Analysis of Clinico-Pathologic Features and Stromal Cell-Derived Factor (SDF)-1/CXCR4 in Myeloid Sarcoma
Authors: Schmitt-Graeff Annette H , Bertz Hartmut , Metzger Moritz , Strahm Brigitte , Stein Harald , Burger Jan A. 
Published: April 2020

Abstract
Myeloid sarcoma (MS) are extramedullary tumor masses composed of immature myeloid cells. Currently, the key pathogenetic processes involved in the in homing of leukemic cells to extramedullary niches are not well understood. Our study focuses on the role of the chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 in this rare condition. A cohort of 76 MS was obtained from the archives of our institutions and evaluated for clinical, morphological and phenotypic features. Immunohistochemical staining was performed for myeloperoxidase, CD33, lysozyme, CD3, CD4, CD20, CD33, CD34, CD56, CD61, CD68, CD99, CD117, CD123, CD163, haemoglobin, nucleophosphamin 1, and occasionally complemented by fluorescent in situ hybridization or karyotyping. Single and double Immunohistochemistry and immunoflorescence for SDF-1 (CXCL12), CXCR4, retinol-binding protein-1 (CRBP-1), S-100 protein, alpha-smooth muscle actin (SMA) and inhibitor of DNA binding/differentiation (ID)3 were performed on tissue specimens. Clinical data could be obtained from 65 patients (63% male, 37% female; median age of 47 years, range 1 to 80) presenting with solitary (n=42) or multiple (n=23) lesions. The MS fell into 3 broad categories:
de novo nonleukemic MS with normal bone marrow, n=11; de novo MS in conjunction with acute myeloid leukaemia (AML), n=10; secondary MS in patients with an underlying AML, classical or atypical myeloproliferative neoplasm, myelodysplastic syndrome or rare haematological disorders, n=43.
This category included MS occurring as an isolated extramedullary relapse of AML in remission after chemotherapy or allogeneic bone marrow/hematopoietic stem cell transplantation (alloBM/HSCT). The immunophenotypes were blastic (22,9%), monoblastic (13,1%), myelomonocytic (39,3%), megakaryoblastic (1,6%) or differentiated (22,9%). A monoblastic/myelomonocytic differentiation significantly correlated with involvement of skin and gingiva (p&lt;0,05). Survival analyses showed no significant differences for the 3 different categories of MS. However, overall survival (OS) was significantly shorter in the older age group (&gt;30years) than in younger patients (p&lt;0.05). Moreover, OS of patients of all age groups treated with allogeneic bone marrow transplantation was significantly superior to those treated with conventional chemotherapy (p&lt;0,005). Among patients not undergoing alloBM/HSCT normal laboratory values at initial diagnosis were associated with an longer OS (p&lt;0.05). Imaging studies including confocal laser scanning microscopy provided evidence of a SDF-1 positive stromal cell populations. Subpopulations of mesenchymal cells coexpressed SMA, CRBP1, S-100 and ID3. Strong overexpression of CXCR4 by the AML cells was particularly prominent in cases of nonleukemic de novo MS. Moreover, in a subset of cases, coexpression of SDF-1 and CXCR4 by the tumor cells was observed. Our clinical data furthermore support the favorable impact of BM/HSCT on the outcome of MS. The imaging studies showed that the microenvironment of MS contains SDF-1 positive stromal cells which may promote the access, survival and retention of CXCR4 positive leukemia cells in extramedullary sites. Furthermore, the overexpression of both SDF-1 and CXCR4 in a subset of myeloid cells suggests an autocrine/paracrine mechanism that may contribute to cell proliferation and self-renewal. In the future, the disruption of the SDF-1-CXCR4 axis by CXCR4 antagonists may play a potential role in the treatment of patients developing MS.