Pancreatic Ductal Adenocarcinoma

Introduction

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of less than 10%, and accounts for 90% of all pancreatic tumors. It remains one of the most difficult challenges in oncology because patients are typically asymptomatic until the disease is in an advanced stage. It is also not unusual to present with symptomatic metastases in the presence of a small primary tumor. Furthermore, many of its symptoms are nonspecific and overlap with a variety of other diseases such as cholecystitis, pancreatitis, and bowel disorders.

Effective treatment of PDAC requires multidisciplinary cooperation amongst surgeons, oncologists, radiation oncologists, and radiologists. The standard therapy for resectable PDAC is surgery. Neoadjuvant chemotherapy with or without radiation is being increasingly adopted as treatment for borderline resectable tumors to improve the rate of negative resection margins. Chemotherapeutic agents like FOLFIRINOX and gemcitabine plus nanoparticle albumin-bound paclitaxel are approved for patients with distant metastases or locally advanced tumors.

Imaging is critical in the management of these patients, as it has an important role in tumor staging, determining resectability, and predicting patient outcome.

Epidemiology and Risk Factors

PDAC is the fourth leading cause of cancer-related mortality in both males and females. An estimated 45,750 PDAC-related deaths have occurred in the United States thus far in 2019. PDAC is typically seen in the elderly, with a slight predilection for men over women in most countries. Exposure to cigarette smoke is a significant risk factor and is implicated in as many as 20% to 30% of pancreatic cancers. Although excessive alcohol consumption is a common risk factor for chronic pancreatitis, it has not been shown to result in an increased risk of PDAC. However, chronic pancreatitis itself is strongly related to the development of PDAC. PDAC is often diagnosed within 2 years of a diagnosis of chronic pancreatitis. Therefore, close follow-up in the first years following a diagnosis of chronic pancreatitis is necessary.

PDAC itself can induce diabetes mellitus secondary to its destructive effects on the pancreatic parenchyma. Approximately 8% patients with PDAC have comorbid type 3c diabetes. On the other hand, a metaanalysis showed a twofold increase in the pooled relative risk for PDAC in patients suffering from diabetes for 5 years. Although the mechanism of diabetes is complex, the increased risk has been found to be secondary to insulin deficiency, potential immunopathogenesis, reduced incretin effect, peripheral insulin resistance, and hepatic insulin resistance.

Other risk factors include inherited genetic risk, pancreatitis, pancreatic cyst, physical inactivity, and obesity.

A variety of syndromes are also associated with an increased risk of PDAC, including hereditary pancreatitis, Peutz–Jeghers syndrome, Lynch syndrome, familial adenomatous polyposis, familial atypical multiple mole melanoma, and ataxic telangiectasia.

Molecular Biomarkers

Activation of oncogenes and inactivation of tumor suppressor genes play a significant role in the manifestation of PDAC. Mutations in genes such as DPC4, P53 , and P16 are present in over half of all cases. Carriers of germline BRCA2 mutation have up to tenfold higher risk for developing PDAC than the general population. Moreover, several molecular biomarkers, including SMAD4, Ki-67 index, Vimentin, E-cadherin, and TWIST, have been reported as predictive factors for overall survival. Among them, Vimentin, E-cadherin, and Twist are associated with epithelial-to-mesenchymal transition, which is a key step in primary tumor progression to metastasis. E-cadherin–negative PDACs have been shown to have a worse prognosis than positive cases (hazard ratio, 2.21). Irregular tumor margins are more frequently observed in E-cadherin–negative PDACs than in E-cadherin–positive PDACs.

Anatomy and Pathology

The pancreas, measuring between 12 and 15 cm in length, is located deep within the retroperitoneum and lacks a capsule. This allows adjacent fat to extend within the clefts between glandular components.

