Total pancreatectomy (Uptodate, 2016)

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Introduction

The pancreas has exocrine and endocrine functions that are essential to life. A loss of such functions can result from either disease (eg, chronic pancreatitis, cystic fibrosis) or surgery (total pancreatectomy). The development of long-acting insulin and effective digestive enzymes have made it possible for patients to sustain a reasonable quality of life after a total pancreatectomy.

Total pancreatectomy has been performed since the 1970s, and its frequency has increased over the last two decades. The anatomy of the pancreas makes it difficult to remove. Along its length, the pancreas contacts almost all structures of the upper abdomen, and the head of the pancreas is densely adherent to the duodenum and envelops the distal common bile duct. As a result, a total pancreatectomy most often requires a concomitant duodenectomy, and subsequent gastric and biliary anastomoses to the jejunum to preserve gastrointestinal continuity.

The indications for and techniques of total pancreatectomy are discussed in this topic. Techniques of partial pancreatic resection are discussed in other topics.

Indications for total pancreatectomy

Total pancreatectomy is a major operation with potential for mortality and severe morbidity. It is reserved for patients who have failed medical management and are not candidates for less extensive surgery. The indications for total pancreatectomy:

  • Severe benign or intractable conditions that cannot be effectively treated medically or with less extensive resection:
    • Chronic pancreatitis
    • Hereditary pancreatitis
    • Trauma
  • Premalignant conditions that cannot be effectively treated medically or with less extensive resection:
    • Intraductal papillary mucinous neoplasm (IPMN)
  • Malignant conditions that cannot be treated by a less extensive resection:
    • Pancreatic adenocarcinoma
    • Pancreatic neuroendocrine tumors (PNETs)
    • Metastatic renal cell cancer

Occasionally, the decision to perform a total pancreatectomy is made intraoperatively to prevent a pancreatic fistula in patients with soft pancreatic parenchyma, or when resection margins remain positive for malignancy after a more limited pancreatic resection. In addition, a completion total pancreatectomy may be required to treat complications resulting from a prior partial pancreatic resection.

In a single center study of 136 patients, 82 percent had planned total pancreatectomy, 11 percent had conversion from pancreaticoduodenectomy, and 7 percent had completion total pancreatectomy [1]. The indications for planned pancreatectomies included adenocarcinoma (46 percent), chronic pancreatitis (18 percent), IPMN (12 percent), metastatic renal cell cancer (10 percent), and PNET (8 percent). This and other studies reported increasing numbers of total pancreatectomies being performed for hereditary pancreatitis and IPMNs, both strong risk factors for pancreatic ductal adenocarcinoma [1,2].

Planned total pancreatectomy

Chronic pancreatitis

Total pancreatectomy is typically performed for patients with chronic pancreatitis to palliate unremitting pain, especially after they have developed diabetes. For those without diabetes, total pancreatectomy should, if possible, be performed with pancreatic islet autotransplantation.

Chronic pancreatitis is a morbid, debilitating condition often associated with chronic abdominal pain, narcotic addiction, multiple hospitalizations, and decreased quality of life [3]. Patients with chronic pancreatitis often develop diabetes or pancreatic exocrine insufficiency, and are 10 to 20 times more likely to develop pancreatic cancer than the general population [4,5]. Chronic pancreatitis often leads to multiple diagnostic and therapeutic procedures, including surgery. Although chronic pancreatitis is an indication for total pancreatectomy, conventional endoscopic and surgical treatment options should be exhausted before attempting a total pancreatectomy [3].

Hereditary pancreatitis

Total pancreatectomy may be performed for patients with hereditary pancreatitis to improve quality of life and eliminate the risk of pancreatic cancer [1,2,6]. In this patient population, early total pancreatectomy before the onset of diabetes is preferred so that islet autotransplantation can be performed.

Hereditary pancreatitis is a genetic disorder most commonly caused by mutations in autosomal genes such as protease, serine 1 (PRSS1), serine protease inhibitor Kazal type 1 (SPINK 1), and cystic fibrosis transmembrane conductance regulator (CFTR). In adolescents and children with chronic pancreatitis, 50 to 70 percent have predisposing genetic mutations [7].

