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1 Chapter 1 : Endocrine Tumors of the Pancreas NIDDK This variant of pancreatic cancer is important to recognize because it is associated with a particularly poor prognosis, and in some instances is treated differently. Colloid Carcinomas - Colloid carcinoma is a distinctive cancer of the pancreas associated with a better prognosis than the more common ductal adenocarcinoma. Yellowing of your skin and the whites of your eyes jaundice When to see a doctor See your doctor if you experience unexplained weight loss or if you have persistent fatigue, abdominal pain, jaundice, or other signs and symptoms that bother you. Many conditions can cause these symptoms, so your doctor may check for these conditions as well as for pancreatic cancer. Doctors have identified factors, such as smoking, that increase your risk of developing the disease. Understanding your pancreas Your pancreas is about 6 inches 15 centimeters long and looks something like a pear lying on its side. It releases secretes hormones, including insulin, to help your body process sugar in the foods you eat. And it produces digestive juices to help your body digest food. How pancreatic cancer forms Pancreatic cancer occurs when cells in your pancreas develop mutations in their DNA. These mutations cause cells to grow uncontrollably and to continue living after normal cells would die. These accumulating cells can form a tumor. Untreated pancreatic cancer spreads to nearby organs and blood vessels. Most pancreatic cancer begins in the cells that line the ducts of the pancreas. This type of cancer is called pancreatic adenocarcinoma or pancreatic exocrine cancer. Rarely, cancer can form in the hormone-producing cells or the neuroendocrine cells of the pancreas. These types of cancer are called islet cell tumors, pancreatic endocrine cancer and pancreatic neuroendocrine tumors. Risk factors Factors that may increase your risk of pancreatic cancer include: Chronic inflammation of the pancreas pancreatitis Diabetes Family history of genetic syndromes that can increase cancer risk, including a BRCA2 gene mutation, Lynch syndrome and familial atypical mole-malignant melanoma FAMMM syndrome Family history of pancreatic cancer Smoking Obesity Older age, as most people are diagnosed after age 65 A large study demonstrated that the combination of smoking, long-standing diabetes and a poor diet increases the risk of pancreatic cancer beyond the risk of any one of these factors alone. A thin, flexible tube endoscope with a camera on the end is passed down your throat and into your small intestine. The dye enters the ducts through a small hollow tube catheter passed through the endoscope. As pancreatic cancer progresses, it can cause complications such as: A number of factors may cause weight loss in people with pancreatic cancer. The cancer itself may cause weight loss. Nausea and vomiting caused by cancer treatments or a tumor pressing on your stomach may make it difficult to eat. Your doctor may recommend pancreatic enzyme supplements to aid in digestion. Try to maintain your weight by adding extra calories where you can and making mealtime as pleasant and relaxed as possible. Signs include yellow skin and eyes, dark-colored urine, and pale-colored stools. Jaundice usually occurs without abdominal pain. Your doctor may recommend that a plastic or metal tube stent be placed inside the bile duct to hold it open. This is done with the help of a procedure called endoscopic retrograde cholangiopancreatography ERCP. During ERCP an endoscope is passed down your throat, through your stomach and into the upper part of your small intestine. Finally, images are taken of the ducts. A growing tumor may press on nerves in your abdomen, causing pain that can become severe. Pain medications can help you feel more comfortable. Radiation therapy might help stop tumor growth temporarily to give you some relief. In severe cases, your doctor might recommend a procedure to inject alcohol into the nerves that control pain in your abdomen celiac plexus block. This procedure stops the nerves from sending pain signals to your brain. Pancreatic cancer that grows into or presses on the first part of the small intestine duodenum can block the flow of digested food from your stomach into your intestines. Your doctor may recommend a tube stent be placed in your small intestine to hold it open. Prevention You may reduce your risk of pancreatic cancer if you: If you smoke, try to stop. Talk to your doctor about strategies to help you stop, including support groups, medications and nicotine replacement therapy. Maintain a healthy weight. If you are at a healthy weight, work to maintain it. If you need to lose weight, aim for a slow, steady weight loss â 1 to 2 pounds 0. Combine daily exercise with a diet rich in vegetables, fruit and whole grains with smaller portions to help you lose weight. Choose a healthy diet. A diet full of colorful fruits and vegetables and whole grains Page 1

2 may help reduce your risk of cancer. Consider meeting with a genetic counselor if you have a family history of pancreatic cancer. He or she can review your family health history with you and determine whether you might benefit from a genetic test to understand your risk of pancreatic cancer or other cancers. Page 2

