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Surgery_Schwartz. every time. The duct-to-mucosa anastomosis results in a low pancreatic fistula rate, particularly in patients with a large pancreatic duct and a fibrotic pancreas.354Use of a pancreatic duct stent across the anastomosis has been suggested as a means of preventing a pancreatic leak and as an aid in technical precision. Both internal stenting as well as external stenting have been practiced. A recent Cochrane analysis of eight randomized, controlled trials failed to iden-tify any convincing evidence of benefit with internal or external pancreatic duct stents.355 Some previous studies indicated that stents might be harmful. A recent multicenter randomized trial comparing external to internal pancreatic duct stents during pan-creaticoduodenectomy showed a lower rate of pancreatic fistula with internal stents, so this controversy is likely to continue.356Reconstruction with an isolated Roux-en-Y pancreatico-enteric anastomosis has been suggested as a method do decrease postoperative


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Surgery_Schwartz. with internal stents, so this controversy is likely to continue.356Reconstruction with an isolated Roux-en-Y pancreatico-enteric anastomosis has been suggested as a method do decrease postoperative pancreatic leak.357-358 The logic behind this tech-nical modification is that the use of separate Roux-en-Y limbs for biliary and pancreatic secretions may protect the pancreatic anastomosis from activated pancreatic enzymes. However, data is limited, and this is not a common practice.Avoiding the pancreatic anastomosis altogether by ductal ligation or occlusion has also been evaluated as a potential technique to reduce the rate of postoperative pancreatic fistula.359-360 Ductal occlusion with neoprene or prolamine, which are nonresorbable glues, has been abandoned due to pancreatic atrophy and loss of exocrine function. Duct occlusion in pancreaticojejunostomy significantly increases the risk of endocrine insufficiency without a decrease in the postoperative complication rate. To avoid


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Surgery_Schwartz. and loss of exocrine function. Duct occlusion in pancreaticojejunostomy significantly increases the risk of endocrine insufficiency without a decrease in the postoperative complication rate. To avoid long-term loss of function, absorbable glues, such as fibrin glue, have been evaluated to limit the action of pancreatic enzymes until the anastomosis is healed. Fibrin glue has been used for both duct occlusion and has also been applied to the surface of the pancreatic stump and anastomotic site without clear improvement in pancreatic fistula rate. The effect of BioGlue applied to the anastomotic surface after the Whipple procedure and pancreatic stump after distal pancreatectomy was evaluated in a retrospective cohort study. There were no statistically significant differences in the incidence or severity grades of postoperative pancreatic fistulas.361 A randomized prospective trial of application of fibrin glue to the surface of the pancreaticojejunostomy in high-risk patients did not


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Surgery_Schwartz. or severity grades of postoperative pancreatic fistulas.361 A randomized prospective trial of application of fibrin glue to the surface of the pancreaticojejunostomy in high-risk patients did not reduce the incidence of pancreatic fistula or total complications after pancreaticoduodenectomy.362If not combined with a biliary leak, pancreatic fistula, although serious, can usually be managed conservatively. In about 95% of cases, reoperation is not indicated, and prolonged drainage, using drains placed in the original operation or percu-taneously after resection, results in spontaneous closure of the fistula.363Hemorrhage can occur either intraoperatively or postop-eratively. Intraoperative hemorrhage typically occurs during the dissection of the portal vein. A major laceration of the portal vein can occur at a point in the operation at which the portal vein is not yet exposed. Temporary control of hemorrhage is gener-ally possible in this situation by compressing the portal vein and


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Surgery_Schwartz. vein can occur at a point in the operation at which the portal vein is not yet exposed. Temporary control of hemorrhage is gener-ally possible in this situation by compressing the portal vein and superior mesenteric vein against the tumor with the surgeon’s left hand behind the head of the pancreas. An experienced assis-tant is needed to divide the neck of the pancreas to the left of the portal vein and achieve proximal and distal control. Sometimes, the vein can be sutured closed with minimal narrowing. Other times, a segmental resection and interposition graft (internal jugular vein) may be needed.Postoperative hemorrhage can occur from inadequate liga-ture of any one of numerous blood vessels during the procedure. Brunicardi_Ch33_p1429-p1516.indd 149701/03/19 6:46 PM 1498SPECIFIC CONSIDERATIONSPART IIHemorrhage can also occur due to digestion of retroperitoneal blood vessels due to a combined biliary-pancreatic leak. Uncom-monly, a stress ulcer, or later, a marginal ulcer, can


Surgery_Schwartz

Surgery_Schwartz. can also occur due to digestion of retroperitoneal blood vessels due to a combined biliary-pancreatic leak. Uncom-monly, a stress ulcer, or later, a marginal ulcer, can result in GI hemorrhage. Typically, a vagotomy is not performed when pan-creaticoduodenectomy is performed for pancreatic cancer, but patients are placed on proton pump inhibitors.Outcome and Value of Pancreaticoduodenectomy for Cancer. Survival figures indicate that perhaps few patients are cured indefinitely of pancreatic cancer with pancreaticoduode-nectomy. This has led to a nihilistic view toward patients with this disease which has further contributed to poor outcomes. Using the National Cancer Data Base (1995–2004), Bilimoria reported on 9559 patients with early stage potentially resect-able tumors (pretreatment clinical Stage I: T1N0M0 and T2N0M0).364 Multivariate models were employed to identify factors predicting failure to undergo surgery and assess the impact of pancreatectomy on survival. This study


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Surgery_Schwartz. clinical Stage I: T1N0M0 and T2N0M0).364 Multivariate models were employed to identify factors predicting failure to undergo surgery and assess the impact of pancreatectomy on survival. This study identified a striking underuse of pancreatectomy in the United States. Of clinical stage I patients, 71.4% (6823/9559) did not undergo surgery; 6.4% (616/9559) were excluded due to comorbidi-ties; 4.2% (403/9559) refused surgery; 9.1% (869/9559) were excluded due to age; and 38.2% (3644/9559) with potentially resectable cancers were not offered surgery. Patients were less likely to undergo surgery if they were older than 65 years, were black, were on Medicare or Medicaid, had pancreatic head lesions, earned lower annual incomes, or had less education. Patients were less likely to receive surgery at low-volume and community centers. Patients who were not offered surgery had worse survival than patients who underwent resection. Over-all survival from PDAC would significantly increase if more


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Surgery_Schwartz. at low-volume and community centers. Patients who were not offered surgery had worse survival than patients who underwent resection. Over-all survival from PDAC would significantly increase if more patients with stage I tumors were identified and offered surgery at high-volume centers (Fig. 33-76).Although pancreaticoduodenectomy may be performed with the hope of the rare cure in mind, the operation more importantly provides better palliation than any other treatment, and it is the only modality that offers any meaningful improve-ment in survival. If the procedure is performed without major complications, many months of palliation are usually achieved. However, it is the surgeon’s duty to make sure patients and their families have a realistic understanding of the true goals of pan-creaticoduodenectomy in the setting of pancreatic cancer.Adjuvant Chemotherapy and Radiation. Small studies in the 1980s suggested that adjuvant chemotherapy with 5-FU combined with radiation improves


