Successful robot-assisted minimally invasive surgery for scirrhous gastric conduit cancer after esophagectomy: A case report.

Introduction
The occurrence of squamous-cell carcinoma (SCC) in the oral cavity, larynx, trachea, lungs, and residual esophagus as metachronous malignancies after esophageal cancer surgery is crucial from a clinical perspective. A history of heavy drinking and/or smoking, presence of oral flora, and preoperative presence of periodontal disease are reported as strongly relevant factors (1–3). Conversely, gastric conduit cancer (GCC) after digestive reconstruction often occurs due to chronic inflammation caused by preoperative Helicobacter pylori (HP) infection, patients' lifestyle, postoperative bile and intestinal juice reflux, and resulting intestinal metaplasia (1–5). Cases detected in the early stage can be treated via endoscopic submucosal dissection (ESD); however, in cases with advanced or widespread cancer, surgical gastric conduit resection with lymph-node (LN) dissection around the residual stomach and digestive tract reconstruction are required (6–14).
Robot-assisted minimally invasive esophagectomy (RAMIE) has recently been gaining global popularity as a high-definition, high-quality radical surgery that uses robotic technology for minimally invasive esophagectomy (8). Robot-assisted surgery (RAS) provides several advantages, such as a three-dimensional (3D) magnified view, high degree of freedom for surgical maneuvers, and reduced misses due to hand tremors, allowing easier, more precise, and gentle manipulation that is required for intrathoracic esophageal resection and mediastinal LN dissection (15–19). These advantages may also prove effective for adhesion dissection that is required for gastric conduit resection, avoidance of collateral damage to important organs, and accurate recognition of modified anatomy in reoperation cases.
Here, we report a case with metachronous scirrhous GCC originating along the entire conduit, which was safely and radically resected by robot-assisted transthoracic surgery.

Case report
A 69-year-old Japanese man had undergone RAMIE for thoracic esophageal SCC without synchronous gastric cancer 5 years ago. The surgical procedure involved complete mediastinal LN dissection and esophagectomy in the left-lateral position, abdominal LN dissection, and gastric conduit creation. Cervical LN dissection was omitted for minimal invasiveness. For gastrointestinal reconstruction, a gastric conduit was created via the posterior mediastinal route, and esophagogastric anastomosis was performed at the cervical site. Postoperatively, pneumonia and respiratory failure occurred, necessitating temporary tracheotomy. A pathological diagnosis of multiple early esophageal cancers was made [1) Mt, 10×10 mm, SCC, pType 0-IIc, INFb, ly1, v0, pIM0, pT1a-MM; 2) Mt, 5×3 mm, SCC, pType IIb, pTis, pN0 (0/48), M0, pStage 0, pPM0, pDM0, pRM0, D2, Cur A]. Curative resection was performed (Fig. 1). Postoperatively, anastomotic stenosis occurred repeatedly, requiring multiple endoscopic balloon dilation (EBD) procedures over the 5-year follow-up period. Although the patient was a habitual drinker and smoker preoperatively, he abstained from alcohol and smoking after esophageal cancer surgery. He had already undergone HP eradication therapy successfully before the primary RAMIE for esophageal SCC.
Five years after surgery, he presented with the digestive passage disorder. Esophagogastroduodenoscopy (EGD) performed at Kanazawa University Hospital (Kanazawa, Japan) revealed circumferential stenosis at the esophagogastric anastomosis, for which EBD was repeated. Retrospectively, no obvious tumor lesion was observed at the esophagogastric anastomosis and remnant stomach in the annual screening endoscopic findings from one year before the cancer diagnosis (Fig. 2A and B). An 0-I-type elevated lesion protruding into the lumen was observed on the posterior wall of the anastomotic site (Fig. 2C and D); consequently, a biopsy was performed, indicating a poorly differentiated carcinoma. The patient was thereafter referred to our hospital, Kanazawa Medical University Hospital (Kahoku, Japan), for further examination and treatment. On repeat EGD, we observed diffuse mucosal hardening, disappearance of folds, and redness from the upper part to the antrum of the reconstructed gastric conduit (Fig. 2E and F). Further, specimens from several sites along the gastric conduit were biopsied, and histopathological findings revealed poorly differentiated carcinomas in all specimens. Immunohistochemical staining revealed strong AE1/3 and carcinoembryonic antigen (CEA) positivity, supporting a diagnosis of adenocarcinoma (por-tub2). Fluorography indicated anastomotic stenosis with a wall irregularity. The expansion of the gastric conduit was poor because of the wall hardness (Fig. 2G). On contrast-enhanced computed tomography (CT), diffuse wall thickening was noted along the entire reconstructed gastric conduit along with mediastinal LN enlargement (Fig. 3A-C). 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography indicated faint abnormal 18F-FDG accumulation in the wall of the reconstructed gastric conduit (Fig. 3D and E). No obvious distant metastasis, pleural effusion, or ascites was observed.
