PDF 41-08: Carcinoma of the Pancreas & Ampulla of Vater 2024

Universidad Peruana de Ciencias Aplicadas Access Provided by: Current Medical Diagnosis & Treatment 2024 4108: Carcinoma of the Pancreas & Ampulla of Vater Sunny Wang; Tiffany O. Dea; Lawrence S. Friedman; Carling Ursem; Kenneth R. McQuaid; Marc A. Dall’Era ESSENTIALS OF DIAGNOSIS ESSENTIALS OF DIAGNOSIS Obstructive jaundice (may be painless). Enlarged gallbladder (may be painful). Upper abdominal pain with radiation to back, weight loss, and thrombophlebitis are usually late manifestations. GENERAL CONSIDERATIONS Carcinoma is the most common neoplasm of the pancreas. About 75% are in the head and 25% in the body and tail of the organ. Pancreatic carcinomas account for 3% of all cancers and 7% of cancer deaths. The incidence is increasing. and by 2040 pancreatic cancer is expected to surpass colorectal cancer as the second leading cause of cancerrelated deaths in the United States. The rate is rising rapidly in Latina, nonHispanic White, and non Hispanic Black women younger than age 55 years. Ampullary carcinomas are much less common. Risk factors for pancreatic cancer include age, tobacco use (which is thought to cause 20–25% of cases), heavy alcohol use, obesity, chronic pancreatitis, diabetes mellitus, prior abdominal radiation, family history, and possibly gallstones, gastric ulcer, and exposure to arsenic and cadmium. Newonset diabetes mellitus after age 45 years occasionally heralds the onset of pancreatic cancer, and weight loss may precede the diagnosis. In patients with diabetes, metformin use and possibly aspirin use may reduce the risk of pancreatic cancer slightly, but insulin use and glucagonlike peptide1–based therapy (eg, sitagliptin) may increase the risk. A risk model for pancreatic cancer in persons with newonset diabetes mellitus has been proposed and includes the following factors: age, BMI, change in BMI, smoking, use of PPIs and diabetes medications as well as levels of hemoglobin A1C, cholesterol, hemoglobin, creatinine, and alkaline phosphatase. About 7% of patients with pancreatic cancer have a family history of pancreatic cancer in a firstdegree relative, compared with 0.6% of control patients. Point mutations in codon 12 of the KRAS oncogene are found in 70–100% of pancreatic cancers; inactivation of the tumor suppressor genes CDKN2A on chromosome 9, TP53 on chromosome 17, and SMAD4 on chromosome 18 is found in 95%, 75%, and 55% of pancreatic cancers, respectively; mutation of the palladin gene (PALLD) is reported to be common. A subset of pancreatic cancers is associated with DNA mismatch repair deficiency and have better outcomes after surgery and responsiveness to immunotherapy. Most pancreatic cancers originate from pancreatic intraepithelial neoplasias, which measure less than 5 mm in diameter and can only be seen with a microscope. In 10–15% of cases, pancreatic cancer occurs as part of a hereditary syndrome, including familial breast cancer (carriers of BRCA2 have a 7% lifetime risk of pancreatic cancer), hereditary pancreatitis (PSS1 pathogenic variant), familial atypical multiple mole melanoma (p16/CDKN2A), PeutzJeghers syndrome (STK11/LKB1 pathogenic variant), ataxiatelangiectasia (ATM pathogenic variant), and Lynch syndrome (hereditary nonpolyposis colorectal cancer [MLH1, MSH2, MSH6 pathogenic variants]). Polymorphisms of the genes for methylene tetrahydrofolate reductase and thymidylate synthase have been reported to be associated with pancreatic cancer. Neuroendocrine tumors account for 1–2% of pancreatic neoplasms and may be functional (producing gastrin, insulin, glucagon, vasoactive intestinal peptide, somatostatin, growth hormone–releasing hormone, ACTH, and others) or nonfunctional. Cystic neoplasms account for less than 10% of pancreatic neoplasms, but they are important because pancreatic cysts are common and may be mistaken for pseudocysts. A cystic neoplasm should be suspected when a cystic lesion in the pancreas is found in the absence of a history of pancreatitis or trauma. At least 15% of all pancreatic cysts are neoplasms. Serous cystadenomas (which account for 32–39% of cystic