Pancreaticoduodenectomy (Whipple Resection)

Number: 0365


Aetna considers pancreaticoduodenectomy (also known as Whipple resection) medically necessary for the treatment of intraductal papillary mucinous neoplasm of the pancreas (IPMN) with high-grade dysplasia or invasive cancer.

Aetna considers pancreaticoduodenectomy (also known as Whipple resection or proximal pancreatectomy) experimental and investigational for the treatment of members with Zollinger-Ellison syndrome because the value of pancreaticoduodenectomy in this condition remains to be established.  Furthermore, the morbidity and mortality related to this approach may outweigh its potential benefits.


Zollinger-Ellison syndrome (ZES) is characterized by severe peptic ulcer disease that results from non-beta islet cell tumors, gastrinomas, of the gastrointestinal tract.  The mean age at presentation is 45 to 50 years, and men are affected more often than women.  Gastrinomas can be subdivided into tumors that are sporadic, constituting about 75 % of patients with ZES, and those that are genetically transmitted and associated with multiple endocrine neoplasia type 1 (MEN 1), constituting about 25 % of patients with ZES.  Zollinger-Ellison tumors associated with MEN-1 occur at an earlier age than the sporadic tumors and have been characterized by some researchers to follow a more benign course.

Currently, the literature states that proton-pump inhibitors (PPIs) such as lansoprazole (Prevacid) and omeprazole (Prilosec) are the treatment of choice for ZES.  For patients who have difficulty controlling gastric acid hyper-secretion with oral PPIs, intravenous pantoprazole (Protonix I.V.) has been reported to be effective.  Most ZES patients (93 %) maintained effective control of acid output previously established with oral PPIs when switched to twice-daily 80 mg of intravenously administered pantoprazole.  In patients with sporadic ZES, the literature suggests that exploratory surgery with tumor resection is also appropriate.  According to accepted guidelines, surgical resection of a single gastrinoma may be attempted if there is no evidence that it has spread to other organs (e.g., lymph nodes or the liver).  Gastrectomy to control acid over-production is rarely indicated.  However, the role of pancreaticoduodenectomy (Whipple resection, or proximal pancreatectomy) in patients with sporadic gastrinomas and in patients with MEN-1 is controversial.  Furthermore, the effect of aggressive surgery, such as the Whipple resection, on survival is unclear.

In a review on surgical treatment and prognosis of gastrinoma, Norton (2005) noted that Whipple pancreaticoduodenectomy results in the highest probability of cure in both sporadic and MEN-1 gastrinoma patients as it removes the entire gastrinoma triangle.  However, the excellent long-term survival of these patients with lesser operations and the increased operative mortality and long-term morbidity of Whipple pancreaticoduodenectomy make its current role unclear until further studies are done.

Bartsch et al (2007) stated that gastrinoma is the most frequent functional pancreaticoduodenal endocrine tumor in patients with MEN-1 and a major determinant of mortality in this syndrome.  Whether routine surgical exploration should be performed in patients with MEN-1 associated ZES to possibly decrease the malignant spread and eventually increase survival still remains controversial.  There is not only disagreement about the indication for surgical exploration, but also what type of procedure should be performed, since sufficient evidence-based data are not available.

In a review on surgical management of ZES, Morrow and Norton (2009) stated that much has been learned about the diagnosis and treatment of ZES, and certain questions require further investigation.  Delay in diagnosis of ZES is still a significant problem, and clinical suspicion should be elevated.  The single best imaging modality for localization and staging of ZES is somatostatin receptor scintigraphy.  Goals of surgical treatment for ZES differ between sporadic and MEN-1-related cases.  All sporadic cases of ZES should be surgically explored (including duodenotomy) even with negative imaging results, because of the high likelihood of finding and removing a tumor for potential cure.  Surgery for MEN-1-related cases should be focused on prevention of metastatic disease, with surgery being recommended when pancreatic tumors are greater than 2 cm.  The authors noted that the role of Whipple procedure, especially for MEN-1 cases, should be explored further.  Laparoscopic and endoscopic treatments are more experimental, but may have a role.

An UpToDate review on “Pancreaticoduodenectomy (Whipple procedure): Techniques” (Reber, 2013) does not mention Zollinger-Ellison syndrome as an indication of pancreaticoduodenectomy.  Furthermore, an UpToDate review on “Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)” (Goldfinger, 2013) does not mention pancreaticoduodenectomy as a therapeutic option.

