Ann Surg Oncol (2010) 17:1621–1627 DOI 10.1245/s10434-010-0949-8
ORIGINAL ARTICLE – PANCREATIC TUMORS
Parenchyma-Preserving Resections for Small Nonfunctioning Pancreatic Endocrine Tumors Massimo Falconi, MD1, Alessandro Zerbi, MD2, Stefano Crippa, MD1, Gianpaolo Balzano, MD2, Letizia Boninsegna, MD1, Vanessa Capitanio, MD2, Claudio Bassi, MD1, Valerio Di Carlo, MD2, and Paolo Pederzoli, MD1 1
Chirurgia Generale B (Pancreas Unit), Department of Surgery, University of Verona, Policlinico ‘‘GB Rossi,’’ Verona, Italy; 2Department of Surgery, Vita e Salute University, San Raffaele Scientific Institute, Milan, Italy
ABSTRACT Background. Parenchyma-preserving resections (PPRs), including enucleation and middle pancreatectomy (MP), are accepted procedures for insulinomas, but their role in the treatment of nonfunctioning pancreatic endocrine tumors (NF-PETs) is debated. The aim of this study was to evaluate perioperative and long-term outcomes after PPRs for NF-PETs. Methods. All patients who underwent PPRs for NF-PETs between 1990 and 2005 were included. Patients with multiple endocrine neoplasia type 1 were excluded. Results. Overall, 50 patients (23 men, 27 women, median age 59 years) underwent 26 enucleations and 24 MP. A total of 58% of NF-PETs were incidentally discovered. Median size of the tumors was 13.5 mm with no preoperative suspicion of malignancy in all patients. Overall morbidity and pancreatic fistula rates were 58 and 50%, respectively. Reoperation rate was 4%, with no mortality. Postoperative complications were higher in the MP group. At pathology, there were 34 (68%) benign lesions, 13 (26%) neoplasms of uncertain behavior, and 3 (6%) welldifferentiated carcinomas. Forty-one patients (82%) had tumors B2 cm in size. Only eight patients (16%) had at least one lymph node removed. After a median follow-up of 58 months, no patient died of disease. Overall, four patients (8%) experienced tumor recurrence after a mean of
Paolo Pederzoli and Valerio Di Carlo contributed equally to this article. Ó Society of Surgical Oncology 2010 First Received: 13 October 2009; Published Online: 17 February 2010 M. Falconi, MD e-mail:
[email protected]
68 months. The incidence of exocrine/endocrine insufficiency was 8%. Conclusions. PPRs are generally safe and effective procedures for treating small NF-PETs. However, better selection criteria must be identified, and lymph node sampling should be performed routinely to avoid understaging. Long-term follow-up evaluation ([5 years) is of paramount importance given the possible risk of late recurrence. In recent years, the number of incidentally discovered nonfunctioning neuroendocrine tumors of the pancreas (NFPETs) has greatly increased because of the widespread use of high-quality imaging techniques.1,2 A great number of patients with small (B2 cm) NF-PETs is observed, and most of these neoplasms are likely benign or intermediate-risk lesions.3,4 Therefore, indications for surgery should be carefully weighted with postoperative and long-term complications associated with standard pancreatic resections (i.e., pancreaticoduodenectomy and left pancreatectomy), which represent the treatment of choice for NF-PETs.5–7 On the other hand, parenchyma-preserving resections (PPRs) of the pancreas, including enucleation and middle pancreatectomy (MP), have largely been performed to treat insulinomas. For this latter disease, enucleation is the universally accepted procedure.8–11 PPRs have the advantage of greatly lowering the risk of developing both endocrine and exocrine insufficiency compared to standard resection, but the rate of postoperative complications and particularly of pancreatic fistula is higher.12–14 In this light, PPRs have also been proposed for treating small NF-PETs without overt malignant features.9,14–16 However, the usefulness and oncological safety of PPRs in NF-PETs remains debated because specific analysis of their outcomes in large cohorts of patients is lacking.3
1622
The primary end point of the present study was to analyze perioperative and long-term oncological and functional results after PPRs for small-size NF-PETs. A secondary end point was to compare different parenchymapreserving procedures, namely MP and enucleation. MATERIALS AND METHODS After obtaining Institutional review board approval, prospective databases maintained at the departments of surgery at the University of Verona and at San Raffaele Hospital were queried to identify patients who underwent MP or enucleation for histologically confirmed NF-PETs between 1990 and 2005. Demographic characteristics, clinical presentation, preoperative workup, intraoperative and postoperative data, complications, and pathology were collected. Patients with MEN1 syndrome were excluded from the study. Tumor staging was performed by conventional imaging procedures including ultrasound, computed tomography, magnetic resonance imaging, and endoscopic ultrasound. Since 1998, all patients with a