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Surgery_Schwartz. pancreatectomy or pancreaticoduodenectomy. Intraop-erative US is useful to determine the tumor’s relation to the main pancreatic duct and guides intraoperative decision making. Approximately 90% of insulinomas are sporadic, and 10% are associated with the MEN1 syndrome. Insulinomas associated with the MEN1 syndrome are more likely to be multifocal and have a higher rate of recurrence.Noninsulinoma Hyperinsulinemia Hypoglycemia SyndromeA syndrome of noninsulinoma pancreatogenous hypoglycemia was described by Service et al in 1999.299 The syndrome is asso-ciated with beta-cell hypertrophy, islet hyperplasia and increased beta-cell mass. When these findings are accompanied by ectopic islet tissue, multilobulated islets, and ductuloinsular complexes, the definition of nesideoblastosis is met. Nesideoblastosis accompanied by hyperinsulinism was previously considered a disease of neonates, where subtotal or total pancreatectomy was required to correct potentially fatal neonatal


Surgery_Schwartz

Surgery_Schwartz. is met. Nesideoblastosis accompanied by hyperinsulinism was previously considered a disease of neonates, where subtotal or total pancreatectomy was required to correct potentially fatal neonatal hyperinsulinism. However, dozens of cases of nesideoblastosis associated with hyperinsulinism have now been reported in patients 2 to 5 years after Roux-en-Y gastric bypass for obesity.300 Many of these patients have undergone partial or total pancreatectomy to prevent potentially fatal hypoglycemia. The illness in former bariatric surgery patients appears to result from an idiosyncraticallyprolonged hypersecretion of the incretin hormones GIP and GLP-1 after the gastric bypass. GLP-1 is a potent stimulant of the expression of the transcription factor PDX-1, which nor-mally regulates beta-cell development and growth. The correct treatment of this condition to prevent episodes of hypoglycemia is conversion of the gastric bypass to a form of bariatric proce-dure that restores normal intestinal


Surgery_Schwartz

Surgery_Schwartz. and growth. The correct treatment of this condition to prevent episodes of hypoglycemia is conversion of the gastric bypass to a form of bariatric proce-dure that restores normal intestinal flow of nutrients, such as the gastric sleeve, or the addition of a restriction element such as an adjustable gastric band. Pancreatic resection without conversion of the Roux-en-Y gastric bypass is not appropriate because this allows the abnormal enteroinsular relationship to continue and hyperinsulinemia persists or recurs after partial pancreatectomy.GastrinomaZollinger-Ellison syndrome (ZES) is caused by a gastrinoma, an endocrine tumor that secretes gastrin, leading to acid hyper-secretion and peptic ulceration. Many patients with ZES present with abdominal pain, peptic ulcer disease, and severe esopha-gitis. However, in the era of effective antacid therapy, the pre-sentation can be less dramatic. Although most of the ulcers are solitary, multiple ulcers in atypical locations that fail to


Surgery_Schwartz

Surgery_Schwartz. esopha-gitis. However, in the era of effective antacid therapy, the pre-sentation can be less dramatic. Although most of the ulcers are solitary, multiple ulcers in atypical locations that fail to respond to antacids should raise suspicion for ZES and prompt a work-up. At the time of diagnosis, 21% of patients with gastrinoma have diarrhea.The diagnosis of ZES is made by measuring the serum gastrin level. It is important that patients stop taking proton pump inhibitors for this test. In most patients with gastrinomas, the level is >1000 pg/mL. Gastrin levels can be elevated under conditions other than ZES. Common causes of hypergastrin-emia include pernicious anemia, treatment with proton pump inhibitors, renal failure, G-cell hyperplasia, atrophic gastritis, retained or excluded antrum, and gastric outlet obstruction. In equivocal cases, when the gastrin level is not markedly elevated, a secretin stimulation test is helpful.Brunicardi_Ch33_p1429-p1516.indd 148101/03/19 6:46 PM


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Surgery_Schwartz. and gastric outlet obstruction. In equivocal cases, when the gastrin level is not markedly elevated, a secretin stimulation test is helpful.Brunicardi_Ch33_p1429-p1516.indd 148101/03/19 6:46 PM 1482SPECIFIC CONSIDERATIONSPART IIIn 70% to 90% of patients, the primary gastrinoma is found in Passaro’s triangle, an area defined by a triangle with points located at the junction of the cystic duct and common bile duct, the second and third portion of the duodenum, and the neck and body of the pancreas (Fig. 33-65). However, because gastri-nomas can be found almost anywhere, whole-body imaging is required. The test of choice is SSTR (octreotide) scintigraphy in combination with CT. The octreotide scan is more sensitive than CT, locating about 85% of gastrinomas and detecting tumors <1 cm. With the octreotide scan, the need for tedious and techni-cally demanding selective angiography and measurement of gas-trin gradients has declined. EUS is another modality that assists in the


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Surgery_Schwartz. <1 cm. With the octreotide scan, the need for tedious and techni-cally demanding selective angiography and measurement of gas-trin gradients has declined. EUS is another modality that assists in the preoperative localization of gastrinomas. It is particularly helpful in localizing tumors in the pancreatic head or duodenal wall, where gastrinomas are usually <1 cm in size. A combina-tion of octreotide scan and EUS detects >90% of gastrinomas.It is important to rule out MEN1 syndrome by checking serum calcium levels before surgery because resection of the gastrinoma(s) in these patients rarely results in normalization of serum gastrin concentrations or a prolongation of survival. Only one-fourth of gastrinomas occur in association with the MEN1 syndrome. One-half of patients with gastrinomas will have soli-tary tumors while the remainder will have multiple gastrino-mas. Multiple tumors are more common in patients with MEN1 syndrome. Aggressive surgical treatment is justified in


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Surgery_Schwartz. will have soli-tary tumors while the remainder will have multiple gastrino-mas. Multiple tumors are more common in patients with MEN1 syndrome. Aggressive surgical treatment is justified in patients with sporadic gastrinomas. If patients have MEN1 syndrome, the parathyroid hyperplasia is addressed with total parathyroid-ectomy and implantation of parathyroid tissue in the forearm.Approximately 50% of gastrinomas metastasize to lymph nodes or the liver and are therefore considered malignant. Patients who meet criteria for operability should undergo exploration for possible removal of the tumor. Although the tumors are submu-cosal, a full-thickness excision of the duodenal wall is performed if a duodenal gastrinoma is found. All lymph nodes in Passaro’s triangle are excised for pathologic analysis. If the gastrinoma is found in the pancreas and does not involve the main pancreatic duct, it is enucleated. Pancreatic resection is justified for solitary Figure 33-65. Passaro’s triangle.


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Surgery_Schwartz. analysis. If the gastrinoma is found in the pancreas and does not involve the main pancreatic duct, it is enucleated. Pancreatic resection is justified for solitary Figure 33-65. Passaro’s triangle. The typical location of a gastrinoma is described by this anatomic region, including the head of the pancreas, duodenum, and the lymphatic bed posterior and superior to the duodenum, as originally described by E. Passaro. (Reproduced with permission from Stable BE, Morrow DJ, Passaro E: The gastrinoma triangle: operative implications, Am J Surg. 1984 Jan;147(1):25-31.)gastrinomas with no metastases. A highly selective vagotomy can be performed if unresectable disease is identified or if the gastrinoma cannot be localized. This may reduce the amount of expensive proton pump inhibitors required. In cases in which hepatic metastases are identified, resection is justified if the pri-mary gastrinoma is controlled and the metastases can be safely and completely removed. Debulking or incomplete


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Surgery_Schwartz. In cases in which hepatic metastases are identified, resection is justified if the pri-mary gastrinoma is controlled and the metastases can be safely and completely removed. Debulking or incomplete removal of multiple hepatic metastases is probably not helpful, especially in the setting of MEN1. The application of new modalities such as radiofrequency ablation seems reasonable, but data to sup-port this approach are limited.301 Postoperatively, patients are followed with fasting serum gastrin levels, secretin stimulation tests, octreotide scans, and CT scans. In patients found to have inoperable disease, chemotherapy with streptozocin, doxorubi-cin, and 5-fluorouracil (5-FU) is used. Other approaches such as somatostatin analogues, interferon, and chemoembolization also have been used in gastrinoma with some success.Unfortunately, a biochemical cure is achieved in only about one-third of the patients operated on for ZES. Despite the lack of success, long-term survival rates are good,


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Surgery_Schwartz. gastrinoma with some success.Unfortunately, a biochemical cure is achieved in only about one-third of the patients operated on for ZES. Despite the lack of success, long-term survival rates are good, even in patients with liver metastases. The 15-year survival rate for patients without liver metastases is about 80%, while the 5-year survival rate for patients with liver metastases is 20% to 50%. Pancreatic tumors are usually larger than tumors arising in the duodenum, and more often they have lymph node metastases. In gastrinomas, liver metastases decrease survival rates, but lymph node metastases do not. The best results are seen after complete excision of small sporadic tumors originating in the duodenum. Large tumors associated with liver metastases, located outside of Passaro’s triangle, have the worst prognosis.Vasoactive Intestinal Peptide-Secreting TumorIn 1958, Verner and Morrison first described the syndrome associated with a pancreatic neoplasm secreting VIP. The clas-sic


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Surgery_Schwartz. have the worst prognosis.Vasoactive Intestinal Peptide-Secreting TumorIn 1958, Verner and Morrison first described the syndrome associated with a pancreatic neoplasm secreting VIP. The clas-sic clinical syndrome associated with this pancreatic endocrine neoplasm consists of severe intermittent watery diarrhea leading to dehydration, and weakness from fluid and electrolyte losses. Large amounts of potassium are lost in the stool. The vasoac-tive intestinal peptide-secreting tumor (VIPoma) syndrome is also called WDHA syndrome due to the presence of watery diarrhea, hypokalemia, and achlorhydria. The massive (5 L/d) and episodic nature of the diarrhea associated with the appropriate electrolyte abnormalities should raise suspicion of the diagnosis. Serum VIP levels must be measured on multiple occasions because the excess secretion of VIP is episodic and single measurements might be normal and misleading. A CT scan localizes most VIPomas, although as with all islet cell tumors, EUS is


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Surgery_Schwartz. occasions because the excess secretion of VIP is episodic and single measurements might be normal and misleading. A CT scan localizes most VIPomas, although as with all islet cell tumors, EUS is the most sensitive imaging method. Electrolyte and fluid balance is sometimes dif-ficult to correct preoperatively and must be pursued aggressively. Somatostatin analogues are helpful in controlling the diarrhea and allowing replacement of fluid and electrolytes. VIPomas are more commonly located in the distal pancreas and most have spread outside the pancreas. Palliative debulking operations can some-times improve symptoms for a period, along with somatostatin analogues. Hepatic artery embolization also has been reported as a potentially beneficial treatment.302GlucagonomaDiabetes in association with dermatitis should raise the suspi-cion of a glucagonoma. The diabetes usually is mild. The classic necrolytic migratory erythema manifests as cyclic migrations of lesions with spreading margins


