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Jpn J Clin OncoI1998;28(9)559-562

Production of Granulocyte-macrophage Colony-stimulating Factorin a Patient with Metastatic Chest Wall Large Cell CarcinomaMasazumi Watanabe1, Katsuaki On02, Yuichi Ozeki2, Susumu Tanaka2, Shinsuke Aida3 andYutaka Okun041Department of Surgery, School of Medicine, Keio University, Tokyo, Departments of 2Surgery II and 3LaboratoryMedicine, National Defense Medical College, Saitama and 4Kenseido Hospital, Chichibu, Saitama, Japan

Recent reports of cancers that produce colony-stimulating factors (CSF) and which are associatedwith leukocytosis indicate that most are granulocyte CSF-producing tumors. A 71-year-old manwith metastatic chest wall tumors from large cell lung cancer with marked leukocytosis andeosinophilia was reported. His maximal leukocyte count was 48 300/111 with 37.5% eosinophils.Granulocyte-macrophage CSF (GM-CSF) activity detected by enzyme-linked immunosorbentassay (ELISA) in serum was 112 pg/ml (normal range

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560 GM-CSFproducing carcinoma

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Figure 3. The clinical course of the patient. WEe. leukocy te count; CRP,C-reactive protein; Gy, gray.

Figure 2. (A) Photomicrograph of the biopsy specimen from the chest walltumor, showingsolid growth of large anaplasticcells compatible with metastasisfrom large cell carcinoma of the lung. (x400, hematoxylin and eosin stain). (E)Immunohistochemistry using rabbit anti-human granulocyte-macrophage colony-stimulating factor polyclonal antibody, show ing scattered foci of positivestaining (arrows). (x400. immunoperoxidase sta in by avidin-biotin complexmethod) .

I irradia t ion 4 Gy I day I

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Figure 1.Chest CT scans show a round-shaped mass with blurred margin inthesuperior segment of the right lower lobe with lymph node enlargement of thehilum (arrow) (A) and a large chest wall tumor which invades to r ibs andabdominal cavity (E).

and he complained of gradual onset of severe chest wall pain. Torelieve his pain, irradiation to the chest wall tumor was started 20days after admission.After 36Gy Linac irradiationof the chest walltumor, local pain was well controlled and the leukocyte countdecreased to 21 SOO/Ill with 29.5% eosinophils. However, tumormetastases extended to multiple organs and he died of respiratoryfailure 56 days after admission. Fig. 3 shows the clinicalcourse andthe leukocyte count and CRP value that moved independently.DISCUSSIONGM-CSF is usually produced and secreted by stromal cells inbone marrow, but may occasionally be secreted by lymphocytesand macrophages following endotoxic stimulation. GM-CSFmay induce myeloid stem cells to proliferate and differentiate andincreases neutrophils, eosinophils and monocytes numbers invivo (5). Clinical trials for patients with leukopenia usingintravenous GM-CSF have demonstrated a leukocytosis that isfrequently associated with substantial eosinophilia (6).

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Table 1. Reported cases of granulocyte-macrophage colony-stimulating factor producing cancer with leukocytosis

Case Age Gender Origin Histology Leukocyte Eosinophil Serum GM-CSF Other means of detection Referencecount (/111) (%) by ELISA (pg/ml)

65 M Lung Sq 90500 31 3800 (pleural fluid) Biological activity of CFU-GM 122 68 M Lung Ad 36900 37 1000 (pleural fluid) Biological activity of CFU-GM 123 61 M Thyroid Undiff 105600 106.4 134 72 F Thyroid Undiff 116900 32 459 145 67 F Kidney Transit 45000 132 Biological activity of CFU-GM 156 71 M Lung Lg 48300 38 112 Immunohistochemistry Present caseGM-CSF, granulocyte-macrophage colony-stimulating factor; ELISA, enzyme-linked immunosorbent assay; CFU-GM, colony-forming unit granulocyte-macro-phage; Sq, squamous cell carcinoma; Ad, adenocarcinoma; Undiff, undifferentiated carcinoma; Transit, transitional cell carcinoma; Lg, large cell carcinoma.

