AMPULLARY ADENOMA CASE - BASED DISCUSSION

Case discussion

1. CASE PRESENTATION By Dr. Vemuri Prasanna Kumar From Dept of Surgical Gastroenterology & Liver Transplant at Institute Of Gastroenterology Sciences And Organ Transplantation 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

2. CASE SUMMARY A 67 years old male, farmer by occupation from Yadagiri . C/O upper abdominal pain the last 3 month’s Insidious in onset, Gradually progressive, Dull aching type, Precipitated by meals. No H/O Vomiting, Hematemesis, Malena, Fever, Weight loss. No H/O previous surgical history Habits are Nill 1 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

3. GENERAL PHYSICAL & SYSTEMIC EXAMINATION Moderately built and nourished. Conscious, co-operative and oriented to time, place and person. PICCLE – Negative V ITALS – Stable BMI - O n Abdominal examination – Soft, Non Tenderness in the epigastric region, No palpable lump , Guarding, Rigidity, Hepatosplenomegaly. PR - Normal 2 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

4. LFT 0n 24/01/23 0n 25/04/23 Reference TOTAL BILIRUBIN 2.1 0.78 Up to 1.2 mg/dl DIRECT / INDIR 1.1 0.29 0.3 / 0.6 mg/dl SGOT -------- 18 <50 IU/L SGPT 56 09 <41 IU/L ALP -------- 96 Up to 115 IU/L TOTAL PROTEIN -------- 7.1 6.0 – 8.5 gm/dl S. ALBUMIN -------- 4.5 3.5 – 5.5 gm/dl GLOBULIN -------- 2.6 gm/dl GGT -------- 14 < 55 IU/L 3 NECESSARY INVESTIGATIONS 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

5. CBC 25/04/2023 Reference HAEMOGLOBIN 12.7 12-15 gm/dl PCV 39.3 40-50 % TLC 7880 4,000 – 11,000 Cells/ cmm NEUTROPHILS 61 40-75 % PLATELETS 3.41 1.4 – 4.50 Lakhs/ cumm 4 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

6. SERUM TUMOUR MARKERS On 26/04/23 Reference CA19.9 * 2.9 0-37 U/ml COAGULATION PROFILE On 25/04/23 Reference PT / INR 11.5 / 1.0 11.6 SEC / 5 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

7. USG ABDOMEN & PELVIS (24/01/23) IMPRESSION: Visualized part of common bile duct is dilated in calibre and measures ~ 2.5 cm with a suspicious intraluminal obstructive hyperechoic lesion ~ 1.4 x 1.5 cm in its terminal portion. Main pancreatic duct is dilated in calibre, ~5.7mm ? Sludge. Focal GB wall thickening / adherent sludge noted. 6 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

8. MRI ABDOMEN on 25/01/2023 Liver: shows normal size and significant IHBRD with right & left hepatic duct dilatation. CBD: Gross dilatation of the proximally measuring approximately 29 mm & the mid portion measures 7 mm and at the distal portion measures 11 mm. Tiny calculi with sludge noted in the dependent part of the CBD at the lower 1/3 rd region. Gall bladder: is distended and shows few calculi, largest measuring approximately 5mm. Pancreas: shows significant dilatation of the pancreatic duct measuring approximately 5.7mm abrupt tapering of the distal CBD and pancreatic duct noted near the ampullary region. Possible T2 isointense lesion seen involving the ampulla measuring approximately 6 × 7.5mm. The lesion exhibits subtle enhancement on post contrast study. Sub-centimetric nodes seen at the porta hepatis and aortocaval region. 7 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

9. CECT ABDOMEN on 05/03/2023 Liver: shows normal size shape and shows significant IHBRD with right hepatic duct m/s 10 mm and left hepatic duct m/s 8 mm. CBD: is significantly dilated m/s 23 mm at its proximal portion and 15 mm at its distal portion. Tiny calculus seen at the distal CBD m/s 3 mm. There is evidence of abrupt termination of the dilated CBD due to possibly polyp like mass lesion at the ampullary region. Pancreas: shows normal size and attenuation value with dilatation of the pancreatic duct m/s 5 mm. Gall bladder: is contracted and shows thickened wall, with wall thickness m/s 5.6 mm 8 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

