Bone Marrow Recovery by Morphometry during Induction Chemotherapy for Acute Lymphoblastic Leukemia in Children.

Tuong-Vi Nguyen,Andrew Zannettino,Anna Melville,Shriram Nath,Stuart Howell,Rosemary Sutton,Colin Story,Tamas Revesz,Obul Reddy Bandapalli

doi:10.1371/journal.pone.0126233

Abstract

Bone marrow architecture is grossly distorted at the diagnosis of ALL and details of the morphological changes that accompany response to Induction chemotherapy have not been reported before. While marrow aspirates are widely used to assess initial response to ALL therapy and provide some indications, we have enumerated marrow components using morphometric analysis of trephine samples with the aim of achieving a greater understanding of changes in bone marrow niches. Morphometric analyses were carried out in the bone marrow trephine samples of 44 children with ALL, using a NanoZoomer HT digital scanner. Diagnostic samples were compared to those of 32 control patients with solid tumors but without marrow involvement. Samples from patients with ALL had significantly increased fibrosis and the area occupied by bony trabeculae was lower than in controls. Cellularity was higher in ALL samples due to leukemic infiltration while the percentage of normal elements such as megakaryocytes, adipocytes, osteoblasts and osteoclasts were all significantly lower. During the course of Induction therapy, there was a decrease in the cellularity of ALL samples at day 15 of therapy with a further decrease at the end of Induction and an increase in the area occupied by adipocytes and the width of sinusoids. Reticulin fibrosis decreased throughout Induction. Megakaryocytes increased, osteoblasts and osteoclasts remained unchanged. No correlation was found between clinical presentation, early response to treatment and morphological changes. Our results provide a morphological background to further studies of bone marrow stroma in ALL.

Highlights

Bone marrow aspiration and trephine biopsy are standard procedures in diagnosing acute lymphoblastic leukemia (ALL) in children
While bone marrow aspirates are informative for most aspects of diagnostic value for leukemia patients, bone marrow trephine biopsy specimens have the advantage of showing the extent of disruption in bone marrow integrity associated with the development of leukemia and can be a valuable source for diagnostic tests in case of a ‘dry tap’
Noren-Nystrom et al reported that elevated reticulin fibrosis was a common finding in diagnosis trephine biopsy specimens which returns to normal levels following response to chemotherapy [1]

Summary

Introduction

Bone marrow aspiration and trephine biopsy are standard procedures in diagnosing acute lymphoblastic leukemia (ALL) in children. Most children with ALL show extensive infiltration of the bone marrow spaces by leukemic blasts and there is very little evidence of normal haemopoiesis. Noren-Nystrom et al reported that elevated reticulin fibrosis was a common finding in diagnosis trephine biopsy specimens which returns to normal levels following response to chemotherapy [1]. We were able to confirm these findings [2] and hypothesized that high reticulin fibre content in the marrow ‘anchors’ leukemic cells and is associated with lower blood blast counts [3]

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Results

Discussion

Conclusion