The American Journal of 214 (2017) 347e357

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The American Journal of Surgery

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Review Operative management of : A review

John D. Tillou, M.D. a, Jacob A. Tatum, B.S. b, Joshua S. Jolissaint, M.D. b, Daniel S. Strand, M.D. c, Andrew Y. Wang, M.D. c, Victor Zaydfudim, M.D., M.P.H. b, * Reid B. Adams, M.D. b, Kenneth L. Brayman, M.D., PhD. b, a Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA b Department of Surgery, The University of Virginia Health System, Charlottesville, VA, USA c Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA, USA article info abstract

Article history: Background: Pain secondary to chronic pancreatitis is a difficult clinical problem to manage. Many pa- Received 5 September 2016 tients are treated medically or undergo endoscopic therapy and surgical intervention is often reserved for Received in revised form those who have failed to gain adequate pain relief from a more conservative approach. 26 November 2016 Results: There have been a number of advances in the operative management of chronic pancreatitis over Accepted 8 March 2017 the last few decades and current therapies include drainage procedures (pancreaticojejunostomy, etc.), resection (pancreticoduodenectomy, etc.) and combined drainage/resection procedures (Frey procedure, Keywords: etc.). Additionally, many centers currently perform total with islet autotransplantation, Pancreatitis in addition to minimally invasive options that are intended to tailor therapy to individual patients. Chronic Discussion: Operative management of chronic pancreatitis often improves quality of life, and is associ- Pancreatectomy ated with low rates of morbidity and mortality. The decision as to which procedure is optimal for each Pancreaticojejunostomy patient should be based on a combination of pathologic changes, prior interventions, and individual surgeon and center experience. © 2017 Elsevier Inc. All rights reserved.

1. Introduction employed before considering more invasive therapies such as splanchnic nerve ablations, endoscopic interventions, or surgery.2 Chronic pancreatitis (CP) places an immense burden on patients However, these less invasive methods are often ineffective or un- and physicians alike, costing the United States healthcare system an satisfactory and many patients eventually undergo more invasive estimated $2.6 billion annually.1 As the disease progresses, the procedures.3 In recent years, a number of randomized trials gland undergoes irreversible destruction of its architecture; wors- comparing the various surgical approaches available to those who ening small and large ductal disease, calcification, and fibrosis, ul- have failed conservative techniques have been reported, but there timately lead to a loss of functional parenchyma and subsequent is still a clear need for further study. In this article we aim to give an chronic pain, endocrine and/or exocrine insufficiency and increased overview of the etiology, pathophysiology, clinical presentation, susceptibility for developing pancreatic ductal adenocarcinoma. diagnosis and surgical management of CP. Repeated bouts of acute pancreatitis, chronic abdominal pain and glandular dysfunction are the primary targets for initial med- 2. Epidemiology, etiology and pathophysiology ical, many of which are associated with only short-term improve- ments and high rates of recurrence. Non-operative strategies for The incidence of CP is estimated to be between 2 and 200/ managing pain, such as lifestyle modifications (dietary modifica- 100,000 individuals per year worldwide, depending on the popu- e tion, cessation of smoking and alcohol), pancreatic enzyme lation, and rising.4 6 The most common etiological risk factors for replacement and various methods of analgesia, are typically the development of CP can be grouped according to the TIGAR-O classification system as reviewed in Table 1.5,7,8 While the exact pathophysiological mechanism(s) of CP is un- known, a number of hypotheses have been presented to account for * Corresponding author. Box 800709, Department of Surgery, University of Vir- ginia Health System, 1215 Lee Street, Charlottesville, VA 22908, USA. the observed features commonly encountered. Many of the causes E-mail address: [email protected] (K.L. Brayman). in the TIGAR-O scheme are likely unified by a similar process of http://dx.doi.org/10.1016/j.amjsurg.2017.03.004 0002-9610/© 2017 Elsevier Inc. All rights reserved. 348 J.D. Tillou et al. / The American Journal of Surgery 214 (2017) 347e357

Table 1 TIGAR-O classification of chronic pancreatitis.

