Acute leukemia presenting with extramedullary diseases and completely normal hemogram: An extremely unusual manifestation unique to pre‐B ALL
Authors: Chih‐Cheng Chen, Hsu‐Huei Weng, Cih‐En Hwang, Chang‐Hsien Lu, Ping‐Tsung Chen, Jyh‐Pyng Gau
Journal: American Journal of Hematology (2010)

Acute lymphoblastic leukemia (ALL) is a clonal hematological disease characterized by inadequate normal hematopoiesis secondary to excessive proliferation of leukemic blasts and their impaired differentiation. As a result, patients usually manifested symptoms related to bone marrow failure. It's very uncommon for ALL patients to present with normal hemogram. Herein, we describe two patients who presented with excruciating bone pain at orthopedic clinics. Osteopathy involving multiple bones was noted initially, but acute leukemia was never considered as one of the differential diagnoses because of the completely normal hemogram in both cases. Consequently, the diagnosis of leukemia was slightly delayed. Upon literature review, we found that ALL patients with solely extramedullary diseases and nearly normal hemogram had exclusively pre-B disease. We also propose a putative hypothesis for this interesting finding. Osteopathy is not an uncommon initial manifestation of ALL. In a pediatric population, radiological abnormalities in the musculoskeletal system were demonstrated in about 40% of ALL patients [1]. Bone pain, resulting from either bone erosion, periosteal lesions, or massive proliferation of blasts in the medullary canal and under the periosteum, is one of the most common presenting symptoms of ALL. In patients with ALL, who presented with prominent skeletal symptoms, they tended to have no lymphoadenopathy, organomegaly, or leukocytosis. As a result, the diagnosis of leukemia is often delayed [2-4]. Here, we described our two unique cases of ALL, who presented musculoskeletal manifestations with completely normal hemograms. There were no other leukemia-related symptoms that could have led to the suspicion of the disease. Early accurate diagnosis in these patients can be extremely difficult. We would like to use our cases as a reminder that acute leukemia may be taken into account in the differential diagnosis of bone lesions, even in patients with normal hemograms. The first case was a 35-year-old male, who experienced 2-week-long migratory pain in abdomen, neck, and back. Other than exquisitely sensitive tenderness in the back and sacral area, physical examination upon admission was negative. There were no palpable peripheral lymph nodes or hepatosplenomegaly. Lab studies showed completely normal hemogram with a white cell differential count of 71% neutrophils and 26% lymphocytes, although there were markedly elevated levels of alkaline phosphatase (263 U/L; normal < 100 U/L) and lactate dehydrogenase (LDH, 978 U/L; normal < 213 U/L). Although imaging studies, including X-ray examination of the spine, pelvis and sacrum, and abdominal sonography failed to detect any abnormality, a bone scan revealed numerous foci of increased radioactivity scattered in the skull, sternum, rib cage, spine, and bilateral sacroiliac regions, suggesting metastatic bone lesions (Fig. 1A). Systemic work-up failed to identify any primary tumor from other organs. Ten days after admission, follow-up blood work revealed pancytopenia with WBC: 2410/μL, Hb: 10.9 g/dL, and platelets: 16,000/μL. A bone marrow study showed a markedly hypercellular marrow with over 95% blasts. Surface marker analysis revealed that these malignant cells were positive for CD 19, CD10, and HLA-DR, suggesting a pre-B phenotype. Immunohistochemistry showed positive stains for CD34 and TdT. Moreover, chromosomal abnormalities of t(9;22) and 47 XY, +X were found and reverse transcription-polymerase chain reaction (RT-PCR) detected bcr-abl (e1a2) fusion gene. The final diagnosis was Ph-chromosome positive pre-B ALL. The patient was treated with chemotherapy combined with imatinib and achieved complete remission. He subsequently underwent successful allogeneic peripheral blood stem cell transplantation (PBSCT) and has been in stable condition since. A follow-up bone scan performed a year after initial diagnosis showed complete regression of bone lesions (Fig. 1B). (A) The bone scan study of the first case at diagnosis. It shows numerous foci of increased radioactivity in various skeletal regions, suggesting metastatic bone lesions. (B) Bone scan images of the same patient obtained at one year after diagnosis. It shows complete regression of bone lesions. (C) Magnetic resonance imaging (MRI) of lumbosacral spine of the second case. It shows ill-defined masses with various degrees of enhancement involving the L1, L4, L5 and sacral vertebral bodies with cortical destruction. Prominent cortical breakthrough of these masses can be seen at the pre-vertebral body region of S2 through S4 (black arrows). (D) Follow-up MRI of the second patient at the time of remission. It shows apparent regression of spinal lesions and marked reduction of cortical breakthrough caused by leukemic infiltrates (white arrow). The second case was also a 35-year-old male, who suffered from progressive lower back pain. Neither palpable peripheral lymphadenopathy nor hepatosplenomegaly was noted on physical examination. His hemogram, including white cell