Abstract
Introduction
Side-branch intraductal papillary mucinous neoplasms (IPMN) of the pancreatic head/uncinate are an increasingly common indication for pancreaticoduodenectomy (PD). However, enucleation (EN) may be an alternative to PD in selected patients to improve outcomes and preserve pancreatic parenchyma.
Aim
To determine peri-operative outcomes in patients with side-branch IPMN of the pancreatic head/uncinate undergoing EN or PD compared with a cohort of patients with pancreatic adenocarcinoma (PA) undergoing PD.
Methods
Retrospective review of a prospectively collected, combined, academic institutional series from 2005 to 2008. Of 107 pancreatic head/uncinate IPMN, enucleation was performed in 7 (IPMN EN) and PD was performed in 100 (IPMN PD) with 17 of these radiographically amenable to EN (IPMN PDen). During the same time period, 281 patients underwent PD for PA (Control PD).
Results
Operative time was shorter (p < 0.05) and blood loss (p < 0.05) was less in the IPMN EN group compared with all other groups. Peri-operative mortality and morbidity of all IPMN groups (IPMN EN, IPMN PDen) were similar to the Control PD group. Overall pancreatic fistulae rate in the IPMN EN group was higher than in the IPMN PDen and Control PD groups; however, the rate of grade C pancreatic fistulae was the same in all groups.
Conclusions
Pancreaticoduodenectomy for side-branch IPMNs can be performed safely. Compared with PD, enucleation for IPMN has less blood loss, shorter operative time and similar morbidity, mortality, hospital length of stay (LOS) and readmission rate. Enucleation should be considered more frequently as an option for patients with unifocal side-branch IPMN.
Keywords: cystic tumours, resection, outcomes
Despite a decrease in reported mortality, pancreaticoduodenectomy (PD) remains a complex procedure with a high morbidity rate.1–5 Overwhelmingly, this morbidity is as a result of post-operative pancreatic fistula (POPF). Soft textured pancreas, a small pancreatic duct and a fatty pancreas have been identified as strong predictive factors of pancreatic fistula after PD1,5,6 Although the incidence of pancreatic adenocarcinoma has remained stable over the past decade, the frequency with which pancreatic surgery has been undertaken has increased.7 This change has been due, in part, to the increase in detection of cystic tumours such as intraductal papillary mucinous neoplasms (IPMN).8,9 Unfortunately, IPMN have an increased rate of POPF. Thus, patients need to be fully informed of possible post-operative complications for a premalignant and often asymptomatic disease. Enucleation of islet cell tumours located in the head/uncinate process has been shown to reduce post-operative morbidity as compared with PD.10 Therefore, we hypothesized that a similar outcome could be achieved for IPMN. Thus, the aim of the present study was to determine the post-operative course of enucleation vs. PD for IPMN of the head/uncinate of the pancreas.
Methods
Study groups
Patients undergoing pancreatic resection between 1 January 2005 and 12 December 2008 were identified from institutional review board approved prospective databases maintained at Indiana University Hospital (IN, USA) and Institut Paoli Calmettes (Marseille, France). Patients undergoing surgery for IPMN of the pancreatic head/uncinate were divided into those undergoing enucleation (IPMN EN) or pancreaticoduodenectomy (IPMN PD). Patients undergoing PD for pancreatic ductal adenocarcinoma during the same period were identified as a control group (Control PD). Thus, 107 patients underwent pancreatic surgery for IPMN of the pancreatic head/ uncinate, seven underwent enucleation whereas 100 had PD. During the same period, 281 patients who underwent PD for pancreatic adenocarcinoma without any pre-operative treatment comprised the control group.
Enucleation group
All patients with suspected IPMN were staged by endoscopic ultrasound (EUS), thin-section contrast-enhanced helical dual phase computerized tomography scanning (CT scan) and/or pancreatic magnetic resonance imaging (MRI) (Fig. 1). Eligibility criteria for enucleation were (a) absence of previous pancreatic head surgery, (b) side branch IPMN of the head or uncinate process, (c) absence of main pancreatic duct dilatation, (d) absence of mural nodule or thickness of cyst wall, and (e) ability to preserve the main pancreatic duct as assessed by intra-operative ultrasound (IOU).
Figure 1.
