Management of periampullary tumor What are the options for ampullary adenoma? Joint Hospital Surgical Grand Round (July 2017) Presented by Dr. Sin Kar Yan, PMH

Case Study Miss Wong F/64 Hepatitis B carrier Asymptomatic patient OGD for screening for varices No varices Incidental finding of ampulla mass 4x2cm

Case Study What to do next? Biopsy: Tubular adenoma Hb normal LFT normal Referral to surgery What to do next?

Introduction Periampullary tumors Neoplasms that arise within 2cm of the ampulla of Vater Origins Pancreas Distal CBD Ampulla Duodenum Ampulla of Vater Duodenal aspect of sphincter of Oddi muscle Surround confluence of distal CBD and main pancreatic duct and papilla of Vater Ampullary and periampullary tumors are infrequent, but have malignant rate of >90% Periampullary tumor: 5% of all GIT malignancy. Ampullary tumor: 1% of GIT malignancy. Origins Pancreas 60% Distal CBD 10% Ampulla 20% Duodenum 10% Image: Netter, Frank Henry, and Sharon Colacino. Atlas of human anatomy. Ciba-Geigy Corporation, 1989.

Differential Diagnosis Benign Tubular adenoma, tubulovillous or villous adenoma Prevalence: 0.04% to 0.12% Rate of transformation to carcinoma: 30% Hemangioma Leiomyoma Leiomyofibroma Lipoma Lymphangioma Neuroendocrine tumor Malignant (>90%) Adenocarcinoma Ddx - The benign pathology we must rule out upon examining the ampullary and periampullary region is also diverse: choledocholithiasis or microlithiasis, chronic pancreatitis, dysfunction of the sphincter of Oddi and the presence of alterations in biliopancreatic drainage as a periampullary diverticulum, choledochocele or pancreas divisum. 30% transformation rate to carcinoma Adenoma - Associated with FAP and HNPCC Baker HL, Caldwell DW. Lesions of the ampulla of Vater. Surgery. 1947;21:523–531. Sato T, Konishi K, Kimura H, Maeda K, Yabushita K, Tsuji M, Miwa A. Adenoma and tiny carcinoma in adenoma of the papilla of Vater--p53 and PCNA. Hepatogastroenterology. 1999;46:1959–1962. Seifert, Erwin, Ferdinand Schulte, and Manfred Stolte. "Adenoma and carcinoma of the duodenum and papilla of Vater: a clinicopathologic study." American Journal of Gastroenterology 87.1 (1992).

Presentations of Periampullary Tumors Asymptomatic as incidental finding Symptomatic Jaundice Abdominal pain Palpable gallbladder Acute pancreatitis UGIB / obstruction Jaundice intermittent due to erosion / intermittent permeability of bile duct Prevalence 200-300x in patients with FAP (80% can develop SB polyps) / HNPCC

Investigations Blood investigations Imaging and endoscopy Complete blood count Liver function test CA 19.9 Imaging and endoscopy Ultrasound CT MRCP Duodenoscopy ERCP EUS CA19.9 Pancreas / NET Biliary (GB, cholangio, ampullary CA) HCC Gastric, ovarian, colorectal Lung, breast, uterus Benign: cholangitis, cirrhosis Ultrasound Dilated CBD down to level of ampulla. Assess liver metastasis, LN, ascites. CT Locoregional spread and vascular involvement MRCP Less invasive than ERCP for investigation of OJ ERCP Both diagnostic and therapeutic Biopsy / cytology Biliary drainage EUS Transmural information / depth of tumor invasion Peripancreatic LN assessment FNAC Helps to assess small tumors that cannot be assessed by CT

Duodenoscopy / ERCP Visualization of ampulla Assessment of biliary system ± biliary drainage if obstruction Benign and malignant ampullary tumors may not be distinguished on appearance alone Suspicious ampullary lesions should be biopsied before endoscopic resection is attempted. ampullary adenoma is suspected if discolored lobular or pine cone– like lesions are detected. Forceps bx – 30% false negative Malignant Benign

Duodenoscopy / ERCP Characteristics of malignant lesions Induration / rigidity Ulceration Suspicious lesions should be biopsied before endoscopic resection False negative rate up to 30% Comparison of cytologic and histologic results showed the following sensitivity and specificity: DB, 40% and 97%, respectively; AB, 100% each; BB, 75% and 93%, respectively. Ref: Diagnostic value of brush cytology Yamaguchi, Koji, Munetomo Enjoji, and Katsutoshi Kitamura. "Endoscopic biopsy has limited accuracy in diagnosis of ampullary tumors." Gastrointestinal endoscopy 36.6 (1990): 588-592.

