Original Study
Persistent, Unexplained Leukocytosis Is a Paraneoplastic Syndrome Associated With a Poor Prognosis in Patients With Urothelial Carcinoma Jason P. Izard,1 John L. Gore,2 Elahe A. Mostaghel,3 Jonathan L. Wright,2 Evan Y. Yu3 Abstract We sought to evaluate the incidence and outcomes of patients with paraneoplastic leukocytosis in the setting of urothelial carcinoma using a large single-institution data set. Paraneoplastic leukocytosis was frequently associated with advanced disease and was accompanied by other laboratory abnormalities, including anemia and hypercalcemia. Patients with paraneoplastic leukocytosis exhibited a particularly poor prognosis with rapid cancer progression. Background: We sought to define the disease characteristics and outcomes of those patients presenting with urothelial carcinoma and a persistently elevated white blood cell (WBC) count. Materials and Methods: We queried a prospectively maintained institutional database. Patients were included if they had had a histologic diagnosis of urothelial carcinoma and a WBC count of > 20,000 cells/mL on 2 occasions separated by 30 days. The patients’ medical records were reviewed and were excluded from the analysis if an underlying cause for the leukocytosis could be identified. The clinical, histologic, and laboratory data were then collected from the remaining patient cohort. Results: We identified a total of 1410 patients with a histologic diagnosis of urothelial carcinoma, 9 (0.6%) of whom met our inclusion criteria. These 9 patients had a median age of 63 years. At their presentation with leukocytosis, all 9 had muscle-invasive disease and 5 had evidence of metastatic disease. Leukocytosis was frequently associated with hypercalcemia (n ¼ 6), thrombocytosis (n ¼ 5), and anemia (n ¼ 9). Chemotherapy was able to achieve a WBC response in 3 of 5 patients, although only 1 patient demonstrated a substantial reduction in tumor volume radiographically. Extirpative surgery was able to provide a response in the laboratory parameters in 2 of 4 patients. However, all studied patients ultimately developed leukocytosis recurrence after systemic or local therapy and experienced rapid disease progression, with a median interval from leukocytosis until death of 71 days. Conclusion: Paraneoplastic leukocytosis in the setting of urothelial carcinoma is a rare phenomenon but confers a poor prognosis, with a rapid progression to death. Clinical Genitourinary Cancer, Vol. 13, No. 4, e253-8 ª 2015 Elsevier Inc. All rights reserved. Keywords: Bladder cancer, Laboratory markers, Prognostic markers, White blood cell count
Introduction Paraneoplastic leukocytosis has been described in numerous nonhematologic malignancies.1-7 Most commonly, this syndrome has occurred in patients with lung cancer, skin cancer, and 1
Department of Urology, Queen’s University, Kingston, ON, Canada Department of Urology, University of Washington, Seattle, WA 3 Division of Oncology, Department of Medicine, University of Washington, Seattle, WA 2
Submitted: Dec 16, 2014; Accepted: Feb 27, 2015; Epub: Mar 5, 2015 Address for correspondence: Jason P. Izard, MD, MPH, Department of Urology, Queen’s University, Empire 4, 76 Stuart Street, Kingston, ON K7L 2V7, Canada E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2015.02.008
sarcomas.2 In these malignancies, the development of paraneoplastic leukocytosis has been associated with poor patient outcomes. Within the published data on urothelial carcinoma, information regarding this phenomenon has largely been limited to individual case reports.8-15 The largest individual cases series to date included only 4 patients.2 Among those reported cases, the survival times of the patients were generally quite short. In a case series by Granger and Kontoyiannis,2 78% of the patients had either died or been transferred to hospice care within 12 weeks of their leukocytosis. However, this represented a group of patients with a heterogeneous distribution of malignancies, and only 4 patients had bladder cancer. Nonetheless, individual case reports of patients with urothelial carcinoma have corroborated this dismal prognosis. In contrast,
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Persistent Unexplained Leukocytosis patients from a large randomized study of gemcitabine and cisplatin (GC) versus methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) in patients with locally advanced or metastatic bladder cancer had a median survival of 14.0 months in the GC arm and 15.2 months in the MVAC arm.16 Although most of the individual reports of patients with leukocytosis have reported widespread metastatic disease at diagnosis, the median survival of patients with visceral metastases in that same randomized trial was still 10.3 months.16 The discordance between the published survival rates of patients with metastatic urothelial carcinoma and the reports of patients with urothelial carcinoma and leukocytosis may underscore a difference in the pathogenesis of disease progression. Many of the reports documented the concurrent expression of granulocyte colonystimulating factor (G-CSF) by the tumors in conjunction with elevated white blood cell (WBC) counts.9,11-13,15 This is a particularly interesting finding, given that G-CSF was originally cloned from the 5637 bladder cancer cell line.17 Therefore, paraneoplastic leukocytosis might be the result of underlying tumoral G-CSF production that could serve as an etiology of leukocytosis and could have other negative biologic implications on the tumor and the patient. Given the number of published individual case reports, it is possible that this might represent an actual paraneoplastic syndrome among patients with urothelial carcinoma that is both underreported and underrecognized. Many of these case reports involved patients with extreme leukocytosis, with most having a WBC count > 40,000 cells/mL and several having a WBC count > 100,000 cells/mL. We postulated that patients with dramatic paraneoplastic leukocytosis that was less than these extreme levels might still have the same disease process. We, therefore, examined the incidence and the clinical characteristics and outcomes of patients with urothelial cancer who had presented with paraneoplastic leukocytosis with a WBC count > 20,000 cells/mL.
was defined as the date at which they had first been diagnosed with urothelial carcinoma. For those patients who had initially presented with nonmuscle-invasive disease but had experienced disease progressed, this point was determined as the date of their initial tumor diagnosis.
