Pharyngocutaneous fistula (PCF) can be defined as a dehiscence of the closure of the pharyngeal mucosa, resulting in leakage of saliva and communication with the skin.1 It is considered as one of the major complications in the postoperative period after total laryngectomy and pharyngo- laryngectomy, leading to a severe adverse impact for the patient and society.

The reported incidence ranges from 5% to 65% in the years 70th and 80th and between 9% to 25% in the last decade. Its occurrence vastly increases the length of stay and consequently, the costs of treatment.2 Additionally, this complication can lead to a delayed onset of complementary therapies (such as radiotherapy/chemotherapy), which in turn increases the physical and mental weakness of the patient due to the delay of oral feeding onset and voice rehabilitation, thus hampering the postoperative recovery. In rare cases, it can also lead to stenosis and pharyngeal swallowing disorders, with large negative impact on quality of life for patients,1–3 or even salivary dissection, rupture of the carotid artery, sepsis, mediastinitis, pneumonia and death.

Many factors are described as predisposing to fistula formation; they can be divided as patient-, disease-, and treatment-related factors.4,5 However, there is still no consensus among authors regarding the most significant risk factors for the occurrence of this complication.5,6

Therefore, this systematic review was conducted in order to determine the predictive variables associated with pharyngocutaneous fistula development and the existing risk classifications.

A systematic review was performed in order to identify all the studies published through April of 2012, assessing variables and risk classifications for pharyngocutaneous fistula occurrence prediction in accordance with the methodology described in the Cochrane Handbook for Systematic Reviews of Interventions, 2008.7

The research sources used were: MEDLINE, Scopus, Cochrane Central, Cochrane Database of Systematic Reviews and clinicaltrials.gov, as well as reference lists from selected articles and pertinent systematic reviews.

The survey was conducted through MeSH terms (postoperative complications, fistula, pharyngocutaneous fistula, cutaneous fistula, risk factors, laryngectomy and pharyn- golaryngectomy) and their combination through Boolean operators. The inclusion criteria were: a) primary site of the tumor: laryngeal and/or hypopharynx, subdivided into supraglottic, glottic, infraglottic and hypopharynx that included primary neoplasm of pyriform sinus; b) type of surgery performed: total laryngectomy, total laryngectomy with partial pharyngectomy with or without neck dissection, salvage surgery for primary tumor of the larynx and hypopharynx; c) reconstruction: surgery with primary pharyngeal closure; and d) studies evaluating the association of risk factors with pharyngocutaneous fistula.

The exclusion criteria were: a) studies of opinion, case series and reviews; b) studies with outcome of general complications related to the intervention without the individual analysis of outcome data for the fistula formation; and c) studies written in foreign languages without adequate translation into English, Spanish, French, or Portuguese.

In the first stage, 846 studies were retrieved. After each article’s title and abstract were analyzed, 83 studies were selected. In the second phase, after the articles’ full analysis, 36 studies were selected. In each stage, the articles were assessed by two investigators and any divergence was solved by consensus. The two investigators worked independently and were blinded to each other’s assessments. Finally, after analyzing the reference list of all the selected studies, three new articles were included. A total of 39 studies were included in this systematic review and from each the following data was collected: title; author(s); publication date; journal; outcome definition and prevalence; study design; setting; sample size; association of risk factors with pharyngocutaneous fistula development; and time until outcome occurrence. The quality of the articles was assessed by the first author, following the Strengthening of the Reporting of Observational Studies in Epidemiology (STROBE) checklist for observational studies. This checklist has multiple components per item, resulting in a score of quality for observational studies.8 Two studies assessed risk classification systems.9,10 The study selection process is described in Fig. 1. The studies were first divided according to the intervention performed: total laryngectomy/primary pharyngolaryngectomy and “salvage surgery”. Then, they were ordered according to the design and quality assessment using the STROBE checklist (Table 1).

Figure 1.

Flowchart of article selection.

