Clinical Outcome of Low Grade Non Hodgkin’s Lymphoma Patients with Bone Marrow Involvement Detected by Flow Cytometry Alone.
Authors: Lishner Michael , Radnay Judith , Shapiro Hava , Manor Yosef , Lahav Meir , Gronich Naomi 
Published: October 2019

Abstract
Bone marrow (BM) involvement in low grade NHL patients results in stage IV clinical classification and has a negative impact on survival. Standard practice includes morphologic examination of BM biopsy at diagnosis. In many institutions flow cytometry (FC) is also routinely performed on BM aspirates accompanying respective biopsies. FC is believed to increase the sensitivity of the morphologic analysis by detecting occult lymphoma cells evading the pathologist’s eyes. However, the prevalence of such finding and especially its clinical significance are largely unknown. In our institute BM biopsies of NHL patients conducted after 1993 were routinely accompanied by BM aspirates with FC analysis. We retrospectively reviewed the charts of all low grade NHL patients (small lymphocytic lymphoma, follicular small cleaved cell NHL, follicular mixed small and large cell, marginal zone B-cell lymphoma, mantle cell lymphoma and Waldenstrom macroglobulinemia) diagnosed or followed at the Hematology Unit (1994–2004), who had undergone BM biopsies and aspirates as part of their diagnostic workup or before treatment. FC results were considered positive if they showed either a ratio of immunoglobulin light chain expression of kappa: lambda >3:1 or lambda: kappa >2:1 in at least 2% of the gated population. Cell analysis included: CD5 versus CD19, CD20 versus CD10, and kappa light chain versus lambda light chain occasionally with the addition of CD19 or CD20. Lymphoma involving BM by morphology was found in the biopsies of 43 patients (61.4%) (BM+ group). Of the remaining 1 patient had inconclusive results and 26 patients had normal BM biopsies. Of these 27 patients the FC analysis was positive in 9 patients (BM-FC+ group) and negative in 18 (BM-FC- group). We could not compare the groups using FLIPI or IPI scores as a whole since both include the stage as one of the five summed parameters while BM involvement was different by definition between the groups. However, the groups had similar parameters that are prognostically important and are part of the FLIPI scoring system including age, hemoglobin and LDH levels and also the number of involved extranodal sites. Splenic involvement and number of involved nodal sites were higher in BM+ and BM-FC+ groups than in BM-FC- group. Significant differences in disease progression as indicated by time-to-treatment were observed. The median treatment-free period was shorter in the BM+ and BM-FC+ groups (1 month and 4 months, respectively) as compared with the BM-FC- group (31 months) (log rank test p=0.0195). BM-FC- patients had significantly longer survival time than BM+ and BM-FC+ groups. Median survival time was not reached for the BM-FC- patients while in the BM+ and BM-FC+ groups median survival times were 129 and 89 months respectively with no significant difference between them. (Log rank test=0.029 for the difference between BM-FC- and the two other groups). We conclude that the outcome of low grade NHL patients found to have malignant cells by FC analysis while their BM morphology is normal is the same as that of patients with histological involvement. This may imply that patients with localized disease who have BM involvement by FC should be regarded as advanced stage disease.