Coolsen and colleagues (2014) stated that few randomized controlled trials (RCTs) have been performed in patients undergoing pancreatico-duodenectomy (PD).  An important factor contributing to this is the large number of patients needed to adequately power RCTs for relevant clinical single endpoints.  A PD-specific composite end-point (CEP) could solve this problem.  The aim of the present study was to develop a PD-specific CEP, consisting of complications related to PD, allowing reduction in sample sizes and improving the ability to compare outcomes.  PD-specific CEP components were selected after a systematic review of the literature and consensus between 25 international pancreatic surgeons.  Ultimately, prospective cohorts of patients who underwent PD in 2 high-volume HPB centers (London, UK, and Maastricht, NL) were used to assess the event rate and effect of implementing a PD-specific CEP.  From a total of 18 single-component end-points, 8 were selected to be included the PD-specific CEP: (i) intra-abdominal abscess, (ii) sepsis, (iii) post-PD hemorrhage, (iv) bile leakage, (v) gastro-jejunostomy leakage, (vi) leakage of the pancreatic anastomosis, (vii) delayed gastric emptying, and (viii) operative mortality within 90 days.  All 8 components had consensus definitions and a Dindo-Clavien classification of 3 or more.  The incidence of the PD-specific CEP was 24.7 % in the Maastricht cohort and 23.3 % in the London cohort.  These incidence rates led to a 2-fold reduction in the theoretical calculated sample size for an adequately powered RCT on PD using this CEP as a primary end-point.  The authors concluded that the proposed PD-specific CEP enables clinical investigators to adequately power RCTs on PD and increases the feasibility, comparability, and utility in meta-analysis.

Tenner et al (1996) stated that intraductal mucin-hypersecreting neoplasm (IMHN), also termed mucinous ductal ectasia, is a rare disorder of the pancreas characterized by distension of the pancreatic duct with mucus.  This study attempted to clarify the clinical, radiographic, histological, and treatment approaches to this entity.  The medical records, radiological imaging studies, and pathology specimens of 8 patients with IMHN seen during a 3-yr period were reviewed.  The diagnosis of IMHN was established by findings during ERCP, which included mucin plugging of the papilla, mucin extrusion from the papillary orifice after intraductal injection of contrast medium, mucinous filling defects in the main pancreatic duct, and dilated main and branch pancreatic ducts in the absence of obstructing ductal strictures.  All patients presented with an initial clinical diagnosis of acute or chronic pancreatitis, suspected cystic neoplasm, or biliary obstruction.  Non-invasive imaging studies such as trans-abdominal ultrasonography or CT and laboratory evaluation did not seem to help in defining the disease.  Five patients underwent Whipple resection; pathology included papillary ductal hyperplasia in 1, dysplastic mucinous epithelium in 2, and mucinous cystadenocarcinoma in 2.  All 5 patients had associated histological evidence of chronic pancreatitis.  All patients are alive and well after 21 to 53 months without evidence of residual disease.  The authors concluded that IMHN has a wide spectrum of clinical, radiological, and histological features.  The indolent biologic behavior and favorable prognosis of IMHN suggested that it is one of the most curable forms of pancreatic malignancy.

Paal et al (1999) noted that intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas are rare lesions.  These researchers undertook this study to analyze these tumors by focusing on the diagnostic criteria and correlating the histologic features with clinical prognosis.  A total of 22 cases of IPMN were retrieved from the Endocrine Tumor Registry of the Armed Forces Institute of Pathology.  Blocks or unstained slides were available for histochemical and immunohistochemical studies (including proliferative markers and cell cycle regulators) and K-ras oncogene mutations in 15 cases.  Patient follow-up was obtained in all of the cases.  IPMN occurs in both genders with a slight male predominance, with a mean age at presentation of 64.4 years (range of 48 to 85 yrs).  The patients presented with abdominal pain.  The neoplasms were radiologically and grossly cystic, usually (18 cases of 22) located in the head of the pancreas.  Histologically, the tumors consisted of intraductal papillary proliferations protruding into and expanding the pancreatic ducts.  Invasion into the surrounding pancreatic parenchyma was detected in 15 cases.  Chronic pancreatitis was present in all of the cases.  p27 immunoreactivity always exceeded the immunoreactivity of cyclin E.  K-ras oncogene mutations were detected in 2 cases.  Patients were treated with a complete surgical resection (n = 7) or a Whipple procedure (n = 13).  Only 2 of 22 patients died of disease (3 died immediately post-operatively and 3 died of unrelated causes), whereas the remaining 14 patients were alive at last follow-up, without evidence of disease, an average of 58.2 months after initial presentation.  IPMNs are rare, distinctive neoplasms, with complex intraductal papillae, that can be easily separated from in-situ ductal adenocarcinoma and mucinous cystic neoplasms.  The high ratio of p27 protein to cyclin E supports the excellent prognosis of these neoplasms, despite the presence of invasion and K-ras oncogene mutation.

