Pancreatic cancer overview

# Overview
Pancreatic cancer is a malignant tumour within the pancreatic gland. In 1679, Morgagni was the first to recognize cancer of the pancreas and described the pancreas of one of his patients as a dry white pancreas of a scirrhous nature with pretty hard distinct lobules. Pancreatic cancers can be classified based on the production of hormones into exocrine and endocrine cancers. About 95 percent of pancreatic tumors are adenocarcinomas, which are exocrine tumors. The remaining 5 percent include other tumors of the exocrine pancreas (e.g. serous cystadenomas), acinar cell cancers, and pancreatic neuroendocrine tumors (such as insulinomas). These tumors have a completely different diagnostic and therapeutic profile, and generally a more favorable prognosis.  The progression and development of pancreatic cancer is influenced by complex interactions and crosstalk between several cellular signaling pathways that include inactivation of tumor suppressor genes, activation of oncogenes and deregulation of molecules in various signaling pathways. Pancreatic cancer must be differentiated from other pancreatic pathologies such as chronic pancreatitis, autoimmune pancreatitis, pancreatic pseudocyst, choledocholithiasis, and neuroendocrine tumors of the pancreas. Pathologies of the bile duct and duodenum such as choledocholithiasis, gallstones (cholelithiasis), choledochal cysts, cholangiocarcinoma, bile duct strictures and ampullary cancer should be differentiated from pancreatic cancer based on imaging and biopsy findings. The most potent risk factors for pancreatic cancer include smoking, alcoholism, increased BMI, diabetes mellitus, chronic pancreatitis and a family history of pancreatic cancer. The most common symptoms of pancreatic cancer include mid-epigastric pain, jaundice, sudden unexplained weight loss and dark urine and light-colored or greasy stools. CT scan is the preferred diagnostic modality and findings that may be suggestive of pancreatic cancer include morphological changes of the gland, destruction of the peripancreatic fat and loss of the sharp margins with surrounding structures, involvement of the regional lymph nodes and adjacent vasculature, pancreatic ductal dilatation, pancreatic atrophy and obstruction of the common bile duct. In patients with pancreatic cancer, surgery is the primary modality of treatment. Extrapancreatic disease, in contrast, requires palliative therapy and curative resection is not performed in such patients.

# Historical prospective
Herophilus of Chalcedon (circa 300 B.C.), the father of scientific anatomy, was the first to describe the pancreas but he had no conception of its function. Rufus of Ephesus (circa 100 A.D)  coined the term pancreas (from the Greek words pan which means all and kreas which means flesh). It literally means all flesh due to its homogeneous composition. In 1679, Morgagni was the first to recognize cancer of the pancreas and described the pancreas of one of his patients as a dry white pancreas of a scirrhous nature with pretty hard distinct lobules. By the late 1800s, the clinical symptoms, signs and histology of pancreatic cancer had been defined. Bard and Pit differentiated between duct, acinar cell and islet cell cancers. Trendelenburg was the first to successfully excise a solid tumor of the pancreas and  Kappeler described the first cholecystojejunostomy performed as palliative therapy in a pancreatic cancer patient. In February 1955, Whipple performed a two stage operation for carcinoma of the ampulla, where a cholecystojejunostomy and total duodenectomy were performed. This was the first total duodenectomy to be recorded in a human subject. In 1940, Whipple and Nelson performed the first ever recorded one-stage pancreaticoduodenectomy followed by occlusion of  the pancreas.Post 1940, the one-stage has been modified repeatedly by surgeons world wide. The treatment of pancreatic cancer continues to be a dilemma. However, the mortality rate for pancreatoduodenal resection has declined from 21 percent before 1970 to 0 percent after 1970.

# Classification
Pancreatic cancers can be classified based on the production of hormones into exocrine and endocrine cancers. Pancreatic exocrine tumors include different types such as adenocarcinoma, acinar cell carcinoma, adenosquamous carcinoma and pancreatoblastomas. Pancreatic endocrine tumors include insulinomas, glucagonomas, VIPomas, somatostatinomas and Ppomas.

