Pancreatic cancer

Epidemiology

Pancreatic cancer is the fourth commonest cause of cancer-related death in the Western world. More than 43,000 new cases in the United States and more than 7500 cases in the United Kingdom are diagnosed yearly with a slightly increased incidence in males.1,2 More than 75% of pancreatic cancer occurs in patients older than 65 years and peak incidence occurs in the seventh and eighth decades of life.2 The majority of pancreatic cancers are incurable at presentation and these patients have a median survival of 5–8 months.3,4 Only 20% of patients present with localized disease that is potentially resectable, yet only 20% of these survive 5 years.5,6

Histology of pancreatic tumors

Exocrine carcinomas represent more than 95% of all pancreatic carcinomas and the majority (>90%) of these are adenocarcinomas with more than 75% occurring in the head of the gland. Other types include cystic tumors of the pancreas and endocrine tumors.

Molecular biology of pancreatic carcinomas

Pancreatic ductal carcinoma results from the accumulation of acquired mutations. The multigenic nature of most pancreatic ductal cancer is reflected in the abnormalities of three broad classifications of genes: oncogenes such as K-ras; tumor-suppressor genes such as p16, p53,
and SMAD4; and genomic maintenance genes such as hMLH1 and MSH2.6 The K-ras oncogene, which mediates signal transduction in the growth factor receptors, undergoes a point mutation and is present in almost 75–100% of pancreatic tumors.7,8 The P16 tumor-suppressor gene is inactivated in around 95% of pancreatic cancers and typically occurs later in pancreatic carcinogenesis.9,10 Similarly, p53, another tumor-suppressor gene, is also inactivated late in the progression of pancreatic carcinoma, prior to metastatic spread, and is present in 50–75% cases.11,12

It is suggested that the mutations occur in a predictable time course, leading to the development of a progression model, which describes the changes that occur as normal pancreatic epithelium transforms into intraepithelial neoplasia and finally to invasive cancer. The concept was first suggested when atypical ductal papillary hyperplasia was noticed adjacent to resected adenocarcinomas.13 Subsequently, a unified nomenclature to classify intraductal precursor lesions of the pancreas, known as pancreatic intraepithelial neoplasia (PanINs), has been proposed.14PanIN-1A lesions are flat, tall columnar cells with basally located nuclei. PanIN-1B lesions exhibit papillary architecture. PanIN-2 lesions are characterized by nuclear abnormalities such as loss of polarity or nuclear crowding and PanIN-3 have marked nuclear and cytological abnormalities and were previously referred to as carcinoma in situ. Invasion through the basement membrane marks the transition from PanIN-3 to invasive carcinoma.15 Genetic aberrations are apparent at different stages through the PanIN sequence; for example, K-ras mutations are observed as early as the PanIN-1 stage16 and P16 inactivation usually occurs by the PanIN-2 stage.17 In addition, loss of BRCA2 function,18DPC4 and p53 tumor-suppressor genes, occurs in advanced PanIN lesions.17,19

Adenocarcinoma of the pancreas

Risk factors and prevention

Smoking

Smoking is the only preventable risk factor. It increases the risk of pancreatic cancer up to 2.5-fold compared with that of nonsmokers and is estimated to be responsible for 20% of pancreatic cancers. The risk increases with greater tobacco use and longer exposure, although does drop off significantly after cessation of smoking.3,20,21 The pathophysiology behind nicotine-induced pancreatic carcinoma is unclear, but it is believed that N-nitroso compounds in tobacco are carried to the pancreas in the blood.22

Diabetes mellitus

A systematic review and meta-analysis concluded that type I diabetes mellitus increases the risk of pancreatic carcinoma by twofold.23 Similarly, a meta-analysis of 36 studies concluded that type II diabetics have a 1.8-fold increased risk of developing pancreatic cancer. The study also concluded that risk was 50% higher if diabetes was diagnosed within the preceding 5 years.24

Chronic pancreatitis

Chronic pancreatitis is defined as a progressive inflammatory disease of the pancreas, associated with irreversible histological changes and subsequent loss of function. Chronic pancreatitis increases the risk of pancreatic cancer, which increases over time.25,26

