44 Pancreatic Cancers and Cystic Neoplasms
Omer Basar and William R. Brugge
Most pancreatic cancers are ductal adenocarcinomas arising from the exocrine pancreas. Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and age, male gender, tobacco consumption, chronic pancreatitis, and some hereditary syndromes are risk factors. Most patients are diagnosed with advanced disease usually by cross-sectional imaging. Currently endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA) is the standard approach for tissue sampling of a mass lesion. Surgery is the only curative therapy. In contrast, pancreatic neuroendocrine tumors (pNETs) are less common and have a better prognosis.
Pancreatic cystic lesions (PCLs) are increasingly recognized as premalignant precursor lesions and offer the opportunity to intervene early in pancreatic cancer. Computed tomography/magnetic resonance imaging (CT/MRI) is frequently used for the initial evaluation; however, EUS-FNA is the preferred imaging tool for tissue sampling and clinical guidance. Biochemical, cytological, and DNA analysis of aspirated cyst fluid aids in the differentiation between benign, premalignant, and malignant lesions. Options for treatment include surgery and endoscopic ablation therapies. Some lesions should also be followed up conservatively.
Although pancreatic malignancies may arise from exocrine and endocrine pancreas, most cancers originate from the ductal epithelium and are termed PDACs) 1 (▶Table 44.1). Because of its aggressive behavior, PDAC is one of the most common cancer-related deaths in United States. Screening, early diagnosis, and treatment strategies are challenging.
Ductal adeno CA
Mucinous adeno CA
Signet-ring cell CA
Undifferentiated CA with osteoclast-like cells
Acinar cell CA
Acinar cell cystadeno CA
IPMN with an associated invasive CA
Mixed acinar-ductal CA
Mixed acinar-neuroendocrine CA
Mixed acinar-neuroendocrineductal CA
Mixed ductal-neuroendocrine CA
MCN with an associated invasive CA
Serous cystadeno CA
Solid pseudopapillary neoplasm
Solitary fibrous tumor
Desmoplastic small round cell tumor
Perivascular epithelioid cell neoplasm
Pancreatic neuroendocrine microadenoma
Large-cell neuroendocrine CA
Small-cell neuroendocrine CA
Enterochromaffin cell, serotonin-producing NET
Insulin-producing CA (insulinoma)
Diffuse large B-cell lymphoma
CA, carcinoma; MCN, mucinous cystic neoplasm; NET, neuroendocrine tumor.
pNETs were formerly named islet cell tumors and are mostly indolent, with a small percentage demonstrating malignant behavior. 2 pNETs are usually an incidental finding on cross-sectional imaging.
PCLs are mostly recognized coincidentally 3 , 4 with a prevalence of 1.2 to 19% in different studies. 3 , 4 , 5 , 6 Nowadays the term, pancreatic cystic neoplasms (PCNs), is more preferred instead of PCL and these lesions are usually classified as either neoplastic or nonneoplastic (▶Table 44.2). Most PCLs are nonneoplastic and account for 80% of the pancreatic cysts. 3 , 4 , 7 PCNs are composed of cysts with either a mucinous or serous epithelial lining. Mucinous cysts have a malignant potential whereas serous cystic neoplasm (SCN) are typically benign.
This chapter reviews the major advances in the diagnosis and management of pancreatic cancers and PCNs.
44.2 Pancreatic Cancers
44.2.1 Ductal Adenocarcinoma of the Pancreas
PDAC risk increases with age (age at median diagnosis is 71) 8 and men are slightly more affected. 9 About 80% of cases have advanced disease at diagnosis and the 5-year survival rate is only 4% in these patients. 10 The risk factors for PDAC include advanced age, male gender, “non-O” blood group, and obesity. External risk factors include exposure to high-fat diets, smoking, occupational exposure to nickel, petroleum, and wood pulp. Medical risk factors include a history of partial gastrectomy and chronic pancreatitis, or diabetes. Inherited genetic predispositions to PDAC include familial adenomatous polyposis syndrome, Lynch’s syndrome, Peutz–Jeghers syndrome, hereditary pancreatitis, hereditary breast–ovarian cancer syndromes, ataxia telangiectasia, Li–Fraumeni syndrome, familial atypical multiple mole melanoma syndrome (FAMMMS). 1 , 11 , 12 , 13
PDAC has a progressive cancer development pathway, which is similar to the adenoma–carcinoma sequence. Pancreatic intraepithelial neoplasias (PanIn) are the initiating precursor lesions and the degree of dysplasia increases from PanIn 1 to 3. Most of these lesions contain KRAS mutations, moreover PanIn 2 and 3 lesions are found to contain p53, SMAD4, and CDKN2A mutations. 14 Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasm (MCN) may also initiate the tumorigenesis process, and almost half of IPMN cases contain a KRAS mutation (40–65% of cases). 13
