Fever and leukemoid reaction in bladder cancer: a

case report and review of the literature

Tianrun Huang
Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai Unicersity of Traditional
Chinese Medicine
Jiguo Xu
Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai Unicersity of Traditional
Chinese Medicine
Jingyuan Lu
Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai Unicersity of Traditional
Chinese Medicine
Parehe Alimu
Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai Unicersity of Traditional
Chinese Medicine
Chunlei Chen
Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai Unicersity of Traditional
Chinese Medicine
Chenlong Chu
Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai Unicersity of Traditional
Chinese Medicine
Jianhe Liu (  ljianh@126.com )
Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai Unicersity of Traditional
Chinese Medicine

Short Report

Keywords: Leukemoid reaction, Bladder cancer, Case report

Posted Date: January 11th, 2023

DOI: https://doi.org/10.21203/rs.3.rs-2459100/v1

License:   This work is licensed under a Creative Commons Attribution 4.0 International License.
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Abstract
Background: to discuss the diagnosis, treatment and mechanism of leukemoid reaction in bladder cancer.

Methods: to present and analyze the clinical data of a patient who had urothelial carcinoma complicated
with leukemoid reaction

Result: The patient had years of smoking history. He underwent six TURBT operations during the time of
31st Aug 2015 to 26th Oct 2022. Pathological diagnosis deteriorated from low-grade papillary urothelial
carcinoma to high-grade. The patient did not keep to regular bladder perforation or routine follow-
up cystoscopy. He also refused radical resection intervention. Last CT results show the following:
multiple tumors in the bladder, bilateral ureter bladder entrance invasion, bilateral renal pelvis and ureter
dilatation , multiple lymphadenopathy in the pelvis and along the right iliac artery. After cystoscopy
examination and urethral catheter was placed, creatinine level gradually decreased. However, body
temperature raised from 38 oC to 40o C. White blood cell count increased from 67.83*109/L
(neutrophils being 64.5*109/L) to 72.17*109/L (neutrophils being 70.27*109/L). The patient was
considered to have leukemoid reaction complicated with bladder cancer. The patient refused to have
bone marrow biopsy, palliative care was provided instead. The patient passed away on 28th Oct 2022.

Conclusion: Bladder cancer patients complicated with leukemoid reactions are rarely reported clinically.
Even after surgical resection, the outcome was poor. Monitoring of G-CSF level in blood can help to make
predictions of the patient’s health condition. Blocking the G-CSF signaling pathway might work as a
future therapeutic target for bladder cancer complicated with leukemia reaction.

Introduction
The incidence of bladder cancer ranks 9th among malignant tumors in the world, 7th for men. Muscular
invasive bladder cancer is a fatal malignant tumor and ranks 13th in mortality for malignant tumors.[1]
Smoking is a well-evidenced risk factor for developing bladder cancer, and increases the risk of bladder
cancer by 2–3 fold. Risk of bladder cancer increases with duration and amount smoked.[2–4] Common
treatments of bladder cancer include transurethral resection of bladder tumors (TURBT), bladder irrigation
and radical cystectomy.

Paraneoplastic syndromes refer to groupings of symptoms that occur in patients with malignant tumors
that cannot be readily explained by local invasion or distant metastasis of the tumor. Instead, these
symptoms might be related to primary tumor autocrine hormone or cytokine. A white blood cell count
exceeding 50*109/L associated with a cause outside evidence of leukemia or infection is termed as
leukemoid reaction[5]. Leukemoid reaction has been reported in nearly all solid tumor types as a
paraneoplastic syndrome, ranging from 1–4%[6]. Furthermore, the leukemoid reaction has been widely
observed clinically to appear at an advanced stage of cancer in association with highly invasive and
metastatic [7–9]. Bladder cancer, especially urothelial carcinoma, is rarely associated with leukemoid

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reaction. In the world literature, there have been with less than 40 cases reported over the past 40 years,
most of them got poor outcome within months[7, 10, 11]. Here, we present a rare case of urothelial
carcinoma complicated with leukemoid reaction. The clinical and histological features are described, and
the literature describing these rare cases are also reviewed.

Case Presentation
The patient had underwent several TURBT surgeries and he had been having hematuria and decreased
urine for 2 months before he was admitted into the hospital. He was a Shanghai native, aged 62 with
approximately 40 years of smoking. The patient visited doctor for hematuria on Aug 31st 2015.
Cystoscopy examination was performed and the results showed cauliflower-like in right wall of bladder.
TURBT was then performed. Pathological diagnosis after surgery was papillary urothelial carcinoma, UC,
pTa, low grade.

