Chronic Pancreatitis, Pancreatic Cysts, and Pancreatic Neoplasms: Pancreatic Cysts and Neoplasms: Two Solid Tumors

0:00Welcome to Board Pearls. This is episode five of five of the Chronic Pancreatitis, Pancreatic Cysts, and Pancreatic Neoplasms chapter, in the Pancreatic and Biliary Disease module. This episode is the two solid tumor families of the pancreas. The first patient is a woman with painless jaundice and new diabetes, and her case shows pancreatic ductal adenocarcinoma: which test comes first and which stages it, what carbohydrate antigen 19-9 can and can't show, how tissue is obtained, what makes a tumor resectable, borderline, or locally advanced, why chemotherapy now often comes first, and why germline testing matters. The second patient is a woman with episodes of low glucose, and her case shows pancreatic neuroendocrine tumors: proving an insulinoma and excluding injected insulin, finding it, and checking for an inherited syndrome. Short cases then show the rarer hormone-secreting tumors, a small tumor found by chance, and the treatment of spread.

0:57Here's the first patient. A sixty-six-year-old woman has had yellow skin, dark urine, and itching for three weeks, without pain, and has lost five kilograms. She smoked for thirty years and quit five years ago, and she was diagnosed with diabetes eight months ago. Her bilirubin is nine, her alkaline phosphatase five times normal, and her carbohydrate antigen 19-9, CA 19-9, eight hundred.

1:22Painless jaundice, weight loss, new diabetes, and a smoking history in an older woman point to adenocarcinoma of the pancreatic head. Pancreatic ductal adenocarcinoma is the third leading cause of cancer death in the United States, and it arises in the head in sixty to seventy percent of cases, which is why obstructive jaundice, present in about fifty-five percent at diagnosis, is its signature. Smoking accounts for eleven to thirty-two percent of pancreatic cancer deaths and is the largest modifiable risk. Obesity, physical inactivity, and chronic pancreatitis, especially from PRSS1, add risk, and long-standing diabetes is both a consequence and a possible cause, so her recent diabetes belongs in her story. The cancer develops from pancreatic intraepithelial neoplasia through accumulating mutations in KRAS, TP53, CDKN2A, and SMAD4, and its desmoplastic stroma produces a poorly enhancing mass on contrast imaging.

2:21Her imaging comes in two steps, because the first question is where her obstruction is. In a jaundiced patient, transabdominal ultrasound confirms extrahepatic obstruction first. Then a pancreas-protocol contrast computed tomography, CT, or magnetic resonance imaging defines the mass, its relationship to the vessels, and any metastases. Her ultrasound shows dilated bile and pancreatic ducts. Her CT shows a two-point-eight-centimeter poorly enhancing mass in the head, in contact with the superior mesenteric vein over a short segment that could be reconstructed and touching the superior mesenteric artery over less than one hundred eighty degrees, without liver or peritoneal metastases.

3:04Her CA 19-9 of eight hundred is less useful than it looks. Its sensitivity is seventy to ninety-two percent and its specificity sixty-eight to ninety-two. It's falsely low in people who are Lewis antigen-negative, about five percent of the population, and falsely raised in cholestasis from any cause. So her value of eight hundred with a bilirubin of nine is hard to interpret, and a normal value wouldn't have excluded cancer. It's most useful for tracking response to treatment, not for diagnosis or screening.

3:36She needs tissue before treatment. Endoscopic ultrasound, EUS, guided fine-needle biopsy is preferred over fine-needle aspiration, because the core preserves tissue architecture and raises the diagnostic yield, and rapid on-site evaluation raises it further. When imaging shows small, node-negative disease under two centimeters and immediate resection is planned, neither EUS nor endoscopic retrograde cholangiopancreatography, ERCP, is strictly required. But most centers now offer neoadjuvant therapy and prefer tissue before surgery plus biliary drainage when the patient is jaundiced. Her biopsy confirms adenocarcinoma, and a biliary stent placed at ERCP relieves her obstruction, as chapter twenty-nine covers.