Results At the point of our data set query, we identified a total of 1440 patients with a histologic diagnosis of urothelial carcinoma. Of these, 45 patients (3.2%) had had multiple WBC counts of > 20 103 cells/mL separated by 30 days. Individual medical record abstraction was then able to identify a specific underlying cause for all but 9 patients (0.6%). The most common causes identified were infectious etiologies and transient increases related to growth factor support during chemotherapy. These remaining 9 patients served as our study cohort. The patient characteristics are listed in Table 1. The cohort included 8 patients with bladder cancer and 1 with renal pelvic urothelial carcinoma. Most patients had pure urothelial cell carcinoma, with only 2 having mixed histologic features. One patient had squamous components to the tumor, and the other had extensive sarcomatoid differentiation. The onset of leukocytosis was highly variable in the patient cohort, ranging from an onset concurrent with the cancer diagnosis to 1 patient who developed leukocytosis almost 15 years after his original diagnosis of carcinoma in situ (Table 2). This prolonged period likely did not reflect the natural history of the development of leukocytosis. Rather, patient 1 had a long period in which he was disease free. He subsequently presented again with locally advanced
Table 1 Patient Characteristics (n [ 9) Characteristic
Patients (n)
Age (years)
Materials and Methods The University of Washington institutional review board provided permission for study implementation before this project began. We performed a retrospective review of a prospectively maintained genitourinary oncology database housed at the Fred Hutchinson Cancer Center (Seattle, WA). The database was queried for all patients with a histologic diagnosis of urothelial carcinoma and 2 distinct WBC counts > 20,000 cells/mL on 2 occasions. The elevated WBC count were required to have been separated by a minimum of 30 days to screen out temporary increases from specific underlying causes such as transient infections. Individual data abstraction was then used to identify any underlying cause. At a minimum, all patients had to have undergone urine and blood cultures and a chest radiograph, with negative findings for infectious etiologies from all to be considered eligible for inclusion in the study population. Repeated transient WBC elevations associated with growth factor support during chemotherapy were identified, and these patients were excluded. For those patients meeting the inclusion criteria, detailed clinical, demographic, pathologic, and treatment-related information was abstracted from the medical records. The time of onset of leukocytosis was defined as the date of the first elevated WBC count. The time of diagnosis
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Median
63
Range
34-86
Race White
8
Unknown
1
Sex Male
6
Female
3
Primary tumor site Bladder
8
Kidney
1
Stage at presentation with leukocytosis Nonmuscle invasive
0
Muscle invasive
9
Metastatic at presentation with leukocytosis No
4
Yes
5
Histopathologic type Pure urothelial
7
Mixed
2
Jason P. Izard et al Table 2 Disease Course of Patient Cohort
Pt. No. 1 2 3 4 5 6 7 8 9
Stage at Cancer Diagnosis
Cystectomy Performed
Pathologic Stage at Cystectomy
Interval From Diagnosis to Leukocytosis (d)
Interval From Leukocytosis to Death (d)
cTisN0M0 cT2N0M0 cT2N0M1 cT3N0M0 cT3N2M0 cT1N0M0 cTaN0M0 cT4N0M0 cT3N2M0
Yes Yes No Yes No No No Yes No
pT3aN0MX pT3bN0MX NA pT3bN0MX NA NA NA pT4N0M1 NA
5387 51 149 126 Concurrent 333 5747 8 Concurrent
71 115 47 67 139 15 8 251 282
Abbreviations: NA ¼ not applicable; Pt. No. ¼ patient number.
disease (pT3a) and leukocytosis many years later. Similarly, patient 7 did not exhibit features of leukocytosis when he had noninvasive, stage 0, Ta disease. Many years later, when he represented with locally advanced and metastatic disease, he developed leukocytosis in this setting. However, once these patients had developed leukocytosis, disease progression was rapid. Of the 9 patients analyzed, all died of their disease, with a median and mean interval from leukocytosis until death of 71 and 109 days, respectively. Of the 9 patients, 4 underwent extirpative surgery for their disease. In 2 of these 4 patients, this resulted in improvement in the leukocytosis. This was a partial improvement in 1 case and a resolution in the second. However, all patients developed recurrence of their leukocytosis that surpassed their preoperative levels, with rapid disease progression and death. At the time that patient 1 underwent palliative cystectomy, his WBC count was 23.6 103 cells/mL. Postoperatively, his WBC count decreased to 13.2 103 cells/mL. However, it quickly began to increase and by 8 days after his surgery, his WBC count had returned to > 20 103 cells/mL. His WBC count eventually peaked at 34.3 103 cells/mL before his death. Patient 4 had a borderline elevation of his WBC count before surgery at 12.4 103 cells/mL immediately before cystectomy. This did not meet our criteria for leukocytosis. This borderline elevation normalized postoperatively. However, on postoperative day 67, his WBC count was 18.1 103 cells/mL, and 1 month later had increased to 24.1 103 cells/mL.
Five patients received systemic therapy after the onset of leukocytosis (Table 3). In 2 patients, this was palliative, and in 3, this was intended to be neoadjuvant chemotherapy. However, 1 patient developed progression during chemotherapy and never underwent cystectomy. Only 2 patients demonstrated a radiographic response to systemic therapy (both a partial and not a complete response). Patient 8 received neoadjuvant GC and had a > 50% reduction in her tumor volume. Patient 9 received palliative gemcitabine and carboplatin and had a modest 20% reduction in his tumor volume. Of the 5 patients, 3 demonstrated a laboratory response of their leukocytosis to chemotherapy, with a WBC count that decreased to less than the upper limit of normal. One additional patient, patient 8, experienced a 30% reduction in her WBC count to a level less than our cutoff of 20 103 cells/mL. However, her WBC count remained elevated at greater than the upper limit of normal. Two patients in the data set complained of constitutional symptoms. Both patients experienced unexplained fever and weight loss. Of these 2 patients, 1 also experienced drenching night sweats. Thus, 1 of these patients was administered systemic oral steroid therapy, without any improvement in the constitutional symptoms or leukocytosis. Associated laboratory abnormalities were common (Table 4). Anemia, hypercalcemia, and thrombocytosis were frequently observed. Peripheral blood smears revealed toxic granulations or Döhle bodies in 5 and 2 patients, respectively.
