There are very few reports of esophageal G-CSF-producing cancer. This report describes a case of G-CSF-producing esophageal squamous cell carcinoma we recently encountered. A 70-year-old male patient had Stage III esophageal squamous cell carcinoma. The patient received preoperative chemotherapy, and therapeutic response for the primary lesion was rated as complete response and that of the lymph node metastasis as stable disease. A radical operation was then performed. A relapse to neutrophilia occurred as liver metastasis recurred postoperation, and serum G-CSF level was high. Immunohistochemical staining of the resected specimen with anti-G-CSF antibody was positive. The patient died about 1 year after the operation. According to our search of the literature, there are 22 cases of esophageal G-CSF-producing cancer. Carcinosarcoma was more frequent as compared to esophageal non-G-CSF-producing cancer. The prognosis was graver in those cases of G-CSF-producing squamous cell carcinoma, relative to cases of non-G-CSF-producing esophageal squamous cell carcinoma.
The number of papers reporting cases of granulocyte colony-stimulating factor (G-CSF)-producing tumors has been increasing in recent years, but there are very few reports of G-CSF-producing esophageal tumor.1−6 This report describes a case of G-CSF-producing esophageal squamous cell carcinoma that we recently encountered.
A 70-year-old male patient had a chief complaint of dysphagia. The patient was hypertensive and diabetic under management with oral medications. He had been smoking 40 cigarettes daily and drank alcohol (shochu; 1 L daily) for a period of 40 years.
The patient consulted a nearby clinic because he had been aware of choking on liquid/food when swallowing since September 2007. An upper gastrointestinal endoscopy led to a diagnosis of type 2 advanced esophageal cancer in the lower intrathoracic esophagus, and the patient was admitted to our hospital.
On admission, no anemia or jaundice was noted. No superficial lymph nodes were palpable. An esophagography and esophagoscopy revealed a type 2 cancer of the esophagus measuring approximately 5 cm in major axis on the anterior wall of the lower intrathoracic esophagus (Fig. 1 a, b).
Computed tomography of the chest and abdomen demonstrated irregular thickening of the wall and narrowing of the lumen of the lower intrathoracic esophagus. An unhomogeneously visualized mass about 5 cm in diameter was noted at the esophago-gastric junction and was judged to be a lymph node metastasis (Fig. 1c). These findings led to a diagnosis of Lt, type 2, T3 N2 M0 cStage III, moderately differentiated squamous cell carcinoma.7 The patient received 3 courses of preoperative FAP (5FU, ADM, and CDDP) chemotherapy, following which the therapeutic response of the primary lesion was rated as complete response (Fig. 2a, b) and that of the lymph node metastatic lesion as partial response (Fig. 2c). A radical operation was then performed. Middle-to-lower esophagectomy via right thoracolaparotomy, two-area lymphadenectomy, and high intrathoracic gastroesophagostomy were performed. When the surgical intervention was undertaken, the mass at the cardia had further increased in size forming a lump with the gastric wall, and was resected en bloc.
Histopathologic examination of the resected specimens revealed that the primary lesion, with no demonstrable cancer cells at all, was Grade 3 according to the histologic criteria for chemotherapy (Fig. 3a). The mass at the esophago-gastric junction, which was judged to be a lymph node metastasis prior to the operation, was finally diagnosed as gastric intramural metastasis rather than lymph node metastasis, so that the lesion was rated as Grade 1a according to the criteria for chemotherapy (Fig. 3b).
The patient had been noted to have neutrophilia without signs of infection prior to the chemotherapy and showed improvement in this respect in harmony with his favorable therapeutic response (Table 1). Nevertheless, a relapse to neutrophilia occurred as liver metastasis recurred 3 months post operation; therefore, a G-CSF producing tumor was suspected and laboratory tests revealed a serum G-CSF level as high as 254 pg/mL using ELISA (the reference value: ≤39.0 pg/mL). Immunohistochemical staining of the resected tissue specimen with anti-G-CSF antibody was positive, and the condition was diagnosed as G-CSF-producing esophageal cancer (Fig. 4). The patient died of the primary disease about 1 year after the operation despite subsequent chemotherapy (Fig. 5).
In healthy individuals, G-CSF is produced mainly in vascular endothelial cells, fibroblasts, monocytes, and macrophages. G-CSF-producing tumors give rise to clinical manifestations due to neutrophilia etc. caused by excessive production of G-CSF. This concept was elaborated by Fahey8 in 1951 who pointed out the possibility that tumor per se produces myelostimulant substances. In 1974, Robinson9 reported elevated plasma and urine G-CSF levels in patients with malignant tumor presenting with neutrophilia, and Asano et al10 demonstrated G-CSF production in lung cancer patients. Subsequently, there have been increasing reports documenting G-CSF production in lung cancer,10−13 gastric cancer,14−16 and liver cancer,17 but there are few reports on this condition in cases of esophageal cancer.1−6,18−32
Diagnostic criteria for G-CSF-producing tumors include: (1) a marked increase in leukocyte count, (2) elevated G-CSF activity, (3) a decrease in leukocyte count following tumor resection, and (4) verification of G-CSF production in tumor.10 This case fulfilled all 4 criteria for G-CSF-producing tumors. According to our search of the literature, there have been 22 cases of G-CSF-producing esophageal cancer reported in Japan, including the 2 herein described cases; hence it is remarkably uncommon (Table 2).1−6,18−32 Characteristic features of those documented cases lie in the age range of 53−80 years, all males, with a higher percentage of a histologic type of carcinosarcoma (12/22 patients, 54.5%) as compared to usual malignant neoplasma of the esophagus. Of 10 cases of squamous cell carcinoma, the lesions were all moderately to poorly differentiated cancers, except 1 case unknown in this respect, while there was no case of well differentiated cancer. The prognosis was graver in those cases of G-CSF-producing squamous cell carcinoma, relative to cases of non-G-CSF-producing esophageal squamous cell carcinoma, in that there was only 1 patient who survived for 2 years after treatment whereas the remaining 9 patients did not survive for 2 years or longer and were not alive when reported. Of 12 patients with carcinosarcoma, in contrast, 6 patients were still alive when reported and the longest duration of survival reported was 57 months,32 the prognosis being relatively more favorable as compared with that of squamous cell carcinoma.
As for G-CSF-producing tumors of other organs, one report stated that squamous cell carcinomas were rather common among lung cancers while relatively undifferentiated or poorly differentiated tumors were frequent among cancers of the gastrointestinal system and that the prognosis was unfavorable in most cases;25 hence seeming similar to esophageal cancer.
As a reason thereof, G-CSF has been suggested to have a bearing as an autocrine growth factor upon tumor growth and metastasis.14 Therefore, it is considered that due caution should be exercised regarding the possibility that administration of G-CSF preparations for the control of neutropenia may favor tumor growth.
In conclusion, we encountered an extremely rare case of G-CSF-producing squamous cell carcinoma of the esophagus. The condition was refractory to chemotherapy and the prognosis was unfavorable.