Compared with chronic pancreatitis, hereditary pancreatitis has similar symptoms but earlier onset without any inciting factors. Patients with hereditary pancreatitis are 50 to 70 times more likely to develop pancreatic cancer than the general population [8,9]. Because the entire pancreas is affected by the genetic mutation, endoscopic or surgical interventions other than total pancreatectomy are rarely successful in mitigating symptoms or preventing cancer.

Total pancreatectomy may be performed for tropical pancreatitis, which is also a condition with a possible genetic predisposition. Tropical pancreatitis is most commonly seen in southern India and sub-Saharan Africa, where it is the most common cause of chronic pancreatitis. Children are commonly affected, and often die in early adulthood from endocrine and exocrine dysfunction. Although the etiology is unknown, mutations in the serine protease inhibitor SPINK1 gene have been identified in some patients.

Intraductal papillary mucinous neoplasm

IPMN is a premalignant condition that can occur in either the main pancreatic duct or the branch ducts. Total pancreatectomy can be necessary to achieve a negative resection margin in patients with diffuse main duct or multifocal branch duct IPMNs [10-12].

Main duct IPMNs have a greater malignant potential than branch duct IPMNs. In one study, malignancy was found in 62 and 26 percent of resected main-duct and branch-duct IPMNs, respectively, of which 43 and 18 percent contained invasive disease [13]. The treatment of IPMN, which is controversial [14], is discussed in detail elsewhere.

Pancreatic cancer

Total pancreatectomy can be performed for pancreatic ductal adenocarcinoma but does not confer any advantage over standard partial pancreatectomy techniques (eg, pancreaticoduodenectomy or distal pancreatectomy) [2,15-19]. In two large retrospective studies, total and partial pancreatectomy resulted in similar 30-day perioperative mortality rates (approximately 5.5 percent) and long-term survival rates (approximately 22 percent).

Thus, total pancreatectomy should not be performed routinely as it obliges significant exocrine and endocrine replacement therapies without offering a survival benefit over a more limited pancreatic resection [20,21].

On rare occasions, however, total pancreatectomy may be performed in patients who require concomitant excisions of the cancer and another lesion (eg, main duct IPMN), and in those who have disease burdens large enough to render the remnant pancreas insufficient.

Patients with metastatic pancreatic cancer are not candidates for pancreatic resection, total or partial, because of a dismal prognosis with or without surgery.

Pancreatic neuroendocrine tumor

PNETs are malignant lesions of the pancreas. In patients with multifocal PNETs, total pancreatectomy may be required to remove all of the lesions [2,22]. For patients with sporadic or familial metastatic PNETs, total pancreatectomy may be performed if secondary control of the metastases is feasible and/or to palliate hormonal secretion.

In patients with functional PNETs, surgical resection of all tumor masses to negative margins is the standard of care and is associated with decreased risk of death and metastases [23,24].

Pancreatic surgery for PNETs associated with MEN-1 syndrome is controversial and is discussed elsewhere.

Total pancreatectomy is also a treatment for pancreatogenous hypoglycemia syndrome, also known as nesidioblastosis. Patients with nesidioblastosis have overactive pancreatic islets that are difficult to isolate, which can cause recurrent symptoms after a more limited pancreatectomy [25,26].

Pancreatic metastasis of renal cell cancer

Total pancreatectomy may be performed for patients with renal cell carcinoma who develop extensive metastases to the pancreas [1,6,22]. For those who have no additional metastasis outside of the pancreas, total pancreatectomy offers a complete metastasectomy, which is associated with excellent survival outcomes [27,28].

However, total pancreatectomy is not advocated for other types of metastases (eg, from lung cancer or melanoma) because such patients have a dismal prognosis, even with surgery.

Conversion total pancreatectomy

Total pancreatectomy is advocated for those who are at an exceptionally high risk for developing pancreatic fistula [29]. The decision to perform a total pancreatectomy in this setting is usually made intraoperatively based upon the consistency of the pancreatic parenchyma and the caliber of the pancreatic duct (a soft pancreas with a small pancreatic duct is prone to developing fistula).

Additionally, a pancreaticoduodenectomy may also need to be converted to a total pancreatectomy when there is evidence of tumor extension beyond the neck of the pancreas, or when technical difficulty precludes a safe partial pancreatic resection [1]. Pancreatic islet autotransplantation is usually not possible under these unplanned circumstances.

