Neoplasms of the Pancreas

Vic V. Vernenkar, D.O. St. Barnabas Hospital Dept. Of Surgery From Greenfields Surgery 2006 4th edition

Introduction
Estimates:33000 cases, 32000 die in 2005. 4th leading cause of cancer death. Non-specific symptoms, inaccessibility to examination, aggressiveness, technical difficulties associated with surgery.

Epidemiology/Risk Factors
Increase threefold since the beginning of the century. Age, race, sex, tobacco, diet, specific genetic syndromes. More than 80% of cases between 60-80 years of age, rare under 40. African-American of both sexes

Epidemiology/Risk Factors
Men over women Cigarette smoking increased risk 1.5-5 times. Increased consumption of total calories, CHO, cholesterol, meat, salt, fried food, refined sugar, soy beans, nitrosamines.

Epidemiology/Risk Factors
A protective effect for dietary fiber, vitamin C. fruits and veggies. Long standing diabetes is not a risk factor.

Epidemiology/Risk Factors
Chronic pancreatitis of any cause has been associated with a 25-year cumulative risk of 4%. Other conditions for which a possible connection to pancreatic cancer are: thyroid cancer, cystic fibrosis, pernicious anemia. Most cases of pancreatic cancer have no predisposing factors, however it is estimated that between 5-10% arise because of a familial disposition.

Epidemiology/Risk Factors
Six genetic syndromes associated with an increased risk of pancreatic cancer are: HNCC, BRCA-2 associated familial breast cancer, PJ syndrome, ataxia-telangietasia, hereditary pancreatitis, familial molemelanoma syndrome.

Molecular Genetics
Tumor suppressor genes: p53, p16, DPC4, BCA2. P53 is inactivated in 75% of all pancreatic cancers.

Molecular Genetics
DPC4 is on Chromosome 18q. The Chromosome is missing in 90% of all pancreatic cancers, the gene inactive in 50%. The mutations are more specific for pancreatic cancer than p53 or p16 mutations. Oncogenes, when over expressed encode proteins with transforming qualities. Activating point mutations in the k-ras oncogene is the most common genetic alteration in pancreatic cancer, found in 80-90% of pancreatic cancers.

Pathology
Classified based on cell of origin. Most common are ductal adenocarcinomas. 65% of ductal cancers arise in the head, neck, or uncinate process; 15% originate in the body or tail; 20% diffuse.

Solid Epithelial Tumors

Adenocarcinomas: 75%, white yellow, poorly defined, often obstruct bile duct or main pancreatic duct. Often associated with a desmoplastic reaction that causes fibrosis and chronic pancreatitis.

Solid Epithelial Tumors

Infiltrate into vascular, lymphatic, perineural spaces. At resection, most mets to lymph nodes. Mets to liver (80%), peritoneum (60%), lungs and pleura (50-70%), adrenal (25%). Direct invasion of adjacent organs as well. Others include adenosquamous, acinar cell (1%, better prognosis), giant cell (5%, poorer prognosis), pancreatoblastoma (children 1-15 years, more favorable).

Cystic Epithelial Tumors

Less common than ductal, more in women, throughout the gland. Vast majority of cysts are benign pseudocysts.

Cystic Epithelial Tumors

Important to recognize cystic neoplasms because management is very different from non-neoplastic cysts. Many can have malignant potential.

Cystic Epithelial Tumors

Serous Cystic Neoplasms more common in women (2:1).Uniform cuboidal, glycogen rich cells. 30% asymptomatic, most have symptoms of pain, N/V. Can be anywhere in the gland, does not communicate with ducts. Most are benign. Symptomatic cysts that cannot be differentiated from other potentially malignant cysts should be excised.

Cystic Epithelial Tumors

Mucinous Cystic Neoplasms (MCN) are mucin producing epithelial cells associated with an ovarian-type stroma. Most in body and tail. Columnar mucin producing cells. 1/3 associated with invasive cancer. Lesions should be completely resected as invasive and in-situ carcinomas can be very focal. So cannot say benign on biopsy alone. Benign can progress to malignancy as well.