The patient had bladder irrigation ( epirubicin ) on regular basis for one year. During the year, he also had
cystoscopy examination regularly and there was no sign of recurrent bladder cancer. On Oct 13th 2016,
when the patient had his regular cystoscopy examination, tumor was found on right and top wall of
bladder. He then had another TURBT operation. Pathological diagnosis after the operation was papillary
urothelial carcinoma, UC, pTa, low grade. In the following year, he had bladder irrigation on regular basis.
On Mar 23rd 2018, the patient had visible blood in his urine. Cystoscopy results showed tumors on right
and top walls of bladder. TURBT was performed again. Pathological diagnosis after surgery was
papillary urothelial carcinoma, high grade, non-muscle invasive. On June 15th 2018, tumors were found
on both walls of bladder during the patient’s regular cystoscopy examination. TURBT was once again
performed. Pathological diagnosis after surgery was papillary urothelial carcinoma, high grade. On Aug
26th 2019, the patient had his regular cystoscopy examination and tumor was found once again on left,
right and top walls of the bladder. The patient refused further treatment and there was no follow-up visits.

On May 17th 2021, the patient was admitted into hospital for hematuria. Cystoscopy examination
showed multiple tumors in urethra, trigone and both walls of the bladder. He had another TURBT on May
19th 2021. Pathological diagnosis after surgery was papillary urothelial carcinoma, high grade. Post-
surgery treatment was still bladder irrigation. On July 1st 2021, the patient had his regular cystoscopy
examination and the result still showed multiple tumors in urethra, trigone and both walls of the bladder.
Radical cystectomy was then suggested, but the patient refused it. Rather, TURBT was performed on July
2nd 2021. Pathological diagnosis after surgery was papillary urothelial carcinoma, high grade. After the
surgery, the patient did not keep to regular bladder irrigation nor follow-up cystoscopy.

In August 2022, the patient started to have painless visible hematuria and decreased urine without an
obvious cause. He was then admitted into hospital on Oct 26th 2022. Body temperature was 38oC.
Urinalysis showed 500/µL leukocyte and 3 + leukocyte esterase. Blood analysis showed WBC of
67.83*109/L with neutrophils 64.5*109/L, CRP 150.43mg/L and creatinine 1006 µmol/L.

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Urology CT scan results were: 1. multiple tumors in the bladder, bilateral ureter bladder entrance invasion,
bilateral renal pelvis and ureter dilatation 2. multiple lymphadenopathy in the pelvis and along the right
iliac artery (show in Fig. 1). Meropenem was given as anti-infective therapy. Cystoscopy under local
anesthesia: multiple tumors in posterior urethra, bladder urethra and bladder walls; no tumors in bilateral
ureter. A biopsy sample was taken and urinary catheter was placed. Pathological diagnosis was papillary
urothelial carcinoma, high grade, massive necrosis (show in Fig. 2)

On Oct 27th 2022, the patient’s body temperature increased to 39.2 C. Blood analysis showed WBC of
72.17*109/L with neutrophils 70.27*109/L, CRP 95.65 mg/L and creatinine 577 µmol/L. The patient
refused to have bone marrow biopsy. Taking into account the patient’s poor health condition as well as
high risk of surgery and anesthesia, palliative care was provided instead. Body temperature dropped to
38.6 C after injection of aminopyrine during night time. On Oct 28th 2022, the patient’s body temperature
increased again to 40 C. Blood analysis showed WBC of 53.89*109/L with neutrophils 50.87*109/L, CRP
60.65 mg/L and creatinine 480 µmol/L. The patient passed away that afternoon. The time course of the
disease is summarized in Table 1. The graph demonstrates changes in temperature, white blood cell
count, CRP and creatinine showed in Fig. 3.

Table 1
Timeline of the disease
Date Treatment Findings

2015.8.31 TURBT1+ Bladder Irrigation UC, pTa, low grade,

2016.10.31 TURBT2+ Bladder Irrigation UC, pTa, low grade,

2018.3.23 TURBT3+ Bladder Irrigation UC, pTa, low grade,

2018.6.15 TURBT4+ Bladder Irrigation UC, pTa, high grade,

2019.8.26 Cystoscopy Bladder tumor and refused further treatment

2021.5.19 TURBT5+ Bladder Irrigation UC, pTa, high grade

2021.7.2 TURBT6+ Bladder Irrigation UC, pTa, high grade and reject total cystectomy

2022.10.26 CT and Cystoscopy Multiple tumors in the bladder, multiple

lymphadenopathy, bilateral ureter bladder entrance
invasion, bilateral renal pelvis and ureter dilatation

2022.10.28 Palliative treatment The patient passed away

Discussion
In urology malignancies, renal tumor associated with leukemia reactions is most commonly observed.
Bladder tumor, especially urothelial carcinoma, associated with leukemia reactions are extremely rare[12].
The likelihood of leukemia reactions is higher for cancer patients with an older age or a higher grade of
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tumor. Leukemia reactions, according to the type of leukocytes, can be divided into: neutrophilic
leukemoid reactions, lymphocytic leukemoid reactions, monocytic leukemoid reactions, eosinophilic
leukemoid reactions, of which neutrophilic leukemoid reactions are the most common[13].