Magnetic resonance cholangiopancreatography (MRCP) of a patient with intraductal papillary mucinous neoplasms (IPMN) of the uncinate process eligible for enucleation. White arrow shows the communicating duct
Thus, 24 patients were identified for possible enucleation. Ultimately, the surgical procedure performed was decided according to institutional and individual surgeon preference. Seventeen of these patients underwent PD while seven side-branch IPMNs were enucleated. After a generous Kocher manoeuvre, the entire pancreatic head was exposed. Intra-operative ultrasound imaging was routinely done to assess absence of (a) involvement of the main pancreatic duct, (b) mural nodules and (c) additional IPMNs. Pancreatic parenchyma was carefully opened with ligation of any vessels using fine sutures or cautery. The side-branch IPMN was entirely dissected; and when possible, the communicant duct was identified and ligated (Fig. 2). Frozen section examination was undertaken to be sure that no carcinoma in situ or invasive cancer was present. Closure of the pancreatic parenchyema was left to the discretion of the individual surgeon. A Jackson–Pratt drain was routinely positioned close to the resection field. PD was performed as previously described.3
Figure 2.
Intra-operative photograph showing enucleation of the uncinate process with identification of the communicating duct (white arrow). Haemostasis of pancreatic parenchyma was perform with 6/0 Prolene
Outcomes
The variables evaluated included age, gender, operative duration (min), blood loss (ml), IPMN size (cm) defined as maximum diameter at pathological analysis, presence of invasion, POPF according to the International Study Group on Pancreatic Fistula (ISGPF),11 overall morbidity including post-operative bleeding and reoperation, mortality, hospital length of stay (LOS) (days) and readmission rate.
Statistical analysis
Data analyses were carried out with GraphPad Prism (GraphPad Software Inc., La Jolla, CA, USA) and Excel 2004 (Microsoft, Seattle, WA, USA). Statistical associations between categorical factors were assessed using Fisher's exact test. Statistical significance was set at a P-value < 0.05.
Results
IPMN patients
During the study period, 107 patients underwent pancreatic surgery for IPMN of the pancreatic head/uncinate, while 281 patients underwent pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (Control PD). Using the pre-operative and intra-operative assessment criteria, 24 of 107 patients (22%) with IPMN met the criteria for enucleation (Table 1). However, only seven underwent enucleation (IPMN EN) while 100 patients underwent pancreaticoduodenectomy (IPMN PD). One patient who initially underwent enucleation was converted to a PD because of concerning findings on frozen section. This patient was included in the IPMN PD group. The IPMN EN and IPMN PD patients were similar with respect to age and presenting symptoms. Most presented with pain whereas pancreatitis, jaundice and weight loss were less common. The IPMN EN and IPMN PD cyst size was similar (2.4 vs. 2.2 cm). All seven of the IPMN EN patients had side-branch cysts whereas 39% of the IPMN PD patients had main duct involvement (P < 0.05). None of the seven IPMN EN patients had invasive cancer while 20% of the IPMN PD patients had an invasive IPMN (P < 0.05).
Table 1.
Age, symptoms and pathological findings of IPMN patients
| IPMN EN | IPMN PD | |
|---|---|---|
| n | 7 | 100 |
| Median age (range) | 61 (35–81) | 66 (38–87) |
| IPMN-related symptoms (%) | 7 (100) | 85 (85) |
| Pain (%) | 5 (71) | 64 (64) |
| Pancreatitis (%) | 2 (29) | 10 (10) |
| Jaundice (%) | 0 (0) | 5 (5) |
| Weight loss (%) | 0 (0) | 6 (6) |
| IPMN size (cm) (range) | 2.4 (1.2–4.2) | 2.2 (0.4–5.2) |
| Branch duct IPMN (%) | 7 (100) | 61 (61)a |
| Mixed duct IPMN (%) | 0 (0) | 29 (29) |
| Main duct IPMN (%) | 0 (0) | 10 (10) |
| Margin with invasive IPMN (%) | 0 (0) | 1 (1) |
| Margin with non invasive IPMN (%) | 0 (0) | 8 (8) |
| Invasive IPMN (%) | 0 (0) | 20 (20)a |
P < 0.05 vs. IPMN EN.
IPMN, intraductal papillary mucinous neoplasms.
Operative outcomes
Operative time was shortest in the IPMN EN patients (185 min, P < 0.05). Operative duration also was shorter in the IPMN PD than in the Control PD patients (309 vs. 382 min, P= 0.03). Median blood loss was lowest in the IPMN EN patients (125 ml, P < 0.05). Median blood loss was lower in IPMN PD than in Control PD patients (592 vs. 859 ml, P= 0.06).
Post-operative outcomes
Postoperative outcomes of IPMN EN, IPMN PD and Control PD patients are presented in Table 2. No mortality was observed in the 107 IPMN patients whereas 5 of 281 Control PD patients (1.8%) died post-operatively. Overall, morbidity was similar in IPMN EN (43%), IPMN PD (36%) and Control PD (42%) patients. However, post-operative pancreatic fistulae were more common in IPMN EN (43%) and IPMN PD (25%) than in Control PD (14.2%) patients (P < 0.05). On the other hand, non-fistula complications were not seen in IPMN EN patients and were less common in IPMN PD (10%) than in Control PD (27.7%) patients (P < 0.05). No differences were observed in reoperation rates, hospital LOS or 30-day readmission rates.