The pancreas can be divided into five components: the head, uncinate process, neck, body, and tail ( Fig. 12.1 ). The pancreatic head is defined as the portion to the right of the left border of the superior mesenteric vein (SMV). The pancreatic head is bounded on the right by the descending portion of the duodenum and inferiorly by the horizontal portion of the duodenum. To the left of the pancreatic head is a narrow projection called the uncinate process, which lies posterior to the SMV. The neck is a narrow segment that joins the pancreatic head to the body. The body is located between the left border of the SMV and the left aortic margin. The pancreatic body is located posterior to the stomach. The tail extends from the left border of the body laterally into the splenic hilum.

Vascular structures also provide important anatomical boundaries to localize the extent of disease. The gastroduodenal artery (GDA), originating from the common hepatic artery (CHA), forms the right lateral and anterior boundary of the pancreatic head. The inferior pancreaticoduodenal artery courses along the posterior border of the pancreatic head, and the SMV, as described previously, is an important landmark. Knowledge of the vascular supply is important because it also provides a pathway for spread of tumor.

The pancreas receives its arterial supply from the GDA from above and the inferior pancreaticoduodenal artery from below. These supply the anterior and posterior pancreaticoduodenal arcades to supply the pancreatic head and the uncinate process. Branches of the dorsal pancreatic artery, which typically arises from the celiac trunk, also provide supply to the pancreatic head and anastomoses with the pancreaticoduodenal arcade and small vascular branches from the GDA and CHA. The pancreatic body is supplied by branches of the dorsal pancreatic artery and the great pancreatic artery, which in turn arises from the splenic artery. Multiple splenic artery branches provide supply to the pancreatic tail.

The venous drainage is via branches that drain into the SMV and splenic veins. These then join to form the portal vein (PV) at the splenoportal confluence posterior to the pancreatic neck. The splenic vein runs along the posterior pancreatic body, and this proximity leads to its frequent occlusion secondary to pancreatic cancer or pancreatitis.

Both sympathetic and parasympathetic innervations of the pancreas are present. The sympathetic supply controls pancreatic blood flow, and the parasympathetic innervations, originating from the posterior vagus nerve and celiac plexus, promote pancreatic secretions. Both the parasympathetic and the sympathetic tracts contain nerve fibers that transmit pain. These nerve fibers provide a means for tumor spread, and their involvement results in debilitating pain. Extrapancreatic neural invasion by PDAC can occur along any of the following four pathways: the plexuses pancreaticus capitalis 1 and 2, anterior pathway along the GDA plexus and CHA plexus, and root of the mesentery pathway.

Histologically, the pancreas is composed of both exocrine and endocrine cell types. The exocrine component consists of acinar and ductal cells responsible for a variety of digestive enzymes and bicarbonate that are ultimately emptied into the duodenum at the ampulla of Vater to facilitate digestion. The endocrine cellular types include alpha cells (that produce glucagon), beta cells (that produce insulin), delta cells (that produce somatostatin), and PP cells (that produce pancreatic polypeptides).

PDAC represents an invasive epithelial tumor type that, at least focally, shows sites of ductal or glandular differentiation. Typically, it induces an intense desmoplastic reaction made up of a variety of cellular types, including myofibroblasts, inflammatory cells such as lymphocytes and plasma cells, and dense collagen. Tumor cells, in the well-differentiated type, form well-defined glands with mild pleomorphism. Moderately differentiated forms exhibit poorly defined glands, whereas poorly differentiated forms do not show well-defined glands. The poorly defined forms grow as individual cells or in sheets and with extensive nuclear pleomorphism. Growth tends to be haphazard, and most forms show vascular invasion and lymphatic, as well as perineural, invasion. On gross examination, these tumors form firm but poorly defined masses that are white to yellow in color. They are typically of variable size, and vary from poorly seen small forms to large forms with central regions that can be necrotic, show cystic change, or manifest mucinous features.