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Surgery_Schwartz. in the setting of pancreatic cancer.Adjuvant Chemotherapy and Radiation. Small studies in the 1980s suggested that adjuvant chemotherapy with 5-FU combined with radiation improves survival by about 9 months after pancreatic resection for pancreatic adenocarcinoma.365 Subsequent, noncontrolled studies have reinforced that concept; however, the data have been criticized due to the low number of patients and low dose of radiation therapy that was given. In addition, gemcitabine has replaced 5-FU as standard therapy in pancreatic cancer but is thought to be too toxic when given with radiotherapy without dose reduction. A recent large European multicenter trial concluded that there was no value to chemo-radiotherapy, although the study suggested the possibility that chemotherapy alone might have survival benefit.366 Random-ized trials have failed to resolve the debate regarding the role of adjuvant radiation therapy in resectable pancreas cancer. A reasonable consideration in a disease


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Surgery_Schwartz. have survival benefit.366 Random-ized trials have failed to resolve the debate regarding the role of adjuvant radiation therapy in resectable pancreas cancer. A reasonable consideration in a disease with high rates of distant metastases is to begin with adjuvant chemotherapy, followed by radiation therapy in patients who do not progress, particularly in patients where there may be increased concern about local recurrence such as in patients with close margins.Remarkable results in adjuvant therapy were reported by the Virginia Mason Clinic with combination 5-FU, cisplatinum, interferon-〈, and external beam radiation.367 Although the toxic-ity was high (42% hospitalized for GI toxicity), the promising results prompted larger confirmatory studies. Unfortunately, one such study was stopped due to toxicity, and this protocol has not been widely adopted. More recent results with FOLFIRINOX in the setting of metastatic disease have encouraged clinical tri-als using this regimen in the


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Surgery_Schwartz. due to toxicity, and this protocol has not been widely adopted. More recent results with FOLFIRINOX in the setting of metastatic disease have encouraged clinical tri-als using this regimen in the adjuvant setting, which are cur-rently underway (ClinicalTrials.gov identifier: NCT02172976). Nevertheless, pending further study, it is typical in the United States for patients with acceptable functional status to receive some form of adjuvant chemotherapy and sometimes chemora-diotherapy after surgery.Neoadjuvant Treatment. There are several potential advan-tages to the use of chemotherapy or chemoradiation before an attempt at surgical resection. For example, it avoids the risk that adjuvant treatment is delayed by complications of surgery. Neoadjuvant treatment also may decrease the tumor burden at operation, increasing the rate of resectability and killing some tumor cells before they can be spread intraoperatively. Another potential advantage is that it allows patients with occult


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Surgery_Schwartz. burden at operation, increasing the rate of resectability and killing some tumor cells before they can be spread intraoperatively. Another potential advantage is that it allows patients with occult meta-static disease to avoid the morbidity of pancreatic resection. As many as 20% of patients treated with neoadjuvant chemoradia-tion develop metastatic disease detected by restaging CT and do not go on to surgery. This approach may separate patients into a subset likely to benefit from resection and a subset in whom sur-gery would be unlikely to provide clinical benefit. Preoperative chemoradiation has been shown not to increase the periopera-tive morbidity or mortality of pancreaticoduodenectomy. It may even decrease the incidence of pancreatic fistula. Prospective randomized trials investigating this concept are ongoing but are difficult to complete due to the high number of patients who fail to complete or receive a full course of either therapy. Studies have shown that neoadjuvant


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Surgery_Schwartz. this concept are ongoing but are difficult to complete due to the high number of patients who fail to complete or receive a full course of either therapy. Studies have shown that neoadjuvant therapy is associated with a lower rate of lymph node positivity and improved survival is achieved among the patients who do not develop disease progression dur-ing neoadjuvant therapy and go on to resection. Neoadjuvant therapy should be considered an acceptable alternative to sur-gery first followed by adjuvant therapy for resectable pancre-atic cancer. Patients should be encouraged to consider available 000.20.40.6Cause-specific survival0.81.0Performed, med. survival = 36 months (N = 724)Refused, med. survival = 7 months (N = 82)1020304050Months60708090Figure 33-76. Effect of surgery on survival in early stage pan-creas cancer. Survival comparison for cases (combined stages IA and IB) for which resection was recommended, and resection was either performed or refused. (Reproduced with


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Surgery_Schwartz. in early stage pan-creas cancer. Survival comparison for cases (combined stages IA and IB) for which resection was recommended, and resection was either performed or refused. (Reproduced with permission from Chiari ST, Kelly K, Hollingsworth MA, et al. Early detection of sporadic pancreatic cancer: summative review, Pancreas. 2015 Jul;44(5):693-712.)Brunicardi_Ch33_p1429-p1516.indd 149801/03/19 6:46 PM 1499PANCREASCHAPTER 33clinical trials of neoadjuvant therapy for resectable pancreatic cancer.368 Unfortunately, a recent trial attempting to random-ize patients with resectable pancreatic cancer to neoadjuvant versus adjuvant therapy failed to demonstrate an advantage for the neoadjuvant approach. However, the study was inconclu-sive because it was stopped after 73 of a planned 254 patients due to slow accrual, with only 66 eligible for analysis. Other trials are ongoing. The NEOPA trial (ClinicalTrials.gov iden-tifier: NCT01900327) is a prospectively randomized phase 3 trial of


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Surgery_Schwartz. due to slow accrual, with only 66 eligible for analysis. Other trials are ongoing. The NEOPA trial (ClinicalTrials.gov iden-tifier: NCT01900327) is a prospectively randomized phase 3 trial of patients receiving neoadjuvant chemoradiation followed by curative surgery vs. primary surgery followed by adjuvant therapy with a primary endpoint of 3-year overall survival.369Most pancreatic surgeons agree that neoadjuvant chemo-therapy, and perhaps chemoradiotherapy, should be offered to patients with locally advanced but resectable disease (vein involvement) and to patients with “borderline resectable dis-ease” (abutment of ≤180 degrees of the circumference of the SMA, celiac axis, or hepatic artery or if there is a short segment of vein occlusion, CT findings suspicious for metastatic disease, like 1 mm liver lesions too small to characterize or biopsy, and patients with multiple comorbidities or marginal performance status). This strategy acknowledges the fact that these patients are at


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Surgery_Schwartz. like 1 mm liver lesions too small to characterize or biopsy, and patients with multiple comorbidities or marginal performance status). This strategy acknowledges the fact that these patients are at high risk of early distant recurrence and/or R1 resection with early local recurrence. Neoadjuvant treatment helps select the right patients for surgery and may reduce the incidence of a margin positive resection.Postoperative Surveillance. Recurrence after successful resection usually manifests as hepatic metastases. Adjuvant che-motherapy with or without radiation is usually administered for 6 months. During this time period, patients are monitored with frequent physical examinations and laboratory tests, including CA19-9. CT scans are typically ordered every 3 months in the first 2 years after resection or when a rising CA19-9 or new symptoms suggest recurrence. Surgical therapy for recurrent disease is usually reserved only for select patients with lim-ited disease who remain reasonable


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Surgery_Schwartz. resection or when a rising CA19-9 or new symptoms suggest recurrence. Surgical therapy for recurrent disease is usually reserved only for select patients with lim-ited disease who remain reasonable operative candidates who develop symptomatic gastric outlet or bowel obstruction.Ampullary and Periampullary Cancer. Ampullary cancers need to be distinguished from periampullary cancers. The ampulla is the junction of the biliary and pancreatic ducts within the duodenum. Periampullary cancer includes tumors arising from the distal bile duct, duodenal mucosa, or pancreas just adjacent to the ampulla, and the ampulla can be overgrown by cancers that arise from these adjacent areas, making it impos-sible to determine the true site of origin. Clinically, the term periampullary cancer is, therefore, a nonspecific term used to refer to a variety of tumors arising at the intersection of these four sites. The term ampullary cancer is more specific and is reserved for tumors that arise at the