3 Chapter 2 : Signs and Symptoms of Pancreatic Cancer Pancreatic neuroendocrine tumors form in hormone-making cells (islet cells) of the pancreas. The pancreas is a gland about 6 inches long that is shaped like a thin pear lying on its side. Types[ edit ] The pancreas has multiple functions, served by the endocrine cells in the islets of Langerhans and the exocrine acinar cells. Pancreatic cancer may arise from any of these and disrupt any of their functions. The many types of pancreatic cancer can be divided into two general groups. There are several sub-types of exocrine pancreatic cancers, but their diagnosis and treatment have much in common. The small minority of cancers that arise in the hormone -producing endocrine tissue of the pancreas have different clinical characteristics and are called pancreatic neuroendocrine tumors, sometimes abbreviated as "PanNETs". Both groups occur mainly but not exclusively in people over 40, and are slightly more common in men, but some rare sub-types mainly occur in women or children. Other exocrine cancers include adenosquamous carcinomas, signet ring cell carcinomas, hepatoid carcinomas, colloid carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with osteoclast -like giant cells. Solid pseudopapillary tumor is a rare low- grade neoplasm that mainly affects younger women, and generally has a very good prognosis. They are being detected at a greatly increased rate as CT scans become more powerful and common, and discussion continues as how best to assess and treat them, given that many are benign. Pancreatic neuroendocrine tumor The small minority of tumors that arise elsewhere in the pancreas are mainly pancreatic neuroendocrine tumors PanNETs. NETs can start in most organs of the body, including the pancreas, where the various malignant types are all considered to be rare. The functioning types secrete hormones such as insulin, gastrin, and glucagon into the bloodstream, often in large quantities, giving rise to serious symptoms such as low blood sugar, but also favoring relatively early detection. The most common functioning PanNETs are insulinomas and gastrinomas, named after the hormones they secrete. The non-functioning types do not secrete hormones in a sufficient quantity to give rise to overt clinical symptoms. For this reason, non-functioning PanNETs are often diagnosed only after the cancer has spread to other parts of the body. Since pancreatic cancer usually does not cause recognizable symptoms in its early stages, the disease is typically not diagnosed until it has spread beyond the pancreas itself. Exceptions to this are the functioning PanNETs, where over-production of various active hormones can give rise to symptoms which depend on the type of hormone. Pain in the upper abdomen or back, often spreading from around the stomach to the back. The location of the pain can indicate the part of the pancreas where a tumor is located. The pain may be worse at night and may increase over time to become severe and unremitting. In the UK, about half of new cases of pancreatic cancer are diagnosed following a visit to a hospital emergency department for pain or jaundice. This results when a cancer in the head of the pancreas obstructs the common bile duct as it runs through the pancreas. The undigested fat leads to foul-smelling, fatty feces that are difficult to flush away. The depression sometimes appears before the diagnosis of cancer, suggesting that it may be brought on by the biology of the disease. Typically, pancreatic adenocarcinoma first spreads to nearby lymph nodes, and later to the liver or to the peritoneal cavity, large intestine or lungs. Kidney cancer is by far the most common cancer to spread to the pancreas, followed by colorectal cancer, and then cancers of the skin, breast, and lung. Surgery may be performed on the pancreas in such cases, whether in hope of a cure or to alleviate symptoms. Most cases occur after age 65, [6] while cases before age 40 are uncommon. The disease is slightly more common in men than women, and in the United States is over 1. The risk declines slowly after smoking cessation, taking some 20 years to return to almost that of non-smokers. Peutzâ Jeghers syndrome due to mutations in the STK11 tumor suppressor gene very rare, but a very strong risk factor ; dysplastic nevus syndrome or familial atypical multiple mole and melanoma syndrome, FAMMM-PC due to mutations in the CDKN2A tumor suppressor gene; autosomal recessive ataxia-telangiectasia and autosomal dominantly inherited mutations in the BRCA2 gene and PALB2 gene; hereditary non-polyposis colon cancer Lynch syndrome ; and familial adenomatous polyposis. However, considerable research has failed to firmly establish alcohol consumption as a direct risk factor for pancreatic cancer. Overall, the association is consistently weak and the majority of studies have found no association, Page 3

4 with smoking a strong confounding factor. The evidence is stronger for a link with heavy drinking, of at least six drinks per day. Page 4

5 Chapter 3 : Article: Cystic tumors of the pancreas Most pancreatic cancer patients do not qualify for a pancreas transplant because of their advanced disease; most pancreas transplants are done in patients with diabetes that results from the removal of the endocrine portion of the pancreas and not for pancreatic cancer. Cancer starts when cells in the body begin to grow out of control. Cells in nearly any part of the body can become cancer, and can spread to other areas of the body. Pancreatic cancer starts when cells in the pancreas start to grow out of control. The pancreas is an organ that sits behind the stomach. The head of the pancreas is on the right side of the abdomen belly, behind where the stomach meets the duodenum the first part of the small intestine. The body of the pancreas is behind the stomach, and the tail of the pancreas is on the left side of the abdomen next to the spleen. The pancreas has 2 main types of cells: Most of the cells in the pancreas form the exocrine glands and ducts. The exocrine glands make pancreatic enzymes that are released into the