The stromal composition of malignant lymphoid aggregates in bone marrow: variations in architecture and phenotype in different B-cell tumours Francisco Vega, L. Jeffrey Medeiros, Wen-Hua Lang, Adnan Mansoor, Carlos Bueso-Ramos and Dan Jones Division of Pathology and Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Received 11 September 2001; accepted for publication 6 December 2001 Summary. We present evidence that different B-cell tumours, in bone marrow, have different relationships to stroma. Marrow core biopsies from 46 patients with B-cell tumours were immunostained with antibodies for distinct stromal cells. Cases included follicular lymphoma (FL), chronic lymphocytic leukaemia/small lymphocytic lym- phoma (CLL/SLL), mantle cell lymphoma (MCL), lympho- plasmacytic lymphoma (LPL), and nodal, extranodal and splenic marginal zone lymphoma (NMZL, MALT, SMZL). In normal marrow, low-affinity nerve growth factor receptor (LNGFR) highlighted a fine network of adventitial reticular cells (ARC). The nodular aggregates of CLL/SLL, NMZL, MALT and SMZL were characterized by distortion of the ARC network and downregulation of LNGFR. In contrast, the aggregates of FL, LPL and MCL were composed of linear arrays of ARC in tight association with individual tumour cells. LNFGR + was upregulated in ARC associated with the aggregates in FL, LPL and focally in MCL. Upregulation of CD35, vascular cell adhesion molecule (VCAM-1) and CD40 on ARC was noted exclusively in FL. Marrow lymphoid aggregates in CLL/SLL, NMZL, MALT and SMZL probably grow by displacing the pre-existing marrow stroma, while FL and LPL maintain a close association with the ARC network. In FL, expression of follicular dendritic cell-asso- ciated markers is modulated in pre-existing marrow stromal cells. Keywords: adventitial/perisinusoidal reticular cells, B-cell lymphoma, bone marrow stroma, immunohistochemistry, low-affinity nerve growth factor. The biological behaviour of small B-cell lymphomas, e.g. follicular lymphoma (FL), chronic lymphocytic leukaemia/ small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL), is regulated by a balance between growth and apoptosis. In lymph nodes, survival of tumour cells is influenced by interactions with co-stimulatory T cells and with specialized stromal populations (Petrasch et al, 1992; Schmitter et al, 1997). This is clearly demonstrated by the fact that FL, MCL and CLL/SLL cells are difficult to culture in vitro and rapidly undergo apoptosis, in contrast to high- grade B-cell tumours, which are easily propagated (Collins et al, 1989; McConkey et al, 1991; Ghia et al, 1998). Probably the best-studied stromal interaction is between FL cells and the germinal centre (GC) dendritic cells present within neoplastic follicles (Petrasch et al, 1992; Walker et al, 1997). In the early stages of disease, FL is dependent on interactions with GC dendritic cells and only assumes a diffuse extrafollicular growth pattern with disease progression. Although each low-grade B-cell lymphoma type has a distinctive pattern of infiltration in lymph nodes, most display a high incidence of bone marrow involvement (Foucar et al, 1982; Schmid & Isaacson, 1992). Thus, for these tumours, bone marrow provides a preferred microenvironment for migration, growth and persistence. The bone marrow medullary space is a highly ordered microenvironment with developing haematopoietic cells interspersed between blood vessels and interstitial stromal cell populations that include fibroblasts, adipocytes and cells with a dendritic morphology (Dorshkind, 1990). These bone marrow stromal elements normally provide structural and physio- logical support for the developing haematopoietic cells. The morphology and immunophenotype of different stromal populations in normal bone marrow has been previously investigated in monolayer cultures and in bone marrow aspiration and core biopsy samples (Wilkins & Jones, 1995, 1998). Distinct stromal populations have been Correspondence: Dan Jones, MD, PhD, Department of Hemato- pathology, Box 72, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. E-mail: dajones@mdanderson.org British Journal of Haematology, 2002, 117, 569–576 Ó 2002 Blackwell Science Ltd 569