Classification Example

Toxic-metabolic Alcohol Induced (up to 70% of cases in developed countries) Idiopathic Tropical pancreatitis Genetic SPINK1, PRSS1, CASR, or CFTR polymorphisms Autoimmune Recurrent severe acute pancreatitis Necrosis-fibrosis model Obstructive Stones, plugs, strictures and pseudocysts

pancreatic auto-digestion in the setting of pancreatic ductal system the mid/upper back, nausea with inability to tolerate PO intake, e obstruction.9 12 An often cited theory is the necrosis-fibrosis model weight loss, and endocrine/exocrine dysfunction. In contrast to which postulates that CP is simply the end result of numerous acute pancreatitis, the elevation of amylase and lipase levels is episodes of severe acute pancreatitis, whatever the cause, with uncommon and measuring c-reactive protein, procalcitonin levels repeated episodes of necrosis eventually leading to fibrosis of the and leukocytosis are unhelpful. However, other syndromes may e gland.13 15 The most complete and commonly accepted model for present with a similar clinical picture, complicating diagnosis. Of the development of CP is the so-called Sentinel Acute Pancreatitis note is Disconnected Syndrome (DPDS) in which a Event (SAPE) hypothesis by Whitcomb et al..16 This model attempts viable left side of the pancreas cannot drain due to separation of the to provide a unifying theory for the etiology of CP by suggesting pancreatic duct, usually in the neck of the pancreas. Most often that a “sentinel event” (e.g. alcohol induced stress) leads to the associated with acute necrotizing pancreatitis, this syndrome can initiation of an inflammatory response. This event may resolve also occur in chronic pancreatitis due to a longstanding stone completely; however, persistence of this inflammatory response impaction or stricture impeding drainage. DPDS typically presents leads to recruitment, activation and proliferation of pancreatic as abdominal pain and exocrine dysfunction and is very resistant to stellate cells and macrophages. Unchecked, this sensitizes the medical management. Left unchecked, the uncontrolled drainage pancreas to further injurious events leading to stellate cell stimu- ultimately leads to fistula and pseudocyst formation. As such, it lation, progressive fibrosis, and parenchymal destruction. Fig. 1 requires careful consideration as the syndrome can masquerade as depicts the SAPE model as described above.11,16,17 CP, particularly if medical management is attempted first, pro- longing the course.40 When the diagnosis of CP is in question, or if 3. Clinical presentation and diagnosis there is concern for other pathology such as a pseudocyst or mass, then cross-sectional imaging of the gland is often obtained. While chronic abdominal pain is the most common, and most consternating, presenting symptom of chronic pancreatitis, mani- 4. Endoscopic diagnosis and management festations of glandular dysfunction, such as steatorrhea, diarrhea, weight loss and the onset of brittle diabetes mellitus due to the loss Endoscopic ultrasonography (EUS) and endoscopic retrograde of a, b and g islet cells may also be present.5,9,17,18 Chronic pain is cholangiopacreatography (ERCP) have well defined roles in the certainly the most debilitating symptom associated with CP and is diagnosis and management of chronic pancreatitis.11 While CT and experienced by 85% or more of individuals at some point.19 Chronic MRI do offer noninvasive means of assessing the pancreas, EUS pain is also the most important and common reason for patients to offers a minimally-invasive approach able to better visualize the seek medical care. The exact origins of pancreatitis related pain are pancreatic parenchyma and ductal system, and EUS-guided fine- not completely understood but are thought to be multi-factorial in needle aspiration or core biopsy enables the sampling of solid and nature, attributable to either intrapancreatic processes, including cystic lesions, which can affect the surgical approach in cases where inflammation, increased ductal/interstitial pressures or neural solid neoplasms or intrapapillary mucinous neoplasms are found signaling changes, or extrapancreatic processes such as biliary that can be the cause of acute pancreatitis and masquerade as e stricture or duodenal obstruction.20 28 chronic pancreatitis. Additionally, ERCP offers the potential of Some authors suggest that, in the majority of patients, CP “burns accessing both the major and minor papillae, and offers both out” with time regardless of intervention, resulting in partial to diagnostic and therapeutic capabilities as well, such as brushing of complete pain relief around four to five years after initial pain strictures for cytopathology, pancreatoscopy, papillotomy, and onset.29,30 Others report that fewer than 50% of patients become pancreatic duct stenting. However, this approach must be used pain-free over a ten year time frame.31,32 Whether or not this “burn with caution given the risk of post-procedural pancreatitis associ- out” phenomenon occurs in conjunction with the loss of endocrine ated with its use, as well as risk of pancreatic infection, bleeding and exocrine function remains controversial.33 and duodenal perforation.41 Pancreatic pseudocysts, a consequence of acute pancreatitis and ERCP is provides an effective therapy for proximal pancreatic ductal injury, may be present in 20e40% of patients with CP and and distal biliary strictures that arise from chronic pancreatitis, and when symptomatic may be managed via percutaneous, surgical or, it can be effective in treating patients with dilated pancreatic ducts preferably, endoscopic drainage.34 Some pseudocysts regress due to strictures or stone disease. Strictures are a common occur- spontaneously, only requiring supportive medical care while rence in CP, with biliary strictures complicating a quarter of pa- others, particularly those associated with alcohol, can reoccur in up tients.42 Balloon dilation or stent placement has a success rate e to 50% of cases.35 38 Additional complications associated with ranging from 75 to 94% with regard to acute pain relief. Likewise, chronic pancreatitis include duodenal obstruction, biliary tree stenting provides an effective treatment in cases of ductal strictures, pancreatic ascites or pleural effusion from disruption of leakage.41 Stent occlusion and migration have been longstanding pancreatic ducts or pseudocysts.21,39 problems stymying the effectiveness of these techniques. However, The diagnosis of chronic pancreatitis is typically made clinically fully covered self-expandable metal stents have been develop to based on the classic symptoms of epigastric pain often radiating to prolong patency, addressing the former concern and increasing J.D. Tillou et al. / The American Journal of Surgery 214 (2017) 347e357 349