Surgery_Schwartz

Surgery_Schwartz. with dermatitis should raise the suspi-cion of a glucagonoma. The diabetes usually is mild. The classic necrolytic migratory erythema manifests as cyclic migrations of lesions with spreading margins and healing centers typically on Brunicardi_Ch33_p1429-p1516.indd 148201/03/19 6:46 PM 1483PANCREASCHAPTER 33the lower abdomen, perineum, perioral area, and feet. Patients also complain of an enlarged, sensitive tongue. The diagnosis is confirmed by measuring serum glucagon levels, which are usu-ally >500 pg/mL. Glucagon is a catabolic hormone, and most patients present with malnutrition. The rash associated with glucagonoma is thought to be caused by low levels of amino acids. Preoperative treatment usually includes control of the dia-betes, parenteral nutrition, and octreotide. Like VIPomas, glu-cagonomas are more often in the body and tail of the pancreas and tend to be large tumors with metastases. Again, debulking operations are recommended in good operative candidates to relieve


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Surgery_Schwartz. glu-cagonomas are more often in the body and tail of the pancreas and tend to be large tumors with metastases. Again, debulking operations are recommended in good operative candidates to relieve symptoms.SomatostatinomaBecause somatostatin inhibits pancreatic and biliary secretions, patients with a somatostatinoma present with gallstones due to bile stasis, diabetes due to inhibition of insulin secretion, and steatorrhea due to inhibition of pancreatic exocrine secretion and bile secretion. Most somatostatinomas originate in the proximal pancreas or the pancreatoduodenal groove, with the ampulla and periampullary area as the most common site (60%). The most common presentations are abdominal pain (25%), jaundice (25%), and cholelithiasis (19%).303 This rare type of pancreatic endocrine tumor is diagnosed by confirming elevated serum somatostatin levels, which are usually >10 ng/mL. Although most reported cases of somatostatinoma involve metastatic disease, an attempt at complete


Surgery_Schwartz

Surgery_Schwartz. tumor is diagnosed by confirming elevated serum somatostatin levels, which are usually >10 ng/mL. Although most reported cases of somatostatinoma involve metastatic disease, an attempt at complete excision of the tumor and cholecystectomy is warranted in fit patients.Nonfunctioning Pancreatic Endocrine TumorsAlthough some pancreatic endocrine neoplasms secrete one or more hormones and are associated with interesting characteristic clinical syndromes, most are not associated with elevated serum hormone levels that cause symptoms. Pancreatic endocrine tumors are considered functional if they are associated with a clinical syndrome and nonfunctioning if not associated with clinical symptoms. The majority of pancreatic endocrine tumors (PET), also called pancreatic neuroendocrine tumors (pNET), are malignant because they have the potential for uncontrolled growth and metastasis. Immunohistochemical markers such as synaptophysin, chromogranin A (CgA), and neuron-specific enolase can be


Surgery_Schwartz

Surgery_Schwartz. are malignant because they have the potential for uncontrolled growth and metastasis. Immunohistochemical markers such as synaptophysin, chromogranin A (CgA), and neuron-specific enolase can be helpful in the diagnosis, but the gross histology is not a reliable predictor of biologic behavior. CgA is used by some as a serum marker to monitor patients for disease recur-rence or response to treatment, but the test performs poorly for this purpose. Patients often present similar to patients with pancreatic adenocarcinoma with vague pain or weight loss, but pNETs are increasingly discovered incidentally when imaging is performed for another reason. The tumor frequently enhances with arterial contrast (Fig. 33-66). Sometimes a cystic compo-nent is seen due to central necrosis. Octreoscan (somatostatin receptor scintigraphy) can be helpful to stage the disease. Sur-gical resection is typically recommended in fit patients in the absence of metastatic disease. For patients with tumors in the


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Surgery_Schwartz. receptor scintigraphy) can be helpful to stage the disease. Sur-gical resection is typically recommended in fit patients in the absence of metastatic disease. For patients with tumors in the body and tail of the pancreas, this typically includes splenec-tomy. Enucleation and splenic preservation, although tempting in small tumors, fails to remove regional lymph nodes.With advances in imaging, small indolent pNETs are being discovered with increasing frequency, and some surgeons are considering observation in these cases.304 There are several argu-ments in favor of observation of small (<2 cm) nonfunctional pNETs, particularly in MEN-1 patients. Pancreatic resection has significant morbidity and mortality. In the setting of MEN-1, resection is rarely curative, and most patients require reopera-tion. Also, the survival of these patients, even with metastatic dis-ease, is generally excellent at least compared to pancreatic ductal adenocarcinoma. However, the 5-year survival with


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Surgery_Schwartz. reopera-tion. Also, the survival of these patients, even with metastatic dis-ease, is generally excellent at least compared to pancreatic ductal adenocarcinoma. However, the 5-year survival with metastatic pNET is only 16% and radical surgery with curative intent is the standard of care, particularly in sporadic cases that are fit surgical candidates where the primary tumor can be completely excised.Adjuvant treatment after resection is withheld in the absence of radiographically demonstrable metastatic disease even if CgA levels remain elevated. Although these tumors have a slow growth pattern compared to pancreatic ductal adenocar-cinoma, many patients with pNETs will die of their disease even after an apparent complete resection, making surveillance after complete resection important. CT scan and or octreotide scan is recommended annually for 5 years after resection.ABCFigure 33-66. Pancreatic neuroendocrine tumor (PNET) demonstrating enhancement during arterial phase of computed


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Surgery_Schwartz. CT scan and or octreotide scan is recommended annually for 5 years after resection.ABCFigure 33-66. Pancreatic neuroendocrine tumor (PNET) demonstrating enhancement during arterial phase of computed tomography scan. Pancreatic head PNET seen in (left) sagital, (middle) coronal, and (right) lateral views of the abdomen.Brunicardi_Ch33_p1429-p1516.indd 148301/03/19 6:46 PM 1484SPECIFIC CONSIDERATIONSPART IIIncomplete resection (debulking) for locally advanced or metastatic pNETs of the pancreas is controversial because of the favorable survival duration of patients without surgery. How-ever, in carefully selected fit patients with a pNET in the head of the pancreas and minimal disease in the liver, a pancreaticoduo-denectomy with wedge resection of the liver metastasis might be appropriate because this avoids the morbidity of gastroin-testinal hemorrhage and biliary and gastric outlet obstruction before death from the metastatic disease. The role of cytoreduc-tive surgery in


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Surgery_Schwartz. because this avoids the morbidity of gastroin-testinal hemorrhage and biliary and gastric outlet obstruction before death from the metastatic disease. The role of cytoreduc-tive surgery in metastatic pNET is controversial, but consensus guidelines agree that aggressive resection of the primary tumor, regional lymph nodes, and liver/distant metastases should be pursued if greater than 90% of the tumor burden can be resected, which is the case in only about 10% of patients with metastatic disease.Treatment of metastatic pancreatic neuroendocrine cancer requires a multidisciplinary approach often including a com-bination of cytoreductive surgery when appropriate, directed therapy for the treatment of liver metastases when possible, and systemic medical therapy. Local ablative therapies include radiofrequency ablation (RFA), cryotherapy, microwave coagu-lation, and ethanol injection, although RFA is the most popular and widely studied. These therapies can be performed percuta-neously or


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Surgery_Schwartz. radiofrequency ablation (RFA), cryotherapy, microwave coagu-lation, and ethanol injection, although RFA is the most popular and widely studied. These therapies can be performed percuta-neously or during surgery via laparotomy or laparoscopy, can be repeated, and have been shown to complement resection of the primary tumor and amenable liver metastases; making pallia-tive surgery possible for patients that would otherwise not meet criteria. This approach often improves symptoms and 5-year survival is improved to 48%.305Transarterial chemoembolization (TACE) can be employed as palliative therapy in patients with liver metastases not amenable to surgical resection and/or ablation. It relies on the principle that metastatic tumor cells derive the majority of their oxygen supply from the hepatic artery as opposed to hepa-tocytes, which receive oxygen primarily from the portal vein. Performed via angiography, embolization may be performed alone (bland embolization) or in combination with


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Surgery_Schwartz. artery as opposed to hepa-tocytes, which receive oxygen primarily from the portal vein. Performed via angiography, embolization may be performed alone (bland embolization) or in combination with chemothera-peutic agents (chemoembolization). Radioembolization, the selective distribution of radioactive yttrium-90 microspheres into the peritumoral vasculature via branches of the hepatic artery, is another alternative.Somatostatin analogs can inhibit release of hormones from functional pNETS and reduce diarrhea in patients with VIPo-mas, glucagonomas, and somatostatinomas, and it can also help the rash of glucagonomas. Somatostatin analogs such as octreotide (Sandostatin LAR Depot), lanreotide (Somatuline Depot), and a new analog pasireotide (Sifnifor LAR) are also used to slow the growth of some functional and nonfunctional pNETS. Disease seen on an octreotide scan has somatostatin receptors and would be expected to respond. Patients with unre-sectable disease are often treated with


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Surgery_Schwartz. of some functional and nonfunctional pNETS. Disease seen on an octreotide scan has somatostatin receptors and would be expected to respond. Patients with unre-sectable disease are often treated with somatostatin analogs first before targeted therapy and cytotoxic chemotherapy are utilized because the side effects are minimal.Some targeted drugs can be helpful in treating advanced pNETs that progress despite somatostatin analogs. Sunitinib (Sutent) attacks new blood vessel growth and other targets that help cancer cells grow. Everolimus (Afinitor) works by block-ing a cell protein known as mammalian target of rapamycin (mTOR) and the VEGF pathway, which normally helps cells grow and divide. These targeted agents induce stabilization much more frequently than response, but they tend to carry fewer side effects than traditional cytotoxic chemotherapy. Cytotoxic chemotherapy for pNETS is usually reserved for large tumors or quickly growing tumors that are causing symptoms, or tumors that


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Surgery_Schwartz. fewer side effects than traditional cytotoxic chemotherapy. Cytotoxic chemotherapy for pNETS is usually reserved for large tumors or quickly growing tumors that are causing symptoms, or tumors that progressed despite somatostatin analogs and targeted ther-apy. Platinum-based chemotherapy does, however, remain the standard of care for high-grade (poorly differentiated) pNET, yielding high response rates but typically short-lived benefit. The newer cytotoxic combination of capecitabine and temozolo-mide has shown activity in well-differentiated pNET.306Neoplasms of the Exocrine PancreasEpidemiology and Risk Factors. It is estimated that in 2017, 53,670 Americans will be diagnosed with pancreatic cancer and 43,090 will die from the disease. Overall, pancreatic cancer has the worst prognosis of all malignancies with a 5-year survival rate of only 7.2%.307 The incidence of pancreatic cancer continues to increase, perhaps related to the increased incidence of risk factors such as obesity