In the present case, GM-CSF production by tumor cells wassuggested because of leukocytosis with marked eosinophiliawhich is dependent on tumor growth. High GM-CSF activity inserum with normal G-CSF activity was shown by ELISA.Immunohistochemical staining of a biopsy specimen showed thatGM-CSF protein was localized in tumor tissue. A number ofcases of G-CSF-producing tumors with associated leukocytosishave recently been reported and were most frequently lungcancers. However, GM-CSF-producing tumor with accompanying leukocytosis appear to be very uncommon. Several investigators have reported GM-CSF expression in tumor cell lines (7-9)or of tumor in nude mice (10) and elevation of serum GM-CSFactivity in clinical lung cancer patients (11). However, to ourknowledge only five cases of clinical leukocytosis, two lungcancers (12), two undifferentiated thyroid cancers (13,14) and arenal pelvic transitional cell carcinoma (15) have been reported(Table 1). GM-CSF was detected by ELISA in all five patientswith leukocytosis, three in serum and two in pleural effusion andby biological activity assay in three cases; however, immunohistochemical detection of GM-CSF in tumor tissue has not beenreported. Two reports failed to detect GM-CSF protein usingautopsy specimens several hours after death, whereas we wereable to detect GM-CSF in large specimens obtained by biopsy.Katsumata et al. (11) showed elevation of GM-CSF serum levelin nine of 183 primary lung cancer patients; however, each valuewas less than twice the cut-off level. Wespeculate that in spite ofa relatively high GM-CSF positive rate in lung cancer cells,clinical leukocytosis is uncommon.An important characteristic of this case is rapid tumor

progression, which is frequently observed in CSF-producingtumors. Our patient died of progressive tumor growth within 2months of admission. In three of five cases of GM-CSFproducing tumors whose prognosis has been described, twopatients with thyroid cancer died 1 and 4 months after diagnosisand in a patient with renal transitional cell carcinoma systemicand local multiple recurrence was observed 7 months aftercurative resection. Recent studies of cytokines have demonstratedthat they may play an important role in tumor growth. Severalreports have shown GM-CSF-induced proliferation of humannon-hematopoietic malignant cell lines and transplanted tumorsin mice (16-19). We speculate that GM-CSF-producing cells

may stimulate themselves in an autocrine manner leading to rapidproliferation.In conclusion, a cancer patient with marked leukocytosis and

eosinophilia despite no infectious signs may be suspected to havea GM-CSF-producing tumor and should be evaluatedaccordingly. To improve poor prognosis in patients with GMCSF-producing tumors, one potential therapeutic approach mayinvolve blocking of autocrine stimulation of proliferation.

AcknowledgmentWethankDrYoshiroOshika for his suggestion of a immunohistochemical study.

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2. Suda T,Miura Y,Mizokuchi H, Kubota K, Takaku F.A case of lung cancerassociated with granulocytosis and production of colony-stimulating activityby the tumour. BrJ Cancer 1980;41:980--4.

3. Kimura N, Niho S,Yanase T.A high level of colony-stimulating activity in alung cancer patient with extensive leucocytosis and the establishment of aCSA producing cell line (KaNT). ScandJ HaematolI982;28:417-24.4. Shijubo N, Inoue Y, Hirasawa M, Igarashi T, Mori M, Matsuura A, et aI.Granulocyte colony-stimulating factor-producing large cell undifferentiatedcarcinoma of the lung. Inte171 Med 1992;31:277-80.5. Gasson Jc . Molecular physiology of granulocyte-macrophage colonystimulating factor.Blood 1991;77:1131.6. Antman KS, Griffin JD, Elias A, Socinski MA, Ryan L, Cannistra SA, etal.Effect of recombinant human granulocyte-macrophage colony-stimulatingfactor on chemotherapy-induced myelosuppression. N Engl J Med1988;319:593-8.

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8. Manao H, Nishida J, Usuki K, Maru Y, Kobayashi Y, Hirai H, et al.Constitutive expression of the granulocyte-macrophage colony-stimulatingfactor gene in human solid tumors. Jpn J CancerRes 1987;78:1041-3.

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10. Asano S,Sato N, Mori M, Ohsawa N, Kosaka K, Ueyama Y.Detection andassessment of human tumours producing granulocyte-macrophage colonystimulating factor (GM-CSF) by heterotransplantation into nude mice. Br JCancer 1980;41:689-94.

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