Completion (rescue) pancreatectomy

Completion pancreatectomy may be performed to control abdominal sepsis or massive hemorrhage arising from complications of a prior partial pancreatic resection [2,30-32]. However, a completion pancreatectomy is infrequently required because most of these complications can be managed medically or with interventional radiology procedures such as percutaneous drainage.

Surgical complications most commonly occur at the pancreatic anastomosis. Three different grades of postoperative pancreatic fistula (grades A, B, C) have been defined according to their clinical impact on the patient’s hospital course. While most grade A and B pancreatic fistulas can be managed with supportive care and/or drainage, grade C fistulas can be life-threatening and may require reoperative intervention [33].

At the reoperation, effective reanastomosis of the pancreatic duct to the bowel is nearly impossible because of inflammation. Thus, a completion pancreatectomy may be required but has not been demonstrated to have a survival advantage over other surgical techniques [1,19-21,34].

Preoperative preparation

Although there are well-defined disease indications for total pancreatectomy, there is a lack of consensus regarding patient selection criteria. Instead, patients should be evaluated by a multidisciplinary team of professionals at a center that offers all services necessary for the management of pancreatic disease.

Patient screening

Except in emergency situations (trauma or completion [rescue] total pancreatectomy), patients should be screened and prepared for consequences of a total pancreatectomy.

Most importantly, patients should be prepared intellectually, emotionally, financially, and physically to manage insulin-dependent diabetes, which is expected to develop following total pancreatectomy. Patients who are unable or unwilling to do so should not be offered a total pancreatectomy.

Patients should be free from drug addiction or other psychosocial impairments that may interfere with compliance. Patients who are on narcotics for chronic abdominal pain must only take medications that are prescribed to them at the appropriate dose.

For patients who have already developed exocrine or endocrine insufficiency, weight stability and low HgbA1c levels are good indicators that a patient is dedicated to maintaining his/her personal health. Patients who do not have diabetes should be evaluated for pancreatic islet autotransplantation.

Patients who have strong family support, employment stability, established relationships with physicians, and compliance with appointments have better disease management after a total pancreatectomy. Thus, before surgery, patients should establish a professional relationship with an endocrinologist who is comfortable managing an apancreatic patient; narcotic-dependent patients should begin working with a pain management physician who can assist with postoperative pain management and narcotics weaning, a process that can sometimes takes years to complete [7].

Imaging studies

High resolution (2.5 mm or thinner cuts), contrast-enhanced abdominopelvic computed tomography is typically performed prior to a total pancreatectomy in order to identify vascular planes, anomalous vasculature, and the location of any malignant lesions.

Vaccination

Splenectomy is usually performed in conjunction with total pancreatectomy.

Patients undergoing total pancreatectomy with splenectomy require vaccination against encapsulated bacteria to decrease the risk of overwhelming postsplenectomy sepsis. Specifically, patients should receive vaccination against Streptococcus pneumonia, Haemophilus influenzae type B, and Neisseria meningitides at 14 or more days prior to surgery [35].

Intraoperative management and techniques

Prophylaxis

Prophylactic antibiotics should be administered within an hour of incision based upon hospital protocols. Patients should receive both pharmacologic and mechanical venous thromboembolism prophylaxis.

Anesthesia

Total pancreatectomy is performed under general endotracheal anesthesia. In the absence of contraindications (eg, anticoagulation), spinal or epidural anesthesia can be used to augment general anesthesia and help with perioperative pain control.

Standard technique

Although operative techniques vary, a total pancreatectomy involves resection of the entire pancreas along with the duodenum and spleen followed by reconstruction in most patients [22,29,36]. Resource-permitting, nondiabetic patients should also receive islet autotransplantation (figure 1).

Incision

Either a midline or limited bilateral subcostal incisions can be used for total pancreatectomy, depending upon patient body habitus.

Pancreatectomy

The pancreas is resected following the steps described below.