differential count, and biochemical data (including LDH and alkaline phosphatase) were completely normal. Magnetic resonance imaging (MRI) of the lumbosacral spine revealed ill-defined masses with various degrees of enhancement involving the L1, L4, L5, and sacral vertebral bodies with cortical destruction (Fig. 1C). Prominent cortical breakthrough of these masses could be seen at the prevertebral body region of S2 through S4 (Fig. 1C, black arrows). Other systemic work-up, including whole-body computed tomography, failed to identify any additional abnormalities. Computed tomography-guided biopsy obtained tumor tissue mainly consisted of lymphoblasts. Random bone marrow biopsy over the left iliac crest showed markedly cellular marrow consistent with acute leukemia. On immunophenotyping, these blasts stained positive for CD34, CD10, CD19, CD38, and HLA-DR. Cytogenetic study disclosed clonal hyperploidy changes: 52–61, X, −Y, +X, +1, +iso(1)(q10), +4, +5, +7, +8, +8, +10, +14, +18, +19, −20, +21. The final diagnosis was pre-B ALL. The patient received induction chemotherapy, which resulted in complete remission, with rapid resolution of clinical symptoms. Follow-up MRI at the time of remission disclosed apparent regression of spinal lesions with marked reduction of cortical breakthrough by the leukemic infiltrates (Fig. 1D, white arrow). The patient has been doing well after successful allogeneic PBSCT. Our cases are unique as both patients presented musculoskeletal manifestations with completely normal hemograms. Early diagnosis of acute leukemia in such patients can be extremely difficult as physicians would not consider it during differential diagnosis. Laboratory data would be of limited diagnostic help, as happened with our second case, who had a normal biochemical profile. The association between bone pain and hematological findings at ALL diagnosis has been noted before [3]. Jonsson et al. identified 52 cases (18%) from 296 ALL patients, who experienced prominent bone pain that overshadowed other manifestations of acute leukemia [3]. The aforementioned cases have hemogram values closer to normal than others; this often led to a delayed accurate diagnosis. It is very rare for ALL patients to present extramedullary lesions and a completely normal hemogram. We searched the English literature and found scattered reports of ALL with near-normal hemograms at presentation. Excluding those diagnosed before immunophenotyping became common, the list of such cases is very short (Table I). Interestingly, almost all of them had immunophenotypes consistent with pre-B ALL, as with our cases. It seems that in these reported pre-B ALL cases, the actively proliferating lymphoblasts "skip" peripheral blood and directly disseminate into the extramedullary space or organs. The actual cause of this phenomenon is unknown, but several relevant facts have been noted in the past few years. Chemokine receptor CXCR4 and its ligand, stromal cell-derived factor-1 (SDF-1), have been prominently linked to extramedullary organ infiltration of ALL [5-7]. Overexpression of CXCR4 could lead to transendothelial migration of ALL blasts [6]. SDF-1/CXCR4 signaling is especially important in the regulation of leukemic pre-B cells as the chemokine enhances their adhesion, whereas its inhibitors attenuate the chemotaxis and migration of these cells [8-10]. The assumption here is that in the early stages of pre-B ALL disease, some leukemic blasts "leak" into the peripheral blood. Through cellular SDF-1/CXCR4 signaling, these "leaked" pre-B lymphoblasts migrate through the endothelium and enter the extramedullary space or organs, taking them as their new "habitat." Other than CXCR4 signaling, another molecule potentially involved is vascular endothelial growth receptor 1. Fragoso et al. demonstrated that it is an important regulator in the onset of ALL extramedullary diseases [11]. Whether or not its activation specifically modulates the behavior of pre-B ALL cells is not clear, yet it is quite interesting that the four cell lines used in their experiments were either B-cell precursors or Pre-B cells [11]. Immunohistochemical staining on the patients' cells shall help to prove our hypothesis. Unfortunately, there was insufficient tissue in retrospect to assay our patients' leukemia cells for the expression of CXCR4 and other chemokine receptors. In conclusion, our cases serve as a reminder that ALL diagnosis should be considered for all patients with unexplained bone pain, bone lesions, or other musculoskeletal manifestations, even if the hemogram is completely normal. Almost all ALL patients with solely extramedullary diseases and nearly normal hemogram had exclusively pre-B disease. Further study of extramedullary ALL could lead to important information about the role of chemokines in leukemia cell trafficking. Chih-Cheng Chen* , Hsu-Huei Weng§, Cih-En Hwang*, Chang-Hsien Lu* , Ping-Tsung Chen* , Jyh-Pyng Gau¶ **, * Division of Hematology/Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Tao-Yuan, Taiwan, School of Nursing, Chang Gung Institute of Technology, Chiayi, Taiwan, § Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Chiayi, Taiwan, ¶ Division of Hematology/Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ** School of Medicine, National Yang-Ming University, Taipei, Taiwan.