intestines to help you digest foods especially fats. The enzymes are first released into tiny tubes called ducts. These merge to form larger ducts, which empty into the pancreatic duct. The pancreatic duct merges with the common bile duct the duct that carries bile from the liver, and empties into the duodenum the first part of the small intestine at the ampulla of Vater. Endocrine cells make up a much smaller percentage of the cells in the pancreas. These cells are in small clusters called islets or islets of Langerhans. These islets make important hormones like insulin and glucagon which help control blood sugar levels, and release them directly into the blood. Types of pancreatic cancer The exocrine cells and endocrine cells of the pancreas form different types of tumors. They have distinct risk factors and causes, have different signs and symptoms, are diagnosed with different tests, are treated in different ways, and have different outlooks. Exocrine pancreatic cancers Exocrine cancers are by far the most common type of pancreas cancer. These cancers usually start in the ducts of the pancreas. Less often, they develop from the cells that make the pancreatic enzymes, in which case they are called acinar cell carcinomas. Less common types of exocrine cancer: Other, less common exocrine cancers include adenosquamous carcinomas, squamous cell carcinomas, signet ring cell carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with giant cells. Ampullary cancer carcinoma of the ampulla of Vater: This cancer starts in the ampulla of Vater, which is where the bile duct and pancreatic duct come together and empty into the small intestine. This blockage causes bile to build up in the body, which leads to yellowing of the skin and eyes jaundice. Because of this, these cancers are usually found earlier than most pancreatic cancers, and they usually have a better prognosis outlook. As a group, they are often called pancreatic neuroendocrine tumors NETs or islet cell tumors. Pancreatic NETs can be benign not cancer or malignant cancer. Sometimes it only becomes clear that an NET is cancer when it spreads outside the pancreas. There are many types of pancreatic NETs. About half of pancreatic NETs make hormones that are released into the blood and cause symptoms. These are called functioning tumors. Each one is named for the type of hormone the tumor cells make. Gastrinomas come from cells that make gastrin. About half of gastrinomas are cancers. Insulinomas come from cells that make insulin. Most insulinomas are benign not cancer. Glucagonomas come from cells that make glucagon. Most glucagonomas are cancers. Somatostatinomas come from cells that make somatostatin. Most somatostatinomas are cancers. Most VIPomas are cancers. PPomas come from cells that make pancreatic polypeptide. Most PPomas are cancers. Most functioning NETs are gastrinomas or insulinomas. The other types are rare. They are more likely to be cancer than are functioning tumors. These NETs are much more common in other parts of the digestive system, although rarely they can start in the pancreas. The treatment and outlook for pancreatic NETs depend on the specific tumor type and the stage extent of the tumor, but the outlook is generally better than that of pancreatic exocrine cancers. Benign and precancerous growths in the pancreas Some growths in the pancreas are simply benign not cancer, while others might become cancer over time if left untreated known as precancers. Because people are getting imaging tests such as CT scans more often than in the past for a number of reasons, these types of pancreatic growths are now being found more often. Serous cystic neoplasms SCNs also known as serous cystadenomas are tumors that have sacs cysts filled with watery fluid. Page 5

6 Mucinous cystic neoplasms MCNs also known as mucinous cystadenomas are slow-growing tumors that have cysts filled with a jelly-like substance called mucin. These tumors almost always occur in women. While they are not cancer, some of them can progress to cancer over time if not treated, so these tumors are typically removed with surgery. Intraductal papillary mucinous neoplasms IPMNs are benign tumors that grow in the pancreatic ducts. Like MCNs, these tumors make mucin, and over time they sometimes become cancer if not treated. Some IPMNs can just be followed closely over time, but some might need to be removed with surgery if they have certain features, such as if they are in the main pancreatic duct. Solid pseudopapillary neoplasms SPNs are rare, slow-growing tumors that almost always develop in young women. Even though these tumors tend to grow slowly, they can sometimes spread to other parts of the body, so they are best treated with surgery. The outlook for people with these tumors is usually very good. Page 6

7 Chapter 4 : The Pancreas and Its Functions Columbia University Department of Surgery The symptoms of exocrine pancreatic cancers and pancreatic neuroendocrine tumors (NETs) are often different, so they are described separately. Having one or more of the symptoms below does not mean you have pancreatic cancer. In fact, many of these symptoms are more likely to be caused by other. Neuroendocrine secretory protein, a member of the chromogranin family, is seen in pancreatic endocrine tumors but not intestinal NETs. This is because of its ability to not only identify sites of disease but also characterize them. Neuronedocrine tumours express somatostatin receptors providing a unique target for imaging. Octreotide is a synthetic modifications of somatostatin with a longer half-life. Tumors that grow more quickly use more sugar. Using this scan, the aggressiveness of the tumor can be assessed. This is enabling better selection of the most appropriate therapy for an individual patient. NETs show tissue immunoreactivity for markers of neuroendocrine differentiation pan-neuroendocrine tissue markers and may secrete various peptides and hormones. There is a lengthy list of potential markers in neuroendocrine tumors; several reviews provide assistance in understanding these markers. Neuron-specific enolase NSE is less specific. The overlying mucosa may be either intact or ulcerated. The cells may align variously in islands, glands or sheets. High power examination shows bland cytopathology. Electron microscopy can identify secretory granules. There is usually minimal pleomorphism but less commonly there can be anaplasia, mitotic activity, and necrosis. This avidity can assist in diagnosis and may make some tumors vulnerable to hormone targeted therapies. