Korean J Urol Oncol 2015;13(3):134-137 Case Report

Leukemoid Reaction, a Rare in Urothelial Cell Carcinoma: Is It an Indicator of a Poor Prognosis? Ho Seok Chung, Bo Sung Shin, Ho Song Yu, Eu Chang Hwang, Sun-Ouck Kim, Sung Il Jung, Taek Won Kang, Dong Deuk Kwon, Kwangsung Park

Department of Urology, Chonnam National University Medical School, Gwangju, Korea

A leukemoid reaction is usually associated with malignancies of the lung, stomach, and thyroid. In contrast, urothelial cell carcinoma is rarely associated with leukemoid reactions, with few cases reported over the past 30 years. Here, we describe a patient with urothelial cell carcinoma who exhibited a leukemoid reaction. The patient had an elevated count and experienced a rapid and aggressive clinical course, terminating in death. For urothelial cell carcinoma patients exhibiting a leukemoid reaction, removal of the inciting tumor is the definitive treatment. However, considering the aggressive nature of these tumors, if the patient is unsuitable for radical surgical management, palliative chemotherapy should be considered. (Korean J Urol Oncol 2015;13:134-137) 󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏 Key Words: Urothelial cell carcinoma, Leukemoid reaction, Prognosis, Chemotherapy

A leukemoid reaction, defined as persistent of 30.0-50.0K/ml or greater without evidence of or in- CASE REPORT fection, is common in certain , including those of the lung, stomach, thyroid, kidney, and adrenal gland.1,2 However, A 67-year-old male with a 50 pack/year history of smoking the occurrence of leukemoid reactions in a patient with ur- presented with gross hematuria that had started 1 month earlier. othelial cell carcinoma, which is associated with a particularly His past medical history was significant for paraplegia with an poor outcome, has rarely been reported. Herein, we describe a indwelling cystostomy catheter and colostomy secondary to a patient with a rapidly progressive primary urinary bladder ur- spinal injury that occurred 40 years earlier. On admission, he othelial carcinoma who presented with a leukemoid reaction de- was febrile (101.4oF) with an elevated white blood cell (WBC) spite palliative chemotherapy. count (43.5K/ml), platelet count (499x109/L), serum calcium level (12.5mg/dl), and decreased hemoglobin level (7.6g/dl). A urine test showed hematuria (≥100/HPF), pyuria (≥100/HPF), and proteinuria (200mg/dl). Following a urine culture that was positive for extended-spectrum β-lactamase, the patient re-

Received August 5, 2015, Revised November 5, 2015, ceived intravenous imipenem for 2 weeks. Urine cultures were Accepted November 23, 2015 negative but WBC count showed no significant difference after Corresponding Author: Eu Chang Hwang, Department of Urology, antibiotics treatment. Contrast-enhanced abdominal and pelvic Chonnam National University Medical School, 42 Jebongro, Donggu, Gwangju 61469, Korea. computed tomography (CT) scans showed a large mass (5cm) Tel: 82-61-220-6700, Fax: 82-62-227-1643, in the right lateral wall of the urinary bladder with no meta- E-mail: [email protected] stasis (Fig. 1). To distinguish the mass from other infectious

134 Ho Seok Chung, et al：Leukemoid Reaction in Urothelial Cell Carcinoma 135 and malignant hematologic diseases, a peripheral blood smear, G-CSF (90.0mU/ml), LAP (293IU/L), and PTH-related peptide aspirate, and levels of JAK2, BCR-ABL, gran- (PTH-RP; 7.2pmol/L), and a decreased PTH level (1.6pg/ml). ulocyte colony-stimulating factor (G-CSF), leukocyte alkaline The peripheral blood smear showed thrombocytosis and leuko- phosphatase (LAP), and parathyroid hormone (PTH) were cytosis, with predominant mature neutrophilia and a left shift, evaluated. These examinations revealed elevated levels of but no immature forms. In addition, a chromosome analysis and bone marrow aspiration showed no abnormalities in JAK2 and BCR-ABL; thus, a leukemoid reaction due to a G-CSF-secret- Table 1. Summary of the patient’s laboratory findings ing tumor was suspected (Table 1). Age (years) 67 The patient underwent incomplete transurethral resection of Sex Male Primary tumor Bladder the bladder tumor because of the large tumor’s size with bleed- WBC count (K/ml) 43510 (4.0-10.8) ing and contracted bladder. A pathologic examination revealed 9 Platelet count (10 /L) 499 (130-450) a high-grade muscle-invasive urothelial cell carcinoma. After Serum calcium (mg/dl) 12.5 (8.4-10.2) surgery, the patient was afebrile with a high WBC count Peripheral blood smear , thrombocytosis G-CSF (mU/ml) 90 (4.3-32.9) (37.8K/ml). Unsuitable for radical surgical management be- PTH (pg/ml) 1.6 (11-54) cause of his performance status, the patient received palliative PTH-RP (pmol/L) 7.2 (0-1.1) 2 gemcitabine (1000mg/m on days 1, 8, and 15) and cisplatin Bone marrow aspiration Paraneoplastic leukemoid reaction 2 due to a G-CSF-secreting tumor (70mg/m on day 2) (GC) chemotherapy every 4 weeks. Before BCR-ABL Negative the first cycle of GC chemotherapy, baseline abdominal and JAK2 Negative chest CT scans showed aggravation of the bladder mass with