Fig. 1. The SAPE Hypothesis showing early damage and a sentinel event ulitmately leading to fibrosis seen in chronic pancreatitis. Adapted from Schneider A, Whitcomb DC. Hereditary pancreatitis: a model for inflammatory diseases of the pancreas. Best Pract Res Clin Gastroenterol 2002; 16:347e63.17 time to re-intervention, while use of anchoring flaps address the pancreaticojejunostomy better treated ductal obstructions.42,47 In latter. A “double lasso” may also be incorporated for easy practice, might also help identify those patients with retrieval.43 chronic pancreatitis who might benefit the most from surgical duct More complex interventions utilizing endoscopic techniques decompression, as in our experience those patients often achieve have also been reported in recent literature. These include the some pain relief from antecedent, temporary pancreatic duct ability to drain pancreatic pseudocysts, occurring in 20e40% of stenting. patients, as well as performing necrosectomies in severe cases of necrotizing pancreatitis.42,44 The aforementioned self-expanding 5. Operative management stents have additionally been used to address pancreatic or duodenal fistulas caused by CP and there has been as least one case Nearly half of all patients with CP will eventually require some where CP-induced gastric outlet obstruction was resolved via form of surgical intervention in order to treat chronic pain that is endoscopic gastroduodenostomy.45,46 unmanageable via lesser means.8,48,49 In addition to addressing At present, there is no consensus or guidelines dictating on intractable abdominal pain,50 surgical treatment of CP can mitigate when endoscopy should be utilizing prior to or instead of surgical the risk of recurrent acute episodes of pancreatitis or developing options. Reports have shown similar outcomes between both malignancy,51 or treat biliary or gastrointestinal obstructive com- endoscopic and surgical approaches, and in some cases surgery plications.48 For the purposes of this paper, the various surgical tends to outperform as in one randomized controlled trial where techniques employed in the management of chronic pancreatitis 350 J.D. Tillou et al. / The American Journal of Surgery 214 (2017) 347e357 are divided into drainage, resection and combined drainage/re- morbidity rates are less than PD or PPPD at approximately sections procedures. See Fig. 2 for a flowsheet detailing decision 22%.54,56,57,59,62,63 The risk of worsening pancreatic glandular making and Table 2 for a summary of the relevant data for the function associated with the procedure appears to be less signifi- various procedures detailed in this review. cant when compared to other resection procedures, with endocrine insufficiency developing in 10e20% of patients and Frey et al. fi 6. Combined drainage/resection reporting post-operative exocrine insuf ciency in only 11% of in- dividuals. This is an early advantage, however, and does not hold fi 54,57,59,62 6.1. Frey procedure after more than ve years of follow up. Variations on the Frey procedure have been developed in an The Frey procedure is a modified version of the Partington- attempt to improve the technique. In 1997, Izbicki proposed a fi Rochelle operation. It combines the lateral main ductotomy with modi cation in which a triangular wedge of parenchyma is resec- a partial pancreatic head resection by “coring out” the parenchyma ted from the ventral surface of the pancreas along the main in the central portion of the head of the gland. The anterior head, pancreatic duct with subsequent anastomosis to a roux-en-Y loop 64 body and tail portions of the main pancreatic duct are opened of . Known now as the longitudinal V-shaped incision or “ fi ” widely and a Roux-en-Y loop of jejunum is anastomosed to the the Hamburg modi cation, this method is indicated for small edges of the open ductal system.52,53 duct disease and retains comparable pain control, morbidity and Indications for this procedure include dilated pancreatic ducts in mortality rates to the original Frey procedure with seemingly the setting of a thickened pancreatic head that is unlikely to be reduced rates of post-operative endocrine/exocrine 64,65 drained by other techniques, like the lateral pan- dysfunction. creaticojejunostomy, which do not fully decompress the accessory pancreatic or duct to the uncinate.55,56 The Frey procedure provides 6.2. Beger procedure e effective long-term pain relief in 75e91%54 58 of patients. When compared to either PD, PPPD, or the Beger procedure, the Frey The Beger procedure is intended for individuals with CP and procedure showed comparable long-term clinical outcomes, such or biliary stenosis secondary to inflammation e as rates of long term glandular dysfunction and pain relief.59 61 of the pancreatic head.66 The neck of the pancreas is transected and Mortality appears lower than the 3% reported for PD or PPPD and the duodenum spared by resecting all but a small portion of