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. November Learn how and when to remove this template message NETs from a particular anatomical origin often show similar behavior as a group, such as the foregut which conceptually includes pancreas, and even thymus, airway and lung NETs, midgut and hindgut ; individual tumors within these sites can differ from these group benchmarks: Foregut NETs are argentaffin negative. Despite low serotonin content, they often secrete 5-hydroxytryptophan 5-HTP, histamine, and several polypeptide hormones. There may be associated atypical carcinoid syndrome, acromegaly, Cushing disease, other endocrine disorders, telangiectasia, or hypertrophy of the skin in the face and upper neck. Midgut NETs are argentaffin positive, can produce high levels of serotonin 5-hydroxytryptamine 5-HT, kinins, prostaglandins, substance P SP, and other vasoactive peptides, and sometimes produce corticotropic hormone previously adrenocorticotropic hormone [ACTH]. Bone metastasis is uncommon. Bone metastases are not uncommon. Treatment[ edit ] Several issues help define appropriate treatment of a neuroendocrine tumor, including its location, invasiveness, hormone secretion, and metastasis. Treatments may be aimed at curing the disease or at relieving symptoms palliation. Observation may be feasible for non-functioning low grade neuroendocrine tumors. If the tumor is locally advanced or has metastasized, but is nonetheless slowly growing, treatment that relieves symptoms may often be preferred over immediate challenging surgeries. In this study, lanreotide showed a statistically significant improvement in progression-free survival, meeting its primary endpoint. Some PanNETs are more responsive to chemotherapy than gastroenteric carcinoid tumors. Several agents have shown activity [47] and combining several medicines, particularly doxorubicin with streptozocin and fluorouracil 5-FU or f5u, is often more effective. This type of radiotherapy is a systemic therapy and will impact somatostatin positive disease. The radioactively labelled hormones enter the tumor cells which, together with nearby cells, are damaged by the attached radiation. Not all cells are immediately killed; cell death can go on for up to two years. Compared with systemic chemotherapy, a higher proportion of the chemotherapy agents are in theory delivered to the lesions in the liver. The spheres not only block blood flow to the lesions, but by halting the chemotherapy agents in the neighborhood of the lesions, they provide a much better targeting leverage than chemoinfusion provides. In contrast to hormone-delivered radiotherapy, the lesions need not overexpress peptide receptors. The mechanical targeting delivers the radiation from the yttrium-labeled microspheres selectively to the tumors without unduly affecting the normal liver. The prevalence has been estimated as 35 per,, [88] and may be considerably higher if clinically silent tumors are included. An autopsy study of the pancreas in people who died from unrelated causes discovered a remarkably Page 7

8 high incidence of tiny asymptomatic NETs. Routine microscopic study of three random sections of the pancreas found NETs in 1. Carcinoid heart disease was identified in, and carcinoid fibrosis in Although this behavior was also part of the disproven hypothesis that these cells might all embryologically arise from the neural crest, [54] [64] [65] neuroendocrine cells sometimes produce various types of hormones and amines, [65] and they can also have strong receptors for other hormones to which they respond. There have been multiple nomenclature systems for these tumors, [2] and the differences between these schema have often been confusing. Nonetheless, these systems all distinguish between well- differentiated low and intermediategrade and poorly differentiated high-grade NETs. Cellular proliferative rate is of considerable significance in this prognostic assessment. Page 8

9 Chapter 5 : Neuroendocrine tumor - Wikipedia This type of cancer is called pancreatic adenocarcinoma or pancreatic exocrine cancer. Rarely, cancer can form in the hormone-producing cells or the neuroendocrine cells of the pancreas. These types of cancer are called islet cell tumors, pancreatic endocrine cancer and pancreatic neuroendocrine tumors. An Islet cell tumor is a very rare type of tumor. The only known risk factor for developing such a tumor is having a disease called multiple endocrine neoplasia type 1 syndrome MEN1 or having a family history of the syndrome. MEN1 is an inheritable disease that causes one or more endocrine glands to be overactive or to grow a tumor. The endocrine glands affected by MEN1 include the pancreas, parathyroid, and pituitary gland. There are several ways your doctor may diagnosis an islet cell tumor. The first step is to complete an overall physical exam and review of medical and family