4:23Her treatment depends on resectability, which is decided by her vessels. On multiphasic CT, the tumor's relationship to the celiac trunk, common hepatic artery, superior mesenteric artery, superior mesenteric vein, and portal vein sets the category. Resectable disease has no contact with the major arteries and limited or no contact with the superior mesenteric or portal vein. Borderline resectable disease has limited arterial contact, under one hundred eighty degrees of the superior mesenteric artery or celiac trunk, or venous involvement that can be reconstructed. Locally advanced, unresectable disease has more than one hundred eighty degrees of arterial encasement or venous involvement that can't be reconstructed. Metastatic disease, typically to the liver, peritoneum, or distant nodes, is unresectable and treated systemically. Her arterial contact under one hundred eighty degrees and her reconstructable vein make her borderline resectable.

5:20For her, chemotherapy comes before surgery, because surgery alone rarely cures. Only fifteen to twenty percent of patients can be resected at diagnosis, and resection is the only potential cure. Five-year survival is about thirty percent after a complete, node-negative resection and about ten percent after a complete, node-positive one, and under fifteen percent across all stages. So borderline resectable patients, and many resectable ones, now receive neoadjuvant modified FOLFIRINOX, which is five-fluorouracil, leucovorin, irinotecan, and oxaliplatin, for four to six months before restaging and surgery. That treats micrometastases earlier and converts some borderline tumors to a complete resection.

6:05Her response is tracked, now that her marker can be read. With her cholestasis relieved, her CA 19-9 follows her response. After five months her tumor is smaller and her marker has fallen sharply, and she has a pancreaticoduodenectomy. A rising marker would have warned of non-response. For patients who have surgery first instead, adjuvant modified FOLFIRINOX is the preferred regimen in fit patients, improving median overall survival to more than fifty months in a randomized trial, with gemcitabine plus capecitabine, or gemcitabine alone, for less fit patients.

6:41She's also tested for germline mutations, because the result can change her treatment and her family's screening. Inherited predisposition includes PRSS1 hereditary pancreatitis; Peutz-Jeghers syndrome, from STK11, with the highest relative risk, about one hundred thirty-two; familial atypical multiple-mole melanoma, from CDKN2A; Lynch syndrome; Li-Fraumeni syndrome, from TP53; ATM; and BRCA1, BRCA2, and PALB2. The Cancer of the Pancreas Screening consortium recommends annual magnetic resonance imaging alternating with EUS in those who meet criteria, starting at forty for PRSS1, thirty-five for Peutz-Jeghers, forty for CDKN2A, and fifty for Lynch syndrome and for BRCA1, BRCA2, or PALB2 when a first-degree relative is affected, as chapter thirty-six covers. If she carried a germline BRCA2 mutation and later developed metastatic disease, she'd receive olaparib, a poly adenosine diphosphate-ribose polymerase inhibitor, as maintenance after a response to first-line platinum, because the tumor's defect in homologous recombination makes it selectively vulnerable to that inhibition. Her children who carried it would qualify for surveillance from fifty.

8:02Patients who aren't headed for surgery are treated systemically and palliated. Metastatic disease is treated first line with FOLFIRINOX, NALIRIFOX, a liposomal irinotecan regimen approved in February twenty twenty-four, or gemcitabine plus nab-paclitaxel, chosen by performance status. Locally advanced disease may receive chemotherapy followed by selective consolidative chemoradiation in a minority. When surgery isn't planned, a self-expanding metal biliary stent relieves jaundice, and a celiac plexus block relieves pain.

8:33The second patient's tumor comes from a different cell, and it announces itself through a hormone. A forty-three-year-old woman has had six months of sweating, shakiness, and confusion, usually before breakfast and once after a long run, relieved within minutes by eating. She's gained eight kilograms, having learned to eat to prevent the episodes. During one episode a paramedic measured her glucose at thirty-eight, and intravenous glucose corrected it. She doesn't have diabetes. Her sister is a nurse who uses insulin at work.

9:04Fasting hypoglycemia relieved by glucose, in a woman without diabetes, suggests an insulinoma, a functioning pancreatic neuroendocrine tumor, though her sister's access to insulin has to be excluded. Pancreatic neuroendocrine tumors arise from islet-derived endocrine cells and are distinct from ductal adenocarcinoma. About half are non-functioning, found incidentally or by mass effect, and half are functioning, causing a hormone syndrome: insulinoma, gastrinoma, VIPoma, glucagonoma, and somatostatinoma. Grade, by Ki-67 and mitotic count, predicts behavior: well-differentiated, low-grade tumors are indolent, and poorly differentiated neuroendocrine carcinoma is aggressive.

