Pancreatic Fistula

Etiology

Pancreatic fistulas develop due to abnormal communication between the pancreatic ductal system and surrounding structures, leading to the leakage of pancreatic secretions. These fistulas can be classified into iatrogenic and noniatrogenic causes. Iatrogenic causes are the most common and primarily result from surgical or procedural interventions, including operative trauma, pancreatic resection (such as pancreaticoduodenectomy or distal pancreatectomy), a biopsy of a pancreatic mass, complications from endoscopic interventions, and percutaneous drainage of pancreatic fluid collections, such as pseudocysts. Postoperative pancreatic fistula is a significant complication, with risk factors including soft pancreatic texture, high pancreatic ductal pressure, and inadequate anastomotic techniques. Most external pancreatic fistulas result from direct pancreatic duct disruption from iatrogenic sources.

Noniatrogenic causes include traumatic injuries, inflammatory conditions, chronic pancreatitis, and neoplastic processes.[3][5] Blunt or penetrating abdominal trauma can lead to pancreatic ductal disruption, particularly at the neck or body of the pancreas, where it is compressed against the spine. Inflammatory causes, such as acute and chronic pancreatitis, contribute to fistula formation through ductal obstruction, stricture formation, or pseudocyst rupture into adjacent organs like the stomach, duodenum, or peritoneal cavity.

Severe acute necrotizing pancreatitis may also result in pancreatic ductal disruption, leading to pancreatic ascites or pleural effusions. Neoplastic causes include pancreatic adenocarcinoma, neuroendocrine tumors, or cystic neoplasms, which can erode into adjacent structures and form fistulas. Malignant pancreatic fistulas are often more resistant to healing due to progressive disease, fibrosis, or tissue necrosis. Other rarer causes include congenital anomalies such as pancreatic divisum, infections, radiation therapy, and ischemic insults leading to pancreatic tissue necrosis and fistulization.

Epidemiology

Pancreatic fistulas, particularly postoperative pancreatic fistulas (POPFs), are a significant complication in patients having pancreatic surgery. Using the International Study Group for Pancreatic Surgery criteria, the rates of POPFs range from approximately 17% to 39% following pancreatic surgery, making them the most frequent harmful complication of these procedures.[6][7] The incidence varies based on factors such as surgical technique, pancreatic tissue quality, and patient comorbidities. A systematic review of 40 studies found the rate of clinically relevant pancreatic fistulas to be 22% to 26% in patients after a Whipple procedure (pancreaticoduodenectomy).[8][9]

The overall incidence of pancreatic fistulas ranges from 5% to 30% following pancreaticoduodenectomy and 30% to 40% after distal pancreatectomy, with soft pancreatic tissue and altered pancreatic anatomy being significant risk factors. Though earlier literature reported wider variations (likely due to inconsistencies in definitions), advances in surgical techniques, prophylactic measures, and advancements in patient care have reduced the incidence of clinically significant fistulas.[10][11]

Pancreatic fistulas also arise from noniatrogenic causes, including abdominal trauma, acute pancreatitis, and chronic pancreatitis. The incidence of fistulas in cases of chronic pancreatitis or pancreatic tumors is higher due to the underlying ductal obstruction and fibrosis. In the context of trauma, particularly blunt or penetrating injuries, fistulas are more common in younger individuals. Malignant pancreatic fistulas are usually seen in advanced pancreatic cancer, most commonly in older adults. While the overall incidence of pancreatic fistulas has decreased with better surgical techniques and earlier detection, they still represent a significant healthcare burden, contributing to extended hospital stays, complications such as abscesses and sepsis, and a high risk of mortality.[6]

Pathophysiology

Pancreatic duct disruption causes both internal and external pancreatic fistula pathophysiology. Depending on the anatomical location of the interruption, fluid leakage produces erosion and forms abnormal pathways. For example, an anterior pancreatic duct disruption can communicate freely with the peritoneal cavity, while a posterior pancreatic duct disruption can create a path to the pleural space and mediastinum.

The etiology of pancreatic duct disruption can vary greatly, including causes of pancreatitis, trauma, operative trauma, or pancreatic resection. The location of each pancreatic duct disruption can generally be predicted based on the underlying cause. For example, in gallstone pancreatitis, there is usually a pancreatic duct disruption at the genu of the pancreatic neck.[4] The most significant risk factors for POPFs include smoking and distal pancreatectomy, while diabetes mellitus plays a protective role in reducing the incidence.[12] Overweight, male sex, older age, prolonged operative time, and nonligation of the main pancreatic duct are risk factors.[13]

According to the  International Study Group for Pancreatic Surgery (ISGPS), a POPF is any measurable drain output on or after postoperative day 3 with an amylase level greater than 3 times the upper limit of normal for each specific institution. This event must also have a clinically relevant impact on the patient to meet the full criteria for the definition.[14][15] In 2016, the ISGPS revised its grading system, which can only be applied after the fistula's clinical course has ended. The obsolete term "grade A POPF" no longer exists, as this condition was defined as being clinically insignificant. This term has been redefined as a 'biochemical leak,' which consists of drainage of a fluid rich in amylase that does not clinically impact the patient.