history. The next step is to either run a blood test or perform an imaging technique to look for a tumor. Blood tests look for increased levels of hormones such as insulin, glucagon, and gastrin, as well as glucose levels in the bloodstream. These levels can indicate an islet cell tumor. Imaging tests allow your doctor to visualize your pancreas and look for the presence of a tumor. These tests may include an ultrasound, magnetic resonance imaging, or a CT scan. Another way to get an image of the pancreas is to perform minor exploratory surgery. Your doctor may want to insert a small camera called an endoscope to view your pancreas or to take a small sample of the tissue for a biopsy. Surgery is the most common treatment for cancerous tumors. The purpose of the surgery is to remove as much of the tumor as possible. If the tumor is present in other areas of your body, such as the liver, your surgeon may remove it from those locations as well. If the cancer is widespread throughout your body, you may need chemotherapy to decrease the size of the tumors. When an islet cell tumor is benign, the treatment may simply involve medications that treat the symptoms of the overproduced hormone. A functional tumor is typically benign. If the symptoms are severe, surgery to remove the tumor may be necessary. What Is the Long-Term Outlook? If your doctor finds a cancerous tumor before it spreads beyond the pancreas, the outlook is good. Surgery to remove it usually cures the cancer. The more the cancer cells spread throughout the body, the lower the chances of recovery are. If the tumor is benign, the outlook is also good. Doctors can usually remove the benign tumor and cure the disease through surgery. Medications can relieve symptoms brought about by excess hormones. Page 9

10 Chapter 6 : Pancreatic islet cell tumor: MedlinePlus Medical Encyclopedia Pancreatic endocrine tumors (PETs) or pancreatic neuroendocrine tumors (PNETs) account for 1 percent to 10 percent of tumors arising in the pancreas, and represent a wide array of tumors that are mostly characterized by their secreted hormone, when functional. What is Pancreatic Cancer? The Pancreas The pancreas is a small, spongy organ which lies just under the curvature of the stomach and deep within the abdomen. The function of the pancreas is a complicated, but one could say that it primarily does two things. It produces enzymes which are useful for the digestion of food AND it secretes hormones which, among other things, help maintain and regulate body sugar levels. The clumps of acinar cells are found gathered throughout the pancreas; these cells release salts and enzymes into small tributaries which collect and transport this pancreatic fluid. These small creeks eventually gather and coalesce into the river known as the pancreatic duct. This sixteenth-of-an inch wide duct runs from left-to-right along the length of the pancreas, eventually usually joining up with the bile duct and emptying its combined digestive contents into the first part of the small bowel called the duodenum. For example, inside of specialized groupings of cells called the Islets of Langerhans, the pancreas produces hormones which are secreted directly into the blood stream. These hormones have numerous effects, and will be addressed in a simplistic fashion here. Insulin produced by so-called beta cells has effects, among which it lowers the level of glucose in the blood. Glucagon produced by alpha cells tends to increase the level of blood sugar. Other hormones, as well as various peptides, are produced by the endocrine pancreasâ including also somatostatin, a hormone which inhibits the secretion of insulin. Pancreatic Cancer Malignant cancer is a tumor or growth in which an aggregation of individual cells begins to grow in a rapid, uncontrolled and abnormal manner; and which may spread by aggressive local extension or by the seeding of other organs through blood vessel channels or via the lymphatic system. There also exist benign tumors which tend to be but are not always less serious, which tend to grow more slowly and orderly, and which tend not to spread by colonizing into other parts of the body this process known as metastasis. Cancer can arise from virtually any kind of cell in the body. The least common exocrine pancreatic cancer comes from acinar cells. These tumors are classified as carcinomas, a word that refers to tumors arising from a lining cell. About three-quarters of exocrine pancreatic cancer arises in the head and neck of the pancreas the anatomic parts through which the pancreatic duct runs just before it meets the duodenum. It is now understood that cancer is caused by the mutations of a gene which confer increased abnormal growth potential to cells. Genes in which this potential is directly conferred are called oncogenes. Other kinds of genes whose role includes that of preventing this phenomenon from happening are called tumor-suppressor genes. And finally there is a third kind of gene, called DNA-repair genes, the loss of function through mutation which may allow both activated oncogenes and thwarted tumor-suppressor genes to lead to cancer. It is generally believed that more than one mutation, modifying more than one regulatory pathway, is necessary for cancer to occur. Common known tumor-suppressor genes which are inactivated by mutation in this kind of pancreatic cancer are the p53 and p16 genes. Still other genetic mutations have been found. This area of inquiry is currently a source of a great deal of interest and research, with an eye toward finding effective treatment or earlier diagnosis of pancreatic cancer. There appears to be a mild correlation between the onset of diabetes and pancreatic cancer, but it is