Fig. 2. The selection of proper procedure for each patient is a complex decision based on etiology as well as surgeon preference and comfort. A wide array of options are available and careful consideration should precede progression to procedure. J.D. Tillou et al. / The American Journal of Surgery 214 (2017) 347e357 351

Table 2 Overview of procedures for treatment of chronic pancreatitis.

Procedure Pain relief Morbidity and mortality Endocrine and/or exocrine Notes insufficiency

Surgical drainage For pain in those with obstructed/distended main ducts e Pancreaticojejunostomy: 53e93%84,141,146,150 154 6e19% morbidity, 0e4.2% 11% insulin dependent at Jejunal anastomosis > 6cm e Partington-Rochelle/Modified mortality141,147,151 154 3 months, 25% by 5 years153 provides better long term pain Puestow control151 Surgical resection Indicated for small duct disease, obstruction of the , possibility of carcinoma or if prior drainage procedure e fails6,84 86 e Distal Pancreatectomy 55e81%50,69,138 140,142 15e35% morbidity, 0e5% 38e69%endocrine and Up to 95% resection, disease in e mortality50,69,138 140 29e47% exocrine body/tail and best those with insufficiency69,138,139,141,142 pseudocysts, suggestion that if spleen preservation spleen can be spared disease is reduces diabetes less severe, hence lower rates of risk from 57% to 13.6%139,142 diabetes with spleen-sparing procedures109 e Whipple Procedure/Pylorus 34e100%50,60,126,128 131,134 16e53% morbidity, 0e3% 12e48% endocrine Used when pancreatic head is e Preserving mortality50,57,126,128 133 and 24e51% source of pain and exocrine adenocarcinoma cannot be e insufficiency69,126,128 130 ruled out, little difference in complication rates between PD/ PPPD75,99,134,135 e Total Pancreatectomy 82e100%88 40-50% morbidity, up to 6% Total Dysfunction88,95 97 Best in those with existing mortality, diabetes, intraductal papillary e 40% risk of late death88,95 97 mucinous neoplasm or for cancer prophylaxis. Resulting diabetes difficult to control.88,90 e93,98 e Total Pancreatectomy w/Islet 80e90þ%90,107,117 120 See Table 3 Minimize developing diabetes Autotransplantation by preserving glycemic control.91,99 Combined drainage/resection e Frey 74.5e94.7%54,56 58,62,79 Morbidity up to 22%, 0e3% 10e20% endocrine Combines coring out head with e mortality54,56 58,62,79 (6% if “minimal Frey”55) lateral pancreaticojejunostomy, and 11% exocrine good when decompressing insufficiency54,56,62 smaller ducts.54,55 Hamburg modification allows drainage of smaller ducts while retaining tissue for good post- op glandular function64,65 e Beger 50e94%66,68 71,78 Morbidity 15e20%, less than 10e26% endocrine and Transection, resection and e 1% mortality66,68 71,78 10e34% exocrine roux-en-y anastomosis. Up to insufficiency.68,69,71,125 25% need bile duct anastomosis 10% may have improved as well. Those with portal endocrine hypertension or biliary stenosis function66,71 due to head inflammation.66 Berne 55%82 Morbidity 16%, mortality 1%82 Cores out head and subsequent anastomosis. Comparable to Frey and Beger but with shorter operative and recovery times.83

