Prognostic Importance of Bone Marrow Uptake on Baseline 18 F-FDG Positron Emission Tomography in Diffuse Large B Cell Lymphoma

Abstract

Aim:

To define the role of ¹⁸F-flourodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in the detection of bone marrow (BM) involvement in patients with diffuse large B cell lymphoma (DLBCL).

Materials and Methods:

Fifty-four (mean age: 55.5 ± 18.3 years, 20 female and 34 male) DLBCL patients who underwent pretreatment ¹⁸F-FDG PET/CT were included to the study. Focal or diffuse BM ¹⁸F-FDG uptake that is higher than mediastinal blood pool uptake was accepted as positive. After staging of disease by CT and ¹⁸F-FDG PET/CT, all the patients received R-CHOP treatment after diagnostic blinded bone marrow biopsy (BMB). Presence of positive BM uptake in ¹⁸F-FDG PET/CT and histopathological examination results of BMBs were analyzed by Chi-square test. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of ¹⁸F-FDG PET/CT in the detection of BM involvement were calculated. Prognostic importance of the presence of BM ¹⁸F-FDG uptake was analyzed by Kaplan–Meier analysis.

Results:

BM ¹⁸F-FDG uptake was detected in 8 patients. Histopathological examination of BMB revealed BM involvement in 6 out of 8 patients. BMB was negative in all patients who have no ¹⁸F-FDG uptake in the evaluation of PET/CT images. Sensitivity, specificity, accuracy, PPV, and NPV of ¹⁸F-FDG PET/CT in the detection of BM involvement were calculated as 100%, 96%, 96%, 75%, and 100%, respectively. In the Kaplan–Meier analysis, we found that presence of pretreatment ¹⁸F-FDG uptake in BM has a prognostic importance. Whereas mean time to progression (TTP) in patients with BM uptake was 32.25 ± 10.9 months and mean TTP in those without was 51.69 ± 3.6 months (p = 0.013).

Conclusions:

BM uptake in pretreatment ¹⁸F-FDG PET/CT is an important prognostic factor in DLBCL patients. Moreover, in consideration of high NPV, ¹⁸F-FDG PET/CT could eliminate unnecessary BMB in FDG-negative patients.

Introduction

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) subtype and it accounts to 30%–35% of the patients.¹ Presence of bone marrow (BM) involvement is an important prognostic factor because its presence effects disease stage and has a prognostic role.² BM assessment could be performed by bone marrow biopsy (BMB). European Society of Clinical Oncology (ESMO) guidelines recommend blind BMB in all patients who were diagnosed with DLBCLs and were candidates for curative treatments.³ However, BMB is a painful and invasive process and it may be false negative because it represents a small proportion of BM.^4

–8 For this reason, its routine performance has been controversial.⁹

¹⁸F-flourodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) is the method of choice in DLBCL patients to evaluate disease spread because most of the DLBCLs are FDG positive.¹⁰ The role of ¹⁸F-FDG PET/CT in the evaluation of BM involvement is controversial.^11
–13 Some of the reported studies included were mixed types of NHLs with combination of low and high ¹⁸F-FDG avid tumors and some were performed by PET-only systems.¹⁴ In a recent meta-analysis and review, Adams et al. reported that sensitivity and specificity of ¹⁸F-FDG PET/CT in the detection of BM involvement were 88.7% and 99.8%, respectively, from pooled data. They suggested that ¹⁸F-FDG PET/CT is accurate and complementary to BMB in the evaluation of BM involvement in DLBCL patients.¹³

In this study, we aimed to review our results in the evaluation of BM involvement in DLBCL patients who underwent ¹⁸F-FDG PET/CT followed by BMB.

Materials and Methods

Patients

Retrospectively, ¹⁸F-FDG PET/CT images of 54 (mean age: 55.5 ± 18.3, 20 female and 34 male) patients who underwent PET/CT for staging of disease after histopathological confirmation of DLBCL were included in the analysis. Patient follow-up data were searched to detect presence of disease progression and progression-free survival times. Mean follow-up period was 66.57 ± 15.4 months.

