Iatrogenic Oesophageal Perforations in Neoplastic Lesions: Management with Covered Self-Expanding Prostheses

Background: Perforation of the oesophagus is a serious condition. Most of them are iatrogenic and are associated with significant morbidity and mortality, especially with late diagnosis. Aim: To prospectively analyse the results of the endoscopic management of iatrogenic perforations in oesophageal neoplasia, through the immediate insertion of a covered self-expanding prosthesis (CSES). Materials and Methods: Between 01.01.2006 and 12.30.2016, a series of 19 consecutive patients attended the Teaching Unit of Endoscopic Surgery of the Regional de Concepción Hospital, Chile, with the diagnosis of oesophageal neoplasia confirmed by biopsy were prospectively studied. All were subjected to a prior evaluation by the oncology team and subsequently referred for endoscopic palliative management of dysphagia. The average age was 77 ± 9.3 years, 8 (42.1%) were female and 11 (57.9%) were male. In 17 patients (89.5%) the stenosis compromised the oesophagus, in 2 (10.5%) the gastro-oesophageal junction, 16 had a squamous carcinoma (84.2%) and 3 an adenocarcinoma (15.8%). Results: Perforation was diagnosed during the procedure in neoplastic dysphagia. In 10 of the 18 cases that survived more than a month, there were late complications (55.6%), none of them associated with the perforation itself. The only death (5.3%) was due to an oesophagus-pleural fistula, associated with an early prosthetic migration. Recovery of the oral intake occurred, on average, at 3.7 days. The hospital stay averaged 9.6 days. Conclu-sion: The use of CSES for the treatment of iatrogenic oesophageal perforations in the context of neoplasia, is a safe and effective method, with low morbidity, adequate recovery of the oral intake and prompt discharge from hospital.


Introduction
Perforation of the oesophagus remains one of the most feared adverse events of diagnostic and therapeutic endoscopy. Iatrogenic injuries represent up to 60% of all cases [1]. However, these are not frequent; their incidence fluctuates between 3.1 to 4.7/1,000,000 per year [2] [3].
Endoscopic dilation of the oesophagus is a long-established technique for treating benign strictures of this organ [4]. It has also been used to manage dysphagia in unresectable malignant lesions as a sole palliative measure [5] or as a step before endoprosthesis implantation [6].
The main complication of oesophageal dilation is perforation; this is associated with morbidity that can reach up to 40% and a mortality of 27% [7] [8] [9].
Advances in endoscopic equipment have improved the safety of the procedure [10]. However, complications still occur, even in the most experienced hands.
For most of the 20 th century, surgical therapy was considered the norm in managing acute perforation of the oesophagus. Although surgery continues to play an important role, in the last decade, treatment has evolved towards a significant reduction in its use, with an increase in non-surgical procedures such as interventional endoscopic and radiology [11].
The use of endoluminal therapies to treat oesophageal leaks and perforations has grown exponentially over the last decade. In the right circumstances, it offers many advantages compared to traditional surgical intervention [12].
In recent years, new therapeutic endoscopic techniques have been developed to treat oesophageal perforation and reduce the morbidity and mortality associated with it; these include clips, sutures, self-expanding covered metal prostheses (CSES), and endoluminal vacuum therapy [12].
Stents appear to be the best option in perforations that occur in the context of a malignant lesion because clips and sutures tend to tear the neoplastic tissue and do not hold the edges of the perforation [13].
The time interval between the perforation and the start of treatment is one of the most important factors affecting the therapeutic outcome. Indeed, most authors suggest that when there is a delay in treatment greater than 24 h., mortality doubles or triples [20] [21] [22] [23].
The ideal treatment for iatrogenic oesophageal perforation would minimize the negative impact of the treatment while sealing the organ's continuity solution as early as possible.
This study aims to prospectively analyse the results of the endoscopic management of iatrogenic oesophageal neoplastic perforations through the immediate insertion of a covered self-expanding prosthesis.