According to the 15th edition of the Japanese classification of gastric carcinoma (20), all the above findings indicated advanced gastric scirrhous carcinoma [M-5-TE, circ, adenocarcinoma (tub2-tub1), cType 4, 170 mm, cT3N2M0P0CYX cStage IIIA] originating along almost the entire reconstructed gastric conduit with esophageal infiltration. Thereafter, we planned to perform gastric conduit resection and mediastinal LN dissection through RAS as a curative treatment.

Surgical procedure
We planned to perform a radical surgery using the DaVinci Xi Surgical System that allows RAS to be conducted with the patient in a prone position. The first port was carefully inserted during intrathoracic manipulation, and the extensive intrathoracic adhesions between the lung surface and chest wall were carefully dissected via thoracoscopic and robotic manipulation; thereafter, the remaining ports were inserted and the robot setup was completed. Cytological examination of the pleural lavage was negative for cancer cells. However, the patient's respiratory function was poor because of coexisting chronic obstructive pulmonary disease; therefore, bilateral lung ventilation was performed. The hard adhesions between the lung surface, reconstructed gastric conduit, and membranous portion of the trachea were dissected under 3D magnified observation (Fig. 4A-D). Using the third robotic arm's forceps to maintain a good surgical field, the right lung was gently compressed with using gauze (Fig. 4B). The reconstructed gastric conduit could not be grasped because of diffuse wall hardening and thickening, so we tried to secure the dissection layer under 3D magnified observation using an appropriate counter traction with repeated changing of the third-arm compression points. Minute traumatic injuries to the lung surface resulting in air leakage were repaired with sutures each time. Hard scarring also was observed around the esophagogastric anastomosis, probably due to repeated EBD procedures; hence, precise tracing of the excisional line was needed to expose the contours of the surrounding adherent organs (Fig. 4E). Consequently, there was no clear exposed cancer tissue on the serosal surface of the reconstructed gastric conduit and it could be resected without any visible remnant tumor. This was accompanied by LN dissection around the right-gastroepiploic artery and right-gastric artery without injuring the tracheal membranous portion, anterior surface of the descending aorta, or pericardium. At the upper-mediastinal level, the ZEOCLIP® (Zeon Medical, Tokyo, Japan) marked on the oral side of the tumor was identified using indocyanine green (ICG) fluorescence, and an automatic stapler was used to resect the remaining esophagus on the oral side of the ZEOCLIP® (Fig. 4F). The intrathoracic operation time, console time, and blood loss were 498 min, 439 min, and 520 g, respectively.
Abdominal manipulation involved gastric conduit resection and LN dissection, with transection of the right-gastroepiploic and right-gastric arteries and veins, followed by extraction of the resected specimen. The small intestine and right colon mesentery was then dissected and mobilized from the retroperitoneum, securing it such that the pedicled jejunum could be elevated to the neck. For digestive reconstruction, the pedicled jejunum was elevated via an anterior-thoracic subcutaneous route in the anterior chest, and a circular stapler was used to perform end-to-side esophagojejunal anastomosis. Blood flow evaluation using ICG fluorescence and Doppler monitoring confirmed that there was no ischemia or congestion in the reconstructed jejunum; therefore, additional revascularization procedures, such as supercharge and superdrainage, were not performed. The overall intraoperative time was 871 min and the total blood loss was 860 g.

Histological findings of the resected specimens
Macroscopically, the resected residual esophagus and gastric conduit exhibited continuous wall thickening and hardening from the esophagogastric anastomosis to almost the entire gastric conduit (Fig. 5A). Histologically, the gastric conduit exhibited notably broad and thick proliferation of fibrous scar tissue along most of the stomach wall, except for the area near the pylorus (Fig. 5B). In addition, adenocarcinoma cells were diffusely and noncohesively scattered in and under the mucosa along most of the gastric conduit and had also infiltrated into the resected residual esophageal wall (Fig. 5C-E) but no cancer cells were present at the oral resection edge. The serosa of the resected gastric conduit had been peeled off during the surgery, but no obvious cancer cells were exposed on the surface. The deepest part of the cancer tissues invaded the subserous layer of the stomach. Apparent metastases were evident in multiple dissected perigastric and intra-abdominal LNs (Fig. 5F). Immunohistochemical staining was negative for squamous epithelial markers p40 (Fig. 6C) and CK5/6 (Fig. 6D) in the cancerous area but positive for CEA (Fig. 6A) and CK7 (Fig. 6B); these findings are characteristic of adenocarcinoma.