Fig. 1. Abdominal and pelvic CT scans of bladder with a leukemoid reaction. Images showing an (A) axial view and (B) coronal view revealed a large mass in the right lateral wall of the urinary bladder.

Fig. 2. Baseline abdominal and chest CT scans before the first cycle of GC chemotherapy demonstrated aggravation of the bladder mass with protrusion to the lower anterior abdominal wall and cystostomy site (A and B). 136 대한비뇨기종양학술지：제13권 제3호 2015 protrusion to the lower anterior abdominal wall and cystostomy from leukemia. Leukemoid reactions are characterized by ele- site, and bilateral pleural effusion (Fig. 2). After the first cycle vated levels of mature polymorphonuclear cells, whereas im- of GC chemotherapy, the patient’s WBC count was decreased mature cells are prominent in leukemia. Further, the LAP level to 1.4K/ml and his vital signs were stable; thus, he was dis- is normal or elevated in leukemoid reactions, whereas it is low charged from the hospital. in leukemic diseases. In addition, chromosome analysis can dis- However, at the start of the second cycle of GC chemo- tinguish a leukemoid reaction from a leukemic state, as the oth- therapy, a small mass was newly detected at the suprapubic er is typically positive for , which is cystostomy catheter insertion site, and the patient’s general con- seen in chronic myelogenous leukemia. dition was poor. A biopsy was performed, and a pathologic ex- In our case, the patient had bladder cancer with a fever and amination revealed a high-grade urothelial cell carcinoma. leukocytosis; thus, the complication of a urinary tract infection Additional chemotherapy was halted and the patient received was suspected. However, the laboratory findings revealed palliative care in a nursing home, terminating in death after 2 thrombocytosis, hypercalcemia, and an elevated LAP score. months. Moreover, a peripheral blood smear showed thrombocytosis and neutrophilia with a left shift. In addition, bone marrow aspira- DISCUSSION tion revealed a leukemoid reaction due to a G-CSF-secreting tumor and no chromosomal abnormalities. Paraneoplastic syndromes, defined as nonmetastatic systemic Several studies have described the role of G-CSF in leuke- effects, occur in 10-15% of all solid malignancies. A few para- moid reactions and its ability to promote leukocytosis asso- neoplastic syndromes have been reported in bladder cancer, in- ciated with bladder cancer. Turalic et al.7 reviewed 27 previous cluding hypercalcemia, thrombocytosis, nephrotic syndrome, cases of bladder cancer with a leukemoid reaction associated polymyositis, and leukemoid reaction.1 Leukemoid reactions in with G-CSF and coexisting hypercalcemia caused by increased urothelial cell carcinoma are an especially rare occurrence, al- production of PTH-RP. In addition, it has been found that ur- though urothelial cell carcinoma is a common urologic disorder. othelial cell carcinomas simultaneously express functional In addition, patients who have had indwelling catheters for G-CSF or -macrophage colony-stimulating factor more than 10 years have prevalence of squamous cell carcino- (GM-CSF) receptors with resultant autocrine and paracrine ma of the bladder.3 In our case and other previously reported growth stimulation, which could explain the aggressive nature cases, the extremely aggressive nature of these tumors, as com- of these cancers.8 Furthermore, Chakraborty et al.9 demon- pared to the usual course of urothelial cell carcinoma, indicate strated that expression of G-CSF/G-CSFR in bladder carcinoma that these tumors represent a highly aggressive subtype and promotes the adherence and invasion of bladder cancer cells by have an abysmal prognosis. Therefore, a diagnosis should be a mechanism involving integrin-β1. Increasing numbers of made immediately and accurately. these reports have shown rapid tumor recurrence and metastasis A leukemoid reaction might be misdiagnosed because of ex- with a poor prognosis; thus, leukemoid reactions and G-CSF treme leukocytosis. An elevated WBC count represents a diag- have been widely accepted as useful markers in estimating the nostic dilemma because of the need to rule out conditions such prognosis of bladder urothelial cell carcinoma.10 as infection, hematologic malignancies, massive , use Currently, there are no standard clinical guidelines for the of corticosteroids or hematologic growth factors, and metastases treatment of urothelial carcinoma with a leukemoid reaction. to bone with necrosis.2,4 In patients presenting with marked leu- There are no randomized