Familial pancreatic cancer

Familial pancreatic cancer is defined as ductal adenocarcinoma of the pancreas affecting at least two first-degree relatives who do not fulfil the criteria for another inherited tumor syndrome.3 Inherited mutations account for 2–10% of all pancreatic cancers.15 Individuals with one, two, or three first-degree relatives with a history of pancreatic cancer demonstrate a 6-, 18- and 57-fold increase risk, respectively, compared with the normal population.27

Hereditary syndromes/conditions associated with pancreatic cancer

Five hereditary tumor predisposition syndromes/conditions have been identified that increase the risk of pancreatic cancer.

Peutz–Jeghers syndrome

Peutz–Jeghers syndrome (PJS) is a rare autosomal-dominant condition with an incidence of 1:25,000 births. It is characterized by mucocutaneous pigmentation and hamartomatous gastrointestinal polyps. These patients have a 132-fold increase in developing pancreatic cancer and a lifetime risk of greater than 30%.28

Hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal-dominant disorder and has an incidence of 1:174 births. It is responsible for 20% of all colorectal carcinomas.29 In addition to a 1–5% increased risk of developing pancreatic cancer, patients have an increased risk of developing extracolonic cancers such as endometrial (60%), stomach (10%), ovarian (12%), genitourinary (4%), biliary (2%), nervous system (4%), and small bowel cancer (1–4%).15,30,31

Familial atypical multiple mole melanoma

Familial atypical multiple mole melanoma (FAMMM) is an autosomal-dominant condition characterized by multiple nevi, melanomas, and extracutaneous tumors. It accounts for 12% of all familial pancreatic cancers and affected individuals have a 20-fold increased risk of developing pancreatic cancer and a lifetime risk of 15%.31,32

Hereditary breast and ovarian cancer carriers

Familial breast and ovarian cancer syndromes are due to mutations in the BRCA1 or BRCA2 genes. Patients with the BRCA1 mutation have a twofold risk increase of pancreatic cancer and those with BRCA2 mutation (responsible for 17% of all familial pancreatic carcinomas) have between 4- and 13-fold risk increase. The risk is highest in Ashkenazi Jews as 1% of the population have the BRCA2 mutation.15,33,34

Hereditary pancreatitis

Sufferers of hereditary pancreatitis, an autosomal-dominant disease causing 1% of all cases of pancreatitis, have a 50-fold increase risk of developing pancreatic cancer and their lifetime risk approaches 40%.35

Presentation and diagnosis

In order to understand the presentation of pancreatic lesions, it is imperative to appreciate pancreatic anatomy. The pancreas is a retroperitoneal structure, divided into the head, neck, body, and tail. It lies in a C-shaped groove formed by the first three parts of the duodenum and is intimately attached to it. It is formed by the fusion of dorsal and ventral buds, by the ventral bud rotating posteriorly to fuse with the dorsal bud. The ventral duct, which becomes the main pancreatic duct (of Wirsung), fuses with the dorsal duct, also referred to as the minor pancreatic duct (of Santorini), which drains the body and tail of the pancreas. The ventral duct usually joins the common bile duct in the head of the pancreas and continues forward as a “common channel” before entering the midpoint of the second part of the duodenum as the ampulla of Vater.

The majority of exocrine pancreatic tumors occur in the head of the gland and often the patient may present with painless jaundice due to compression of the common bile duct.36 This is in keeping with Courvoisier’s law which states that “a palpable gallbladder in the setting of painless jaundice is rarely due to stone disease.” However, the patient may present with a myriad of vague symptoms including anorexia, weight loss, and abdominal pain. In addition, compression of structures intimately related to this part of the gland such as the duodenum and coeliac nerves may present as gastric outlet obstruction and severe epigastric and back pain, respectively. Rarely, the tumor may cause obstruction of the pancreatic duct causing the patient to present with acute pancreatitis.