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Surgery_Schwartz. of all malignancies with a 5-year survival rate of only 7.2%.307 The incidence of pancreatic cancer continues to increase, perhaps related to the increased incidence of risk factors such as obesity and diabetes, and as a result, it is predicted that pancreatic cancer will become the leading cause of cancer deaths in the United States by 2050. Pancreatic cancer recently surpassed breast cancer and is now the third leading cause of cancer death behind lung and colorectal cancer. Despite its ubiquity, this dis-ease is extremely difficult to treat, and its exact cause is unknown. However, epidemiologic studies linking various environmental and host factors provide some clues. Recent discoveries using modern molecular biologic techniques have also improved our understanding of the causes of pancreatic cancer. The etiology of pancreatic cancer likely involves a complex interaction of genetic and environmental factors. These factors will become more fully understood as DNA sequencing is used


Surgery_Schwartz

Surgery_Schwartz. cancer. The etiology of pancreatic cancer likely involves a complex interaction of genetic and environmental factors. These factors will become more fully understood as DNA sequencing is used to screen populations at risk for developing pancreatic cancer.Pancreatic cancer is more common in older adults with most patients being 75 to 84 years old. Pancreatic cancer is more common in African Americans and slightly more com-mon in men than women. The risk of developing pancreatic cancer is two to three times higher if a parent or sibling had the disease. Another risk factor that is consistently linked to pan-creatic cancer is cigarette smoking. Smoking increases the risk of developing pancreatic cancer by at least twofold due to the carcinogens in cigarette smoke.308 Coffee and alcohol consump-tion have been investigated as possible risk factors, but the data are inconsistent. As in other GI cancers, diets high in fat and low in fiber, fruits, and vegetables are thought to be associated


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Surgery_Schwartz. have been investigated as possible risk factors, but the data are inconsistent. As in other GI cancers, diets high in fat and low in fiber, fruits, and vegetables are thought to be associated with an increased risk of pancreatic cancer.Diabetes has been known to be associated with pancreatic cancer for many years. In fact, glucose intolerance is present in 80% of patients with pancreatic cancer, and approximately 20% have overt diabetes, a much greater incidence than would be expected to occur by chance. Preexisting type 2 diabetes increases the risk for development of pancreatic cancer by about twofold.309 The new onset of diabetes also can be an early mani-festation of otherwise occult pancreatic cancer. Thus, the new onset of diabetes, or a sudden increase in insulin requirement in an older adult patient with preexisting diabetes, should provoke concern for the presence of pancreatic cancer.Recent epidemiologic studies have confirmed the fact that patients with chronic


Surgery_Schwartz

Surgery_Schwartz. in an older adult patient with preexisting diabetes, should provoke concern for the presence of pancreatic cancer.Recent epidemiologic studies have confirmed the fact that patients with chronic pancreatitis, especially familial pan-creatitis, have an increased risk of developing pancreatic can-cer.124,196-198 Large, retrospective cohort studies of patients with pancreatitis have revealed up to a 20-fold increase in risk for pancreatic cancer. This increased risk seems to be independent of the type of pancreatitis, a finding consistent with the fact that most studies have shown little effect of alcohol ingestion per se Brunicardi_Ch33_p1429-p1516.indd 148401/03/19 6:46 PM 1485PANCREASCHAPTER 33on the risk of pancreatic carcinoma. The mechanisms involved in carcinogenesis in patients with preexisting pancreatitis are unknown. However, the mutated K-ras oncogene, which is pres-ent in most cases of pancreatic cancer, has been detected in the ductal epithelium of some patients with


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Surgery_Schwartz. with preexisting pancreatitis are unknown. However, the mutated K-ras oncogene, which is pres-ent in most cases of pancreatic cancer, has been detected in the ductal epithelium of some patients with chronic pancreatitis.Genetics of Pancreatic Cancer. Pancreatic carcinogenesis probably involves multiple mutations that are inherited and acquired throughout aging. The K-ras oncogene is currently thought to be the most commonly mutated gene in pancreatic cancer, with approximately 90% of tumors having a mutation.310 This prevalent mutation is present in precursor lesions and is therefore thought to occur early and be essential to pancre-atic cancer development. K-ras mutations can be detected in DNA from serum, stool, pancreatic juice, and tissue aspirates of patients with pancreatic cancer, suggesting that the presence of this mutation or others may provide the basis for diagnostic testing in select individuals. The HER2/neu oncogene, homolo-gous to the epidermal growth factor receptor


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Surgery_Schwartz. suggesting that the presence of this mutation or others may provide the basis for diagnostic testing in select individuals. The HER2/neu oncogene, homolo-gous to the epidermal growth factor receptor (EGFr), is over-expressed in pancreatic cancers.310 This receptor is involved in signal transduction pathways that lead to cellular proliferation. Multiple tumor-suppressor genes are deleted and/or mutated in pancreatic cancer, including p53, p16, and DPC4 (Smad 4), and in a minority of cases, BRCA2.311 Most pancreatic cancers have three or more of the aforementioned mutations.The genetic landscape of pancreatic adenocarcinoma has recently been investigated using exome capture technol-ogy combined with the SOLiD or Illumina next generation sequencing platforms and copy number analysis. Detailed analysis of 99 tumors reaffirmed the importance of the already known mutations such as KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A, and SF3B1 in pancreatic cancer and identified eight novel


Surgery_Schwartz

Surgery_Schwartz. analysis of 99 tumors reaffirmed the importance of the already known mutations such as KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A, and SF3B1 in pancreatic cancer and identified eight novel significantly mutated genes involved in chromatin modification (EPC1 and ARID2), DNA dam-age repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4, and MAGEA6). Pathway-based analysis of recurrently altered genes also revealed the involvement of axon-guidance genes, particularly SLIT/ROBO signaling, in pancreatic carcinogenesis.312 Rapid and sensitive sequencing techniques will hopefully lead to better diagnostic and thera-peutic approaches for pancreatic cancer.It is estimated that up to 10% of pancreatic cancers occur as a result of an inherited genetic predisposition. A family his-tory of pancreatic cancer in a first-degree relative increases the risk of pancreatic cancer by about twofold. Rare familial cancer syndromes that are associated with an increased risk of pancreatic


Surgery_Schwartz

Surgery_Schwartz. of pancreatic cancer in a first-degree relative increases the risk of pancreatic cancer by about twofold. Rare familial cancer syndromes that are associated with an increased risk of pancreatic cancer include BRCA2, the familial atypical multiple mole–melanoma syndrome, hereditary pancreati-tis, familial adenomatous polyposis (FAP), hereditary non-polyposis colorectal cancer, Peutz-Jeghers syndrome, and ataxia-telangiectasia.311Pathology. Pancreatic cancer probably arises through a stepwise progression of cellular changes, just as colon cancer progresses by stages from hyperplastic polyp to invasive cancer. Systematic histologic evaluation of areas surrounding pancreatic cancers has revealed the presence of precursor lesions that have been named pancreatic intraepithelial neoplasia (Fig. 33-67). Three stages of pancreatic intraepithelial neoplasia have been defined. These lesions demonstrate the same oncogene mutations and loss of tumor-suppressor genes found in invasive cancers, the


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Surgery_Schwartz. 33-67). Three stages of pancreatic intraepithelial neoplasia have been defined. These lesions demonstrate the same oncogene mutations and loss of tumor-suppressor genes found in invasive cancers, the frequency of these abnormalities increasing with progressive cellular atypia and architectural disarray.313 The ability to detect these precursor lesions in humans at a stage where the cancer can still be prevented or cured is an important goal of current pancreatic cancer research.About two-thirds of pancreatic adenocarcinomas arise within the head or uncinate process of the pancreas; 15% are in the body, and 10% are in the tail, with the remaining tumors demonstrating diffuse involvement of the gland. Tumors in the pancreatic body and tail are generally larger at the time of diagnosis, and therefore, less commonly resectable. Tumors in the head of the pancreas are typically diagnosed earlier because they cause obstructive jaundice. Ampullary carci-nomas, carcinomas of the distal bile


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Surgery_Schwartz. therefore, less commonly resectable. Tumors in the head of the pancreas are typically diagnosed earlier because they cause obstructive jaundice. Ampullary carci-nomas, carcinomas of the distal bile duct, and periampullary duodenal adenocarcinomas present in a similar fashion to pan-creatic head cancer but have a slightly better prognosis, prob-ably because early obstruction of the bile duct and jaundice leads to the diagnosis.In addition to ductal adenocarcinoma, which makes up about 75% of nonendocrine cancers of the pancreas, there are a variety of less common types of pancreatic cancer. Adenosquamous carcinoma is a variant that has both glandular and squamous differentiation. The biologic behavior of this lesion is unfortunately no better than the typical ductal adenocarcinoma.314 Acinar cell carcinoma is an uncommon type of pancreatic cancer that usually presents as a large tumor, often 10 cm in diameter or more, but the prognosis of patients with these tumors may be better than


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Surgery_Schwartz. cell carcinoma is an uncommon type of pancreatic cancer that usually presents as a large tumor, often 10 cm in diameter or more, but the prognosis of patients with these tumors may be better than with ductal cancer.Diagnosis and Staging. Exact pathologic staging of pancre-atic cancer is important because it allows accurate quantitative assessment of results and comparisons between institutions. The tumor-node-metastasis (TNM) staging of pancreatic cancer was updated by the American Joint Committee on Cancer in 2017 (AJCC) (Table 33-21).The important changes in the staging include more stratification for tumor size and stratification for number of lymph nodes involved. In the new system, tumors ≤2 cm remain as T1 lesions but are subcategorized as T1a (≤0.5 cm), T1b (>0.5–>1 cm), and T1c (1–2 cm). Tumors that are >2–≤4 cm are categorized as T2, and tumors >4 cm are categorized as T3. Tumors that involve the celiac axis, superior mesenteric artery, and/or common hepatic artery are still


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Surgery_Schwartz. cm). Tumors that are >2–≤4 cm are categorized as T2, and tumors >4 cm are categorized as T3. Tumors that involve the celiac axis, superior mesenteric artery, and/or common hepatic artery are still categorized as T4 regardless of size. Metastasis in one to three regional lymph nodes is considered N1 disease, and involvement of ≥4 regional lymph nodes is N2. Patients without nodal involvement (N0) are stages IA, IB, and IIA based on tumor size (T1–T3, respectively). Patients with one to three regional lymph nodes involved (N2) are stage IIB regardless of tumor size. All patients with N2 disease without distant metastases are considered stage III regardless of tumor size. Patients with vascular involvement (T4) are stage III regardless of nodal involvement, and patients with distant metastases are, of course, stage IV.Ten percent of pancreas cancer cases are diagnosed while the cancer is still confined to the primary site (localized stage); 29% are diagnosed after the cancer has spread