Fernandez-Cruz et al (2006) stated that the standard surgical procedure for IPMN of the main duct (IPMN-M) or side branch ducts (IPMN-Br) is pancreaticoduodenectomy.  IPMN-BR is a more indolent disease with a lower incidence of malignancy.  These investigators evaluated the usefulness of organ-preserving pancreatic resections (OPPR) including duodenum-preserving pancreatic head resection (DPHR) and pancreatic head resection with segmental duodenectomy (PHRSD) in patients with IPMN-BR.  Surgical outcomes were evaluated in 8 IPMN-Br patients: DPHR was performed in 4 patients and PHRSD was performed in 4 patients.  In addition, 13 IPMN patients with Whipple resections were included in the analysis.  The incidence of post-operative complications was 38 % after Whipple resection, 100 % after DPHR and 25 % after PHRSD.  The mean length of hospital stay was 27 days after DPHR, 22 days after Whipple resection and 16 days after PHRSD.  Invasive IPMN was found in 38 % of the patients in the Whipple group, and non-invasive IPMN was found in 100 % of patients who underwent organ-preserving surgery.  The authors concluded that pancreaticoduodenectomy remains the treatment of choice in patients with invasive IPMN.  PHRSD appears to be a useful procedure for IPMN-Br located in the head of the pancreas.

Beger et al (2013) stated that cystic neoplasms of the pancreas are being detected and surgically treated increasingly more frequently.  Intraductal papillary mucinous neoplasms and mucinous cystic neoplasms (MCN) are primary benign lesions; however, the 5-year risk for malignant transformation has been estimated to be 63 % and 15 %, respectively.  Surgical extirpation of a benign cystic tumor of the pancreas is a cancer preventive measure.  The duodenum-preserving total pancreatic head resection technique (DPPHRt) is being used more frequently for cystic neoplasms of the pancreatic head.  The complete resection of the pancreatic head can be applied as a duodenum-preserving technique or with segmental resection of the peri-papillary duodenum.  Borderline lesions, carcinoma in situ or T1N0 cancer of the papilla and the peri-papillary common bile duct are also considered to be indications for segmental resection of the peri-papillary duodenum.  A literature search for cystic neoplastic lesions and DPPHRt revealed the most frequent indications to be IPMN, MCN and SCA lesions and 28 % suffered from a cystic neoplasm with carcinoma in-situ or a peri-papillary malignoma.  The hospital mortality rate was 0.52 %.  Compared to the Whipple type resection the DPPHRt exhibits significant benefits with respect to a low risk for early post-operative complications and a low hospital mortality rate of less than 1 %.  Exocrine and endocrine pancreatic functions after DPPHR are not impaired compared to the Whipple type resection.

Aimoto et al (2013) investigated the clinicopathological features of borderline resectable invasive carcinomas (BRICs) derived from IPMNs and examined the significance of the aggressive "surgery first" approach compared with the treatment of conventional borderline resectable pancreatic ductal adenocarcinomas (BRPDAs).  These researchers retrospectively studied 7 patients with BRICs derived from IPMNs and 14 patients with conventional BRPDAs.  Several factors were reviewed: initial symptoms, pre-operative imaging, serum level of CA19-9, peri-operative factors, pathological findings, adjuvant chemotherapy, and outcome.  All BRICs derived from IPMN were huge tumors (more than 3 cm in diameter) suspected to involve less than 180° of the circumference of the vessel.  Five patients (71 %) underwent a modified Whipple procedure, and 2 (29 %) underwent distal pancreatectomy.  Only 3 patients (43 %) required vascular resection.  Curative resection was achieved in all 7 patients, who are alive with no evidence of recurrence.  There were no severe post-operative complications.  With regards to the pathological IPMN subtype, 2 tumors (29 %) were gastric and 5 (71 %) were intestinal.  Only 2 patients (29 %) had lymph node metastasis.  The final stage was II in 4 (57 %) cases and IVa in 3 cases (43 %).  The 3-year survival rate was 100 %.  Tumors of BRICs derived from IPMNs were larger than those of conventional BRPDAs (p < 0.05).  The BRICs derived from IPMN less frequently metastasized to lymph nodes (p < 0.05) and were of an earlier stage (p < 0.05) than were conventional BRPDAs.  The 3-year survival rate was significantly higher for BRICs derived from IPMNs (100 %) than for conventional BRPDAs (19 %, p < 0.001).  The authors concluded that the BRICs derived from an intestinal or gastric IPMN are less aggressive than conventional BRPDAs and have a more favorable prognosis. In addition, aggressive "surgery first" approach may contribute to this better prognosis.

