Cholecystocutaneous fistula incidence, Etiology, Clinical Manifestations, Diagnosis and treatment. A literature review

Cholecystocutaneous Fistula (CCF) is a type of external biliary fistula, which connects the gallbladder with the skin. Thilesus first described this phenomenon in 1670. There is usually a history of calculi in the gallbladder or neglected gallbladder disease. The incidence of CCF is rare, most patients are elderly females with the mean age of 72.8 years old. They usually present with chronic calculus cholecystitis or a history of a previous surgical intervention. US, CT, MRI, MRCP and (CT or X-ray) fistulogram are used to confirm the diagnosis. CT was more significant than US in identifying the track of the fistula and the fluid that runs throw it. CCF patients presented with systemic symptoms (fever, nausea and vomiting) or local symptoms. RUQ region is the most common site of external opening. Open cholecystectomy with excision of the fistulous tract is considered an acceptable option for treatment and it is curative in most cases. However, laparoscopic approach can be another option with experience surgeons.


Introduction
Fistula is an abnormal condition, which results from abnormal connection between two epithelialized surfaces. Biliary fistulas are rare complications of gallstone, that connect between the biliary tract and other organs, there are two main groups of biliary fistulas: external and internal [1].
Internal biliary fistula connects the gallbladder with gastrointestinal tract, it is induced by chronic cholecystitis [2].
External biliary fistula connects the gallbladder with abdominal wall, it could be spontaneous, postoperative or post-traumatic or caused by iatrogenic injury of biliary tract [1,3].
Cholecystocutaneous fistula is a type of external biliary fistula, which connects the gallbladder with skin (Fig. 1).
Untreated or neglected gallbladder disease may lead to CCF are the main risk for CCF cases. Most patient presented with a history of calculi in the gallbladder or neglected gallbladder disease and they treated with conservative or surgical way.
There are less than 100 cases of cholecystocutaneous fistula reported in the medical literature [4]. The first reported case of CCF was in 1670 by Thilesus, who described this phenomenon for the first time.
CCF can be spontaneous after cholethiasis and neglected gallbladder disease (5), or following previous surgery such as percutaneous cholecystostomy drain removal [4].
This study reviews the Incidence, Etiology, Clinical Manifestations, Diagnosis and Management for Cholecystocutaneous Fistula patients, using data of pervious case report in the medical literature.

Methods
We conducted a literature search for relevant studies that have been published between 1954 and 2020 in Pubmed database by using the following search term "Cholecystocutaneous Fistula". There were no restrictions on country, or language. Articles were excluded if they were animal studies or uncompleted data. We reviewed 48 case report articles that were published between 1954 and 2020.

Incidence and etiology
The incidence of CCF is rare, most patients are elderly females (M/F: 18/29) with the mean age of 72.8 years old (Table .1) (see Table 2).
CCF mainly is a result of neglected gallbladder disease. Most cases presented with chronic calculus cholecystitis or with a history of previous surgical intervention as a case of subtotal cholecystectomy for acute cholecystitis [6][7][8][9][10][11].
Increasing pressure in the gallbladder after calculus cholecystitis, which leads to fistula formation, is believed to be the pathophysiology mechanism of this condition.
Most common cases of CCF are related to bacterial infection in the gallbladder, but there are few cases of CCF arising from adenocarcinoma of gallbladder [12,13].
Escherichia coli is the most common microorganism found in cholecystocutaneous fistula cases followed by Coliforms and klebsiella pneumonia. (Table. 2).
Also retained stones after laparoscopic cholecystectomy and traumatic rupture of the gallbladder are considered as predisposing factors for cholecystocutaneous fistula [14,15].

Clinical Manifestations
The general condition of the patient variable is depending on the age and past medical history. There is usually a history of calculi in the gallbladder or neglected gallbladder disease.
CCF patients presented with systemic symptoms or specific symptoms.
However, patients may present with pain and swelling in the RUQ or epigastric region [6,18], discharging sinus from the anterior abdominal wall [15,19], erythematous mass [20], subcostal abscess [18] (Table .1). The most common site of external opening is in the right upper quadrant of the abdominal wall. It can also be seen in right flank, right subcostal area, epigastric region, right breast, para-umbilical site (Table .3).

