Successful treatment of cervical and upper thoracic esophageal adenocarcinoma using induction chemotherapy followed by surgery: a case report

Cervical esophageal adenocarcinoma has a low incidence rate and its treatment involves various strategies. We report a patient with locally advanced cervical to upper esophageal adenocarcinoma who was able to undergo induction chemotherapy and radical surgery. A 55-year-old man was diagnosed with a poorly differentiated adenocarcinoma between the cervical and upper thoracic esophagus. The primary lesion had infiltrated into the tracheal membrane and had metastasized into the cervical lymph nodes. The initial diagnosis was T4bN1M1 stage IVB. The lower edge of the tumor was close to the tracheal bifurcation, making it difficult to create a longitudinal tracheal foramen during surgery. Therefore, when biweekly-DCF therapy was performed as induction chemotherapy, the tumor shrank sufficiently and its infiltration into the tracheal membrane decreased subsequently. We performed total laryngopharyngoesophagectomy with three-field lymph node dissection and reconstruction using free jejunal grafts and subtotal stomach via a posterior mediastinum route and a permanent tracheal foramen as a radical surgery. The pathological diagnosis was T2/MP, N1, and the effect of chemotherapy was grade 2. Cervical esophageal adenocarcinoma was rare, but technically reliable and safe oncologic surgery was possible after induction chemotherapy.


Introduction
Esophageal cancer is the eighth most common cancer worldwide and the sixth most common cause of death from cancer [1]. Based on histopathology, esophageal cancer is divided into squamous cell carcinoma (SCC) and adenocarcinoma. These two forms have different pathogenesis, epidemiology, tumor biology, and prognosis, thus requiring different therapeutic strategies [2]. SCC is the most common histology globally, while adenocarcinoma is the most common histology in Western countries [3]. The incidence rate of esophageal adenocarcinoma has been increasing worldwide [4]. The main tumor is located at the lower thoracic esophagus and esophagogastric junction (EGJ) because it is related to reflux-associated Barrett's esophagus (BE) [3].
Cervical esophageal adenocarcinoma is extremely rare, with cervical SCC accounting for 13.6% of esophageal SCC and cervical esophageal adenocarcinoma accounting for 0.3% of esophageal adenocarcinoma [2]. However, these papers have been published and various treatment strategies have been reported accordingly [5][6][7]. No standard treatment exists for cervical adenocarcinoma. Herein, we report a patient with highly locally advanced cervical esophageal adenocarcinoma with tracheal infiltration, in whom induction chemotherapy was effective and radical resection was possible. Therefore, this report can serve as a valuable example of successful multidisciplinary treatment combining chemotherapy and surgery.

Case report
A 55-year-old man, with a complaint of throat stuffiness, was referred to our hospital for diagnosis and treatment. The patient was 165 cm tall and had a body mass index of 21.0.
He had no history of drinking and smoking. EGD at our hospital showed a type 2 tumor, 5 cm in diameter, located 20 cm from the incisors (Fig. 1a). Histopathological findings of a biopsy sample showed poorly differentiated adenocarcinoma with invasive growth, and the background mucosa showed glandular ducts consisting of a highly columnar epithelium with abundant mucus (considered to be ectopic gastric mucosa). Contrast-enhanced CT showed swollen bilateral recurrent nerve lymph nodes and left supraclavicular lymph node, but no distant metastases. The primary lesion extending from the cervical esophagus to the upper thoracic esophagus was in contact with the tracheal membrane (Fig. 1b). Bronchoscopy showed no abnormal findings in the mucosal blood vessels and the tumor was not exposed, but the tracheal membrane was excluded and raised by the tumor (Fig. 2a). An MRI scan showed a partially obscured tracheal membrane, suggesting tracheal infiltration of the tumor (Fig. 2b). Upper gastrointestinal series (UGI) revealed a tumor of 5 cm-diameter at the cervical and upper thoracic esophagus. The distance between esophageal orifice and oral edge of tumor was approximately 1 cm, and horizontal location was the entire circumference. The lower edge of the tumor was 5 cm above the bifurcation of the trachea (Fig. 3a). PET-CT showed high FDG accumulation in the tumor, with SUVmax of 13.29 (Fig. 3b). Based on these findings, the initial diagnosis was cervical and upper thoracic adenocarcinoma, T4b/main bronchus, N1, M1 stage IVB, according to the TNM classification in the UICC 8th edition. If we performed total pharyngeal-laryngeal esophagectomy, including the trachea, the position of the mediastinal tracheal foramen was expected to be in the chest, which could significantly decrease the patient's quality of life (QOL) because of the significant distance between the lower edge of the tumor and tracheal bifurcation. Therefore, first, the plan was to shrink the tumor by induction chemotherapy. The patient received two courses of chemotherapy, with a biweekly-DCF regimen: docetaxel 35 mg/m 2 with cisplatin 40 mg/m 2 on days 1 and 15, and 5-fluorouracil 400 mg/m 2 on days 1-5 and 15-19 every 4 weeks. The treatment led to the development of Grade 4 neutropenia as an adverse event, but there was no sign of infection. After completion of the chemotherapy at 100% dose, EGD and enhanced CT showed tumor shrinkage, and all of the metastatic lymph nodes, including the left supraclavicular lymph node, had disappeared. The clinical effect was that of a partial response (PR) (Fig. 1c, d). Bronchoscopy showed improved tumor exclusion of the tracheal membrane (Fig. 2c). In addition, bronchoscopic ultrasound confirmed the absence of tumor infiltration in the tracheal membrane and MRI also confirmed a boundary between the tumor and the tracheomembrane (Fig. 2d). In UGI, it was observed that the tumor shrank from the upper thoracic esophagus toward the cervical esophagus, and the distance between esophageal orifice and oral edge of tumor remained unchanged at approximately 1 cm. However, the distance between the lower edge of the tumor and the tracheal bifurcation was sufficient at 8 cm or more (Fig. 3c). PET-CT showed that FDG accumulation in the tumor had disappeared (Fig. 3d). Therefore, the post-chemotherapy diagnosis was cyT3, cyN0, cyM0 stage IIA (UICC8th), and a down stage was achieved accordingly. We then planned to perform radical surgery (Fig. 3e).
