/38), kid- ney (4/38) and peritoneum (4/38). Our analysis showed that the SUVmax of involved lymph nodes was positively correlated with the SUVmax of extranodal lesions (r = 0.639, P = 0.000) and the SUVmax of involved lymph nodes was significantly higher than that of the extranodal lesions (t = 11.145, P = 0.000). Patients in the IPI high- risk group were more likely to have lung involvement (χ2 = 2.632, P = 0.046) and no significant difference was detected in other extranodal lesions (P > 0.05).
Twenty-five MCL patients had spleen invasion, among whom 24 patients were manifested by spleen diffu- sive lesions and one patient was manifested by multi- ple lesions of the spleen. Analysis based on grouping of whether there was spleen invasion showed that MCL patients with spleen invasion were more likely to have reduced Hgb (Z = −3.902, P = 0.000) and Plt (Z = −2.997, P = 0.003) and increased CRP (Z = −2.785, P = 0.005). Atotal of 18 MCL patients showed bone marrow invasion in PET/CT, and all were diffusely invaded. Bone marrow biopsy confirmed that 18 MCL patients had bone marrow involvement, with an incidence rate of 54.44% (18/33). The sensitivity, specificity, NPV, PPV and accuracy of PET/CT in detecting MCL bone marrow involvement were 77.78% (52–94%), 86.67% (59–98%), 76.47% (50–93%), 87.50% (62–98%) and 81.82% (64–93%), respec-tively. Our analysis showed that MCL patients with bone marrow invasion confirmed by biopsy were more likely to have nasopharyngeal invasion (χ2 = 3.016, P = 0.035), lung invasion (χ2 = 3.016, P = 0.035) and kidney invasion (χ2 = 3.066, P = 0.037) (Fig. 3). PET/CT showed that 10 MCL patients had gastrointestinal invasion, which was most common in the colon (9/10), followed by the small intestine (6/10), rectum (6/10) and stomach (5/10).
Treatments
Thirty-three MCL patients underwent chemotherapy, among whom 11 were treated with R-CHOP, 13 with alternative R-CHOP and R-DHAP, three with hyper- CAVD and four with other chemotherapy plans. Thirty patients were followed up effectively, and the median fol- low-up duration was 6 months (1–88 months). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 73.33 and 87.50%, respectively. And the 5-year OS and PFS were 33.33 and 0%, respectively. Among these patients, 12 cases showed complete remission, eight patients showed partial remission, four cases showed dis- ease progression, four cases showed recurrence and two patients died due to disease progression. A total of 21 MCL patients underwent PET/CT examination after treatment. The results showed that nine of them were PET-positive and 12 were PET-negative. One of them was false-positive, the hypermetabolic lesions in the lung were confirmed to be inflammatory by biopsy. Two cases were false-negative, the bone marrows were involved by biopsy, but without hypermetabolism in PET/CT images.
The sensitivity, specificity, NPV, PPV and accuracy of PET/CT in the evaluation of MCL efficacy were 80% (44–97%), 90.91% (59–100%), 88.89% (52–100%), 83.33%(52–98%) and 85.71% (64–97%), respectively.
Discussion
MCL is a highly invasive form of NHL that is common among older males, and the majority of patients are at an advanced stage when diagnosed [3,10,11]. This study recruited a total of 39 MCL patients, including 30 males (76.92%), with an average age of 58.49 years. The patients with clinical stages of III–IV accounted for approximately 92.31% (36/39), and patients with a high-risk IPI score accounted for approximately 56.42% (22/39).
Retrospective analysis of the PET/CT images of the39 MCL patients acquired before treatment showed that they all had increased metabolism of involved lymph nodes and extranodal lesions. The SUVmax val- ues of the involved lymph nodes and extranodal lesions were 8.38 ± 4.99 (3.3–24.1) and 7.34 ± 3.31 (2.4–14.3),respectively, consistent with previous studies [12,13]. The SUVmax values of the involved lymph nodes and extranodal lesions strongly suggest that MCL is a highly metabolic tumor type that can be recognized by FDG and that 18F-FDG PET/CT imaging can be applied to the staging, diagnosis and evaluation of the prognosis of MCL. In this study, all 39 MCL patients had multiple lymph node invasions, among which 33.33% of patients had conglomerate lymph nodes. Further analysis showed that the SUVmax of the involved lymph nodes was pos- itively correlated with their maximum diameter. This study found that 97.43% of MCL patients had extranodal invasion, which was most common in the spleen (25/38), bone marrow (18/38), parotid gland (17/38) and gastroin- testinal tract (10/38). These results indicate that PET/ CT is highly sensitive in detecting MCL extranodal lesions. We further analyzed the PET/CT characteristics of the 39 MCL patients, as shown in Table 1. There were several features of MCL patients on PET/CT examina- tion. First, multiple lymph nodes were involved and the involved lesions were enlarged obviously. Second, the bone marrow and spleen were mostly diffusely involved with diffusely increased uptake and diffuse enlargement. Third, the affected gastrointestinal tract, lung and other cavity organs were mostly multifocal and hypermeta- bolic. Fourth, the bilateral parotid gland was commonly involved in MCL patients and with high FDG uptake. Although these characteristics are not enough to distin- guish MCL from other malignancies, the combined char- acteristics can be used to indicate disease involvement in a patient with histologically proven MCL from lymph nodal biopsy. What’s more, PET/CT examination is sys- temic and detected more lesions than conventional tests (such as CT, MRI and B ultrasound).