not entirely clear if this is fully a cause or perhaps an effect of the cancer. There does not appear to be a strong correlation between the onset of pancreatic cancer and the drinking of alcohol or of coffee though these have been issues of some controversy. Metastasis and endocrine tumors are two topics which are addressed in more detail in later questions. The most common sites of metastasis of pancreatic cancer adenocarcinoma are the liver, the peritoneum â which is the thin lining which contains many structures in the abdominal cavity, and the lungs. Cancers of the endocrine portion of the pancreas neuroendocrine tumors are less common than exocrine cancer of the pancreas â about two to three thousand cases are diagnosed each year in the U. They are typically referred to as neuroendocrine tumors â or otherwise known as islet cell tumors. Carcinoid tumors are a typically slow growing type of neuroendocrine tumor. Although they arise from the hormone producing area Page 10

11 of the organ, neuroendocrine tumors can be either functioning demonstrating excess hormone secretion which produces symptoms or non-functioning. Endocrine tumors have a different natural history than the exocrine tumors. As a whole, they tend to be slower growing and have a better prognosis than standard pancreatic cancer. The treatment of neuroendocrine tumors of the pancreas is distinct from that of adenocarcinoma of the pancreas. This above description of tumor types is somewhat superficial as there really exists a large number of types of pancreatic cancer many of these are very rare, some of which have shared characteristics and which may be very difficult to classify. From this, one can perhaps get a better sense of the complexity of the subject. The Toll of Pancreatic Cancer Each year more than 50, people in the United States are diagnosed with adenocarcinoma of the pancreas and more than twice that in Europe. Most of these people will have passed away by the end of the first year. The incidence of pancreatic cancer increases with age; most people are between the ages of 60 to 80 when they receive the diagnosis. Men have tended to be over-represented, though in recent years the gap between men and women has shrunk, possibly due to increased cigarette smoking among women. The median survival period from the time of diagnosis until demise is arguably the worst of any of the cancers. Page 11

12 Chapter 7 : Pancreatic cancer: MedlinePlus Medical Encyclopedia What Are Pancreatic Neuroendocrine Tumors (NETs)? It's natural to feel a little overwhelmed when you get news that you have a pancreatic neuroendocrine tumor (NET). If you're like most folks, it's. Early Detection, Diagnosis, and Staging Signs and Symptoms of Pancreatic Cancer The symptoms of exocrine pancreatic cancers and pancreatic neuroendocrine tumors NETs are often different, so they are described separately. Having one or more of the symptoms below does not mean you have pancreatic cancer. In fact, many of these symptoms are more likely to be caused by other conditions. Signs and symptoms of exocrine pancreatic cancer Early pancreatic cancers often do not cause any signs or symptoms. By the time they do cause symptoms, they have often already spread outside the pancreas. Jaundice and related symptoms Jaundice is yellowing of the eyes and skin. Most people with pancreatic cancer and nearly all people with ampullary cancer will have jaundice as one of their first symptoms. Jaundice is caused by the buildup of bilirubin, a dark yellow-brown substance made in the liver. Normally, the liver excretes bilirubin as part of a liquid called bile. Bile goes through the common bile duct into the intestines, where it helps break down fats. It eventually leaves the body in the stool. Cancers that start in the head of the pancreas are near the common bile duct. These cancers can press on the duct and cause jaundice while they are still fairly small, which can sometimes lead to these tumors being found at an early stage. By this time, the cancer has often spread beyond the pancreas as well. When pancreatic cancer spreads, it often goes to the liver. This can also lead to jaundice. Sometimes, the first sign of jaundice is darker urine. As bilirubin levels in the blood increase, the urine becomes brown in color. Light-colored or greasy stools: Bilirubin normally helps give stools their brown color. If the bile duct is blocked, stools might be pale or gray. When bilirubin builds up in the skin, it can start to itch as well as turning yellow. Pancreatic cancer is not the most common cause of jaundice. Other causes, such as gallstones, hepatitis, and other liver and bile duct diseases, are much more common. Belly or back pain Pain in the abdomen belly or back is common in pancreatic cancer. Cancers that start in the body or tail of the pancreas can grow fairly large and start to press on other nearby organs, causing pain. The cancer may also spread to the nerves surrounding the pancreas, which often causes back pain. Of course, pain in the abdomen or back is fairly common and is most often caused by something other than pancreatic cancer. Weight loss and poor appetite Unintended weight loss is very common in people with pancreatic cancer. These people often have little or no appetite. Nausea and vomiting If the cancer presses on the far end of the stomach it can partly block it, making it hard for food to get through. This can cause nausea, vomiting, and pain that tend to be worse after eating. Gallbladder or liver enlargement If the cancer blocks the bile duct, bile can build up in the gallbladder, making it larger. Sometimes a doctor can feel this as a large lump under the right side of the ribcage during a physical exam. It can also