Endoscopic Ultrasound Identify small lesions Assess intraductal extension and extension beyond muscularis propia Obtain tumor biopsy Assess lymph node status + biopsy Intraductal ultrasounds Precise of T staging Assess depth of involvement AdenoCA: hypoechoic and heterogenous Ref: Role of endoscopy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999148/ The courses of lymphatic drainage of the papilla and the periampullary region move toward the chains of the posterior and anterior pancreatoduodenal arteries, the hepatic artery and the superior mesenteric artery. The lymph nodes which are furthest away, the splenic ones or those of the celiac trunk, are considered distant metastases Ddx – inflammatory pseudotumors, chronic pancreatitis, periampullary diverticulum, choledochocele, pancreatic divism Adler, Douglas G., et al. "The role of endoscopy in ampullary and duodenal adenomas." Gastrointestinal endoscopy 64.6 (2006): 849-854. Onkendi, Edwin O., et al. "Adenomas of the ampulla of Vater: a comparison of outcomes of operative and endoscopic resections." Journal of Gastrointestinal Surgery 18.9 (2014): 1588-1596.

Endoscopic Ultrasound Who should undergo EUS? No consensus Lesions >1cm Lesions with suspicion of malignancy

Narrow Band Imaging Imaging features Irregular villous arrangement Irregular villous size Disappearance of ridges Demarcation of normal villi Abnormal microvasculatures

Narrow Band Imaging Features of irregular villous arrangement + abnormal microvasculatures Diagnose adenocarcinoma with a sensitivity of 69% and specificity of 100% Irregular villi size, disappearance of the ridge, and demarcation of villi could not predict the diagnosis of ampullary tumor in multivariate analysis, even though they were detected more frequently in ampullary tumors than in infl ammatory diseases All adenoCA has the two features All adenoma has one or both of the NBI features Irregular villous arrangement + abnormal microvasculatures: sensitivity of 69% and specificity of 100%, PPV, NPV, and accuracy of 69%, 100%, 100%, 85%, and 89%, respectively. Ref: Usefulness in whitelight imaging guided NBI Park, Jin-Seok, et al. "Usefulness of white-light imaging–guided narrow-band imaging for the differential diagnosis of small ampullary lesions." Gastrointestinal endoscopy 82.1 (2015): 94-101.

Narrow Band Imaging Guide target biopsy site Not suitable as a screening tool due to the low sensitivity Role of NBI is still being investigated Large scale prospective study is required

Treatment: Ampullectomy

Ampullectomy Surgical ampullectomy Transduodenal local excision Involves reimplantation of the distal CBD and pancreatic duct within the duodenal wall Endoscopic ampullectomy “papillectomy” Resection of mucosa and submucosa of the duodenal wall, in the area of the anatomical attachments of the ampulla of Vater, including the tissue around the bile duct and the pancreatic-duct orifices

Surgical Ampullectomy Classic treatment for ampullary adenoma Schneider, Lutz, et al. "Surgical ampullectomy: an underestimated operation in the era of endoscopy." HPB: the official journal of the International Hepato Pancreato Biliary Association 18.1 (2016): 65.

Surgical Ampullectomy Laparotomy Kocharization of duodenum Longitudinal duodenotomy of D2 Lesion excised Reimplantation of CBD and PD Duodenotomy with ampullary adenoma exposed Reimplantation of CBD and PD Ángel, José Manuel Ramia, et al. "Ampulectomía transduodenal como tratamiento del adenoma de ampolla de Vater." Cirugía Española 87.3 (2010): 184-185.