Table 3 Patients Receiving Systemic Therapy
Pt. No. 2 3 5 8 9
Chemotherapy Regimen
Radiographic Response
Leukocytosis Response
Interval From Chemotherapy Cessation to Recurrence of WBC Count >20 3 103 Cells/mL (d)
MVAC Docetaxel, pemetrexeda MVAC GC G-C
No No No >50% reduction 20% reduction
Yes No Yes No Yes
21 NA 14 NA Unknownb
Abbreviations: G-C ¼ gemcitabine, carboplatin; GC ¼ gemcitabine, cisplatin; MVAC ¼ methotrexate, vinblastine, doxorubicin, cisplatin; NA ¼ not applicable; WBC ¼ white blood cell. a Gemcitabine cisplatin chemotherapy before the development of leukocytosis had already failed; the patient then experienced disease progression with docetaxel therapy and was switched to pemetrexed. b The patient entered hospice care and had no additional blood testing performed.
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Persistent Unexplained Leukocytosis In all patients, the leukocytosis was predominantly a neutrophilia. The neutrophil counts were elevated in all 9 patients. Two patients had elevations in both the monocyte and the eosinophil counts that periodically varied between normal and elevated levels throughout their disease course.
Discussion Our study had several key findings. First, although paraneoplastic leukocytosis in the setting of urothelial carcinoma represents a rare finding—< 1% in our series—it results in a particularly poor prognosis. The median interval from leukocytosis to death was 71 days. Granger and Kontoyiannis2 described the MD Anderson Cancer Center experience in 758 patients with extreme leukocytosis and nonhematologic malignancies. Most of these patients had an underlying cause, with only 77 of these patients considered to have a paraneoplastic syndrome. Only 4 patients in their series had bladder cancer. However, of the 77 patients with paraneoplastic leukocytosis, 78% had either died or been discharged to hospice care within 12 weeks of their first elevated WBC count. Our study found that the elevated WBC counts were predominantly a result of elevated neutrophil counts, with all patients having lymphocyte counts that were less than the upper limit of normal. The neutrophil/lymphocyte ratio has prognostic significance in numerous nonurothelial-based tumors.18-20 Recently, several reports have been published of an elevated neutrophil/lymphocyte ratio having similar prognostic significance in those with urothelial carcinoma. An elevated neutrophil/lymphocyte ratio before cystectomy has been associated with decreased overall and
Table 4 Associated Laboratory Test Result Anomalies (n [ 9) Laboratory Test Result Abnormality
Patients (n)
Hypercalcemia Yes
6
No
3
Hypophosphatemia Yes
3
No
6
Hyperuricemia Yes
2
No
7
Anemia Yes
9
No
0
Thrombocytosis Yes
5
No
4
Toxic granulations Yes
5
No
4
Döhle bodies
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-
Yes
2
No
7
Clinical Genitourinary Cancer August 2015
cancer-specific survival.21-24 One possible mechanism to explain this is that circulating neutrophils might be an important source of vascular endothelial growth factor (VEGF).25 Increased expression of VEGF has been linked to both increased recurrence and increased progression rates of urothelial cancer.26 Another possibility is that the leukocytosis is not the cause of the rapid disease progression in these patients but simply an indicator of the underlying pathologic process. Several case reports have been published of high levels of G-CSF in the serum of patients with bladder cancer and extreme leukocytosis.9,11-13,15 Tachibana et al27 demonstrated both G-CSF mRNA and G-CSF receptor mRNA was present within the cultured cancer cells of 1 of these patients. The growth of this cell line was directly stimulated by exogenous G-CSF administration and inhibited by antieG-CSF antibodies. This would suggest that the rapid cell proliferation experienced by these patients might be the result of autocrine and paracrine stimulation by simultaneous G-CSF production and G-CSF receptor activation directly on the cancer cells. G-CSF functions by promoting the production of both neutrophils and other myeloid progenitor cells. However, it selectively enhances the differentiation of these precursor cells into neutrophils instead of other cell types.28 Therefore, autocrine and paracrine signaling through G-CSF would explain not only the rapid progression of these tumor cells but also the associated elevated WBC counts. Our second principle finding was the high rate of associated laboratory test result abnormalities. Similar to previous reports, leukocytosis was frequently associated with hypercalcemia. Several case reports have linked paraneoplastic leukocytosis in the setting of bladder cancer to tumor-related G-CSF production and tumoral production of parathyroid hormone-related protein (PTH-rp).9,13,29 Within our data set, we did not have the results of assays to assess for PTH-rp expression in our patients’ tumors. However, given the high rate of hypercalcemia (6 of 9 patients), it is reasonable to assume that a similar pathologic process could have been occurring. The most common laboratory anomaly was anemia, which was present in all patients to varying degrees. Several possibilities could explain this finding. Papaldo et al30 conducted a randomized control study of patients with breast cancer receiving epirubicin and cyclophosphamide. Patients were randomized to receive factor support with G-CSF to prevent low neutrophil counts or to no factor support with dose reduction in the case of low neutrophil counts. Although the patients as a whole had decreasing hemoglobin (Hb) levels as the study progressed, they found that the patients who received G-CSF support had significantly lower Hb levels than those without G-CSF support. Additionally, the dosing schedules of G-CSF varied among the patients. A trend was seen toward a lower incidence of anemia in those patients receiving fewer G-CSF injections. The investigators proposed that G-CSF might cause anemia by causing stem cells to differentiate into more committed hematopoietic cell lines, thereby reducing the stem cell pool available for erythropoiesis. Another possible explanation is that the anemia is simply a function of the aggressive nature of the cancer. At autopsy, the bone marrow of our patient 2 had largely been replaced with dense collections of tumor deposits, likely explaining his anemia. Our third principle finding was the limited radiographic, clinical, and laboratory response of the disease of these patients
