**2. Epidemiology**

Cancer of the exocrine pancreas was diagnosed in 45,220 patients in the United States in 2013. Underscoring its fatal nature, during the same year, 85% of patients (38,460) died from this disease [2]. Thus, despite only comprising 3% of all new cancer diagnoses, pancreatic cancer accounted for 6-7% of all deaths related to cancer [2]. Over the past 10 years, the similar incidence and the death rates emphasize that most pancreatic cancers are fatal as a result of late stage at diagnosis (Figure 1) [2-12]. Although, the gap between the yearly incidence and mortality of pancreatic cancer has slightly widened over the past ten years, most patients diagnosed with cancer will succumb to this deadly disease (Figure 2).

The average age at diagnosis is 60 to 65 years. The etiology of pancreatic cancer is not known, but several risk factors have been identified. For instance, men have a slightly higher incidence compared to women (Relative Risk [RR] 1.35) and Black men have a 30-40% higher rate in incidence compared to White men [13]. Cigarette smoking is the best well-recognized envi‐ ronmental risk factor for the development of pancreatic cancer. Current smokers have a RR of

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#### Incidence and Mortality of Pancreatic Adenocarcinoma in the United States

**Figure 1.** Incidence of Adenocarcinoma of the pancreas in the United States over the past ten years.

**Figure 2.** The incidence divided by the mortality in the Unites States over the past.

up to 3.6 compared to non-smokers and smoking is estimated to contribute to 25% as an etiology of pancreatic cancer [14;15]. Other risk factors for pancreatic cancer include: diabetes, obesity, Helicobacter *pylori* infection, non-O blood group and chronic pancreatitis [16-20].

Most forms of pancreatic cancer are sporadic. However, familial pancreatic cancer accounts for 5-10% of all pancreatic cancers [21]. Data from the National Familial Tumor Registry demonstrates that the risk of pancreatic cancer of the pancreas is 18-fold higher if two firstdegree relatives are involved and 57-fold higher if three first-degree family members are affected [22]. This risk is conferred by an increased risk in several recognized genetic syn‐ dromes caused by germline mutations leading to familial syndromes. For instance Peutz-Jeghers Syndrome results from a germline mutation of the *STK11* gene. Affected individuals have a 132-fold increased risk for pancreatic cancer [23]. Familial Atypical Mole Multiple 39

Melanoma Syndrome patients with a germline mutation of the *CDKN2A* gene have a 46-fold increased risk for the development of pancreatic cancer. Individuals with mutations of the *PRSS1* gene have an increase in trypsin activity, which in turn causes chronic inflammation of the pancreas. These patients suffer from hereditary pancreatitis and have a 50-fold increase risk of pancreatic cancer [23]. Other genetic syndromes that confer a higher risk include cystic fibrosis (CTFR gene mutation), Fanconi Anemia, familial breast or ovarian cancer (BRCA2 gene mutations), familial adenomatous polyposis (*APC* gene mutations), Li-Fraumeni syndrome (*p53* gene mutation) and Lynch II syndrome (MLH1 gene mutation) [24].

## **3. Pathology**

up to 3.6 compared to non-smokers and smoking is estimated to contribute to 25% as an etiology of pancreatic cancer [14;15]. Other risk factors for pancreatic cancer include: diabetes, obesity, Helicobacter *pylori* infection, non-O blood group and chronic pancreatitis [16-20].

Incidence and Mortality of Pancreatic Adenocarcinoma in the United States

28000

**Figure 2.** 

2003

2004

**Figure 2.** The incidence divided by the mortality in the Unites States over the past.

2005

**Figure 1.** Incidence of Adenocarcinoma of the pancreas in the United States over the past ten years.

2006

2007

2008

2009

2010

2011

2012

2013

39

32000

36000

40000

44000

48000

226 Updates on Cancer Treatment

Incidence Mortality

Most forms of pancreatic cancer are sporadic. However, familial pancreatic cancer accounts for 5-10% of all pancreatic cancers [21]. Data from the National Familial Tumor Registry demonstrates that the risk of pancreatic cancer of the pancreas is 18-fold higher if two firstdegree relatives are involved and 57-fold higher if three first-degree family members are affected [22]. This risk is conferred by an increased risk in several recognized genetic syn‐ dromes caused by germline mutations leading to familial syndromes. For instance Peutz-Jeghers Syndrome results from a germline mutation of the *STK11* gene. Affected individuals have a 132-fold increased risk for pancreatic cancer [23]. Familial Atypical Mole Multiple Pancreatic ductal carcinomas arising from the exocrine pancreas is the most common type accounting for 95% of these tumors. Two- thirds of these tumors occur in the head of the pancreas and have an aggressive behavior [25]. The vast majority of malignancies of the pancreas are infiltrating ductal adenocarcinomas and the term pancreatic cancer generally refers to adeno‐ carcinoma of the pancreas. Pancreatic cancer can originate from each of the cell types that form the pancreas. For instance, neuroendocrine tumors arise from the pancreatic islet cells. Unlike ductal adenocarcinoma, many of the endocrine tumors are benign. Small subsets are endo‐ crine carcinomas and make up around 1% of pancreatic cancers. Pancreatic cystic neoplasms include a group of tumors having varying malignant potential. Uncommonly, extrapancreat‐ ic tumors can metastasize to the pancreas and have been reported from renal cell carcinoma, non-small cell lung cancer, sarcoma, melanoma, and bladder cancers (Figure 3) [26].

**Figure 3.** Incidence of malignancies of the pancreas.

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*, and *SMAD4* [29].

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

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

**Figure 5.** H&E stains of normal and adjacent ductal adenocarcinoma 40X (panel A). Panel B demonstrates invasive ad‐ enocarcinoma (100X). Perineural invasion is demonstrated in panel C.