Approximately 3 months after chemotherapy initiation, we performed total laryngopharyngoesophagectomy with three-field lymph node dissection and reconstruction using free jejunal grafts and subtotal stomach via a posterior mediastinum route and jejunostomy (Fig. 4a). The surgery was performed jointly by gastrointestinal surgery, head and neck surgery, and plastic surgery specialists, and the operating time was 12 h and 30 min, and the amount of bleeding was 660 ml. We performed thoracic esophagectomy in the left hemi-prone position using thoracoscopy. In the thoracic cavity, the bilateral bronchial arteries were preserved to maintain blood flow to in the oral side of the trachea. The right bronchial artery diverged from the right subclavian artery (Fig. 4b). The tumor was detached from the tracheal membrane, the trachea was cut between the 5-6th tracheal cartilage, and a permanent tracheal foramen could be constructed at the upper sternal margin level (Fig. 4b, c). The thoracic duct was resected at the left venous angle of the neck. The thyroid gland was not resected, and the isthmus was dissected accordingly. During reconstruction, a free jejunum was placed between the mesopharynx and the subtotal stomach, the jejunal artery and superior thyroid artery were anastomosed, and the jejunal vein and the total facial vein were anastomosed (Fig. 4d).
The resected specimen showed a 2 cm scar-like tumor on the mucosal surface of the cervical esophagus (Fig. 5a,  b). Histopathological findings confirmed a moderately and poorly differentiated adenocarcinoma, and the background mucosa showing ectopic gastric mucosa (Fig. 5c, d). The pathological diagnosis was T2 MP, N1, and induction chemotherapy response was grade 2.
The ventilator was withdrawn on postoperative day (POD) 1, and the patient started to get out of bed. The patient started swallowing training with jelly on POD 9, and eating orally on POD 14. He practiced vocalization using the electrolarynx and was discharged on POD 35. Three months after surgery, we followed -up on our patient in the outpatient clinic.

Discussion
Adenocarcinoma of the cervical and upper thoracic esophagus is very rare. Moreover, it is often found in advanced cancer, and its prognosis is poor [4]. Previously, we reported a patient with adenocarcinoma in the upper thoracic esophagus who underwent surgery [8]. In our department, among all patients who underwent esophageal cancer surgery in the last 10 years, two patients (0.6%) including this case had adenocarcinoma of the cervical to upper thoracic esophagus, which is also rare. Therefore, it is important to diagnose primary esophageal adenocarcinoma. Most primary adenocarcinomas of the esophagus are derived from BE, ectopic gastric mucosa (EGM), or the esophageal glands [9][10][11]. In our case, ectopic gastric mucosa was found in the background mucosa of the tumor in the histopathological findings of biopsy before chemotherapy and in the resected specimen, and no abnormal findings were found between the tumor and EGJ. Furthermore, no neoplastic lesions were found in other organs, and the diagnosis was primary cervical to upper thoracic esophageal adenocarcinoma originating from EGM.
