Japanese Journal of Clinical Oncology Advance Access originally published online on August 24, 2007
Japanese Journal of Clinical Oncology 2007 37(10):793-796; doi:10.1093/jjco/hym094
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© 2007 Foundation for Promotion of Cancer Research
Granulocyte Colony-stimulating Factor Production and Rapid Progression of Gastric Cancer after Histological Change in the Tumor
1 Department of Surgery, Kawachi General Hospital, Higashiosaka, Osaka
2 Department of Pathology, Osaka University Medical School, Suita, Osaka, Japan
For reprints and all correspondence: Tomoki Yamano, Department of Surgery, Kawachi General Hospital, 1–31 Yokomakura, Higasi-Osaka, 578-0954, Japan. E-mail: yamanot{at}kawati.org
Received February 27, 2007; accepted June 3, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONCASE REPORTDISCUSSIONConflict of interest statementReferences |
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Granulocyte colony-stimulating factor (G-CSF)-producing malignancies are thought to be rare and associated with advanced disease and poor prognosis. Here, we report on a 77-year-old patient with G-CSF-producing gastric cancer. We observed this patient from the stage prior to the diagnosis of gastric cancer when leukocyte count was normal to the stage of advanced disease associated with remarkable leukocytosis. Immunohistochemical analysis demonstrated G-CSF expression in the advanced-stage, poorly differentiated adenocarcinoma, but not in the early-stage, well-differentiated adenocarcinoma. G-CSF receptor was not detected to be expressed in the advanced-stage tumor. Based on these results it appears that a histological change in the tumor may influence G-CSF production and the concomitant rapid progression in gastric cancer.
Key Words: granulocyte colony-stimulating factor • gastric cancer • histology
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INTRODUCTION |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONConflict of interest statementReferences |
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More than 100 cases of granulocyte colony-stimulating factor (G-CSF)-producing tumors have been reported for various kinds of malignancies (Fig. 1). However, only a few cases of G-CSF-producing gastric cancer have been reported in the English literature (1,2).
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In most cases, for all types of malignancies, G-CSF-producing tumors were detected at an advanced stage, associated with a poor prognosis.
We have observed a case of gastric cancer from the prediagnosis stage when leukocyte count was normal, to the advanced stage with marked leukocytosis. Immunohistochemical analysis revealed expression of G-CSF only in the advanced stage, despite the fact that G-CSF receptor expression was not detected at the advanced stage. Therefore, the direct interaction between G-CSF and its receptor did not appear to influence the rapid progression of the tumor. Rather, it appears that in this case it may be the biological function of G-CSF itself that affected cancer progression.
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CASE REPORT |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONConflict of interest statementReferences |
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A 77-year-old man was diagnosed with a small benign gastric polyp in the posterior wall of the upper body of the stomach by endoscopy which was performed to elucidate the reason for his anemia (Fig. 2a). Two months later he underwent a colectomy for transverse colon cancer (pT3, pN1, M0, Stage 3B), the apparent cause of his anemia. One month after the operation, early type I gastric cancer was detected in the same region as the benign gastric polyp (Fig. 2b). The tumor was removed by the endoscopic mucosal resection (EMR), because the patient refused gastrectomy. Pathological diagnosis of EMR specimen was a well-differentiated adenocarcinoma with possible invasion to the submucosa. Subsequent endoscopic examination revealed the remnant gastric tumor after EMR. Histological diagnosis of the remnant lesion was a poorly differentiated adenocarcinoma. Two months after EMR, the patient was hospitalized to receive a gastrectomy.
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After admission, endoscopic examination revealed an enlarged Borrmann type I gastric cancer in the same region where EMR was performed (Fig. 2c). Laboratory data showed remarkable leukocytosis (38590/µl; 88% neutrophils) and elevated C-reactive protein (7.2 mg/dl). The leukocyte count and the amount of C-reactive protein level were normal at the time of EMR (5500/µl and 0.2 mg/dl, respectively). The changes in leukocyte count and the amount of C-reactive protein from the time of EMR to the time of death are shown in Fig. 3. The level of carcinoembryonic antigen was found to be high at 32.2 ng/ml (normal < 5 ng/ml). A bone marrow puncture biopsy revealed a hypercellular marrow with a marked predominance of cells of the myeloid series. Cytogenetic analysis showed no chromosome abnormalities, including Ph1 chromosome. There were no results suggestive of a severe infection. From these findings, we assumed that the patient had G-CSF producing gastric cancer, although we could not confirm this until the autopsy.
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The general condition of the patient deteriorated after hospitalization. Melena, abdominal pain, high fever and a general fatigue became apparent. As a result, the operation was cancelled. The leukocyte count rose to 103220/µl (97% neutrophils). In less than 3 months following admission to hospital, the patient died of multiple organ failure.