pancreatic neoplasms and also occur in patients with von HippelLindau disease) are benign. However, mucinous cystic neoplasms (defined by the presence of ovarian stroma and accounting for 10–45% of cystic pancreatic Downloaded 20231130 7:45 P Your IP is 52.36.32.128 neoplasms), intraductal mucinous neoplasms (21–33% of cystic pancreatic neoplasms), solid pseudopapillary tumors (less than 5%, primarily Page 4108: Carcinoma of thepapillary Pancreas &amp; Ampulla of Vater, Sunny Wang; Tiffany O. Dea; Lawrence S. Friedman; Carling Ursem; Kenneth R. 1 / 5 McQuaid; Marc A.and Dall’Era in young women), cystic islet cell tumors (3–5%) may be malignant. Their prognoses are better than the prognosis of pancreatic adenocarcinoma, ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility unless the cystic neoplasm is at least locally advanced. Neuroendocrine tumors account for 1–2% of pancreatic neoplasms and may be functional (producing gastrin, insulin, glucagon, vasoactive intestinal Universidadaccount Peruana Ciencias Aplicadas peptide, somatostatin, growth hormone–releasing hormone, ACTH, and others) or nonfunctional. Cystic neoplasms forde less than 10% of Access Provided by: pancreatic neoplasms, but they are important because pancreatic cysts are common and may be mistaken for pseudocysts. A cystic neoplasm should be suspected when a cystic lesion in the pancreas is found in the absence of a history of pancreatitis or trauma. At least 15% of all pancreatic cysts are neoplasms. Serous cystadenomas (which account for 32–39% of cystic pancreatic neoplasms and also occur in patients with von HippelLindau disease) are benign. However, mucinous cystic neoplasms (defined by the presence of ovarian stroma and accounting for 10–45% of cystic pancreatic neoplasms), intraductal papillary mucinous neoplasms (21–33% of cystic pancreatic neoplasms), solid pseudopapillary tumors (less than 5%, primarily in young women), and cystic islet cell tumors (3–5%) may be malignant. Their prognoses are better than the prognosis of pancreatic adenocarcinoma, unless the cystic neoplasm is at least locally advanced. CLINICAL FINDINGS A. Symptoms and Signs Pain is present in over 70% of cases and is often vague, diffuse, and located in the epigastrium or, when the lesion is in the tail, located in the left upper quadrant of the abdomen. Radiation of pain into the back is common and sometimes predominates. Sitting up and leaning forward may afford some relief, and this usually indicates that the lesion has spread beyond the pancreas and is inoperable. Diarrhea, perhaps due to maldigestion, is an occasional early symptom. Migratory thrombophlebitis is a rare sign. Weight loss is a common finding and may be associated with depression. Hyperglycemia and decreases in subcutaneous abdominal fat and serum lipid levels have been reported to precede a diagnosis of pancreatic cancer. Occasional patients (often aged 40 years or older) present with acute pancreatitis in the absence of an alternative cause. Jaundice is usually due to biliary obstruction by a cancer in the pancreatic head. A palpable gallbladder is also indicative of obstruction by a neoplasm (Courvoisier sign), but there are frequent exceptions. A hard, fixed, occasionally tender mass may be present. In advanced cases, a hard periumbilical (Sister Mary Joseph) nodule may be palpable. B. Laboratory Findings There may be mild anemia. Glycosuria, hyperglycemia, and impaired glucose tolerance or true diabetes mellitus are found in 10–20% of cases. The serum lipase or amylase level is occasionally elevated. Liver biochemical tests may suggest obstructive jaundice. Steatorrhea in the absence of jaundice is uncommon. Occult blood in the stool is suggestive of carcinoma of the ampulla of Vater (the combination of biliary obstruction and bleeding may give the stools a distinctive silver appearance). CA 199, with a sensitivity of 70% and a specificity of 87%, has generally not proven useful for early detection of pancreatic cancer but continues to be studied; increased values are also found in acute and chronic pancreatitis and cholangitis. Plasma chromogranin A levels are elevated in 