9:50Her insulinoma has to be proved biochemically before anyone looks for it. The Whipple triad is symptoms of hypoglycemia, a documented low glucose, and relief with glucose, and she meets it, with symptoms during fasting and exercise and weight gain from eating defensively. The gold standard is a supervised seventy-two-hour fast, measuring glucose, insulin, C-peptide, proinsulin, and beta-hydroxybutyrate when symptoms develop or when the fast ends. At hour twenty-two she's confused, with a glucose of forty and inappropriately high insulin, C-peptide, and proinsulin. C-peptide is high when the pancreas is making the insulin and suppressed with injected insulin, because commercial insulin contains no C-peptide. So her pancreas is making it, whatever her sister's access. Very high insulin with suppressed C-peptide would have meant exogenous insulin.

10:42Then her tumor has to be found, and its size decides how. Insulinomas are small, typically under two centimeters, and lie entirely within the pancreas, and more than seventy percent are negative on somatostatin receptor scintigraphy, because they express few somatostatin receptors. So EUS is critical. Gallium-68 DOTATATE positron emission tomography with CT is more sensitive than older octreotide scans, but EUS finds the small ones. Her CT is normal, and EUS shows a twelve-millimeter round, well-defined lesion in her pancreatic body, aspirated for confirmation.

11:22Before surgery, an inherited syndrome is considered, because it would change her and her family's care. Multiple endocrine neoplasia type one, MEN1, with parathyroid, pituitary, and islet tumors, especially gastrinoma, is the dominant inherited association, and about ten percent of insulinomas occur in it. Von Hippel-Lindau disease, neurofibromatosis type one, and tuberous sclerosis account for others. Her calcium and parathyroid hormone are checked and are normal. Primary hyperparathyroidism would have made MEN1 likely, affected her family, and raised the possibility of more islet tumors. Localized functioning tumors are resected for cure and symptom control, so her insulinoma is resected, and her hypoglycemia stops.

12:11Her tumor made insulin, and other islet tumors make other hormones, each with a recognizable syndrome. Gastrinoma causes Zollinger-Ellison syndrome, whose presentation and testing are covered in chapter seven. About seventy percent of gastrinomas arise in the duodenum and twenty-five percent in the pancreas, mostly within the gastrinoma triangle, bounded by the junction of the cystic and common bile ducts, the junction of the second and third parts of the duodenum, and the pancreatic neck. About twenty-five percent occur in MEN1. Because most are duodenal, DOTATATE PET with CT is the best localization for duodenal tumors and liver metastases, with EUS added for tumors inside the pancreas.

12:53A man with profuse watery diarrhea and a low potassium shows the next one. VIPoma causes the Verner-Morrison syndrome, also called WDHA, for watery diarrhea, hypokalemia, and achlorhydria. It's rare, about one per ten million person-years, ninety percent are pancreatic, more than three-quarters are in the body or tail and larger than five centimeters at diagnosis, and sixty percent are metastatic at presentation. A vasoactive intestinal peptide level above seventy-five picograms per milliliter with a secretory diarrhea confirms it. A secretory diarrhea has a stool osmotic gap under fifty, calculated as two hundred ninety minus twice the sum of stool sodium and potassium. Long-acting octreotide controls the diarrhea by competing at the receptor.

13:43Glucagonoma and somatostatinoma are recognized the same way, by what each hormone does to the body. A glucagonoma presents with dermatitis, diabetes, deep vein thrombosis, and depression, plus weight loss, and its cutaneous hallmark is necrolytic migratory erythema in the groin, buttocks, and thighs. A glucagon level over five hundred picograms per milliliter is diagnostic. These tumors are usually large at diagnosis, often over four to five centimeters, mostly in the body or tail, and half are metastatic, with five-year survival around sixty percent. A somatostatinoma presents with diabetes, gallbladder disease, and steatorrhea, because somatostatin inhibits insulin release, gallbladder motility, and pancreatic enzyme secretion. Sixty percent are pancreatic and forty percent duodenal, the duodenal ones less often causing the syndrome, and they're associated with neurofibromatosis type one and pheochromocytoma.