Jason P. Izard et al to the local and systemic treatments. Only 1 patient had a complete response of his WBC count to extirpative surgery. Of the 5 patients, 3 had a biochemical response of their WBC count to chemotherapy. However, for 2 of the 3 patients, their WBC count returned to levels > 20,000 cells/mL within 4 weeks of the conclusion of chemotherapy. The third patient entered hospice care immediately at the conclusion of his systemic treatment and declined all future blood testing. Therefore, the timeline for the recurrence of his leukocytosis after treatment remains unknown. It is possible that the chemotherapy could have been effective in treating the neoplastic cells. However, on conclusion of the chemotherapy, the aggressive nature of these cells resumed, likely leading to increased WBC counts as a marker of disease activity. Dukes and Tierney8 reported their experience with a patient with paraneoplastic leukocytosis, whose leukocytosis disappeared with successful resection of the tumor by radical cystectomy. However, 8 months later, before radiographic evidence of disease was present, the patient’s leukocytosis had returned and was the initial presentation of disease recurrence. Similar experiences have been reported in several other case reports, indicating that in patients presenting with leukocytosis, an elevated WBC count could be the first sign of relapse.20 However, the recurrence of leukocytosis in these patients occurred months after treatment. In our patients, given the rapid recurrence of leukocytosis after the cessation of systemic therapy in the setting of minimal to no radiographic response, the WBC response might have been more associated with chemotherapyinduced myelosuppression than with the tumoricidal activity of the therapy. Our present study had several limitations. This was a retrospective analysis of a prospectively maintained database. Just as with all retrospective analyses, it was prone to bias. Although corroborating evidence was found in the published data to support our hypothesized link between paraneoplastic leukocytosis and G-CSF, our present study lacked definitive biologic evidence to support this connection. Additionally, we did not have biologic evidence to support our hypothesis of paracrine and autocrine stimulated cell growth as the ultimate cause of rapid disease progression in these patients. Despite these limitations, we believe the present study is a valuable contribution to the existing data on urothelial carcinoma. We have reported a phenomenon occurring in 0.6% of our patients with bladder cancer that is not currently recognized as a paraneoplastic syndrome in this patient population. Its recognition is important, because it portends a poor prognosis with a particularly rapid disease trajectory.
Conclusion Paraneoplastic leukocytosis in the setting of urothelial carcinoma is a rare phenomenon but confers a particularly poor prognosis with a rapid progression to death.
Clinical Practice Points Paraneoplastic leukocytosis represents a rare finding (< 1%) in
patients with urothelial carcinoma and is associated with poor patient outcomes and rapid progression to death.
Patients with urothelial carcinoma tend to have muscle-invasive
disease and frequently have metastatic disease at their presentation with leukocytosis. Local and systemic cancer therapies can produce responses in some patients’ WBC counts. However, these responses tend to be short-lived, with rapid recurrence of the elevated WBC count after treatment. Recurrence of leukocytosis after local and systemic therapy is associated with clinical and radiographic progression of disease. Paraneoplastic leukocytosis is frequently associated with other laboratory abnormalities, including anemia and hypercalcemia.
References 1. Kasuga I, Makino S, Kiyokawa H, Katoh H, Ebihara Y, Ohyashiki K. Tumorrelated leukocytosis is linked with poor prognosis in patients with lung carcinoma. Cancer 2001; 92:2399-405. 2. 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. 3. McKee LC Jr. Excess leukocytosis (leukemoid reactions) associated with malignant diseases. South Med J 1985; 78:1475-82. 4. Schniewind B, Christgen M, Hauschild A, Kurdow R, Kalthoff H, Klomp HJ. Paraneoplastic leukemoid reaction and rapid progression in a patient with malignant melanoma: establishment of KT293, a novel G-CSF-secreting melanoma cell line. Cancer Biol Ther 2005; 4:23-7. 5. 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. 6. Saussez S, Heimann P, Vandevelde L, et al. Undifferentiated carcinoma of the nasopharynx and leukemoid reaction: report of case with literature review. J Laryngol Otol 1997; 111:66-9. 7. Ferrer A, Cervantes F, Hernandez-Boluda JC, Alvarez A, Montserrat E. Leukemoid reaction preceding the diagnosis of colorectal carcinoma by four years. Haematologica 1999; 84:671-2. 8. Dukes JW, Tierney LM Jr. Paraneoplastic leukemoid reaction as marker for transitional cell carcinoma recurrence. Urology 2009; 73:928.e17-9. 9. Hirasawa K, Kitamura T, Oka T, Matsushita H. Bladder tumor producing granulocyte colony-stimulating factor and parathyroid hormone related protein. J Urol 2002; 167:2130. 10. Ito N, Matsuda T, Kakehi Y, Takeuchi E, Takahashi T, Yoshida O. Bladder cancer producing granulocyte colony-stimulating factor. N Engl J Med 1990; 323: 1709-10. 11. Kamai T, Toma T, Masuda H, Ishiwata D. Simultaneous production of parathyroid hormone-related protein and granulocyte colony-stimulating factor in renal pelvic cancer. J Natl Cancer Inst 1998; 90:249-50. 12. Kitayama S, Fujii Y, Kihara K. Urothelial cancer producing granulocyte colonystimulating factor: possible induction of splenomegaly. Urology 2004; 63:377-8. 13. McRae SN, Gilbert R, Deamant FD, Reese JH. Poorly differentiated carcinoma of bladder producing granulocyte colony-stimulating factor and parathyroid hormone related protein. J Urol 2001; 165:527-8. 14. 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 Oncol 2009; 27:e215-7. 15. Satoh H, Abe Y, Katoh Y, Komine Y, Nakamura M, Tamaoki N. Bladder carcinoma producing granulocyte colony-stimulating factor: a case report. J Urol 1993; 149:843-5. 16. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005; 23:4602-8. 17. Welte K, Platzer E, Lu L, et al. Purification and biochemical characterization of human pluripotent hematopoietic colony-stimulating factor. Proc Natl Acad Sci U S A 1985; 82:1526-30. 18. Yamanaka T, Matsumoto S, Teramukai S, Ishiwata R, Nagai Y, Fukushima M. The baseline ratio of neutrophils to lymphocytes is associated with patient prognosis in advanced gastric cancer. Oncology 2007; 73:215-20. 19. Chua W, Charles KA, Baracos VE, Clarke SJ. Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br J Cancer 2011; 104:1288-95. 20. Azab B, Bhatt VR, Phookan J, et al. Usefulness of the neutrophil-to-lymphocyte ratio in predicting short- and long-term mortality in breast cancer patients. Ann Surg Oncol 2012; 19:217-24. 21. Viers BR, Boorjian SA, Frank I, et al. Pretreatment neutrophil-to-lymphocyte ratio is associated with advanced pathologic tumor stage and increased cancer-specific
