**4. Clinical features**

#### **4.1. History**

Current pancreatic cancer models are similar to that of colon cancer, in which there is a progression from precancerous lesions to invasive carcinomas. Pancreatic cancer evolves from normal ductal epithelium, to pancreatic intraepithelial neoplasms/ductal lesions, to invasive adenocarcinomas [27;28]. The ductal epithelium undergoes changes that are characterized by PanIN-1A. Changes continue to accumulate and lead to PanIN-3, which denotes carcinoma *in situ* (Figure 4). This evolution is associated with the acquisition of a large number of genetic alterations that function through a small number of signaling processes and pathways. The stepwise acquisition of genetic abnormalities leading up to invasive ductal adenocarcinoma is now well characterized and includes mutations in *KRAS2*, inactivation of *p16*, *p53*, *PDX1*,

**Figure 4.** Progression of normal epithelium to pancreatic cancer and genes involved in the pathogenesis of sporadic

Comprehensive genetic analysis of pancreatic cancer specimens demonstrated that the most frequent genetic abnormality in invasive pancreatic adenocarcinomas is activation of KRAS2 oncogene, which was present in more than 90% of pancreatic cancers [28]. *KRAS2* mutations are thought to be acquired early in the development of pancreatic cancer as they are found in a large number of ductal lesions and become more prevalent as these lesions progress to invasive adenocarcinoma [27]. In addition to *KRAS2* mutations, several other pathways in cellular signaling have been found to be altered in 67-100% of the tumors. These pathways include: TGF β, JNK, Integrin, Wnt/Notch, Hedgehog, control of G1/S phase transition, apoptosis, DNA damage control, small GTPase, invasion, and homophilic cell adhesion [30].

Histologically, poorly formed glands are present in a dense fibrotic background within the pancreatic parenchyma and sprinkled inflammatory cells. Some of the tumor cells might show some mucin production. Perineural invasion is often seen and can help with the diagnosis in well-differentiated tumors. Other features of malignancy include nuclear pleomorphism,

**Figure 5.** H&E stains of normal and adjacent ductal adenocarcinoma 40X (panel A). Panel B demonstrates invasive ad‐

occasional large nuclei and multiple large nucleoli (Figure 5).

enocarcinoma (100X). Perineural invasion is demonstrated in panel C.

and *SMAD4* [29].

228 Updates on Cancer Treatment

pancreatic cancer.

Currently there are no established screening tests for pancreatic cancer. The vague and nonspecific symptoms in pancreatic cancer contribute to its delay in diagnosis. The location of the tumor within the pancreas dictates some historical features and clinical presentation. The stage of the disease is also important. Because most pancreatic tumors are located in the head of the pancreas and present at an advanced stage, clinical findings suspicious for pancreatic cancer must be rapidly addressed to exclude this lethal diagnosis.

Patients with lesions of the head of the pancreas present with painless jaundice and weight loss, which might be accompanied with anorexia and weakness [31]. The frequency of presenting symptoms in 1175 patients with adenocarcinoma of the pancreas was: 2/3 painless jaundice, ½ weight loss, and about 1/3 abdominal pain [32]. Obstructive cholestasis might lead to dark urine, light stools and pruritus. Distention of the pancreatic capsule causes vague epigastric and/or back pain that poorly localizes to the location of the tumor. Obstruction of the pancreatic duct or perineural invasion also causes pain, but this is less specific and poorly localized. Ten percent of patients have symptoms attributed to cholelithiasis and will have undergone recent cholecystectomy prior to the diagnosis of pancreatic cancer. Similarly, obstruction of the pancreatic duct might lead to acute pancreatitis [13, 33]. Uncommonly, large tumors might present with symptoms of duodenal obstruction such as nausea and vomiting or symptoms associated with a gastrointestinal bleed [31].

Systemic manifestations are more usual in patients with lesions of the body and tail of the pancreas such as weight loss and anorexia [31]. Constant pain is attributed to tumor invasion of the celiac and mesenteric plexuses and occurs with advanced disease. Eight weeks is a typical mean duration of symptoms. New-onset diabetes mellitus may be an initial presenting symptom in patients with pancreatic cancer and glucose intolerance occurs in 15%-20% of these patients. Depression, increased abdominal girth, and a history of panniculitis are rare, but might accompany a diagnosis of pancreatic cancer [31, 34].

#### **4.2. Physical examination**

The physical examination for patients with pancreatic cancer is unyielding. Since two-thirds of pancreatic adenocarcinomas occur in the head of the pancreas, the most common presenting physical finding is evidence of obstructive cholestasis. Painless jaundice in an older patient has been attributed a hallmark of physical findings necessitating careful exclusion of pancreatic cancer. The examiner must investigate for signs of weight loss such as temporal wasting as well as careful interrogation of lymph node basins [31].

Hepatomegaly, ascites or a palpable gallbladder (Courvoisier's sign/law) may be present in some patients with advanced pancreatic cancer. Courvoisier's sign is more likely to be present in patients with pancreatic cancer compared to calculi disease [35]. Physical findings in patients with disseminated disease include supraclavicular lymphadenopathy (Virchow's node). However, pancreatic cancer usually does not metastasize to the supraclavicular nodes and only a few cases have been reported [36]. Cutaneous metastasis in the periumbilical area (Sister Mary Joseph's nodule) [37] and peritoneal seeding (Blumer's shelf) are also rarely found with pancreatic metastatic disease. Migratory thrombophlebitis (Trousseau's sign), which is evidence of intravascular thrombosis, may occur in patients with advanced pancreatic cancer as well as other advanced cancers resulting from a hypercoagulable state from malignant disease [38].

#### **5. Staging**

The AJCC staging system, based on the TNM stage, is most often used staging system for pancreatic cancer. The tumor stage describes the size of the primary tumor, vascular structure involvement and any direct extension of the tumor outside of the pancreas. The nodal stage assesses the presence or absence of any regional lymph node involvement. The metastasis stage describes the presence or absence of any distant disease (Table 1).


**Table 1.** TNM staging system for pancreatic cancer

Common sites of metastatic disease often include the liver, peritoneal cavity, and lungs [39]. The anatomic staging roughly correlates with whether or not the tumor is resectable. Those tumors with Stage IA to IIB are considered resectable. Tumors designated as Stage IV are unresectable and those designated as stage III can be borderline resectable or unresectable. The NCCN classification system which divides tumors into resectable, borderline resectable or unresectable categories may be more applicable clinically [40].