The patient had years of smoking history and did not have regular cystoscopy follow-ups and bladder
irrigation. Since the patient had hematuria, decreased urine and fever, urinalysis also suggesting urinary
tract infection, antibiotic treament was provided, followed by cystoscopy examination. Some
investigators report urinary tract infection rates of 5%-10% after transurethral surgery, despite proper
prophylactic antibiotics[14]. However, antibiotic treatment did not help with continued rising of body
temperature and blood WBC count continued to rise, indicating that anti-infective therapy was ineffective.
Hence, it was deducted that the patient did not have infections, instead, he had leukemia reactions,
mainly neutrophilic leukemoid reactions.

The last CT scan of the patient suggested multiple tumors in the bladder, multiple lymphadenopathy. The
mechanism of fever and leukemia reactions caused by urothelial carcinoma of the bladder may be as
follows: urothelial cancer cells stimulate and infiltrate lymph nodes, macrophages produce a large
number of cytokines, such as IL-6, TNF-α, etc., and malignant tumor cells produce a large amount of
endotoxin after necrosis, causing the patient to have symptoms such as fever.

Meanwhile, cytokines stimulate and activate the production of T cells, or autocrine granulocyte
Granulocyte-colony stimulating factor(G-CSF), promoting the differentiation and proliferation of
granulocytes and significantly increasing peripheral leukocytes and neutrophils. Urothelial carcinoma
may also lead to bone marrow microinvasion, stimulating myelofibrosis leading to extramedullary
hematopoiesis, resulting in further elevation of peripheral leukocytes[7, 15].

Chemotherapy could be an option for patients who refused or no chance for surgical intervention;
however, taking into account the decreased renal function (on 2022.10.26, creatinine was 1006 µmol/L)
and rapid rising of body temperature, the patient was considered not fit for gemcitabine and cisplatin
chemotherapy. Surgical resection is considered to be the most effective treatment for UC combined with
leukemoid reaction[16, 17], the above unusual features normalized after removal of the tumor[18, 19]. But
it often does not guarantee prolonged remission. After developing leukocytosis, patients often die within
months despite surgical intervention[15, 20–24].

In urology malignancies, leukocytosis associated with increased G-CSF expression seems to primarily
relate to bladder cancers and is less prevalent in other malignancies[12]. In the normal physiologic state,
G-CSF stimulates proliferation and differentiation of neutrophil colony forming cells and alters several
functions of mature neutrophils. During leukemoid reaction, increased G-CSF expression is associated
with increased leukocytosis and promote a growth advantage to bladder cancer cells[25]. About 9% of
bladder cancer patients have increased G-CSF level. They have a lower overall 5-year survival rate,
compared with those whose G-CSF level does not increase[26]. Tachibana observed higher G-CSF level
and expression in cancer cells of a 76-year old urothelial carcinom patient complicated with leukemoid

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reaction. It was also found that increasing G-CSF exogenously stimulates cancer cell proliferation, and
this stimulation was inhibited by adding anti-G-CSF antibody[27].

The mechanisms of CSF autocrine and paracrine in bladder malignancies may be associated with re-
arrangement of the G-CSF gene occurring within one of the alleles[28] and intrinsic activation of nuclear
factors that work on the promoter region of the G-CSF gene[29].G-CSF/G-CSFR biological axis promotes
the expression of STAT3 protein, thereby promoting the growth of bladder cancer cells. In addition, G-CSF
can induce the expression of β-1 integrin in bladder malignant tumor cells, and β-1 integrin further acts on
fibronectin and laminin, thereby promoting the invasion and metastasis of bladder cancer cells[30, 31].

Conclusion
Bladder cancer patients complicated with leukemoid reactions are rarely reported clinically. Even after
surgical resection, the outcome was poor. Monitoring of G-CSF level in blood can help to make
predictions of the patient’s health condition. Blocking the G-CSF signaling pathway might work as a
future therapeutic target for bladder cancer complicated with leukemia reaction.