Surgical Ampullectomy Frozen section can be performed Conversion to radical pancreaticoduodenectomy if malignancy is found Mortality 0-3% Morbidity 42-45% Complications Bleeding Cholangitis / pancreatitis Anastomotic / duodenal leakage Papillary stenosis Frozen section Margin analysis Look for malignancy Overall, the frozen section examinations correctly agreed with the final pathology in 75% of the cases. The outcomes of the frozen section examinations in the detection of cancer are as follows: sensitivity—57%, specificity—100%, positive predictive value—100%, and negative predictive value—62% false negative rate of 25%–56% Transduodenal Resection of Peri-Ampullary Lesions Dixon E; Vollmer CM Jr; Sahajpal A; Cattral MS; Grant DR; Taylor BR; Langer B; Gallinger S; Greig PD. World Journal of Surgery. 29(5):649-52, 2005 May. Ceppa, Eugene P., et al. "Endoscopic versus surgical ampullectomy: an algorithm to treat disease of the ampulla of Vater." Annals of surgery 257.2 (2013): 315-322. Grobmyer, Stephen R., et al. "Contemporary results with ampullectomy for 29 “benign” neoplasms of the ampulla." Journal of the American College of Surgeons 206.3 (2008): 466-471.

Endoscopic Ampullectomy “papillectomy” Minimally invasive En bloc resection for small lesions Piecemeal resection for large lesions may be required Benign adenoma / carcinoma in situ / well or mod differentiated tumor T1N0M0 Free lateral and in-depth margin , no lymphovascular infiltration <1cm inside CBD / P duct: Tissue invading to this level can be endoscopically exposed and ablated Piecemeal if >2cm. Pic: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350907/ *EP definition Resection of the mucosa and submucosa of the duodenal wall, in the area of the anatomical attachments of the ampulla of Vater, including the tissue around the bile duct and the pancreatic-duct orifices. SA definition surgical “ampullectomy” which consists of resection of the ampulla of Vater, via a duodenotomy, including resection of pancreatic-head tissue, followed by separate reinsertion of the common bile duct and main pancreatic duct into the duodenal wall. Ref: De Palma, Giovanni D. "Endoscopic papillectomy: indications, techniques, and results." World Journal of Gastroenterology: WJG 20.6 (2014): 1537. Image: Bassan, Milan, and Michael Bourke. "Endoscopic ampullectomy: a practical guide." Journal of interventional gastroenterology 2.1 (2012): 23.

Endoscopic Ampullectomy Patient selection Lesion <4-5cm Histology Benign High grade dysplasia is not a contraindication EUS criteria No invasion of duodenal muscularis propia No tumor growth beyond 1cm inside CBD / pancreatic duct Positive lifting sign Lesion size is not corresponding to intraductal extension or presence of malignancy Elevation after submucosal injection or presence of submucosal mass Tis, focal T1 malignancy has been treated by EA, but long term results are still being investigated Ref: EA vs SA

Endoscopic Ampullectomy De Palma, Giovanni D. "Endoscopic papillectomy: indications, techniques, and results." World Journal of Gastroenterology: WJG 20.6 (2014): 1537.

Endoscopic Ampullectomy Techniques Submucosal injection Lift sign Endoscopic snare and electrocautery En bloc resection for small lesions Piecemeal resection or multiple procedures may be required for larger lesions Electrocautery injuries to tissue fragments can affect pathological analysis Ablation (Argon plasma coagulation) if any residual lesion Sphincterotomy Helps pancreaticobiliary drainage after papillectomy Stent placement Not routine Aim to prevent iatrogenic pancreatitis Ablation APC , laser, monopolar / bipolar Destroy residual / recurrent adenoma Sphinterotomy - No consensus whether it is a must or when to do it Stent placement is not a must ?prevent post-ERCP pancreatitis. (one RCT proved prophylactic pancreatic duct stent placement reduce post-papillectomy pancreatitis, 30 reduced to 10%) Minimize stenosis of orifice PD, and safer use of coagulative tx Some suggest only use stent if pancreatic duct drainage is suboptimal / difficult cannulation of PD after procedure Most pancreatic stents will spontaneously migrate out of the pancreatic duct within 2 wk of insertion.