The autopsy revealed a huge tumor mass (dimension: 17 x 13 cm), which had invaded the spleen and pancreas. Liver metastases were recognized in S4 and S5. The huge mass consisted entirely of cancer cells, and it was classified macroscopically as a Borrmann type 3 tumor, which formed a giant ulcer with ridge. Cancer cells with large nucleoli proliferated in a solid pattern, and few glandular structures were detected. Histological diagnosis of the tumor was a poorly differentiated adenocarcinoma. Prominent neutrophilic infiltration was detected partially in the tumor as previously reported (3).
The specimens obtained at biopsy (EMR) and autopsy were stained following the immunoperoxidase procedure (ABC method). After antigen retrieval in the 0.1 M citrate buffer (pH 6.0) using a Pascal pressurized heating chamber (DAKO A/S, Glostrup, Denmark), the sections were incubated with primary antibodies directed against G-CSF (N-20, goat polyclonal antibody, Santa Cruz Biotech, Santa Cruz, CA, USA) and the G-CSF receptor (S-1284, mouse monoclonal antibody, abcam, Cambridge, UK). Binding of the primary antibodies was detected using biotin-conjugated anti-goat or anti-mouse IgG secondary antibodies (Zymed, South San Francisco, CA, USA), followed by incubation with a peroxidase-conjugated biotin–avidin complex (Vectastain ABC kit, Vector, Burlingame, CA, USA). As a negative control, sections were incubated with nonimmune serum. Color reaction was developed in a 0.02% solution of 3,3'-diaminobenzidine in 0.05 M Tris–HCl buffer (pH 7.2) containing 0.01% H2O2. Results showed that the well differentiated adenocarcinoma found at EMR (Fig. 4a) was negative for G-CSF (Fig. 4b). In contrast, the poorly differentiated adenocarcinoma found at autopsy (Fig. 4c) showed positive immunoreactivity for G-CSF in the cytoplasm of cancer cells (Fig. 4d), but negative reactivity for the G-CSF receptor (Fig. 4e). Histological analysis of the marrow obtained at autopsy revealed hypercellularity with a marked predominance of cells of the myeloid series (Fig. 4f).
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DISCUSSION |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONConflict of interest statementReferences |
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We report a case of G-CSF-producing gastric cancer, which showed rapid progression and pronounced leukocytosis. The leukocytosis was not detected during the early stage of gastric cancer, but rather appeared at an advanced stage. Histologically, the early stage cancer presented as a well-differentiated adenocarcinoma, which changed to a poorly differentiated adenocarcinoma at the advanced stage. These findings indicated that such histological changes might influence the acquisition of G-CSF-producing ability and hence rapid progression of the tumor.
G-CSF is a glycoprotein that influences the survival, proliferation, and maturation of neutrophils through interaction with a specific receptor (4). G-CSF has also been linked to tumor cell growth in vitro (5). In most cases, G-CSF-producing tumors appear to be advanced, and hence its diagnosis has been associated with extremely poor prognosis. It has been reported that genetically modified G-CSF-producing tumor cells suppressed tumor progression in vivo (6–8). In contrast, controversial findings that G-CSF promoted cancer progression have also been reported by others (9–11). However, although a link between G-CSF-production and tumor progression has been suggested, its mechanism has yet to be elucidated.
In a recent study, it was shown that G-CSF could influence the function of T-cells and endothelial cells (12,13), as well as neutrophils. Therefore, G-CSF may modify the microenvironment of malignant cells, which may in turn be advantageous for tumor progression. In the present case, gastric cancer cells expressed G-CSF but not G-CSF receptors. Therefore, it is not likely that rapid tumor progression was caused by the direct effect of G-CSF on the tumor itself.
In breast cancer, neutropenia during chemotherapy is a marker associated with a good prognosis (14,15). Neutropenia has been shown to enhance innate G-CSF production (16). Exogenous G-CSF is administrated in the case of febrile neutropenia or grade 4 neutropenia during chemotherapy treatment of breast cancer. However, this increase in G-CSF levels might promote breast cancer progression. Recent studies have revealed the relationship between neutropenia and breast cancer (17): most breast cancer cells express CXCR4, and the interaction between CXCR4 and its ligand (CXCL12) is crucial for the proliferation and survival of CXCR4-expressing cancer cells. G-CSF down-regulates CXCL12 production; therefore, G-CSF is thought to inhibit breast cancer cell growth via suppression of the interaction between CXCR4 and CXCL12.
In this case, it is possible that the poor prognosis of the G-CSF-producing gastric cancer was dependent on a histological change leading to the formation of more aggressive cancer cells, or on a change in the interstitial cells around the tumor, rather than on a direct interaction between G-CSF and its receptor on the tumor cells.
During the treatment of malignancies, it is possible that massive necrosis of a tumor induces a slight leukocytosis (10 000–15 000/µl) without any evidence of underlying infection. However, we should recognize that an intense leukocytosis in the absence of infection could be induced by G-CSF produced by the malignancies themselves. Though the acquisition of G-CSF production usually indicates a poor prognosis, this condition is not a contraindication for cancer treatment.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONConflict of interest statementReferences |
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