Finally, the pathological diagnosis was remnant scirrhous gastric cancer originating along most of the gastric conduit [M-5-TAE, circ, 203×76 mm, pType 4, moderate-to-well-differentiated adenocarcinoma (tub2-tub1), pT3, INFc, Ly1b, VX, pIM0, pPM0, pDM0, pN3(7/22, #4sax4, #4sbx1, #6×2) M0, CY0, P0, pStage IIIC, D2, Cur A] (20). Surgical treatment resulted in pathological curative resection.

Postoperative clinical course
The patient presented with a minor anastomotic leakage at the esophagojejunostomy and pneumonia; both were successfully resolved through conservative management. Subsequently, he was discharged on postoperative day 47. Given the substantial risk of recurrence, the patient underwent adjuvant chemotherapy with oral tegafur/gimeracil/oteracil (oral 5-fluorouracil prodrug) and triweekly docetaxel for 4 months after the prescribed protocol for adjuvant chemotherapy in gastric cancer (21,22). He remained relapse-free, as shown by periodic CT examinations, and was alive at postoperative 9 months.

Discussion
To the best of our knowledge, this is the first case report on the use of minimally invasive robotic procedure for the successful treatment of scirrhous gastric carcinoma originating in the reconstructed gastric conduit after esophageal cancer surgery.
The benefits of RAS include accurate recognition of microanatomy because of 3D magnification, precise robotic arm operation through the multi-joint function, image stabilization, and surgeon-centered surgical-field development using a third arm (23,24). RAS is also less physically demanding than laparoscopic surgery, which requires long-term static muscle activity with a high physical workload for surgeons (25). Studies comparing robotic vs. laparoscopic gastrectomy for gastric cancer, robotic vs. laparoscopic colectomy for colon cancer, and RAMIE vs. conventional thoracoscopic or open esophagectomy for esophageal cancer have reported that RAS is more useful in the treatment of malignant tumors in many cases (16,19,23,24,26,27).
Recently, thoracoscopic esophagectomy and RAMIE have become increasingly popular for the surgical treatment for resectable esophageal cancer. Warner et al (28) reported that thoracoscopic esophagectomy is acceptable in resectable cases after neoadjuvant CRT without evidence of increased morbidity or mortality. Mederos et al (16) and Tagkalos et al (29) reported the usefulness of RAMIE vs. conventional thoracoscopic or open esophagectomy for esophageal cancer. In addition, Defize et al (30) reported the usefulness of RAMIE as a salvage surgery after definitive chemoradiotherapy for unresectable advanced cancer with infiltration in other organs. They reported that after definitive CRT, normal anatomical structures were restored in 75% of resectable cases, making resection without residual tissue possible. However, in cases where the border between the fibrosis and tumor was unclear, curative resection while recognizing the anatomical structures was challenging. Despite such surgical results, pathologically curative resection was achieved in 92% of cases, suggesting that RAMIE can ensure curability even in salvage surgery after CRT. Alhossaini et al (31) reported that in cases with remnant gastric cancer, RAS is less invasive than laparoscopic surgery in terms of the low rate of conversion to open surgery because of severe adhesions. A review of 10 nonrandomized controlled trials reported that compared with open gastrectomy, laparoscopic gastrectomy for remnant gastric cancer can lead to better short-term outcomes, including lower blood loss, lower postoperative complication rate, and shorter postoperative hospital stay. Although laparoscopic gastrectomy for remnant gastric cancer is technically complex, it is feasible, safe, and is minimally invasive. However, one report stated that conversion to open gastrectomy during laparoscopic gastrectomy is unavoidable in many patients with severe intra-abdominal adhesions and anatomical abnormalities (32).