10. THERAPEUTIC ERCP on 08/02/2023 AMPULLA: Bulky ampulla with nodularity noted CBD: Dilated duct with IHBR dilatation with abrupt narrowing noted at terminal part. Impression: ? Ampullary Malignancy & Biliary Stenting Done 9 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

11. HISTOPATHOLOGY REPORT (17/02/23) BIOPSY No: 2234 /23 MICROSCOPIC EXAMINATION It show villi lined by single layer of columnar epithelium with benign nuclear morphology. One focus show dysplastic changes in the form of nuclear elongation, overlapping and hyperchromasia. No nucleoli seen. No evidence of any infiltration into the deeper connective tissue. The subepithelial tissue show chronic inflammatory infiltrate of lymphocytes and plasma cells. IMPRESSION : CHRONIC INFLAMMATORYPATHOLOGY WITH FOCAL DYSPLASIA. 10 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

12. EUS (LINEAR) on 28/03/2023 Findings: Left lobe of liver normal, dilated intrahepatic biliary radicles. CBD appeared dilated ,measuring 13mm. MPD appeared dilated measuring 5mm Ampulla: Hypoechoic mass measuring 18 × 13mm, with extension into he terminal bile duct. SVE: Ampulla is replaced by mass, CBD cannulated and sphincterotomy extended followed by biopsy taken from ampulla. IMPRESSION: Ampullary mass-likely malignant 11 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

13. HISTOPATHOLOGY REPORT (28/03/23) FNAB No: H3530/23 MICROSCOPIC EXAMINATION EUS FNB of ampullary mass-Very tiny bits of mucosal villous tissue, No definite opinion possible. Ampullary mass biopsy -Mucosal bits show focal atypical superficial glands lined by columnar cells with nuclear hyperchromasia and nucleomegaly and no significant loss of polarity. Adjacent mucosa and remaining bits are unremarkable. IMPRESSION : F/S/O Ampullary adenoma with low grade dysplasia. No evidence of malignancy. 12 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

14. UGI SCOPY on 28/04/2023 Duodenum: Bulb: Normal D2 : Prominent Ampulla with Smooth overlying Mucosa Impression : Ampullary Mass . 13 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

15. PET-CT on 10/04/2023 1.3 x 1.2 x 1.6 cm metabolically active soft tissue lesion involving the lower CBD and ampulla - of neoplastic etiology. Intra - extrahepatic biliary and pancreatic ductal dilatation as described above. Suspicious 3 mm focal enhancement in the right occipital cortex. 14 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

16. PROVISIONAL DIAGNOSIS AMPULLARY ADENOMA ? AMPULLARY NET 15 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

17. PLANNED FOR ? PANCREATICODUODENECTOMY 16 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

18. TUMOR OF AMPULLA AND PERIAMPULLA Neoplasms can arise at the ampulla of Vater / Minor papillae & the surrounding periampullary duodenum at the confluence of the pancreatic and biliary ducts. The ampulla is comprised of several types of epithelia: The intestinal-type duodenal mucosa covering the papilla The PD epithelium Biliary epithelium of the distal CBD Epithelium lining the common channel uniting the PD and CBD within the duodenal wall The lining of the PD / CBD / common channel are histologically similar (pancreatobiliary-type epithelium) Most ampullary neoplasms are adenocarcinomas, but rarely NET also can occur Tumors from this region often extend to involve the pancreas, distal bile duct, and duodenum. 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT) 17