Cystic Epithelial Tumors

Intraductal Papillary-Mucinous Neoplasms (IPMN) extensively involve the main pancreatic duct and branches. Lack ovarian type stroma, more common in men. Older patient 60-80. Symptoms of pain, weight loss, steatorrhea, jaundice, diabetes, chronic pancreatitis. More common in head and neck. On endoscopy, mucin can be seen oozing from ampulla. ERCP for ductal communication. Progress from benign to malignant. Goal is complete surgical excision of benign and malignant lesions with negative margins.

Staging
T1 limited to pancreas, 2cm or less in size. T2 limited to pancreas, >2cm. T3 extends beyond pancreas, but not celiac or SMA. T4 involves celiac or SMA (unresectable). N0, N1 M0, M1

5-Year Survival
Stage 1A, 1B (T1-T2, N0, M0)20-30%. Stage 1B (T2, N0,M0) 20-30%. Stage 2A (T3, N0,M0) 10-25%. Stage 2B (T1, T2, T3, N1, M0)10-15%. Stage 3 (T4, any N, M0) 0-5%. Stage 4 (Any T, any N, M1) 0%.

Diagnosis
Inability to make diagnosis at early stage. Specific symptoms occur after invasion of adjacent structures.

Diagnosis
Most occur at the head, obstructs the bile duct that is intrapancreatic, causing jaundice, dark stools, dark urine, abdominal or back pain that is usually ignored by the patient. Pain may also be caused by invasion of splanchnic plexus and retroperitoneum.

Diagnosis
New onset of diabetes (10-15%), acute pancreatitis. Jaundice is most common(87%), hepatomegaly(83%), palpable gallbladder(29%) may be present. Cachexia, muscle wasting, nodular liver, Virchows node, SMJ node, ascites (15%).

Diagnosis
Amylase, lipase normal, other labs like obstructive jaundice. Ca 19-9, when upper level cutoff is used >200U/mL, accuracy is 95% in diagnosing pancreatic cancer. With CT, ERCP, US and Ca19-9 together, it approaches 100%. Higher levels correlate with prognosis and tumor recurrence, unresectability.

Radiology
CT has replaced US. On CT appears as an area of enlargement with a localized hypodense lesion. Do thin cuts thru pancreas and liver. CT is used to determine size of lesion and involvement of adjacent structures, mets.

Radiology
MRI offers no advantage. MRCP promising in terms of duct evaluations. Next step is ERCP to get anatomy and specimens. Sensitivity of ERCP to diagnose cancer is 90%. Look for long irregular stricture in an otherwise normal duct is highly suggestive. Obstruction with no distal filling. Dont need on everybody. Do it if suspect cancer but no mass seen on CT. Or symptomatic but no jaundice and no mass, chronic pancreatitis patients with development of mass.

Preoperative Staging
Determine feasibility of surgery and optimal treatment for each individual patient. In many cases only CT scan is necessary.

Preoperative Staging
Absence of metastases, patent SMV-portal vein confluence, no direct extension to celiac axis or SMA accuracy for resectability 85%. For tumors of the neck, head, uncinate process, occlusion of the SMA or portal vein along with presence of periportal collateral vessels is a sign of unresectability.

Preoperative Staging
In contrast tumors of the body and tail, occlusion of the splenic vein with perigastric collaterals does not always preclude resection. The extent of further staging depends on the patient and surgeon. If findings of staging can prevent an operation and lead to non-operative palliation, these efforts are worthwhile.

Preoperative Staging
Endoscopic US useful for small lesions, lymph nodes, vascular invasion, EU guided FNA may avoid seeding.