preoperative diagnosis of NF-PETs have undergone somatostatin receptor body scintigraphy (Octreoscan) as part of their workup.17 A NFPET was defined by the lack of any clinical syndrome due to excess hormonal secretion, independent of laboratory data, as suggested by recent guidelines.3,18 Intraoperative ultrasound was performed whenever necessary to study tumor morphology and its proximity to the main pancreatic duct, and to rule out the presence of multifocal lesions. The choice between the two surgical techniques was based primarily on location and size of the tumor. Specifically, for small neoplasms located superficially, enucleation was considered. For NF-PETs in the neck/proximal body of the pancreas embedded deep in the substance of the gland and/or close to the main pancreatic duct, MP was performed according to previously described techniques.14 Perioperative mortality was defined as in-hospital or 30day death. Pancreatic fistula was classified according to International Study Group on Pancreatic Fistula (ISGPF) grading.19 The pathological diagnosis of pancreatic endocrine tumor was based on conventional histological and immunohistochemical examination (chromogranin A, synaptophysin, neuron-specific enolase) on surgical specimen. The Ki-67 proliferative index was expressed as a percentage that was based on the count of Ki-67-positive cells in 2000 tumor cells in areas of the highest immunostaining using the MIB1 antibody (DBA, Milan, Italy). All cases were further reviewed and classified according to the criteria of the World Health Organization (WHO) and staged according to the new tumor, node, metastasis system classification.20–22
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Patients’ follow-up was based on clinical, radiological, and laboratory assessments.23 Specific aims of long-term follow-up were to evaluate tumor recurrence and long-term endocrine and exocrine functions. The presence of newonset or worsening diabetes was demonstrated through serum glucose levels and oral glucose tolerance test.13 Worsening diabetes was defined as deterioration in the metabolic control of previously diagnosed diabetes, requiring modification of the medical treatment. New onset of exocrine insufficiency was defined as patients affected by steatorrhea and weight loss requiring oral pancreatic enzymes in absence of neoplastic recurrence. Data from some patients included in the present study have been included in prior publications of the two institutions.9,14,16 Statistical Analysis The Student t-test and Mann–Whitney test were applied to compare continuous data. The v2 and Fisher exact tests were used to compare categorical variables. A P value of \0.05 was considered statistically significant. Statistical analysis was performed with SPSS statistical software (SPSS 16.0, Chicago, IL). RESULTS A total of 50 patients were identified as having an NFPET who underwent PPRs consisting of enucleation in 26 patients and MP in 24. Overall, 31 patients were treated at the University of Verona and 19 at San Raffaele Hospital. Demographics and Clinical Characteristics The demographics and clinical characteristics of patients with NF-PETs are summarized in Table 1. Most patients were women (56%) with a median age of 59 years. Interestingly, the tumor was incidentally found in 58% of the cases. Among symptomatic patients, abdominal pain was the most frequent complaint. Main pancreatic duct dilatation was found in 16% of patients with NF-PETs. In all patients included in the present study, there was no preoperative suspicion of malignancy. Surgical Procedures and Postoperative Course Surgical variables and postoperative data of patients who underwent PPRs are shown in Table 2. No procedure was performed laparoscopically. Mortality was zero, and overall morbidity in the entire cohort (n = 50) was 58%. The most common complication was pancreatic fistula (50%), but clinically important pancreatic fistula—namely grade B–C fistula—were recorded in 12% of cases. Two
Parenchyma-Sparing Resections for NF-PETs
1623
Weight loss
4 (8%)
Bowel alterations
3 (6%)
patients (6%) had a well-differentiated nonfunctioning endocrine carcinoma, given the presence of lymph node metastases at final histological assessment. Table 3 shows the pathological features of the entire cohort. Positive resection margins were found in one patient (2%) who underwent MP to treat an NF-PET with uncertain behavior. The median size of the resected specimens was 13.5 mm (range 6–50 mm), with no statistically significant differences between patients who underwent enucleation (median 13.5 mm, range 6–50 mm) and those who underwent MP (median 14 mm, range 7–45 mm). Only eight patients (16%) had at least one lymph node removed (median 2.5 lymph nodes, range 1–9 lymph nodes); of these patients, four patients had a benign NF-PET, one patient an NF-PET with uncertain biological behavior, and the remaining three a well-differentiated nonfunctioning carcinoma.