# Pathophysiology
Pancreatic cancer is the result of activation or inactivation of multiple gene subsets. The progression and development of pancreatic cancer is influenced by complex interactions and crosstalk between several cellular signaling pathways that include inactivation of tumor suppressor genes, activation of oncogenes and deregulation of molecules in various signaling pathways. EGFR, Akt, NF-kB and Hedgehog pathways are most commonly involved in the pathogenesis of pancreatic cancer. Majority of ductal adenocarcinomas have varying degrees of mucin production and duct-like structures and present as moderate-poorly differentiated masses.  The ductal adenocarcinomas are referred to as desmoplastic or "scirrhous" carcinomas due to their characteristic dense stromal fibrosis occurring due to alterations in transforming growth factor-beta (TGF-beta) signaling. Local extension of tumor cells may occur into adjacent structures such as superior mesenteric vessels, perineural invasion both inside and outside the pancreas (eg, the retroperitoneum), duodenum, portal vein and stomach. Lymph node spread can occur to the regional peripancreatic, mesenteric, perigastric, portahepatic and omental lymph nodes.

# Causes
Pancreatic cancer may be caused by the inactivation of tumor suppressor genes, activation of oncogenes and the deregulation of molecules in various signaling pathways.

# Differentiating Pancreatic Cancer from other Diseases
Pancreatic cancer must be differentiated from other pancreatic pathologies such as chronic pancreatitis, autoimmune pancreatitis, pancreatic pseudocyst, choledocholithiasis, and neuroendocrine tumors of the pancreas. Pathologies of the bile duct and duodenum such as choledocholithiasis, gallstones (cholelithiasis), choledochal Cysts, cholangiocarcinoma, bile duct strictures and ampullary cancer should be differentiated from pancreatic cancer based on imaging and biopsy findings. Metastasis from different sites and vascular causes such as abdominal aortic aneurysms may also mimic pancreatic cancer.

# Epidemiology and Demographics
In the United States, the age-adjusted prevalence of invasive pancreatic cancer is 11.7 per 100,000 in 2011. Pancreatic cancer is more prevalent in males than females.

# Risk Factors
Pancreatic cancer is associated with number of predisposing risk factors such as age, gender, ethnicity, and environmental exposures. The most potent risk factors for pancreatic cancer include smoking, alcoholism, increased BMI, diabetes mellitus, chronic pancreatitis and a family history of pancreatic cancer. Individuals with hereditary pancreatitis, familial pancreatic cancer, Peutz-Jeghers disease, familial atypical multiple mole melanoma syndrome (FAMMM), Von Hippel-Lindau syndrome, multiple endocrine neoplasia type 1, cystic fibrosis of the pancreas and familial cancer syndromes such as Lynch syndrome, familial adenomatous polyposis (FAP) and hereditary breast and ovarian cancer-BRCA1 and BRCA2 mutations are also at an increased risk of pancreatic cancer. Other medical conditions which pose as a risk factor for pancreatic cancer are inflammatory bowel disease, periodontal disease and peptic ulcer disease.

# Screening
In asymptomatic adults who are at average risk, the USPSTF recommends against routine screening for pancreatic cancer due to the lack of mortality benefit. In high-risk individuals, with familial pancreatic cancer or in those with genetic syndromes predisposing to pancreatic cancer, screening is suggested. In high- risk groups, screening by endoscopic ultrasound (EUS), magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) are recommended.

# Natural History, Complications and Prognosis
The symptoms of pancreatic cancer usually develop in the sixth decade of life, and start with symptoms such as jaundice, light-colored stools, dark urine, pain in the upper or middle abdomen and back, unexplained weight loss, anorexia and fatigue.Symptoms typically develop about 20-30 years after exposure to risk factors such as smoking and alcohol. Genetic factors such as alterations in tumor suppressor genes, oncogenes and different signaling pathways are responsible. If left untreated, patients with pancreatic cancer may progress to develop exocrine pancreatic insufficiency arising from pancreatic duct obstruction leading to malabsorption, malnutrition and cachexia. Dudodenal obstruction and biliary obstruction may cause symptoms of bowel obstruction and jaundice. Common complications of pancreatic cancer may arise as a result of the disease or therapy (surgical or medical). Depending on the extent of the tumor at the time of diagnosis, the prognosis is generally regarded as poor, with complete remission extremely rare.