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Surgery_Schwartz. are, of course, stage IV.Ten percent of pancreas cancer cases are diagnosed while the cancer is still confined to the primary site (localized stage); 29% are diagnosed after the cancer has spread to regional lymph nodes or directly beyond the primary site; 52% are diagnosed after the cancer has already metastasized (distant stage); and for the remaining 9%, the staging information was unknown. The corresponding 5-year relative survival rates were 31.5% for localized, 11.5% for regional, 2.7% for distant, and 5.1% for unstaged. The overall 5-year relative survival rate for patients with pancreatic cancer for 2007 to 2013 from Surveillance, Epidemiology, and End Results (SEER) was 8.2%.3077Brunicardi_Ch33_p1429-p1516.indd 148501/03/19 6:46 PM 1486SPECIFIC CONSIDERATIONSPART IINormalPanIN-1APanIN-1BPanIN-2KI-67, Topo˜˜°, 14-3-3˛p53, DPC4, BRCA2Cyclin D1MesothelinMucin 1Mucin 1p16PSCA, Mucin5, FascinTelomere K-rasshorteningPanIN-3InvasionABCDFigure 33-67. Pancreatic


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Surgery_Schwartz. Topo˜˜°, 14-3-3˛p53, DPC4, BRCA2Cyclin D1MesothelinMucin 1Mucin 1p16PSCA, Mucin5, FascinTelomere K-rasshorteningPanIN-3InvasionABCDFigure 33-67. Pancreatic intraepithelial neoplasia (PanIN). Histology (top panel) showing grades PanIN-1A (A), PanIN-1B (B), PanIN-2 (C), and PanIN-3 (D), and schema of correlation of histology with mutational events (bottom panel) showing cumulative abnormalities of tumor-promoter and tumor suppressor factors such as kRAS, p53, etc, and their corresponding cellular phenotype. (Reproduced with permis-sion from Hruban RH, Takaori K, Klimstra DS, et al: An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms, Am J Surg Pathol. 2004 Aug;28(8):977-987.)The most critical deficit in the ability to treat pancreatic cancer effectively is the lack of tools for early diagnosis. The pancreas is situated deep within the abdomen, and the early symptoms of pancreatic cancer often are too


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Surgery_Schwartz. ability to treat pancreatic cancer effectively is the lack of tools for early diagnosis. The pancreas is situated deep within the abdomen, and the early symptoms of pancreatic cancer often are too vague to raise sus-picion of the disease. Ultimately, the majority of patients present with pain and jaundice. On physical examination, weight loss is evident and the skin is icteric; a distended gallbladder is palpa-ble in about one-fourth of patients. More fortunate patients have tumors situated such that biliary obstruction and jaundice occurs early and prompts diagnostic tests. Unfortunately, however, the vast majority of patients are not diagnosed until weight loss has occurred—a sign of advanced disease.Although it is often taught that carcinoma of the pancreas presents with painless jaundice (to help distinguish it from cho-ledocholithiasis), this aphorism is not accurate. Most patients do experience pain as part of the symptom complex of pancreatic cancer, and it is often the first


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Surgery_Schwartz. (to help distinguish it from cho-ledocholithiasis), this aphorism is not accurate. Most patients do experience pain as part of the symptom complex of pancreatic cancer, and it is often the first symptom. Therefore, awareness of the way pancreatic pain is perceived may help clinicians sus-pect pancreatic cancer. The pain associated with pancreatic can-cer is usually perceived in the epigastrium but can occur in any Brunicardi_Ch33_p1429-p1516.indd 148601/03/19 6:46 PM 1487PANCREASCHAPTER 33the serum of patients with pancreatic cancer. Serum levels are elevated in about 75% of patients with pancreatic cancer. How-ever, CA19-9 is also elevated in about 10% of patients with benign diseases of the pancreas, liver, and bile ducts.15 CA19-9 is thus neither sufficiently sensitive nor specific to allow an early diagnosis of pancreatic cancer. Despite the fact that many tumor markers such as CA19-9 have been studied, there are still no effective screening tests for pancreatic cancer.


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Surgery_Schwartz. to allow an early diagnosis of pancreatic cancer. Despite the fact that many tumor markers such as CA19-9 have been studied, there are still no effective screening tests for pancreatic cancer. Research tak-ing advantage of recent advances in genomics, gene expression analysis, and proteomics has demonstrated thousands of genes and corresponding proteins that are differentially expressed in pancreatic tumors that have potential for early detection of pan-creatic cancer.316 Some of these proteins would be expected to be expressed at the cell surface or in pancreatic juice and may become useful as biomarkers for pancreatic cancer in the future.In patients presenting with jaundice, a reasonable first diagnostic imaging study is abdominal ultrasound. If bile duct dilation is not seen, hepatocellular disease is likely. Demonstra-tion of cholelithiasis and bile duct dilation suggests a diagnosis of choledocholithiasis, and the next logical step would be ERCP to clear the bile duct. In the


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Surgery_Schwartz. disease is likely. Demonstra-tion of cholelithiasis and bile duct dilation suggests a diagnosis of choledocholithiasis, and the next logical step would be ERCP to clear the bile duct. In the absence of gallstones, malignant obstruction of the bile duct is likely, and a CT scan rather than ERCP would be the next logical step. For patients suspected of having pancreatic cancer who present without jaundice, a CT scan should be the first test.The current diagnostic and staging test of choice for pan-creatic cancer is a multidetector, dynamic, contrast-enhanced CT scan, and the techniques for obtaining high-quality images are constantly improving (Fig. 33-68). The accuracy of CT scan-ning for predicting unresectable disease is about 90% to 95%.317 In contrast, CT scanning is less accurate in predicting resect-able disease. CT scanning will miss small liver metastases, and predicting arterial involvement is sometimes difficult. CT find-ings that indicate a tumor is unresectable include


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Surgery_Schwartz. in predicting resect-able disease. CT scanning will miss small liver metastases, and predicting arterial involvement is sometimes difficult. CT find-ings that indicate a tumor is unresectable include involvement of ≥180° of the celiac axis, hepatic or superior mesenteric artery, enlarged lymph nodes outside the boundaries of resection, asci-tes, and distant metastases (e.g., liver). Invasion of the superior mesenteric vein or portal vein is not in itself a contraindication to resection as long as the veins are patent. Tumors are consid-ered “borderline resectable” if there is 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. Also, patients with CT findings suspicious for metastatic disease, like 1 mm liver lesions too small to characterize or biopsy, are considered “borderline resectable” as are patients with multiple comorbidi-ties or marginal performance status. There is growing consensus that


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Surgery_Schwartz. liver lesions too small to characterize or biopsy, are considered “borderline resectable” as are patients with multiple comorbidi-ties or marginal performance status. There is growing consensus that neoadjuvant treatment should be considered in all patients with any radiographic evidence of extension to adjacent vascu-lar structures.Currently, multidetector CT is probably the single most versatile and cost-effective tool for the diagnosis and staging of pancreatic cancer. Abdominal MRI provides essentially the same information as CT scanning. Positron emission tomog-raphy scanning in locally advanced lesions may help rule out distant metastases. EUS can be used to detect small pancreatic masses that could be missed by CT scanning and is commonly used when there is a high suspicion for pancreatic cancer but no mass is identified by the CT scan. EUS has the added advan-tage of providing the opportunity for transluminal biopsy of pancreatic masses, although a tissue diagnosis before


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Surgery_Schwartz. pancreatic cancer but no mass is identified by the CT scan. EUS has the added advan-tage of providing the opportunity for transluminal biopsy of pancreatic masses, although a tissue diagnosis before pancreati-coduodenectomy is not required. However, in specific patients a histologic diagnosis may be necessary such as for those in a part of the abdomen, and often, but not always, penetrates to the back. When questioned in retrospect, patients often recall mild and vague pain for many months before diagnosis. A low thresh-old for ordering a CT scan with “pancreatic protocol” should be maintained for elderly patients with unex-plained, persistent, although vague, abdominal pain. As men-tioned previously, new-onset diabetes in an elderly patient, especially if combined with vague abdominal pain, should prompt a search for pancreatic cancer.Unfortunately, at this time there is no sensitive and spe-cific serum marker to assist in the timely diagnosis of pan-creatic cancer. With jaundice,


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Surgery_Schwartz. pain, should prompt a search for pancreatic cancer.Unfortunately, at this time there is no sensitive and spe-cific serum marker to assist in the timely diagnosis of pan-creatic cancer. With jaundice, direct hyperbilirubinemia and elevated alkaline phosphatase are expected but do not serve much of a diagnostic role other than to confirm the obvious. With long-standing biliary obstruction, the prothrombin time will be prolonged due to a depletion of vitamin K, a fat-soluble vitamin dependent on bile flow for absorption. CA19-9 is a mucin-associated carbohydrate antigen that can be detected in 8Table 33-21Staging of pancreatic cancerTumor (T)TXTumor cannot be assessedT1Tumor limited to the pancreas,* <2 cmT2Tumor limited to the pancreas,* 2–4 cmT3Tumor limited to the pancreas,* >4 cm; or tumor invading the duodenum or common bile ductT4Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels (celiac axis or the superior mesenteric


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Surgery_Schwartz. >4 cm; or tumor invading the duodenum or common bile ductT4Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels (celiac axis or the superior mesenteric artery)Regional Lymph Node (N)NXRegional lymph nodes cannot be assessedN0No regional lymph node involvementN1Regional lymph node involvementDistant Metastasis (M)M0No distant metastasisM1Distant metastasis M1aMetastasis confined to liver M1bMetastases in at least one extrahepatic site (e.g., lung, ovary, nonregional lymph node, peritoneum, bone) M1cBoth hepatic and extrahepatic metastasesTUMORNODEMETASTASISSTAGET1N0M0IT2N0M0IIT3N0M0IIT4N0M0IIIAny TN1M0IIIAny TAny NM1IVUsed with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.Brunicardi_Ch33_p1429-p1516.indd 148701/03/19 6:46 PM 1488SPECIFIC CONSIDERATIONSPART IIPortal veinStomachHepaticarteryCeliac axisSplenic veinDilated