The purpose of any investigations in a patient suspected of pancreatic cancer is to confirm the diagnosis, the stage of the disease, assess resectability, and, if unresectable, plan palliative interventions. Investigations include basic blood tests including full blood count, which may demonstrate anemia due to occult loss from tumor invasion of the duodenum. Liver function tests may demonstrate an obstructive picture with high conjugated bilirubin and raised alkaline phosphatase. A raised amylase may demonstrate pancreatitis, and in addition, a low albumin may reflect the patient’s low nutritional state. Carbohydrate antigen 19.9 (CA19.9) is the only tumor marker that is sensitive and specific for pancreatic tumors. Preoperatively, it has been demonstrated as a useful predictor of resectability, and postoperatively, it is a useful predicator of recurrence, disease-free, and median survival.37–40 However, it must be used with caution as it has been demonstrated to be elevated in benign causes of obstructive jaundice,41 although levels should return to normal post relief of jaundice. It is also reported to be absent in patients with blood Lewis antigen a or b deficiency despite advanced malignancy.42 As always, the clinical picture in addition to thorough radiological or histological investigations must be taken into account when interpreting abnormal levels of any tumor markers.

Cross-sectional imaging of the thorax, abdomen, and pelvis by thin cut intravenous contrast-enhanced multidetector computerized tomography (CT) scan is the radiological investigation of choice.43 Other investigations such as magnetic resonance cholangiopancreatography (MRCP) is usually reserved for patients where the diagnosis of pancreatic carcinoma is in doubt and an intraductal or periampullary lesion has to be excluded prior to endoscopic retrograde cholangiography (ERCP). Tissue diagnosis, either in the form of ultrasound or CT-guided biopsy or endoscopic ultrasound-guided fine needle aspiration, is essential. Patients with liver metastases may undergo biopsy of the liver lesions on the background of strong radiological suspicion of pancreatic carcinoma.

Cancer management

Surgical resection provides the only possible cure. All patients should be discussed by a multidisciplinary team involving surgeons, anesthetists, oncologists, radiologists, hepatobiliary nurse specialists, and nutritionists. According to the TNM staging for pancreatic exocrine tumors (Table 8.1), T1, 2, and 3 are potentially resectable; however, any evidence of locally advanced carcinoma, particularly major vascular involvement, such as superior mesenteric artery or coeliac axis involvement, precludes curative resection. Patients with local invasion of portal vein with no evidence of thrombosis should be treated on their merit, as vein excision with reconstruction can be successful in experienced hands.44 All patients suitable for resection should be considered for a staging laparoscopy and intraoperative ultrasound scan. This not only provides a real-life simulation of a general anesthetic but it has also been shown to detect occult peritoneal or locally invasive tumor, thus altering the prognosis in up to 20% of patients.45 Preoperative drainage of biliary obstruction has been shown to increase postoperative sepsis, pancreatic fistula, and wound infections46,47, and most centers now follow a policy of early resection. However, if there is an envisaged delay in treatment, then often patients undergo preoperative relief of obstruction either via a percutaneous route or an ERCP.

Table 8.1 TNM staging of pancreatic cancer.131

The operation depends on the location of the tumor. A head or neck of pancreas tumor requires a pancreaticoduodenectomy (the Whipple procedure) and tumors involving the tail should undergo a distal pancreatectomy.

Allen Oldfather Whipple first described the procedure synonymous with his name in 1935.48 Initially a two-stage procedure, it was later developed as a one-stage procedure. Considerable advances in preoperative patient selection restricting surgery to high volume centers with expert surgical knowledge and skill along with improved intra- and postoperative anesthetic expertise has remarkably reduced the morbidity and mortality associated with this procedure.49 Numerous variations of the surgical technique, dissection, and anastomotic reconstruction have been described, but the end result involves resection of the head and neck of pancreas, together with the attached duodenum (some surgeons prefer to resect the pylorus to aid gastric emptying while others preserve it in the belief that it prevents biliary reflux) and reconstruct drainage of the bile duct, stomach, and the pancreas using the jejunum as conduits. Most high volume centers (>18 procedures/year) report a mortality of less than 5% and this has decreased considerably over the last two decades. In addition, the 5-year survival is 20% in experienced centers and is influenced by tumor size of less than 3 cm, negative margins, negative nodal involvement, low-grade tumor, diploid tumor DNA content, and low postoperative CA19.9 levels.5,49–51

Distal pancreatectomy with en-bloc splenectomy is performed for resectable tumors of the body and tail.52 As these patients are often rendered immunocompromised, all patients should be immunized against Streptococcus pneumoniae, Neisseria meningitides, and Haemophilus influenzae (type b) preoperatively and are required to take prophylactic antibiotics, usually in the form of penicillin V for life.

