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Year : 2020  |  Volume : 16  |  Issue : 1  |  Page : 186-188

A case of paraneoplastic hyperleukocytosis closely mimicking chronic neutrophilic leukemia

1 Department of Hematology, SGPGI, Lucknow, Uttar Pradesh, India
2 Department of Pathology, SGPGI, Lucknow, Uttar Pradesh, India

Date of Submission11-Aug-2016
Date of Decision20-Sep-2016
Date of Acceptance01-Oct-2016
Date of Web Publication03-Feb-2017

Correspondence Address:
Navkirti Mittal
Department of Hematology, SGPGI, Lucknow - 226 014, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.199434

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 > Abstract 

Leukemoid reaction and myeloproliferative syndrome are close mimickers and frequently pose a diagnostic dilemma, particularly when the leukocyte count is very high. Leukocyte alkaline phosphatase score frequently aids in diagnosis but may or may not be contributory, especially in differentiating chronic neutrophilic leukemia. Herein, we document a case of leukemoid reaction with extensive hyperleukocytosis in a 46-year-old female with poorly differentiated carcinoma. The tumor itself as well as the associated leukocytosis portends a poor prognosis.

Keywords: Diagnostic dilemma, hyperleukocytosis, leukocyte alkaline phosphatase score, leukemoid reaction, myeloproliferative syndrome

How to cite this article:
Mittal N, Gupta R, Rahman K, Singh P, Panda I, Nityanand S. A case of paraneoplastic hyperleukocytosis closely mimicking chronic neutrophilic leukemia. J Can Res Ther 2020;16:186-8

How to cite this URL:
Mittal N, Gupta R, Rahman K, Singh P, Panda I, Nityanand S. A case of paraneoplastic hyperleukocytosis closely mimicking chronic neutrophilic leukemia. J Can Res Ther [serial online] 2020 [cited 2022 Jan 18];16:186-8. Available from: https://www.cancerjournal.net/text.asp?2020/16/1/186/199434

 > Introduction Top

Hyperleukocytosis is defined as a leukocyte count >100,000 cells/μL.[1] It is usually associated with myeloproliferative neoplasms (MPNs) or a consequence to varied etiologies such as infections, malignancies, intoxications, severe hemorrhage, and acute hemolysis.[1] Reported here is a case of paraneoplastic hyperleukocytosis associated with a total leukocyte count (TLC) of more than 200 × 109/L and absolute neutrophil count of 197 × 109 cells/μL, thereby closely mimicking chronic neutrophilic leukemia (CNL). To the best of our knowledge, this is the first case report of paraneoplastic hyperleukocytosis with such high counts.