The greater omentum is opened to expose the pancreas behind the stomach. The inferior border of the pancreas is identified to the left of the superior mesenteric vein and dissected from the retroperitoneum, taking care to preserve the inferior mesenteric vein if possible. The superior border of the pancreas is dissected to the left of the celiac axis, identifying the origin of the splenic and left gastric arteries. The duodenum and head of the pancreas are mobilized from the retroperitoneum anterior to the vena cava and the renal veins. Next, the superior mesenteric vein is identified and a tunnel created between it and the posterior surface of the pancreas.

Cephalad to the pancreas, the gastroduodenal artery is dissected, which exposes the portal vein and permits management of the hepatoduodenal ligament. The spleen is completely mobilized out of the retroperitoneum with the distal pancreas towards the confluence of the splenic, superior mesenteric, and portal veins.

If there are no contraindications to resection, the gastroduodenal artery is ligated and divided. The bile duct is divided and a cholecystectomy is performed. The stomach is transected pre- or postpyloric, and the proximal jejunum is transected distal to the ligament of Treitz. The splenic artery is ligated and divided, and the left gastric artery must be preserved as the only remaining blood supply to the stomach. The tail of the pancreas is then lifted anteriorly and the splenic vein ligated without tension to avoid narrowing the portal vein. The neck of the pancreas is dissected off the portal vein. The specimen is brought to the right so the uncinate process can be dissected off the superior mesenteric artery under direct vision.

Reconstruction

Following resection of the pancreatic parenchyma and duodenum, reconstruction is required to restore gastrointestinal and biliary continuity.

The proximal jejunum is brought through a defect in the mesocolon and an anastomosis created between the bile duct and the jejunum. Approximately 30 to 40 cm distally, the jejunum is anastomosed to the stomach anterior to the colon. The distance between the two anastomoses helps to prevent bile gastritis. A decompressive tube gastrostomy may be placed in patients with severe diabetic gastroparesis, which is often exacerbated in the postoperative period. Feeding tubes and drains are otherwise not routinely required.

Islet cell transplantation

Since 1977, islet autotransplantation has become an important option for patients with preserved insulin production when undergoing total pancreatectomy for benign indications such as chronic or hereditary pancreatitis [37,38]. A successful autotransplantation affords patients tighter glycemic control, fewer diabetic complications, and better quality of life after surgery. Islet transplantation is contraindicated for malignant pancreatic conditions.

Pancreatic islet cells are autotransplanted via infusion into the portal vein at the time of a total pancreatectomy. Autologous islet cell transplantation does not require immunosuppression as does heterologous islet cell or pancreatic transplantation.

Other techniques

Alternative open techniques of total pancreatectomy, which allow preservation of the spleen or duodenum, have been described primarily for patients with chronic pancreatitis. Although minimally invasive total pancreatectomy has also been reported, open surgery remains the standard surgical approach.

  • Spleen-preserving total pancreatectomy – Total pancreatectomy may be performed without splenectomy. In patients with chronic pancreatitis, however, preservation of the splenic vein may be difficult because of inflammatory adherence to the pancreas and inability to ligate branching vessels. In such patients, the Warshaw technique, which divides the splenic vein and artery but preserves short gastric vessels, may permit splenic preservation [39].
  • The spleen should not be preserved in patients with known or suspected malignancy, or in those with confirmed high-grade dysplasia, because of the risk of lymphovascular invasion and the need to appropriately stage the disease.
  • Duodenum-preserving total pancreatectomy – Total pancreatectomy with preservation of the duodenum has been reported for benign indications such as chronic pancreatitis [40]. Although gastrointestinal continuity is not disrupted with this technique, a Roux-en-Y anastomosis is still required to drain the bile duct or any residual pancreatic tissue when necessary.
  • Minimally invasive total pancreatectomy – Although minimally invasive pancreatic surgery has been performed for over two decades, it is investigational. Open surgery remains the standard of care for patients who require a total pancreatectomy.

In the published literature, there have been fewer than a dozen reported cases of laparoscopic or robotic total pancreatectomy [41-45]. In the largest series, five robotic total pancreatectomies were performed without any mortality and only one major complication [46]. Only one of the five cases in that series, however, was for chronic pancreatitis, which is the most technically challenging indication for total pancreatectomy.

