Leukocytosis, defined as an elevated white blood cell (WBC) count above the normal threshold of >11,000 cells/cumm, is a common clinical finding. Extreme leukocytosis (EL) is characterized by a markedly elevated WBC count, often exceeding twice the upper normal limit. However, the specific cut-off to define EL remains variable across studies, ranging from >25,000 to >50,000cell/cumm.(8,9,10) EL can result from a variety of causes, including infections, haematological malignancies, corticosteroid use, growth factors, haemorrhage, and solid tumours.(8,9,13)

Infections, particularly urinary tract infections and bacterial pneumonia are frequently cited as common causes of EL when lower WBC cut-offs are applied.(8,12) Clostridium difficile has also been implicated in EL, particularly in septic patients, where prolonged EL can indicate poor prognosis and increased mortality.(14) Conversely, haematological malignancies, such as chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML), are strongly associated with extreme leukocytosis.(1,15) Studies suggest that higher WBC counts, particularly that >50,000cells/cumm, are more indicative of malignant rather than infectious causes.(8,11)

The administration of corticosteroids and granulocyte colony-stimulating factor (G-CSF) are also known to induce EL by causing demargination of neutrophils or promoting granulocyte production.(12) EL in solid malignancies is frequently associated with poor prognosis. This study analyses the aetiological factors and clinicopathological profile of patients with EL presenting to a tertiary hospital in Rajkot, Gujarat.

Objective:

To analyse the etilogical factors and clinicopathological profile in patients with extreme leukocytosis.

In the present study, retrospective analysis of extreme leukocytosis (>50,000cells/cumm) cases, comprising total 74 cases was carried out over a period of 7 months   (between January 2024 to July 2024), in the Central Clinical Laboratory (CCL), Department of Pathology, PDU Medical College and Hospital, Rajkot, Gujarat. Detailed medical history was taken. On automated haematology analysers, complete blood counts were performed and all the haematological parameters were noted. The peripheral blood smears were stained with Leishman stain.

Patient Demographics:

A total of 74 patients with extreme leukocytosis (EL), defined as a WBC count of ≥ 50,000cells/cumm, were included in the study. In our study, adult patients (78.37%) were more affected than children (21.62%), (TABLE 1). Males (54.05%) were more affected than Females (45.94%).

TABLE 1: DISTRIBUTION OF EL IN ADULTS AND CHILDREN:

Etiological Factors:

Among 74 patients, malignant conditions accounted for 48.64% of cases. Infections were the second most common cause of EL, observed in 43.25% of cases. Other causes, including corticosteroid use, growth factors and haemorrhage, were responsible for 8.10% of cases (CHART 1).

TABLE 2: DISTRIBUTION AND TYPE OF HAEMATOLOGICAL MALIGNANCIES

Table 2 shows that acute myeloid leukemia and acute lymphoblastic leukemia were found in 13 (36.11%) and 6 (16.66%) patients respectively. Of chronic type leukemia, 8(22.22%) patients had chronic myeloid leukemia and 9(25.01%) patients had chronic lymphoblastic leukemia

This study provides important insights into the etiological factors and clinical profiles of patients with extreme leukocytosis (EL) in PDU Medical College and Hospital, Rajkot. Our findings demonstrate that EL is more frequently Associated with malignant etiologies, particularly haematological malignancies (48.64%), compared to infections (43.25%) when a WBC count cut-off of ≥50,000 cells/cumm is used. This is consistent with ADAMU ET AL. study in which malignant conditions accounted for 47.2% and infections 43.1 %.⁽¹⁾ Haematological malignancies, mainly acute myeloid leukaemia (AML), accounted for most extreme leukocytosis cases (36.11%). This is consistent with previous studies of CHEN ET AL. and HUMAYAN ET AL. in which acute myeloid leukemia was more common with 36.8% and 46.8% respectively.^(3,4) (TABLE 3)

TABLE 3: VARIOUS STUDIES SHOWING DISTRIBUTION OF LEUKEMIAS

Our study found that patients with malignancies had significantly higher median WBC counts compared to those with infections, further supporting the idea that extreme elevations in WBC counts are more likely to be indicative of malignant processes.⁽¹²⁾ While infections were the second most common cause of extreme leukocytosis in our study (43.25% of cases), they were more likely to be associated with lower WBC counts. This finding aligns with other studies using lower WBC cut-offs (e.g., 25,000 to 30,000 cells/cumm) and found infections to be the predominant cause.⁽¹¹⁾

The clinical profiles of patients with EL differed based on the underlying aetiology. Patients with malignant conditions were more likely to present with symptoms such as bleeding, bone pain, and B symptoms (fever, night sweats, weight loss), as well as splenomegaly, hepatomegaly, and lymphadenopathy. These findings are consistent with prior reports highlighting these symptoms as characteristic of haematological malignancies.⁽²⁾ In contrast, fever was more commonly observed in patients with infections, a finding that aligns with infection-related leukocytosis.