19. ADENOMA & NON-INVASIVE INTRA-AMPULLARY PAPILLARY-TUBULAR NEOPLASM This entity has two subtypes based on the location and histologic phenotype of the neoplasm: Those arising from the duodenal surface mucosa overlying the ampulla are intestinaltype adenomas which are similar to colorectal adenomas and can occur in association with FAP or Lynch syndromes Those arising within the intra ampullary channel (distal CBD and PD) are usually pancreatobiliary-type and designated as intra ampullary papillary-tubular neoplasm (IAPN) Most patients with ampullary adenomas and IAPNs are asymptomatic when the tumors are small. Larger tumors can cause jaundice, cholangitis, and pancreatitis secondary to obstruction of CBD or PD. 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT) 18

20. Microscopically, intestinal-type ampullary adenomas resemble their colorectal counterparts and may have a tubular, villous, or tubulo-villous configuration. The intestinal-type epithelium reveals nuclear pseudo stratification of tall-columnar cells with elongated nuclei, and the degree of dysplasia is assessed based on cytologic atypia and architectural complexity. High-grade dysplasia is characterized by complex, cribriform glands with significant nuclear atypia and loss of epithelial polarity. Immunohistochemistry reveals expression of intestinal markers, such as CK20, MUC2, and CDX2, and generally a lack of expression of CK7 and MUC1. 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT) 19

21. ADENOCARCINOMA AND THE VARIANTS The ampulla is the most common site for small intestinal adenocarcinoma @15% of all pancreatoduodenectomies. Because of the complex anatomy at the papillae and biliary / pancreatic effluents, many carcinomas arising in the duodenum, pancreas, CBD can secondarily extend into the ampulla and may be incorrectly designated as an primary ampullary tumor. Establishment of the tumor’s ampullary origin may be challenging preoperatively and may ultimately require the examination of the pancreatoduodenectomy specimen. The typical presentation is biliary obstruction showing cholestasis and jaundice which lead to a relatively early diagnosis. Periampullary duodenal carcinomas can cause GI bleeding because of mucosal ulceration. Patients with ampullary carcinomas have a relatively favorable survival prognosis compared with those with pancreatic ductal carcinomas. 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT) 20

22. Ampullary adenocarcinomas can arise from: Periampullary duodenal mucosa, usually with an associated adenoma and prevalent in patients with FAP The intra-ampullary channel, either with an associated IAPN or flat dysplasia of ampullary ducts. The macroscopic appearance of ampullary adenocarcinomas depends on the specific subtype: Tumor involves surface duodenal mucosa  it will be a polypoid or ulcerated mass evident at the endoscopic evaluation Intra-ampullary carcinomas are relatively small and covered by intact duodenal mucosa & presents as raised nodule from the duodenal mucosa. 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT) 21

23. Microscopically most ampullary carcinomas have gland formation + intestinal or pancreatobiliary phenotype & about 30% to 40% of cases have mixed phenotype INTESTINAL-TYPE ADENOCARCINOMA: This subtype of carcinoma usually arises in association with an ampullary adenoma & resembles its large intestinal adenocarcinoma counterpart. The tumors are composed of cribriform glands with tall columnar cells that have elongated nuclei. The intestinal phenotype can be confirmed by immunohistochemistry with positive reactivity for CDX2 and MUC2 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT) 22

24. NEUROENDOCRINE CARCINOMA: Poorly differentiated NECs represent a rare phenotype of ampullary carcinoma. Many NECs arise in association with an adenoma and may have mixed components of glandular or squamous differentiation. The NEC subtype of small-cell carcinoma has fusiform cells with minimal cytoplasm, hyperchromatic chromatin, and nuclear molding. The large-cell variant NECs have moderate amounts of cytoplasm and round nuclei with prominent nucleoli. Poorly differentiated NECs are high-grade, aggressive malignancies and geographic necrosis is commonly observed. Neuroendocrine differentiation is required for the diagnosis and is generally assessed by checking the expression of chromogranin or synaptophysin. 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT) 23