Head-neck
17 (34%)
Long-Term Follow-up
Body-tail
33 (66%)
TABLE 1 Demographic and clinical characteristics of patients who underwent parenchyma-sparing resections for nonfunctioning pancreatic endocrine tumors Characteristic
Value
No. of patients
50
Sex, n (%) Female Male
27 (54%) 23 (46%)
Age (median) (y)
59
Preoperative diabetes, n (%)
3 (6%)
Incidental diagnosis, n (%)
29 (58%)
Symptoms, n (%) Abdominal pain
13 (26%)
Anorexia
1 (2%)
Tumor site, n (%)
Main pancreatic duct dilation, n (%)a
8 (16%)
Malignancy-related features (n)b
0
a
Main pancreatic duct diameter of [5 mm at high-resolution imaging b
Presence of locoregional or distant metastases, infiltration of peripancreatic vessels/viscera
patients required reoperation, and for the entire population, the median length of stay was 10.5 days (range 6–30 days). After MP, a pancreojejunostomy was performed in 18 cases, pancreogastrostomy was performed in 1 patient, and in the remaining 5 patients, a glue occlusion of the main pancreatic duct was carried out without any pancreatic anastomosis. Comparing enucleation and MP groups, length of surgery was longer in MP one (median 240 vs. 120 min, P = 0.001). Overall, 15 patients underwent intraoperative ultrasound, which was more frequently performed in enucleations than MPs (46% vs. 12.5%, P = 0.02). The rate of abdominal complications was higher in the MP group (70% vs. 38% P = 0.02). Patients who underwent MP had also a longer median length of stay in the hospital (13 vs. 9 days, P = 0.001). The rate of overall, grade A, and grade B–C pancreatic fistula, pancreatitis, hemorrhage, nonsurgical complication, abdominal collections, and reoperation did not differ statistically significantly between the two groups. Pathology We classified tumor according to WHO classification; overall, 34 patients (68%) had a benign tumor, 13 (26%) had an NF-PET of uncertain biological behavior, and 3
After a median follow-up of 58 months (range 12– 185 months, mean 70 months), two patients died of unrelated causes, while all the remaining 48 patients are alive. Overall, four patients (8%) developed tumor recurrence after a mean of 68 months. The first patient underwent MP for a benign NF-PET (pT1Nx, size 18 mm, Ki-67 1%, R0 resection) and experienced local recurrence in the head of the pancreas associated with a single liver metastasis 129 months after initial surgery. He underwent a further pancreaticoduodenectomy and radiofrequency ablation of the liver metastasis. The second patient had an NF-PET with uncertain biological behavior (pT1Nx, size 15 mm, Ki-67 3%, R0 resection) that was enucleated and developed liver metastases 86 months after initial surgery. No pancreatic recurrence was present. The third patient underwent MP for a well-differentiated nonfunctioning endocrine carcinoma (pT2N1, size 25 mm, Ki-67 8%, presence of angioinvasion, one metastatic node out of seven resected nodes, R0 resection). He developed multiple liver metastases 35 months after MP. The last two patients underwent transarterial chemoembolization of the liver. All these three patients are alive: one patients is free of disease, while the remaining two have stable metastatic disease. The fourth patient was treated with MP for a well-differentiated nonfunctioning endocrine carcinoma (pT1N1, size 12 mm, Ki-67 2%, two metastatic nodes out of two resected nodes, R0 resection). She developed lymph node metastases near the celiac trunk 21 months after initial surgery, and she underwent distal pancreatectomy, splenectomy, and extended lymphadenectomy. Regarding long-term functional follow-up, overall, four patients (8%) developed new exocrine insufficiency, and
1624 TABLE 2 Intraoperative data, postoperative course, and surgical complications of patients who underwent enucleation or middle pancreatectomy for nonfunctioning pancreatic endocrine tumors