88–100% of patients with pancreatic neuroendocrine tumors (NETs). C. Imaging Multiphase thincut helical (pancreatic protocol) CT is generally the initial diagnostic procedure and detects a mass in 76–96% of cases. CT identifies metastases, delineates the extent of the tumor, and allows percutaneous FNA for cytologic studies and tumor markers. MRI is an alternative to CT. Ultrasonography is not reliable because of interference by intestinal gas. PET is a sensitive technique for detecting pancreatic cancer and metastases, but PETCT is not a routine staging procedure. Selective celiac and superior mesenteric arteriography may demonstrate vessel invasion by cancer, a finding that would preclude attempts at surgical resection, but it is used uncommonly since the advent of multiphase helical CT. EUS is more sensitive than CT for detecting pancreatic cancer and is equivalent to CT for determining nodal involvement and resectability; contrastenhanced EUS improves accuracy. A normal EUS excludes pancreatic cancer. EUS may also be used to guide FNA or biopsy for tissue diagnosis, tumor markers, and DNA analysis. ERCP may clarify an ambiguous CT or MRI study by delineating the pancreatic duct system or confirming an ampullary or biliary neoplasm. MRCP appears to be at least as sensitive as ERCP in diagnosing pancreatic cancer. In some centers, pancreatoscopy or intraductal ultrasonography is used to evaluate filling defects in the pancreatic duct and assess resectability of intraductal papillary mucinous cancers. With obstruction of the splenic vein, splenomegaly or gastric varices are present, the latter detected by endoscopy, EUS, or angiography. Cystic neoplasms can be distinguished by their appearance on CT, EUS, and ERCP and features of the cyst fluid on gross, cytologic, and genetic analysis. For example, serous cystadenomas may have a central scar or honeycomb appearance; mucinous cystadenomas are unilocular or multilocular and contain mucinrich fluid with low glucose levels, high carcinoembryonic antigen levels (greater than 200 ng/mL [200 mcg/L]), and KRAS pathogenic variants; and intraductal papillary mucinous neoplasms are associated with a dilated pancreatic duct and extrusion of gelatinous material from the ampulla. STAGING The TNM system is the commonly used classification to stage pancreatic cancer. Staging is important not only because it correlates with the patient’s longterm survival but also7:45 because it is IP used to determine which patients should receive adjuvant or neoadjuvant therapy. Localized pancreatic cancer Downloaded 20231130 P Your is 52.36.32.128 Page includes resectable,ofborderline resectable major vascular andO. locally disease.Ursem; Over 30% of patients 4108: Carcinoma the Pancreas &amp;(involving Ampulla of Vater, Sunny structures), Wang; Tiffany Dea;advanced Lawrence(unresectable) S. Friedman; Carling Kenneth R. 2 / 5 McQuaid; Marc A. Dall’Era present with locally advanced disease and over 50% with metastatic disease. ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Staging of pancreatic cancer by the TNM classification includes the following definitions: Tis: carcinoma in situ; T1a: tumor limited to the pancreas, 0.5 material from the ampulla. Universidad Peruana de Ciencias Aplicadas STAGING Access Provided by: The TNM system is the commonly used classification to stage pancreatic cancer. Staging is important not only because it correlates with the patient’s longterm survival but also because it is used to determine which patients should receive adjuvant or neoadjuvant therapy. Localized pancreatic cancer includes resectable, borderline resectable (involving major vascular structures), and locally advanced (unresectable) disease. Over 30% of patients present with locally advanced disease and over 50% with metastatic disease. Staging of pancreatic cancer by the TNM classification includes the following definitions: Tis: carcinoma in situ; T1a: tumor limited to the pancreas, 0.5 cm or less in greatest dimension; T1b: tumor more than 0.5 cm and less than 1 cm; T1c: tumor 1–2 cm; T2: tumor limited to the pancreas, more than 2 cm and less than or equal to 4 cm in greatest