The query used was: (postoperative complications[MeSH Terms]) OR postoperative complications[Title/Abstract]) OR postoperative complication[Title/ Abstract]) OR postoperative complication[MeSH Terms]) OR complications, postoperative[MeSH Terms]) OR complications, postoperative[Title/Abstract]) OR complication, postoperative[Title/Abstract]) OR complication, postoperative[MeSH Terms]) OR surgical wound dehiscence[MeSH Terms]) OR surgical wound dehiscence[Title/Abstract]) OR dehiscence surgical wound[Title/ Abstract]) OR dehiscence surgical wound[MeSH Terms]) OR anastomotic leaks[MeSH Terms]) OR anastomotic leaks[Title/Abstract]) OR anastomotic leakage[Title/Abstract]) OR anastomotic leakage[MeSH Terms]) OR anastomotic leakage[MeSH Terms]) OR anastomotic leakage[Title/Abstract]) OR healing wound[Title/Abstract]) OR healing wound[MeSH Terms]) OR fistula[MeSH Terms]) OR fistula[Title/Abstract]) OR pharyngocutaneous fistula[Title/Abstract]) OR pharyngocutaneous fistula[MeSH Terms]) OR cutaneous fistula[MeSH Terms]) OR cutaneous fistula[Title/Abstract]) OR skin fistula[Title/ Abstract]) OR skin fistula[MeSH Terms]) OR external fistula[MeSH Terms]) OR external fistula[Title/Abstract]) OR salivary gland fistula[Title/Abstract]) OR salivary gland fistula[MeSH Terms]) OR pharyngostoma[MeSH Terms]) OR pharyngostoma[Title/Abstract]) OR postla ryngectomy pharyngocutaneous fistula[Title/Abstract]) OR postlaryngectomy pharyngocutaneous fistula[MeSH Terms]) AND (factor risk[MeSH Terms]) OR factors risk[MeSH Terms]) OR risk factor[MeSH Terms]) OR risk factors[Title/Abstract]) OR causalities[Title/Abstract]) OR causalities[MeSH Terms]) OR multifactorial causality[MeSH Terms]) OR multifactorial causality[Title/Abstract]) OR predisposing factors[Title/ Abstract]) OR predisposing factors[MeSH Terms]) OR prognostic factors[MeSH Terms]) OR prognostic factors[Title/Abstract]) OR etiology[Title/Abstract]) OR etiology[MeSH Terms])) AND (laryngectomy[MeSH Terms]) OR laryngectomy[Title/ Abstract]) OR pharyngectomy[Title/Abstract]) OR pharyngectomy[MeSH Terms]) OR pharyngolaryngectomy[MeSH Terms]) OR pharyngolaryngectomy[Title/ Abstract]) OR laryngectomies[Title/Abstract]) OR laryngectomies[MeSH Terms]) OR neoplasms laryngeal[MeSH Terms]) OR cancer of larynx[MeSH Terms]) OR cancer of larynx[Title/Abstr act]) OR larynx cancer[Title/Abstract]) OR larynx cancer[MeSH Terms]) OR head neck cancer[MeSH Terms]) OR head neck cancer[Title/Abstract]) OR laryngeal cancer[Title/Abstract]) OR laryngeal cancer[MeSH Terms]) OR laryngopharyngectomy[MeSH Terms]) OR laryngopharyngectomy[Title/Abstract]).

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Thereafter, all risk factors evaluated were extracted and listed individually by the type of statistical analysis/ methodology performed in each study, and also in relation to positive or negative association for the development of the pharyngocutaneous fistula (Table 2). The final analysis and synthesis of risk factors for development of pharyngo- cutaneous fistula is shown in Table 3.

Analyzing the systematic review, it is clear that there is still no consensus among studies on the role and relevance of each risk factor for the development of pharyngocutaneous fistulas. It is also clear that, depending on the population studied, some factors are more significant and consistent than others.

A single meta-analysis developed in the literature for pharyngocutaneous fistula after laryngectomy was performed by Paydarfar et al.42 and observed that postoperative hemoglobin less than 12.5g/dL, tracheotomy performance prior to surgery and radiotherapy previous to surgery with or without neck dissection were the most significant risk factors for the development of pharyngocutaneous fistula after total laryngectomy. However, the authors were limited to primary cancer of the larynx and did not include any study that addressed the treatment of primary neoplasm of the hypopharynx. While it may represent a selection bias, it is believed that the inclusion of studies whose intervention goes beyond the standard laryngectomy, is including partial laryngectomy with pharyngectomy is relevant, since the results of these studies should also be evaluated and reported with regard to their weight and their importance to the development of the pharyngocutaneous fistula.

In the present review, Esteban et al.2 developed a model using logistic analysis to assess risk factors for the development of pharyngocutaneous fistula in 442 patients who underwent total laryngectomy. The authors included variables before, during, and after surgery, such as the amount of alcohol consumption, lack of involvement of the pyriform sinus and base of the tongue, surgeon’s experience, the use of biological glue during surgery and the presence or absence of fever in the postoperative period. However, the model proposed did not provide diagnostic measures, such as calculations for sensitivity, specificity, positive and negative predictive values and area under the receiver operating characteristic (ROC) curve. Furthermore, the model cannot be applied to the present patients, since it involved a specific surgeon working at the university hospital of the study population and the use or nonuse of Tissucol for calculating the risk of fistula development, factors inherent in this very specific study.

The present systematic review also had limitations: the exclusion of studies whose translation was not possible; the assessment of trial quality and the fact that data extraction was performed only by the main author. The absence of prospective studies in the literature is noteworthy.

In summary, despite the difficulty in reaching a consensus regarding the most important risk factors for the development of the pharyngocutaneous fistula, this review considered studies with larger samples and with better quality in the overall assessment by the STROBE scale, as they are able to show greater evidence and the importance of some risk factors. Likewise, some factors were considered to be non-significant in the development of fistula and other factors need further analysis to demonstrate evidence and their role in this aspect (Table 3).

It can be concluded that there is still no appropriate classification for stratifying the risk of appearance of pharyngo- cutaneous fistulas. Therefore, the selection and synthesis of the most significant risk factors for fistula development were: hemoglobin pre- and post-surgery<12.5g/dL; pre- and postsurgery albumin<3.7g/L; presence of comorbidities; performance of previous RT or CRT; long duration of surgery; blood transfusion during operation and little experience of the main surgeon. Finally, the need for further studies with larger sample size, multicenter design and adequate methodology is emphasized, in order to obtain scientific evidence and consolidate the knowledge on the subject.

It is also necessary to create new levels of risk stratification that are appropriate to the different realities and greater efforts by experts in the evaluation and study of all possible variables related to fistulization. Only in this way can the occurrence of postoperative complications, which are so painful for the patient and the surgeon, be successfully avoided.

The authors declare no conflicts of interest.