be seen on imaging tests. Pancreatic cancer can also sometimes enlarge the liver, especially if the cancer has spread to the liver. The doctor might be able to feel this below the right ribcage as well on an exam, or it might be seen on imaging tests. Blood clots Sometimes, the first clue that someone has pancreatic cancer is a blood clot in a large vein, often in the leg. This is called a deep vein thrombosis or DVT. Symptoms can include pain, swelling, redness, and warmth in the affected leg. Sometimes a piece of the clot can break off and travel to the lungs, which might make it hard to breathe or cause chest pain. A blood clot in the lungs is called a pulmonary embolism or PE. Still, having a blood clot does not usually mean that you have cancer. Most blood clots are caused by other things. Fatty tissue abnormalities Some people with pancreatic cancer develop an uneven texture of the fatty tissue underneath the skin. This is caused by the release of the pancreatic enzymes that digest fat. Diabetes Rarely, pancreatic cancers cause diabetes high blood sugar because they destroy the insulin-making cells. Symptoms can include feeling thirsty and hungry, and having to urinate often. Signs and symptoms of pancreatic neuroendocrine tumors Pancreatic neuroendocrine tumors NETs often release excess hormones into the bloodstream. Different types of tumors make different hormones, which can lead to different symptoms. Gastrinomas These tumors make gastrin, a hormone that tells the stomach to make more acid. Too much gastrin causes a condition known as Zollinger-Ellison syndrome, in which the stomach makes too much acid. This leads to stomach ulcers, Page 12

13 which can cause pain, nausea, and loss of appetite. Severe ulcers can start bleeding. If the bleeding is mild, it can lead to anemia too few red blood cells, which can cause symptoms like feeling tired and being short of breath. If the bleeding is more severe, it can make stool black and tarry. Severe bleeding can itself be life-threatening. If the stomach acid reaches the small intestine, it can damage the cells of the intestinal lining and break down digestive enzymes before they have a chance to digest food. This can cause diarrhea and weight loss. Glucagonomas These tumors make glucagon, a hormone that increases glucose sugar levels in the blood. Most of the symptoms that can be caused by a glucagonoma are mild and are more often caused by something else. Excess glucagon can raise blood sugar, sometimes leading to diabetes. This can cause symptoms such as feeling thirsty and hungry, and having to urinate often. People with these tumors can also have problems with diarrhea, weight loss, and malnutrition. The nutrition problems can lead to symptoms like irritation of the tongue and the corners of the mouth. The symptom that brings most people with glucagonomas to their doctor is a rash called necrolytic migratory erythema. This is a red rash with swelling and blisters that often travels from place to place on the skin. Insulinomas These tumors make insulin, which lowers blood glucose levels. Too much insulin leads to low blood sugar, which can cause symptoms like weakness, confusion, sweating, and rapid heartbeat. When blood sugar gets very low, it can lead to a person passing out or even going into a coma and having seizures. Somatostatinomas These tumors make somatostatin, which helps regulate other hormones. Symptoms of this type of tumor can include belly pain, nausea, poor appetite, weight loss, diarrhea, symptoms of diabetes feeling thirsty and hungry, and having to urinate often, and jaundice yellowing of the skin and eyes. The early symptoms of a somatostatinoma tend to be mild and are more often caused by other things, so these tumors tend to be diagnosed at an advanced stage. Often, they are not found until they spread to the liver, when they cause problems like jaundice and pain. Too much VIP can lead to problems with diarrhea. This may be mild at first, but gets worse over time. By the time they are diagnosed, most people have severe, watery diarrhea. Other symptoms can include nausea, vomiting, muscle cramps, feeling weak or tired, and flushing redness and warmth in the face or neck. People with these tumors also tend to have low levels of acid in their stomachs, which can lead to problems digesting food. PPomas These tumors make pancreatic polypeptide PP, which helps regulate both the exocrine and endocrine pancreas. They can cause problems such as belly pain and an enlarged liver. Some people also get watery diarrhea. Carcinoid tumors These tumors often make serotonin or its precursor, 5-HTP. When a pancreatic tumor makes these substances, they first travel to the liver. The liver breaks these substances down before they can reach the rest of the body and cause problems. When these tumors do spread, it is most often to the liver. There, the cancer cells can release hormones directly into the blood leaving the liver. This can cause the carcinoid syndrome, with symptoms including flushing redness and warmth in the face or neck, diarrhea, wheezing, and a rapid heart rate. These symptoms often occur in episodes, between which the person may feel fine. Over a long time, the hormone-like substances released by these tumors can damage heart valves, causing shortness of breath, weakness, and a heart murmur an abnormal heart sound. Most of these are cancers and start to cause problems as they get larger or spread outside the pancreas. Symptoms can be like those from exocrine pancreas cancers, including jaundice yellowing of the eyes and skin, belly pain, and weight loss. Symptoms caused by the cancer spreading When pancreatic NETs spread, most often they go to the liver. This can enlarge the liver, which can cause pain and loss of appetite. It can also affect liver function, sometimes leading to jaundice yellowing of the skin and eyes and abnormal blood tests. These cancers can also spread to other organs and tissues. The symptoms depend on where the cancer is growing. For example, cancer spread to the lungs can cause shortness of breath or a cough. Spread to bones can cause pain in those bones. Page 13