dimension; T3: tumor more than 4 cm in greatest dimension; T4: tumor involves the celiac axis, superior mesenteric artery, or common hepatic artery regardless of size; N1: metastasis to one to three regional lymph nodes; N2: metastasis to four or more regional lymph nodes; M1: distant metastasis. TREATMENT Abdominal exploration is usually necessary when cytologic diagnosis cannot be made or if resection is to be attempted (in up to 30% of patients with pancreatic carcinoma). In a patient with a localized mass in the head of the pancreas and without jaundice, laparoscopy may detect tiny peritoneal or liver metastases and thereby avoid resection in 4–13% of patients. Radical pancreaticoduodenal (Whipple) resection is indicated for cancers strictly limited to the head of the pancreas, periampullary area, and duodenum (T1, N0, M0). The 5year survival rate is 20–25% in this group and as high as 40% in those with negative resection margins and without lymph node involvement. Preoperative endoscopic decompression of an obstructed bile duct is often achieved with a plastic stent or short metal stent but does not reduce operative mortality and is associated with complications. The best surgical results are achieved at centers that specialize in the multidisciplinary treatment of pancreatic cancer. Adjuvant chemotherapy with gemcitabine, 5fluorouracil, or gemcitabine with capecitabine is superior to no adjuvant therapy. Gemcitabine with capecitabine and a modified FOLFIRINOX (5fluorouracil, leucovorin, irinotecan, oxaliplatin) regimen have been found to be superior to gemcitabine alone. The role of adjuvant chemoradiation is controversial but often used in the United States. Neoadjuvant chemotherapy with or without radiation is increasingly being used to downstage patients and in those with resectable cancer. Common chemotherapy regimens for this purpose include FOLFIRINOX and gemcitabine with nanoparticle albuminbound (nab)paclitaxel. S1, an oral combination fluoropyrimidine, is used in Japan and other Asian countries. Chemoradiotherapy downstages about 30% of patients with locally advanced disease to allow resection. When resection is not feasible, endoscopic stenting of the bile duct is performed to relieve jaundice. A plastic stent has generally been preferred if the patient’s anticipated survival is less than 6 months (or if surgery is planned). A metal stent is preferred when anticipated survival is 6 months or greater. Whether covered metal stents designed to prevent cancer ingrowth offer an advantage over uncovered stents is uncertain because covered stents are associated with higher rates of migration and acute cholecystitis due to occlusion of the cystic duct. Surgical biliary bypass may be considered in patients expected to survive at least 6 months. Surgical duodenal bypass may be considered in patients in whom duodenal obstruction is expected to develop; alternatively, endoscopic placement of a selfexpandable duodenal stent may be feasible. Chemoradiation may be used for palliation of unresectable cancer confined to the pancreas. In metastatic pancreatic cancer, improved response rates have been reported with FOLFIRINOX and with the combination of gemcitabine and nab paclitaxel. In patients who have received prior chemotherapy, a regimen of 5fluorouracil and leucovorin in combination with nanoliposomal irinotecan has resulted in improved survival compared with 5fluorouracil and leucovorin alone. Immune checkpoint inhibitors and other novel agents are under study. In patients with a BRCA1 or BRCA2 germline mutation, olaparib, a poly(adenosine diphosphateribose) polymerase inhibitor, has been reported to improve progressionfree survival in metastatic pancreatic cancer. Celiac plexus nerve block (see Chapter 5) done under CT or endoscopic ultrasound guidance or thoracoscopic splanchnicectomy may improve pain control. Photodynamic therapy is under study. Surgical resection is the treatment of choice for NETs, when feasible. Lesions that are less than 1 cm in diameter and nonfunctioning without evidence of local invasion or metastasis may be followed expectantly. Metastatic disease may be controlled