Severe thrombocytopenia (platelet count <50,000 cells/cumm) was significantly more common in patients with malignant conditions. This finding suggests that thrombocytopenia, particularly when severe, may be a valuable marker for distinguishing between malignant and non-malignant causes of EL. Prior studies have also identified thrombocytopenia as a significant feature of haematological malignancies.^(5,12)

In conclusion, this study demonstrates that extreme leukocytosis with WBC counts ≥50,000cells/cumm is more commonly associated with malignant etiologies, particularly haematological malignancies, than infections. Clinicians should remain vigilant for malignancies in patients with EL and perform appropriate diagnostic testing to guide management. Early diagnosis and intervention are crucial to improving outcomes for patients with extreme leukocytosis

1. AdamuKilungu1,3*, Anitha Mrosso2: "Aetiological Factors and Clinical Profile of Patients with Extreme Leukocytosis: A Hospital-Based Study in Tanzania. https://www.mwdrxiv.org/content/10.1101/2025.03/18.25324160v1.full.pdf.
2. American Academy of Family Physicians. "Unexplained Lymphadenopathy: Evaluation and Differential Diagnosis." American Family Physician. Accessed October 1, 2024. https://www.aafp.org/afp/2020/0215/p210.html.”
3. B chen Z Huang X Zhang J Ou-Yang J Li Y Zhai An epidemiological investigation of leukemia incidence between 2003 and 2007 in Nanijing China J Hematol Oncol2003321.
4. M Humayun S A Khan W Muhammad Investigation on the prevelance of Leukemia in north west frontier province of pakistanTJ2005353119122.
5. Chalasani, Naga, Kiran Patel, W. Scott Clark, and C. Mel Wilcox. 1998. “The Prevalence and Significance of Leukocytosis in Upper Gastrointestinal Bleeding.” The American Journal of the Medical Sciences 315 (4): 233–36. https://doi.org/10.1016/s0002-9629(15)40318-0.
6. N Nasim K Malik N K Malik S Mobeen S Awan M Mazhar Investigation on the prevalence of leukemia at e tertiary care hospital, LahoreBiomed2013291922.
7. D’Costa G, Siddiqui HM, Pradhan RM, Gupte SS. Pattern of leukemia: a ten year incidence study of 242 cases. J Postgard Med. 1989 Oct;35(4):191-5.
8. Reding, Mark T., Jonathan R. Hibbs, Vicki A. Morrison, William R. Swaim, and Gregory A. Filice. 1998. “Diagnosis and Outcome of 100 Consecutive Patients with Extreme Granulocytic Leukocytosis.” American Journal of Medicine 104 (1): 12–16. https://doi.org/10.1016/S0002-9343(97)00273-8.
9. Granger, John M., and Dimitrios P. Kontoyiannis. 2009. “Etiology and Outcome of Extreme Leukocytosis in 758 Nonhematologic Cancer Patients: A Retrospective, Single-Institution Study.” Cancer 115 (17): 3919–23. https://doi.org/10.1002/cncr.24480.
10. Viner, Esther, Judith Berger, and Victoria Bengualid. 2023. “Etiologies of Extreme Leukocytosis.” Cureus 15 (4): 4–9. https://doi.org/10.7759/cureus.38062.
11. Lawrence, Y. R., D. Raveh, B. Rudensky, and G. Munter. 2007. “Extreme Leukocytosis in the Emergency Department.” Qjm 100 (4): 217–23. https://doi.org/10.1093/qjmed/hcm006.
12. Widick, Page, and Eric S. Winer. 2016. “Leukocytosis and Leukemia.” Primary Care Clinics in Office Practice 43 (4): 575–87. https://doi.org/10.1016/j.pop.2016.07.007.
13. Zachary P. Hugo, MD, Michael C. Perry, MD, David P. Steensma, MD, FACP. 2008. “Extreme Leukocytosis in the 21st Century Is Often Iatrogenic.” Blood 112 (11). Naaraayan, Ashutossh, Melissa Aleta, Prasanta Basak, Stephen Jesmajian, and Robert Goldstein. 2015. “Leukemoid Reaction to Clostridium Difficile Infection.” Anaerobe 34: 158–60. https://doi.org/10.1016/j.anaerobe.2015.05.005
14. Bewersdorf, Jan Philipp, and Amer M. Zeidan. 2020. “Hyperleukocytosis and Leukostasis in Acute Myeloid Leukemia: Can a Better Understanding of the Underlying Molecular Pathophysiology Lead to Novel Treatments?” Cells 9 (10). https://doi.org/10.3390/cells9102310