25. PANCREATOBILIARY-TYPE ADENOCARCINOMA: This subtype of carcinoma shares morphologic features and immunophenotype with PDAC. The tumors are composed of simple or branching glands lined by a single layer of cuboidal cells with round or pleomorphic nuclei and prominent stromal desmoplasia. The tumor cells are immunoreactive to CK7 and MUC1 OTHER HISTOLOGY VARIANTS Adeno-squamous carcinoma Mucinous adenocarcinoma Signet ring cell carcinoma Medullary carcinoma Undifferentiated carcinoma 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT) 24

26. NEUROENDOCRINE TUMORS Duodenal NETs are rare among intestinal NETs (2%–3%) and represent the most diverse group of neoplasms, often present with multiple hereditary associations. Ampullary NETs predominantly involve the submucosa and muscularis mucosa of the duodenum and ampulla although extension into the mucosa with subsequent bleeding can occur. The diagnosis can be established via endoscopic mucosal biopsy. Ampullary duodenum is the primary location of somatostatin producing D-cell NET (somatostatinoma) and gangliocyticparaganglioma constitute about 30% of all duodenal NETs. These are associated with the hereditary conditions of NF1 and MEN1 but the hereditary association is much less in gangliocyticparaganglioma. Somatostatinoma presents as somatostatin hypersecretion related symptoms of diarrhea, cholelithiasis, dyspepsia, and diabetes, somatostatinoma of the duodenum is almost never functional. Given its exclusive location at around the major / minor ampulla, somatostatinomas frequently cause obstructive symptoms such as AP, jaundice, and intestinal bleeding. 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT) 25

27. Somatostatin-producing D-cell NETs commonly exhibit a glandular growth pattern with psammomatous calcifications present in the lumen of the glands they are also known as glandular carcinoid and psammomatous somatostatinoma. They are usually less than 1 to 3 cm in size and typically located in either the major or minor ampulla or periampullary region. The presence of calcification phenomena is associated with 100% of NF1-associated tumors and 60% of sporadic somatostatinomas. When present in the submucosa, they may have an appearance mimicking benign Brunner’s glands of the duodenum. The tumor does not form a well-circumscribed border and infiltrates deeply into the smooth muscle of the Sphincter of Oddi, abutting or invading the pancreas is common without eliciting a desmoplastic reaction. As a result, negative deep resection margins can be difficult to achieve from local excisions via either endoscopic intervention or papillectomy. Given the combined clinical presentation of jaundice and the glandular forming histology, it is not uncommon for somatostatinomas to be misinterpreted as adenocarcinoma of the ampulla in biopsy specimens. 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT) 26

28. Somatostatinomas exhibit relatively homogenous and round to ovoid nuclei with stippled chromatin and a moderate amount of granular cytoplasm at the cytologic level. Tumor necrosis is almost never seen in small tumors and mitotic activity is in the range of 0 to 2 mitoses/10 high power fields (WHO G1 grade), although Ki67 proliferative index of greater than 2% may place them in the WHO G2 grade. Gangliocyticparaganglioma may present as a polypoid or pedunculated ampullary or periampullary lesion and usually measure 1 to 3 cm 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT) 27

29. It is a unique type of neuroendocrine tumor with trilineage differentiation, including neuroendocrine epithelium, schwannian/nerve sheath, and ganglion components. Immunohistochemically, the tumor cells are generally reactive for chromogranin and synaptophysin. The epithelial component may not be immunoreactive to cytokeratin in up to 50% cases, but the tumor cells are usually positive for pancreatic polypeptide, somatostatin, or vasoactive intestinal peptide (VIP). The schwannian competent of the tumor is immunoreactive for S100 Although lymph node metastasis (30%) and liver metastasis (5%) occur in somatostatinoma and gangliocyticparaganglioma, most patients have favourable outcomes after complete removal of the disease but may require pancreatoduodenectomy because of the ampullary location of the tumor, with a 10-year survival of over 70%. 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT) 28

30. REFERENCES 29 02-05-2023 From Dept of Surgical Gastroenterology & Liver Transplant (IGOT)

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