with longacting somatostatin analogs, interferon, chemotherapy, peptidereceptor radionuclide therapy (PRRT), and chemoembolization. There is a consensus that asymptomatic incidental pancreatic cysts 2 cm or smaller are at low risk for harboring invasive carcinoma. The cysts may be monitored by imaging tests (MRI) in 1 year and then every 2 years for 5 years and probably longer if no changes are observed, with EUS and FNA performed if a cyst enlarges to 3 cm and another highrisk feature (dilated main pancreatic duct, presence of a solid component) develops. The optimal approach is uncertain, however, and other guidelines have been proposed. Surgical resection is indicated for mucinous cystic neoplasms, symptomatic serous cystadenomas, solid pseudopapillary tumors (which have a 15% risk of malignant transformation), and cystic tumors larger than 2 cm in diameter that remain undefined after helical CT, EUS, and diagnostic aspiration. All intraductal papillary mucinous neoplasms of the main Downloaded 20231130 7:45 P Your IP is 52.36.32.128 pancreatic duct should be resected, but those of branch ducts may be monitored with serial imaging if they (1) are asymptomatic and exhibit benign Page 4108: Carcinoma of the Pancreas &amp; Ampulla of Vater, Sunny Wang; Tiffany O. Dea; Lawrence S. Friedman; Carling Ursem; Kenneth R. 3 / 5 features; haveA.a diameter McQuaid;(2) Marc Dall’Era less than 3 cm (some authorities recommend a diameter of 1.5 cm or smaller, but even lesions 3 cm or larger may be monitored in older adults with no other worrisome cyst features); and (3) lack nonenhancing mural nodules, a thick wall, or an abrupt change in the ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility caliber of the pancreatic duct with distal pancreatic atrophy, or possibly bile duct dilatation and gallbladder adenomyomatosis. Most lesions with such There is a consensus that asymptomatic incidental pancreatic cysts 2 cm or smaller are at low risk for harboring invasive carcinoma. The cysts may be Universidad Peruana deEUS Ciencias Aplicadas monitored by imaging tests (MRI) in 1 year and then every 2 years for 5 years and probably longer if no changes are observed, with and FNA Access Provided by: performed if a cyst enlarges to 3 cm and another highrisk feature (dilated main pancreatic duct, presence of a solid component) develops. The optimal approach is uncertain, however, and other guidelines have been proposed. Surgical resection is indicated for mucinous cystic neoplasms, symptomatic serous cystadenomas, solid pseudopapillary tumors (which have a 15% risk of malignant transformation), and cystic tumors larger than 2 cm in diameter that remain undefined after helical CT, EUS, and diagnostic aspiration. All intraductal papillary mucinous neoplasms of the main pancreatic duct should be resected, but those of branch ducts may be monitored with serial imaging if they (1) are asymptomatic and exhibit benign features; (2) have a diameter less than 3 cm (some authorities recommend a diameter of 1.5 cm or smaller, but even lesions 3 cm or larger may be monitored in older adults with no other worrisome cyst features); and (3) lack nonenhancing mural nodules, a thick wall, or an abrupt change in the caliber of the pancreatic duct with distal pancreatic atrophy, or possibly bile duct dilatation and gallbladder adenomyomatosis. Most lesions with such benign features remain stable on followup, but a risk of malignancy persists for more than 10 years. Moreover, the risk of pancreatic ductal carcinoma and of nonpancreatic cancers is also increased in this group of patients. In the absence of locally advanced disease, survival is higher for malignant cystic neoplasms than for adenocarcinomas. The role of EUSguided ablative treatment of potentially premalignant pancreatic cysts is under study. Endoscopic resection or ablation, with temporary placement of a pancreatic duct stent, may be feasible for ampullary adenomas, but patients must be followed for recurrence. PROGNOSIS Carcinoma of the pancreas, especially in the body or tail, has a poor prognosis; 80–85% of patients present with advanced unresectable disease, and