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mortality among patients with urothelial carcinoma of the bladder undergoing radical cystectomy. Eur Urol 2014; 66:1157-64. Gondo T, Nakashima J, Ohno Y, et al. Prognostic value of neutrophil-tolymphocyte ratio and establishment of novel preoperative risk stratification model in bladder cancer patients treated with radical cystectomy. Urology 2012; 79: 1085-91. Hermanns T, Bhindi B, Wei Y, et al. Pre-treatment neutrophil-to-lymphocyte ratio as predictor of adverse outcomes in patients undergoing radical cystectomy for urothelial carcinoma of the bladder. Br J Cancer 2014; 111: 444-51. Krane LS, Richards KA, Kader AK, Davis R, Balaji KC, Hemal AK. Preoperative neutrophil/lymphocyte ratio predicts overall survival and extravesical disease in patients undergoing radical cystectomy. J Endourol 2013; 27:1046-50. Kusumanto YH, Dam WA, Hospers GA, Meijer C, Mulder NH. Platelets and granulocytes, in particular the neutrophils, form important compartments for circulating vascular endothelial growth factor. Angiogenesis 2003; 6:283-7.
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26. Crew JP, O’Brien T, Bradburn M, et al. Vascular endothelial growth factor is a predictor of relapse and stage progression in superficial bladder cancer. Cancer Res 1997; 57:5281-5. 27. Tachibana M, Miyakawa A, Tazaki H, et al. Autocrine growth of transitional cell carcinoma of the bladder induced by granulocyte-colony stimulating factor. Cancer Res 1995; 55:3438-43. 28. Zsebo KM, Cohen AM, Murdock DC, et al. Recombinant human granulocyte colony stimulating factor: molecular and biological characterization. Immunobiology 1986; 172:175-84. 29. Vaidyanathan S, Mansour P, Ueno M, et al. 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 hormonerelated protein by squamous cell carcinoma of urinary bladder. BMC Urol 2002; 2:8. 30. Papaldo P, Ferretti G, Di Cosimo S, et al. Does granulocyte colony-stimulating factor worsen anemia in early breast cancer patients treated with epirubicin and cyclophosphamide? J Clin Oncol 2006; 24:3048-55.
Persistent, Unexplained Leukocytosis Is a Paraneoplastic Syndrome Associated With a Poor Prognosis in Patients With Urothelial Carcinoma Jason P. Izard,1 John L. Gore,2 Elahe A. Mostaghel,3 Jonathan L. Wright,2 Evan Y. Yu3 Abstract We sought to evaluate the incidence and outcomes of patients with paraneoplastic leukocytosis in the setting of urothelial carcinoma using a large single-institution data set. Paraneoplastic leukocytosis was frequently associated with advanced disease and was accompanied by other laboratory abnormalities, including anemia and hypercalcemia. Patients with paraneoplastic leukocytosis exhibited a particularly poor prognosis with rapid cancer progression. Background: We sought to define the disease characteristics and outcomes of those patients presenting with urothelial carcinoma and a persistently elevated white blood cell (WBC) count. Materials and Methods: We queried a prospectively maintained institutional database. Patients were included if they had had a histologic diagnosis of urothelial carcinoma and a WBC count of > 20,000 cells/mL on 2 occasions separated by 30 days. The patients’ medical records were reviewed and were excluded from the analysis if an underlying cause for the leukocytosis could be identified. The clinical, histologic, and laboratory data were then collected from the remaining patient cohort. Results: We identified a total of 1410 patients with a histologic diagnosis of urothelial carcinoma, 9 (0.6%) of whom met our inclusion criteria. These 9 patients had a median age of 63 years. At their presentation with leukocytosis, all 9 had muscle-invasive disease and 5 had evidence of metastatic disease. Leukocytosis was frequently associated with hypercalcemia (n ¼ 6), thrombocytosis (n ¼ 5), and anemia (n ¼ 9). Chemotherapy was able to achieve a WBC response in 3 of 5 patients, although only 1 patient demonstrated a substantial reduction in tumor volume radiographically. Extirpative surgery was able to provide a response in the laboratory parameters in 2 of 4 patients. However, all studied patients ultimately developed leukocytosis recurrence after systemic or local therapy and experienced rapid disease progression, with a median interval from leukocytosis until death of 71 days. Conclusion: Paraneoplastic leukocytosis in the setting of urothelial carcinoma is a rare phenomenon but confers a poor prognosis, with a rapid progression to death. Clinical Genitourinary Cancer, Vol. 13, No. 4, e253-8 ª 2015 Elsevier Inc. All rights reserved. Keywords: Bladder cancer, Laboratory markers, Prognostic markers, White blood cell count
Introduction Paraneoplastic leukocytosis has been described in numerous nonhematologic malignancies.1-7 Most commonly, this syndrome has occurred in patients with lung cancer, skin cancer, and 1
Department of Urology, Queen’s University, Kingston, ON, Canada Department of Urology, University of Washington, Seattle, WA 3 Division of Oncology, Department of Medicine, University of Washington, Seattle, WA 2
Submitted: Dec 16, 2014; Accepted: Feb 27, 2015; Epub: Mar 5, 2015 Address for correspondence: Jason P. Izard, MD, MPH, Department of Urology, Queen’s University, Empire 4, 76 Stuart Street, Kingston, ON K7L 2V7, Canada E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2015.02.008
sarcomas.2 In these malignancies, the development of paraneoplastic leukocytosis has been associated with poor patient outcomes. Within the published data on urothelial carcinoma, information regarding this phenomenon has largely been limited to individual case reports.8-15 The largest individual cases series to date included only 4 patients.2 Among those reported cases, the survival times of the patients were generally quite short. In a case series by Granger and Kontoyiannis,2 78% of the patients had either died or been transferred to hospice care within 12 weeks of their leukocytosis. However, this represented a group of patients with a heterogeneous distribution of malignancies, and only 4 patients had bladder cancer. Nonetheless, individual case reports of patients with urothelial carcinoma have corroborated this dismal prognosis. In contrast,