Surgery_Schwartz

Surgery_Schwartz. a nonspecific term used to refer to a variety of tumors arising at the intersection of these four sites. The term ampullary cancer is more specific and is reserved for tumors that arise at the ampulla. Based on their location, ampullary cancers are usually detected relatively early due to the appearance of jaundice and have a more favorable prognosis. The ampulla of Vater is lined by an epithelial layer that transitions from pancreatic and biliary ductal epithelium to duodenal mucosal epithelium. Ampullary adenocarcinomas can therefore have an intestinal and/or pancreaticobiliary his-tologic morphology, with the former having a better progno-sis. Patients with ampullary cancer have a 10-year survival of about 35%, which is a much better prognosis than patients with pancreatic adenocarcinoma. The difference in survival is not entirely explained by an earlier presentation and lower inci-dence of lymph node metastases. There are biologic, particularly molecular, differences between


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Surgery_Schwartz. The difference in survival is not entirely explained by an earlier presentation and lower inci-dence of lymph node metastases. There are biologic, particularly molecular, differences between ampullary and pancreatic adenocarcinoma of the pancreas.370 Intestinal type ampullary cancers have a lower incidence of EGFr and mutant p53 over-expression, and fewer activating K-ras mutations. These tumors are more likely to have genetic changes similar to colon cancer such as microsatellite instability and adenomatous polyposis coli mutations.Management of Periampullary Adenomas. Benign tumors such as ampullary adenomas can also originate at the ampulla. The accuracy of endoscopic biopsy in distinguishing ampullary cancer from benign adenoma is poor, with false-negative rates from 25% to 56% even if sphincterotomy precedes the biopsy. However, benign villous adenomas of the ampullary region can be excised locally. This technique is applicable only for small tumors (approximately 2 cm or less)


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Surgery_Schwartz. if sphincterotomy precedes the biopsy. However, benign villous adenomas of the ampullary region can be excised locally. This technique is applicable only for small tumors (approximately 2 cm or less) with no evidence of malig-nancy upon biopsy. EUS may help to accurately determine if there is invasion into the duodenal wall. In the absence of inva-sion, adenomas may be amenable to an endoscopic or trans-duodenal excision. A longitudinal duodenotomy is made and the tumor is excised with a 2to 3-mm margin of normal duo-denal mucosa. In some centers, small periampullary adenomas can also be removed endoscopically. A preoperative diagnosis of cancer is a contraindication to transduodenal excision, and pancreaticoduodenectomy should be performed. Likewise, if final pathologic examination of a locally excised tumor reveals invasive cancer, the patient should be returned to the operat-ing room for a pancreaticoduodenectomy. An important sub-set of patients are those with FAP who develop


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Surgery_Schwartz. a locally excised tumor reveals invasive cancer, the patient should be returned to the operat-ing room for a pancreaticoduodenectomy. An important sub-set of patients are those with FAP who develop periampullary or duodenal adenomas. These lesions have a high incidence of harboring carcinoma and frequently recur unless the mucosa at risk is resected. A standard (not pylorus-sparing) Whipple is the procedure of choice in FAP patients with periampullary lesions.Cystic Neoplasms of the Pancreas. A cystic neoplasm needs to be considered when a patient presents with a fluid-containing pancreatic lesion. Asymptomatic cystic neoplasms of the pancreas may be more frequent than previously recognized and are being identified with increasing frequency as the use of abdominal CT scanning and MRI has increased. Pancreatic cysts are now thought to be present in about 9% of the popula-tion age 80 and older.371 When symptoms are clearly attributable to a pancreatic cyst, resection is indicated in


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Surgery_Schwartz. increased. Pancreatic cysts are now thought to be present in about 9% of the popula-tion age 80 and older.371 When symptoms are clearly attributable to a pancreatic cyst, resection is indicated in patients who are fit candidates for surgery. However, management of asymp-tomatic pancreatic cysts is nuanced and can trigger significant anxiety for patients and their surgeons. Invasive surveillance and aggressive surgical intervention can cause harm, decrease quality of life, and increase costs. While the overall risk that an incidental pancreatic cyst is malignant is very low (about 1 in 10,000), the risks of surgery are very significant with a 2% to 5% mortality and 30% to 40% morbidity. However, some of these neoplasms slowly undergo malignant transformation and thus represent an opportunity for surgical cure, which is uncom-mon after transformation to invasive pancreatic adenocarci-noma. The dilemma for the surgeon is to identify the minority of cysts that pose a significant risk and


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Surgery_Schwartz. for surgical cure, which is uncom-mon after transformation to invasive pancreatic adenocarci-noma. The dilemma for the surgeon is to identify the minority of cysts that pose a significant risk and provide individual patients with an accurate assessment of their unique risk-benefit ratio of resection vs. surveillance.Surveillance programs are of questionable value in patients who are not candidates for surgery due to age and or multiple comorbidities and limited life expectancy. Surgeons also need to clearly explain to the patient the risks and benefits of surveil-lance itself. MRI is the preferred surveillance imaging modality Brunicardi_Ch33_p1429-p1516.indd 149901/03/19 6:46 PM 1500SPECIFIC CONSIDERATIONSPART IIover computed tomography because MRI does not expose the patient to radiation and better demonstrates the structural rela-tionship between the pancreatic duct and associated cyst. Also, MRI is less invasive than EUS. EUS is therefore reserved for further evaluation of


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Surgery_Schwartz. and better demonstrates the structural rela-tionship between the pancreatic duct and associated cyst. Also, MRI is less invasive than EUS. EUS is therefore reserved for further evaluation of higher risk cysts. Another problem to con-front is when to stop surveillance in a cyst that has been stable during observation. Some clinicians stop following after 5 years but data is lacking to guide this decision. In addition, patients who have undergone resection of a pancreatic cystic neoplasm with high grade dysplasia may warrant continued surveillance after surgery particularly when there is a possible field effect such as in IPMN or concern that all of the disease has not been resected. Individualized decision-making and multidisciplinary input is ideal.372Pseudocysts. The most common cystic lesion of the pancreas is the pseudocyst, which, of course, has no epithelial lining and is a nonneoplastic complication of pancreatitis or pancreatic duct injury. As discussed in “Complications of


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Surgery_Schwartz. lesion of the pancreas is the pseudocyst, which, of course, has no epithelial lining and is a nonneoplastic complication of pancreatitis or pancreatic duct injury. As discussed in “Complications of Chronic Pancreatitis,” the diagnosis is usually straightforward from the clinical history. Although not usually necessary, analysis of pseudocyst fluid would reveal a high amylase content. The danger comes in mistaking a cystic pancreatic neoplasm for a pseudocyst and incorrectly draining a cystic neoplasm into the GI tract rather than resecting the neoplasm. For this reason, biopsy of the pseudocyst wall is a requirement in the management of pancreatic pseudocysts.Cystadenoma. Serous cystadenomas are essentially considered benign tumors without malignant potential. Serous cystadenocarcinoma has been reported very rarely (<1%). Therefore, malignant potential should not be used as an argument for surgical resection, and the majority of these lesions can be safely observed in the absence of