the reported 5year survival rate is 2–5%. From 1980 to 2010, mortality from pancreatic cancer in the United States did not decrease, but it has since started to improve. Obesity may adversely affect mortality in Western countries. Metformin may improve survival in patients with diabetes and pancreatic adenocarcinoma, and use of statins preceding a diagnosis of pancreatic cancer may improve survival. Tumors of the ampulla have a better prognosis, with a reported 5year survival rate of 20–40% after resection; jaundice and lymph node involvement are adverse prognostic factors. In carefully selected patients, resection of cancer of the pancreatic head is feasible and results in reasonable survival. In persons with a family history of pancreatic cancer in at least two firstdegree relatives, or with a genetic syndrome associated with an increased risk of pancreatic cancer, annual screening with EUS and alternating with MRI should be considered, generally beginning at age 50 years (age 40 years in CKDN2A or PRSS1 pathogenic variant carriers and age 35 years in those with PeutzJeghers syndrome) or 10 years before the age at which pancreatic cancer was first diagnosed in a family member. For those patients whose disease progresses despite treatment, meticulous efforts at palliative care are essential (see Chapter 5). WHEN TO REFER All patients with carcinoma involving the pancreas and the ampulla of Vater should be referred to a specialist. WHEN TO ADMIT Patients who require surgery and other interventions should be hospitalized. Aslanian HR et al. AGA Clinical Practice Update on pancreas cancer screening in highrisk individuals: expert review. Gastroenterology. 2020;159:358. [PubMed: 32416142] DuBois JS et al. Case 192022: A 29yearold woman with jaundice and chronic diarrhea. N Engl J Med. 2022;386:2413. [PubMed: 35731657] Fahrmann JF et al. Leadtime trajectory of CA199 as an anchor marker for pancreatic cancer early detection. Gastroenterology. 2021;160:1373. [PubMed: 33333055] Huang J et al. Worldwide burden of risk factors for, and trends in pancreatic cancer. Gastroenterology. 2021;160:744. [PubMed: 33058868] Lennon AM et al. Pancreatic cyst surveillance. Clin Gastroenterol Hepatol. 2022;20:1663. [PubMed: 35397230] Park W et al. Pancreatic cancer: a review. JAMA. 2021;326:851. [PubMed: 34547082] Downloaded 20231130 7:45 P Your IP is 52.36.32.128 Page 4108: Carcinoma of the Pancreas &amp; Ampulla of Vater, Sunny Wang; Tiffany O. Dea; Lawrence S. Friedman; Carling Ursem; Kenneth R. 4 / 5 Sawhney MS et al. ASGE guideline on screening for pancreatic cancer in individuals with genetic susceptibility: summary and recommendations. McQuaid; Marc A. Dall’Era Gastrointest Endosc. 2022;95:817. ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility [PubMed: 35183358] Lennon AM et al. Pancreatic cyst surveillance. Clin Gastroenterol Hepatol. 2022;20:1663. [PubMed: 35397230] Universidad Peruana de Ciencias Aplicadas Access Provided by: Park W et al. Pancreatic cancer: a review. JAMA. 2021;326:851. [PubMed: 34547082] Sawhney MS et al. ASGE guideline on screening for pancreatic cancer in individuals with genetic susceptibility: summary and recommendations. Gastrointest Endosc. 2022;95:817. [PubMed: 35183358] Smith ZL et al. Intracystic glucose and carcinoembryonic antigen in differentiating histologically confirmed pancreatic mucinous neoplastic cysts. Am J Gastroenterol. 2022;117:478. [PubMed: 35034045] Wang L et al. Costeffectiveness of a risktailored pancreatic cancer early detection strategy among patients with newonset diabetes. Clin Gastroenterol Hepatol. 2022;20:1997. [PubMed: 34737092] Wood LD et al. Pancreatic cancer: pathogenesis, screening, diagnosis, and treatment. Gastroenterology. 2022;163:386. [PubMed: 35398344] Downloaded 20231130 7:45 P Your IP is 52.36.32.128 Page 4108: Carcinoma of the Pancreas &amp; Ampulla of Vater, Sunny Wang; Tiffany O. Dea; Lawrence S. Friedman; Carling Ursem; Kenneth R. 5 / 5 McQuaid; Marc A. Dall’Era ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility

PDF 41-08: Carcinoma of the Pancreas & Ampulla of Vater 2024

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