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Persistent Unexplained Leukocytosis patients from a large randomized study of gemcitabine and cisplatin (GC) versus methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) in patients with locally advanced or metastatic bladder cancer had a median survival of 14.0 months in the GC arm and 15.2 months in the MVAC arm.16 Although most of the individual reports of patients with leukocytosis have reported widespread metastatic disease at diagnosis, the median survival of patients with visceral metastases in that same randomized trial was still 10.3 months.16 The discordance between the published survival rates of patients with metastatic urothelial carcinoma and the reports of patients with urothelial carcinoma and leukocytosis may underscore a difference in the pathogenesis of disease progression. Many of the reports documented the concurrent expression of granulocyte colonystimulating factor (G-CSF) by the tumors in conjunction with elevated white blood cell (WBC) counts.9,11-13,15 This is a particularly interesting finding, given that G-CSF was originally cloned from the 5637 bladder cancer cell line.17 Therefore, paraneoplastic leukocytosis might be the result of underlying tumoral G-CSF production that could serve as an etiology of leukocytosis and could have other negative biologic implications on the tumor and the patient. Given the number of published individual case reports, it is possible that this might represent an actual paraneoplastic syndrome among patients with urothelial carcinoma that is both underreported and underrecognized. Many of these case reports involved patients with extreme leukocytosis, with most having a WBC count > 40,000 cells/mL and several having a WBC count > 100,000 cells/mL. We postulated that patients with dramatic paraneoplastic leukocytosis that was less than these extreme levels might still have the same disease process. We, therefore, examined the incidence and the clinical characteristics and outcomes of patients with urothelial cancer who had presented with paraneoplastic leukocytosis with a WBC count > 20,000 cells/mL.
was defined as the date at which they had first been diagnosed with urothelial carcinoma. For those patients who had initially presented with nonmuscle-invasive disease but had experienced disease progressed, this point was determined as the date of their initial tumor diagnosis.
Results At the point of our data set query, we identified a total of 1440 patients with a histologic diagnosis of urothelial carcinoma. Of these, 45 patients (3.2%) had had multiple WBC counts of > 20 103 cells/mL separated by 30 days. Individual medical record abstraction was then able to identify a specific underlying cause for all but 9 patients (0.6%). The most common causes identified were infectious etiologies and transient increases related to growth factor support during chemotherapy. These remaining 9 patients served as our study cohort. The patient characteristics are listed in Table 1. The cohort included 8 patients with bladder cancer and 1 with renal pelvic urothelial carcinoma. Most patients had pure urothelial cell carcinoma, with only 2 having mixed histologic features. One patient had squamous components to the tumor, and the other had extensive sarcomatoid differentiation. The onset of leukocytosis was highly variable in the patient cohort, ranging from an onset concurrent with the cancer diagnosis to 1 patient who developed leukocytosis almost 15 years after his original diagnosis of carcinoma in situ (Table 2). This prolonged period likely did not reflect the natural history of the development of leukocytosis. Rather, patient 1 had a long period in which he was disease free. He subsequently presented again with locally advanced
Table 1 Patient Characteristics (n [ 9) Characteristic
Patients (n)
Age (years)
Materials and Methods The University of Washington institutional review board provided permission for study implementation before this project began. We performed a retrospective review of a prospectively maintained genitourinary oncology database housed at the Fred Hutchinson Cancer Center (Seattle, WA). The database was queried for all patients with a histologic diagnosis of urothelial carcinoma and 2 distinct WBC counts > 20,000 cells/mL on 2 occasions. The elevated WBC count were required to have been separated by a minimum of 30 days to screen out temporary increases from specific underlying causes such as transient infections. Individual data abstraction was then used to identify any underlying cause. At a minimum, all patients had to have undergone urine and blood cultures and a chest radiograph, with negative findings for infectious etiologies from all to be considered eligible for inclusion in the study population. Repeated transient WBC elevations associated with growth factor support during chemotherapy were identified, and these patients were excluded. For those patients meeting the inclusion criteria, detailed clinical, demographic, pathologic, and treatment-related information was abstracted from the medical records. The time of onset of leukocytosis was defined as the date of the first elevated WBC count. The time of diagnosis
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Median
63
Range
34-86
Race White
8
Unknown
1
Sex Male
6
Female
3
Primary tumor site Bladder
8
Kidney
1
Stage at presentation with leukocytosis Nonmuscle invasive
0
Muscle invasive
9
Metastatic at presentation with leukocytosis No
4
Yes
5
Histopathologic type Pure urothelial
7
Mixed
2
Jason P. Izard et al Table 2 Disease Course of Patient Cohort
Pt. No. 1 2 3 4 5 6 7 8 9
Stage at Cancer Diagnosis
Cystectomy Performed
Pathologic Stage at Cystectomy
Interval From Diagnosis to Leukocytosis (d)
Interval From Leukocytosis to Death (d)
cTisN0M0 cT2N0M0 cT2N0M1 cT3N0M0 cT3N2M0 cT1N0M0 cTaN0M0 cT4N0M0 cT3N2M0
Yes Yes No Yes No No No Yes No
pT3aN0MX pT3bN0MX NA pT3bN0MX NA NA NA pT4N0M1 NA
5387 51 149 126 Concurrent 333 5747 8 Concurrent
71 115 47 67 139 15 8 251 282
Abbreviations: NA ¼ not applicable; Pt. No. ¼ patient number.
disease (pT3a) and leukocytosis many years later. Similarly, patient 7 did not exhibit features of leukocytosis when he had noninvasive, stage 0, Ta disease. Many years later, when he represented with locally advanced and metastatic disease, he developed leukocytosis in this setting. However, once these patients had developed leukocytosis, disease progression was rapid. Of the 9 patients analyzed, all died of their disease, with a median and mean interval from leukocytosis until death of 71 and 109 days, respectively. Of the 9 patients, 4 underwent extirpative surgery for their disease. In 2 of these 4 patients, this resulted in improvement in the leukocytosis. This was a partial improvement in 1 case and a resolution in the second. However, all patients developed recurrence of their leukocytosis that surpassed their preoperative levels, with rapid disease progression and death. At the time that patient 1 underwent palliative cystectomy, his WBC count was 23.6 103 cells/mL. Postoperatively, his WBC count decreased to 13.2 103 cells/mL. However, it quickly began to increase and by 8 days after his surgery, his WBC count had returned to > 20 103 cells/mL. His WBC count eventually peaked at 34.3 103 cells/mL before his death. Patient 4 had a borderline elevation of his WBC count before surgery at 12.4 103 cells/mL immediately before cystectomy. This did not meet our criteria for leukocytosis. This borderline elevation normalized postoperatively. However, on postoperative day 67, his WBC count was 18.1 103 cells/mL, and 1 month later had increased to 24.1 103 cells/mL.
Five patients received systemic therapy after the onset of leukocytosis (Table 3). In 2 patients, this was palliative, and in 3, this was intended to be neoadjuvant chemotherapy. However, 1 patient developed progression during chemotherapy and never underwent cystectomy. Only 2 patients demonstrated a radiographic response to systemic therapy (both a partial and not a complete response). Patient 8 received neoadjuvant GC and had a > 50% reduction in her tumor volume. Patient 9 received palliative gemcitabine and carboplatin and had a modest 20% reduction in his tumor volume. Of the 5 patients, 3 demonstrated a laboratory response of their leukocytosis to chemotherapy, with a WBC count that decreased to less than the upper limit of normal. One additional patient, patient 8, experienced a 30% reduction in her WBC count to a level less than our cutoff of 20 103 cells/mL. However, her WBC count remained elevated at greater than the upper limit of normal. Two patients in the data set complained of constitutional symptoms. Both patients experienced unexplained fever and weight loss. Of these 2 patients, 1 also experienced drenching night sweats. Thus, 1 of these patients was administered systemic oral steroid therapy, without any improvement in the constitutional symptoms or leukocytosis. Associated laboratory abnormalities were common (Table 4). Anemia, hypercalcemia, and thrombocytosis were frequently observed. Peripheral blood smears revealed toxic granulations or Döhle bodies in 5 and 2 patients, respectively.
Table 3 Patients Receiving Systemic Therapy
Pt. No. 2 3 5 8 9
Chemotherapy Regimen
Radiographic Response
Leukocytosis Response
Interval From Chemotherapy Cessation to Recurrence of WBC Count >20 3 103 Cells/mL (d)
MVAC Docetaxel, pemetrexeda MVAC GC G-C
No No No >50% reduction 20% reduction
Yes No Yes No Yes
21 NA 14 NA Unknownb
Abbreviations: G-C ¼ gemcitabine, carboplatin; GC ¼ gemcitabine, cisplatin; MVAC ¼ methotrexate, vinblastine, doxorubicin, cisplatin; NA ¼ not applicable; WBC ¼ white blood cell. a Gemcitabine cisplatin chemotherapy before the development of leukocytosis had already failed; the patient then experienced disease progression with docetaxel therapy and was switched to pemetrexed. b The patient entered hospice care and had no additional blood testing performed.
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Persistent Unexplained Leukocytosis In all patients, the leukocytosis was predominantly a neutrophilia. The neutrophil counts were elevated in all 9 patients. Two patients had elevations in both the monocyte and the eosinophil counts that periodically varied between normal and elevated levels throughout their disease course.