 > Case Report Top

A 46-year-old female presented with pain in the left lumbar region radiating to groin with loss of appetite, dyspepsia, and intermittent fever of 15 days duration. There was no history of associated constitutional symptoms such as night sweats or weight loss. There was no history of recent drug intake, particularly growth factors and corticosteroids. On examination, she had tenderness in the left iliac fossa on deep palpation; however, there was no palpable organomegaly. Computed tomography (CT) of the abdomen showed a large well-defined, hypodense, heterogeneous space occupying lesion of size 7.5 cm × 7.2 cm × 10.4 cm in the retroperitoneum occupying the left lumbar fossa and iliac fossa region. The mass was present along the belly of left psoas muscle. Magnetic resonance imaging scan revealed well-defined heterogeneously enhancing mass in the retroperitoneum at the level of organ of Zuckerkandl. The left adrenal and kidney were identified separately from the mass. CT-guided paravertebral mass biopsy revealed a malignant tumor, the cells of which showed moderate to severe nuclear pleomorphism, hyperchromatic nuclei, occasional prominent nucleoli, and scant to moderate amount of eosinophilic cytoplasm. On immunohistochemistry (IHC), the tumor cells were positive for cytokeratin (CK) (strong and diffuse), vimentin (moderate and focal), and CK7 and thyroid transcription factor 1 (faintly positive). The cells were negative for CD10 and CK20, overall suggesting a poorly differentiated malignant epithelial tumor with sarcomatoid differentiation [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d. Further, synaptophysin, S100 (IHC stains) were negative and 24 h urine metanephrine and normetanephrine levels were near-normal, ruling out the possibility of paraganglioma. Her complete blood count analysis revealed a TLC of 215 × 109/L, hemoglobin of 8.7 g/dl, platelet count of 274 × 109/L. Other comprehensive blood tests, including kidney function, liver function test, and electrolytes, were normal. Peripheral blood smears showed striking neutrophilia [Figure 2] with the absence of shift cells such as myelocytes, metamyelocytes, or band cells. A few activated neutrophils showing toxic granules and cytoplasmic vacuoles were noted. Besides, there was no basophilia, eosinophilia, monocytosis, or any dysplasia feature. Leukocyte alkaline phosphatase (LAP) score was high normal [Figure 2] inset]. Blood and urine cultures were sterile. Qualitative as well as quantitative polymerase chain reaction for JAK2V617F and all three BCR-ABL transcripts, namely p190, p210, and p230, were negative [Figure 3]. Immunophenotypic characteristics of neutrophils gated in bright CD45 region with high-side scatter showed CD13 positive, CD15 positive while being negative for CD34 and Human Leucocyte Antigen-D related (HLA-DR). The patient had a rapid downhill course and was subsequently lost to follow-up.
Figure 1: Histological section (a) showing malignant tumor cells with moderate to severe nuclear pleomorphism, hyperchromatic nuclei, occasional prominent nucleoli, and moderate amount of eosinophilic cytoplasm. Immunohistochemistry (b-d) showing tumor cell positivity for cytokeratin (b) (strong and diffuse), vimentin (c) (moderate and focal), and negative for leukocyte common antigen (d); (a: H and E, oil immersion, b: IHC, oil immersion, c and d: ×40)

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Figure 2: Peripheral blood smears showing neutrophilia with the absence of shift cells such as myelocytes and metamyelocytes. Other cell lines such as eosinophils, basophils, and monocytes are not seen (Leishman, ×40). Inset – Stain with leukocyte alkaline phosphatase was high normal in the neutrophils (oil immersion)

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Figure 3: Polymerase chain reaction for JAK2V617F (a) and BCR-ABL (b) showing negative results

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 > Discussion Top

Paraneoplastic hyperleukocytosis is a rare condition that can be challenging to diagnose and requires a comprehensive workup. Hyperleukocytosis has been described in patients with varied solid malignancies such as lung, skin, urothelial cancer and sarcomas.[2],[3],[4] A retrospective study by Granger et al . over a period of 3 years revealed approximately 20% (758/3770) cases of solid tumors associated with leukocytosis, of which 10% (77) patients had a paraneoplastic etiology, whereas others were found to be associated with infections and drugs, particularly growth factors.[2] Lung cancer was found to be the most common culprit malignancy. The mechanism of neutrophilia is attributed to an accelerated release of neutrophils from the bone marrow, which might be the result of underlying tumoral secretion of cytokines, granulocyte colony-stimulating factor (G-CSF), and interleukin-6.[5],[6] G-CSF is a pleiotropic cytokine known for its specific effects on the proliferation and activation of hematopoietic cells of the neutrophilic granulocyte lineage. G-CSF-producing tumors are typically poorly differentiated, rapidly progressing and with a large tumor burden and have been found to have a dismal prognosis.[7] Stathopoulos et al . analyzed the prognostic significance of G-CSF in nonsmall cell lung cancers and observed a shorter survival in patients with high leukocyte count and is elevated G-CSF levels.[8] Dorn et al . described a case of 57-year-old woman with very high leukocyte count, having a poorly differentiated neoplasm which was associated with rapidly progressive course suggesting that hyperleukocytosis in solid tumors, invariably portents an inferior outcome.[9]

