Clinical Presentation

The diagnosis of pancreatic cancer is typically a devastating experience for patients. These malignancies often arise silently, invade locally, and spread distantly prior to any clinical signs or symptoms. The symptoms that bring these tumors to clinical attention vary, based upon the location of the tumor within the pancreas and the stage at presentation. The majority of resectable pancreas cancers occur in the right side of the pancreas, in the head or uncinate process of the gland. Classic symptoms from these right-sided tumors include jaundice from biliary obstruction, often accompanied by pruritis, and epigastric pain radiating to the back from tumor involvement of the celiac plexus. Less commonly, persistent nausea or vomiting as a result of gastric outlet obstruction from tumor narrowing at the duodenal C-loop is the initial symptom. Additionally, pancreatitis in the absence of cholelithiasis or ethanol abuse should arouse suspicion for cancer in patients age 60 years or older. Tumors arising in the left side of the pancreas typically cause few symptoms until they are locally advanced or metastatic. For such left-sided tumors, pain is the most common presenting symptom, and jaundice is rare.

Nonspecific symptoms often occur in association with pancreatic cancer. Nausea, anorexia, weight loss, and fatigue are commonly reported and often are present for some time before diagnosis. Because of the generalized and quite common nature of these symptoms, they rarely lead directly to a diagnosis unless they become profound. Significant weight loss without gastric outlet obstruction is often indicative of advanced disease.

Typically, jaundice is the only physical finding in “early” stage pancreatic cancer. The classic physical findings of left supraclavicular adenopathy (Virchow node), periumbilical adenopathy (Sister Mary Joseph node), or a firm circumferential rim of tumor at the top of the rectum on digital rectal examination (Blumer shelf from drop metastases) are found only with advanced, disseminated disease. Less specific findings that also typically indicate advanced disease include temporal wasting, ascites, hepatomegaly from metastatic disease, or a palpable abdominal mass.

Laboratory analysis is of limited benefit in the diagnosis of pancreatic cancer. Elevated liver function tests are nonspecific and require imaging to investigate their etiology. It is not uncommon to have hyperbilirubinemia with marked increases in the alkaline phosphatase and γ-glutamyl transpeptidase (GGT), with mild elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). New-onset diabetes mellitus is often associated with pancreatic cancer. However, such new-onset diabetes has a low sensitivity and specificity for the diagnosis of pancreatic cancer, and significant overlap is found between the typical age of onset of diabetes mellitus and pancreatic cancer. The incidence of diabetes mellitus is also much greater than that of pancreatic cancer, further limiting its utility as a diagnostic sign.

Ongoing research has produced a multitude of potential biomarkers for pancreatic cancer (Harsha et al, 2009). The only biomarker that has recognized clinical utility is carbohydrate antigen 19-9 (CA19-9); however, its usefulness has two significant limitations. First, it is not specific for pancreatic cancer because it can be elevated in benign conditions, particularly those that cause obstructive jaundice. Second, its sensitivity is reduced by the fact that patients who test negative for Lewis blood group antigens A and B are unable to synthesize CA19-9 and therefore do not express it in their serum. The percentage of pancreatic cancer patients who fall into this group has been reported to range from 10% to 34% (Berger et al, 2008; Tempero et al, 1987). Thus CA19-9 best serves as a marker of treatment response and recurrence in patients who have a pathologic diagnosis of pancreatic cancer.

Diagnosis

Once suspicion is sufficient for pancreatic cancer, high-quality imaging is critical for diagnosis and treatment planning. Many patients initially undergo an abdominal ultrasound (US) or a limited computed tomography (CT) scan of the abdomen. These modalities will suggest processes in the pancreas that require appropriate evaluation. Currently, the best diagnostic modality for imaging the pancreas is a pancreas protocol multidetector CT with dedicated arterial and venous phases and three-dimensional (3D) reconstruction (see Chapter 16; Buchs et al, 2010; Horton & Fishman, 2002). Water is given orally, and contrast is given intravenously. Such scans typically demonstrate the tumor as a low-density (hypodense) lesion within the pancreas, best seen during the venous phase of contrast enhancement. Importantly, these high-quality imaging studies show the important relationship between the tumor and the surrounding visceral vessels, including the superior mesenteric vein, portal vein, splenic vein, superior mesenteric artery (SMA), and the branches of the celiac axis. Such high-quality CT imaging can reliably predict visceral vessel involvement, and thereby surgical respectability, approximately 80% to 90% of the time (House et al, 2004; Karmazanovsky et al, 2005). Additionally, the arterial phase with 3D reconstruction can assist in surgical planning by identifying variations in hepatic arterial anatomy and other vascular anomalies preoperatively, most notably a “replaced” right hepatic artery originating from the SMA, which is seen in one of six patients (see Chapter 1B).

