Introduction

Aero-digestive stulas (ADF) are pathological communications between any part of the digestive system (more commonly the esophagus) and the respiratory tract, congenital or acquired, resulting from various causes but mainly from tumor invasion through the esophagus and the tracheal or bronchial walls. They are often called tracheoesophageal, bronchoesophageal, or esophagealpulmonary stulas, and they can be benign or malignant in origin. In the last case, they represent serious complications of neoplasms that arise in the esophagus, lung, or mediastinum.

Most of the malignant ADF arise from digestive tumors and only a small proportion is due to lung tumors. Other tumors such as thyroid, larynx, or mediastinal metastatic nodes represent only a very low percentage of causes of ADF. Ninety percent of patients with malignant ADF have advanced or metastatic disease with high Eastern Cooperative Oncology Group (ECOG) scores.

Authors have no confict of interest to declare.

A. N. Rodríguez

School of Medicine, National University of Mar del Plata, Buenos Aires, Argentina

J. P. Díaz-Jiménez (*)

Interventional Pulmonary Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain

e-mail: pablodiaz@pablodiaz.org

Spontaneous closure of the stula is rare. The evolution is usually morbid due to the dramatic clinical implications and subsequent infections. Once symptoms of respiratory infection begin, in most cases, these complications cause aspiration pneumonia leading to sepsis, mediastinitis, acute respiratory distress syndrome (ARDS), and a fatal outcome. The prognosis is serious and the patient usually dies within a few weeks.

The main goals of management of a patient with ADF should be to treat recurrent infections with antibiotics and seal the communication between the esophagus and the airway, and ensure proper enteral feeding.

Non-malignant causes can occur as a consequence of treatments such as surgery, radiotherapy, chemotherapy, or radiotherapy associated with some angiogenic drugs, resections with laser, manipulations with esophageal or tracheobronchial prostheses, infectious diseases, granulomatous processes, chest trauma, necrosis caused by pressure from the cuff of the endotracheal intubation or tracheostomy tube, foreign bodies, and/or ingestion of caustics. Surgical repair, when possible, is the best option for non-­malignant ADF.

Etiology

Congenital ADF

They are due to failure of the embryonic organs to fully form and are usually associated with other

congenital abnormalities, vertebral, esophageal,­

or anal atresias, and especially cardiac abnormalities as part of the vertebral defects, anal atresia, cardiac defects, tracheo-esophageal stula, renal anomalies, and limb abnormalities, vertebral defects, anal atresia, tracheo-esophageal stula with esophageal atresia, and radial and renal dysplasia (VACTERL/VATER) Association [1] and are usually diagnosed on all in early childhood. They arise when there are abnormalities in the formation of the laryngotracheal tubes (which divide into trachea and esophagus) in the fourth week of embryonic development [2].

Congenital stulas are rare and usually occur in 0.04% of all births. Their discussion is out of the scope of the present chapter.

Malignant ADF

Most acquired aero-digestive stulas result from cancer, and emerge due to tumor invasion or from a complication of oncological treatments such as surgery, radiotherapy/chemotherapy, laser resections, necrosis caused by the pressures produced by intubation, or direct pressure coming from esophageal or tracheobronchial prostheses.

The pathogenesis of the stulas is favored by the proximity of both neighboring organs. On the one hand, the trachea and the left main bronchus are closely linked to the esophagus, so tumors originating in any of these adjoining parts can invade the thin layer that separates them and end up communicating both organs.

On the other hand, the mediastinal nodes, especially in the subcarinal area, can also invade and communicate with the airway and the digestive tract, since they are part of the lymphatic drainage on both systems.

From the anatomical point of view, both benign and malignant ADF are located in 57% of cases between the esophagus and the trachea and 37% between the esophagus and one or both of the main bronchi. Fistulas between the esophagus and the lung parenchyma are usually the least frequent, close to 10% [3]. Quite less frequent are bronchopleural, bronchovascular, and bronchoperitoneal stulas.

Martini et al. [4] reported the largest study on ADF and showed that it occurred in 5% of 1943

esophageal cancer patients, 0.16% of 5714 lung cancer patients, and 15% of 41 tracheal cancer patients.

Burt et al. [5], in an excellent retrospective study including 207 patients with ADF, showed that for most of the aero-digestive stulas, primary tumor site was esophagus in 161 (77%), lung in 33 (16%), trachea in 5 (2%), metastatic nodes in 4 (2%), larynx in 3 (1%), and thyroid in 1. The risk of developing malignant ADF was also higher in patients with esophageal carcinoma. The incidence of ADF in patients with esophageal cancer was 4.5%, and 0.3% in patients with primary lung cancer.

Balazs et al. [6], in a series of 264 patients with malignant stulas, found that 243 had esophageal cancer, 19 had lung tumors, and 2 had mediastinal tumors.

