MINI-REVIEW Pancreatic Cancer: Pathogenesis and Diagnosis

Pancreatic cancer is a fatal malignancies which is predominantly seen in men and at advanced age (40-85 years) and has an aggressive course. Its frequency is gradually increasing over the past years. It accounts for 2% of all cancers and 5% of cancer-related deaths. Pancreatic cancer takes the first place among asymptomatic cancers. Ninety percent of cases are adenocarcinomas. Ten percent of the patients have a familial disposition. The disease is very difficult to detect as it has no early signs and spreads rapidly to surrounding organs is one of the most deadly types of cancer. Pancreatic cancer may result from hereditary germline or somatic acquired mutations in cancer-related genes and mutations also cause cancer progression and metastasis.


Introduction
Pancreas is an important retroperitoneal organ with exocrine and endocrine functions. Tumors of pancreas are divided into two groups (Wolfgang et al., 2013). 1) Non-endocrine pancreas tumors 2) Endocrine pancreas tumors. Non-endocrine pancreas tumors are categorized as benignant and malignant. Benignant non-endocrine tumors of the pancreases: adenoma, cystadenoma, lipoma, fibroma, hemangioma, lymphangioma and neuroma. Malignant tumors of the pancreases have different histological features i.e. 1) Ductal adenocarcinoma 2) Cystadenocarcinoma and 3) Other (sarcomas, metastatic etc) malignant tumors. Diabetes Mellitus (DM) with an onset after 45 years of age may sometimes foresee pancreatic cancer. Pancreatic cancer may sometimes manifest as acute pancreatitis. Today, there are opinions that pancreatic cancer originates from a genetic disposition (stem cell disease) (Hezelet al., 2006;Jamiesen et al., 2012;Avila et al., 2013;Fang et al., 2013;Gnoni et al., 2013;Wood et al., 2013). Presence of some colonic polyp types or cancer in the family or personal history increases the likelihood of pancreas cancer.

Pancreatic Cancer: Pathogenesis and Diagnosis
Vedat Goral pancreatic cancers in smokers compared to pancreatic cancers in non-smokers. Long-term DM is associated with increased pancreatic cancer. In addition, new-onset DM may be the initial sign of pancreatic cancer. Increased body mass index (BMI) is associated with increased pancreatic cancer. Higher alcohol consumption is associated with increased pancreatic cancer compared to lower alcohol intake. Low to moderate alcohol consumption does not increase the risk. Chronic pancreatitis increases the risk of pancreatic cancer by 2.71 fold compared to people without chronic pancreatitis.

Hereditary Risk Factors
Individuals with familial history of pancreatic cancer are at an increased risk of cancer. Several germline genetic mutations are involved in pancreatic cancer development (Table 2). In the BRCA2 mutation, pancreatic cancer, breast, ovarian, prostate cancer risk is increased. Hereditary pancreatitis, Lynch syndrome and Peutz-Jeghers syndrome is associated with increased pancreatic cancer risk (Wolfgang et al., 2013).

Screening groups
Patient groups with conditions including hereditary pancreatitis, familial pancreatic cancer, Peutz-Jeghers disease, familial atypical mole melanoma, cystic fibrosis of pancreas, familial cancer syndromes [(Lynch syndrome, familial adenomatous polyposis (FAP), hereditary breast and ovarian cancer-BRCA1 and BRCA2 mutations)] are at an increased risk of pancreatic cancer and should therefore be screened for pancreatic cancer using specific methods (Lee et al., 2009).

Causes of Pancreatic Cancer
Pancreatic cancer results from hereditary germline or somatic acquired mutations in cancer-related genes (oncogenes, tumor suppressor genes, cell cycle genes, apoptosis and genome maintenance genes), and mutations also case cancer progression and metastasis (Hezelet al., 2006;Jamiesen et al., 2012;Avila et al., 2013;Fang et al., 2013;Gnoni et al., 2013;Wood et al., 2013). In addition, cell turnover, shortened telomerase and genomic instability have significant roles in progression of pancreatic epithelial cells to pancreatic cancer ( Figure 1).
2) IPMN: It is usually small and asymptomatic. It progresses slowly and is more common among smokers (Gnoni et al., 2013). It may be together with Peutz-Jeghers syndrome, FAP, familial pancreatic carcinoma (FPC). It has 2 subtypes: 1) IPMN-MD (main duct type) and 2) IPMN-BD (branch duct type). It accounts for 1-2% of all pancreatic exocrine tumors and 20-50% of all cystic tumors. Its actual incidence is not known as it is small and asymptomatic. It develops from the main pancreatic duct or branch ducts and releases mucin. In 2010, WHO classified IPMNs by malignant transformation properties as low, intermediate, high grade dysplasia and by invasive cancer characteristics. They can be differentiated by mucin antibody staining properties using immunohistochemical dyes in 4 subgroups as gastric, intestinal, pancreatobiliary and oncocytic. The intestinal type is the most common one. It is usually seen at the head of the pancreas, around the ampulla of Vater, at the inlet of the pancreatic duct.  Genes involved in IPMN are listed in Table 3. Main duct type IPMN is treated surgically. For IPMN from branch ducts, yearly or 6-12-monthly checks are performed if the tumor is <10 or 10-20 mm respectively, while mm whereas >20 mm tumors are resected surgically.
3) MCN: It is generally solitary and may vary between 5 and 35 cm in size. It has thick/fibrotic wall and may contain mucin, hemorrhagic fluid pr necrotic material. It is rare, has a female to male ratio of 20:1 and the median age of onset is around 40-50 years. Its diagnosis is usually incidental and it is asymptomatic. Nausea, weight loss and back pain can be seen. It is usually located at the head and tail. Microscopically, it is divided into 3 groups by dysplasia severity as a) mild MCN b) moderate MCN and c) severe MCN. Macroscopically, it is divided into 3 groups as solitary, multilocular and unilocular. Genes responsible in MCN are listed in Table 3. They usually grow slowly, may cause epigastric discomfort and distension and are incidentally detected during abdominal mass screening. Nausea, vomiting and back pain may occur. If malignant changes occur, lack of appetite and weight loss may be seen. Five-year survival is about 20-60% in invasive MCN (Gnoni et al., 2013).