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Surgery_Schwartz. been reported very rarely (<1%). Therefore, malignant potential should not be used as an argument for surgical resection, and the majority of these lesions can be safely observed in the absence of symptoms due to mass effect or rapid growth. The average rate of growth is about 0.5 cm per year. About 50% of cystadenomas are asymptomatic and detected as an incidental finding. Most symptomatic patients have mild upper abdominal pain, epigastric fullness, or moderate weight loss. Occasionally, cystadenomas can grow to a size capable of producing jaundice or GI obstruction due to mass effect (Fig. 33-77). For symptomatic patients with serous cystadenoma, surgical resection is indicated. For lesions in the tail, splenectomy is not necessary, given the benign nature of the tumor. In appropriate candidates, a laparoscopic approach to distal pancreatectomy with or without splenic preservation can be considered. These cysts are frequently found in older women in which pancreatic resection for


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Surgery_Schwartz. candidates, a laparoscopic approach to distal pancreatectomy with or without splenic preservation can be considered. These cysts are frequently found in older women in which pancreatic resection for a benign neoplasm should be avoided in the absence of significant symptoms. All regions of the pancreas are affected, with half in the head/uncinate process, and half in the neck, body, or tail of the pancreas. They have a spongy appearance, and multiple small cysts (microcystic) are more common than larger cysts (macrocystic or oligocystic). These lesions contain thin serous fluid that does not stain positive for mucin and is low in CEA (<200 ng/mL). Typical imaging characteristics include a well-circumscribed cystic mass, small septations, fluid close to water density, and sometimes, a central scar with calcification. If a conservative management is adopted, it is important to be sure of the diagnosis. EUS-FNA should yield nonviscous fluid with low CEA and amylase levels, and if cells


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Surgery_Schwartz. scar with calcification. If a conservative management is adopted, it is important to be sure of the diagnosis. EUS-FNA should yield nonviscous fluid with low CEA and amylase levels, and if cells are obtained, which is rare, they are cuboidal and have a clear cytoplasm.Mucinous Cystadenoma and Cystadenocarcinoma. Muci-nous cystic neoplasms (MCNs) encompass a spectrum ranging from benign but potentially malignant to carcinoma with a very aggressive behavior (Table 33-23). There is often heterogene-ity within the lesions with benign and malignant-appearing regions, making it impossible to exclude malignancy with biopsy. MCNs are commonly seen in perimenopausal women, and about two-thirds are located in the body or tail of the pan-creas. Like cystadenomas, most MCNs are now incidental find-ings identified during imaging performed for other reasons. When symptoms are present, they are usually nonspecific and include upper abdominal discomfort or pain, early satiety, and weight loss. On


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Surgery_Schwartz. identified during imaging performed for other reasons. When symptoms are present, they are usually nonspecific and include upper abdominal discomfort or pain, early satiety, and weight loss. On imaging studies, the cysts have thick walls and do not communicate with the main pancreatic duct (Fig. 33-78). There may be nodules or calcifications within the wall of the cyst. The cysts are lined by tall columnar epithelium that fills the cyst with viscous mucin. The submucosal layer consists of a highly cellular stroma of spindle cells with elongated nuclei similar to the “ovarian stroma,” which is a key pathologic feature distinguishing these lesions. Elevated CEA levels in the fluid (≥200 ng/mL) are consistent with mucinous lesions and may suggest malignant transformation.373 Solid areas may con-tain atypical cells or invasive cancer, and extensive sampling of the specimen is necessary to accurately predict prognosis. Figure 33-77. Mucinous cystic neoplasm in tail of pancreas.Table


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Surgery_Schwartz. may con-tain atypical cells or invasive cancer, and extensive sampling of the specimen is necessary to accurately predict prognosis. Figure 33-77. Mucinous cystic neoplasm in tail of pancreas.Table 33-23World Health Organization classification of primary tumors of the exocrine pancreas A. Benign 1. Serous cystadenoma (16%) 2. Mucinous cystadenoma (45%) 3. Intraductal papillary-mucinous adenoma (32%) 4. Mature cystic teratoma B. Borderline 1. Mucinous cystic tumor with moderate dysplasia 2. Intraductal papillary mucinous tumor with moderate dysplasia 3. Solid pseudopapillary tumor C. Malignant 1. Ductal adenocarcinoma 2. Serous/mucinous cystadenocarcinoma (29%) 3. Intraductal mucinous papillary tumorBrunicardi_Ch33_p1429-p1516.indd 150001/03/19 6:46 PM 1501PANCREASCHAPTER 33NoYes<1 cm1–2 cm2–3 cm>3 cmNoNoa. Pancreatitis may be an indication for surgery for relief of symptoms.b. Differential diagnosis includes mucin. Mucin can move with change in patient position, may be dislodged


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Surgery_Schwartz. cm2–3 cm>3 cmNoNoa. Pancreatitis may be an indication for surgery for relief of symptoms.b. Differential diagnosis includes mucin. Mucin can move with change in patient position, may be dislodged oncyst lavage and does not have Doppler ’ow. Features of true tumor nodule include lack of mobility, presence ofDoppler ’ow and FNA of nodule showing tumor tissuec. Presence of any one of thickened walls, intraductal mucin or mural nodules is suggestive of main ductinvolvement. In their absence main duct involvement is inconclusive.d. Studies from Japan suggest that on follow-up of subjects with suspected BD-IPMN there is increased incidenceof pancreatic ductal adenocarcinoma unrelated to malignant transformation of the BD-IPMN(s) being followed.However, it is unclear if imaging surveillance can detect early ductal adenocarcinoma, and, if so, at what intervalsurveillance imaging should be performed.Are any of the following high-risk stigmata of malignancy present?i) obstructive jaundice in a


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Surgery_Schwartz. detect early ductal adenocarcinoma, and, if so, at what intervalsurveillance imaging should be performed.Are any of the following high-risk stigmata of malignancy present?i) obstructive jaundice in a patient with cystic lesion of the head of the pancreas,ii) enhancing solid component within cyst, iii) main pancreatic duct ‰10 mm in sizeAre any of the following worrisome features present?Clinical: PancreatitisaImaging: i) cyst ‰3 cm, ii) thickened/enhancing cyst walls, iii) main duct size 5–9 mm, iii) non-enhancingmural nodule iv) abrupt change in caliber of pancreatic duct with distal pancreatic atrophy.What is the size of largest cyst?InconclusiveIf yes, perform endoscopic ultrasoundConsidersurgery,if clinicallyappropriateAre any of these features present?i) Deÿnite mural nodule(s)bii) Main duct features suspicious for involvementciii) Cytology: suspicious or positive for malignancyCT/MRIin 2–3 yearsdCT/MRIyearly × 2 years,then lengthenintervalif no changedEUS in 3–6 months,


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Surgery_Schwartz. Main duct features suspicious for involvementciii) Cytology: suspicious or positive for malignancyCT/MRIin 2–3 yearsdCT/MRIyearly × 2 years,then lengthenintervalif no changedEUS in 3–6 months, thenlengthen interval alternating MRIwith EUS as appropriate.dConsider surgery in young,ÿt patients with need forprolonged surveillanceClose surveillance alternatingMRI with EUS every 3–6 months.Strongly consider surgery in young,ÿt patientsYesFigure 33-78. Algorithm for management of pancreatic cystic neoplasms. CEA = carcinoembryonic antigen; CT = computed tomography; ERCP = endoscopic retrograde cholangiopancreatography; EUS = endoscopic ultrasound; FNA = fine-needle aspiration; Hx = history; IPMN = intraductal papillary mucinous neoplasm of the pancreas; MCN = mucinous cystic neoplasm; MRCP = magnetic resonance cholangiopancreatography. (Reproduced with permission from Tanaka M, Adsay V, Chari S, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the