14:46Non-functioning tumors are often found by chance, and their size decides the plan. A fifty-eight-year-old man's CT for kidney stones shows a fourteen-millimeter hypervascular, well-circumscribed lesion in his pancreatic tail, without hormone symptoms. On imaging, neuroendocrine tumors are typically smooth, round, homogeneous, hypervascular, and often encapsulated, unlike the poorly enhancing desmoplastic mass of adenocarcinoma. EUS aspiration confirms a well-differentiated, low-grade neuroendocrine tumor, and gallium-68 DOTATATE PET, preferred over indium-111 octreotide scanning for its resolution and sensitivity, shows no other disease. Sporadic non-functioning tumors under one centimeter may be observed, because metastatic risk is low and resection carries real morbidity. Those over two centimeters are resected, because the risk rises and resection may cure. Tumors of one to two centimeters, like his, are individualized, so his decision is shared, weighing a pancreatic operation against a small, indolent tumor. A high Ki-67 and mitotic count would make his size no longer reassuring.

15:53When a neuroendocrine tumor has spread, the goal changes to control. Unresectable or metastatic disease is treated with long-acting octreotide or lanreotide, which control hormone symptoms and have an antiproliferative effect shown in randomized trials. Progressive disease gets everolimus, an mTOR inhibitor, or the tyrosine kinase inhibitors sunitinib and cabozantinib, the latter approved for previously treated pancreatic neuroendocrine tumors in March twenty twenty-five. Peptide receptor radionuclide therapy with lutetium-177 DOTATATE treats advanced disease that expresses somatostatin receptors, and liver-predominant disease may be resected, embolized, or ablated. A positive DOTATATE PET predicts response to a somatostatin analog and eligibility for lutetium-177.

16:43Here are the traps the boards set in adenocarcinoma. Ultrasound comes first in jaundice, and staging needs a pancreas-protocol study. CA 19-9 isn't trusted in cholestasis, a normal value doesn't exclude cancer, and it isn't a screening test. A core biopsy is preferred over an aspirate. Arterial contact under one hundred eighty degrees is borderline, not unresectable, and borderline disease gets neoadjuvant chemotherapy rather than surgery first. Adjuvant modified FOLFIRINOX follows upfront resection in fit patients. And germline BRCA and PALB2 testing is done, with olaparib given only after a response to platinum.

17:23For neuroendocrine tumors, the traps are these. Insulinoma is diagnosed with the Whipple triad and a seventy-two-hour fast. Injected insulin is excluded by checking C-peptide. EUS, not a receptor scan, finds an insulinoma. MEN1 is considered, starting with the calcium. Gastrinoma is looked for in the duodenum, not just the pancreas. Watery diarrhea with hypokalemia can be a VIPoma. Not every small non-functioning tumor is resected, but one over two centimeters isn't observed. And somatostatin analogs slow growth as well as controlling symptoms.

17:58So, start to finish. Adenocarcinoma usually arises in the head and presents with painless jaundice. Confirm obstruction with ultrasound, stage with pancreas-protocol CT or MRI, and get tissue by EUS core biopsy, with biliary drainage when neoadjuvant therapy is planned. CA 19-9 tracks treatment but fails in Lewis-negative patients and in cholestasis. Borderline disease gets neoadjuvant modified FOLFIRINOX, and after upfront resection, fit patients get adjuvant modified FOLFIRINOX. Metastatic disease gets FOLFIRINOX, NALIRIFOX, or gemcitabine with nab-paclitaxel, and germline BRCA or PALB2 carriers get olaparib maintenance after a platinum response.

18:45Insulinoma presents with the Whipple triad and hypoglycemia during fasting or exercise. Prove it with a seventy-two-hour fast showing high insulin, C-peptide, and proinsulin, find it with EUS, and check for MEN1. Gastrinoma is mostly duodenal and localized with DOTATATE PET, while VIPoma, glucagonoma, and somatostatinoma are rare, large, and often metastatic. Observe non-functioning tumors under one centimeter, resect those over two, and individualize those in between. For metastatic disease, use a somatostatin analog, then everolimus, sunitinib, cabozantinib, or lutetium-177 DOTATATE.

19:29That completes chapter twenty-six. Chapter twenty-seven is biliary tract disease.

19:36For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode five of five of chapter twenty-six, and I'll see you in the next one.