Oncogenes
Oncogenes are involved in cancer development when they are mutated and activated. They are activated by different mechanisms (point mutation, amplification). Increasing numbers of oncogenes responsible for pancreatic cancer have been identified recently (Hezelet al., 2006;Avila et al., 2013;Fang et al., 2013;Gnoni et al., 2013;Wood et al., 2013). Genetic alternations, germline and somatic mutations were held responsible in pancreatic cancer. Sixteen mutated oncogenes have been identified in this disease, including KRAS, TP53, CDKNA2A, SMAD4, MLL3, TGFBR2, ARID1A, SF3B1, EPC1, ARID2, ATM, ZIM2, MAP2K4, NALCN, SLC16A4, MAGEA6. Mutation in oncogene KRAS is most frequently at codon 12 and was found in 90% of pancreatic cancer cells and 20% of whole body cancer cells. KRAS oncogene adversely affects cell life and cellular functions such as cell differentiation and cell proliferation.
KRAS mutation occurs in codon 12 but sometimes in codon 61 or 13. KRAS mutation induces formation of ductal precancerous formations and causes multifocal hyperplastic focus at the pancreatic duct. These are precancerous formations. KRAS also activates many signaling pathways. P13K-AKT pathway is activated (affects cell life and cell circulation). It activates MEK and ERK1/2 pathway (affects angiogenesis, cell proliferation, cell apoptosis, cancerous cell migration and cell cycle regulation). It also activates NOTCH pathway (affects cell proliferation, cell differentiation and cell apoptosis). It affects Hedgehog pathway (causes metastases). STAT3 activation is also observed in patients with pancreatic cancer (STAT3 inhibitors are used in cancer treatment).
MiRNA micRNAs are small uncoded RNA molecules and regulate gene expressions. miRNAs are about 1000 and are involved in pancreatic tumor development and have oncogenic functions.  have important roles in the development of pancreatic cancer ( Jamiesen et al., 2012).

Tumor suppressor genes
Tumor suppressor genes (TSG) protect cell cycle or cell apoptosis from tumorogenesis. p53 mutation is seen in 75% of pancreatic cancer cases. DPC4 (deleted in pancreatic cancer, locus 4), LKB1 (liver kinase B1) mutation, deletion and mutation in INK4a are found in 95% of the cases. MKK4 (mitogene activated protein kinase 4) deletion are seen in patients with pancreas cancer. DPC4 causes distant metastases in pancreatic cancer. LKB1 gene mutation causes Peutz-Jeghers syndrome and therefore pancreas cancer.

Symptoms
Approximately 70-80% of the patients with pancreatic cancer has pain in the epigastrium. The pain is in the stomach area and may sometimes radiate to sides and back. Sitting still or bending forward alleviates the pain. Jaundice, findings of cholestasis, lack of appetite, unexplained weight loss, depression and sometimes diarrhea/steatorrhea are seen. In cancers at the head of the pancreas, a progressive and dark jaundice is seen due to the obstruction of the bile duct. The physician should consider the possibility of pancreas cancer especially in the presence of permanent-persistent pain around the abdomen, navel and stomach, indigestion, swelling, weight loss and lack of appetite. Gallbladder will be palpable as vesicle hydrops (Courvoisier-Terrier findings) if the bile ducts are constricted by the tumor.

ERCP
It is performed to diagnose cancer in the head of the pancreas, for biopsy and stent insertion (Figure 4). It allows biopsy from ampulla of Vater tumors. If cholestasis has developed at the pancreas head, plastic or metallic stent needs to be inserted into the choledoch (Lee et al., 2009;Kaur et al., 2012;Ozkan et al., 2012). During ERCP, pancreatic fluid can be taken and CEA, IGFBP2 (Insülin-like growth factor binding protein-2), MMP-9, DJ-1, AIBG etc. can be investigated.

MRCP
It should be performed before ERCP, and information about bile ducts and pancreatic ducts should have been collected (Lee et al., 2009).

Abdominal MR and Abdominal CT
They are helpful in detecting pancreatic cancer, determining its location and metastases.

PET
It provides information regarding the diagnosis, differential diagnosis of pancreatic cancer and extrapancreatic involvement (Lee et al., 2009). By performing pancreaticoscopy, endoscopic investigation of the interior pancreatic duct is performed (Ozkan et al., 1995).With intraductal ultrasonography ( Figure 5) and EUS (Figure 6), information are obtained on the location of the tumor and peripancreatic invasion (Cote et al., 2013;Munroe et al., 2013).

Conclusions
In conclusion, pancreatic cancer is a fatal malignant disease. Pancreatic cancer results from hereditary germline or somatic acquired mutations in cancer-related genes and mutations also case cancer progression and metastasis. In addition, cell turnover, shortened telomerase and genomic instability have significant roles in progression of pancreatic epithelial cells to pancreatic cancer. We need much more studies and research about this disease.