Declarations
Acknowledgements

Not applicable.

Authors’ contributions

Performed the analysis: Tianrun Huang, Jiguo Xu, Jingyuan Lu, Parehe Alimu, Chunlei Chen, Chenlong
Chu and Jianhe Liu Wrote the Manuscript: Tianrun Huang and Jiguo Xu. All authors read and approved
the final manuscript.

Funding

No Funding

Availability of data and materials

Please contact author for data requests.

Ethics approval and consent to participate

All procedure was approved by Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai
Unicersity of Traditional Chinese Medicine

Consent for publication

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Not applicable.

Competing interests

The authors declare that they have no competing interests.

References
1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer
Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185
Countries. Cancer J Clin. 2021;71(3):209–49.
2. Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, Kassouf W, Kiemeney LA, La
Vecchia C, Shariat S, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol.
2013;63(2):234–41.
3. Chavan S, Bray F, Lortet-Tieulent J, Goodman M, Jemal A. International variations in bladder cancer
incidence and mortality. Eur Urol. 2014;66(1):59–73.
4. van Osch FH, Jochems SH, van Schooten FJ, Bryan RT, Zeegers MP. Quantified relations between
exposure to tobacco smoking and bladder cancer risk: a meta-analysis of 89 observational studies.
Int J Epidemiol. 2016;45(3):857–70.
5. Yu G, Ji H, Meng C, Huang Y, Gao G, Liu C, Wang S, Zhang L, Ju J. Esophageal adenocarcinoma with
leukemoid reaction: a case report. J Cardiothorac Surg. 2019;14(1):66.
6. Qing L, Xiang T, Guofu Z, Weiwei F. Leukemoid reaction in cervical cancer: a case report and review of
the literature. BMC Cancer. 2014;14:670.
7. Kumar AK, Satyan MT, Holzbeierlein J, Mirza M, Van Veldhuizen P. Leukemoid reaction and autocrine
growth of bladder cancer induced by paraneoplastic production of granulocyte colony-stimulating
factor–a potential neoplastic marker: a case report and review of the literature. J Med Case Rep.
2014;8:147.
8. Tachibana M, Murai M. G-CSF production in human bladder cancer and its ability to promote
autocrine growth: a review. Cytokines Cell Mol Ther. 1998;4(2):113–20.
9. Ishida K, Yuhara K, Kanimoto Y. [A case of bladder tumor producing granulocyte colony-stimulating
factor]. Hinyokika Kiyo. 2004;50(4):253–6.
10. Turalic H, Deamant FD, Reese JH. Paraneoplastic production of granulocyte colony-stimulating
factor in a bladder carcinoma. Scand J Urol Nephrol. 2006;40(5):429–32.
11. Kato T, Yasuda K, Iida H, Watanabe A, Fujiuchi Y, Miwa S, Imura J, Komiya A. Trousseau's syndrome
caused by bladder cancer producing granulocyte colony-stimulating factor and parathyroid hormone-
related protein: A case report. Oncol Lett. 2016;12(5):4214–8.
12. Shapiro DD, Potretzke A, Downs TM. Leukemoid reaction: a rare paraneoplastic syndrome in bladder
cancer associated with a grave prognosis. Urology. 2014;83(2):274–7.