Continuing improvement in the technology that produces magnetic resonance imaging (MRI) has resulted in image quality and resultant diagnostic sensitivities that approach those of CT (see Chapter 17). A recent meta-analysis of 68 articles calculated an overall diagnostic sensitivity of 91% for CT, compared with 84% for MRI, and reported diagnostic specificities of 85% and 82%, respectively (Bipat et al, 2005). Regarding determination of resectability, CT had a sensitivity and specificity of 81% and 82% compared with MRI at 82% and 78%, respectively. No advantage has been demonstrated by obtaining both CT and MRI for uncomplicated patients who display classic symptoms of pancreatic cancer, and this practice should be discouraged. We typically reserve the use of MRI for patients with renal impairment or sensitivity to the intravenous contrast used for CT. The use of MR cholangiopancreatography (MRCP) is valuable in evaluating and following small cystic lesions of the pancreas, but a detailed discussion of these lesions is outside the scope of this chapter (see Chapters 17 and 57).

Endoscopic evaluation of patients with classic symptoms of pancreatic cancer is appropriate in specific situations. Esophagogastroduodenoscopy (EGD) is appropriate in cases of gastric outlet obstruction to assess the anatomy and presence of other diagnoses. In the presence of metastatic or unresectable disease, or when a patient is not physiologically appropriate for immediate surgical intervention, a therapeutic EGD combined with duodenal stenting can be of some benefit, allowing the patient to return to oral intake (see Chapter 27). Endoscopic retrograde cholangiopancreatography (ERCP) was once commonly used as a diagnostic modality for patients with a suspected periampullary pancreatic cancer. With the improvement of cross-sectional imaging, the use of strictly diagnostic ERCP is currently unsupported. Therapeutic ERCP with stenting of biliary strictures can be of benefit in the same patient population (metastatic, unresectable, or physiologically unfit) as therapeutic EGD (see Chapters 14, 18, and 27). However, the routine placement of a biliary endoprosthesis for all patients seen with jaundice without cholangitis should be discouraged. Multiple studies have shown a doubling of the wound infection risk and a slight increase in overall complication risk with preoperative biliary stenting (Pisters et al, 2001a; Sohn et al, 2000). For most patients seen initially with a pancreatic mass and jaundice, early surgery is preferable to endoscopic stenting and delayed surgical resection (Kennedy et al, 2010).

Endoscopic ultrasound (EUS) is a relatively new imaging and diagnostic technology compared with those previously discussed (see Chapter 14). Well established at specialty referral centers, it is rapidly becoming more widely available. Interpretation of EUS imaging is operator dependent, a factor that may account for the wide range of diagnostic sensitivities reported in the literature and encountered in real-world clinical settings (Ahmad et al, 2000; Gress et al, 1999; Hunt & Faigel, 2002; Palazzo et al, 1993; Rösch et al, 1991; Varadarajulu & Eloubeidi, 2010). Reported sensitivities for the diagnosis of pancreatic neoplasia have ranged from 69% to 94%. Several studies have found EUS to be superior to CT for the detection of lesions smaller than 2 cm. EUS is of particular utility when a patient has a presentation consistent with pancreatic cancer (biliary or pancreatic duct obstruction) but no evidence of mass on cross-sectional imaging. The ability of EUS to accurately estimate T-stage decreases compared with CT for larger lesions. Additionally, EUS has shown some superiority over CT for the detection of venous invasion, but it is less useful for the determination of arterial involvement (Varadarajulu & Eloubeidi, 2010). An important additional advantage of EUS is the ability to obtain tissue via fine needle aspiration (FNA) for diagnostic purposes at the time of evaluation. This can be of great benefit to unresectable or marginally resectable patients who need a confirmed tissue diagnosis prior to the initiation of chemotherapy. However, for the vast majority of patients with a symptomatic pancreatic mass that appears completely resectable by CT or MR imaging, EUS with FNA is not needed; in most cases the mass will require resection regardless of the EUS and FNA results.