Grade B is characterized by clinically relevant drainage, either from a persistently draining POPF (>3 weeks) or a drain requiring endoscopic or percutaneous repositioning. Notably, in grade B, there is no sign of organ failure. Lastly, grade C POPFs are those that require reoperation or are marked by severe complications, such as sepsis and organ failure, and up to 35% of such cases result in death.[15] Grade B & C POPFs in patients with postpancreaticoduodenectomy are most likely to occur when drain fluid grows a polymicrobial culture or Candida species, and grade C POPFs in this same group of patients are best predicted when the drain fluid grows Gram-negative rods or Candida spp.[16]

Histopathology

Leakage of enzyme-rich pancreatic fluid often yields pathology that can be identified under a microscope. Histologically, POPFs typically show granulation tissue formation, fatty infiltration, and a significant inflammatory response. In severe cases, leaked fluids can even create abscesses and may erode into nearby blood vessels.[17]

One study analyzed the relationship between histologic pancreatic texture and predicting the development of a POPF after pancreaticoduodenectomy. Surgeons often subjectively describe the texture of the pancreas as "soft" or "hard." A "hard pancreas" with more extensive fibrosis is considered easier to handle for surgeons during surgery. On the other hand, a "soft pancreas" is a widely accepted risk factor for POPF formation due to difficulties in suturing and maintaining the integrity of the pancreatic blood supply.[17][18]

History and Physical

A thorough history and physical examination are crucial in recognizing a pancreatic fistula, as symptoms vary based on location, size, and output. Some patients may remain asymptomatic, while others present with severe fluid accumulation and systemic complications.[3] Pancreatic fistulas are classified as internal or external, each with distinct clinical presentations. Internal pancreatic fistulas occur when pancreatic secretions drain into the peritoneal or thoracic cavity, leading to ascites or pleural effusions. These patients commonly present with:

• Abdominal pain, nausea, vomiting, distension, loss of appetite, and weight loss due to fluid accumulation or bowel obstruction are common.[19][20]
• Ascites are evident on physical examination by abdominal distention, a fluid wave, shifting dullness, and flank dullness to percussion.
• Thoracopancreatic fistulas can lead to pancreatic pleural effusions, presenting with dyspnea, cough, wheezing, or pleuritic chest pain.[20] On exam, these patients may have diminished breath sounds and dullness to percussion at the lung bases, corresponding to large pleural effusions.

External pancreatic fistulas result in effluent discharge from a surgical wound or percutaneous drain. Clinical manifestations include:

• There may be visible pancreatic fluid leakage from the abdominal wall that is often clear or bile-stained.
• Skin irritation, erythema, and excoriation can develop due to the caustic nature of pancreatic enzymes.
• Dehydration, malnutrition, and weight loss are secondary to loss of digestive enzymes and high-output fistula losses.

Regardless of the type, pancreatic fistulas can lead to fever and systemic signs of infection if they are complicated by secondary bacterial infection or abscess formation.[19] They can also cause electrolyte imbalances, metabolic acidosis, and progressive malnutrition, necessitating early recognition and intervention.

Evaluation

Imaging plays a primary role in differentiating the cause of abdominal pain or dyspnea. A chest x-ray will readily provide information about some etiologies. Computed tomography (CT) will be a first-line imaging modality to evaluate the cause of abdominal pain. Although CT scans may not be able to visualize and assess pancreatic fistulas directly, recent studies have shown that contrast-enhanced CTs can often identify fluid collections and changes in pancreatic tissue density.[13]

Other modalities, including magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and fistulography, can provide further insight. MRCP is a noninvasive technique that uses magnetic resonance imaging (MRI) to provide a more precise view of the pancreatic duct and the biliary tree. MRCP is increasingly utilized for its benefit in early fistula detection. ERCP utilizes endoscopy and fluoroscopy to visualize the pancreatic duct and biliary tree at high resolution, identify any sites of ductal disruption, and can be used for therapeutic interventions such as sphincterotomy of either or both of the pancreatic or bile duct or stent placement. Fistulography involves injecting contrast dye into the fistula to map out the fistula's full extent.[21][22][23][24] 

In addition to imaging, blood testing should be performed for further evaluation, including a comprehensive metabolic panel, a complete blood count, amylase, and/or lipase. Any fluid sample collected via thoracentesis, paracentesis, or external fistula should have its volume and appearance monitored, and it should be analyzed for the following:

• Amylase
  • A level greater than 3 times the high-normal serum amylase level (with the high-normal level usually being about 300 IU/L) is confirmatory of a pancreatic fistula. Thus, fistula fluid amylase levels are typically over 1000 U/dL.[4] 
• Protein
  • A high level of protein suggests inflammation or tissue injury as a cause of the fistula.
• Culture and sensitivity
  • Bacterial infection is often associated with a brown color of the fistula fluid. The workup includes a Gram stain, a white blood cell count, and a bacterial culture.
• In some cases, albumin, glucose, lactate dehydrogenase, and adenosine deaminase measurements have some utility.

