Choroidal metastasis from granulocyte colony‐stimulating factor‐producing esophageal squamous cell carcinoma: a case report

Key Clinical Message Granulocyte colony‐stimulating factor (G‐CSF)‐producing esophageal squamous cell carcinoma (ESCC) is rare. Esophageal cancer is a highly aggressive disease and often spreads hematogenously; however, choroidal metastases are rarely seen. This report detailed an extremely rare case of G‐CSF‐producing ESCC with choroidal metastasis.


Background
Granulocyte colony-stimulating factor (G-CSF) is a cytokine that contributes to neutrophil production. G-CSFproducing tumors have been reported in a variety of organs, such as the lungs, gallbladder, liver, and pancreas [1][2][3][4]. However, G-CSF-producing esophageal squamous cell carcinomas (ESCCs) have rarely been reported. Esophageal cancer is a highly aggressive disease and rapidly develops metastasis of the lymph nodes [5]. Esophageal cancer also often spreads to other organs, such as the lungs, bone, liver, skin, and brain [6]; however, choroidal metastases are rarely seen. Here, we report an extremely rare case of G-CSF-producing ESCC with choroidal metastasis.

Case Presentation
A 50-year-old Japanese man was referred to our hospital with a chief complaint of dysphagia. The patient reported a 10-kg weight loss in a few months. The patient also complained of blurred vision, oppressed feeling, and hyperemia in the left eye. The patient had no history of smoking and drinking alcohol. Moreover, the patient had no personal or family history of illness. Physical examination revealed no swelling of superficial lymph nodes. Laboratory data showed an increased white blood cell (WBC) count, 27,100/lL, with 85.0% neutrophils, and increased C-reactive protein concentration, 12.3 mg/dL. All tumor markers, including carcinoembryonic antigen, fragment of cytokeratin subunit 19, and squamous cell carcinomaassociated antigen, were within the normal ranges. The serum G-CSF level was elevated by 60.2 pg/mL (normal level < 39.0 pg/mL). Bone marrow aspiration revealed no possibility of haematological neoplasms.
Contrast-enhanced computed tomography (CT) from the neck to pelvis revealed thickened wall of the esophagus and several enlarged mediastinal/abdominal lymph nodes. An upper gastrointestinal endoscopy showed a protruding esophageal tumor 30 cm from the incisors extended to the gastric cardia (Fig. 1). The specimens taken by endoscopic biopsy were histologically confirmed to be poorly differentiated squamous cell carcinoma ( Fig. 2A). Immunohistochemistry showed positive staining for anti-G-CSF antibody in the cytoplasm of cancer cells (Fig. 2B).
Ophthalmologic examination revealed that corrected visual acuity and intraocular pressure were normal in the left eye. Fundus examination of the left eye revealed a well-circumscribed yellowish-white choroidal mass at the inner upper side of the posterior pole (Fig. 3). CT of the orbit showed thickness at the inner upper side of the posterior pole of the left eye (Fig. 4). Based on these findings, a diagnosis of left choroidal metastasis was made.
The patient was diagnosed with G-CSF-producing ESCC T3N2M1, stage IV (according to the Union for International Cancer Control TNM classification of malignant tumors, 7th edition); therefore, radical resection was not recommended. Chemotherapy consisted of cisplatin at 70 mg/m 2 administered by rapid intravenous infusion on day 1 and 5-fluorouracil at 700 mg/m 2 administered by continuous intravenous infusion on days 1 through 5, which was performed with 60 Gy concurrent irradiation in 30 fractions of 2 Gy. Two courses of chemotherapy were performed, separated by a 4-week interval. A total dose of 30 Gy was also given in 10 fractions of 3 Gy to the left retina, including the right retina for the prevention of metastasis. The treatment was well tolerated, with no grade 3 adverse events.
After chemoradiation therapy, the primary tumor of the esophagus decreased, and food intake increased.
Moreover, CT showed that thickness at the posterior pole of the left eye became ambiguous (Fig. 5). However, multiple liver metastases soon appeared after chemoradiation therapy, and the patient died 3 months after diagnosis.
During the treatment, the WBC count and serum G-CSF level shifted as shown in Fig. 6. The WBC count reached to 71,800/lL at the start of the chemoradiation therapy and decreased to 5650/lL at the end of therapy. After occurrence of multiple liver metastases, the WBC count increased to 64,000/lL before his death. The serum G-CSF level decreased from 60.2 to 40.3 pg/mL after the chemoradiation therapy.

