The Significance of Leukocytosis in Malignancies: A Novel Paradigm Between Leukocytosis, G-CSF, Myeloid-Derived Suppressor Cells and Prognosis
Authors: Tavakkoli Montreh , Wilkins Cy , Mones Jodi V , Mauro Michael J. 
Published: October 2019

Abstract
In clinical practice, leukocytosis is often overlooked after infectious and hematologic disease are ruled out, particularly in patients with solid tumors. This is unfortunate, as the mechanisms that mediate paraneoplastic leukocytosis may play a significant role in the underlying pathophysiology of cancer progression and prognosis. The relatively new discovery of neutrophilic and monocytic myeloid-derived suppressor cells (MDSCs) and their role in mediating tumor metastasis has particularly shed light into this process [Annu Rev Med, 66:97-110 (2015)].
Here, we present the case of a 58-year old gentleman with non-small cell lung cancer complicated by brain metastasis, status post resection who presented with sepsis and acute kidney injury (AKI) requiring ICU care for worsening AKI, hypoxic respiratory failure and leukocytosis. His peak WBC count, absolute neutrophilia and monocytosis were: 178.1, 172.7 and 4.2k/µL, respectively. His peripheral blood smear revealed mature neutrophils with left-shift and no blast forms. The underlying etiology of his leukocytosis was initially attributed to steroids administration and infection (Figure 1). His leukocytosis progressed, however, despite improvement in his sepsis and tapering of his steroids. Thus, we suspected either an evolving hematologic neoplasm or exogenous secretion of G-CSF by his tumor. Nonetheless, given his worsening clinical status, we initiated empiric hydroxyurea and leukapheresis. His FISH and PCR for BCR-ABL were negative in addition to the absence of leukemia-associated mutations and gene fusions and a normal phenotype by flow cytometry. However, we detected the highest documented level of G-CSF secreted by any tumor in the literature at 41,108.6pg/mL (normal <39.1pg/mL), confirming that the etiology of his marked leukocytosis was indeed exogenous secretion of G-CSF by his cancer.
On evaluation of this patient's clinical history, his malignancy and white count were stable until day 388 of his diagnosis when he developed new onset leukocytosis and neutrophilia associated with disease progression and metastasis. Furthermore, he died within 23 days of developing peak leukocytosis, neutrophilia and monocytosis and the discovery of his profoundly elevated G-CSF level. The association between the onset of his leukocytosis with the discovery of his disease progression and metastasis suggest that G-CSF secretion and leukocytosis may have been linked to his poor prognosis.
We performed an extensive literature review and found that neutrophilic and monocytic MDSCs may provide a potential explanation for this phenomenon. We believe that leukocytosis in the setting of solid neoplasms may be driven by increased G-CSF secretion by tumors or tumor microenvironments. Additionally, G-CSF secretion fosters the expansion of neutrophilic and monocytic MDSCs, which play a significant role in tumor progression and metastasis and may contribute to poor prognosis [PNAS 106(16): 6742-7 (2009), PNAS 107(50): 21248-55 (2010)]. Consequently, we believe that the significance of leukocytosis in patients with solid tumors should not be overlooked and that there may exist a novel, untapped paradigm between paraneoplastic G-CSF secretion, leukocytosis, neutrophilic and monocytic MDSCs and prognosis.

Disclosures
Mauro: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy.