Kaohsiung J Med Sci February 2007 • Vol 23 • No 2 89 © 2007 Elsevier. All rights reserved.
Carcinomas producing granulocyte colony-stimulating factor (G-CSF) are known to be extremely malignant and to carry a poor prognosis [1]. Primary neoplasms manifesting granulocytosis were first reported in 1951 [2]. Bradley and Metcalf [3] have demonstrated the biologic effects of G-CSF on granulocytic and mononuclear cell proliferation.
Renal pelvic carcinoma producing G-CSF is rare, which is reported in the English literature. We provide a case of leukemoid reaction from G-CSF producing urothelial carcinoma (UC) of the renal pelvis.
C
ASEP
RESENTATIONA 75-year-old man presented with left flank pain and gross hematuria for 3 months. He was admitted to our
hospital and underwent serial examinations. Physical examination showed a left flank mass with tender-ness. The leukocyte count was 39,800/μL with 88% segmented form. There was no evidence of infectious disease. No abnormal finding in urinary bladder was noted on cystoscopic examination. The report of urine cytology was negative. Abdominal computed tomog-raphy (Figure 1A) showed a mass measuring 12× 13 cm in the upper pole of the left kidney with lung metastasis. Then, angiography (Figure 1B) showed a hypervascular mass, which was supplied by the anterior division of the left renal artery. Under impres-sion of renal cell carcinoma due to the hypervascular pattern seen with angiography, the tumor was selec-tively embolized by gelfoam pledgets and metallic coil preoperatively (Figure 1C). The patient underwent radical nephrectomy and para-aortic lymphadenec-tomy. The course of treatment was smooth and he was discharged on the 10thpostoperative day.
To our surprise, the diagnosis on the pathologic report was not renal cell carcinoma as we had sus-pected preoperatively. It was reported as infiltrating UC of the renal pelvis (staging: pT4N0M1) with direct Received: August 1, 2006 Accepted: August 18, 2006
Address correspondence and reprint requests to: Dr Wen-Jeng Wu, Department of Urology, Kaohsiung Medical University Hospital, 100 Tzyou 1stRoad, Kaohsiung 807, Taiwan.
E-mail: [email protected]
L
EUKEMOID
R
EACTION
R
ESULTING FROM
G
RANULOCYTE
C
OLONY
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STIMULATING
F
ACTOR
P
RODUCING
U
ROTHELIAL
C
ARCINOMA OF
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ENAL
P
ELVIS
Han-Ching Lin,1Chee-Yin Chai,2,3Yue-Chiu Su,2Wen-Jeng Wu,1,4and Chun-Hsiung Huang1,4
Departments of 1Urology and 2Pathology, Kaohsiung Medical University Hospital, and
Departments of 3Pathology and 4Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Leukemoid reaction is defined as a reactive leukocytosis in response to infection, inflammation, or therapeutic agents such as growth factors and malignancy. We report a case of leukemoid reac-tion resulting from granulocyte colony-stimulating factor producing urothelial carcinoma of the renal pelvis as evidenced on immunohistochemical analysis.
Key Words:granulocyte colony-stimulating factor, leukemoid reaction, renal pelvis, urothelial carcinoma
Kaohsiung J Med Sci February 2007 • Vol 23 • No 2 90
H.C. Lin, C.Y. Chai, Y.C. Su, et al
adrenal gland invasion. Furthermore, the tumor cells were immunoreactive for G-CSF, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor 1 (HIF-1) (Figure 2).
The white blood cell (WBC) count normalized within 2 weeks postoperatively. Subsequently, systemic chemotherapy with MVAC was started. Unfortunately, the WBC count gradually increased without any infec-tious focus, and he died 10 weeks postoperatively.
D
ISCUSSIONMalignant neoplasms are often accompanied by leukocytosis in the absence of any acute infectious disease or blood disorder [4]. The G-CSF secreted by
tumor cells has been considered to be a cause of leukocytosis. Several studies have demonstrated G-CSF producing tumors, which are characterized by leukemoid reaction and mainly involve mature neutrophils.
Elevated serum G-CSF level was shown to be associated with poor prognosis in patients with uri-nary bladder tumor [5].
It was reported that G-CSF produced by transi-tional cell carcinoma (TCC) of the bladder augments its autocrine growth [6]. Hematopoietic differentia-tion of TCC, resulting in acquisidifferentia-tion of G-CSF pro-duction and G-CSF receptor expression, is another possibility supported by the same study [6].
Renal pelvic carcinoma producing G-CSF is rare. Higaki et al reported the first case in 2001 [7], followed
A B C
Figure 1.(A) Computed tomography: coronal reconstructional section shows a 12× 13 cm mass in the upper pole of the left kidney (star). (B) Angiography shows a hypervascular mass located in the left upper kidney (circle). (C) Selective embolization of the tumor by the metallic coil is successful (arrow).
B A
Figure 2.(A) Infiltrating hyperchromatic cancer cells (star) with high N/C ratio in desmoplastic fibrous stroma (hematoxylin & eosin, 100×). (B) Immunohistochemical stain shows that the tumor cells are immunoreactive for G-CSF (arrow).
G-CSF producing UC of the renal pelvis
Kaohsiung J Med Sci February 2007 • Vol 23 • No 2 91
by Terao et al [8] in 2005. Although neither of them received surgical resection, both of them died within 8 weeks of diagnosis.
In this case, the initial diagnosis was renal cell carci-noma due to its hypervascularity in the angiography films and negative findings on urine cytology and cys-toscopy. Therefore, embolization was done routinely before radical nephrectomy to avoid excess blood loss intraoperatively.
Although the operation went quite smooth and leukemoid reaction subsided 2 weeks after operation, he died 10 weeks postoperatively.
Like the previous two cases [7,8], the tumor cells were immunoreactive for G-CSF. The result of immuno-histochemistry study of the tumor cells can make sense of the interrelationships between leukemoid reaction and the G-CSF producing tumor cells in our case. Radical nephrectomy offers a cytoreduction effect and normalization of the leukocyte count can be obtained postoperatively even if the tumor has metastasized to the lung.
Overexpression of proangiogenic factors by tumor cells is one mechanism by which tumors can promote neovascularity. VEGF has also been shown to be proangiogenic and to promote invasion and metastasis of human TCC [9]. Transcription of the VEGF gene is known to be driven by HIF-1, and recent evidence has suggested that cellular HIF-1 levels are raised not only by hypoxia but are also increased in the presence of reactive oxygen species [10].
Hypervascularity is an uncommon character of UC of renal pelvis. Interestingly, it was well demon-strated in the case we presented here. We found that it may be explained by the ability of the tumor cells to produce VEGF and HIF-1.
VEGF is a survival factor that protects both tumor and endothelial cells from exposure to environmental stresses such as hypoxia or acidosis [11]. Recent reports indicate that VEGF also protects tumor cells against chemotherapy-induced apoptosis [12]. It was proved previously by the relative overexpression of VEGF observed within residual tumors after MVAC chemo-therapy [9]. It may reflect the clonal selection resulting from the death of tumor cells expressing low levels of VEGF and the survival of tumor cells expressing relatively high levels of VEGF, which rendered them relatively resistant to chemotherapy-induced apop-tosis [9]. Regarding our case, this may explain the poor response to chemotherapy since the tumor was
immunoreactive for VEGF. Although the results of his treatment course were disappointing, radical sur-gery seems to be the most effective treatment. Enhance-ment of tumor growth by many cytokines was proved by our immunohistochemical study. Target therapy to the specific cytokine is likely to be an alternative treatment in the future.
R
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