Discussion Our study had several key findings. First, although paraneoplastic leukocytosis in the setting of urothelial carcinoma represents a rare finding—< 1% in our series—it results in a particularly poor prognosis. The median interval from leukocytosis to death was 71 days. Granger and Kontoyiannis2 described the MD Anderson Cancer Center experience in 758 patients with extreme leukocytosis and nonhematologic malignancies. Most of these patients had an underlying cause, with only 77 of these patients considered to have a paraneoplastic syndrome. Only 4 patients in their series had bladder cancer. However, of the 77 patients with paraneoplastic leukocytosis, 78% had either died or been discharged to hospice care within 12 weeks of their first elevated WBC count. Our study found that the elevated WBC counts were predominantly a result of elevated neutrophil counts, with all patients having lymphocyte counts that were less than the upper limit of normal. The neutrophil/lymphocyte ratio has prognostic significance in numerous nonurothelial-based tumors.18-20 Recently, several reports have been published of an elevated neutrophil/lymphocyte ratio having similar prognostic significance in those with urothelial carcinoma. An elevated neutrophil/lymphocyte ratio before cystectomy has been associated with decreased overall and
Table 4 Associated Laboratory Test Result Anomalies (n [ 9) Laboratory Test Result Abnormality
Patients (n)
Hypercalcemia Yes
6
No
3
Hypophosphatemia Yes
3
No
6
Hyperuricemia Yes
2
No
7
Anemia Yes
9
No
0
Thrombocytosis Yes
5
No
4
Toxic granulations Yes
5
No
4
Döhle bodies
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Yes
2
No
7
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cancer-specific survival.21-24 One possible mechanism to explain this is that circulating neutrophils might be an important source of vascular endothelial growth factor (VEGF).25 Increased expression of VEGF has been linked to both increased recurrence and increased progression rates of urothelial cancer.26 Another possibility is that the leukocytosis is not the cause of the rapid disease progression in these patients but simply an indicator of the underlying pathologic process. Several case reports have been published of high levels of G-CSF in the serum of patients with bladder cancer and extreme leukocytosis.9,11-13,15 Tachibana et al27 demonstrated both G-CSF mRNA and G-CSF receptor mRNA was present within the cultured cancer cells of 1 of these patients. The growth of this cell line was directly stimulated by exogenous G-CSF administration and inhibited by antieG-CSF antibodies. This would suggest that the rapid cell proliferation experienced by these patients might be the result of autocrine and paracrine stimulation by simultaneous G-CSF production and G-CSF receptor activation directly on the cancer cells. G-CSF functions by promoting the production of both neutrophils and other myeloid progenitor cells. However, it selectively enhances the differentiation of these precursor cells into neutrophils instead of other cell types.28 Therefore, autocrine and paracrine signaling through G-CSF would explain not only the rapid progression of these tumor cells but also the associated elevated WBC counts. Our second principle finding was the high rate of associated laboratory test result abnormalities. Similar to previous reports, leukocytosis was frequently associated with hypercalcemia. Several case reports have linked paraneoplastic leukocytosis in the setting of bladder cancer to tumor-related G-CSF production and tumoral production of parathyroid hormone-related protein (PTH-rp).9,13,29 Within our data set, we did not have the results of assays to assess for PTH-rp expression in our patients’ tumors. However, given the high rate of hypercalcemia (6 of 9 patients), it is reasonable to assume that a similar pathologic process could have been occurring. The most common laboratory anomaly was anemia, which was present in all patients to varying degrees. Several possibilities could explain this finding. Papaldo et al30 conducted a randomized control study of patients with breast cancer receiving epirubicin and cyclophosphamide. Patients were randomized to receive factor support with G-CSF to prevent low neutrophil counts or to no factor support with dose reduction in the case of low neutrophil counts. Although the patients as a whole had decreasing hemoglobin (Hb) levels as the study progressed, they found that the patients who received G-CSF support had significantly lower Hb levels than those without G-CSF support. Additionally, the dosing schedules of G-CSF varied among the patients. A trend was seen toward a lower incidence of anemia in those patients receiving fewer G-CSF injections. The investigators proposed that G-CSF might cause anemia by causing stem cells to differentiate into more committed hematopoietic cell lines, thereby reducing the stem cell pool available for erythropoiesis. Another possible explanation is that the anemia is simply a function of the aggressive nature of the cancer. At autopsy, the bone marrow of our patient 2 had largely been replaced with dense collections of tumor deposits, likely explaining his anemia. Our third principle finding was the limited radiographic, clinical, and laboratory response of the disease of these patients
Jason P. Izard et al to the local and systemic treatments. Only 1 patient had a complete response of his WBC count to extirpative surgery. Of the 5 patients, 3 had a biochemical response of their WBC count to chemotherapy. However, for 2 of the 3 patients, their WBC count returned to levels > 20,000 cells/mL within 4 weeks of the conclusion of chemotherapy. The third patient entered hospice care immediately at the conclusion of his systemic treatment and declined all future blood testing. Therefore, the timeline for the recurrence of his leukocytosis after treatment remains unknown. It is possible that the chemotherapy could have been effective in treating the neoplastic cells. However, on conclusion of the chemotherapy, the aggressive nature of these cells resumed, likely leading to increased WBC counts as a marker of disease activity. Dukes and Tierney8 reported their experience with a patient with paraneoplastic leukocytosis, whose leukocytosis disappeared with successful resection of the tumor by radical cystectomy. However, 8 months later, before radiographic evidence of disease was present, the patient’s leukocytosis had returned and was the initial presentation of disease recurrence. Similar experiences have been reported in several other case reports, indicating that in patients presenting with leukocytosis, an elevated WBC count could be the first sign of relapse.20 However, the recurrence of leukocytosis in these patients occurred months after treatment. In our patients, given the rapid recurrence of leukocytosis after the cessation of systemic therapy in the setting of minimal to no radiographic response, the WBC response might have been more associated with chemotherapyinduced myelosuppression than with the tumoricidal activity of the therapy. Our present study had several limitations. This was a retrospective analysis of a prospectively maintained database. Just as with all retrospective analyses, it was prone to bias. Although corroborating evidence was found in the published data to support our hypothesized link between paraneoplastic leukocytosis and G-CSF, our present study lacked definitive biologic evidence to support this connection. Additionally, we did not have biologic evidence to support our hypothesis of paracrine and autocrine stimulated cell growth as the ultimate cause of rapid disease progression in these patients. Despite these limitations, we believe the present study is a valuable contribution to the existing data on urothelial carcinoma. We have reported a phenomenon occurring in 0.6% of our patients with bladder cancer that is not currently recognized as a paraneoplastic syndrome in this patient population. Its recognition is important, because it portends a poor prognosis with a particularly rapid disease trajectory.
Conclusion Paraneoplastic leukocytosis in the setting of urothelial carcinoma is a rare phenomenon but confers a particularly poor prognosis with a rapid progression to death.
Clinical Practice Points Paraneoplastic leukocytosis represents a rare finding (< 1%) in
patients with urothelial carcinoma and is associated with poor patient outcomes and rapid progression to death.
Patients with urothelial carcinoma tend to have muscle-invasive
disease and frequently have metastatic disease at their presentation with leukocytosis. Local and systemic cancer therapies can produce responses in some patients’ WBC counts. However, these responses tend to be short-lived, with rapid recurrence of the elevated WBC count after treatment. Recurrence of leukocytosis after local and systemic therapy is associated with clinical and radiographic progression of disease. Paraneoplastic leukocytosis is frequently associated with other laboratory abnormalities, including anemia and hypercalcemia.
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