pancreatic head adjacent to the bile duct and a portion of the un- found improved immediate pain relief and glycemic control in cinate process. A Roux-en-Y loop of jejunum is then anastomosed to those undergoing the Beger but with little long term outcome both the preserved head tissue and the transected neck.67,68 In up differences between the two.59,70,72 In a non-randomized trial by to 25% of cases choledochojejunostomy to the same Roux limb is Witzigmann et al.,73 individuals with an inflammatory pancreatic also required during the subtotal head resection to treat biliary head mass undergoing the Beger procedure reported better post- stricture.66 The Beger procedure produces significant long term operative quality of life and less glandular dysfunction than pa- pain improvement in 86e94% of individuals with an operative tients who underwent PD, a trend that continued through five year mortality of less than one percent and post-operative morbidity follow-up.74 A number of reports have demonstrated that e ranging from 15 to 20%.66,68 71 Long term pancreatic glandular duodenum-preserving pancreatic head resections, such as the insufficiency is comparable to the Frey procedure with 10e26% and Beger and Frey procedures, have been shown to be just as effective 10e34%59,66,69,71 of patients developing post-operative endocrine as PD at relieving pain and both have similar rates of overall long- or exocrine dysfunction, respectively. Beger et al.66 and Izbicki term morbidity and postoperative exocrine and endocrine insuffi- et al.71 also both noticed improved post-procedural pancreatic ciency but the duodenum-preserving procedures may be superior endocrine function in around 10% of patients. in some regards including operative times and postoperative e Multiple trials comparing the Beger procedure with PPPD have quality of life.59,75 77 352 J.D. Tillou et al. / The American Journal of Surgery 214 (2017) 347e357

Both randomized and non-randomized trials, including one trial preservation and delivery of islet cells with the goal of maximizing e with 16 years of follow-up,77 comparing the Frey and Beger pro- islet yields and the likelihood of insulin independence.100 105 The cedures have demonstrated little difference in pain relief, late general process is similar at most institutions: after resection, the mortality, quality of life improvement or the development of new pancreas is mechanically and enzymatically digested by a stan- onset glandular insufficiency. Morbidity was slightly higher in pa- dardized method106,107 and the resulting islet cell extract is auto- tients who underwent the Beger (20%) than the Frey (9%) proced- transplanted to the via infusion into the portal vein or to the ure.78,79 The Frey procedure also benefits from requiring only a spleen via the short gastric or left gastroepiploic veins.102,108,109 The single jejunal anastomosis unlike the Beger procedure which re- spleen has been shown to be a less favorable transplantation site quires two and is more technically difficult to perform.80 than the liver due to the difficulty of preserving the short gastric vessels during pancreatic resection, the risk of pulmonary emboli 6.3. Berne technique after islet cell infusion and the risk of splenic infarction.108,109 Recent series using animal models suggest that islet cells A combination of the Beger and Frey procedure, known as the “seeded” into an omental “pouch” may present a feasible alterna- Berne technique, has been described for managing individuals with tive transplantation site.110,111 A potential drawback to the wide- an inflammatory head mass. The pancreatic head is “cored out” and spread use of islet autotransplantation is that islet cell harvesting anastomosed to a Roux-en-Y loop of jejunum without longitudinal requires the use of a specialized, certified processing facility.112 opening of the main pancreatic duct or transection of the pancre- However, multiple studies, with wide variability in series size atic neck.81,82 Because this procedure does not involve decom- have shown the feasibility of using off-site processing facilities pression of the entire length of the main pancreatic duct, its utility while still achieving initial insulin independence in 33e88% of e is limited in patients with multiple ductal obstructions or strictures. patients.113 115 Postoperative mortality and morbidity rates of one percent and Even though the majority of patients do not gain long-term sixteen percent, respectively, have been reported alongside pain insulin independence, islet autotransplantation helps maintain relief in 55% of patients at a median follow-up of 41 months.82 In a glycemic control by providing functioning islet cells. In a recent randomized trial comparing the Berne technique to the Beger series of over 500 cases, the University of Minnesota found that procedure, similar levels of morbidity and quality of life improve- 92.6% of patients were pain following TP-IAT. Graft failure occurred ment were observed, but the Berne technique required less oper- in 12.5%.116 This series, as do all others unless specified, used the ative time and a shorter duration of recovery.83 Islet Collaboration Registry definition of failure as a serum level of c-peptide of less than 0.3 ng/mL. Other series have demonstrated 7. Surgical resection pain relief ranging from 80 to 90% and 26e55% insulin indepen- dence rates, with one group finding that upwards of 33% of patient The resection of pancreatic tissue is indicated in the treatment had no insulin requirement at ten years after TP-IAT with some e of “small duct” disease when the main pancreatic duct is less than remaining so at 20 years.90,107,117 120 three mm in diameter.84,85 Resection is also employed when a prior Many authors have established a direct positive correlation drainage procedure was ineffective, the common bile duct is between the total number of islet cells infused at the time of obstructed, there is an inflammatory pancreatic head mass, or there transplantation and the level of glycemic control ultimately ach- e is possibility of carcinoma.6,86 ieved90,98,113,118,120 122 with optimal results when 300,000 islet cells or 2500IEQ/kg body weight are infused.113,119,120 Seventy 7.1. Total pancreatectomy/total pancreatectomy with islet four percent of patients who receive greater than 300,000 islet cells autotransplantation (TP-IAT) may be insulin independent for over two years after implantation, increasing to 80% of patients if over 600,000 islet cells are trans- First performed by Priestly87 in 1942, total pancreatectomy re- fused.120,121 Of patients who receive an islet cell yield of 2501e5000 sults in complete endocrine and exocrine insufficiency. Total IE/kg, 27e50% may be insulin independent after one year. Table 3 pancreatectomy provides long term pain relief in 80e85% of pa- summarizes the data from many of these studies. Conflicting re- tients, a rate similar to pancreaticoduodenectomy,59 though one ports by several groups, however, have not reported these corre- study reported relief in 100% of their patients.88 Pain may recur in lations between infused islet cell burden and resultant glycemic up to one third of those undergoing the procedure.88,89 control with one series finding no significant predictive factors of Total pancreatectomy is associated with a high rate of post- insulin independence at all.118,122,123 Argo el al118 reported that, at operative morbidity (40e50%) and the resultant brittle form of short-term follow up, all patients undergoing TP-IAT or PD com- insulin-dependent diabetes mellitus is especially difficult to bined with islet autotransplantation developed insulin dependent manage. Total pancreatectomy occasionally is required in patients diabetes, although the mean number of islet cell equivalents with CP due to intraductal papillary mucinous neoplasm meeting transplanted was only 82,094, appreciably lower than what is criteria for resection. In addition, it is indicated as prophylactic thought to be needed. treatment in patients with hereditary forms of pancreatitis (i.e. One of the critical barriers to the widespread use of this tech- PRSS-1) who have significantly increased risk of developing nique, besides the paucity of processing facilities, is the expense pancreatic adenocarcinoma and special consideration may be given and lack of reimbursement for transplantation.124 While short term to patients with existing diabetes who may benefit from an islet cell insulin independence is reasonable, the majority of patients will e autotransplant.88,90 93 Barbier et al.94 compared the work of mul- require some insulin use as they get further out from their trans- tiple groups, demonstrating mortality ranging from 2 to 8% and plantations. Because of its potential to maintain endocrine function only two studies showing late deaths from hypoglycemia (rates of along with significant pain relief, TP-IAT can be an excellent e 1.5% and 3%).88,90,94 98 Therefore, total pancreatectomy has the approach, but this has yet to be born out in any randomized trial. potential to provide pain relief, but currently is reserved as end-of- the-line treatment.91,99 7.2. Pancreaticoduodencetomy (whipple procedure) and pylorus Islet autotransplantation aims to minimize the aforementioned preserving pancreaticoduodenectomy endocrine complication by improving glycemic control. Research currently is underway to optimize the procurement, purification, Between 18 and 50% of patients with chronic pancreatitis J.D. Tillou et al. / The American Journal of Surgery 214 (2017) 347e357 353