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Surgery_Schwartz. Manual, 8th Ed. Springer New York, 2017.Brunicardi_Ch33_p1429-p1516.indd 148701/03/19 6:46 PM 1488SPECIFIC CONSIDERATIONSPART IIPortal veinStomachHepaticarteryCeliac axisSplenic veinDilated pancreatic ductin body of pancreasGallbladderPortal veinPortal veinVena cavaDilated bile ductwith stentBody of pancreasGallbladderSplenoportalconfluenceDuodenumMass in headof pancreasMass in head,uncinate processof pancreasSMASMASMADuodenumBile duct stentFat plane between massin head of pancreasand portal veinFigure 33-68. Computed tomography scan demonstrating resectable pancreatic cancer. SMA = superior mesenteric artery.neoadjuvant clinical trial or before chemotherapy in advanced tumors. EUS is a sensitive test for portal/superior mesenteric vein invasion, although it is somewhat less effective at detect-ing superior mesenteric artery invasion. When all of the current staging modalities are used, their accuracy in predicting resect-ability has improved.As imaging continuously improves and


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Surgery_Schwartz. at detect-ing superior mesenteric artery invasion. When all of the current staging modalities are used, their accuracy in predicting resect-ability has improved.As imaging continuously improves and high-quality imag-ing is always obtained before surgery, the chance of bringing a patient to the operating room with the intent of a curative resec-tion and finding upon exploration that the patient has unresect-able disease is becoming increasingly uncommon.In an attempt to avoid such futile laparotomies, prelimi-nary laparoscopy has been advocated for patients with disease felt to be resectable by CT imaging (Fig. 33-69). Diagnostic laparoscopy with the use of US is reported to improve the accu-racy of predicting resectability to about 98%.318 The technique involves more than simple visualization with the scope and requires the placement of multiple ports and manipulation of the tissues. A general exploration of the peritoneal surfaces is carried out. The ligament of Treitz and the base


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Surgery_Schwartz. with the scope and requires the placement of multiple ports and manipulation of the tissues. A general exploration of the peritoneal surfaces is carried out. The ligament of Treitz and the base of the transverse mesocolon are examined for tumor. The gastrocolic ligament is incised, and the lesser sac is examined. The ultrasound probe is used to examine the liver, porta hepatis and the portal vein, the celiac axis, and the superior mesenteric artery.The percentage of patients in whom a positive laparoscopy helps avoid a nontherapeutic laparotomy varies from 10% to 30% in carcinoma of the head of the pancreas, but it may be as high as 50% in patients with tumors in the body and tail of the gland. Resection for pancreatic cancer is being approached laparoscopically, particularly for tumors in the body and tail of the pancreas thus eliminating the need for any separate stag-ing laparoscopy procedure. Also, as the quality of CT scanning has improved, the value of routine diagnostic


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Surgery_Schwartz. in the body and tail of the pancreas thus eliminating the need for any separate stag-ing laparoscopy procedure. Also, as the quality of CT scanning has improved, the value of routine diagnostic laparoscopy has decreased. The morbidity of diagnostic laparoscopy is less than that of laparotomy, and the procedure can be performed on an outpatient basis. Patients who are found to have unresectable disease recover more rapidly from a laparoscopy than a lapa-rotomy and can receive palliative chemotherapy and radiation sooner. The potential immunosuppressive effects of a major surgical procedure also are avoided, as well as the negative psy-chologic impact of a major painful operation with little benefit.Biliary obstruction can be relieved with an endoscopic approach in almost all cases. When large (10F) plastic stents are used, most patients do not require replacement for about 3 months. Metallic wall stents last about 5 months on average and usually fail only with tumor ingrowth.319


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Surgery_Schwartz. large (10F) plastic stents are used, most patients do not require replacement for about 3 months. Metallic wall stents last about 5 months on average and usually fail only with tumor ingrowth.319 Keeping in mind that patients with unresectable pancreatic cancer usually live <1 year, the requirement for numerous stent changes is unlikely.Diagnostic laparoscopy is possibly best applied to patients with pancreatic cancer on a selective basis. Diagnostic laparos-copy will have a higher yield in patients with large tumors (T3, Figure 33-69. Liver metastases identified at diagnostic laparoscopy.Brunicardi_Ch33_p1429-p1516.indd 148801/03/19 6:46 PM 1489PANCREASCHAPTER 33>4 cm), tumors located in the body or tail, patients with equivo-cal findings of metastasis or ascites on CT scan, and patients with other indications of advanced disease such as marked weight loss or markedly elevated CA19-9 (>1000 U/mL). An algorithm for the diagnosis, staging, and treatment of pan-creatic cancer is


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Surgery_Schwartz. with other indications of advanced disease such as marked weight loss or markedly elevated CA19-9 (>1000 U/mL). An algorithm for the diagnosis, staging, and treatment of pan-creatic cancer is shown in Fig. 33-70. In practice, many of these patients are selected for neoadjuvant chemotherapy and then undergo restaging CT and staging laparoscopy prior to surgery.Palliative Surgery and Endoscopy. Most patients with pan-creatic cancer (85–90%) have disease that clearly precludes surgical resection. For these patients, appropriate and effective palliative treatment is critical to the quality of their remaining life. Because of the poor prognosis of the disease, it is not appro-priate to use invasive, toxic, and expensive regimens in patients with extremely advanced disease and poor performance status. When patients do desire antineoplastic therapy, it is important to encourage them to enroll in clinical trials so that therapeutic advances can be made. In general, there are three clinical


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Surgery_Schwartz. status. When patients do desire antineoplastic therapy, it is important to encourage them to enroll in clinical trials so that therapeutic advances can be made. In general, there are three clinical prob-lems in advanced pancreatic cancer that require palliation: pain, jaundice, and duodenal obstruction. The mainstay of pain con-trol is oral narcotics. Sustained-release preparations of morphine sulfate are frequently used. Invasion of retroperitoneal nerve trunks accounts for the severe pain experienced by patients with advanced pancreatic cancer. A celiac plexus nerve block can control pain effectively for a period of months, although the procedure sometimes needs to be repeated.320Jaundice is present in the majority of patients with pan-creatic cancer, and the most troublesome aspect for the patient is the accompanying pruritus. Biliary obstruction may also lead to cholangitis, coagulopathy, digestive symptoms, and hepato-cellular failure. In the past, surgeons traditionally


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Surgery_Schwartz. for the patient is the accompanying pruritus. Biliary obstruction may also lead to cholangitis, coagulopathy, digestive symptoms, and hepato-cellular failure. In the past, surgeons traditionally performed a biliary and enteric bypass when unresectable disease was found at laparotomy. This is an increasingly uncommon situation for the surgeon because locally advanced unresectable disease is now detected by high-quality preoperative imaging. Metastatic disease is also more reliably predicted by preoperative imaging and, in select cases, staging laparoscopy.In current practice, jaundice is usually palliated by an endoscopic biliary stent, often prior to surgical referral. Duo-denal obstruction is usually a late event in pancreatic cancer and occurs in only about 20% of patients.321 In cases of biliary and duodenal obstruction, several options need to be consid-ered. Endoscopic metallic duodenal stents are an option, but the patient’s poor prognosis, the cost, and the fact that duodenal


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Surgery_Schwartz. of biliary and duodenal obstruction, several options need to be consid-ered. Endoscopic metallic duodenal stents are an option, but the patient’s poor prognosis, the cost, and the fact that duodenal stents often do not result in ideal palliation has to be considered. The results of three RCTs examining endoscopic metallic stent-ing for malignant gastric outlet obstruction demonstrated that major and minor complications were comparable to gastrojeju-nostomy but time to tolerating oral intake and hospital stay was shorter.322 Robot-assisted laparoscopic biliary-enteric bypass is now available at many centers. Although this should result in similar palliation as an open bypass and may be associated with more rapid recovery, the potential complications, the patient’s life expectancy, and cost of this procedure must be considered. As many patients today already have a bile duct stent in place by the time of referral to a surgeon, it is not clear that operative biliary bypass is required.


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Surgery_Schwartz. of this procedure must be considered. As many patients today already have a bile duct stent in place by the time of referral to a surgeon, it is not clear that operative biliary bypass is required. In patients with extensive metastases, an alternative short-term palliative option to consider in patients with gastric outlet obstruction is a percutaneous endoscopic gas-trostomy tube or gastrojejunal feeding tube that allows decom-pression of the stomach and feeding into the jejunum.If an operative bypass is performed, choledochojejunos-tomy is the preferred approach. Although an easy procedure to perform, choledochoduodenostomy is felt to be unwise because of the proximity of the duodenum to tumor. Some have discour-aged the use of the gallbladder for biliary bypass; however, it CT scanQuad phaseMultidetectorFine cutsUnresectablemassCT or EUSguided biopsyClinicaltrialResectable massNo mass butsuspicion remainsClinical trialDiagnosticlaparoscopy(selective)EUS


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Surgery_Schwartz. however, it CT scanQuad phaseMultidetectorFine cutsUnresectablemassCT or EUSguided biopsyClinicaltrialResectable massNo mass butsuspicion remainsClinical trialDiagnosticlaparoscopy(selective)EUS biopsydiagnosticlaparoscopyNeoadjuvantclinicaltrialERCP / EUSObserve/reimageWhippleprocedureFigure 33-70. Diagnostic and treatment algorithm for pancreatic cancer. If computed tomography (CT) scan demonstrates a potentially resectable tumor, patients are offered participation in a clinical trial after histologic confirmation by CT or endoscopic ultrasound (EUS)-guided biopsy. If CT scan demonstrates resectable disease, diagnostic laparoscopy is used selectively in patients with tumors in the body/tail, equivocal findings of metastasis or CT scan, ascites, high CA19-9, or marked weight loss. Patients also have diagnostic laparoscopy if they elect to participate in a neoadjuvant clinical trial. In cases where no mass is demonstrated on CT scan, but suspicion of cancer remains, EUS or endoscopic


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Surgery_Schwartz. also have diagnostic laparoscopy if they elect to participate in a neoadjuvant clinical trial. In cases where no mass is demonstrated on CT scan, but suspicion of cancer remains, EUS or endoscopic retrograde cholangiopancreatography (ERCP) with brushings are performed, and the CT may be repeated after an interval of observation.Brunicardi_Ch33_p1429-p1516.indd 148901/03/19 6:46 PM 1490SPECIFIC CONSIDERATIONSPART IIis suitable as long as the cystic duct clearly enters the common duct well above the tumor. The jejunum is brought anterior to the colon, if possible, rather than retrocolic, where the tumor potentially would invade the bowel sooner. Some surgeons use a loop of jejunum with a jejunojejunostomy to divert the enteric stream away from the biliary-enteric anastomosis. Others use a Roux-en-Y limb with the gastrojejunostomy located 50 cm downstream from the hepaticojejunostomy (Fig. 33-71). Poten-tial advantages of the defunctionalized Roux-en-Y limb include the ease with