# Diagnosis

## Staging
The exocrine and endocrine tumors of the pancreas are staged with the help of a single pancreatic staging system. Staging of Pancreatic cancer aids in determining the extent of the disease and helps in arriving at the diagnosis. Staging plays a major role in planning effective treatment and assessing the prognosis. Staging of pancreatic adenocarcinoma is done with the TNM staging system based on the results of imaging modalities such as CT, MRI, PET, TUS, endoscopic studies such as EUS and biopsy with ERCP. The American Joint Committee on Cancer (AJCC) TNM system is most often used to stage cancers of the pancreas based on the information from three variables, namley the T, N, and M. T - Indicates the size of the primary tumor and the extent of it's growth outside the pancreas and into nearby organs. N - Indicates the spread to the regional lymph nodes, where the cancers usually first spread. M - Indicates the metastasis (spread) of cancer to other parts (organs) of the body. The most common sites for the spread of pancreatic cancer are the liver, lungs, and the peritoneum.

## History and Symptoms
A positive history of cigarette smoking, alcoholism, diabetes mellitus, chronic pancreatitis and family history of pancreatic cancer are considered as risk factors for developing pancreatic cancer. The most common symptoms of pancreatic cancer include mid-epigastric pain, jaundice, sudden unexplained weight loss and dark urine and light-colored or greasy stools.

## Physical Examination
Patients with pancreatic cancer are usually in the sixth decade of life and appear cachectic, with signs of malnutrition. Patients mostly present with palpable abdominal mass, epigastric tenderness radiating to the back, hepatospleenomegaly and signs of metastasis in advanced stages. These signs of metastasis include left supraclavicular lymphadenopathy (Virchow's node), palpable periumbilical mass (Sister Mary Joseph's node), metastatic palpable mass in the rectal pouch (Blumer's shelf) and the involvement of other nodes in the cervical area.

## Laboratory Findings
Laboratory findings in pancreatic cancer  patients are often non specific and include abnormal liver function tests such as elevated serum bilirubin levels (conjugated and total), elevated alkaline phosphatase and gamma-glutamyl transpeptidase levels. Patients may have evidence of malnutrition, mild normocytic normochromic anemia and elevated CA 19-9 levels.

## Chest X-ray
There are no chest X-ray findings associated with Pancreatic cancer

## CT
Findings on CT scan that may be suggestive of pancreatic cancer include morphological changes of the gland, destruction of the peripancreatic fat and loss of the sharp margins with surrounding structures, involvement of the regional lymph nodes and adjacent vasculature, pancreatic ductal dilatation, pancreatic atrophy and obstruction of the common bile duct . MDCT (Multi-detector row computed tomography) the imaging modality widely used in suspected pancreatic cancer patients as the pre-operative examination. MDCT is used as the primary imaging modality, and is used in conjunction with PET/CT. MDCT helps in local and distant disease assessment in a single scan. MDCT is useful in the evaluation of vascular involvement, which helps in predicting the tumor resectability.

## MRI
MRI is considered when there is a diagnostic difficulty even after performing a CT scan. MRI is helpful in staging the extent and spread of pancreatic carcinoma rather than for detecting tumors or lesions less than 2 cm in size. MRI scan while determining pancreatic adenocarcinoma relies on the assessment of the size, shape, contour of the gland. MRI is helpful in characterizing cystic lesions of the pancreas and can aid in arriving at the diagnosis. MRI scan of the pancreas while assessing for pancreatic cancer presents as hypointense on T1-weighted images and hyperintense  or isointense on T2-weighted images. During dynamic MR imaging, the tumor of pancreatic cancer in the early phase shows diminished enhancement and in the late phase shows gradual enhancement.

## Ultrasound
Pancreatic cancer has a variable appearance on USG. The appearance relative to normal pancreatic tissue may be hypoechoic, isoechoic or hyperechoic. In majority of the cases, an ill defined hypoechoic mass is seen infiltrating into a bright pancreatic parenchyma.  Pancreatic and biliary duct dilatation is seen in case of carcinoma of the head of pancreas (Double duct sign). The disadvantage of a transabdominal USG is its inability to clearly demarcate lymphadenopathy, tumor margins and the relation of the tumor to vessels around the pancreas. Endoscopic Ultrasound (EUS) has a high efficacy in the detection of tumors smaller than 2 cm, for local T and N staging, and prediction of vascular invasion. It has a higher resolution than transabdominal ultrasound, due to the small distance between the endoscope and pancreas through the wall of the duodenum. EUS plays an important role in the preoperative staging of pancreatic cancer particularly in cases where CT evaluation suggests equivocal findings. Moreover, EUS-guided fine needle aspiration biopsy (FNA) is the best modality for obtaining a tissue diagnosis.

