International Journal for Doctor of Medicine and  Medical Students (IJDMMS)

Introduction

A common hematological finding in clinical practice, leukocytosis can result from a wide range of benign and malignant disorders. The leukemoid reaction (LR), a reactive and non-neoplastic process marked by significantly elevated white blood cell (WBC) counts, frequently exceeding 50,000 cells/µL, is one of the most difficult causes of extreme leukocytosis to diagnose. In both laboratory and clinical presentation, LR closely resembles leukemia (Sakka et al., 2006; Bain, 2020). A leukemia-like appearance without malignant clonal development is referred to as "leukemoid," highlighting the potential for diagnostic misunderstanding during first assessment.

Severe physiological stressors like severe infections, extensive tissue damage, hypoxia, severe bleeding, hemolysis, inflammatory disorders, intoxications, and some solid tumors that produce granulocyte colony-stimulating factors (G-CSF) are common causes of leukemoid reactions (Hoffman et al., 2018). Although benign and reversible, LR can mimic acute or chronic leukemias by presenting with significant leukocytosis, left-shifted granulopoiesis, toxic granulations, and occasionally circulating immature cells.

Leukemia, on the other hand, is a malignant clonal growth of hematopoietic progenitor cells that eventually results in marrow failure and systemic symptoms. It is characterized by dysregulated proliferation, poor apoptosis, and bone marrow infiltration (Arber et al., 2022). Confusion between LR and leukemia has important therapeutic ramifications because misdiagnosis can lead to greater morbidity, psychological discomfort, and financial burden, as well as needless exposure to cytotoxic chemotherapy and delayed treatment of the underlying cause.

Although diagnosis accuracy has increased with to developments in hematopathology, molecular diagnostics, and immunophenotyping, there are still many obstacles to overcome, especially in settings with limited resources and atypical presentations.

In addition to discussing the clinical, laboratory, cytogenetic, and molecular methods necessary for a precise diagnosis, this article attempts to give a thorough overview of leukemoid reaction, highlighting the diagnostic difficulties in distinguishing it from leukemia.

Methods

An exhaustive study of peer-reviewed English-language literature was used to perform this narrative review. Hematology textbooks, review articles, clinical studies, case reports, and consensus guidelines obtained from major medical journals, PubMed, and Scopus were among the sources. Leukemoid reaction, hyperleukocytosis, leukemia differential diagnosis, leukocyte alkaline phosphatase, chronic myeloid leukemia, chronic neutrophilic leukemia, bone marrow examination, and molecular diagnostics were among the keywords utilized in the literature search. Articles about laboratory indicators, clinical differentiation, diagnostic criteria, and developing molecular approaches were given special attention. The IMRaD framework was followed in the synthesis and thematic presentation of the data.

Results

1. Leukemoid Reaction Definition and Epidemiology

A leukemoid reaction is a physiological reaction to systemic stress that is characterized by a non-malignant leukocytosis greater than 50,000 cells/µL, mostly comprising mature neutrophils and their progenitors (Sakka et al., 2006). Eosinophilic, lymphocytic, and monocytic variations have also been documented, however neutrophilic leukemoid reactions are the most prevalent.

Due to underreporting and overlap with other leukocytosis causes, it is challenging to ascertain the actual incidence of LR. Hospitalized patients especially those in intensive care units as well as those with serious infections, cancers, or inflammatory diseases are more likely to experience it (Bain, 2020).

2. The pathological evaluation

Leukemoid response is caused by cytokine-mediated bone marrow stimulation, which speeds up granulopoiesis and releases leukocytes into the peripheral bloodstream too soon. G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) are important mediators (Hoffman et al., 2018).

Tumor cells may ectopically create hematopoietic growth factors in paraneoplastic leukemoid reactions, causing chronic leukocytosis that only goes away when the underlying cancer is treated. Crucially, unlike the autonomous clonal proliferation observed in leukemia, hematopoiesis in LR remains polyclonal and controlled despite high leukocytosis.