Clinical Presentation

Because the pancreas is located deep within the retroperitoneum, clinical symptoms typically manifest when the tumor has involved local vessels, caused perineural infiltration, or caused biliary obstruction. Accordingly, patients present with jaundice, weight loss, and/or abdominal pain. Symptomatology depends on tumor location and extent of metastatic disease. Tumors in the pancreatic head, neck, and sometimes body often obstruct the common bile duct and cause jaundice. Pancreatic tail tumors often cause left-sided abdominal pain, whereas those in the pancreatic body often manifest with midepigastric pain. Other symptoms include fatigue, new-onset diabetes, and steatorrhea related to pancreatic insufficiency. Physicians should have a high suspicion for PDAC when patients without discernible risk factors present with pancreatitis.

Unfortunately, such nonspecific symptoms often result in a delayed diagnosis, with a median time of 6 months between onset of symptoms and presentation. Uncommon symptoms include nausea and vomiting secondary to gastric outlet obstruction and increasing abdominal distention secondary to accumulation of ascites. Unexplained progressive weight loss is a common symptom and can be related to jaundice, nausea, or catabolic syndrome. It can be seen in patients with resectable as well as advanced tumors. Patients with PDAC are prone to hypercoagulable state, and the initial presentation can be deep venous thrombosis, pulmonary embolism, or, less commonly, aseptic/marantic endocarditis.

Biliary obstruction typically causes elevated serum bilirubin levels and transaminases. Liver function tests can be significantly abnormal, with extensive liver metastases as well. Serum amylase may be normal, but when greater than 300 U/L, advanced disease is typically present. Often, serum glucose levels are mildly to moderately elevated.

A variety of tumor markers have been considered for screening PDAC, such as carcinoembryonic antigen, CA50, and cell adhesion molecule 17-1, but the most useful so far has been carbohydrate antigen (CA)19-9. Although CA19-9 is not specific for PDAC, it serves as a prognostic indicator in some patients. Besides in PDAC, CA19-9 can be elevated in various gastrointestinal tumors, including stomach, colon, and biliary tree tumors, and is often elevated in the setting of biliary obstruction alone.

Classification

Accurate tumor staging is vital to stratify patients correctly to the most appropriate treatment. It is important to balance the need to perform potentially curative surgery on the small percentage of patients who may benefit, at the cost of remaining months of fair to good quality of life, with postoperative morbidity in patients who undergo surgery without potential benefit because of locally advanced or metastatic disease. When patients presenting with all stages were pooled, it was found that the 5-year survival rate overall was only 8%. Importantly, patients who show negative resection margins (R0 resection) have significantly better overall survival than those with positive resection margins (R1 or R2 resections).

The staging system most extensively used is from the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer ( Table 12.1 ). This system evaluates the primary tumor (T), the presence or absence of nodal disease (N), and the presence or absence of metastatic disease (M), to come up with TNM grades that are, in turn, used to determine staging. For the 8th edition, staging of exocrine and endocrine pancreatic cancer is separated.

Primary Tumor (T)

As shown in Table 12.1 and Fig. 12.2 , T staging is based on tumor size, tumor confinement within the pancreas, and involvement of major local arterial structures (celiac artery, SMA, and CHA). Tumors that are 2 cm or less in size are identified as T1. T2 is identified if the tumor measures between 2.1 cm and 4 cm in its greatest dimension. Tumors that are more than 4 cm in greatest dimension are identified as T3. When the extension is such that it involves the celiac axis, SMA and/or CHA, it is identified as T4.

Nodal Disease (N)

The N descriptor in TNM staging refers to regional nodal disease ( Fig. 12.3 ). This criterion is very difficult to assess preoperatively and is further described under “Imaging.” It commonly indicates pathologic staging and therefore requires an adequate lymphadenectomy. Typically, the histologic evaluation should include no less than 10 regional nodes located in the celiac, CHA, gastric (pyloric), and splenic regions. Although N stage is more specialized, no significant differences were found in the median overall survival between pN1 and pN2 stages (18.1 vs. 16.9 months).