In the present case, we opted for robotic remnant gastrectomy for a thorough and less invasive mediastinal LN dissection. Although RAMIE was conducted for the previous esophageal cancer, the right lung was firmly adhered to the chest wall, trachea, pericardium, and anterior surface of the aorta. The esophagogastric anastomosis and surrounding organs had developed hard cicatricial adhesions to the lungs and tracheal membranous portion after undergoing multiple EBD procedures; however, RAS enabled the detachment and resection of these adhesions without severe secondary injury. Moreover, using the robotic forceps to suture partially injured lung surfaces was also effective in tissue repair. Using all the advantages offered by RAS and by performing careful intrathoracic manipulations, the surgery was completed without any major intraoperative complications, although it was time-consuming. RAS may enable easy adhesion removal, provide accurate anatomical recognition, and be less invasiveness in patients with a history of laparotomy or thoracotomy.
Several reports have been published on the epidemiology, etiology, diagnostic methods, and treatment of GCC after esophageal cancer surgery. Lee et al (7) reported that the incidence rate of reconstructed GCC is 2.4% per 5 years and 5.7% per 10 years, and the average occurrence-to-diagnostic time is 55.8 months (4–236 months) after esophagectomy, with 92% histological types being adenocarcinoma. A nationwide study in Japan by Ota et al (13) reported that the proportion of early cancer (T1) was ~60% in primary gastric cancer but 81.5% in GCC, which is high. This may be because of the continued postoperative follow-up for patients with esophageal cancer and the accessibility of EGD in Japan (33,34). The median interval between esophagectomy and GCC diagnosis was 6 years, with ~25% of patients being diagnosed >10 years later. The 5-year overall survival (OS) rates after endoscopic and surgical treatments for GCC were 75.9 and 52.7%, respectively. In a study by Gentile et al (10), 41.6% of GCC cases were treated via endoscopic resection while avoiding gastric conduit resection. Close monitoring and long-term follow-up may be useful in the early detection of GCC and appropriate therapeutic intervention. Yearly endoscopic follow-up >10 years after esophageal cancer surgery has been recommended (9,10,13). However, in cases of resectable advanced cancer where early detection through meticulous screening is not possible, surgery is the only curative treatment.
The etiology of GCC includes chronic gastritis because of HP infection and subsequent intestinal metaplasia (35,36). Various other factors, such as relaxation of the pylorus ring due to vagotomy, decreased peristalsis of the gastric conduit, and intestinal metaplasia due to bile reflux caused by negative intrathoracic pressure, may be involved. Histologically, primary gastric cancer caused by chronic inflammation can be intestinal and well-differentiated (37). In this case, HP had been eradicated before the initial surgery, and the patient had chronic gastritis along with moderate mucosal atrophy; therefore, GCC onset at 5 years was probably earlier than the average. Palmes et al (38) reported that bile reflux can cause chronic inflammation and intestinal metaplasia in the reconstructed gastric conduit; therefore, pyloric drainage (pyloroplasty or pyloromyotomy) after esophagectomy with esophagogastrostomy and vagotomy are not recommended. In fact, in the present case, clear bile reflux was observed in the reconstructed gastric conduit during the annual screening EGD up to the previous year. Shirakawa et al (9) and Ota et al (13) reported that ~60% of GCC cases occurred in the lower third portion of the gastric conduit. In cases where GCC was of detected early through appropriate screening, endoscopic treatment in accordance with the indications for ESD for normal early gastric cancer can be expected to cure GCC in a less invasive manner (8,11,14,39). Furthermore, abstinence from alcohol and smoking after treatment for initial esophageal cancer significantly reduces the incidence of pharynx and laryngeal, oral, and residual esophageal cancers (1,2,4); however, GCC occurred in this case despite strict abstinence from alcohol and smoking since the initial esophageal cancer diagnosis.