## Other imaging findings
ERCP and PTC are other imaging techniques that can be used to diagnose pancreatic cancer.

## Other Diagnostic Studies
There are no other diagnostic studies associated with Pancreatic cancer.

# Treatment

## Medical Therapy
The therapy for pancreatic cancer depends largely on the disease progression and the stage of cancer. There are five different types of treatment for patients with pancreatic cancer: surgery, radiation therapy, chemotherapy, chemoradiation therapy and targeted therapy. In patients with pancreatic cancer, surgery is the primary modality of treatment. Extrapancreatic disease, in contrast, requires palliative therapy and curative resection is not performed in such patients. Patients with unresectable disease may be treated with chemotherapy and/or radiation therapy as a part of adjuvant or neoadjuvant therapy. Chemotherapy may be administered when surgical intervention is not deemed appropriate. The National Comprehensive Cancer Network (NCCN) has recommended guidelines for treatment in patients based on their performance status, which is a major prognostic factor. Performance status assesses extent of metastatic disease, size of the tumor and degree of weight loss. In patients with locally advanced unresectable or metastatic disease with good performance status,  a combination of Leucovorin,5-fuorouracil, Oxaliplatin and Irinotecan (FOLFIRINOX) is preferred. Radiotherapy may form part of neoadjuvant therapy to attempt to shrink a tumor to a resectable state, but its use on unresectable tumors remains controversial. Neoadjuvant therapy may be used as the toxic effects of chemotherapy can be tolerated more easily before surgery as compared to after resection. Moreover, shrinkage of the tumor with neoadjuvant therapy makes resection easier and improves patient prognosis.

## Surgery
The mainstay of therapy for pancreatic cancer is surgery. Various methods of surgical resection may be employed and each of these has its own sets of risks and perioperative complications. The method of surgical resection depends on the locally invasive characteristics and size of the neoplasm.  The different surgical techniques that may be used for resectable pancreatic cancer include pancreaticoduodenectomy (Whipple Procedure), pylorus sparing Whipple procedure, distal pancreatectomy and total pancreatectomy. The National Comprehensive Cancer Network (NCCN) has recommended certain guidelines on resectability of pancreatic neoplasms based on resection margins, probability of cure, age and comorbidities. Curative resection is not contraindicated in all patients with vascular invasion, especially in cases with venous invasion. Extrapancreatic disease requires palliative therapy and curative resection is not performed in such patients. CA19-9 levels are not used to dictate the initial strategy for treatment of pancreatic cancer. However, elevated levels of CA19-9 can help predict the likelihood of complete resection, the prognosis of patients with resectable disease and the presence of occult metastasis.

## Primary Prevention
Primary prevention of pancreatic cancer involves the cessation of cigarette smoking, regular exercise and a healthy diet as per the American Cancer Society (ACS) guidelines. Cigarette smoking is considered to be the most significant modifiable risk factor for the development of pancreatic cancer. The risk of developing pancreatic cancer becomes almost equivalent to that of a nonsmoker after five years of smoking cessation. The  American Cancer Society (ACS) has issued guidelines for diet and physical activity at both individual and community levels and advocates the intake of plenty of vegetables and fruits, protein from fowl and plant sources like whole grains and consumption of tuna, mackerel or salmon that are major sources of protein and long-chain omega-3 fatty acids.

## Secondary Prevention
Secondary prevention of pancreatic cancer involves proper diet based on American Cancer Society (ACS) guidelines and palliative therapy for patients. Malabsorption may arise when pancreatic duct obstruction leads to exocrine pancreatic insufficiency. The diet proposed for pancreatic cancer patients is based on ACS guidelines and advocates administration of pancreatic enzyme replacement therapy, avoidance of high-protein/high-fat diets, individualized dietary prescriptions from a registered dietitian and dietary supplementation with omega-3 fatty acids. Palliative therapy is considered as an important part of secondary prevention and includes adequate analgesia, treatment of jaundice and duodenal obstruction, arising as complications of surgery.