Table 2.
Post-operative outcomes of IPMN and control patients
| IPMN EN | IPMN PD | Control PD | |
|---|---|---|---|
| N | 7 | 100 | 281 |
| Mortality (%) | 0 | 0 | 5 (1.8%) |
| Morbidity | |||
| POPF (%) | 3 (43) | 25 (25)a | 40 (14.2%) |
| Grade A (%) | 2 (29) | 9 (9) | 14 (5) |
| Grade B (%) | 1 (14) | 15 (15) | 22 (7.8) |
| Grade C (%) | 0 (0) | 1 (1) | 4 (1.4) |
| Bleeding (%) | 0 (0) | 2 (2) | 5 (1.8) |
| Cardiovascular/pulmonary (%) | 0 (0) | 8 (8) | 29 (10.3) |
| Gastric emptying (%) | 0 (0) | 6 (6) | 22 (7.8) |
| Biliary leak (%) | 0 (0) | 3 (3) | 6 (2.1) |
| Wound infection (%) | 0 (0) | 4 (4) | 8 (2.8) |
| Fascia dehiscence (%) | 0 (0) | 2 (2) | 15 (5.3) |
| Other (%) | 0 (0) | 6 (6) | 10 (3.6) |
| Overall morbidity (%) | 3 (43) | 36 (36) | 118 (42) |
| Morbidity without POPF (%) | 0 (0) | 11 (11)a | 78 (27.7) |
| Reoperation | 0 (0) | 7 (7) | 15 (5.3) |
| Length of stay (median days) (range) | 12 (11–27) | 14 (5–60) | 14 (6–66) |
| Readmission (%) | 1 (14) | 14 (14) | 35 (12.5) |
P < 0.05 vs. Control PD.
POPF, post-operative pancreatic fistula.
The post-operative outcomes of the seven IPMN EN and the 17 IPMN patients eligible for enucleation who underwent PD IPMN PDen are presented in Table 3. No differences were observed in mortality (0%), overall morbidity (43% vs. 35%), pancreatic fistula (43% vs. 12%), reoperation rate (0% vs. 12%), hospital LOS (12 days) or 30-day readmission rates (14% vs. 12%).
Table 3.
Post-operative outcomes of IPMN EN and IPMN PDen patients
| IPMN EN | IPMN PDen | P-value | |
|---|---|---|---|
| N | 7 | 17 | – |
| Mortality | 0 (0) | 0 (0) | NS |
| Morbidity | |||
| POPF (%) | 3 (43) | 2 (12) | NS |
| Grade A (%) | 2 (29) | 0 (0) | NS |
| Grade B (%) | 1 (14) | 2 (12) | NS |
| Grade C (%) | 0 (0) | 0 (0) | NS |
| Bleeding (%) | 0 (0) | 2 (12) | NS |
| Cardiovascular/pulmonary (%) | 0 (0) | 1 (6) | NS |
| Delayed gastric emptying (%) | 0 (0) | 1 (6) | NS |
| Overall morbidity (%) | 3 (43) | 6 (35) | NS |
| Reoperation (%) | 0 (0) | 2 (12) | NS |
| Length of stay (median days) (range) | 12 (11–27) | 12 (7–35) | NS |
| Readmission (%) | 1 (14) | 2 (12) | NS |
POPF, post-operative pancreatic fistula.
Discussion
Pancreatic surgery remains a challenge with significant short- and long-term morbidity.1–5 The management of side-branch IPMN continues to be controversial because many of the lesions are small and benign.11–17 Enucleation is an uncommon operation which has been applied to other benign cystic and neuroendocrine tumours.4,7,18–20 The present study documents the enucleation of seven side-branch IPMN of the head/uncinate of the pancreas and compares outcomes of 100 patients with IPMN and 281 with pancreatic cancers undergoing PD. Enucleation was associated with less blood loss and shorter operative time. Overall mortality and morbidity were similar among the three groups. However, the only morbidity associated with enucleation was low grade pancreatic fistulae.