Table 3 Results of total pancreatectomy with islet autotransplantation series (TP-IAT).

Series Year N Insulin independence Follow up time C-peptide >0.3 Mean IEQ Mean IEQ/kg body weight ng/mL (%) (þ/ SD or range) (þ/ SD or range)

Johnston et al.113 2015 36 33% 28 months 70% 282,612 ± 156,248 3824 ± 1952 Tai et al.115 2015 9 37.5% 2 months 67% 271,643 (4660e499,996) 4899 (one lost to follow-up) Chinnakotla et al.116 2015 581 12.5% (in 378) 12 months 87.5% Unreported Categorical: (>0.5 in this study) <2000 up to >5000 Balamurugan et al.121 2014 537 75-80% Unreported Unreported 416,000 ± 156,900 3600 ± 3100 (if > 600,000 IEQ infused), 55% (if < 600,000 IEQ infused) Wilson et al.122 2014 112 27% 60 months 0.1e5.3 415,518 ± 26,528 6027 ± 595 (subset of 21 patients) Argo et al.119 2008 26 0% 6.5 months mean 1.7 ± 0.57 (for 9) 82,094 ± 18,223 1331 ± 304 Webb et al.123 2008 46 26% 16.5 months mean 1.44 ± 0.35 130,029 (24,332e958,078) 2245 (405e20,385) at 10 years Gruessner et al.93 2003 112 39% Unreported Unreported Unreported 23-12,601 Rodriguez Rilo et al.117 2003 22 40% (of 5) 19 months Unreported 245,457 (20,850e607,466) 4611 (287e10,419) Wahoff et al.120 1995 48 34% 24 months Unreported 238,010 ± 35,471 Unreported