Alavi et al. [3] have shown that PET is superior to con- ventional imaging (CT/MRI) in detecting lymph nodeinvolvement in MCL, characterizing extranodal involve- ment and detecting spleen involvement. In our study, similarly, PET/CT is highly sensitive in detecting MCL intranodal and extranodal lesions, such as the lymph nodes and spleen without obvious enlargement in CT can be easily detected in PET/CT due to high metabo- lism. We further analyzed the correlation between spleen involvement and clinical indicators and found that MCL patients with spleen involvement were more prone to anemia and low Plt. In assessing bone marrow invasion, Bodet-Milin et al. reported that the diagnostic rate of PET/CT was low (approximately 25%, 2/8). The sensi- tivity of bone marrow invasion in our study was 77.78%, which is higher than previous studies, and we believethat this discrepancy might be related to the larger sam- ple size and the accuracy of bone marrow biopsy [14]. In a study of voxel-based analysis of PET/CT, Morgan et al. [15] found that at one cut point which more than 38% of voxels (an average of 1734 voxels) showed an SUV of <0.95, the sensitivity and specificity of PET/ CT in detecting MCL bone marrow involvement were 100% and 80%, indicating that PET/CT could accurately detect bone marrow involvement. These results indicate that PET/CT may be a powerful method for determin- ing accurate staging, treatment maintenance and prog- nosis of MCL. By analyzing the clinical data and PET/ CT systemic imaging results of MCL patients with bone marrow involvement, our study found that MCL patientswith bone marrow invasion were more likely to have ane- mia, low Plt and elevated β2-MG, as well as combined involvement of the nasopharynx, lung and both kidneys.
18F-FDG PET/CT plays an important role in evaluat- ing the prognosis of MCL. In assessing the staging of malignant tumors, a higher SUV of PET/CT often indi- cates a higher degree of malignancy of the tumor and poorer prognosis. Karam et al. found that the 5-year OS rate of MCL patients with an initial SUVmax =<5 was significantly higher than that of MCL patients with an initial SUVmax > 5 (87.7% vs. 34%, P < 0.01), and the disease-free survival time was also significantly extended (45.3 months vs. 10.6 months, P < 0.001). We also found that, after 5 years of effective follow-up, all patients totally with an initial SUVmax >5 had progressed and their 5-year OS was 33.33%. It was at par with the cur- rent literature, indicating that PET/CT assessment prior to MCL treatment could help select patients with good prognosis. Additionally, PET/CT also plays an important role in the evaluation of prognosis after autologous stem cell transplantation in MCL patients. Cohen et al. [16] analyzed the correlation of PET/CT of 29 MCL patients before autologous stem cell transplantation with progno- sis and found that both OS and PFS were significantly reduced among patients with positive PET/CT before transplantation, which strongly indicated poor prognosis. Magnusson et al. [17] assessed the residual lesion status of MCL patients before transplantation using bone mar- row biopsy and PET/CT and found that patients with positive residual lesions before transplantation had sig- nificantly higher recurrence 2 years after autologous transplantation (46% vs. 19%) and a significantly reduced 5-year disease-free survival rate (46% vs. 68%).
MCL responds to combination therapy but is prone to recurrence and has a poor prognosis. Therefore, the clini- cal treatment of MCL remains challenging. Among the 30MCL patients who underwent chemotherapy and were followed-up effectively, 20 patients showed complete or partial remission, and 10 patients had disease progression, recurrence or even death. Treatments targeting MCL, such as renewal of treatment plans, the development of new drugs and hematopoietic cell transplantation, are being developed rapidly and should help prolong the survival and improve the prognosis of MCL patients [18,19]. In this study, based on the follow-up PET/CT findings and biopsy, the efficacy of PET/CT evaluation in MCL was assessed. We found that according to the unique advantage of 18F-FDG uptake, 18F-FDG PET/ CT is highly sensitive, specific, NPV, PPV and accurate to monitor therapy response in MCL, which were 80% (44–97%), 90.91% (59–100%), 88.89% (52–100%), 83.33%(52–98%) and 85.71% (64–97%), respectively.
Nevertheless, the study had some limitations. First, the sample size of the study was 39 and relatively small. Second, this study was a retrospective study that was subject to some potential bias. Therefore, a prospective study with more cases is needed to further verify the con- clusions. Third, it was the non-availability of pathological confirmation of all extranodal lesions detected on PET/ CT. Although desirable, pathological confirmation from all involved extranodal sites may be difficult to obtain or not feasible all the time.
Conclusion
MCL is a type of lymphoma with strong invasiveness, poor therapeutic response, easy recurrence and poor prognosis, and most patients are at an advanced stage when they are diagnosed. Multiple lymph node involve- ment is present in all MCL patients, and the SUVmax of involved lymph nodes is positively correlated with the largest diameter of those lymph nodes. The most com- mon extranodal sites invaded by MCL are the spleen and bone marrow. MCL patients at advanced stages withbone marrow involvement are more prone to invasions of the nasopharynx, lung or kidney. Our study further found that some clinical biochemical indicators of MCL were helpful in better understanding the MCL extranodal lesions present in FDG PET/CT imaging. The PET/CT findings suggested that MCL patients with lung involve- ment and elevated LDH and CRP had higher IPI scores and poorer prognosis. Due to the relatively small sam- ple size, more samples are needed to further validate the conclusions of this study.
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