M. Falconi et al.
Variable
Overall
Enucleation
Middle pancreatectomy
P
No. of patients
50
26
24
Median tumor size (mm)
13.5
13.5
14
NS
Median duration of surgery (min)
200
120
240
0.001
Intraoperative ultrasound, n (%)
15 (30%)
12 (46%)
3 (12.5%)
0.02
Patients requiring blood transfusions, n (%)
2 (4%)
0
2 (8%)
NS
Mortality, n
0
0
0
Overall morbidity, n (%)
29 (58%)
12 (46%)
17 (70%)
NS
Abdominal complications, n (%)
27 (54%)
10 (38%)
17 (70%)
0.02
Pancreatic fistula, n (%)
TABLE 3 Histopathological features of patients who underwent parenchyma-sparing resections for nonfunctioning pancreatic endocrine tumors
Overall
25 (50%)
10 (38%)
15 (62.5%)
NS
Grade A Grade B–C
19 (38%) 6 (12%)
7 (27.5%) 3 (11.5%)
12 (50%) 3 (12.5%)
NS NS
Grade B
4 (8%)
2 (7.5%)
2 (8%)
NS
Grade C
2 (4%)
1 (4%)
1 (4%)
NS
Pancreatitis, n (%)
3 (6%)
1 (4%)
2 (8%)
NS
Hemorrhage, n (%)
2 (4%)
1 (4%)
1 (4%)
NS
Abdominal collections, n (%)
6 (12%)
3 (11.5%)
3 (12.5%)
NS
Nonsurgical complications, n (%)
6 (12%)
3 (11.5%)
3 (12.5%)
NS
Median length of hospital stay (d)
10.5
9
13
0.001
Reoperation, n (%)
2 (4%)
1 (4%)
1 (4%)
NS
Variable
Benign tumor (n)
Tumor with uncertain behavior (n)
Carcinoma (n)
Overall (n)
No. of patients
34
13
3
50
Enucleation
16
9
1
26
Middle pancreatectomy
18
4
2
24
11.7
25.6
12, 25, and 40
16.4
B20 mm
34
6
1
41
[20 mm
9
Type of surgery
Tumor size (mm) Size
TNM tumor, node, metastasis system a
Two of these patients showed also microscopic neuroinvasion
b
Three patients had nodal metastases
c
According to Rindi et al.21
–
7
2
Mean Ki-67 value (%)
1.2
2.7
2, 2, and 8
1.9
Angioinvasion
–
4a
1
5
Metastases R1 resection
– –
– 1
–b –
2 1
pT1 N0-x (stage I)
34
5
–
39
pT2 N0-x (stage IIa)
–
7
–
7
pT3 N0-x (stage IIb)
–
2
–
2
pT1N1 (stage IIIa)
–
–
1
1
pT2N1 (stage IIIb)
–
–
2
2
TNM stagingc
another four (8%) developed new-onset or worsening diabetes. Exocrine insufficiency was detected only after MP (P = NS). Postoperative endocrine insufficiency was more frequent after MP than enucleation (3 patients, 12.5%, vs. 1 patient, 4%; P = NS).