Preoperative Staging
Percutaneous FNA should not be used on potentially resectable tumors for two reasons. First even if the result is negative it does not rule out malignancy, in fact the small, potentially curable lesions will be the ones that are missed by the needle. Second is potential for seeding along tract or intraperitoneally. FNA should be done on patients deemed unresectable for direction of chemotherapy, or patients in whom neoadjuvant chemo is being considered. Currently EUS is the preferred technique for this in these situations.

Preoperative Staging
At the time of diagnosis, only 10% tumors confined to pancreas. 40% have locally advanced disease, 50% distant spread. Overall only 10-20% of all patients are candidates for pancreatic resection.

Preoperative Staging
Diagnostic laparoscopy on potentially resectable patients may find mets to liver and peritoneum not seen on CT because they are small. 50% of tumors of body and tail will have unexpected mets to peritoneum, whereas in head and neck, only 15% unexpected mets seen.

Resection of Pancreatic Carcinoma

Head, Neck, Uncinate: 1912 Kaush first successsful resection of duodenum and portion of pancreas for ampullary cancer.

Resection of Pancreatic Carcinoma

1935- Whipple described a technique for radical excision of a periampullary cancer. Was originally performed in two stages, first stage was a cholecystogastrostomy and gastrojejunostomy. Second stage was done after nutritional status better and jaundice improved was en-bloc resection of second portion of duodenum, head of pancreas without reestablishing pancreas-GI continuity. Since then many modifications done.

Resection of Pancreatic Carcinoma

Operative management of pancreatic cancer consists of two phases: first assessing tumor resectability, second completing a pancreaticiduodenectomy and restoring GI continuity.

Resection of Pancreatic Carcinoma

1. Search first for mets, extrapancreatic involvement. Send frozen sections on suspect lesions. 2. Assess primary tumor, for resectabilty, look for IVC, Aorta, SMA, SMV, Portal vein. To do this you do a Kocher maneuver to mobilize duodenum and head from IVC and aorta, once mobilized can assess relationship of tumor to SMA. Inability to find a plane between pulsation of SMA and tumor means unresectable.

Resection of Pancreatic Carcinoma

3. Dissect out SMV and Portal vein to rule out tumor invasion. 4. Once this is negative go to pancreaticoduodenectomy (pylorus preserving or classic).

Kocherizing

Determining Resectability

Resected Head

Pylorus Preserving

Postoperative Results
During the 1960s and 1970s, many centers reported operative mortality in range of 2040%, with postoperative morbidity rates of 40-60%.

Postoperative Results
During last two decades rates reported down to 2-3% mortality. Reasons why fewer, more experienced surgeons are performing the operation on a more frequent basis, pre and post op care has improved, anesthesia has improved, large number of patients are being treated at high volume centers.

Postoperative Results
Complication rates remain high (30%). Pancreatic fistula remains the most frequent serious complication (5-15%). The mortality from this has decreased though. Other common complications include delayed gastric emptying, abscess, bleeding, infection, diabetes, exocrine insufficiency.

Long-term Survival
Historically, 5% 5-year survival post resection. More recent studies suggest improved survival.

Long-term Survival
In 2000, Sohn, et al. on 616 patients resected with a 17% 5-year survival, median survival of 17 months. Factors found to be important predictors of survival included tumor diameter (<3cm), negative resection margin, well/mod tumor differentiation, postop chemoradiatioin treatment. Most favorable were small tumors, margin negative, node negative resections, median survival was 33 months and 5-year survival was 31%.

Adjuvant Therapy
Radiation 5-FU

Palliation
Jaundice: Choledochojejunostomy, cholecystojejunostomy. Stent placement. With stents, may need frequent exchanges, may migrate, recurrent jaundice is higher. Metallic stents stay open longer. Lower complication rates with respect to surgical palliation. Surgical palliation for patients expected to live longer than 6 months only.

Palliation
Duodenal Obstruction:Gastrojejunostomy do it or not if the patient is not obstructed. Studies say do it. No difference in length of stay post op, morbidity, mortality. Pain: Long-acting morphine derivatives, percutaneous blocks are successful at eliminating pain in majority.