Page 7/11
13. Harsha BS, Manikandan R, Sreerag KS, Dorairajan LN, Rajesh NG, Kar R. Eosinophilic Leukemoid
Reaction with Eosinophilic Tumor Tissue Infiltration as an Extermely Poor Prognostic Factor in
Urinary Bladder Cancer- a Known Entity Revisited. Pathol Oncol Res. 2020;26(4):2817–9.
14. Stricker PD, Grant AB. Relative value of antibiotics and catheter care in the prevention of urinary tract
infection after transurethral prostatic resection. Br J Urol. 1988;61(6):494–7.
15. Perez FA, Fligner CL, Yu EY. Rapid clinical deterioration and leukemoid reaction after treatment of
urothelial carcinoma of the bladder: possible effect of granulocyte colony-stimulating factor. J Clin
oncology: official J Am Soc Clin Oncol. 2009;27(34):e215–217.
16. Gaisa NT, Braunschweig T, Reimer N, Bornemann J, Eltze E, Siegert S, Toma M, Villa L, Hartmann A,
Knuechel R. Different immunohistochemical and ultrastructural phenotypes of squamous
differentiation in bladder cancer. Virchows Arch. 2011;458(3):301–12.
17. Matsuzaki K, Okumi M, Kishimoto N, Yazawa K, Miyagawa Y, Uchida K, Nonomura N. [A case of
bladder cancer producing granulocyte colony-stimulating factor and interleukin-6 causing respiratory
failure treated with neoadjuvant systemic chemotherapy along with sivelestat]. Hinyokika Kiyo.
2013;59(7):443–7.
18. Hirasawa K, Kitamura T, Oka T, Matsushita H. Bladder tumor producing granulocyte colony-
stimulating factor and parathyroid hormone related protein. J Urol. 2002;167(5):2130.
19. Stav K, Leibovici D, Siegel YI, Lindner A. Leukemoid reaction associated with transitional cell
carcinoma. Isr Med Assoc J. 2002;4(3):223–4.
20. Fernandez J, Claria J, Amoros A, Aguilar F, Castro M, Casulleras M, Acevedo J, Duran-Guell M, Nunez
L, Costa M, et al. Effects of Albumin Treatment on Systemic and Portal Hemodynamics and
Systemic Inflammation in Patients With Decompensated Cirrhosis. Gastroenterology.
2019;157(1):149–62.
21. Hoshi S, Numahata K, Morozumi K, Katumata Y, Kuromoto A, Takai Y, Hoshi K, Bilim V, Sasagawa I.
Bladder cancer metastasis producing beta-human chorionic gonadotropin, squamous cell carcinoma
antigen, granulocyte-colony stimulating factor, and parathyroid hormone-related protein. IJU Case
Rep. 2019;2(1):47–50.
22. Vaidyanathan S, Mansour P, Ueno M, Yamazaki K, Wadhwa M, Soni BM, Singh G, Hughes PL, Watson
ID, Sett P. Problems in early diagnosis of bladder cancer in a spinal cord injury patient: report of a
case of simultaneous production of granulocyte colony stimulating factor and parathyroid hormone-
related protein by squamous cell carcinoma of urinary bladder. BMC Urol. 2002;2(1):8.
23. Lin HC, Chai CY, Su YC, Wu WJ, Huang CH. Leukemoid reaction resulting from granulocyte colony-
stimulating factor producing urothelial carcinoma of the renal pelvis. Kaohsiung J Med Sci.
2007;23(2):89–92.
24. Sawazaki H, Taki Y, Takeuchi H. Granulocyte colony-stimulating factor (G-CSF) producing bladder
cancer subsequently developed from recurrent non-muscle invasive bladder cancer. Int J urology:
official J Japanese Urol Association. 2010;17(8):741–2.

Page 8/11
25. Chakraborty A, Guha S. Granulocyte colony-stimulating factor/granulocyte colony-stimulating factor
receptor biological axis promotes survival and growth of bladder cancer cells. Urology.
2007;69(6):1210–5.
26. Mizutani Y, Okada Y, Terachi T, Kakehi Y, Yoshida O. Serum granulocyte colony-stimulating factor
levels in patients with urinary bladder tumour and various urological malignancies. Br J Urol.
1995;76(5):580–6.
27. Tachibana M, Miyakawa A, Tazaki H, Nakamura K, Kubo A, Hata J, Nishi T, Amano Y. Autocrine
growth of transitional cell carcinoma of the bladder induced by granulocyte-colony stimulating
factor. Cancer Res. 1995;55(15):3438–43.
28. Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor. Blood.
1991;78(11):2791–808.
29. Nishizawa M, Tsuchiya M, Watanabe-Fukunaga R, Nagata S. Multiple elements in the promoter of
granulocyte colony-stimulating factor gene regulate its constitutive expression in human carcinoma
cells. J Biol Chem. 1990;265(10):5897–902.
30. Chakraborty A, White SM, Guha S. Granulocyte colony-stimulating receptor promotes beta1-integrin-
mediated adhesion and invasion of bladder cancer cells. Urology. 2006;68(1):208–13.
31. Chakraborty A, White SM, Lerner SP. Granulocyte colony-stimulating factor receptor signals for beta1-
integrin expression and adhesion in bladder cancer. Urology. 2004;63(1):177–83.

Figures

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Figure 1

Urology CT scan shows multiple tumors in the bladder (A), multiple lymphadenopathy in the pelvis and
along the right iliac artery (B), bilateral ureter bladder entrance invasion (C), resulting in bilateral renal
pelvis and ureter dilatation (D) (indicated by arrowheads).

Figure 2

2022.10.26 cystoscopy and bladder biopsy. Pathological diagnosis was papillary urothelial carcinoma,
high grade, massive necrosis (10x40).

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Figure 3

The graph demonstrates changes in temperature (A)，white blood cell count (B)，CRP (C) and creatinine
(D).

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