IPMN of the pancreas may involve the main pancreatic duct, side branches or both. Because of the relatively increased risk of invasive cancer, resection is generally recommended for patients with main duct or mixed IPMN.11–17 Resection is also accepted for side-branch IPMN associated with symptoms or mural nodules as well as in those larger than 3 cm in diameter.11–17 However, the management of smaller side-branch IPMN in the absence of symptoms or mural nodules, especially in elderly and/or frail patients, remains controversial. When these lesions are in the head/uncinate of the pancreas, the decision to observe or operate becomes even more difficult because of the increased risk of PD compared with distal pancreatectomy or enucleation.4,7
In the present study, the pancreatic fistula rate was significantly higher in patients undergoing PD for IPMN than for pancreatic cancer (25 vs. 14%, P < 0.05). This observation is not surprising as most patients with IPMN have a relatively normal, soft pancreas whereas those with pancreatic cancer tend to have associated chronic pancreatitis with a dilated pancreatic duct. On the other hand, the non-fistula morbidity was significantly lower in the IPMN patients compared with the pancreatic cancer patients undergoing PD (11 vs. 28%, P < 0.05). This observation may be because of pre-operative differences in jaundice, biliary sepsis and/or nutrition.
The pancreatic fistula rate was highest in patients with side-branch IPMN who underwent enucleation (43%). However, this rate was not statistically significantly higher than in the patients undergoing PD for IPMN (25%) or pancreatic cancer (14%) because of the small number of patients undergoing enucleation. In addition, the three pancreatic fistulae in the enucleation patients included two Grade A, one Grade B and no Grade C fistulae. In comparison, Grade B and C fistulae occurred in 64% of the IPMN and 65% of the pancreatic cancer patients who developed pancreatic fistulae after PD. Again, this difference in Grade B/C fistulae between enucleation and PD patients (14 vs. 65%) is not statistically significant. However, the small number of patients undergoing enucleation may be the explanation as other reports suggest that Grade B and C fistulae are uncommon after enucleation.10,18–20
Several authors have reported enucleation of mucinous cystic neoplasms (MCN) and serous cystadenomas (SCA).18–20 In these analyses the blood loss and operative times were shorter than comparable patients who underwent pancreatic resection. This finding was also observed in the current report. While the initial manoeuvres of enucleation and PD are the same, both the resection and the reconstruction, or lack thereof, are simpler with enucleation. This difference explains why the blood loss and operative time is less with enucleation. Multiple strategies have been employed to reduce the risk of pancreatic fistula after PD.21–29 In this regard, several technical aspects of enucleation are important.
First, with respect to enucleation, identification of the communicating duct on a preoperative MRI scan can be very helpful.30,31 Second, determination of the relationship between the cyst and the main pancreatic duct with IOU is key, both with respect to the decision to perform enucleation and to prevent a Grade B/C pancreatic fistula. Third, operative identification and ligation of the communicating duct is an additional factor in patients with side-branch IPMN as opposed to MCN, SCA or neuroendocrine tumours (NET). Fourth, closure of the residual cavity in the pancreas may be a factor in reducing the incidence of Grade A fistulae.19 Finally, the use and management of drains in these patients may be more important than previously recognized.32,33
Historically, when the mortality of pancreatic resection was very high, enucleation was recommended for small neuroendocrine tumours.10,21,34 In recent years, however, the mortality of pancreatic resection has decreased to less than 3% at high-volume centres.1–5 Nevertheless, the morbidity of PD remains quite high; and therefore, enucleation of small NET of the head/uncinate may again be the procedure of choice.10,35 In a recent four-institution comparison, enucleation of 23 head/uncinate NETs was associated with shorter operative times, less blood loss, fewer complications and shorter hospital LOS.10 In addition, no local recurrences were observed among 37 enucleated patients and long-term survival was similar to pancreatic resection. In the current report of enucleation for side-branch IPMN in seven patients many of these same trends were observed despite the small number of patients.
Another potential advantage of enucleation over resection is preservation of pancreatic parenchyema. Both exocrine and endocrine function are diminished by pancreatic resection.36,37 In comparison, enucleation preserves the entire pancreas. A limitation of this analysis is that neither exocrine nor endocrine function was analysed in the enucleation or resection patients. Another limitation is the relatively short follow-up. However, while complete follow-up is not available in the 100 IPMN patients undergoing PD, no recurrence has occurred in the seven IPMN patients who underwent enucleation. As mentioned above, the small number of patients managed with enucleation is the most significant limitation of this analysis.
Several conclusions can be drawn from this report. For patients with IPMN of the pancreatic head/uncinate, both PD and enucleation can be performed safely. Enucleation is associated with improved operative outcomes. While the pancreatic fistula rate is high after enucleation, the majority are Grade A fistulae with little clinical significance. Although not confirmed by this analysis, enucleation may be associated with other improved post-operative outcomes such as reoperation, hospital LOS and readmissions. For these reasons, enucleation should be considered more often in patients with a side-branch IPMN in the head/uncinate of the pancreas.
Conflicts of interest
None declared.
References
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