DISCUSSION In the last decade, parenchyma-sparing techniques have gained increased interest in pancreatic surgery.15,24,25 Benign or low-grade malignant neoplasms of the pancreas
Parenchyma-Sparing Resections for NF-PETs
have been diagnosed more frequently.1,2 Therefore, the need for a proper treatment of these neoplasms has to be balanced with the risk of long-term impairment of the exocrine/endocrine function of the gland, which has a striking impact in patients treated for benign diseases who have a long life expectancy. We recently reported our experience with parenchyma-sparing resections (PPRs) of the pancreas, showing that these procedures are safe and effective for the treatment of well-selected benign or borderline tumors, and are associated with good long-term outcomes.9,13,14,16 In the setting of incidentally diagnosed pancreatic tumors, special attention should be reserved for endocrine tumors. These tumors provide a substantial challenge to clinicians because of their heterogeneity and their considerable prognostic variability.1–4 This is particularly true for nonfunctioning endocrine tumors (i.e., NF-PETs), which can express a benign to highly malignant biological behavior.3 PPRs have been proposed in the management of NF-PETs, especially when unexpected, small (B2 cm), well-demarcated neoplasms with no extrapancreatic disease are detected at imaging.3,15,26 Although for insulinomas, depending on the size and site of the lesions, the procedures of choice are enucleation and MP, the oncological effectiveness of PPRs in NF-PETs is still debated; large series with long-term follow-up are still lacking.10,11 Here we report what is to our knowledge the first study to evaluate perioperative and long-term outcomes in a large cohort of patients who underwent enucleation and MP for small-size NF-PETs. No patient included in the study had a preoperative suspicion of malignancy or MEN1 syndrome. In the setting of MEN1 syndrome, multifocal neoplasms are usually present, and current guidelines recommend surgical resection for lesions [2 cm in size, which usually require standard resection for the high risk of malignancy.23,27,28 Moreover, MEN1 patients are at higher risk of recurrence, given the presence of this inherited disorder.29 For these reasons, MEN1 patients were excluded. The results of the present study confirm that PPRs are surgical procedures associated with marked postoperative morbidity but good long-term functional results. In the entire cohort, 27 patients (54%) had an abdominal complication and 25 (50%) had pancreatic fistula, with a reoperation rate of 4%. Postoperative complications were more frequent in patients who underwent MP than enucleation. Remarkably, there was no postoperative mortality. In this light, performance of these procedures in high-volume centers with experience in pancreatic surgery is of paramount importance.30,31 After a median follow-up of approximately 5 years, four patients (8%) developed new exocrine insufficiency, and another four (8%) developed new-onset or worsening diabetes. Therefore, despite
1625
marked morbidity, PPRs can preserve good pancreatic function in long-term follow-up. In the present series, 58% of NF-PETs were incidentally discovered, and 82% of them had a size of B2 cm. The treatment of small and asymptomatic NF-PETs is controversial, also considering the marked morbidity that can be associated with surgical resection. Some authors suggest that for NF-PETs of B2 cm a nonoperative management can be considered, and surgical indication should be balanced with the operative mortality, morbidity, and longterm complications associated with pancreatic surgery.3,32 Others suggest that surgery is indicated in any case because NF-PETs should be always considered as potentially malignant tumors, and a proper histological examination of the tumor—including mitotic and Ki-67 indexes—is possible only on the resected specimen.3,20–22,33 According to the WHO classification of NF-PETs, tumor size correlates with the potential for malignancy, and localized tumor of [2 cm should preferentially be treated with standard pancreatic resections.3,20 Interestingly, Ferrone et al., who studied a cohort of 183 patients with pancreatic endocrine tumors (130 NF-PETs and 53 functioning neoplasms), reported that tumor size was not associated with the probability of nodes metastases and positive lymph nodes were identified in 5 (26%) of 19 patients with tumors B2 cm in diameter.34 In our experience, 1 (2.5%) of 41 patients with NF-PETs with a size of B2 cm and 2 (22%) of 9 patients with NF-PETs with a size of [2 cm had a carcinoma. Therefore, the risk of malignancy cannot be excluded even in small NF-PETs, and in our opinion, surgical resection has to be considered in all surgically fit patients. At present, no consensus exists on the type of pancreatic resection when NF-PET is B2 cm in size. A possible option for small NF-PETs with benign radiological features may be a parenchyma-sparing resection. NF-PETs patients included in this study have been treated according to this strategy and were equally submitted to enucleation (52%) or MP (48%). Most of the lesions were benign (68%) or tumors with uncertain behavior (26%). Surprisingly, despite the careful preoperative workup, histological examination of the surgical specimens showed the presence of a well-differentiated carcinoma in the remaining three patients (6%), with lymph node metastases in the peripancreatic nodes. Despite intraoperative examination of the surgical margins, one patient with NF-PET who underwent MP had R1 status after definitive histological examination. During follow-up, after a mean of 70 months from surgery, four patients experienced tumor recurrence. All the patients had an NF-PET with R0 resection. As of this writing, the patient who underwent R1 resection did not develop tumor recurrence, and he is under strict follow-up. Interestingly, the first patient had a pT1Nx NF-PET that