Evaluation of BM ¹⁸F-FDG uptake

PET/CT images were acquired using a GE Discovery ST PET/CT (General Electric, Milwaukee, WI) scanner. Whole body ¹⁸F-FDG PET/CT imaging was performed ∼1 hour after an intravenous injection of 8–10 mCi ¹⁸F-FDG. Images from the vertex to the proximal femur were obtained while the patients were in the supine position. Emission PET images were reconstructed with noncontrast CT images that were also obtained from the patient's integrated ¹⁸F-FDG PET/CT with the use of a standardized protocol of 140 kV, 70 mA, tube rotation time of 0.5 second per rotation, a pitch of 6, and a slice thickness of 5 mm. PET/CT images were evaluated and confirmed visually and semiquantitatively with standardized uptake value by consensus of two experienced nuclear medicine specialists. Focal or diffuse BM ¹⁸F-FDG uptake that is higher than mediastinal blood pool uptake was accepted as positive.

Data and statistical analyses

SPSS software (version 20.0; SPSS, Inc.; Chicago, IL) was used for statistical analysis. Continuous data are expressed as the mean and standard deviation or as the median and interquartile range. Categorical data are presented as number of patients and percentages. Presence of positive BM uptake in ¹⁸F-FDG PET/CT and histopathological examination results of BMBs were analyzed by Chi-square test. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of ¹⁸F-FDG PET/CT in the detection of BM involvement were calculated. Prognostic importance of the presence of BM ¹⁸F-FDG uptake was analyzed by Kaplan–Meier analysis.

Results

While 34 out of 54 patients had been diagnosed with lymph node, 20 patients had been diagnosed with extra-nodal organ biopsies (soft tissue,⁵ bowel,⁵ stomach,³ tonsil,³ nasopharynx,¹ bone,¹ spleen,¹ and lung¹). Disease stages were I, II, III, and IV in 14, 10, 7, and 23 patients, respectively. Mean serum LDH level was calculated as 296 ± 43.7 U/L (range 82–1489). Demographic data of patients is demonstrated in Table 1.

Table 1.

Demographic Features of Patients

Features
Gender, n (%)
Female	20 (37)
Male	34 (63)
Age, mean ± SD	55.5 ± 18.3
Site of diagnosis
Lymph node, n (%)	34 (63)
Extranodal organs, n (%)	20 (37)
Soft tissue	5
Bowel	5
Stomach	3
Tonsil	3
Nasopharynx	1
Bone	1
Spleen	1
Lung	1
Serum LDH level, mean ± SD	296 ± 43.7
Stage of disease, n (%)
I	14 (25)
II	10 (19)
III	7 (13)
IV	23 (43)

LDH, lactate dehydrogenase.

In ¹⁸F-FDG PET/CT images, while extranodal FDG uptake was seen in 36 (67%) patients (stomach in 6, lung in 6, spleen in 6, skin soft tissue in 6, liver in 4, bowel in 4, tonsil in 4, nasopharyngeal region in 3, pancreas in 3, thyroid in 2, peritoneum in 1 patients), BM uptake was observed in 8 (15%) patients. BM ¹⁸F-FDG uptake was detected in 8 patients. Histopathological examination of BMB revealed BM involvement in 6 out of 8 patients. BMB was negative in all patients who have no ¹⁸F-FDG uptake in the evaluation of PET/CT images. Sensitivity, specificity, accuracy, PPV, and NPV of ¹⁸F-FDG PET/CT in the detection of BM involvement were calculated as 100%, 96%, 96%, 75%, and 100%, respectively. Findings of ¹⁸F-FDG PET/CT and BMB are summarized in Table 2. PET/CT images of patients with false and true positive BM ¹⁸F-FDG uptake are shown in Figures 1 and 2.

FIG. 1.

Maximum intensity projection PET/CT images of two patients with true positive BM ¹⁸F-FDG uptake. BM, bone marrow; ¹⁸F-FDG, flourodeoxyglucose; PET/CT, positron emission tomography/computed tomography.

FIG. 2.

Maximum intensity projection PET/CT image of one patient with false positive bone marrow ¹⁸F-FDG uptake.

Table 2.