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Surgery_Schwartz. use a Roux-en-Y limb with the gastrojejunostomy located 50 cm downstream from the hepaticojejunostomy (Fig. 33-71). Poten-tial advantages of the defunctionalized Roux-en-Y limb include the ease with which it will reach up to the hepatic hilum, prob-able decreased risk of cholangitis, and easier management of biliary anastomotic leaks. If a gastrojejunostomy is performed, it should be placed dependently and posterior along the greater Figure 33-71. Biliary-enteric bypass to palliate unresectable pan-creatic cancer. (Reproduced with permission from Bell RH, Rikkers LF, Mulholland M: Digestive Tract Surgery: A Text and Atlas. Philadelphia, PA: Lippincott Williams & Wilkins; 1996.)Figure 33-72. Expandable metallic biliary stent. After ERCP cannulation of the distal bile duct (left) the stent is advanced over the cannula and placed across the obstruction in the distal bile duct (right).curvature to improve gastric emptying, and a vagotomy should not be performed. Endoscopic stents are


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Surgery_Schwartz. is advanced over the cannula and placed across the obstruction in the distal bile duct (right).curvature to improve gastric emptying, and a vagotomy should not be performed. Endoscopic stents are definitely not as dura-ble as a surgical bypass. Recurrent obstruction and cholangitis is more common with stents and results in inferior palliation. However, the endoscopic approach is associated with consider-ably less initial morbidity and mortality than surgical bypass. Expandable metallic wall stents have superior patency and pro-vide better palliation than plastic stents (Fig. 33-72).If an initial diagnostic laparoscopy reveals a contraindica-tion to the Whipple procedure, such as liver metastases, it is not appropriate to perform a laparotomy simply to create a biliary bypass. In such a patient, it is better to place an endoscopic stent. In contrast, in the uncommon scenario where a laparotomy has already been performed as part of the assessment of resectability and the Whipple


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Surgery_Schwartz. a patient, it is better to place an endoscopic stent. In contrast, in the uncommon scenario where a laparotomy has already been performed as part of the assessment of resectability and the Whipple procedure is not possible, a surgical bypass is usually performed. However, if the patient has a functioning endoscopic stent already in place, it may be reasonable to forego surgical bypass.Chemotherapy and Radiation for Locally Advanced/ Metastatic Disease. Patients with locally advanced unresectable disease are treated with chemotherapy and possibly radiation, and patients with stage IV metastatic disease are treated with systemic chemotherapy. The role of RT in unresectable, locoregionally advanced pancreas cancer remains controversial. RT may slow the progression of local disease and possibly alleviate or prevent symptoms including pain, biliary obstruction, bleeding, and bowel obstruction. However, the likelihood of micrometastatic distant disease is high, treatment is not expected to


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Surgery_Schwartz. alleviate or prevent symptoms including pain, biliary obstruction, bleeding, and bowel obstruction. However, the likelihood of micrometastatic distant disease is high, treatment is not expected to be curative, and radiation can result in toxicity. Stereotactic body radiotherapy (SBRT) has been used to limit toxicity by targeting high-dose short-course radiation to enhance local response prior to surgery. In a phase 2 multi-institutional trial evaluating gemcitabine and SBRT in patients with locally advanced unresectable pancreatic cancer, 10% of patients with locally advanced disease who would not have been candidates for initial surgery were deemed to have resectable tumors following therapy, and 8% ultimately underwent R0 and node-negative resection.323 A number of chemotherapy regimens are available for pancreatic cancer, but the results are not impressive. Gemcitabine (Gemzar) was approved by the U.S. Food and Drug Administration (FDA) for use in pancreatic cancer in 1996. In


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Surgery_Schwartz. are available for pancreatic cancer, but the results are not impressive. Gemcitabine (Gemzar) was approved by the U.S. Food and Drug Administration (FDA) for use in pancreatic cancer in 1996. In patients with unresectable pancreatic cancer, gemcitabine results in symptomatic Brunicardi_Ch33_p1429-p1516.indd 149001/03/19 6:46 PM 1491PANCREASCHAPTER 33improvement, improved pain control and performance status, and weight gain.324 However, survival is improved by only 1 to 2 months. Prior to gemcitabine, 5-fluorouracil (5-FU) was used as the standard treatment for unresectable pancreatic cancer. Both of these drugs are still used today. 5-FU or capecitabine (Xeloda), a similar but orally administered drug, are frequently used as a radiosensitizer during radiation therapy. Single-agent gemcitabine is still commonly used in patients with a poor performance status.Erlotinib (Tarceva) was approved in 2005 based on very minimal improvement in overall survival in combination with


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Surgery_Schwartz. gemcitabine is still commonly used in patients with a poor performance status.Erlotinib (Tarceva) was approved in 2005 based on very minimal improvement in overall survival in combination with gemcitabine.325 The study showed that erlotinib in combination with gemcitabine results in a statistically significant improve-ment in overall survival in patients with advanced pancreatic cancer in the first-line setting. Although the absolute benefit in overall survival was modest with a median survival difference between the two arms of only 2 weeks.FOLFIRINOX, a combination of three chemotherapy drugs (5-FU/leucovorin, irinotecan, and oxaliplatin) is now commonly used as first-line treatment for metastatic pancreatic adenocarcinoma in patients with a relatively good performance status. In 2010, a Phase 3 clinical trial showed positive results for patients treated with FOLFIRINOX.326 The objective response rate was improved from 9% to 32%, and median overall survival of patients with


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Surgery_Schwartz. 2010, a Phase 3 clinical trial showed positive results for patients treated with FOLFIRINOX.326 The objective response rate was improved from 9% to 32%, and median overall survival of patients with metastatic pancreatic cancer improved from 7 to 11 months, but the improvement was associated with increased toxicity, so patient selection is important. Patients treated with FOLFIRINOX may experience more severe side effects than those treated with gemcitabine alone, so this combination is usu-ally reserved for patients with a good performance status.In 2013, another combination therapy was approved as first-line treatment for metastatic pancreatic adenocarcinoma.327 Albumin-bound paclitaxel (Abraxane) was approved to be used in combination with gemcitabine (Gemzar). The median overall survival was improved to 8.5 months in the nabpaclitaxel–gemcitabine group as compared with 6.7 months in the gemcitabine group. Progression-free survival and the response rate were also improved. Rates of


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Surgery_Schwartz. was improved to 8.5 months in the nabpaclitaxel–gemcitabine group as compared with 6.7 months in the gemcitabine group. Progression-free survival and the response rate were also improved. Rates of peripheral neuropathy and myelosuppression were increased, but this regimen is less toxic than FOLFIRINOX.In 2015, Irinotecan (ONIVYDE), in combination with 5-FU (fluorouracil) and leucovorin, was approved as treatment for met-astatic pancreatic adenocarcinoma that has progressed following treatment with a gemcitabine based therapy.328 The median over-all survival in patients assigned to nanoliposomal irinotecan plus fluorouracil and folinic acid was 6.1 months vs. 4.2 months with fluorouracil and folinic acid. Common side effects for this second-line therapy were neutropenia, diarrhea, vomiting, and fatigue.These results may warrant treatment in patients who understand the benefits and risks. However, the lack of signifi-cant survival advantage should encourage physicians to refer motivated


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Surgery_Schwartz. and fatigue.These results may warrant treatment in patients who understand the benefits and risks. However, the lack of signifi-cant survival advantage should encourage physicians to refer motivated patients for experimental protocols because it is only through continued clinical research that more meaningful treat-ments for pancreatic cancer will be developed.Ablation for Locally Advanced Unresectable Disease. Persistent arterial vascular encasement after neoadjuvant therapy contraindicates resection. Irreversible electroporation utilizes delivery of high-voltage millisecond electrical pulses resulting in permanent disruption of the cellular membranes and subsequent apoptosis. This process leads to cell death, but does not injure the extracellular matrix, thus allowing cellular tumor ablation while preserving structural components of tissues. Collagen-based structures such as vessels or the pancreatic duct are not disrupted. Furthermore, because IRE is not based on thermal damage of


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Surgery_Schwartz. while preserving structural components of tissues. Collagen-based structures such as vessels or the pancreatic duct are not disrupted. Furthermore, because IRE is not based on thermal damage of cancer cells, the heat-sink phenomenon is not a concern, and even lesions abutting large vessels can be ablated with radical intent. Irreversible electroporation using the Nanoknife is reported to enable treatment of pancreatic tumors abutting vascular structures without compromise of the vessels or concern for the heat sink effect of nearby blood flow.329 Martin has created a registry and accumulated multi-institutional data on 200 patients with locally advanced pancreatic cancer showing OS of 28.3 months for patients with borderline resectable pancreatic cancer and 23.2 months in patients with unresectable pancreatic cancer. Those numbers compare favorably with the survival of patients treated with chemoradiation alone, which is 13 months in historical controls.330 This modality is new, but


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Surgery_Schwartz. pancreatic cancer. Those numbers compare favorably with the survival of patients treated with chemoradiation alone, which is 13 months in historical controls.330 This modality is new, but these early reports indicate it may be safe in combination with chemotherapy and are of particular interest because of the potential to down stage and offer surgery to patients initially diagnosed with locally advanced unresectable disease. It is also important to understand that a significant learning curve exists to achieve safety and optimization of the technique. Proper patient selection, technical ability with intraoperative ultrasound to allow precise IRE electrode bracketing, and standardization of the IRE energy delivery is important. Randomized prospective trials are needed before adoption of this technique can be expanded.Surgical Resection: Pancreaticoduodenectomy. In a patient with appropriate clinical and/or imaging indications of pancreatic cancer, a tissue diagnosis before performing a


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Surgery_Schwartz. technique can be expanded.Surgical Resection: Pancreaticoduodenectomy. In a patient with appropriate clinical and/or imaging indications of pancreatic cancer, a tissue diagnosis before performing a pancreaticoduo-denectomy is not essential. Although percutaneous CT-guided biopsy is usually safe, complications such as hemorrhage, pan-creatitis, fistula, and abscess can occur. Tumor seeding along the subcutaneous tract of the needle is uncommon. Likewise, FNA under EUS guidance is safe and well tolerated. The prob-lem with preoperative or even intraoperative biopsy is that many pancreatic cancers are not very cellular and contain a significant amount of fibrous tissue, so a biopsy may be misinterpreted as showing chronic pancreatitis if it does not contain malignant glandular cells. In the face of clinical and radiologic preoperative indications of pancreatic cancer, a negative biopsy should not preclude resection. In patients who are not candidates for resec-tion because of metastatic


Surgery_Schwartz

Surgery_Schwartz. face of clinical and radiologic preoperative indications of pancreatic cancer, a negative biopsy should not preclude resection. In patients who are not candidates for resec-tion because of metastatic disease, biopsy for a tissue diagnosis becomes important because these patients may be candidates for palliative chemotherapy trials. It is especially important to make an aggressive attempt at tissue diagnosis before surgery in patients whose clinical presentation and imaging studies are more suggestive of alternative diagnoses such as pancreatic lym-phoma or pancreatic islet cell tumors. These patients might avoid surgery altogether in the case of lymphoma or warrant an aggres-sive approach in the case of islet cell carcinoma.Pancreaticoduodenectomy can be performed through a midline incision from xiphoid to umbilicus or through a bilat-eral subcostal incision. The initial portion of the procedure is an assessment of resectability. The liver and visceral and parietal peritoneal surfaces