Patients with unresectable disease require symptom control. Jaundice is usually relieved by stenting the common bile duct via ERCP. Often a combination of external biliary drainage and radiologically guided internal biliary drainage is required if ERCP is unable to stent the common bile duct due to distortion of anatomy by local invasion of the pancreatic tumor. If unresectable disease is encountered at laparotomy, a biliary bypass should be performed and a gastrojejunostomy should be considered as 20% of patients with inoperable pancreatic cancer may develop duodenal obstruction during the course of their disease.53 Pain and nausea control usually requires the input of palliative care nurses.

Neoadjuvant and adjuvant treatment of pancreatic cancer

The aim of surgery is to resect the tumor with normal pancreas at the margin and no evidence of residual tumor, commonly referred to as R0 resection. Preoperative chemoradiotherapy can be beneficial as it theoretically increase the likelihood of R0 resection margins by reducing tumor load. However, in patients with resectable disease, it may deem them unresectable while undergoing treatment and the toxicity of the treatment itself may delay them undergoing potentially curative surgery. Neoadjuvant chemoradiotherapy therefore is reserved for patient with nonmetastatic unresectable carcinoma with a view to shrinking the tumor and deeming patients resectable. All trials involve the use of external beam radiotherapy and usually multimodal chemotherapy agents with the greatest success achieved by gemcitabine-based regimens.54,55 It is reported that up to a third of patients initially deemed unresectable may become resectable post-neoadjuvant therapy with similar median survival to those who initially underwent resection.4 Local policies and a wide variation in treatment protocols make conducting large multicenter trials difficult.

Controversies exist regarding the optimal adjuvant treatment of patients postpancreatic resection. Unsurprisingly, patients with R0 resection have significantly prolonged survival compared with those with a R1 resection margin. The Gastrointestinal Tumour Study Group was one of the first of its kind to demonstrate improved survival and establish the role of 5-FU-based adjuvant chemoradiotherapy in patients undergoing pancreatic cancer surgery.56 This study, however, was criticized for its poor accrual, low statistical power, suboptimal radiotherapy schedule, and low chemotherapy compliance.57 Following this, the European Study Group for Pancreatic Cancer (ESPAC) conducted a large phase III trial and demonstrated improved survival with adjuvant 5-FU-based chemotherapy compared with chemoradiotherapy and concluded that chemoradiotherapy should be abandoned as it can lead to delay in starting chemotherapy.58 However, this trial again generated significant controversy as it was criticized for its use of suboptimal radiotherapy schedule and nonstandardized randomization criteria.57 Several studies have reanalyzed the data from the original ESPAC trial and have all concluded that adjuvant chemotherapy has significant benefit compared with chemoradiotherapy.59 The Radiation Therapy Oncology Group trial 97-04 (RTOG 97-04) established the superior nature of gemcitabine-based chemoradiotherapy regimens for patients with resected head of pancreas tumors and other trials including the latest results from the ESPAC-3 trial tend to support the use of gemcitabine-based adjuvant chemotherapy compared with 5-FU due to its superior safety profile.60,61 The need for good quality, randomized, multicentre trials still remain, particularly those comparing chemotherapy and chemoradiotherapy and in patients with R1 resections.