Diagnosis
CCF is diagnosed usually using imaging studies, or exploratory laparotomy in special cases.

Imaging studies include
US provides good assessment for CCF diagnosis by showing abnormal findings such as abscess, gallbladder stones, edema, thickened in gallbladder wall and dilated biliary ducts [5,15,17,21] but often fails to confirm the CCF diagnosis. In a few cases, US was able to demonstrate the track of CCF [12,19].
CT confirmed the diagnosis by identifying the track between the gallbladder and the skin in several cases [22][23][24][25]. Furthermore, CT fistulogram can also show the track of CCF which confirm the diagnosis [21]. CT couldn't identify the track of CCF in a few cases where it just showed abnormal findings which point toward the diagnosis [19,23,26,27].
In total, CT was more significant than US in identifying the track of the fistula and the fluid that runs throw it.
MRI was able to detect gallstones, gallbladder perforation, and the fluid, which extruded through the abdominal wall [5,18].
MRI could be more accurate when CT detects no abnormalities. MRCP increases the confirmed cases [7,17,19,28]. The results of MRCP are identical to US and CT.
Hepatobiliary iminodiacetic acid scan was used in two cases; it failed to demonstrate the fistula in one case (4) and showed obstruction in biliary tracks in the second one [29].
In addition, exploratory laparotomy may be the only diagnosis methods especially in old reported cases, in poor countries or with shortage of appropriate equipment and laparoscopic experience.
CT Fistulogram or X-ray Fistulogram have been used to demonstrate track of the fistula accurately [14,21,30], although in most cases Fistulogram was not used and the diagnose was made by another method.
There are problem and the difficulties facing the diagnosis such as absence of radiological expertise, it is uncommon to consider CCF as deferential diagnosis since it is a rare condition and presence of mucous discharge rather than yellowish discharge if there is an obstruction in the cystic duct makes it hard to diagnose especially in the early stages.

Management
The management of CCF vary according to disease severity, age, and the patient's preference.
There is no standard base line management for cholecystocutaneous fistula, due to the fewness of the number of cases and the differences in patients' illness quality.
The medical literature mentioned different ways of CCF management, either conservative or surgical management.

Conservative management
Conservative management includes antibiotics, fluids or ERCP. Percutaneous abscess drainage is performed immediately with the   [4,7,16,17,23,26]. Conservative management is performed to elderly patients who are unable to tolerate surgery [17].
Few cases were treated by using endoscopic retrograde cholangiopancreatography (ERCP) for CCF treatment, by removing calculi using ERCP balloon trawl and sphincterotomy [31].
Chemotherapy is applied for CCF patients due to carcinoma of the gallbladder [13].
Percutaneous transhepatic gallbladder drainage (PTGBD) can be applied to treat CCF. Where the fistula heals under secondary intention after removing drainage tube [32].
Conservative management cured few cases, helped relieve symptoms and improved patient's condition.
Surgical management: Surgical management includes open cholecystectomy and laparoscopic cholecystectomy.
Open cholecystectomy with excision of the fistulous tract is considered as a standard option for management and it is curative in most cases. In the other hand, laparoscopic cholecystectomy with excision of the tract can be another acceptable and preferable option with advance experienced laparoscopic surgeons.
Presence of comorbidity in patients lead to failure of healing, also difficulty in performing surgery for cachectic or elderly patients.
Lack of adequate surgical experience can lead to serious complications and difficulty in treatment.

Conclusion
CCF diagnosis and management represent one of the surgical obstacles, which we still encountered from time to time. We noticed through our review different ways of diagnosis and management. Most of them were dependent on the surgical experience and the advanced medical investigation equipment.
In conclusion, there is no standard ways for diagnosis and management of CCF but according to our review; we think that each surgeon should choose the best way to deal with CCF patients depending on patients 'quality, available equipment and advanced experienced surgeons.

Ethical approval
Not required.

Sources of funding
The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Funding
The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Ethics
Not required.

Patient consent for publication
Not required.

Provenance and peer review
Not commissioned, externally peer reviewed.

Declaration of competing interest
None declared.

Table 2
Presenting microorganism found in cholecystocutaneous fistula cases.