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Surgery_Schwartz. from xiphoid to umbilicus or through a bilat-eral subcostal incision. The initial portion of the procedure is an assessment of resectability. The liver and visceral and parietal peritoneal surfaces are thoroughly assessed. The gastrohepatic omentum is opened, and the celiac axis area is examined for enlarged lymph nodes. The base of the transverse mesocolon is examined for tumor involvement.The ascending and hepatic flexure of the colon are mobi-lized off the duodenum and head of the pancreas and reflected medially. A Kocher maneuver is performed by dissecting behind Brunicardi_Ch33_p1429-p1516.indd 149101/03/19 6:46 PM 1492SPECIFIC CONSIDERATIONSPART IIthe head of the pancreas. The superior mesenteric vein is identi-fied early in the case and dissected up toward the inferior border of the neck of the pancreas. The gastroepiploic vein and artery are ligated to prevent any traction injury. Often, the middle colic vein and right gastroepiploic vein share a common trunk before


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Surgery_Schwartz. of the neck of the pancreas. The gastroepiploic vein and artery are ligated to prevent any traction injury. Often, the middle colic vein and right gastroepiploic vein share a common trunk before entering into the superior mesenteric vein. Knowledge of this anatomy helps reduce injury to the veins and unnecessary blood loss. The relation of the tumor to the superior mesenteric vein and artery cannot be accurately assessed by palpation at this point and is not completely determined until later in the opera-tion when the neck of the pancreas is divided and the surgeon is committed to resection. Mesenteric vascular involvement is best determined by a high quality preoperative CT scan.It is important to assess for an aberrant right hepatic artery, which is present in 20% of patients. The aberrant artery com-monly arises from the superior mesenteric artery posterior to the pancreas and ascends parallel and adjacent to the superior mesenteric and portal veins. The presence of an aberrant


Surgery_Schwartz

Surgery_Schwartz. artery com-monly arises from the superior mesenteric artery posterior to the pancreas and ascends parallel and adjacent to the superior mesenteric and portal veins. The presence of an aberrant right hepatic artery should be apparent on the preoperative CT scan and can be identified intraoperatively by palpation on the back side of the hepatoduodenal ligament, where a prominent pulse will be felt posterior and to the right of the portal vein.The porta hepatis is examined. Enlarged or firm lymph nodes that can be swept down toward the head of the pancreas with the specimen do not preclude resection. If the assessment phase reveals no contraindications to the Whipple procedure (Table 33-22), the resection phase commences.If the pylorus is to be preserved, the stomach and proximal duodenum are mobilized off the pancreas, preserving the gastroepiploic vessels down to the pylorus. The proximal hepatic artery is identified usually by removing a lymph node that commonly lies just anterior to


Surgery_Schwartz

Surgery_Schwartz. mobilized off the pancreas, preserving the gastroepiploic vessels down to the pylorus. The proximal hepatic artery is identified usually by removing a lymph node that commonly lies just anterior to the artery. The hepatic artery is dissected and traced toward the porta hepatis. The gastroduodenal branch of the hepatic artery is identified. A test clamping is performed to ensure that a strong pulse remains in the proper hepatic artery before division of the gastroduodenal artery. In cases of celiac occlusion, flow comes from the superior mesenteric artery and retrograde through the gastroduodenal artery to the proper hepatic artery. Ligation of the gastroduodenal in this case would be equivalent to hepatic artery ligation. A bypass to the hepatic artery would be required. Once the test clamping is negative and the gastroduodenal artery is divided, the hepatic artery is retracted medially, and the common bile duct is retracted laterally to reveal the anterior surface of the portal vein


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Surgery_Schwartz. is negative and the gastroduodenal artery is divided, the hepatic artery is retracted medially, and the common bile duct is retracted laterally to reveal the anterior surface of the portal vein behind them. Dissection is performed only on the anterior surface of the vein. If there is no tumor involvement, the neck of the Table 33-22Findings at explorationFindings contraindicating resection Liver metastases (any size) Celiac lymph node involvement Peritoneal implants Hepatic hilar lymph node involvementFindings not contraindicating resection Invasion at duodenum or distal stomach Involved peripancreatic lymph nodes Involved lymph nodes along the porta hepatis that can be swept down with the specimenpancreas will separate from the vein easily. A large, blunt-tipped clamp is a safe instrument to use for this dissection. The tunnel under the neck of the pancreas can then be completed mostly under direct vision from inferior and superior.The gallbladder is then mobilized from the liver,


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Surgery_Schwartz. to use for this dissection. The tunnel under the neck of the pancreas can then be completed mostly under direct vision from inferior and superior.The gallbladder is then mobilized from the liver, the cystic duct and artery are ligated, and the gallbladder is removed. The common hepatic duct is circumferentially dissected. Either the duodenum is divided 2 cm distal to the pylorus (which defines the procedure as a pylorus-preserving pancreaticoduodenectomy, or PPPD) or the antrum is divided, as classically described by Whipple. The jejunum is divided beyond the ligament of Treitz, and the mesentery is ligated until the jejunum can be delivered posterior to the superior mesenteric vessels from left to right.The common hepatic duct is then divided usually just above the entrance of the cystic duct, and the bile duct is dis-sected down to the superior margin of the duodenum. Inferior traction on the distal bile duct opens the plane to make visible the anterior portion of the portal vein.


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Surgery_Schwartz. duct, and the bile duct is dis-sected down to the superior margin of the duodenum. Inferior traction on the distal bile duct opens the plane to make visible the anterior portion of the portal vein. The pancreatic neck is divided anterior to the portal vein (Fig. 33-73). The use of cau-tery is avoided in the area of the pancreatic duct. The pancreatic head and uncinate process then are dissected off of the right lateral aspect of the superior mesenteric vein, ligating the fragile branches draining the head and uncinate process into the portal vein (Fig. 33-74). The uncinate process is then dissected off of the posterior and lateral aspect of the superior mesenteric artery. This can be the most tedious portion of the operation, Figure 33-73. Division of the pancreatic neck. The pancreatic neck is separated from the anterior surface of the portal vein and then divided. If there is no tumor involvement, the neck of the pan-creas will separate from the vein easily. A large, blunt-tipped


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Surgery_Schwartz. neck is separated from the anterior surface of the portal vein and then divided. If there is no tumor involvement, the neck of the pan-creas will separate from the vein easily. A large, blunt-tipped clamp is a safe instrument to use for this dissection. (Reproduced with per-mission from Bell RH, Rikkers LF, Mulholland M: Digestive Tract Surgery: A Text and Atlas. Philadelphia, PA: Lippincott Williams & Wilkins; 1996.)Brunicardi_Ch33_p1429-p1516.indd 149201/03/19 6:46 PM 1493PANCREASCHAPTER 33Figure 33-74. Dissection of the pancreatic head and uncinate pro-cess. The pancreatic head and uncinate process are dissected off of the right lateral aspect of the superior mesenteric vein and portal vein by ligating the fragile venous branches. (Reproduced with per-mission from Bell RH, Rikkers LF, Mulholland M: Digestive Tract Surgery: A Text and Atlas. Philadelphia, PA: Lippincott Williams & Wilkins; 1996.)but thoroughly clearing all tissue from the mesenteric vessels helps avoid


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Surgery_Schwartz. Rikkers LF, Mulholland M: Digestive Tract Surgery: A Text and Atlas. Philadelphia, PA: Lippincott Williams & Wilkins; 1996.)but thoroughly clearing all tissue from the mesenteric vessels helps avoid incomplete resection. The wound is irrigated and meticulous hemostasis is assured at this point because the view of the portal vein area and retroperitoneum is more difficult after the reconstruction phase is completed.The reconstruction involves anastomoses of the pancreas first, then the bile duct, and, finally, the duodenum or stomach. There are various techniques for the pancreatic anastomoses. After the pancreatic anastomosis is completed, the choledocho-jejunostomy is performed about 10 cm down the jejunal limb from the pancreatic anastomosis. This is usually performed in an end-to-side fashion with one layer of interrupted sutures. The duodenojejunostomy or gastrojejunostomy is performed another 10 to 15 cm downstream from the biliary anastomosis, using a two-layer


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Surgery_Schwartz. an end-to-side fashion with one layer of interrupted sutures. The duodenojejunostomy or gastrojejunostomy is performed another 10 to 15 cm downstream from the biliary anastomosis, using a two-layer technique.Pancreaticoduodenectomy With Vascular Resection. Accurate staging of pancreatic cancer with a high-quality pre-operative CT scan is extremely important. Involvement of the superior mesenteric artery, the celiac axis, or hepatic artery indicate a T4/stage 3 tumor that is locally advanced and unre-sectable. However, involvement of the portal vein or superior mesenteric vein does not necessarily preclude resection as long as there is a patent superior mesenteric vein-portal vein conflu-ence. Reconstruction can often be accomplished with a primary anastomosis of the vein. When resection of more than 2 cm of vein is required, an interposition graft such as the internal jugu-lar vein can be used for a tension-free reconstruction.In a systematic review of 28 retrospective studies from


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Surgery_Schwartz. of more than 2 cm of vein is required, an interposition graft such as the internal jugu-lar vein can be used for a tension-free reconstruction.In a systematic review of 28 retrospective studies from high-volume pancreas centers, the morbidity, mortality, and survival outcome after undertaking extended pancreaticoduodenectomy with vascular resection for pancreatic cancer with venous involvement and/or limited arterial involvement was acceptable.331 Another more recent report from five teaching hospitals demonstrated that the Whipple procedure combined with vascular resection and reconstruction could achieve complete removal of tumors without significantly increasing the mortality rate, and the median survival time was higher than that of patients who underwent palliative treatment.332 However, contrary to the findings of analyses from expert pancreas centers, a retrospective cohort analysis using the National Surgical Quality Improvement Program data from 2005 to 2009 demonstrated


Surgery_Schwartz

Surgery_Schwartz. However, contrary to the findings of analyses from expert pancreas centers, a retrospective cohort analysis using the National Surgical Quality Improvement Program data from 2005 to 2009 demonstrated increased 30-day postoperative morbidity and mortality in pancreaticoduodenectomy with vein resection when compared with pancreaticoduodenectomy alone.333 These data indicate that pancreaticoduodenectomy with vascular resection is only a reasonable option when it is performed after neoadjuvant therapy and at very-high-volume centers where the morbidity of the operation can be kept to a minimum.Minimally Invasive Pancreatectomy. Laparoscopic distal pancreatectomy has been proven to be safe and is appropriate for essentially all indications for pancreatectomy. This approach is associated with decreased blood loss and quicker recovery. Centrally located lesions near the splenoportal confluence must be approached laparoscopically with caution. Robotic technology may make dissection and