Furthermore, an UpToDate review on “Diagnosis and treatment of intraductal papillary mucinous neoplasm of the pancreas” (Sheth et al, 2015) states that “Surgery is the only treatment option in patients with intraductal papillary mucinous neoplasm of the pancreas (IPMN) with high-grade dysplasia or invasive cancer …. Surgical series have described a variety of operations for IPMN, including total pancreatectomy, pancreaticoduodenectomy, distal pancreatectomy, and segmental resection of the tumor.  The choice of surgery will be determined by the location of the tumor and the extent of involvement of the gland …. The most common operation is pancreaticoduodenectomy (70 %) because most tumors are in the head of the pancreas”.

CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
48150 Pancreatectomy, proximal subtotal with total duodenectomy, partial gastrectomy, choledochoenterostomy and gastrojejunostomy (Whipple-type procedure); with pancreatojejunostomy
48152     without pancreatojejunostomy
CPT codes not covered for indications listed in the CPB:
48153 Pancreatectomy, proximal subtotal with near-total duodenectomy, choledochoenterostomy and duodenojejunostomy (pylorus-sparing, Whipple-type procedure); with pancreatojejunostomy
48154     without pancreatojejunostomy
ICD-9 codes covered if selection criteria are met:
157.3 Malignant neoplasm of pancreas, pancreatic duct
211.6 Benign neoplasm of other parts of the digestive system, Pancreas except islets of Langerhans
211.7 Benign neoplasm of other parts of the digestive system, Pancreas islets of Langerhans
ICD-9 codes not covered for indications listed in the CPB:
251.5 Abnormality of secretion of gastrin [Zollinger-Ellison syndrome]
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
ICD-10 codes will become effective as of October 1, 2015 :
CPT codes covered if selection criteria are met:
48150 Pancreatectomy, proximal subtotal with total duodenectomy, partial gastrectomy, choledochoenterostomy and gastrojejunostomy (Whipple-type procedure); with pancreatojejunostomy
48152     without pancreatojejunostomy
CPT codes not covered for indications listed in the CPB:
48153 Pancreatectomy, proximal subtotal with near-total duodenectomy, choledochoenterostomy and duodenojejunostomy (pylorus-sparing, Whipple-type procedure); with pancreatojejunostomy
48154     without pancreatojejunostomy
ICD-10 codes covered if selection criteria are met:
C25.3 Malignant neoplasm of pancreatic duct
D13.6 Benign neoplasm of pancreas
D13.7 Benign neoplasm of endocrine pancreas
ICD-10 codes not covered for indications listed in the CPB:
E16.4 Increased secretion of gastrin [Zollinger-Ellison syndrome]