Discussion
Granulocyte colony-stimulating factor is a cytokine that contributes to production of neutrophils and inducing leukocytosis. G-CSF is mainly produced endogenously by monocytes, macrophages, mesothelial cells, fibroblasts, endothelial cells, and bone marrow stromal cells [7]. Recently, a variety of tumors have been reported to produce G-CSF [1][2][3][4]. G-CSF-producing tumors are diagnosed on the basis of elevated serum G-CSF levels and evidence of G-CSF production in the tumor [2]. In our case, the serum G-CSF level was elevated, and an immunohistochemical examination showed the cytoplasm of cancer cells to be stained for G-CSF. Therefore, we diagnosed the patient with G-CSF-producing ESCC. To the best of our knowledge, G-CSF-producing ESCCs are rare, with only 12 cases reported in English literature, including this report [8][9][10][11][12][13][14][15][16][17][18]. In particular, this report is the first case of G-CSF-producing ESCC with choroidal metastasis.
Intraocular metastases of malignant tumors are rare. The choroid is the most common intraocular site for the development of metastases due to the vascular  architecture of the choroid and local microenvironmental factors [19,20]. Choroidal metastases have been described frequently for lung and breast cancer [20,21]; in contrast, only a few cases have been reported regarding esophageal cancer [22][23][24][25]. Choroidal metastasis is usually diagnosed by ophthalmoscopy and various imaging modalities, such as CT, ultrasonography, and magnetic resonance imaging. However, choroidal metastasis is rarely diagnosed by biopsy because of a risk of seeding tumor cells [19]. The common ophthalmologic symptoms are blurred vision, flashes, floaters, and pain; however, some patients have no symptoms [26,27]. The treatment options include chemotherapy, hormonal therapy, radiation therapy, immunotherapy, photodynamic therapy, thermotherapy, and enucleation [19,26]. Choroidal metastasis has an unfavorable prognosis, with a median survival of 6-9 months [19]; therefore, the treatment strategy must be chosen carefully, considering the general outcome. In this  study, a combination of chemotherapy and radiation therapy was employed, and the choroidal mass decreased without major adverse events. Previous reports showed that radical tumor resection induced a rapid decrease in both WBC count and serum G-CSF levels [17,18]. In this study, chemoradiation therapy was performed instead of radical tumor resection, which induced normalization of WBC count. However, the serum G-CSF level was slightly over the normal level, which would be due to multiple liver metastases. This study suggested that serum G-CSF level may be a more sensitive metric to discern the viability of cancer cells compared with WBC count. Table 1 shows 12 cases previously reported in English, including this report. Eleven of the 12 patients (91.7%) were male, with a median age of 66 years (range 30-92 years). None of cases involved the cervical or upper thoracic esophagus. Previous reports seemed to indicate a poor prognosis of G-CSF-producing tumors [3,13]; however, it remains unclear whether the prognosis of G-CSFproducing ESCC is indeed worse than that of normal ESCC. In fact, three patient cases (cases 4, 5, and 11) in Table 1 without other organ metastasis and multiple lymph node metastasis, in which radical resection was performed, survived more than 18 months. This result suggested that early detection and radical resection may improve survival, even among G-CSF-producing ESCCs. G-CSF-producing ESCCs are relatively rare as aforementioned; therefore, the number of patients treated in a single institution limits the amount of insight that can be gleaned about the landscape of this rare tumor. The accumulation of prospective evidence from multiple case reports and institutions is needed to clarify the clinicopathological features and adequate treatment strategy of G-CSF-producing ESCC.
This report has highlighted an extremely rare case of G-CSF-producing ESCC with choroidal metastasis. In the case of an ESCC patient with leukocytosis, the possibility of G-CSF-producing cancer should be considered. Moreover, when ESCC patients display ophthalmologic symptoms, we should be aware of potential choroidal metastasis.