Identification of risk factors for pancreatic pseudocysts formation, intervention and recurrence: a 15-year retrospective analysis in a tertiary hospital in China

According to the revised Atlanta classification [1], acute fluid collections and pseudocyst formation are the most common complications in patients with acute and chronic pancreatitis. A cute peripancreatic fluid collections often lack a wall of granulation or fibrous tissue, which occurred in 30% to 50% of acute pancreatitis (AP) patients within 48 h of AP onset. More than 50% of AP cases disappear spontaneously, or develop into PPC surrounded by a well-defined wall [2]. PPC incidence ranged from 5 to 16% in AP patients, while 20–40% in patients with CP [3–6].

Large PPC is uaually known to cause compressive symptoms and a variety of treatment methods has been proposed such as conservative treatment (watchful monitoring), surgical drainage (open or laparoscopic), percutaneous drainage and endoscopic drainage. Traditionally, the indications for therapeutic intervention of PPC are more than 6 cm in size and persisted for more than 6 weeks. In practice, large pseudocysts are less likely to resolve spontaneously. However, prolonged observation of spontaneous PPC resolution may expose patients to unwarranted risks, including bleeding, perforation, jaundice and infection. Therefore, in order to design effective treatment strategies for patients with PPC, clinical studies should be performed on the basis of an appropriate plan of investigation reflecting the latest scientific and technical knowledge.

To our knowledge, after implementation of the 2012 revised Atlanta classification for AP, the number of retrospective studies focusing on PPC is relatively limited, and most of them has become obsolete. Given these circumstances, further studies are warranted to systematically sought out the incidence, risk factors and intervention effect for PPC. Accordingly, this study aimed to identify the potential risk factors for PPC, with regards to its formation, intervention and recurrence.

PPC, a begin complication of pancreatitis, can be predictors of a malignant outcome, especially among patients with severe AP. The two main indications for some type of invasive drainage procedure are persistent patient symptoms or the presence of complications such as bleeding, infection, gastric outlet and biliary obstruction [8]. To date, the guidelines on minimally invasive management of PPC demonstrated a lack of consensus in clinical recommendations, and few recommendations have been graded according to the strength of supporting evidence. The identification and prediction of risk factors for PPC formation, intervention and recurrence may help to distinguish the high-risk PPC group from patients with pancreatitis. Thus, early detection and treatment can be considered for patients at high-risk of PPC. Additionally, identification of risk factors may reduce surgical adverse events, avoid delay in inappropriate interventions and improve the prognosis of PPC patients.

In the present study, data of 5106 pancreatitis patients was retrieved from a prospective database and was retrospectively analyzed. After reviewing the English-language articles published in PubMed with MeSH terms of “pancreatitis”, “pancreatic pseudocyst”, “pancreatic necrosis”, “infected pancreatic necrosis”, or “pancreatic fluid collections”, we believed that this study contained the largest population of PPC patients at a single center, reporting the risk factors of PPC formation, intervention and recurrence. Alcoholic and chronic pancreatitis remained the main risk factors for PPC formation and intervention. Although the recurrence rate of PPC treated with percutaneous drainage was ranked the highest, there was no difference in the rate of complications among the three types of interventions.

Biliary pancreatitis is ranked the most common cause of PPC among Asian countries, followed by alcoholic pancreatitis. However, more severe forms of AP and local complication, such as pseudocyst formation, have been associated with alcoholic AP compared to biliary AP [9]. Alcohol acts to worsen pancreatitis by its effects on pancreatic mitochondria to promote necrosis, which has been proved by in vitro experiments and clinical research [10, 11]. Besides, nonalcoholic acute pancreatitis is associated with a lower incidence of pseudocyst formation when compared with acute alcoholic pancreatitis. Alcoholism etiology has been reported as one of the risk factors for pancreatic fluid collections [12]. On the other hand, a high incidence of pseudocyst formation has been found among patients with CP. A multicenter study from China reported that 26.25% of CP patients are more likely to develop pseudocysts [13]. PPC due to CP, is often accompanied by secondary complications, including duodenal and/or biliary obstruction, splenic vein thrombosis and rarely infection [14]. These complications are primarily treated by surgery and less amenable to endoscopic therapy, especially for common bile duct stricture, main pancreatic duct obstruction and pseudocysts [15]. Furthermore, alcoholism exhibits a worse effect on pancreatic function and is the most common cause of CP. These findings suggest the importance of alcoholic pancreatitis and CP as new combinational risk factor for PPC formation.

IPN, a local complication of severe AP, is commonly accompanied with PPC, due to the collection of pancreatic necrotic tissues by PPC. Typically, pancreatic necrosis is a late complication of AP, resulting in considerable morbidity and mortality. The necrotic pancreatic tissues can remain solid or liquefy, and remain sterile or become infected. Among the patients with necrotizing pancreatitis, 33% of them may develop infected necrosis. The prevalence of organ failure in necrotizing pancreatitis is 54% and even higher among patients with infected necrosis [16]. To the best of our knowledge, no studies have reported on the association between IPN and PPC. The present study revealed that IPN was significantly correlated with PPC formation (OR, 4.253; 95% CI, 3.574–7.339; p = 0.021). Therefore, it is noted that an active and effective treatment for IPN can prevent the development of PPC, improve the prognosis of pancreatitis patients, and even lower the morbidity and mortality rate.