No standard treatment exists for cervical adenocarcinoma and various treatment strategies have been reported [7]. Our patient had highly locally advanced cervical esophageal adenocarcinoma with tracheal infiltration, but induction chemotherapy was effective and radical resection was possible. Nomura et al. reported that treatment strategies depended on the tumor stage: open chest surgery with or without pre/post adjuvant therapy in 37 patients, endoscopic therapy in 8, chemoradiotherapy in 2, and radiation alone in 2 patients [12]. Moreover, the prognosis for advanced cancer was poor because there was only one survivor with T3-4 stage [12]. In our department, we usually perform chemoradiotherapy (DF + RT) for unresectable, locally advanced esophageal SCC and achieve good results [13]. However, we usually do not actively administer CRT to esophageal adenocarcinoma, including EGJ. All patients who are suitable to undergo operation for esophageal adenocarcinoma that is potentially curable should be considered for neoadjuvant chemotherapy or chemoradiotherapy followed by surgery since esophageal adenocarcinomas are less radiosensitive than esophageal squamous cell carcinomas [14]. Patients who received induction chemotherapy experienced a trend toward superior survival for not only surgery but also chemoradiotherapy [7]. It was thought that tumor shrinkage due to induction chemotherapy reduces the amount of radiation therapy, and controls micrometastasis. Definitive chemoradiation (DCRT) has been adopted in the treatment of upper esophageal cancers and has become the standard modality recommended by most experts [7,15]. However, it is controversial, especially for cervical esophageal adenocarcinoma, and local recurrence rates after definitive chemoradiotherapy are high (40-75%) [3]. Moreover, a higher mortality and morbidity rate, including anastomotic leak and pulmonary complications, was reported after salvage surgery [3,16]. Therefore, we considered that salvage surgery and surgery for recurrent cases after DCRT were technically extremely difficult. From the perspective of prolonging survival, we Fig. 4 Operation findings. a Total laryngopharyngoesophagectomy with three-field lymph node dissection and reconstruction using free jejunal grafts and subtotal stomach via a posterior mediastinum route, a permanent tracheal foramen (arrowhead) and jejunostomy were performed. b The bilateral bronchial arteries were preserved to maintain blood flow to the oral side of the trachea. The right bronchial artery diverged from the right subclavian artery (arrow). The tumor was detached from the tracheal membrane (orange arrowhead). c The trachea was cut between the 5-6th tracheal cartilage, and a permanent tracheal foramen was constructed at the upper sternal margin level (dot-line). d A free jejunum was placed between the mesopharynx and the subtotal stomach (yellow arrow) prioritize surgery for patients who can undergo radical resection.
According to randomized trials, including the OE02 and MAGIC trial, standard chemotherapy is platinum-fluoropyrimidine-based [14]. We usually perform biweekly-DCF (Bi-DCF) chemotherapy for esophageal SCC and EGJ adenocarcinoma with esophageal infiltration, whether it is induction chemotherapy for unresectable or NAC for resectable tumors. According to our clinical trial of Bi-DCF chemotherapy for advanced esophageal SCC, the overall response rate after the chemotherapy was 90.3% (CR 19.4%; PR 71.0%) [17]. The most common grade 3 or 4 toxicities were neutropenia (31.3%) and all toxicities were within limits and were manageable [17]. Furthermore, we have experienced and reported EGJ adenocarcinoma with pathological CR obtained by radical resection after Bi-DCF chemotherapy [18]. Therefore, we selected Bi-DCF chemotherapy because the regimen was considered effective for rare cases of cervical esophageal adenocarcinoma. In our result, as initially aimed, the tumor shrank following induction chemotherapy, the pathological effect of chemotherapy-grade 2 was obtained, and radical resection was possible.
Historically, most patients with upper thoracic esophageal cancer were treated by surgery, including pharyngolaryngo-esophagectomy (PLE) and gastric pull-up. In Japan, we have "Esophageal Cancer Practice Guidelines" for esophageal cancer treatment [19]. In the treatment of cervical esophageal carcinoma, this guideline recommended that we should select chemoradiotherapy or surgery, including laryngectomy, with due consideration given to quality of life. To improve the patient's oncologic prognosis, our treatment strategy for patients with cervical esophageal cancer is laryngectomy in cases of PR or SD, using induction chemotherapy. In a case of complete response (CR), or near CR, we preserve the larynx. We discussed among the staff whether the trachea and larynx should be preserved for this patient. There was a report that pathological complete response was obtained by cervical esophagectomy after chemoradiotherapy [5]. On the other hand, there was also a report of a difficult course of treatment, with local tumor recurrence after chemoradiotherapy followed by cervical esophagectomy and further recurrence after salvage pharyngeal and laryngeal esophagectomy [6]. In our case, we chose PLE with the most favorable prognosis after fully explaining that radical resection would lead to loss of voice and reduced QOL. Since this patient was young and could perform sufficient vocal training, and because this was a case of a rare and untreated cervical esophageal 'adenocarcinoma', a laryngectomy was selected for treatment, with an emphasis on curability. Whether or not the larynx can be preserved has an impact on a patient's postoperative QOL; therefore, it is necessary to carefully consider the balance between curability and the patient's QOL. In the future, we must strive to provide curative laryngeal-sparing surgical procedures for patients with cervical esophageal adenocarcinoma.
In conclusion, our patient had highly locally advanced cervical esophageal adenocarcinoma with tracheal infiltration, but induction chemotherapy was effective and radical resection was possible. Cervical esophageal adenocarcinoma is rare, and no standard treatment exists. Thus, this case can be a valuable example of successful multidisciplinary treatment combining chemotherapy and surgery.