Severe neutrophilic leukocytosis as a progression marker in granulocyte colony‐stimulating factor‐producing squamous cell carcinoma of the esophagus

Key Clinical Message There are very few reports of esophageal carcinoma producing granulocyte colony‐stimulating factor (G‐CSF). G‐CSF‐producing esophageal squamous cell carcinoma is an extremely aggressive carcinoma. Leukocyte counts, neutrophil counts, and serum C‐reactive protein levels may be markers of its progression.


Background
Patients with malignant neoplasms may show various levels of leukocytosis because of accompanying bacterial infections, such as aspiration pneumonia in esophageal cancer and obstructive colitis in advanced colon cancer [1]. The presence of cancer itself can lead to the development of leukocytosis as a reaction against the neoplasm. However, extreme leukocytosis is rarely encountered without a bacterial infection. In 1952, Hughes et al. first reported a case of carcinomatosis in a patient who developed extreme leukocytosis via the production of granulocyte colony-stimulating factor (G-CSF), which originated from the tumor [2]. Although G-CSF-producing cancer has been reported in various organs, including the lung, urinary tract, stomach, and pancreas [3][4][5][6][7], reports of G-CSF-producing esophageal carcinoma are rare. As G-CSF-producing tumors are reported to be a rapidly growing phenotype that is associated with a poor prognosis, it is crucial to correctly diagnose and apply an effective treatment as early as possible [2]. Here, we report a case of G-CSF-producing esophageal squamous cell carcinoma that spread rapidly to the liver within 1 month after its initial presentation. We also discuss the prognosis and treatment of G-CSF-producing esophageal cancer via a review of the literature. endoscopic examination revealed a full-circumferential, type-three neoplasm in the lower esophagus; the scope could not be advanced past the tumor (Fig. 1). A biopsy was performed, and the pathological examination revealed a poorly differentiated squamous cell carcinoma with massive neutrophil infiltration (Fig. 2). The chest CT findings showed a thickened esophageal wall in the middle-lower esophagus, which seemed to be in accordance with the tumor that was found during the endoscopic examination. There were several swollen lymph nodes surrounding the tumor; however, no metastatic nodules were found in distant organs, including the lungs and liver. The clinical diagnosis, according to the seventh edition of the Union for International Cancer Control, was T3N1 M0 c-Stage III esophageal cancer [8]. A radical operation with perioperative chemotherapy was planned; however, the patient's general condition deteriorated due to aspiration pneumonia from the esophageal stenosis. The intravenous administration of antibiotics and the insertion of a stent through the tumor to prevent the pooling of salivary juice in the esophagus seemed to alleviate the patient's aspiration pneumonia in terms of his fever and physical examination results. A chest CT showed no signs of inflammation in the lungs; however, despite the improvement in his condition, his white blood cell (WBC) count markedly increased to 25,100 cells/lL, and his neutrophil count was also elevated at 20,600 cells/ lL. This unreasonable elevation of his blood counts prompted the analysis of his serum G-CSF level, which was elevated (292 pg/mL; normal range, 5.78-27.5 pg/ mL), and an immunohistochemical examination of the biopsy specimens also revealed that the cancer cells were G-CSF-positive (Fig. 2). Although his physical condition recovered 1 month after admission, his WBC and neutrophil counts increased to 55,400 and 48,200 cells/lL, respectively. His serum CRP level was elevated at 10 mg/ dL. An abdominal CT scan showed that multiple liver metastases had developed (Fig. 3). Despite the provision of best supportive care, including administration of an antipyretic to treat the high fever, his WBC and neutrophil counts gradually increased to 112,600 and 108,100 cells/lL, respectively. His serum CRP level elevated to 20 mg/dL (Fig. 4). He died 3 months after the definite diagnosis.