The above policy is based on the following references:
    1. Del Valle J, Scheiman JM. Zollinger-Ellison syndrome. In: Textbook of Gastroenterology. Vol. I. 3rd ed. T Yamada, et al., eds. Philadelphia, PA: Lippincott Williams & Wilkins; 1999; Ch. 65:1445-1462.
    2. Wolfe MM, Jensen RT. Zollinger-Ellison syndrome: Current concepts in diagnosis and management. N Engl J Med. 1987;317(19):1200-1209.
    3. MacFarlane MP, Fraker DL, Alexander HR, et al. Prospective study of surgical resection of duodenal and pancreatic gastrinomas in multiple endocrine neoplasia type 1. Surgery. 1995;118(6):973-979; discussion 979-980.
    4. Meko JB, Norton JA. Management of patients with Zollinger-Ellison syndrome. Ann Rev Med. 1995;46:395-411.
    5. Jensen RT. Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type 1. J Intern Med. 1998;243(6):477-488.
    6. Wells SA, Jr. Surgery for the Zollinger-Ellison syndrome. N Engl J Med. 1999;341(9):689-690.
    7. Norton JA, Fraker DL, Alexander HR, et al. Surgery to cure the Zollinger-Ellison syndrome. N Engl J Med.1999;341(9):635-644.
    8. Maton PN. Review article: The management of Zollinger-Ellison syndrome. Aliment Pharmacol Ther. 1993;7(5):467-475.
    9. Metz DC, Forsmark C, Lew EA, et al. Replacement of oral proton pump inhibitors with intravenous pantoprazole to effectively control gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. Am J Gastroenterol. 2001;96(12):3274-3280.
    10. Witzigmann H, Max D, Uhlmann D, et al. Quality of life in chronic pancreatitis: A prospective trial comparing classical Whipple procedure and duodenum-preserving pancreatic head resection. J Gastrointest Surg. 2002;6(2):173-179; discussion 179-180.
    11. Norton JA, Jensen RT. Current surgical management of Zollinger-Ellison syndrome (ZES) in patients without multiple endocrine neoplasia-type 1 (MEN1). Surg Oncol. 2003;12(2):145-151.
    12. Norton JA, Jensen RT. Resolved and unresolved controversies in the surgical management of patients with Zollinger-Ellison syndrome. Ann Surg. 2004;240(5):757-773.
    13. Campana D, Piscitelli L, Mazzotta E, et al. Zollinger-Ellison syndrome. Diagnosis and therapy. Minerva Med. 2005;96(3):187-206.
    14. Norton JA. Surgical treatment and prognosis of gastrinoma. Best Pract Res Clin Gastroenterol. 2005;19(5):799-805.
    15. Pellicano R, De Angelis C, Resegotti A, Rizzetto M. Zollinger-Ellison syndrome in 2006: Concepts from a clinical point of view. Panminerva Med. 2006;48(1):33-40.
    16. Norton JA, Fraker DL, Alexander HR, et al. Surgery increases survival in patients with gastrinoma. Ann Surg. 2006;244(3):410-419.
    17. Bartsch DK, Langer P, Rothmund M. Surgical aspects of gastrinoma in multiple endocrine neoplasia type 1. Wien Klin Wochenschr. 2007;119(19-20):602-608.
    18. Pedicone R, Adham M, Hervieu V, et al. Long-term survival after pancreaticoduodenectomy for endocrine tumors of the ampulla of Vater and minor papilla. Pancreas. 2009;38(6):638-643.
    19. Mortellaro VE, Hochwald SN, McGuigan JE, et al. Long-term results of a selective surgical approach to management of Zollinger-Ellison syndrome in patients with MEN-1. Am Surg. 2009;75(8):730-733.
    20. Morrow EH, Norton JA. Surgical management of Zollinger-Ellison syndrome; state of the art. Surg Clin North Am. 2009;89(5):1091-1103.
    21. Reber HA. Pancreaticoduodenectomy (Whipple procedure): Techniques. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed February 2013.
    22. Goldfinger SE. Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma). UpToDate [online serial]. Waltham, MA: UpToDate; reviewed February 2013.
    23. Coolsen MM, Clermonts SH, van Dam RM, et al. Development of a composite endpoint for randomized controlled trials in pancreaticoduodenectomy. World J Surg. 2014;38(6):1468-1475.
    24. Tenner S, Carr-Locke DL, Banks PA, et al. Intraductal mucin-hypersecreting neoplasm "mucinous ductal ectasia": Endoscopic recognition and management. Am J Gastroenterol. 1996;91(12):2548-2554.
    25. Paal E, Thompson LD, Przygodzki RM, et al. A clinicopathologic and immunohistochemical study of 22 intraductal papillary mucinous neoplasms of the pancreas, with a review of the literature. Mod Pathol. 1999;12(5):518-528.
    26. Fernandez-Cruz L, Olvera C, Lopez-Boado MA, et al. Organ-preserving resection of the pancreaticoduodenal region in the treatment of intraductal papillary mucinous tumors. Cir Esp. 2006;80(5):295-300.
    27. Beger HG, Siech M, Poch B. Duodenum-preserving total pancreatic head resection: An organ-sparing operation technique for cystic neoplasms and non-invasive malignant tumors. Chirurg. 2013;84(5):412-420.
    28. Aimoto T, Mizutani S, Kawano Y, et al. Significance of aggressive surgery for an invasive carcinoma derived from an intraductal papillary mucinous neoplasm diagnosed preoperatively as borderline resectable. J Nippon Med Sch. 2013;80(5):371-377.
    29. Sheth SG, Howell DA, Kent TS. Diagnosis and treatment of intraductal papillary mucinous neoplasm of the pancreas. UpToDate Inc., Waltham, MA. Last reviewed January 2015.

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