Bone Marrow Biopsy and ¹⁸ F-FDG Positron Emission Tomography/Computed Tomography Findings

	BMB
	Positive	Negative
¹⁸F-FDG PET/CT
Positive	5	3
Negative	0	46

BMB, bone marrow biopsy; ¹⁸F-FDG, flourodeoxyglucose; PET/CT, positron emission tomography/computed tomography.

Disease progression was seen in 14 (25%) patients during the 66.57 ± 15.4 months mean follow-up period. In Kaplan–Meier analysis, we found that presence of pretreatment ¹⁸F-FDG uptake in BM has a prognostic importance. Whereas mean time to progression (TTP) in positive BM patients with bone uptake was 32.25 ± 10.9 months and mean TTP in those without was 51.69 ± 3.6 months (p = 0.013) (Table 3 and Fig. 3).

FIG. 3.

Survival cures for TTP in BM FDG (+) and (−) groups. TTP, time to progression.

Table 3.

Means for Time to Progression in Bone Marrow (+) and (−) Groups

Medians for TTP
	Mean
			95% confidence interval
TTP	Estimate	Standard error	Lower bound	Upper bound
BM FDG (−)	51.69	3.6	44–55	58–83
BM FDG (+)	32.25	10.9	10–73	53–76
Overall	47.55	3.605	40–48	54–62

BM, bone marrow; FDG, flourodeoxyglucose; TTP, time to progression.

Discussion

Presence of BM involvement is an important prognostic factor in NHL patients. For this reason, current ESMO guideline recommends blinded BMB in all new diagnosed DLBCL patients. But, BM infiltration by DLBCLs can be patchy, and because of the skip areas, it is really difficult to document BM involvement by routine BMB. Performing that invasive and painful intervention in all patients is controversial and has been the subject of debate in the past decade.⁹ Adams et al. reviewed studies in this subject and published their meta-analysis. They found that ¹⁸F-FDG PET/CT achieves good sensitivity and almost perfect specificity in the detected of BMB in new diagnosed DLBCL patients. However, they revealed that ¹⁸F-FDG PET/CT can miss bone marrow involvement (BMI) in ∼3.1% of patients. Finally, they concluded that if ¹⁸F-FDG was negative in patients, BM involvement cannot be excluded.¹³ Similarly, their pooled data results we calculated high sensitivity and specificity of ¹⁸F-FDG PET/CT in the detection of BMI in their series. Differently from their suggestion, in our series, ¹⁸F-FDG PET/CT did not miss BMI in any patient. This may be related to difference between criteria for BM positivity during design of the studies. Although interpretation criteria have not been reported in some studies, they have been accepted BM uptake higher than liver in the others.^14

–19 In our analysis, we accepted positive BM uptake higher than mediastinal blood pool. For this reason,¹⁸F-FDG PET/CT could have missed the BMI in those cases. In contrast, our lower threshold could increase false positivity of ¹⁸F-FDG PET/BT. Therefore, we recommend BMB for confirmation of positive BM ¹⁸F-FDG PET/BT in case of possible false positivity.

Cheson et al. reported the recommendation of an international multidisciplinary workshop. They suggested incorporation of 18F-FDG PET/CT into standard staging of FDG avid lymphomas. Moreover, they reported that BMB is no longer indicated for the routine staging of Hodgkin lymphomas and most DLBCLs. Results of our analysis may reveal that patients without BM 18F-FDG uptake could be treated and followed up without BMB.²⁰

The low and statistically significant TTP in BM FDG-positive patients in our study can also emphasize the importance of close follow-up in these patients. With further evaluation, BM involvement may be considered as a risk factor for early relapse and a closer follow-up schedule can be offered for these patients. New studies are needed to support this hypothesis.

Conclusions

Footnotes

Disclosure Statement

No competing financial interests exist.

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Prognostic Importance of Bone Marrow Uptake on Baseline 18 F-FDG Positron Emission Tomography in Diffuse Large B Cell Lymphoma

Abstract

Aim:

Materials and Methods:

Results:

Conclusions:

Introduction

Materials and Methods

Patients

Evaluation of BM 18F-FDG uptake

Data and statistical analyses

Results

Discussion

Conclusions

Footnotes

Disclosure Statement

References

Evaluation of BM ¹⁸F-FDG uptake