Gastric cancer with histological findings of signet ring-cell carcinoma or poorly differentiated adenocarcinoma tends to have an unclear border, exhibits diffuse infiltration, and is often accompanied by significant fibrosis within the wall; therefore, it is called scirrhous gastric cancer. Macroscopically, it is often classified as type 4 and is characterized by hardening and thickening of the wall (40). Compared with other macroscopic types, type-4 gastric cancer is more likely to disseminate peritoneally. This type of cancer is also characterized by the absence of protuberances, depressions, or ulcers in the shape of the tumor, wall hardening, and slow progression, making a qualitative or extensive diagnosis difficult. Histologically, scirrhous gastric cancer is often diffuse and poorly differentiated (por, sig), and chronic gastritis and intestinal metaplasia may not necessarily be present in the background (26,32). In the present case, EGD was performed to examine the wall hardening and the esophagogastric conduit anastomosis stenosis, which indicated the presence of a lesion. However, it cannot be denied that GCC did not exist at that time. Therefore, it is necessary to be fully aware that scirrhous GCC presents as a stenotic lesion with an unclear border, and to consider performing a biopsy if necessary. The primary lesion in the gastric conduit extended not only to the upper stomach but was also accompanied by extensive infiltration of most of the gastric conduit. However, we could not accurately diagnose the extent of the lesion preoperatively. Furthermore, the resected specimen did not include signet ring cells, and the histological type was a mixture of tubular and poorly differentiated adenocarcinoma. At Kanazawa University Hospital where the initial histological diagnosis was made, the diagnosis was not definitively made as adenocarcinoma, but was confirmed by immunostaining in Kanazawa Medica University Hospital. In fact, because only a small portion of the tumor was collected in the biopsy tissue, it is possible that the cancer cells scattered within the fibrous tissue were misdiagnosed as poorly differentiated cancer. Moreover, EBD had been performed multiple times for anastomotic stenosis before the diagnosis of GCC. No obvious tumor lesion was observed at the esophagogastric anastomosis on annual endoscopic screening from the year before the cancer diagnosis (Fig. 2A and B). However, it cannot be confirmed if GCC was present at that time. Therefore, it is necessary to consider that scirrhous GCC can present as a stenotic lesion with an unclear border, and a biopsy should be conducted if necessary. Preoperative images suggested advanced GCC with invasion deeper than the muscular propria layer, and multiple perigastric LN metastases were suspected in the area of the right-gastroepiploic artery, the nutrient vessel of the reconstructed gastric conduit. A nationwide study in Japan reported that the degree of LN metastasis in GCC was strongly associated with prognosis (13). This finding suggests that adequate LN dissection of the gastric conduit basin is necessary in curative GCC surgery. As a result, total resection of the residual esophagus and reconstructed gastric conduit and a thorough regional LN dissection is unavoidable for radical resection. However, given the need for thorough perigastric LN dissection, we consider RAS to be extremely useful in this case.
The pathological diagnosis of the resected specimen was T3N3M0 pStage IIIC. Although robotic resection was considered to be curative, the risk of recurrence was high, leading to DS therapy with docetaxel and S-1 being administered as adjuvant chemotherapy. The JACCRO GC-07 study was a randomized phase-III study that aimed to determine whether adjuvant chemotherapy with DS therapy in pStage-II–III advanced gastric cancer was superior to S-1 alone (21,22,41). DS therapy resulted in a significantly better 3-year relapse-free survival [hazard ratio (HR), 0.632; S-1 plus docetaxel, 65.9%; S-1 alone, 49.5%; P<0.001], and is a commonly used regimen in Japan (22). In addition, the JACCRO GC-07 study reported a better 5-year OS in patients with pathological stage-III gastric cancer treated with DS therapy (HR, 0.752; S-1 plus docetaxel, 67.9%; S-1 alone, 60.3%; P=0.0059) (41). In this case, DS therapy was discontinued at the patient's request after 4 months of treatment. Strict follow-up is necessary as the risk of peritoneal dissemination, pleural dissemination, and LN recurrence is very high as in scirrhous gastric cancer.
The reconstructive route used in prior esophagectomy may influence the success of radical resection for GCC. Koyanagi et al (42) reported a resection rate of 50% in cases where the posterior mediastinal route was used, 77% for those using the retrosternal route, and 93% for those using the anterior-thoracic route. In general, secondary cancers were detected easily in cases with anterior-thoracic route reconstructions, and the operative procedure was less difficult than in those by other routes. Thus, the resection rate was better with the anterior-thoracic reconstruction route than for the other routes (42). Fujisawa et al (43) recently reported a study where transabdominal gastric conduit resection was conducted for metachronous GCC in a gastric conduit reconstructed via a retrosternal route. RAS should be considered to be a useful option, even in cases with severe scar changes, postoperative adhesions, and modified anatomy in reoperation cases.
In summary, we report a rare case of scirrhous GCC originating in the reconstructed gastric conduit after esophageal cancer surgery that was successfully treated through minimally invasive RAS with radical transthoracic and gastric conduit resection and regional LN dissection. Even in cases of reoperation for GCC, RAS can be safely used to perform appropriate radical surgery while minimizing secondary damage, making it a useful option that improves the feasibility of difficult surgeries.