FDG-PET as a Marker of tumor proliferation Compared to Gene-Expression Proliferation Scores, MIB1%, and LDH In Untreated Mantle Cell Lymphoma (MCL)

Mantle cell lymphoma (MCL) is a biologically heterogeneous disease with marked variation in clinical behavior. Many patients are offered high intensity therapy even though a significant minority can be safely monitored for long periods of time. The ability to precisely define this subset at time of diagnosis would greatly enhance clinical decision-making. Tumor proliferation as measured by gene expression profiling (GEP) has proven to be prognostic in MCL and can segregate patients into quartiles with different survival expectations, but is technically challenging, expensive, and not readily available. MIB1, an antibody against the Ki-67 antigen, detects the number of cells actively dividing in a tissue specimen and also has a well-established correlation with outcomes in MCL, but can have significant inter-observer variability.

FDG PET/CT scans are a readily available tool routinely utilized to stage MCL in a qualitative way. Standard uptake values (SUV) on PET scan are assumed to correlate with tumor proliferation, but previous attempts to correlate SUV with markers of proliferation did not include GEP and were not exclusive to patients with MCL. LDH also is a marker of aggressive biology in numerous tumor types and a biologic parameter of the MIPI. Here, we investigated the relationship between SUV values seen on PET scan at baseline in untreated MCL patients as compared to the tumor's proliferation score (PS) as measured by gene expression, MIB1% and serum LDH levels.

The analysis involved untreated MCL patients who had a baseline FDG-PET/CT followed by a pre-treatment biopsy of a lymph node with the highest SUV unless it was considered inaccessible. Analysis of the PET/CT scans was done by an expert in nuclear medicine who was blinded to the outcome of the patients and pathology findings. SUV of biopsied node (SUVnode) and maximum SUV uptake of the entire scan (SUVmax) normalized to body weight were recorded. GEP was done on pre-treatment lymph nodes, and the expression levels of 18 proliferation signature genes were averaged to generate a PS as previously described (Rosenwald, 2003). MIB1% was calculated using image analysis software and was recorded as the number of positive cells/total number of cells in the entire specimen.

39 patients were treated between September 2005 and June 2010. Median age was 58 years (41-73) and 77% of patients were male. Simplified MIPI risk groups included 20 low, 14 intermediate and 5 high. 5 patients (13%) were diagnosed with blastoid variants. Pretreatment PET/CT scans were available in 37 patients, nodal biopsies in 28, and PS in 19.

Median SUVnode was 5.18 (1.81-12.89, n=27) and median SUVmax for the entire group was 6.40 (2.22-17.5, n=37). SUVnode and SUVmax had virtually identical correlations to PS: r=0.59 (p = 0.007) and r=0.61 (p = 0.006), respectively. Tumors classified as high or low proliferation by PS had a median SUVmax of 11.89 and 5.67, respectively (p = 0.004). In blastoid-variant MCL, the median SUVmax was 12.38 (n=5) while in non-blastoid it was 5.68 (n=32), and 3/5 (60%) tumors with SUVmax > 12 were blastoid variant. MIB1% in lymph node biopsies correlated with both SUVmax, r=0.49 (p = 0.015) and PS, r=0.83 (p < 0.001). LDH correlated highly with PS, r=0.74 (p < 0.001) but less so with SUV, r=0.37 (p = 0.02). Table 1 shows the distribution of these parameters within Quartiles based on PS.

SUVmax on baseline FDG-PET scans correlated well with markers of tumor proliferation such as PS and MIB1% in untreated MCL. However, in our data, both MIB1% and LDH correlated better with PS thanSUVmax. Thus, SUVmax as measured by FDG-PET appears less specific for tumor proliferation and may be influenced by other aspects of tumor biology. The possible biologic differences in tumors with high and low SUV are the focus of ongoing investigations. While high SUV values typically identify tumors with high proliferation and/or blastoid morphology, low and intermediate SUV values do not reliably correlate with tumor proliferation. This might be improved with alternative PET radiotracers such as fluorothymidine (FLT) that more specifically measures proliferation.

No relevant conflicts of interest to declare.