1626
was classified as benign tumor according to the WHO criteria, and he developed local recurrence and liver metastasis 129 months after his MP. It is likely that in this case, a metachronous primary pancreatic endocrine carcinoma developed; however, genetic evaluation was negative for MEN1 syndrome. The remaining three patients had NFPETs with uncertain biological behavior or well-differentiated carcinoma, and they developed nodal or liver metastases but no local recurrence. In this light, the appropriate management of patients with an unexpected postoperative diagnosis of NF-PET carcinoma after PPRs is uncertain. Therapeutic strategies can range from strict follow-up to reoperation with standard pancreatic resection to be performed within a few weeks after previous surgery. Patients should be informed of these different scenarios, and their willingness to undergo strict follow-up or reoperation must be taken into account. In our opinion, reoperation should be recommended in all surgically fit patients, especially in young or middle-aged patients with a long life expectancy. However, of the patients with NF-PET carcinoma whose disease recurred, repeat resection would have probably avoided tumor recurrence only in the patient with nodal recurrence, but not in the patient who had only liver metastases. Finally, the possibility of tumor recurrence must also be considered in NF-PETs with benign or uncertain biological behavior, considering that in our experience, recurrence occurred after a mean of 68 months from surgery, and long-term follow-up ([5 years) has to be carried out in all patients. However, it could be also argued that the lack of nodal samples led to an erroneous pathological diagnosis in some cases. This latter consideration raises the concern that PPRs may lack adequate lymph node sampling and evaluation.3 Therefore, the benefits of parenchyma-sparing operations should be balanced with the benefits of the prognostic information obtained with nodal assessment and the risk of potential inadequate resection.34,35 In this study, only 8 (16%) of 50 patients with NF-PETs had at least one lymph node removed. In these eight patients, lymph nodes located near the pancreatic lesion were removed during parenchyma-sparing procedures. Even though there was no suspicion of malignancy in any case, nevertheless, the absence of lymph node histological examination may result in the disease of some patients being understaged. Therefore, we propose that whenever PPRs are performed, lymph node sampling of peripancreatic nodes should be always performed to increase the effectiveness of these procedures. An intraoperative examination of the lymph nodes— as well as that of the surgical margins—is of paramount importance. In cases of positive lymph nodes, standard pancreatic resection must be performed. In conclusion, PPRs are generally safe procedures for the treatment of small (B2 cm) NF-PETs without overt
M. Falconi et al.
malignant features. However, considering a recurrence rate of 8%, better selection criteria must be identified. In this setting, sampling of lymph nodes, and possibly their intraoperative frozen examination, should be performed in all cases to avoid understaging. Reoperation should be considered in all patients with an unexpected postoperative diagnosis of carcinoma. ACKNOWLEDGMENT This study was supported by Fondazione Italiana Malattie Pancreas (FIMP), Verona, Italy.
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1627 28. Triponez F, Goudet P, Dosseh D, et al. Is surgery beneficial for MEN1 patients with small (\ or =2 cm), nonfunctioning pancreaticoduodenal endocrine tumor? An analysis of 65 patients from the GTE. World J Surg. 2006;30:654–62. 29. Gauger PG, Doherty GM, Broome JT, Miller BS, Thompson NW. Completion pancreatectomy and duodenectomy for recurrent MEN-1 pancreaticoduodenal endocrine neoplasms. Surgery. 2009;146:801–6. 30. Balzano G, Zerbi A, Capretti G, et al. Effect of hospital volume on outcome of pancreaticoduodenectomy in Italy. Br J Surg. 2008; 95:357–62. 31. Birkmeyer JD, Stukel TA, Siewers AE, et al. Surgeon volume and operative mortality in the United States. N Engl J Med. 2003; 349:2117–27. 32. Solorzano CC, Lee JE, Pisters PW, et al. Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients. Surgery. 2001;130:1078–85. 33. Vilar E, Salazar R, Pe´rez-Garcı´a J, et al. Chemotherapy and role of the proliferation marker Ki-67 in digestive neuroendocrine tumors. Endocr Relat Cancer. 2007;14:221–32. 34. Ferrone CR, Tang LH, Tomlinson J, et al. Determining prognosis in patients with pancreatic endocrine neoplasms: can the WHO classification system be simplified? J Clin Oncol. 2007;25: 5609–15. 35. Reber HA. Middle pancreatectomy: why I rarely do it. J Gastrointest Surg. 2007;11:726–9.