Discussion
Herein, we report a case of G-CSF-producing esophageal squamous cell carcinoma. The WBC count, neutrophil count, and CRP continued to increase despite the alleviation of pneumonia through intravenous antibiotics and insertion of an esophageal stent. The tumor rapidly spreads to the liver within 1 month of the definitive diagnosis, and he died within 3 months of the definitive diagnosis. Thus, WBC count, neutrophil count, and serum CRP level may reflect the progression of G-CSF-producing esophageal squamous cell carcinoma. The neutrophil counts are especially important as a progression marker.
Granulocyte colony-stimulating factor is a hematopoietic growth factor that regulates the production of granulocytes and macrophages [9]. Several reports have mentioned the diagnostic criteria for a G-CSF-producing tumor, which include the following: (A) marked leukocytosis, (B) a high serum concentration of G-CSF, (C) a decreasing leukocyte count after tumor resection, and   (D) evidence of G-CSF production in the tumor cells [10]. In this case, the leukocyte count was elevated to more than 25,000 cells/lL, and the production of G-CSF from the neoplasm was confirmed by the patient's high serum levels of G-CSF and an immunohistochemical examination. Thus, our case fulfilled parts (A, B, and D) of the diagnostic criteria.
We were able to diagnose G-CSF-producing squamous cell carcinoma using a small block of biopsied specimens. First, the histopathological findings of the biopsied specimens showed atypical findings, such as remarkable neutrophil infiltration surrounding the malignant cells. With suspicion of G-CSF production, we performed an immunohistochemical analysis, which revealed numerous G-CSF-positive malignant cells. In contrast, Shimomura reported that it was difficult to detect G-CSF in an immunohistological examination because G-CSF is rapidly secreted from cancer cells after production in vitro [11]. In the case of esophageal carcinosarcoma, Sasaki et al. reported that G-CSF expression was also detected by an immunohistological examination but only in some of the carcinomatous cells [12]. Thus, when biopsy specimens show remarkable neutrophil infiltration but are negative for G-CSF, an immunohistochemical examination of biopsy specimens should be repeated to determine whether some components include G-CSFpositive cancer cells, which may lead to a definitive diagnosis of a G-CSF-producing tumor and the prompt initiation of treatment.
To the best of our knowledge, there have been only 10 reported cases of G-CSF-producing esophageal squamous cell carcinomas [13][14][15][16][17][18][19][20][21] (Table 1). The majority of patients were male (nine of ten cases), and the average age of the patients was 63.4 AE 14.2 years (range, 30-81 years). As reported in cases involving G-CSF-produ cing tumors in other organs, G-CSF-producing esophageal squamous cell carcinoma is a very aggressive phenotype; in three of the ten reported cases, a radical operation could not be performed due to rapid growth and spread to distant organs. The most common complaint of patients with G-CSF-producing esophageal cancer is dysphagia (seven of ten cases). Moreover, even if radical treatments were performed, early recurrence developed within several months in six of the seven cases. Nine of the ten patients died within 16 months after diagnosis (range: 0.5-16 months). Leukocytosis developed in all nine cases. The serum G-CSF level was elevated in all cases.
Granulocyte colony-stimulating factor is a key regulator of neutrophil production. In addition, the correlation between G-CSF and CRP has been reported in several conditions [22,23]. In this case, parallel increases in neutrophils and CRP were observed. The continuous increase in neutrophils and serum CRP level may reflect tumor progression.
The opportunity to administer radical treatment is often lost in patients with G-CSF-producing esophageal cancer due to the rapid progression of the disease. Similarly, to ordinary esophageal cancer, surgical resection with neoadjuvant therapy is considered to be the mainstay radical treatment for G-CSF-producing esophageal cancer. In Japan, the standard treatment strategy includes radical esophagectomy through a thoracotomy or a thoracoscopic approach with neoadjuvant chemotherapy using 5-FU and CDDP [24]. The theoretical benefit of neoadjuvant chemotherapy is the eradication of cancer cells that spill from the main tumor before definitive resection. As has been reported with neoadjuvant chemotherapy for breast cancer, the achievement of a pathological complete response in the resected specimen is indicative of both an excellent response to chemotherapy and a good postoperative prognosis [25]. Mayanagi et al. reported a patient who had a recurrence of regional and distant lymph node metastases 3 months after surgery, despite neoadjuvant chemoradiotherapy that was extremely effective in achieving a pathological complete response [20]. Shimakawa et al. also reported a patient with G-CSF-producing esophageal cancer who received preoperative chemotherapy (5-FU, ADM, and CDDP) and whose resected specimens revealed no demonstrable cancer cells. However, liver metastasis developed within 3 months after surgery [21]. In our patient, the early metastasis in the liver may imply that the tumor cells had already metastasized at the time of presentation. Therefore, it remains controversial as to whether a radical operation, combined with 5-FU-based chemotherapy or chemoradiotherapy, is feasible for G-CSF-producing esophageal cancer. Several studies have reported that the autocrine and paracrine secretions of G-CSF via the JAK2/STAT3 pathway confer more proliferative, invasive, and chemoresistant features to malignant cells [26]. Furthermore, G-CSF is known to promote tumor growth by stimulating angiogenesis [27]. Thus, novel therapies targeting these molecular mechanisms, such as the JAK2/ STAT3 pathway and angiogenesis, are expected in the future.
In conclusion, we report a case of aggressive G-CSFproducing esophageal squamous cell carcinoma. WBC, neutrophils, and serum CRP levels may be markers of its progression. There is currently no established therapeutic strategy for this disease, and a multidisciplinary approach will be required to overcome G-CSF-producing esophageal squamous cell carcinoma in the future.