In cancer patients with a high leukocyte count, a series of meticulous investigations should be carried out to rule out other secondary causes such as infections, drug intake, or coexistent leukemia. The previously reported leukocyte counts in such scenario usually ranged from 40,600/μL to 115,100/μL, with a mean of 53,000/μL; however, the current case had an extremely high leukocyte count of 215,000/μL, thereby raising the clinical suspicion of a concomitant MPN. However, the absence of splenomegaly, left shift, blasts, eosinophilia, basophilia, thrombocytosis, and BCR-ABL fusion transcript aided in excluding MPN. Nonetheless, differentiating between paraneoplastic hyperleukocytosis and CNL would be challenging because both conditions share identical morphological features, including predominant neutrophilia, a raised LAP score, and the absence of the BCR/ABL translocation.[10] Although few authors have proposed the role of HLA-DR in differentiating reactive neutrophilia from CNL, its validity of immunophenotyping as a differential tool is not established. The neutrophils, in reactive hyperleukocytosis, are negative for HLA-DR, as was seen in our case.[10] A few studies have shown usefulness of human androgen receptor gene assay and presence of cytogenetic abnormalities in some cases.[11] Recently described mutations included in the diagnostic criteria of CNL are CSF 3R T618I or other activating CSF3R mutations.[12] However, owing to the limited availability of these diagnostic tests, the CNL mainly remains a diagnosis of exclusion. Since the present case had a retroperitoneal neoplastic mass, absence of hepatosplenomegaly, and rapid deteriorating condition of the patient, a diagnosis of paraneoplastic hyperleukocytosis was entertained.

 > Conclusion Top

Paraneoplastic leukocytosis is an uncommon manifestation of solid tumors. A thorough workup is required to differentiate it from MPN. Moreover, it requires a timely surgical intervention since it is known to have a poor prognostic impact as was seen in our patient as well.


We would like acknowledge Mr. Akhilesh, Technical Staff, Flow Cytometry Laboratory.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

Nimieri HS, Makoni SN, Madziwa FH, Nemiary DS. Leukemoid reaction response to chemotherapy and radiotherapy in a patient with cervical carcinoma. Ann Hematol 2003;82:316-7.  Back to cited text no. 1
Granger JM, Kontoyiannis DP. Etiology and outcome of extreme leukocytosis in 758 nonhematologic cancer patients: A retrospective, single-institution study. Cancer 2009;115:3919-23.  Back to cited text no. 2
McKee LC Jr. Excess leukocytosis (leukemoid reactions) associated with malignant diseases. South Med J 1985;78:1475-82.  Back to cited text no. 3
Sreevatsa A, Babu SM, Babu GK, Suresh TM. Hyperleukocytosis, an unusual paraneoplastic manifestation of lung cancer: Case report and review of literature. J Cancer Res Ther 2015;11:669.  Back to cited text no. 4
Asano S, Urabe A, Okabe T, Sato N, Kondo Y. Demonstration of granulopoietic factors in the plasma of nude mice transplanted with a human lung cancer and in the tumor tissue. Blood 1977;49:845-52.  Back to cited text no. 5
Sawyers CL, Golde DW, Quan S, Nimer SD. Production of granulocyte-macrophage colony-stimulating factor in two patients with lung cancer, leukocytosis, and eosinophilia. Cancer 1992;69:1342-6.  Back to cited text no. 6
Kasuga I, Makino S, Kiyokawa H, Katoh H, Ebihara Y, Ohyashiki K. Tumor-related leukocytosis is linked with poor prognosis in patients with lung carcinoma. Cancer 2001;92:2399-405.  Back to cited text no. 7
Stathopoulos GP, Armakolas A, Tranga T, Marinou H, Stathopoulos J, Chandrinou H. Granulocyte colony-stimulating factor expression as a prognostic biomarker in non-small cell lung cancer. Oncol Rep 2011;25:1541-4.  Back to cited text no. 8
Dorn C, Bugl S, Malenke E, Müller MR, Weisel KC, Vogel U, et al. Paraneoplastic granulocyte colony-stimulating factor secretion in soft tissue sarcoma mimicking myeloproliferative neoplasia: A case report. BMC Res Notes 2014;7:313.  Back to cited text no. 9
Sakka V, Tsiodras S, Giamarellos-Bourboulis EJ, Giamarellou H. An update on the etiology and diagnostic evaluation of a leukemoid reaction. Eur J Intern Med 2006;17:394-8.  Back to cited text no. 10
Böhm J, Kock S, Schaefer HE, Fisch P. Evidence of clonality in chronic neutrophilic leukaemia. J Clin Pathol 2003;56:292-5.  Back to cited text no. 11
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391-405.  Back to cited text no. 12


  [Figure 1], [Figure 2], [Figure 3]

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