3. Leukemoid Reaction Etiology

1.      Typical causes include of:

2.      Severe bacterial infections, such as pneumonia, TB, and sepsis

3.      Non-hematologic cancers (renal, gastrointestinal, and lung carcinomas)

4.      Hemolysis and acute bleeding

5.      severe metabolic problems, such as diabetic ketoacidosis

6.      Autoimmune and inflammatory diseases

7.      reasons brought on by drugs (corticosteroids, colony-stimulating factors)

8.      Poisoning and intoxications

9.      Stress following surgery and trauma

10.  One of the most important steps in distinguishing leukemia from LR is determining the underlying etiology.

4.Laboratory and Hematological Features

4.1 Differential and Complete Blood Count

LR usually manifests as:

1.      elevated leukocytosis (>50,000/µL)

2.      Mature neutrophils predominate

3.      Myelocytes and metamyelocytes on the left shift

4.      Blasts that are uncommon or nonexistent

5.      Elevated or normal platelet counts

6.  Anemia, thrombocytopenia, and an increased percentage of blasts can accompany leukocytosis in leukemia.

4.2 Smear of Peripheral Blood

1.      Examining peripheral smears is essential. Leukemoid responses show:

2.      Granulations that are toxic

3.      Döhle bodies

4.      Vacuolization of the cytoplasm

5.      Mostly developed cells

6.      Leukemia frequently manifests as:

7.      A rise in explosions

8.      Features of dysplasia

9.      In AML, Auer rods

10.  Populations of monomorphic cells

4.3 score for Leukocyte Alkaline Phosphatase (LAP)

Traditionally, the LAP score is lower in chronic myeloid leukemia (CML) and higher in LR. Due to overlap with other myeloproliferative neoplasms, such as chronic neutrophilic leukemia (CNL), its diagnostic usefulness has decreased despite its prior utility (Bain, 2020).

Table 1. Key Laboratory Differences Between Leukemoid Reaction and Leukemia

5. Bone Marrow Examination's Function

When the diagnosis is still unclear, bone marrow aspiration and biopsy are essential. While leukemia exhibits clonal proliferation, blast excess, and marrow replacement, LR exhibits myeloid hyperplasia with maintained maturation (Arber et al., 2022).

6. Molecular and Cytogenetic Diagnostics

Differentiation is mostly determined by molecular studies:

1.      CML is confirmed by the BCR-ABL1 fusion gene.

2.      Mutations in JAK2 and CSF3R may indicate myeloproliferative tumors.

3.      LR is favored when clonal markers are absent.

By detecting aberrant immunophenotypes typical of leukemia, flow cytometry provides additional support.

Discussion

Due to similar clinical and laboratory characteristics, distinguishing leukemoid reaction from leukemia is still a difficult diagnostic task. Since these disorders may present with comparable WBC counts, extreme leukocytosis alone is insufficient for diagnosis. Integrating clinical context with hematological, cytogenetic, and molecular results is the cornerstone of differentiation.

Reactive alterations in patients with severe infections or malignancy-associated leukocytosis, which closely mimic chronic leukemias, are among the most common diagnostic mistakes. On the other hand, early leukemia may appear subtly at first and be confused with a reactive process.

Although diagnostic ambiguity has been greatly decreased by advances in molecular diagnostics, accessibility is still restricted in many areas. Therefore, it is still crucial to use a step-by-step diagnostic procedure that starts with clinical examination, moves on to peripheral smear analysis, basic laboratory testing, and sophisticated diagnostics when necessary.

Inappropriate management techniques, needless chemotherapy, delayed treatment of underlying causes, and unfavorable patient outcomes could arise from a failure to accurately differentiate leukemia from LR.

Conclusion

A benign yet striking hematological reaction that resembles leukemia is called a leukemoid reaction. Due to significant variations in prognosis and treatment, accurate distinction is crucial. It is essential to use a thorough diagnostic strategy that incorporates molecular research, peripheral smear analysis, bone marrow examination, laboratory evaluation, and clinical assessment. Diagnostic accuracy and patient care will be further enhanced by ongoing developments in diagnostic technologies and clinician knowledge.

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