Surgery_Schwartz

Surgery_Schwartz. with decreased blood loss and quicker recovery. Centrally located lesions near the splenoportal confluence must be approached laparoscopically with caution. Robotic technology may make dissection and control of major vessels in this area easier and perhaps safer. Interest in laparoscopic pancreaticoduodenectomy is increasing throughout the United States with some early adopters reporting excellent outcomes comparable to the open procedure.334 Early results indicate this technique is feasible, but considerable expertise is required in both open pancreatic resection as well as advanced laparoscopic techniques to achieve these outcomes. Whether the advantages seen in other areas of minimally invasive surgery apply to the Whipple procedure is an area of current investigation.Variations and Controversies. The preservation of the pylorus has several theoretical advantages, including preven-tion of reflux of pancreaticobiliary secretions into the stomach, decreased incidence of marginal


Surgery_Schwartz

Surgery_Schwartz. Controversies. The preservation of the pylorus has several theoretical advantages, including preven-tion of reflux of pancreaticobiliary secretions into the stomach, decreased incidence of marginal ulceration, normal gastric acid secretion and hormone release, and improved gastric function. Patients with pylorus-preserving resections have appeared to regain weight better than historic controls in some studies. Return of gastric emptying in the immediate postoperative period may take longer after the pylorus-preserving operation, and it is controversial whether there is any significant improve-ment in long-term quality of life with pyloric preservation.335-336Techniques for the pancreaticojejunostomy include end-to-side or end-to-end and duct-to-mucosa sutures or invagination (Fig. 33-75). Pancreaticogastrostomy has also been investigated.Some surgeons use stents, glue to seal the anastomosis, or octreotide to decrease pancreatic secretions. No matter what com-bination of these


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Surgery_Schwartz. 33-75). Pancreaticogastrostomy has also been investigated.Some surgeons use stents, glue to seal the anastomosis, or octreotide to decrease pancreatic secretions. No matter what com-bination of these techniques is used, the clinically significant pan-creatic leakage rate is always about 10%. Therefore, the choice of techniques depends more on the surgeon’s personal experience.Traditionally, most surgeons place drains around the pan-creatic and biliary anastomoses because disruption of the pan-creaticojejunostomy cannot be avoided in one out of 10 patients. Brunicardi_Ch33_p1429-p1516.indd 149301/03/19 6:46 PM 1494SPECIFIC CONSIDERATIONSPART IIThis complication can lead to the development of an upper abdominal abscess or can present as an external pancreatic fis-tula. Usually, a pure pancreatic leak is controlled by the drains and will eventually seal spontaneously. Combined pancreatic and biliary leaks are cause for concern because bile will activate the pancreatic enzymes. In its


Surgery_Schwartz

Surgery_Schwartz. leak is controlled by the drains and will eventually seal spontaneously. Combined pancreatic and biliary leaks are cause for concern because bile will activate the pancreatic enzymes. In its most virulent form, disruption leads to necrotizing retroperitoneal infection, which can erode major arteries and veins of the upper abdomen, including the exposed portal vein and its branches or the stump of the gastro-duodenal artery. Impending catastrophe is often preceded by a small herald bleed from the drain site. Depending on the clinical situation, such an event is an indication to perform an angio-gram or return the patient to the operating room to widely drain the pancreaticojejunostomy and to repair the involved blood vessel. Open packing may be necessary to control diffuse necro-sis and infection. Some studies have questioned the practice of routine drain placement after pancreatectomy with reliance on postoperative percutaneous drainage when leaks occur.337 How-ever, a randomized,


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Surgery_Schwartz. infection. Some studies have questioned the practice of routine drain placement after pancreatectomy with reliance on postoperative percutaneous drainage when leaks occur.337 How-ever, a randomized, controlled, multicenter trial showed that patients who develop a leak after pancreaticoduodenectomy are ABCDEFigure 33-75. Techniques for pancreaticojejunostomy. A to D. Duct-to-mucosa, end-to-side E. Intraoperative photographs of end-to-side pancreaticojejunostomy. F to J. End-to-end invagination. K to O. End-to-side invagination.Brunicardi_Ch33_p1429-p1516.indd 149401/03/19 6:46 PM 1495PANCREASCHAPTER 33FGHIJFigure 33-75. (Continued)at a substantially increased risk of mortality if a drain was not placed at the time of resection.337 In contrast, the outcome does not seem to be as dramatically affected by drain placement in the setting of distal pancreatectomy.338 In the absence of a fis-tula, drains should be removed early in the postoperative period, preferably by postoperative day


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Surgery_Schwartz. affected by drain placement in the setting of distal pancreatectomy.338 In the absence of a fis-tula, drains should be removed early in the postoperative period, preferably by postoperative day 5.339Many patients with pancreatic cancer are malnourished preoperatively and suffer from gastroparesis in the immedi-ate postoperative period. Routine placement of a feeding jeju-nostomy tube and gastrostomy tube has become less common, and most surgeons use these tubes selectively. Gastrostomy tubes may decrease the length of stay in patients who might Brunicardi_Ch33_p1429-p1516.indd 149501/03/19 6:46 PM 1496SPECIFIC CONSIDERATIONSPART IIKLNOMFigure 33-75. (Continued)be predicted to have severe gastroparesis. Jejunostomy tubes are certainly not benign and can result in leaks and intestinal obstruction. However, parenteral nutrition is also associated with serious complications such as line sepsis, loss of gut muco-sal integrity, and hepatic dysfunction. Enteric tubes should be considered


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Surgery_Schwartz. However, parenteral nutrition is also associated with serious complications such as line sepsis, loss of gut muco-sal integrity, and hepatic dysfunction. Enteric tubes should be considered in patients at risk such as malnourished patients who have received neoadjuvant chemotherapy.Because of the high incidence of direct retroperitoneal invasion and regional lymph node metastasis at the time of surgery, trails of more extended resections including extension of the pancreatic resection to the middle body of the pancreas, segmental resection of the portal vein, if necessary, resection of retroperitoneal tissue along the right perinephric area, and lymphadenectomy to the region of the celiac plexus were exam-ined. In the hands of experienced surgeons, these techniques are associated with greater blood loss but no increase in mortality. However, improved survival has not been demonstrated. Total pancreatectomy has also been considered in the past. Although pancreatic leaks are eliminated,


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Surgery_Schwartz. blood loss but no increase in mortality. However, improved survival has not been demonstrated. Total pancreatectomy has also been considered in the past. Although pancreatic leaks are eliminated, major morbidity from brittle diabetes and exocrine insufficiency outweigh any theoretical benefit.Pancreatic cancer can recur locally after pancreaticoduo-denectomy. Intraoperative radiotherapy (IORT) delivers radia-tion to the operative bed at the time of resection. Radiation to Brunicardi_Ch33_p1429-p1516.indd 149601/03/19 6:46 PM 1497PANCREASCHAPTER 33surrounding normal areas is minimized, but the radiation is delivered all in one setting, rather than in fractionated doses over time. Favorable results were recently reported among a series of patients with locally advanced unresectable or border-line-resectable PDAC who received intensive neoadjuvant treat-ment followed by exploratory laparotomy and IORT.340Complications of Pancreaticoduodenectomy. The operative mortality rate for


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Surgery_Schwartz. or border-line-resectable PDAC who received intensive neoadjuvant treat-ment followed by exploratory laparotomy and IORT.340Complications of Pancreaticoduodenectomy. The operative mortality rate for pancreaticoduodenectomy has decreased to <5% in high-volume centers (where individual surgeons perform more than 15 cases per year), suggesting that patients in rural areas would benefit from referral to large urban centers.341-342 The most common causes of death are sepsis, hemorrhage, and cardiovascular events. Postoperative complications are unfortunately still very common and include delayed gastric emptying, pancreatic fistula, and hemorrhage.Delayed gastric emptying is common after pancreatico-duodenectomy and is treated conservatively as long as complete gastric outlet obstruction is ruled out by a contrast study. In the acute phase, intravenous erythromycin may help, but the prob-lem usually improves with time.Considerable attention has been focused on the preven-tion of


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Surgery_Schwartz. is ruled out by a contrast study. In the acute phase, intravenous erythromycin may help, but the prob-lem usually improves with time.Considerable attention has been focused on the preven-tion of pancreatic leak after pancreas resection. Modifications of the anastomotic technique (end-to-side or end-to-end, duct-to-mucosa, or invaginated), the use of jejunum or the stomach for drainage, the use of pancreatic duct stents, the use of octreotide, and various sealants have all been evaluated.Long-acting synthetic analogues of somatostatin have been evaluated as a pharmacologic therapy to reduce pancreatic secretion and the rate of pancreatic fistula after pancreatic resec-tion. Some European studies supported benefit particularly in selected higher risk patients, while previous North American tri-als concluded there was no benefit.343-349 A recent single-center, randomized trial with pasireotide (a newer analog) suggested potential benefit.350Many technical modifications to the classic


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Surgery_Schwartz. tri-als concluded there was no benefit.343-349 A recent single-center, randomized trial with pasireotide (a newer analog) suggested potential benefit.350Many technical modifications to the classic pancreaticodu-odenectomy have been described. However, numerous technical variations to the pancreaticoenteric anastomosis have not clearly demonstrated an objective method to consistently decrease the rate of clinically significant postoperative pancreatic fistula, which in most series is about 10%. Yeo compared the incidence of pancreatic fistula in patients who had a pancreaticoduode-nectomy with reconstruction via a pancreaticogastrostomy or pancreaticojejunostomy.351 There was no significant difference between the two techniques in the incidence of pancreatic fis-tula. A recent meta-analysis summarized the results of 16 trials comparing pancreaticogastrostomy to pancreaticojejunostomy. All of the observational clinical studies reported superiority of pancreaticogastrostomy over


Surgery_Schwartz

Surgery_Schwartz. summarized the results of 16 trials comparing pancreaticogastrostomy to pancreaticojejunostomy. All of the observational clinical studies reported superiority of pancreaticogastrostomy over pancreaticojejunostomy, most likely influenced by publication bias. In contrast, all random-ized prospective trials failed to show advantage of a particular technique, suggesting both techniques provide equally good results.352Other options to consider when performing the pancre-atic anastomosis are the duct-to-mucosa vs. the invagination techniques. Some surgeons choose the technique at the time of operation, depending on the size of the pancreatic duct and the texture of pancreas favoring invagination when the duct is small and the pancreatic texture is soft.353 Other surgeons use the same technique 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