¹⁸Fluorodeoxyglucose-positron emission tomography (¹⁸FDG-PET) is a functional imaging modality based on the observation that neoplastic cells exhibit accelerated glucose uptake and metabolism (see Chapter 15). Once transported into the cell and phosphorylated by hexokinase, the first step in glycolysis, ¹⁸FDG remains trapped within the cell. Although studies suggest ¹⁸FDG-PET is sensitive for the detection of pancreatic cancer, the precise role of this technique in the diagnosis and staging of patients with localized pancreatic cancer is limited. Its use is confounded by the difficulty ¹⁸FDG-PET has in distinguishing benign from malignant masses as a result of localization, both to sites of inflammation and infection and to neoplasms. ¹⁸FDG-PET is of greater utility in evaluating indeterminate masses in the liver that are not amenable to biopsy. A tissue diagnosis of a primary mass made by EUS, when combined with a PET-positive liver lesion, is adequate to initiate palliative chemotherapy at many centers.

Diagnostic Biopsy

As mentioned above, in low-risk patients with resectable lesions suspicious for periampullary cancer, a tissue diagnosis is not required prior to surgical resection, because a negative or inconclusive biopsy result will not affect the decision to operate. Pancreatic biopsy should be reserved for patients with locally unresectable or metastatic disease or for those clinical situations in which a true diagnostic or management dilemma is present. Such situations would include patients with a history of other cancers that have a realistic chance of having a metastasis to the periampullary region (renal cell cancer, melanoma) or patients with marginal physiologic reserves at prohibitive risk for surgical intervention.

Whenever possible, biopsy of a pancreatic lesion should be performed endoscopically with EUS-FNA. Percutaneous US- or CT-guided pancreatic biopsy should be discouraged, and patients should be referred to centers where EUS-FNA is available. Percutaneous biopsy should be reserved for evaluation of suspected metastatic lesions, typically liver metastases. In the presence of suspected metastatic disease, biopsy of the distant lesion if accessible is preferred over biopsy of the primary pancreatic lesion.

Staging

Pancreatic cancer is staged by the seventh edition (2010) of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, according to clinical parameters that are available from high-quality CT imaging (Edge, 2010). Classic T, N, and M parameters are used for tumor size, nodal involvement, and distant metastases, but stage grouping is performed according to resectability. Patients are classified as having localized resectable disease (stages I and II), locally advanced unresectable disease (stage III), or distant metastatic disease (stage IV; Table 58B.1). A resectable tumor is characterized on CT by no evidence of metastatic disease, a clear tissue (fat) plane between the tumor and the visceral arteries (celiac axis and SMA), and 180-degree or less circumferential involvement of the superior mesenteric vein–portal vein confluence (Fig. 58B.1). In contrast, patients with unresectable disease exhibit distant metastases, ascites, or involvement of the celiac axis or SMA (Fig. 58B.2). Venous vascular involvement is considered potentially resectable in the AJCC system and is therefore categorized as stage II disease, and arterial involvement is considered unresectable and is categorized as stage III disease. A small subset of patients with complete occlusion of the superior mesenteric vein–portal vein confluence and significant collateralization that precludes safe venous resection and reconstruction are typically deemed unresectable but are still classified as stage II in the current AJCC system. This system has been validated by correlation to overall survival (OS) using the National Cancer Database (Table 58B.2; Bilimoria et al, 2007a).

FIGURE 58B.1 Resectable pancreatic adenocarcinoma in the head and uncinate process, showing well-preserved fat plane (arrow) between tumor (T) and superior mesenteric artery (A).

FIGURE 58B.2 Unresectable pancreatic adenocarcinoma in the head and uncinate process, showing loss of fat plane (arrow

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