The surgical techniques and timing of treatment for PPC are still in debate. Most previous studies have shown that PPC larger than 5 or 6 cm are less likely to resolve spontaneously. The intervention for patients with a small pseudocyst and mild symptoms can be delayed for a further 3 months, since the spontaneous resolution of PPC may still occur [17]. A prolonged period of “wait-and-see” policy for more than 6 weeks is suggested for patients with asymptomatic pseudocyst, especially for a single lesion [6]. Spontaneous resolution has occurred in 40% to 50% of PPC patients with no major complications during the period of active observation. As a consequence, intervention is warranted if the patient is symptomatic, a progressive increase in PPC size or if complications occur [18]. However, it has been reported that a delay of surgical intervention in PPC may contribute to higher incidences of postoperative complications, readmission, morbidity, and mortality. Moreover, the increasing application of nonsurgical interventions may require a further evaluation [19]. The concept of practice is that the wait-and-see policy should be carried out for more than 4 to 6 weeks until the appearance of spontaneous remission, unless PPC is associated with other symptoms or complications. Generally, chronic pseudocyst encapsulated with a thicker and more well-defined wall than acute pseudocyst [20]. The surgical intervention is usually performed on PPC with a wall thickness of greater than 1 mm. In addition, patients with first-attack AP and fluid collections at discharge should be examined by ultrasonography at a 3-month follow-up, in order to detect the presence of asymptomatic complications such as PPC.

Thus far, there have been no prospective studies comparing the effects of different intervention techniques (i.e. endoscopic drainage, percutaneous drainage and surgical drainage) on the complication and recurrence rates of PPC. The success rate of PPC after endoscopic drainage is considerably variable, most likely due to the presence of heterogeneity among patient populations and intervention types [21]. Surgery is no longer used as a sole treatment for PPC, ever since the emergence of alternative first-line therapy at most centers. Although both endoscopic and surgical drainages have demonstrated comparable success rates, there is a lack of published data regarding the optimal intervention for PPC patients [22]. Some patients may require multiple endoscopic procedures, and the decision to pursue endoscopic therapy depends on patient preference, underlying medical conditions and whether an additional endoscopic procedure is feasible. In addition, percutaneous drainage has been applied in patients with acute pseudocyst or the presence of physiologic exhaustion or comorbid conditions that prevent surgical intervention [23]. Percutaneous drainage provides a convenient alternative to patients, practitioners and physicians. However, several studies reported an equal effectiveness of percutaneous, endoscopic and surgical drainage [22, 24, 25]. In the present study, surgical drainage has the lowest recurrence rate as compared to endoscopic and percutaneous drainages (OR, 7.812; 95% CI, 3.109–23.072; p = 0.013). For the complication and recurrence rates of PPC among the three intervention groups, surgery is considered as the last remedial step (Figs. 2 and 3). Despite a higher recurrence rate of PPC in percutaneous drainage group, especially for children, PPC can often be managed without surgery, regardless of its size or complexity [26].

The advancement of new techniques in endoscopic and laparoscopic approaches have reduced the postoperative morbidity and mortality rates of PPC patients. Given that severe complications may occur after the procedure (Fig. 2), endoscopic drainage is recommended to be performed at tertiary-care center, by a surgeon with expertise in pancreatic surgery [27]. Both laparoscopic and open pancreatic cystgastrostomy have high primary success rates than endoscopic internal drainage, although repeated endoscopic cystgastrostomy offers a better success rate for selected PPC patients [28]. There have been various surgical approaches for treating PPC, but none of them are used as gold standards, as the choice of treatment is much dependent on the surgeon‘s experience and the clinical characteristics of patient. For patients with symptomatic CP, a multidisciplinary approach appears to have low threshold to surgical intervention, since long-term pain relief is accomplished more often after surgical treatment than after endoscopic treatment [29]. Surgical treatment for PPC patients consistes of open and laparoscopic approaches and includes the following: open drainage, cystogastrostomy, cystojejunostomy, distal pancreatectomy, PPC resection and pancreato-jejunostomy [30]. The laparoscopic approach to cystogastrostomy for PPC is associated with a shorter operating time, a smoother and more rapid postoperative recovery, and a shorter length of hospital stay compared to open surgery. Hence, the laparoscopic approach should be considered as the preferred treatment modality for PPC, when laparoscopic expertise is available [31].

Alcoholic and chronic pancreatitis may serve as the major risk factors for PPC formation and intervention. Moreover, percutaneous drainage is the only independent risk factor for PPC recurrence. The main limitations of this study include its retrospective design and single-institution nature. Therefore, future multi-institutional prospective studies are warranted to provide additional evidence supporting the risk factors for PPC, and the research results should be incorporated into clinical practice guidelines.