Endoscopic Ampullectomy Multiple sessions may be required Mortality 0% Morbidity 18% Complications Early: Pancreatitis, cholangitis, bleeding, perforation Late: Papillary stenosis Post-ampullectomy surveillance endoscopy required 3-12months for at least 2 years More frequently in case of high grade dysplasia Complications Pancreatitis 8-15% , cholangitis 0-2%, perforation 0-4% , bleeding 2-13% Papillary stenosis 0-8% Death rare Stent placement post-ERCP: pancreatitis rate decrease from 33% to 10% Post-EA surveillance perform endoscopic treatment every 2–3 months until there is no residual adenoma, with surveillance every 6–12 months for the next 2 years [9]. If recurrence is not identified, further patient follow-up should be individualized. Surveillance 1 to 6 months after the index procedure followed by repeat examinations with a duodenoscope every 3 to 12 months thereafter for a period of at least 2 years with periodic examinations thereafter. Closer monitoring if HGD FAP - patients who have undergone proctocolectomy are still at high risk for development of ampullary lesions and should undergo periodic surveillance for duodenal and ampullary adenoma and carcinoma. Surgical ampullectomy if not amendable to EA with no malignant features, abdominal exploration for another indication, or as palliative procedure for elderly precluding PD. EA re-op: excise positive margin SA re-op: due to complication of ampullectomy free lateral and in-depth margins and the absence of lymphovascular compromise are required. The histology should correspond to benign adenomas, in situ tumors (Tis) or early well or moderately differentiated type cancer T1N0M0. Ceppa, Eugene P., et al. "Endoscopic versus surgical ampullectomy: an algorithm to treat disease of the ampulla of Vater." Annals of surgery 257.2 (2013): 315-322.

EA vs SA Endoscopic ampullectomy (EA) is superior to surgical ampullectomy (SA) in terms of: Morbidity (18 vs 42%) Length of stay (0.6 vs 10.1days) Readmission rate (16 vs 34%) Endoscopic ampullectomy (EA) is superior to surgical ampullectomy (SA) in terms of: Morbidity (18 vs 42%) Length of stay (0.6 vs 10.1) Readmission rate (16 vs 34%) *Reoperation 26 vs 15% Ceppa, Eugene P., et al. "Endoscopic versus surgical ampullectomy: an algorithm to treat disease of the ampulla of Vater." Annals of surgery 257.2 (2013): 315-322.

EA vs SA Positive margin and recurrence rate for EA are higher than SA 20 vs 10% (no statistical significance) Re-intervention rate for EA is higher than SA 26% vs 15% (no statistical significance) EA: mainly for margin re-excision SA: mainly for complications SA re-operation: wound dehiscence, incisional hernia, and feeding jejunostomy tube. Ceppa, Eugene P., et al. "Endoscopic versus surgical ampullectomy: an algorithm to treat disease of the ampulla of Vater." Annals of surgery 257.2 (2013): 315-322.

EA vs SA Endoscopic ampullectomy is preferred Surgical Ampullectomy Endoscopic Ampullectomy Pros Lower +ve margin rate Lower recurrence rate Frozen section available Minimally invasive Lower morbidity Shorter LOS Lower readmission rate Cons Need of GA Higher morbidity Longer LOS Higher re-intervention rate Higher +ve margin rate Higher recurrence rate Limitations Not for adenomas with >1cm intraductal extension Endoscopic ampullectomy is preferred Surgical ampullectomy for lesions not feasible for endoscopic treatment

Back to our patient… EUS + endoscopic ampullectomy done 4.5cm lateral spreading ampulla tumor No intraductal extension Ampullectomy performed CBD stent and pancreatic ductal stent inserted Ampullectomy done ESD, complete Adrenaline + indocarmine

Submucosal injection Post-ampullectomy Ampullar tumor 45mm x 20mm

Back to our patient… Post-operative course was uneventful Diet was resumed on the next day No fever LFT normal Discharge home on day 4 Pathology: Tubulovillous adenoma with low grade dysplasia Lateral margin clear Plan for surveillance endoscopy 3 months later

Conclusions Ampullary adenomas are rare EUS has an important role in management decision NBI may help improve diagnostic accuracy More study would be needed to assess its efficacy Endoscopic ampullectomy is a more favorable option than surgical ampullectomy Minimally invasive, avoid GA Lower morbidity But the positive margin and recurrence rates are higher Surgical ampullectomy Treatment choice when EA is not feasible

The End