trials, and most published reports of kocytosis, infection and leukemia are usually suspected first. urothelial carcinoma with leukemoid reaction treatment are ret- The administration of antibiotics is unnecessary and will not rospective case series. This clinical association reportedly has resolve leukocytosis or fever; the only treatment for leukocy- a dismal prognosis, with a median survival time of approx- tosis is removal of the primary tumor in patients with a leuke- imately 6 months after radical surgery.7 Early diagnosis and moid reaction.5 Procalcitonin cannot be recommended as a sin- surgical removal of the tumor can produce favorable results,11 gle definitive test, though it may be a useful biomarker for although they do not guarantee prolonged survival, with many diagnosis.6 Also, a leukemoid reaction should be differentiated patients relapsing and capitulating to their malignancy.12 Perez Ho Seok Chung, et al：Leukemoid Reaction in Urothelial Cell Carcinoma 137 et al.10 reported the use of neoadjuvant chemotherapy followed 2. Stav K, Leibovici D, Siegel YI, Lindner A. Leukemoid re- by radical surgery in a bladder cancer patient with a leukemoid action associated with transitional cell carcinoma. Isr Med Assoc J 2002;4:223-4. reaction, but that patient died after 4 months of chemotherapy. 3. Kaufman JM, Fam B, Jacobs SC, Gabilondo F, Yalla S, Kane In the current case, and consistent with previous results, there JP, et al. Bladder cancer and squamous metaplasia in spinal was a partial treatment response to palliative chemotherapy cord injury patients. J Urol 1977;118:967-71 with a significant decline in leukocytosis, but the median sur- 4. Azuma T, Sakai I, Matsumoto T, Ozawa A, Tanji N, Watanabe vival time (3.6 months) was short. Leukocytosis could also be A, et al. Leukemoid reaction in association with bone marrow affected by myelosuppression after chemotherapy. However, it necrosis due to metastatic prostate cancer. Intern Med 2005;44: 1093-6 is reasonable to assume that if the patient had undergone radical 5. Dukes J, Tierney LM Jr. Paraneoplastic leukemoid reaction cystectomy with neoadjuvant/adjuvant chemotherapy, his prog- as marker for transitional cell carcinoma recurrence. Urology nosis may have been better. Additional studies are needed to 2009;73:928.e17-9 clarify the effect of chemotherapy with radical surgery in pa- 6. Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. tients with a leukemoid reaction. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis 2013;13:426-35 In conclusion, a leukemoid reaction in urothelial cell carcino- 7. Turalic H, Deamant FD, Reese JH. Paraneoplastic production ma is a difficult diagnosis to make, requiring differentiation of granulocyte colony-stimulating factor in a bladder carcinoma. from infectious and other hematologic diseases. In patients with Scand J Urol Nephrol 2006;40:429-32 high-grade, locally aggressive urothelial cell cancer and an un- 8. Chakraborty A, Guha S. Granulocyte colony-stimulating fac- explained elevation in WBCs, a leukemoid reaction should be tor/granulocyte colony-stimulating factor receptor biological axis promotes survival and growth of bladder cancer cells. included in the differential diagnosis. Despite the cost and lim- Urology 2007;69:1210-5 ited availability, testing for G-CSF early in the disease course 9. Chakraborty A, White SM, Guha S. Granulocyte colony-stim- may provide valuable information for making an early diag- ulating receptor promotes beta1-integrin-mediated adhesion nosis and selecting an appropriate management option. If the and invasion of bladder cancer cells. Urology 2006;68:208-13 patient is not suitable for radical surgical treatment, palliative 10.Perez FA, Fligner CL, Yu EY. Rapid clinical deterioration and leukemoid reaction after treatment of urothelial carcinoma chemotherapy could be considered as the secondary treatment of the bladder: Possible effect of granulocyte colony‑stimulat- option; however, its efficacy is currently unknown. ing factor. J Clin Oncol 2009;27:e215-7 11. Hirasawa K, Kitamura T, Oka T, Matsushita H. Bladder tu- REFERENCES mor producing granulocyte colony-stimulating factor and par- athyroid hormone related protein. J Urol 2002;167:2130 1. Sacco E, Pinto F, Sasso F, Racioppi M, Gulino G, Volpe A, 12. Shapiro DD, Potretzke A, Downs TM. Leukemoid reaction: et al. Paraneoplastic syndromes in patients with urological a rare paraneoplastic syndrome in bladder cancer associated malignancies. Urol Int 2009;83:1-11 with a grave prognosis. Urology 2014;83:274-7