Abbreviations Used: N- number of participants in the trial IEQ-Islet Cell Equivalents KG-Kilograms SD-Standard Deviation. present with an inflamed pancreatic head which may be the main undergo distal pancreatectomy may experience some degree of source of abdominal pain and some degree of pancreatic head endocrine or exocrine insufficiency, respectively.69,138,139,141,142 resection, such as with Pancreaticoduodenectomy (PD) or pylorus- preserving pancreaticoduodencectomy (PPPD), may provide the 8. Surgical drainage best opportunity for pain relief.56,70 These operations may also be indicated for treating inflammatory disease of the pancreatic head, Surgical drainage procedures are useful for managing pain in small ductal disease, or when pancreatic adenocarcinoma cannot 125,126 patients with obstructed and distended main pancreatic be definitively ruled out. Post-operative pain relief often 59,84,143 e ducts. When performed early in the course of the disease, ranges from 80 to 100%.57,60,126 131 There are conflicting reports on these techniques may prevent the further deterioration of endo- long-term pain control, some showing as few as 34% of individual crine and exocrine function although reports are conflict- experiencing adequate long term pain control.50 In contrast, one ing.141,144,145 Incomplete decompression of the pancreatic head is report from data 15 years post-operatively showed 65% of patients common and may be the cause of persistent post-procedural pain remained free of pain medications use.132 Regardless, both opera- in some patients, occasionally warranting additional tions carry a significant rate of postoperative morbidity (16e53%) 146,147 e interventions. and mortality of three percent or less.50,57,60,126,128 130,133,134 Several series have found no significant differences in delayed gastric emptying post-operatively between the standard PD and 8.1. Pancreaticojejunostomy PPPD.75,99,131,135 PD and PPPD carry a high risk of postoperative pancreatic The caudal pancreaticojejunostomy, involving a Roux-en-Y loop glandular dysfunction with 24e51% of patients developing long- of jejunum anastomosed to an amputated pancreatic tail with term exocrine insufficiency and 12e48% developing symptoms of concurrent splenectomy, was introduced by Duval in 1954 to treat long-term endocrine insufficiency.57,60,69,128,133 PPPD has been patients with an obstruction near the major duodenal papilla by 148 shown to carry higher initial morbidity than duodenum-preserving providing retrograde drainage. It is also the procedure of choice 40 procedures, like Beger's67,68 or Frey's54 procedures, described in in cases of Disconnected Pancreatic Duct Syndrome. Puestow and fi detail in sections above.59 However, long-term rates of mortality, Gillesby modi ed the procedure by coring-out the anterior portion pain relief and glandular dysfunction have been found to be com- of the main pancreatic duct within the body and tail of the pancreas parable between PPPD and the duodenum-preserving combined with a longitudinal anastomosis to a Roux loop of procedures.59 jejunum in order to optimize the ductal drainage in patients with multiple pancreatic duct strictures.149 The Partington-Rochelle procedure, also known as the side-to-side or lateral pan- 7.3. Distal pancreatectomy creaticojejunostomy, is a further modified version of the longitu- dinal pancreaticojejunostomy characterized by a side-to-side Distal pancreatectomy (DP), in which up to 95% of the volume of anastomosis between a surgically opened main pancreatic duct and the pancreas can be removed, was originally described by Mayo in Roux loop of jejunum without tail amputation or splenectomy.150 1913136 and has been used to treat patients with a major obstruc- Lateral pancreaticojejunostomy is a relatively safe procedure e tion or stricture of the main pancreatic duct resulting in disease with a postoperative morbidity rates between 6% and 19%147,151 153 localized to the body and tail of the pancreas.137,138 The efficacy of and a mortality rate of zero to four percent. Upwards of 90% of e DP with respect to long-term pain relief ranges from 55 to individuals will experience initial pain relief80,144,147,151 155 but, e 81%50,69,138 140 with the most favorable outcomes occurring in despite the initial benefit, the rates of long-term relief can decline those treated for a distal pseudocyst.139,140 DP carries a significant to 33e53% by five years.147,151,153 Approximately 40% will need risk of postoperative complications, such as pancreatic fistula for- rehospitalization for their pain and a significant number will need mation. Postoperative morbidity rates range from 15 to 35% and further procedures, including pancreatic resection, to achieve e mortality from zero to five percent.50,138 140 Similar to the lateral adequate control.147,154 Unfortunately, multiple reports have pancreaticojejunostomy, 38e69% and 29e47% of patients who demonstrated progressive deterioration of pancreatic glandular 354 J.D. Tillou et al. / The American Journal of Surgery 214 (2017) 347e357

Table 4 Summary of robotic procedures.