Postoperative management

After surgery, patients are typically placed on an intravenous infusion of insulin to maintain a finger stick blood glucose (FSBG) level of <180 mg/dL. Patients can be started on a clear liquid diet on the first postoperative day if they have an appetite and the abdomen is soft, and their diet can be advanced as tolerated. Once a patient has tolerated a solid diet, they are transitioned from intravenous insulin to longer-acting insulin preparations, including sliding scale coverage for meals. Additionally, pancreatic enzymes are started with solid foods.

Patients are discharged when they are tolerating small meals, their pain is controlled with oral medications, they can ambulate independently, and they are capable of managing their blood glucose at home. Patients are encouraged to follow up with endocrinology shortly after discharge.

Endocrine replacement

Insulin is the mainstay of endocrine replacement therapy after total pancreatectomy. Postsurgical patients should be treated in a manner similar to other patients with adult-onset type 1 diabetes.

An intravenous insulin infusion is typically required for initial glycemic control during the immediate postoperative period because of inconsistent eating, malabsorption, stress hormone release, and lack of glucagon synthesis. Once a patient’s diet becomes more reliable, insulin infusion can be replaced by longer-acting insulin preparations. Basal and prandial insulin doses should be adjusted to achieve euglycemia while avoiding potentially life-threatening hypoglycemia.

After islet autotransplantation

Effective glucose control after islet transplantation depends upon the mass and quality of islets isolated from the resected pancreas [7]. In one study, more than 60 percent of patients who received greater than 5000 islet equivalents per kilogram of recipient body weight achieved insulin independence [37]. In another study, low islet yield, alcoholic pancreatitis, and longer duration of pancreatitis (>5 years) strongly predicted failure of islet autotransplantation [47].

By various reports, at one year after islet autotransplantation, 30 to 38 percent of patients were insulin independent, 38 to 49 percent required less than 20 units of insulin per day, and the rest were dependent upon a higher dose of insulin [47-49]. At five years, the percentage of patients who remained insulin-independent decreased to 27 percent. However, many patients continued to make c-peptide despite receiving exogenous insulin supplementation, suggesting continued graft function, which helps protect against “brittle” diabetes [49].

Exocrine replacement

After total pancreatectomy, patients should be given pancreatic enzyme replacement therapy. Further tests are not required to establish malabsorption or malnutrition.

Patients should only use products that are approved by the US Food and Drug Administration (FDA), such as Creon, Zenpep, and Pancreaze, each of which contains pancrelipase. Unregulated products can cause treatment failure because they have variable efficacy, and contain primarily pancreatin, which is 12 times less effective than pancrelipase [50,51].

Pancrelipase delayed-release capsule (Creon) has been studied in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery [52-54]. In one trial, six month of Creon therapy resulted in decreased stool frequency (one fewer per day), weight gain (approximately 3 kg), and improvements in abdominal pain, flatulence, and stool consistency [52]. Although Zenpep and Pancreaze have not been studied in surgical patients, they contain the same ingredient as Creon, and therefore can be used with a unit-for-unit equivalency to Creon.

 

Pancreatic enzyme replacements should be given before all meals and snacks in doses commensurate with the fat content of the food. Patients should be started at an initial dose of 500 lipase units/kg of body weight per meal, followed by titration based upon symptoms, up to a maximum of 2500 lipase units/kg of body weight per meal or 10,000 lipase units/kg of body weight per day [51]. For patients who remain symptomatic while taking the maximal doses of pancreatic enzyme, a proton-pump inhibitor or H2 blocker may be used to increase fat absorption, as the pancreatic enzyme preparations are pH-sensitive and designed to activate in the duodenum.

In addition to digestive enzyme replacement, patients should receive supplementation of fat-soluble vitamins (ie, A, D, E, K) after total pancreatectomy to prevent conditions such as osteoporosis.

Morbidity and mortality

Short-term

The reported 30-day mortality and serious morbidity rates of total pancreatectomy were 5.4 to 8 percent and 24 percent, respectively [18,55]. Although the mortality rate of total pancreatectomy has declined over the years (1970 to 1989, 40 percent; 1990 to 1999, 8 percent; 2000 to 2007, 2 percent) [18], it remained higher than that of pancreaticoduodenectomy (5.4 versus 2.9 percent) [55]. The overall morbidity is also higher after total pancreatectomy compared with pancreaticoduodenectomy (69 versus 39 percent), but serious morbidity rates are similar (23.5 versus 23.1 percent).