Patients with unresectable pancreatic carcinoma have an extremely dismal prognosis. Traditionally, 5-FU-based chemotherapy regimens in association with radiotherapy demonstrated a survival benefit of up to 44 weeks.62 In addition, there was evidence that radiotherapy palliated the pain,63 a common side effect of locally advanced carcinoma. Newer gemcitabine-based chemotherapy regimens seem to offer an increased survival benefit compared with 5-FU and radiotherapy with comparatively lower toxicity.64 Unfortunately all patients relapse regardless of strategy used and succumb to the debilitating effects of metastatic pancreatic cancer. Patients require specialist palliative care input particularly for the intractable pain, nausea, and cachexia.

Cystic tumors of the pancreas

Intraductal papillary mucinous neoplasms

Intraductal papillary mucinous neoplasm (IPMN) was first described in 198265 and have since been defined as mucin-producing epithelial tumors, often with papillary architecture, of either the main pancreatic duct (main-duct IPMN) or one of its branches (branch-duct IPMN).66 They are estimated to account for 1–3% of all exocrine pancreatic tumors and recognized as a premalignant condition with more than 30–72% of tumors presenting with either invasive carcinoma or carcinoma in situ.67,68 Branch-duct IPMNs are less likely to be associated with malignancy.69,70 IPMN mostly occurs in the sixth to seventh decade and usually presents with abdominal discomfort and weight loss, often mimicking chronic or relapsing pancreatitis, possibly due to intermittent obstruction of the main pancreatic duct by mucus plugs.71 Patients may also present with weight loss, jaundice, vomiting, and diabetes, although these symptoms are highly suggestive of invasive malignancy.72 A thorough history, particularly preceding episodes of alcohol-induced pancreatitis, and targeted investigations help distinguish IPMN from other malignant cystic lesions such as mucinous cystic neoplasm and benign conditions such as chronic pancreatitis and pancreatic pseudocysts. The majority of IPMNs involve the head of the pancreas, and CT and MRCP show a grossly dilated pancreatic duct in main-duct IPMN and “grape-like” dilatations associated with branch-duct IPMN.53 An elevated serum CA19.9 suggests a neoplastic lesion and a patulous ampulla extruding mucus associated with main pancreatic duct filling defects at ERCP is associated with main-duct IPMN. The International Association of Pancreatology recommends that all patients with main-duct IPMN should undergo resection due to their malignant potential and branch-duct should be intensively followed up with a rise in CA19.9, increase in tumor size, or the presence of mural nodules or thick wall cysts either at presentation or on follow-up, an indication for resection.53,73 There is significant morbidity associated with a total pancreatectomy and no added advantage compared with segmental tumor resection with negative margins.74 Postresection, the presence of invasive disease is the main determinant of survival with 5-year survival—up to 100% with noninvasive disease compared with 13–60% in those with incomplete resection.75,76 In addition, jaundice at presentation, tubular tumor type, vascular invasion, and positive lymph node status all relate to poor 5-year survival.53,77

Mucinous cystic neoplasms

Mucinous cystic neoplasms are the commonest cystic neoplasm of the pancreas.78 Eighty percent occur in females, with a median age of 50 and unlike IPMNs almost never communicate with the duct. Histologically, they are formed by mucin-producing epithelial cells supported by an ovarian-type stroma.79 They almost always arise de novo and are often located in the body tail of the pancreas.79,80 They often present with vague symptoms of abdominal pain, weight loss, nausea, and vomiting. The presence of calcifications and multiseptae distinguish this from other cysts.78 The imaging triad of calcifications, thick walls, and mural vegetation on CT scanning is predictive of malignant degeneration in up to 95% of cases.81 A combination of cross-sectional imaging, endoscopic ultrasound assessment, and fine needle aspiration of cyst fluid confirms the diagnosis in the majority of cases.71,78 The prognosis depends on the extent of local tumor invasion, tumor size, location, and type. All tumors resected with oncological techniques have a good prognosis with greater than 50% survival.78,79

Endocrine carcinomas of the pancreas

These tumors are also known as islet cell tumors or neuroendocrine tumors (NET) are part of the diffuse endocrine system (DES) and the gastroenteropancreatic axis (GEP) and are now collectively known as GEP–NETs. They make up around 5% of all pancreatic tumors and can be benign or malignant, functional or nonfunctional, and can often be part of a multiple endocrine neoplasia (MEN) syndrome. They usually take their name from the hormone produced by these cells such as insulinomas, gastrinomas, glucagonomas, VIPomas, somatostatinomas, and carcinoids. The majority are nonfunctional, and insulinomas followed by gastrinomas are the commonest functional tumors.82 It is estimated from postmortem studies that pancreatic NETs are identifiable in up to 10% of individuals.83