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Surgery_Schwartz. = magnetic resonance cholangiopancreatography. (Reproduced with permission from Tanaka M, Adsay V, Chari S, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas, Pancreatology. 2012 May-Jun;12(3):183-197.)Resection is the treatment of choice for most mucin-producing cystic tumors. Malignancy cannot be ruled out without removal and extensive sampling of the entire tumor. Malignancy has been reported in 6% to 36% of MCNs. Current thinking is that all of these tumors will eventually evolve into cancer if left untreated. However, for individual patients, the surgeon is often faced with a difficult decision. The risk of pancreas surgery in an older patient with multiple comorbidities and a relatively short life expectancy regardless of their pancreatic cyst is frequently weighed against the potential future risk that the cyst, particularly a small cyst, will transform into an incurable invasive cancer.The utility of detailed DNA analysis of


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Surgery_Schwartz. cyst is frequently weighed against the potential future risk that the cyst, particularly a small cyst, will transform into an incurable invasive cancer.The utility of detailed DNA analysis of pancreatic cyst fluid to diagnose mucinous and malignant cysts has been evalu-ated in the PANDA study.374 The study concluded that cyst fluid K-ras mutation was helpful in the diagnosis of mucinous cysts with a 96% specificity. Components of DNA analysis detect-ing malignant cysts included allelic loss amplitude over 82% and high DNA amount. The criteria of high amplitude K-ras mutation followed by allelic loss showed maximum specificity (96%) for malignancy. However, this test lacks sensitivity. In clinical practice, the surgeon must take all of these complemen-tary factors into consideration when determining the malignant potential of a pancreatic cystic neoplasm.Because most MCNs are located in the body and tail of the pancreas, distal pancreatectomy is the most common treatment. For small


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Surgery_Schwartz. determining the malignant potential of a pancreatic cystic neoplasm.Because most MCNs are located in the body and tail of the pancreas, distal pancreatectomy is the most common treatment. For small lesions, it may be appropriate to preserve the spleen, but splenectomy ensures removal of the lymph node basin that can potentially be involved. It is very important not to rupture the cyst during resection, and the tumor should be removed intact, not morselized. Therefore, a laparoscopic approach may not be appropriate for larger lesions. Completely resected MCNs without atypia are usually cured especially if small (<3 cm). Even patients with moderate dysplasia or carcinoma in situ are usually cured by complete resection. Noninvasive MCNs require no surveillance after resection. For MCNs with an associated invasive carcinoma, prognosis depends on the extent of the invasive component, tumor stage, and resectability. The 2-year survival rate and 5-year survival rate of patients with


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Surgery_Schwartz. with an associated invasive carcinoma, prognosis depends on the extent of the invasive component, tumor stage, and resectability. The 2-year survival rate and 5-year survival rate of patients with Brunicardi_Ch33_p1429-p1516.indd 150101/03/19 6:46 PM 1502SPECIFIC CONSIDERATIONSPART IIresected MCN with an associated invasive carcinoma are about 67% and 50%, respectively.375Intraductal Papillary Mucinous Neoplasm. Intraductal papillary mucinous neoplasms (IPMNs) usually occur within the head of the pancreas and arise within the pancreatic ducts. The ductal epithelium forms a papillary projection into the duct, and mucin production causes intraluminal cystic dilation of the pancreatic ducts (Fig. 33-79). Imaging studies demonstrate diffuse dilation of the pancreatic duct, and the pancreatic parenchyma is often atrophic due to chronic duct obstruction. However, classic features of chronic pancreatitis, such as calcification and a beaded appearance of the duct, are not present. At


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Surgery_Schwartz. parenchyma is often atrophic due to chronic duct obstruction. However, classic features of chronic pancreatitis, such as calcification and a beaded appearance of the duct, are not present. At ERCP, mucin can be seen extruding from the ampulla of Vater, a so-called fish-eye lesion that is virtually diagnostic of IPMN (Fig. 33-80). Initial reports suggested a male predominance, but more recent series indicate an equal distribution. Patients are usually in their seventh to eighth decade of life and present with abdominal pain or recurrent pancreatitis, thought to be caused by obstruction of the pancreatic duct by thick mucin. Some patients 9Figure 33-79. Computed tomography appearance of massive mul-tiseptated serous cystadenoma in head of pancreas with central stel-late scar (left) and resected specimen (right).Figure 33-80. Intraductal papillary mucinous neoplasm histology. Papillary projections of ductal epithelium resemble villous morphology and contain mucin-filled vesicles.


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Surgery_Schwartz. resected specimen (right).Figure 33-80. Intraductal papillary mucinous neoplasm histology. Papillary projections of ductal epithelium resemble villous morphology and contain mucin-filled vesicles. (Reproduced with permission from Asiyanbola B, Andersen DK. IPMN. Editorial Update. accesssurgery.com McGraw-Hill Education; 2008.)(5–10%) have steatorrhea, diabetes, and weight loss secondary to pancreatic insufficiency.Some IPMNs primarily involve the main pancreatic duct, while others involve the branch ducts. The mean fre-quency of malignancy in main duct IPMN (MD-IPMN) is 62% (Fig. 33-81). Considering this high incidence of malignant lesions and the low 5-year survival rates (31–54%), interna-tional consensus guidelines recommend resection for all surgi-cally fit patients with MD-IPMN.372 If the margin is positive for high-grade dysplasia, additional resection should be attempted to obtain at least moderate-grade dysplasia at the surgical margin.The surgical management of IPMNs is


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Surgery_Schwartz. If the margin is positive for high-grade dysplasia, additional resection should be attempted to obtain at least moderate-grade dysplasia at the surgical margin.The surgical management of IPMNs is complicated by the fact that the lesion itself is small and preoperative imaging stud-ies show a dilated pancreatic duct but not necessarily the mass. Mucus can dilate the duct proximal and distal to the lesion. Fur-thermore, these lesions can spread microscopically along the duct, and there can be skip areas of normal duct between the diseased portions. Therefore, thorough preoperative imaging including EUS, MRCP, or ERCP, and sometimes pancreatic ductoscopy, which can also be repeated intraoperatively, is use-ful (see Fig. 33-80). The surgeon needs to be prepared to extend the resection, if necessary, based on intraoperative findings and frozen section of the margin. Extending the resection to the point of total pancreatectomy is controversial due to the mor-bidity of this operation. Like


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Surgery_Schwartz. based on intraoperative findings and frozen section of the margin. Extending the resection to the point of total pancreatectomy is controversial due to the mor-bidity of this operation. Like MCNs, the IPMNs require careful histologic examination of the entire specimen for an invasive cancer (Fig. 33-82).Survival of patients with IPMN, even when malignant and invasive, can be quite good. As with MCN, patients with bor-derline tumors or carcinoma in situ are usually cured. For this reason, if recurrence occurs in the remaining pancreas, further resection is warranted because several series have shown that some of these cases are salvageable. Patients with IPMN are also at risk for other malignancies and should undergo colonos-copy and close surveillance.Branch-duct type IPMNs (BD-IPMN) are often found in the uncinate process, are sometimes asymptomatic, and are less frequently associated with malignant transformation (6–46%). Asymptomatic, small suspected BD-IPMNs are frequently