Patients and Method
Between 01 January 2006 and 31 December 2016, a series of 19 consecutive patients attended the Teaching Unit of Endoscopic Surgery of the Regional de Concepción Hospital, Chile, with the diagnosis of oesophageal neoplasia confirmed by biopsy. All were subjected to a prior evaluation by the oncology team and referred for endoscopic palliative management of dysphagia.
INCLUSION CRITERIA • Obstructive neoplasm of the oesophagus; • Referred to endoscopic palliation from oncology; • Severe dysphagia; • Iatrogenic oesophageal lesion; • Accepted endoscopic management of iatrogenic complication.
The study was conducted following the ethical standards of Good Medical Practice following current ethical standards (Declaration of Helsinki).
Of the 19 cases studied, 14 (73.7%) attended dilation for the first time, and five (26.3%) had previously been dilated. In eight of them (42.1%), dilation was indicated as a palliative treatment for dysphagia, and in the remaining 11 (57.9%) as a step before the insertion of a self-expanding metal prosthesis. All patients were dilated using Savary-Guillard bougies (Wilson-Cook Medical Inc. Winston-Salem, N.C). In the former, an attempt was made to obtain the largest possible oesophageal lumen in the initial session [5], while in the latter, it was only dilated to 38F [6].
The length of the lesion was determined by radiology and endoscopy. Open Journal of Gastroenterology Seven patients (35%) had a history of having undergone radiotherapy and presented post-radiation tumour recurrence, which in turn was the cause of dysphagia.
In 18 of the 19 patients (94.7%), the diagnosis of perforation was made in the same operative act or immediately afterwards during the routine endoscopic and fluoroscopic review established in the protocol for this type of procedure. In the remaining patient (5.3%), to whom a CSES was inserted as palliation of cardio-oesophagal neoplasia, the diagnosis was made 22 h after the procedure, when he consulted with a clinical picture suggestive of mediastinitis, which was confirmed by a thoracic Computed Tomography (CT).
The procedures were carried out under strict protocols established by our centre, including radiological control with a water-soluble contrast medium (Hypaque ® ) before and after the procedure.
All the interventions were performed by previously obtaining the informed consent of each patient or her legal representative.
Once the complication was established, a self-expanding prosthesis was inserted. All stents were placed in the same operative act or immediately after diagnostic confirmation. The insertion technique was described in a previous study [6].
The dilations and insertion of prostheses were performed with the patient in the left lateral decubitus and under control of their vital signs using a multi-parameter monitor.
Before the intervention, the patients underwent topical pharyngeal anaesthesia with 2% Lidocaine gel or 4% spray. Of the total, 17 patients (89.5%) received intravenous sedation with Midazolam (0.5 -5 mg) and eventual analgesia with Meperidine (10 -30 mg), as is pre-established in the unit's protocol. In the remaining two cases (10.5%), the intervention was performed with anaesthetics support due to their comorbidities.
All procedures were performed by an endoscopic surgeon or endoscopic surgery residents, under the strict supervision of the former.
Prostheses of various types, lengths, diameters, and coverage were used according to the extent of the tumour lesion and perforation, location, and availability of the resource at the time of trauma (Table 1). After the stent was deployed, the leaks of the contrast medium were ruled out by carrying out a new oesophageal transit, then starting endoscopic and fluoroscopic follow-ups at 24 and 48 h, 7 days, and then once per month, as stipulated in the protocols of our unit. If a leak was found, then the sealing process, using a covered stent, started immediately (Figures 1-4).
Once the prosthesis was inserted, the patients were hospitalized. Zero regimens were indicated for 24 to 48 h. Intravenous antibiotics, serial clinical, laboratory and imaging controls, hospital visits, or daily communication with patients    or their treating physicians in search of complications secondary to iatrogenic injury or stent insertion was carried out.
The appearance of symptoms associated with the perforation event was analysed. Immediate complications were considered those that appeared within the first 24 h. after the perforation was established: early, those diagnosed in the first 30 days; and late, those that occurred 30 or more days after the stent was installed.