Presentation

Nonfunctioning tumors usually present with either mass effect secondary to local invasion or due to secondary spread. Functioning tumors present with symptoms secondary to the hormones they produce, for example, Insulinomas present with confusion, sweating, weakness, and unconsciousness relieved by eating or dextrose administration. Gastrinomas (Zollinger–Ellison syndrome) may present with severe peptic ulceration and diarrhea. Glucagonomas present with vague symptoms of necrolytic migratory erythema, weight loss, diabetes mellitus, stomatitis, and diarrhea. VIPomas (Werner-Morrison syndrome) present with profuse watery diarrhea associated with marked hypokalemia and somatostatinomas also present with similar symptoms of diarrhea, steatorrhea, and diabetes mellitus.84,85

Investigations

They can be difficult to investigate due to the site, which can be anywhere in the gastrointestinal tract or the pancreas, lung thyroid, pituitary, and other sites. They are frequently small and can present with unusual symptoms. Usually, the investigations are easier to focus when a functioning tumor is suspected. Biochemical investigations include measuring serum glucose, insulin, C-peptide, chromogranin A, and 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA). A suggestion of MEN-1 (susceptible to parathyroid, pituitary, and pancreas neoplasms) should prompt calcium, parathyroid hormone, calcitonin, and thyroid function tests to be measured. Radiological localization of nonfunctioning tumors is done by high quality CT scanning. Somatostatinomas, VIPomas, and glucagonomas tend to be large and easily identified on imaging, whereas insulinomas and gastrinomas are more difficult to localize. Extrapancreatic sites such as gastric and colonic tumors may require endoscopic evaluation. An “octreoscan” may be useful, particularly when assessing secondaries or following up patients who have had a primary resection. These are usually done in specialized nuclear medicine departments.

Treatment

Patients should be referred to specialist hepatobiliary centers. Surgical treatment offers the best cure, and the extent of disease and completeness of resection are major predictors of survival.82 Insulinomas, which have the lowest chance of malignant potential of all GEP–NETs can occur in extrapancreatic sites and can be difficult to localize. Single, solid, nonfunctioning tumors in MEN syndromes can be excised for cure or surgery can be employed to debulk tumors for the sake of symptom control. Essentially, all patients after undergoing extensive radiological and histological diagnoses, followed by search for metastases, should be offered resection.

Biliary cancer

Epidemiology

Cholangiocarcinoma is the malignant transformation of cholangiocytes, which line the intra- and extrahepatic bile ducts, and gallbladder carcinoma is the commonest biliary tract tumor. Bile duct tumors account for 2% of all reported cancers and 3% of all gastrointestinal cancers. The peak incidence is in the eight decade and is 1.5 times commoner in males than in females.86,87 Southeast Asia has one of the highest rates of cholangiocarcinoma and may be due to the endemic infestation of the liver fluke parasite. Anatomically, cholangiocarcinomas are divided into intra- and extrahepatic tumors. Extrahepatic cholangiocarcinomas are further subdivided into proximal, mid-, and distal carcinomas depending on their location in the bile duct. Due to the unique risk factors, clinical presentation and management of gallbladder cancer compared with other extrahepatic carcinomas, it will be dealt with separately in this chapter. Although intrahepatic cholangiocarcinoma is a relatively rare tumor in the general population, it is the second most common primary liver tumor88 and recent epidemiological studies suggest an increase in incidence in the western world.88,89 Hilar or proximal tumors, also eponymously known as Klatskin tumors, were first described in 196590 and after gallbladder carcinoma are the second commonest site of bile duct tumors.91

Histology of bile duct tumors

Traditionally, extrahepatic cholangiocarcinomas are divided into three main histological subtypes: nodular, sclerosing, and papillary.92

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