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Surgery_Schwartz. are often found in the uncinate process, are sometimes asymptomatic, and are less frequently associated with malignant transformation (6–46%). Asymptomatic, small suspected BD-IPMNs are frequently Brunicardi_Ch33_p1429-p1516.indd 150201/03/19 6:47 PM 1503PANCREASCHAPTER 33ABCFigure 33-81. Intraductal papillary mucinous neoplasm (IPMN). A. Examples of “fish-eye deformity” of IPMN. Mucin is seen extruding from the ampulla. B. Mucin coming from pancreatic duct when neck of pancreas is transected during Whipple procedure (left). Intraoperative pancreatic ductoscopy to assess the pancreatic tail (right). C. Views of pancreatic duct during ductoscopy; normal (left) and IPMN (right).Brunicardi_Ch33_p1429-p1516.indd 150301/03/19 6:47 PM 1504SPECIFIC CONSIDERATIONSPART IIobserved with serial imaging. High-risk features such as mural nodules, a dilated main duct, positive cytology or cyst fluid CEA >200 need to be ruled out. In the absence of these fea-tures, continued observation with


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Surgery_Schwartz. imaging. High-risk features such as mural nodules, a dilated main duct, positive cytology or cyst fluid CEA >200 need to be ruled out. In the absence of these fea-tures, continued observation with serial imaging is appropriate, especially in patients who are not ideal operative candidates. The mean frequency of invasive cancer in resected BD-IPMN is 18%. BD-IPMN mostly occurs in elderly patients, and the annual malignancy rate is only 2% to 3%. These factors support conservative management with follow-up in patients who do not have any symptoms or risk factors predicting malignancy such as mural nodule, rapidly increasing cyst size, and high-grade atypia in cytology. There is insufficient data to support immediate resection for all BD-IPMNs <3 cm without “high-risk stigmata” and “worrisome features.” Branch-duct IPMNs ≥3 cm should be resected.372Four histologic subtypes of IPMNs have been character-ized: gastric, intestinal, pancreatobiliary, and oncocytic. Most of BD-IPMNs are


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Surgery_Schwartz. features.” Branch-duct IPMNs ≥3 cm should be resected.372Four histologic subtypes of IPMNs have been character-ized: gastric, intestinal, pancreatobiliary, and oncocytic. Most of BD-IPMNs are composed of gastric-type epithelium. However, intestinal type is more common in MD-IPMN. In a recent report, the four subtypes of IPMNs were associated with significant dif-ferences in survival.376 Patients with gastric-type IPMN had the best prognosis, whereas those with intestinal and pancreatobili-ary type had a bad prognosis.Workup of Asymptomatic Pancreatic Cystic NeoplasmsIncidentally discovered asymptomatic pancreatic cystic neo-plasms are evaluated by MRI with MRCP to check for “high-risk stigmata or worrisome features.” An enhancing solid component or main pancreatic duct (MPD) dilation ≥10 mm are considered “high-risk stigmata.” Cysts ≥3 cm, thickened enhancing cyst walls, nonenhancing mural nodules, MPD size of 5 to 9 mm, abrupt change in the MPD caliber with distal pancreatic atrophy,


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Surgery_Schwartz. are considered “high-risk stigmata.” Cysts ≥3 cm, thickened enhancing cyst walls, nonenhancing mural nodules, MPD size of 5 to 9 mm, abrupt change in the MPD caliber with distal pancreatic atrophy, and lymphadenopathy are considered “worrisome features.” All cysts with high risk stigmata are resected. All cysts with wor-risome features and cysts > 3 cm without worrisome features are further evaluated with EUS. If EUS shows a definite mural nodule, main duct features suspicious for involvement or the cytology is positive or suspicious for malignancy, then resection is recommended. In the absence of worrisome features, no fur-ther initial work-up is recommended, but surveillance is still required.The interval between surveillance imaging is based on the size of the cyst with a lengthening of the interval once sta-bility is established. Patients with noninvasive MCNs require no surveillance after resection, but patients with IPMNs need surveillance after resection. In the absence of


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Surgery_Schwartz. of the interval once sta-bility is established. Patients with noninvasive MCNs require no surveillance after resection, but patients with IPMNs need surveillance after resection. In the absence of residual lesions, repeat MRI at 2 and 5 years may be reasonable. If there is low or moderate-grade dysplasia at the margin, MRI every 6 months is recommended.Resection is indicated in all surgically fit patients with MD-IPMN, and additional resection is indicated if there is high-grade dysplasia at the margin. Resection is also indicated in all surgically fit patients with MCN. BD-IPMN <3 cm without wor-risome features or high-risk stigmata can undergo surveillance.When patients are deemed unacceptable for resection due to comorbidities, ablation of the cyst can be considered. How-ever, at this time, cyst ablation is considered experimental and should be done as part of a clinical trial. Gastroenterologists have limited experience with injection of a cytotoxic agent into the cyst in an


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Surgery_Schwartz. this time, cyst ablation is considered experimental and should be done as part of a clinical trial. Gastroenterologists have limited experience with injection of a cytotoxic agent into the cyst in an attempt to ablate the cyst epithelium. Ethanol has been used and more recently this has been combined with paclitaxel. The combination of ethanol and paclitaxel injection resulted in elimination of the cysts, as determined by CT scan-ning, in 29 out of 47 (62%) of patients in a median follow-up period of 21.7 months.377Recently, the American Gastroenterological Association (AGA) published guidelines for asymptomatic mucinous cysts (http://www.gastro.org/guidelines/pancreatic-cysts) that are different from all previously published guidelines in the following areas: 2-year interval for cyst of any size undergoing surveillance, stopping surveillance after 5 years if no change, surgery only if more than one concerning feature on MRI confirmed on EUS and only in centers with high volumes of


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Surgery_Schwartz. any size undergoing surveillance, stopping surveillance after 5 years if no change, surgery only if more than one concerning feature on MRI confirmed on EUS and only in centers with high volumes of pancreatic surgery, and no surveillance after surgery if no invasive cancer or dysplasia. Although based on extensive literature review and synthesis, these recommendations have resulted in significant controversy because, in an effort to reduce the costs of health care delivery and perhaps decrease inadvertent harm to patients, they advocate less frequent follow-up and a higher threshold before offering EUS and/or surgery.Solid-Pseudopapillary Tumor. Solid-pseudopapillary tumors are rare and typically occur in young women. Previous names for this entity include, solid and cystic, solid and papillary, cystic and papillary, and papillary-cystic tumor. They are typically well circumscribed on CT (Fig. 33-83). The cysts are not true epithelial-lined cysts but rather represent a


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Surgery_Schwartz. solid and papillary, cystic and papillary, and papillary-cystic tumor. They are typically well circumscribed on CT (Fig. 33-83). The cysts are not true epithelial-lined cysts but rather represent a necrotic/degenerative process. Histology may be similar to neuroendocrine tumors, but they do not stain positive for neuroendocrine markers such as chromogranin. Most are cured by resection, but liver and peritoneal metastases have been reported.Other Cystic Neoplasms. Rarely, typical ductal adenocarci-noma of the pancreas may undergo cystic degeneration due to central necrosis. Occasionally, this will create difficulty in the proper preoperative diagnosis and should be kept in mind when deciding to conservatively follow a cystic pancreatic neoplasm. It is more common, 5% to 10%, for neuroendocrine tumors of the pancreas to contain cysts. These cysts are filled with sero-sanguineous fluid rather than necrotic debris. Lymphoepithelial Figure 33-82. Operative specimen of pancreas with