Treatment / Management

The management of pancreatic fistulas involves both nonoperative and operative measures. In general, pancreatic fistulas with higher output require more aggressive intervention.[25] Regardless of medical presentation, optimizing an individual with these 3 supportive care measures are imperative before turning to any definitive intervention:

• First, the pancreatic exocrine secretion is controlled by keeping the patient nil per os (NPO), and ideally, postpyloric (nasojejunal) feeds or total parenteral nutrition are started. Somatostatin analogs such as octreotide are known to inhibit pancreatic exocrine secretion. However, results from a large study found no significant difference in relevant POPF rates between those individuals given octreotide prophylactically postoperatively and those in the untreated control group.[26] 
• Next, it is essential to correct fluid and electrolyte abnormalities. Individuals with pancreatic fistula are at risk of losing bicarbonate-rich pancreatic fluid, which can lead to metabolic acidosis.
• Last, the surrounding skin near an external pancreatic fistula should be monitored closely and protected from further damage.[4]

Some fistulas require endoscopic or operative intervention in addition to supportive care. Endoscopic interventions, including sphincterotomy and pancreatic stent placement, have been considered the first line of treatment to redirect the drainage into the small intestine.[27] Stent placement decreases the flow through the fistulous tract and facilitates its subsequent closure. However, a meta-analysis of 7 studies comparing the placement of pancreatic duct stents to no stent or drain placement after a pancreaticoduodenectomy showed no benefit from internal stenting in terms of POPFs, in-hospital mortality, need for repeat surgery, reduced gastric motility, or wound infection.[28] (A1)

Fistulas associated with pancreatic fluid collections, often after distal pancreatectomies, have a higher risk of local infection, sepsis, and tissue necrosis. In this situation, endoscopic ultrasound (EUS) guided procedures more often utilized in the context of pseudocysts or perigastric collections complicating acute pancreatitis may be effective. These techniques include the placement of fully covered self-expanding metallic stents or lumen-opposing metal stents.[29](A1)

The surgical approach depends on the ductal anatomy and location of the fistula. Some examples include a pancreaticojejunostomy in patients with large-duct disease, a distal pancreatectomy in patients with ductal injury solely at the pancreatic tail, and a distal pancreatectomy for pancreatic disruption in the pancreatic body. Surgery may also include the placement of 1 or more drains to allow the evacuation of pancreatic juice, blood, bile, and lymphatic fluid.[13][30][31] Still, it has been found that there is a lower risk of POPFs when drains are removed sooner rather than later.[32] However, the optimal timing for removing drains has not yet been determined. The meta-analysis described above showed that there was a reduced incidence of POPFs with the use of external drains.[28] The fistula closure rate with the placement of external drains is 77%.[33](A1)

Differential Diagnosis

The differential diagnosis of a pancreatic fistula is broad and largely depends on how a patient presents based on the location and size of the fistula. The differential diagnosis would include causes of abdominal pain, ascites, and pleural effusions. Causes of abdominal pain include but are not limited to peptic ulcer disease, trauma, retroperitoneal bleeding, intraabdominal malignancy, cholecystitis, pancreatitis, choledocholithiasis, mesenteric ischemia, bowel obstruction, ruptured organs, and infections.[34] Ascites and pleural effusions should prompt evaluation for renal failure, cirrhosis, heart failure, and malignancy when evaluating a patient with a pancreatic fistula.

Prognosis

Pancreatic fistulas can cause significant morbidity if not addressed and adequately treated. Less severe fistulas respond well to supportive and conservative management, which involves optimizing the patient and stabilizing the fistula.[35] Reports have shown about 80% of external fistulas and 50% to 65% of internal fistulas close in 4 to 6 weeks with supportive and conservative management. POPFs that develop after distal pancreatectomy will resolve in an average of 62 days with intervention.[11] With surgical intervention, there is a success rate for the resolution of pancreatic fistula of about 90% to 92%. However, it has a mortality of 6% to 9%.[36]

Complications

Complications associated with pancreatic fistulas can include:

• Walled-off pancreatic necrosis
• Infection, sepsis, and abscesses
• Pseudocyst formation
• Pancreatic pleural effusion
• Pancreatic ascites
• Intraabdominal hemorrhage
• Increased hospitalization duration and cost
• Malnutrition [3][37]