Results
A total of 19 patients were studied. The prostheses were inserted successfully in all cases. This was done during the same procedure in which the perforation occurred in 19/19 patients (100%). In one patient (5.3%), severe desaturation occurred during insertion, which had to be suspended momentarily. This patient was in poor general condition, for which anaesthetic support was requested, and the anaesthesiologist successfully managed the complication. The insertion of the prosthesis was carried out without problems.  Table 3.
In three patients (15.8%), there was the persistence of fever, and in three (15.8%), a pleural effusion appeared, in two of whom drainage using an endopleural tube was required. Furthermore, in two of these cases (10.5%), mediastinitis was confirmed. One presented symptoms suggestive of sepsis with dyspnea, tachycardia, pain, and an effusion secondary to pneumonia. This corresponded to the only case in which the perforation went unnoticed during dilation (38 Fr.) before the insertion of the prosthesis, which was successful. Then, 22 h.
later, a chest CT scan was requested due to the symptoms, which confirmed the  Seventeen days after the insertion of the prosthesis, there is an abrupt change in the evolution of the patient, who had been until that moment satisfactory.
There was a significant increase in the debt due to the endopleura tube and the The patient quickly worsened, and given her condition, she was considered outside the therapeutic scope, maintaining only supportive treatment. The patient died 19 days after the procedure, constituting the only cause of mortality in this series (5.3%).
Once the acute condition secondary to perforation had been overcome, the prosthesis was kept in situ in all patients as a definitive palliation method for dysphagia of neoplastic origin.
Of the 18 cases that survived more than 1 month, 10 (55.6%) had late complications, none of them associated with the perforation itself (Table 4 and Table 5).
There was a late reappearance of dysphagia in six patients (33.3%); this was due in two cases to fracture of the prosthesis and joint epithelial hyperplasia. It was necessary to insert a second stent (86 and 133 days after perforation). In two patients, this was secondary to epithelial hyperplasia at the proximal end of the device, which was resolved in both cases by dilation with bougies.
In one case, an impacted foreign body was found at 34 cm. of the dental arch, which was removed endoscopically and in the remainder, the prosthesis mi-  A patient with a lesion in the distal oesophagus due to the insertion of a transcardial prosthesis without a valve presented gastro-oesophageal reflux whose symptoms resolved with the usual measures.
The average time elapsed between the perforation and the recovery of oral intake was 3.7 days, ranging between 1 to 8 days. In three cases (15.7%), it was restarted in the first 24 h. after inserting the prosthesis.
The hospital stay averaged 9.6 days, with a range between 2 and 21 days. The longest were those of the two patients who developed mediastinitis, one of who corresponds to the case of prosthetic migration and who died on the 19th day of hospitalization.
Patients survived an average of 252 ± 188 days (range 59-814 days). At the end of the follow-up, all 18 patients who survived had regained their ability to feed themselves orally and did not require additional surgical treatment to that described.
Statistical Analysis: Descriptive statistics and percentage relative frequency were used.

Discussion
Oesophageal perforation is a life-threatening entity that requires early diagnosis and treatment [24]. These points are especially important in iatrogenic perforations secondary to endoscopic dilations. In these, complications are unpredictable, despite knowledge of risk factors, such as neoplastic and actinic stenosis and strict adherence to protocols in the safe application of procedures [25] [26]. The patient had already sealed the perforation with the prosthesis, which was found to be properly located. The patient responded satisfactorily to medical management, leaving the hospital 21 days later.
In this series, the early detection rate (<24 h) was 100%, different from that of others, in which figures of up to 63% are reported [27].
Fortunately, iatrogenic oesophageal perforation is a rare complication. Concerning the total number of patients, the incidence found was 0.03%, while concerning the total dilations, it was 0.018% (Table 6 and Table 7  The prostheses were inserted successfully in all cases. During the procedure two patients had problems. One, a severe desaturation, which merited the momentary suspension of the event without preventing it. The other underwent dilation only up to 38 Fr. and then the insertion of a prosthesis, the perforation going unnoticed, which manifested as mediastinitis, making the diagnosis 22 hours later. Both patients evolved satisfactorily.
The most frequent immediate complication was retrosternal pain, which in most cases subsided after 48 hours, as is the case usually in neoplastic strictures [6]. Subcutaneous emphysema, pneumomediastinum, and pneumoperitoneum were gradually reduced until they disappeared. The two cases that presented pneumothorax had to be drained using an endopleural tube, with satisfactory subsequent evolution. After 30 days, the prostheses behave as expected in a device designed to alleviate dysphagia, presenting the same late complications, all of which can be resolved endoscopically [6].
In relation to the economic and practical aspects associated with this complication, an important factor is the hospital stay, which in our series averaged 9.6 days, very similar to that of other publications, in which an average of 10.5 days are reported [36] [37].
Despite this data concordance, regarding this point, we consider that these patients could be discharged earlier and in many cases managed on an outpatient basis, with strict controls in the specialized referral units. In fact, 10 of the 19 patients in this study and after the insertion of the CSES, were transferred to low complexity hospital centres close to their homes for their initial clinical monitoring. These were re-sent to our referral unit to be controlled clinically, radiologically or endoscopically, as established in the protocols for this type of procedure, a limitation of this study is the number of patients, however this is an infrequent disease worldwide. Therefore, so far there are no randomized studies that have compared the results of the different therapeutic options and the recommended therapies vary, rather according to personal preferences or experiences than to the results of controlled studies.
From the results of this study, it can be concluded that the use of CSES for the treatment of iatrogenic oesophageal perforations, in the context of neoplasia, is a safe and effective method, with low morbidity, adequate recovery of the oral intake and prompt discharge from hospital.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this pa-