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Surgery_Schwartz. tumors of the pancreas to contain cysts. These cysts are filled with sero-sanguineous fluid rather than necrotic debris. Lymphoepithelial Figure 33-82. Operative specimen of pancreas with multifocal intraductal papillary mucinous neoplasms (black arrow) and a focus of invasive adenocarcinoma (white arrow). (Reproduced with permission from Asiyanbola B, Andersen DK. IPMN. Editorial Update. accesssurgery.com McGraw-Hill Education; 2008.)Brunicardi_Ch33_p1429-p1516.indd 150401/03/19 6:47 PM 1505PANCREASCHAPTER 33Figure 33-83. Abdominal computed tomographic scan of a 25-year-old woman demonstrating a well-circumscribed cystic lesion with septation in body/tail of pancreas. At surgery, the tumor was adherent to the splenic artery. Pathologic diagnosis was solid-pseudopapillary carcinoma.cysts of the pancreas usually occur in men in their fifth to sixth decade. These benign lesions may be unilocular or multilocular and vary widely in size. The contents of the cyst are also vari-able and


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Surgery_Schwartz. of the pancreas usually occur in men in their fifth to sixth decade. These benign lesions may be unilocular or multilocular and vary widely in size. The contents of the cyst are also vari-able and may be thin serous fluid or cheesy/caseous material if there is increased keratin formation. A substantial number of patients with von Hippel-Lindau syndrome develop pancreatic cysts that resemble serous cystadenomas. There may be mul-tiple lesions scattered throughout the pancreas. Patients with polycystic kidney and hepatic disease may also develop benign pancreatic cysts (cystadenomas). With all of these rare cystic neoplasms, careful clinical history, high-quality pancreatic imaging, and sampling of the cyst fluid for analysis will guide proper treatment.Pancreatic Lymphoma. Lymphoma can affect the pancreas. Primary involvement of the pancreas with no disease outside the pancreas also occurs. The clinical presentation often is similar to pancreatic adenocarcinoma, with vague abdominal


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Surgery_Schwartz. the pancreas. Primary involvement of the pancreas with no disease outside the pancreas also occurs. The clinical presentation often is similar to pancreatic adenocarcinoma, with vague abdominal pain and weight loss. Identification of a large mass often involving the head and body of the pancreas should raise suspicion. Percuta-neous or EUS-guided biopsy will confirm the diagnosis in most cases. If the diagnosis cannot be confirmed preoperatively, lapa-roscopic exploration and biopsy are indicated.378 There is no role for resection in the management of pancreatic lymphoma. Endoscopic stenting to relieve jaundice followed by chemo-therapy is the standard treatment, and long-term remission is often achieved.REFERENCESEntries highlighted in bright blue are key references. 1. Silen W. Surgical anatomy of the pancreas. Surg Clin North Am. 1964;44:1253. 2. Havel PJ, Taborsky GJ, Jr. The contribution of the autonomic nervous system to changes of glucagon and insulin secretion during


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Surgery_Schwartz. Surgical anatomy of the pancreas. Surg Clin North Am. 1964;44:1253. 2. Havel PJ, Taborsky GJ, Jr. The contribution of the autonomic nervous system to changes of glucagon and insulin secretion during hypoglycemic stress. Endocr Rev. 1989;10:332-350. 3. Davenport HW. Pancreatic secretion. In: Davenport HN, ed. Physiology of the Digestive Tract. 5th ed. Chicago: Year Book Medical Publishers; 1982:143. 4. Valenzuela JE, Weiner K, Saad C. Cholinergic stimulation of human pancreatic secretion. Dig Dis Sci. 1986;31:615-619. 5. Konturek SJ, Becker HD, Thompson JC. Effect of vagotomy on hormones stimulating pancreatic secretion. Arch Surg. 1974;108:704-708. 6. Ebert R, Creutzfeldt W. Gastrointestinal peptides and insulin secretion. Diabetes Metab Rev. 1987;3:1-26. 7. Leahy JL, Bonner-Weir S, Weir GC. Abnormal glucose regulation of insulin secretion in models of reduced B-cell mass. Diabetes. 1984; 33:667-673. 8. Brunicardi FC, Sun YS, Druck P, et al. Splanchnic neural regulation of insulin and


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Surgery_Schwartz. Abnormal glucose regulation of insulin secretion in models of reduced B-cell mass. Diabetes. 1984; 33:667-673. 8. Brunicardi FC, Sun YS, Druck P, et al. Splanchnic neural regulation of insulin and glucagon secretion in the isolated perfused human pancreas. Am J Surg. 1987;153:34-40. 9. Yamada Y, Post SR, Wang K, et al. Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney. Proc Natl Acad Sci U S A. 1992;89:251-255. 10. Voss M, Pappas T. Pancreatic fistula. Curr Treat Options Gastroenterol. 2002;5:345-353. 11. Floyd JC, Jr, Fajans SS, Pek S. Regulation in healthy subjects of the secretion of human pancreatic polypeptide, a newly recognized pancreatic islet polypeptide. Trans Assoc Am Physicians. 1976;89:146-158. 12. Adrian TE, Bloom SR, Besterman HS, et al. Mechanism of pancreatic polypeptide release in man. Lancet. 1977;1:161-163.Brunicardi_Ch33_p1429-p1516.indd 150501/03/19 6:47 PM


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Surgery_Schwartz. 1976;89:146-158. 12. Adrian TE, Bloom SR, Besterman HS, et al. Mechanism of pancreatic polypeptide release in man. Lancet. 1977;1:161-163.Brunicardi_Ch33_p1429-p1516.indd 150501/03/19 6:47 PM 1506SPECIFIC CONSIDERATIONSPART II 13. Kono T, Wang XP, Fisher WE, Andersen DK, Brunicardi FC. Pancreatic Polypeptide (PP). In: L Martini, ed. Encyclopedia of Endocrine Diseases. Volume 3. Philadelphia: Elsevier; 2004:488-496. 14. Andersen DK. Mechanisms and emerging treatments of the metabolic complications of chronic pancreatitis. Pancreas. 2007;35:1-5. 15. Wierup N, Svensson H, Mulder H, Sundler F. The ghrelin cell: anovel developmentally regulated islet cell in the human pancreas. Regul Pept. 2002;107:63-69. 16. Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sussel L. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci U S A. 2004;101:2924-2429. 17. Sun Y, Asnicar M, Saha PK, Chan L, Smith RG. Ablation of


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Surgery_Schwartz. cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci U S A. 2004;101:2924-2429. 17. Sun Y, Asnicar M, Saha PK, Chan L, Smith RG. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab. 2006;3:379-386. 18. Westermark P, Wilander E, Westermark GT, et al. Islet amyloid polypeptide-like-immunoreactivity in the islet B-cells of type 2 (non-insulin-dependent) diabetic and non-diabetic individuals. Diabetologia. 1987;30:887-892. 19. Tatemoto K, Efendic S, Mutt V, Makk G, Feistner GJ, Barchas JD. Pancreastatin, a novel pancreatic peptide that inhibits insulin secretion. Nature. 1986;324:476-478. 20. Efendic S, Tatemoto K, Mutt V, Quan C, Chang D, Ostenson CG. Pancreastatin and islet hormone release. Proc Natl Acad Sci U S A. 1987:84:7257-7260. 21. Funakoshi A, Miyasaka K, Nakamura R, Kitani K, Tatemoto K. Inhibitory effect of pancreastatin on pancreatic exocrine secretion in the conscious rat. Reg


