Tumors composed of leukemia cells grow in non-marrow sites in some acute leukemia patients, often without apparent marrow involvement. The majority cannot be eradicated by anti-leukemia agents and lengthy survival is rare. Exceptions are testis and meninges treated by local therapy, with systemic treatment to prevent marrow relapse. Tumor resistance to marrow-directed therapy has not been investigated nor prospective trials done. Only clinically obvious tumors are reported, as scans and autopsies are not routine in acute leukemia, so occult tumor incidence is unknown. It is possible that occult leukemic tumors are common. Finding tumors and targets on them could prevent the high rate of relapse (>50%) and increase cures. To characterize the course of leukemic tumors in one site, 235 cases in breast were analyzed and their subsequent behavior elicited from authors (Cunningham, Am J Hem, 2012). A pattern of leukemic tumor progression was revealed that mimics invasive lobular breast cancer (ILC): to other breast, then abdomen/pelvis, then CSF. We examined 25 paraffin-embedded specimens of leukemic breast tumors. H+E staining showed single-filing and targetoid pattern of leukemic cells in all AML and ALL cases - the classic pattern for ILC, not reported in leukemia. All showed areas of dense keloid-like fibrosis positive for Collagen Type 1 and frequent expression of αSMA-positive cancer cell-adjacent fibroblasts, as seen in advanced breast, rectal, pancreatic, and basal cell cancers. We postulated that altered microenvironment of organs such as breast, a site of fetal hematopoiesis, may foster leukemic cell-stroma interaction leading to tumor growth and migration paralleling epithelial cancers. With immunohistochemistry the leukemia cells were CK18-negative and CD45-positive, negative for hormonal markers (ER, PR, PRLR, Her 2/neu) and E-cadherin and positive for CD44, pSTAT5, TGFβ, FGFR, and SDF-1α. Leukemic cells in breast showed minimal to no CXCR4 staining but in one unusual case with concurrent ER-negative AML tumor and ER-positive ILC, CXCR4 was positive in cancer cells but not AML cells. This may reflect rapid internalization of CXCR4. The present study is the first work documenting many common features of leukemic and epithelial tumors. Our results suggest that pathways of tumorigenesis, and therapeutic targets, may be shared by solid and ‘liquid’ tumors. An innovative approach to relapse caused by tumor formation is long overdue, and could significantly improve survival and chance of curing acute leukemias. Abnormally activated pathways key to retention of stem cells in the marrow niche may be operative in extramedullary niches, where leukemic cells adhere to stroma and are protected from chemotherapy. Our unique collection of leukemic tumors allows us to further elucidate possibly common resistance mechanisms of malignant neoplasms provided by stromal microenvironment.

Citation Format: Isabel Cunningham, Takayuki Shiomi, Jeanine M. D'Armiento, Hallgeir Rui, Carlos Cordon-Cardo, Diane Hamele-Bena. Hiding from chemo: Leukemic cells forming tumors to survive. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1096. doi:10.1158/1538-7445.AM2013-1096