Two-thirds of PDACs are located in the head of the pancreas and present at an earlier stage than malignancies located in the body or tail. Jaundice due to biliary obstruction is the most common presenting symptom and in one-third of patients, Courvoisier’s sign (a palpable gallbladder) is present. Pancreatic body and tail lesions remain asymptomatic until advanced disease progresses. Abdominal (predominantly epigastric) or midback pain, pruritus, asthenia, weight loss, and depression are the most common symptoms. 15 Pancreatic exocrine insufficiency present with steatorrhea and malabsorption, and new-onset diabetes exists in about half of the patients. 16 Migratory thrombophlebitis is another common presentation. 17
Genetic predisposition is present in 5% of patients with PDAC and 95% are sporadic. Although screening programs in high-risk patients are not widely established in the United States, candidates listed in ▶Table 44.3 could be candidates for screening as recommended by the International Cancer of the Pancreas Screening Consortium. 18 , 19
Blood tests usually reveal a mild anemia. Cholestatic enzymes and bilirubin levels are elevated in cases with biliary obstruction. Although having a poor sensitivity in diagnosis, CA 19–9 levels are predictive for recurrent malignancy after surgery. 20
Patients with jaundice are initially evaluated with ultrasonography (US), which has limited access to the pancreas. A hypoechoic mass in the pancreas is typical for PDAC and a “double duct sign” (dilation of both common bile duct and pancreatic duct) is also a common feature. Computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used tools for the diagnosis of PDAC (▶Fig. 44.1). A pancreatic-protocol triphasic CT is one of the best tools for staging. Unnecessary staging laparoscopies and laparotomies are 80% avoided with this protocol. 21 MRI does not usually add extra information over CT. 22 Fluorodeoxyglucose–positron emission tomography (FDG-PET) has a similar accuracy with CT/MRI; on the other hand, it may demonstrate small local and distant metastasis. 23 Nowadays, EUS-FNA is one of the best method for tissue sampling and staging (Video 44.1). Having a low complication rate, 24 EUS is better at detecting small lesions compared to CT/MRI 25 , 26 (▶Fig. 44.2). Along with its usage in cyst fluid sampling, it has a therapeutic role in advanced PDAC (celiac ganglion blockage in cancer pain relief and biliary drainage when endoscopic retrograde cholangiopancreatography [ERCP] is not possible).
Preoperatively, PDAC is staged based on American Joint Committee on Cancer tumor, node, metastasis (TNM) system. 27 Both T1 and T2 lesions are limited to the pancreas, with a tumor dimension less than or equal to 2 cm in T1 and greater than 2 cm in T2. Superior mesenteric vein, portal vein, and splenic vein invasion is considered T3, and superior mesenteric artery and celiac axis invasion are considered T4 tumors. N1 staging describes lymph node metastasis and M1 staging indicates metastatic disease. Potentially resectable tumors are T1, T2, and T3, and T4 lesions are unresectable. Furthermore, National Comprehensive Cancer Network (NCCN) classified PDAC clinically 28 (▶Table 44.4).
A multidisciplinary approach is needed for the treatment of PDAC patients. Radical R0 resection is the only curative treatment and this takes place in less than 20% of patients. In cases with unresectable tumor or when neoadjuvant chemotherapy is planned, a histologic or cytological diagnosis is necessary. Surgically resectable PDAC (stages I–II) patients should undergo a Whipple procedure or distal pancreatectomy depending on the localization of PDAC. Today, laparoscopic distal pancreatectomy is the preferred technique for distal tumors. 13 The recommended therapy for borderline resectable PDAC is neoadjuvant chemoradiation. 13 As an adjuvant therapy, both gemcitabine and 5-fluorouracil (5-FU) were found to improve survival after R0/R1 resection. 29 , 30 , 31 On the other hand, adjuvant radiotherapy is not routinely advised. 29 , 30 Neoadjuvant chemotherapy has a limited efficacy and although no definite optimal treatment is present, nab-paclitaxel (gemcitabine plus albumin-bound paclitaxel particles) and 5-FU, irinotecan, oxaliplatin, and leucovorin combination are commonly used. Locally advanced, unresectable PDAC (stage III) patients should receive folfirinox or gemcitabine–nab-paclitaxel as studies report similar response rates with metastatic tumors. 32 Metastatic PDAC (stage IV) patients should also receive the same regimen as in stage III, resulting in 10% 2-year survival rate. 33 , 34 Endoscopic biliary drainage, expandable metallic stent placement for duodenal obstruction, opioids, and EUS-guided celiac plexus blocks are palliative treatments for advanced PDAC (▶Fig. 44.3).