Procedure Mortality Morbidity (Class IIþ) Conversion to open Operative time (minutes) Length of stay (days)

Distal Pancreatectomy156,157,160 <1% 10e60% 0e12% 163e458 4e12 Pancreatoduodenectomy156 0e5% 0e75% 0e37.5% 420e630 10e13.7 Total Pancreatectomy157,160 0% 40% 20% 389e617 7e18 Middle Pancreatectomy157,160 0% 51e92% 15.30% 302e488 6e19 TP-IAT161 0% 33% 0% 638e786 7e14 Frey160 0% 67% 0% 214e668 5e9

Note: Morbidity rates represent Clavien-Dindo ratings II and above. function, with one quarter of patients ultimately becoming insulin- Frey and Beger procedures, is to minimize the risk of surgical dependent within five years.52,59,153 complications and endocrine and exocrine insufficiency while concurrently providing adequate symptom relief. 9. Minimally invasive With regard to carcinoma, which has a well-established increased incidence in CP patients, tumor location and size dic- Minimally invasive surgical techniques have been increasing for tates the procedure. Tumors of the head or body/tail require a many years, including their use in pancreatic surgery, with lapa- pancreaticoduodenectomy or distal pancreatectomy, respectively, roscopic pancreaticoduodenectomy and distal pancreatectomy while total pancreatectomy is reserved for large or multifocal tu- 158 fi being described in 1994.156 To date, nearly all of the previously mors. Pancreatic carcinomas can be dif cult to separate from described open operation have been performed in a minimally mass-forming CP though pre-operative imaging such as CT, MRI or invasive fashion as can be seen in Table 4. While the minimally endoscopy can be useful in differentiating. Endoscopic ultrasound, fi invasive approaches have a number of purported advantages, their with or without ne needle biopsy, remains the gold standard 159 widespread adoption has been limited other than the performance though in CP patients sensitivity can be as low as 54%. Therefore, of minimally invasive left . A large downside to results of these procedures should be taken in the context of each current minimally invasive techniques for pancreatic resection is individual patient, giving additional suspicion to those etiologies at the steep learning curve and the large amount of time which it even higher risk of transitioning to carcinoma such as hereditary 93 takes to become comfortable with these techniques. Moreover, pancreatitis. reconstruction, particularly the construction of anastomosis, re- Finally, total pancreatectomy with islet autotransplantation mains a challenge in laparoscopic techniques but may be represents an important option for some patients with CP. Though fi fi compensated by hybrid laparoscopic/robotic method which utilize the speci cs of TP-IAT continue to be re ned, particularly which fi the increased dexterity of the robot.156, 157 With more experience populations bene t from this approach, the timing for optimal and the routine incorporation of this skill into surgical training initiation of surgical intervention and the volume of islets needed programs, it is likely that both laparoscopic and robotic techniques for transfusion, long-term glycemic control is possible utilizing this will continue to gain traction. procedure. Unfortunately at this time, for most individuals, this glycemic control does not last long term. Minimally invasive tech- niques continue to expand in pancreatic surgery and remain an area 10. Conclusion of active investigation. At present, cost and operator proficiency with minimally invasive techniques remain barriers to their Chronic pancreatitis, with its intractable abdominal pain and commonplace use. adjacent organ damage, remains a difficult condition to manage Overall, surgical procedures succeed in improving pain and the despite considerable advances in endoscopic techniques and a quality of life for individuals with chronic pancreatitis and may number of randomized surgical intervention trials. Wide variations represent an end of the line option for many patients. However, in the etiology and presentation of the disease makes it difficult to additional randomized controlled trials comparing the different compare the true potential of many currently used techniques and interventions are needed to provide clarity as to the most effective most options still exhibit significant failure and complication rates. treatments for which patients with chronic pancreatitis. Although a number of randomized trials comparing different sur- gical approaches have been reported, there still is a clear need for further study to understand which procedures are optimal for any Disclosures given CP etiologies. The decision as to which procedure is indicated for each patient should be guided by the clinical setting, the in- Andrew Y. Wang, M.D., receives research support from Cook dividual's unique anatomic and pathological findings, and indi- Medical regarding metal biliary stents. vidual surgeon and institutional experience. Drainage only procedures such as the lateral pan- References creaticojejunostomy provide acceptable pain relief initially, but this relief appears to diminish with time. As a result and with improved 1. Chinnakotla S, Beilman GJ, Dunn TB, et al. Factors predicting outcomes after a results from other procedures, they have been supplanted by the total pancreatectomy and islet autotransplantation lessons learned from over 500 cases. 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