Unplanned completion pancreatectomies have the worst outcomes because they are performed as salvage operations for severe complications such as uncontrolled sepsis or massive hemorrhage [56,57]. Compared with planned total pancreatectomies, unplanned pancreatectomies had higher mortality (39 to 47 versus 4.8 to 12.5 percent) and morbidity rates (79 to 100 versus 46 to 54 percent), according to two large retrospective studies [1,2]. (See ‘Completion (rescue) pancreatectomy’ above.)

 

Long-term

The long-term morbidities of total pancreatectomy include late complications of diabetes [58-60] and malnutrition [61-64], both of which have been more extensively studied in cystic fibrosis patients.

Complications of diabetes — Late complications of diabetes that can develop after total pancreatectomy include diabetic retinopathy, nephropathy, cardiac disease, and neuropathy. When present, such complications should be managed in the same way as other patients with diabetes [65]. Patients with diabetes due to total pancreatectomy have similar long-term outcomes as others with type 1 diabetes [1,66-68].

Malnutrition

After total pancreatectomy, patients should be offered intensive nutritional counseling, digestive enzyme supplementation, and gastrointestinal symptom management to prevent malnutrition. Apancreatic patients are unable to synthesize lipase, which is required to metabolize fat. Without supplementation, patients will develop maldigestion and malabsorption of nutrients, eventually leading to malnutrition. Chronic malnutrition leads to delayed growth and puberty in children, and shortened lifespan in adults.

Quality of life

In general, studies show that long-term physical, emotional, and functional quality of life is maintained after total pancreatectomy. Such studies, however, are inherently heterogenous because they enrolled patients with different indications for surgery (eg, benign versus malignant), and patients with different baseline health conditions (eg, diabetic versus nondiabetic).

  • In a single center study, thirteen patients, most of whom had malignant disease, reported good quality of life at six months after total pancreatectomy [22].
  • In a study of patients who underwent total pancreatectomy for benign indications such as chronic or hereditary pancreatitis, total pancreatectomy was associated with significant relief of pain and improved quality of life [38]. Patients who were both pain-free and insulin-independent reported better overall emotional health.
  • Total pancreatectomy was compared with pancreaticoduodenectomy in patients with pancreatic cancer or intraductal papillary mucinous neoplasm in a case-control study [2]. Although some quality of life parameters were reduced in patients after total pancreatectomy compared with pancreaticoduodenectomy, the global health status was not different between the two cohorts.
  • In another study, 34 long-term survivors of total pancreatectomy were surveyed with quality of life questionnaires at an average of 7.5 years after surgery [69]. Although quality of life after total pancreatectomy was reduced compared with matched controls from the general population, it was comparable to that of type 1 diabetics.

Summary and recommendations

  • Total pancreatectomy is a major operation with potential for mortality and severe morbidity. It is reserved for patients who have failed medical management and who are not candidates for less extensive surgery. Most total pancreatectomies are planned for benign (eg, chronic pancreatitis), premalignant (eg, intraductal papillary mucinous neoplasm), or malignant indications (eg, pancreatic cancer). A completion total pancreatectomy may be required as a rescue operation to treat severe complications (eg, uncontrolled sepsis, massive hemorrhage) of a prior, more limited pancreatic resection.
  • Prior to a planned total pancreatectomy, patients should be screened for their ability to manage diabetes after surgery, undergo imaging studies to rule out metastatic disease, and receive vaccination for an anticipated splenectomy.
  • Total pancreatectomy entails resection of the entire pancreatic parenchyma, most often with the duodenum and spleen, followed by gastrointestinal and biliary reconstruction. Resource-permitting, nondiabetic patients should receive islet autotransplantation.
  • Immediately after surgery, patients are typically managed with an intravenous infusion of insulin before being transitioned to longer acting insulin preparations. Patients should begin pancreatic enzyme replacement therapy when they resume a solid diet, using one of the regulated products such as Creon, Zenpep, and Pancreaze.
  • The perioperative mortality and serious morbidity rates after total pancreatectomy are low. All patients develop diabetes postoperatively, and are predisposed to late diabetic complications or malnutrition. The overall functional and emotional quality of life is maintained in long-term survivors of total pancreatectomy.

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