Of all malignant esophageal-pulmonary stulas, 92% have esophageal cancer and 7% have lung cancer. Other neoplasms of different origin, such as thyroid carcinoma, larynx, lymphomas, or malignant mediastinal nodules, correspond to only a small percentage of these stulas [7].

Cancer Treatment-Related ADF

Some therapies used for cancer can result in ADF. Bevacizumab is a monoclonal antibody directed at vascular endothelial growth factor (VEGF). In combination with paclitaxel and carboplatin, it is indicated for the treatment of advanced non-small cell lung carcinoma (NSCLC). This angiogenic agent has been shown to cause the formation of tracheal or bronchoesophageal stulas when administered in combination with radiochemotherapy [8].

Some publications warn of the danger of causing esophageal respiratory stulas due to the combination of bevacizumab and radiochemotherapy for treating both non-small and small cell lung cancer. In a report on small cell carcinoma treated patients, 2/29 developed tracheoesophageal stula and another patient died of aero-­digestive hemorrhage. Of the group of ve patients with advanced non-small cell carcinoma, treated with a combination of bevacizumab and radiochemotherapy, two developed tracheoesophageal stula. With these ndings, both trials were closed to additional enrollment.

All patients and treating physicians were noti ed of these potential safety issues and protocolbased treatment was stopped. Genentech and appropriate regulatory authorities including the U.S. Food and Drug Administration and National Cancer Institute were noti ed. Consequently, a black box warning was issued in the bevacizumab label [9].

As suggested by this and many other reports [9–12], the use of antiangiogenic therapies such as bevacizumab, and especially when associated with concomitant radiotherapy in patients with thoracic malignant neoplasms, can lead to the formation of stulas (which in most cases tend to be fatal), even months after completion of radiotherapy treatment. This complication may be common to all VEGF pathway inhibitors, advising that the safety of bevacizumab treatments in patients previously treated with radiotherapy should be studied with extreme caution, suggesting that these cases should only be included in carefully designed clinical trials [13].

Regarding safety of endoscopic procedures in patients who have been treated with antiangiogenic agents (AAs), Kachaami et al. [14] reported a retrospective multicenter study of a consecutive case series of 445 cancer patients, from 5 oncology hospitals, who underwent endoscopy within 31 days of antiangiogenic agents’ administration.

The most common types of cancer were colorectal, lung, and breast, and most patients had stage III or IV disease at the time of diagnosis.

Among the 445 patients who received a total of 545 endoscopies, 3 procedure-related adverse events (0.7%) occurred within 30 days of the procedure. Two of them were minor, and a third patient developed pancreatitis. The authors concluded that, in this study, the rate of adverse events related to endoscopy procedures in patients with antiangiogenic agents (AAs) seemed to be low, only 0.7% when performed in a specialized cancer center.

The use of immunotherapy agents for advanced lung adenocarcinoma has been associated with rapid development of ADF in a report. In this particular case, after mechanical debulking and stent placement, the patient received nivolumab and 12 days after that, a tracheoesophageal stula was diagnosed related to a metastatic

lymph node [14]. As lung cancer treatments become more complex, special attention should be paid on possible unusual complications.

Benign ADF

Benign non-tumoral acquired ADF can result from different conditions:

•\ Traumatic: blunt or penetrating chest trauma [15]

•\ Infammatory diseases/Infectious diseases (tuberculosis, histoplasmosis)

•\ Iatrogenic: postoperative, post radiotherapy, post intubation, post tracheostomy (particularly percutaneous), post stent placement (esophageal or airways)

•\ Esophageal diverticula •\ Caustic ingestion

•\ Foreign body

•\ Other conditions

Infectious conditions such as granulomatosis processes (i.e., tuberculosis [16], actinomycosis, Wegener’s) can result in ADF as well. Other infections can also be responsible: herpetic esophagitis, acquired immunode ciency syndrome (AIDS)-related esophageal candidiasis, cytomegalovirus, or Staphylococcus aureus

[17].

In ammatory processes resulting from ingestion of foreign bodies or corrosive agents [18] or patients with Zenkel’s diverticulum can also be the cause of aero-digestive stulas [19, 20].

Lenz et al. [21] published a retrospective review between 2001 and 2012, of 123 tracheobronchial esophageal stulas: 53% were malignant and 47% were of benign etiology, 60% of which were postoperative. The rest of the benign etiologies were: mediastinal infammation, radiotherapy, esophageal diverticula, caustic ingestion, broncholithiasis, tracheal stenosis, and actinomycosis. However, Shen et al. [22] found in a retrospective study from 1978 to 2007 that 14% of the 35 benign stulas found were due to granulomatous infections. According to Bixby et al. [23], this discrepancy in ADF etiologies between the two studies can be explained by the decline in granulomatous diseases and better