An unusual case of reactive lymphocytosis mimicking acute leukemia.

The diagnosis of acute leukemia is based on a combination of clinical, hematological, morphological, cytogenetic, and immunophenotypic data. The authors report a case of reactive lymphocytosis with extremely elevated lymphocytic and lymphoblastic leukocytosis that mimicked acute lymphoblastic leukemia, not only morphologically, but also in immunophenotypic analysis. They could not determine any underlying disease marker other than infectious symptoms that were present for 20 days prior to presentation to their clinic. Although this case presented with extremely high lymphocytic leukocytosis, the patient had normal blood cell lineage, a moderate level of blastic cells in bone marrow, and normal physical findings. These findings convinced the authors to follow up the patient before beginning treatment.


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S. Yetgin et al. childhood period and the numbers decrease with age [11,12]. In such cases, lymphocyte morphology in general is dramatically different from what is seen in normal controls. This distinctive type of immature lymphocytosis in blood and bone marrow can be confused with ALL. Lymphocyte precursor cells, termed hematogones, have scant cytoplasm and dense homogeneous nuclear chromatin with absent or indefinite nucleoli. In addition, their immunophenotype (CD45 + , CD19 + , CD10 + , TdT +/− , and surface immunoglobulin − ) is similar to that of pre-B lymphoblasts [5]. However, with four-color flow cytometry using optimal antibody combinations, distinction from neoplastic lymphoblasts can nearly always be made [11,12].
The duration of reactive lymphocytosis can range from weeks to months, depending on the etiological and host factors. Here in, we report a pediatric case of reactive lymphocytosis with extremely high white blood cell (WBC) count, which mimicked ALL with extreme features based on morphological and immunophenotyping analysis.

CASE REPORT
A 26-month-old boy, who was admitted to the Pediatric Hematology Department of Hacettepe Medical Center, had been previously diagnosed with ALL at the referring hospital. He presented with interval fever, mucoid diarrhea, weight loss, and sweating, which had persisted for 20 days. His family history was unremarkable (2 sisters, 2 brothers, and nonconsanguineous parents).
Our findings and the patient's history, which included fever and diarrhea 4-5 times per day, suggested that he also had a concurrent infection. He received intravenous fluid treatment for gastroenteritis. After 2 days of observation, his WBC count declined to 106 × 10 9 /L and his body temperature was normal. Over the following 6 days, he remained clinically stable, and WBC counts gradually dropped to 20 × 10 9 /L within 2 weeks; blast cells also decreased in the peripheral blood and second BM (5%). He was then discharged from the hospital and scheduled for monthly follow-up. During 15 months of follow-up, he had continuously high WBC level (mean: 19.7 × 10 9 /L; range: 16.9 × 10 9 /L to 23.1 × 10 9 /L) with a normal differential count, and both Hb and Plt levels were mildly high (Hb/Hct: range 11.7-14.1 g/dL, 35.7-40.9%; Plt: range 373-539 × 10 9 /L), though they were at times normal.

DISCUSSION
We present the case of a 26-month-old boy with a very high lymphocytic WBC count, in whom the presence of prominent lymphoblasts challenged our diagnostic abilities. The blastic character of the lymphoid cells was determined by peripheral blood smear (20%), BM morphology (45%), and with BM flow cytometric analysis showing a typical CD45/SSC and CD10 positivity. CD45/SSC analysis was used to identify CD45-positive and -negative blast populations as well as CD45 bright lymphoid cells. Morphologic blast count correlated with the percentage of CD10-positive cells.
Our first step was to exclude the existence of any infection superimposed onto leukemia, and no evidence of viral or bacterial infection was found after extensive examinations. WBC count showed a declining trend from 132 × 10 9 /L to 59 × 10 9 /L over the 6 days the patient was under our observation. He was in good physical condition and his gastroenteritis improved.
A variety of hematological disorders, early infancy, postchemotherapic stage, administration of certain drugs and bone marrow regenerative stage are all associated with the presence of cells mimicking lymphoblasts, which are also known hematogones [5][6][7][8][9][10]. A persistent elevation in hematogones may be observed in ALL patients after cessation of chemotherapy [11,13]. These authors have also pointed out that increased marrow hematogones may cause diagnostic confusion following treatment for ALL since they are expanded in regenerating marrow and can potentially be mistaken for residual diseases. This is also the case in post-stage of bone marrow transplantation [11]. Using four-color flow cytometry, McKenna et al. revealed that in all instances, the hematogone population exhibited a typical complex spectrum of antigens that defines the normal evaluations of B-cell precursors. Furthermore, they lacked aberrant or asynchronous antigen expression. Neoplastic lymphoblasts exhibit maturation arrest and over-, under-, and asynchronous expression of antigens observed on normal B-cell precursors and often expressed myeloid-associated antigens. Asynchronous expression of the earliest (CD34) and latest (CD20) antigens was not observed in the hematogone population in the two studies [11,12]. Immunophenotypic analysis (CD10, CD22, HLA-DR, cytoplasmic µ chain in pre-B) is an important adjunct to the morphological classification of blasts in ALL. Clonal gene rearrangements have also rarely been described in clear-cut non-neoplastic processes [14]. Our case was classified as CALLA (+) Bprecursor ALL based on the results of immunophenotyping. He had had a 20-day history of fever, mucoid diarrhea, weight loss, and sweating before admission to our clinic and two blood lineages other than WBC within normal range at the time of admission and also during the follow-up period. In addition to the sound clinical picture of the patient, WBC count and lymphoblasts in peripheral blood and BM dropped rather than progressed during follow-up. This patient was particularly interesting because he had a mildly high WBC count during more than 1 year of follow-up with a normal differential ratio. Plt and Hb levels also mildly rose to or exceeded the normal limit. This finding suggested that the etiological factor, which was most probably viral infection, participated in the regulation of hematopoiesis in all lineage activities. Viral infections may affect the hematopoietic system resulting in various aberrations of hematopoiesis by deteriorating the immune system or the hematological maturation hierarchy [15][16][17][18]. Activated B cells are reported to produce molecules capable of stimulating hematopoietic hyperactivity [19][20][21].
In conclusion, this case report suggests that an ALL patient presenting with two normal blood cell lineages and a moderate level of blastic cells in the BM should undergo an extensive examination of historical and clinical factors associated with increased hematogones and be allowed an adequate follow-up period prior to beginning chemotherapy. The following question should be asked: Why are lymphoid hematopoietic hyperactivity and a leukemia-mimicking state not seen in all patients presenting with the same condition as mentioned above?
Factors responsible for reactive lymphocytosis might be related to an unknown patient characteristic or etiological factors, which may result in some patients having limited proliferative capacity to regress and others to progress to ALL [15].