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Surgery_Schwartz. pancreatic necrosis as determinants of mortality in patients with acute pancreatitis. Gastroenterology. 2010;139:813-820. 26. Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012;143(5):1179-1187. 27. Banks PA. Epidemiology, natural history, and predictors of disease outcome in acute and chronic pancreatitis. Gastrointesi Endosc. 2002;56(6 suppl):S226-S230. 28. Akhtar AJ, Shaheen M. Extrapancreatic manifestations of acute pancreatitis in African-American and Hispanic patients. Pancreas. 2004;29(4):291-297. 29. Lowenfels AB, Maisonneuve P. Acute pancreatitis: is smoking a risk factor for acute pancreatitis. Nat Rev Gastroenterol Hepatol. 2011;8(11):603-604. 30. Acosta JM, Ledesma CL. Gallstone migration as a cause of acute pancreatitis. N Engl J Med. 1974;290(9):484-487. 31. Lee SP, Nicholls JF, Park HZ. Biliary sludge as a cause of acute pancreatitis. N Engl J Med. 1992;326(9):589-593. 32. Lankisch PG, Apte M,


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Surgery_Schwartz. acute pancreatitis. N Engl J Med. 1974;290(9):484-487. 31. Lee SP, Nicholls JF, Park HZ. Biliary sludge as a cause of acute pancreatitis. N Engl J Med. 1992;326(9):589-593. 32. Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet. 2015;386(9988):85-96. 33. Elmunzer BJ, Scheiman JM, Lehman GA, et al. A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012; 66:1414-1422. 34. Akbar A, Abu Dayyeh BK, Baron TH, Wang Z, Altayar O, Murad MH. Rectal non-steroidal anti-inflammatory drugs are superior to pancreatic duct stentsin preventing pancreatitis after endoscopic retrograde cholangiopancreatography: a network meta-analysis. Clin Gastroenterol Hepatol. 2013;13: 778-783. 35. Whitcomb DC. Genetics of alcoholic and nonalcoholic pancreatitis. Curr Opin Gastroenterol. 2012;28(5):501-506. 36. Saluja A, Steer M. Pathophysiology of pancreatitis. Role of cytokines and other mediators of inflammation. Digestion. 1999;60:27-33. 37. Hofbauer B, Saluja AK,


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Surgery_Schwartz. Gastroenterol. 2012;28(5):501-506. 36. Saluja A, Steer M. Pathophysiology of pancreatitis. Role of cytokines and other mediators of inflammation. Digestion. 1999;60:27-33. 37. Hofbauer B, Saluja AK, Lerch MM, et al. Intra-acinar cell activation of trypsinogen during caerulein-induced pancreatitis in rats. Am J Physiol. 1998;275(2 pt 1):G352-G362. 38. Saluja AK, Lerch MM, Phillips PA, Dudeja V. Why does pancreatic overstimulation cause pancreatitis? Annu Rev Physiol. 2007;69:249-269. 39. Dawra R, Sah RP, Dudeja V, et al. Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis. Gastroenterol. 2011;141(6):2210-2217 e2212. 40. Gaiser S, Daniluk J, Liu Y, et al. Intracellular activation of trypsinogen in transgenic mice induces acute but not chronic pancreatitis. Gut. 2011;60(10):1379-1388. 41. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen


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Surgery_Schwartz. mice induces acute but not chronic pancreatitis. Gut. 2011;60(10):1379-1388. 41. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996;14(2):141-145. 42. Kloppel G, Dreyer T, Willemer S, et al. Human acute pancreatitis: its pathogenesis in the light of immunocytochemical and ultrastructural findings in acinar cells. Virchows Arch A Pathol Anat Histopathol. 1986;409(6):791-803. 43. Saluja A, Saluja M, Villa A, et al. Pancreatic duct obstruction in rabbits causes digestive zymogen and lysosomal enzyme colocalization. J Clin Invest. 1989;84(4):1260-1266. 44. Saluja AK, Saluja M, Printz H, Zavertnik A, Sengupta A, Steer ML. Experimental pancreatitis is mediated by low-affinity cholecystokinin receptors that inhibit digestive enzyme secretion. Proc Natl Acad Sci. 1989;86(22):8968-8971. 45. Saluja A, Hashimoto S, Saluja M, et al. Subcellular redistribution of lysosomal enzymes during caerulein-induced


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Surgery_Schwartz. inhibit digestive enzyme secretion. Proc Natl Acad Sci. 1989;86(22):8968-8971. 45. Saluja A, Hashimoto S, Saluja M, et al. Subcellular redistribution of lysosomal enzymes during caerulein-induced pancreatitis. Am J Physiol. 1987;253(4 pt 1):G508-G516. 46. Van Acker GJ, Saluja AK, Bhagat L, et al. Cathepsin B inhibition prevents trypsinogen activation and reduces pancreatitis severity. Am J Physiol Gastrointest Liver Physiol. 2002;283(3):G794-G800. 47. Halangk W, Lerch MM, Brandt-Nedelev B, et al. Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis. J Clin Invest. 2000;106(6):773-781. 48. Saluja AK, Bhagat L, Lee HS, et al. Secretagogue-induced digestive enzyme activation and cell injury in rat pancreatic acini. Am J Physiol. 1999;276(4 pt 1):G835-G842. 49. Fluhr G, Mayerle J, Weber E, et al. Pre-study protocol Mag-PEP: a multicentre randomized controlled trial of magnesium sulphate in the prevention of post-ERCP pancreatitis. BMC


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Surgery_Schwartz. pt 1):G835-G842. 49. Fluhr G, Mayerle J, Weber E, et al. Pre-study protocol Mag-PEP: a multicentre randomized controlled trial of magnesium sulphate in the prevention of post-ERCP pancreatitis. BMC Gastroenterol. 2013;13(1):11. 50. Talukdar R, Sareen A, Zhu H, et al. Release of cathepsin B in cytosol causes cell death in acute pancreatitis. Gastroenterology. 2016;151(4):747-758. 51. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1): 102-111. 52. Windsor JA, Petrov MS. Acute pancreatitis reclassified. Commentary. Gut. 2013;62(1):4-5. 53. Hietaranta AJ, Singh VP, Bhagat L, et al. Water immersion stress prevents caerulein-induced pancreatic acinar cell nf-kappa b activation by attenuating caerulein-induced intracellular Ca2+ changes. J Biol Chem. 2001;276(22):18742-18747. 54. Hofbauer B, Saluja AK, Bhatia M, et al. Effect of recombinant platelet-activating


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Surgery_Schwartz. b activation by attenuating caerulein-induced intracellular Ca2+ changes. J Biol Chem. 2001;276(22):18742-18747. 54. Hofbauer B, Saluja AK, Bhatia M, et al. Effect of recombinant platelet-activating factor acetylhydrolase on two models Brunicardi_Ch33_p1429-p1516.indd 150601/03/19 6:47 PM 1507PANCREASCHAPTER 33of experimental acute pancreatitis. Gastroenterology. 1998;115:1238-1247. 55. Korhonen JT, Dudeja V, Dawra R, Kubes P, Saluja A. Neutrophil extracellular traps provide a grip on the enigmatic pathogenesis of acute pancreatitis. Gastroenterology. 2015;149(7):1682-1685. 56. Merza M, Hartman H, Rahman M, et al. Neutrophil extracellular traps induce trypsin activation, inflammation, and tissue damage in mice with severe acute pancreatitis. Gastroenterology. 2015;149(7):1920-1931. 57. Abu-Zidan FM, Windsor JA. Lexipafant and acute pancreatitis: a critical appraisal of the clinical trials. European Journal of Surgery. 2002;168:215-219. 58. George J, Dixit A, Sareen A, et al.


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