14 Chapter 8 : What are pancreatic tumors Pancreatic cancer starts when cells in the pancreas start to grow out of control. The pancreas is an organ that sits behind the stomach. It's shaped a bit like a fish with a wide head, a tapering body, and a narrow, pointed tail. Types of Pancreas Tumors Types of neoplasms of the pancreas There are two very important things to know about neoplasms of the pancreas. First, some, such as the "intraductal papillary mucinous neoplasm," are curable precancerous lesions. Just as colon cancer arises from curable precancerous colon polyps, so to do some pancreatic cancers arise from curable precancerous lesions. Second, as we alluded to earlier, a variety of different types of neoplasms can arise in the pancreas, such as ductal adenocarcinoma and pancreatic neuroendocrine tumor, and these different tumor types are important to recognize because they are often treated differently, and because they are associated with different prognoses predicted outcomes. Trained expert pathologists usually establish the diagnosis of a specific type of neoplasm. They do this either from biopsies of the tumor or by examining resected removed tumors. Neoplasms of the Exocrine Pancreas This is the form of cancer that most people are talking about when they refer to "cancer of the pancreas. Adenocarcinomas most common - Just as the normal exocrine cells of the pancreas do, adenocarcinomas form microscopic glands collections of cells surrounding an empty space. Adenocarcinomas can grow large enough to invade nerves which can cause back pain. They also frequently spread metastasize to the liver or lymph nodes. If this happens the tumor may be considered unresectable. This is a gland-forming it makes tubes cancer. In this example, the adenocarinoma has wrapped around a nerve center of the image. The following rare exocrine neoplasms of the pancreas are listed alphabetically. Acinar Cell Carcinomas - These rare cancers may produce excess amounts of the digestive enzymes normally produced by the pancreas. These symptoms may include unusual skin rashes, joint pain and an increased number of eosinophils, a type of white blood cell, in the blood. Microscopically, the cytoplasm of the cancerous cells in acinar cell carcinoma has a characteristic granular appearance. This is because the cancerous cells contain large amounts of a cell organelle called the zymogen granule. Special tests performed by pathologists on microscope slides, including immunohistochemistry, can often be used to diagnose this type of cancer. Adenosquamous Carcinomas - This rare variant of pancreatic cancer is similar to adenocarcinoma because it also forms glands. These cancers also show a second component, "squamous differentiation. This variant of pancreatic cancer is important to recognize because it is associated with a particularly poor prognosis, and in some instances is treated differently. Colloid Carcinomas - Colloid carcinoma is a distinctive cancer of the pancreas associated with a better prognosis than the more common ductal adenocarcinoma. Under the microscope small nests of cancer cells appear to be "floating" in pools of extracellular mucin. Many colloid carcinomas arise in association with another type of tumor, the intraductal papillary mucinous neoplasm IPMN of the pancreas. Hepatoid Carcinomas - Hepatoid carcinomas of the pancreas have been reported only extremely rarely in the pancreas. Under the microscope, the cells that form this type of cancer look like the cells of a liver cancer hepatoid means liver-like. IPMNs characteristically grow in the larger ducts of the pancreas hence the name "intraductal! Under the microscope they usually appear as finger-like structures papillae, hence the name papillary projecting into the pancreatic duct. IPMNs are believed to start as curable precancerous lesions, and some, if untreated, may progress to invasive adenocarcinomas. Mucinous Cystic Neoplasms - This is a rare, cystic containing collections of fluid, neoplasm of the pancreas. Most are found in the tail of the pancreas in women. The spaces within this neoplasm are filled with a thick fluid called mucin. Unlike the serous cystadenomas see below, these neoplasms can progress into an invasive cancer over time. Pancreatic Intraepithelial Neoplasia - Pancreatic intraepithelial neoplasia- A small microscopic the size of the head of a pin precancerous lesion in the pancreas. These are also called "PanINs" and are too small to be detected using currently available imaging technologies. They are, however, a very active area of research as some scientists believe they may hold the clue to the early detection of pancreatic cancer. If left untreated, some PanINs will progress over years to invasive ductal adenocarcinoma. Pancreatoblastomas - These rare malignant neoplasms predominantly occur in children. The reason for this is unknown. These cancers are also referred to as the Page 14

15 "pancreatic cancer of infancy. The cells of pancreatoblastomas can also show acinar differentiation and endocrine differentiation. Serous Cystadenomas - These rare tumors are usually benign noncancerous growths. However, they can grow to be quite large and may need to be surgically removed if symptoms such as pain and weight loss occur. They are cystic, fluid containing, tumors with a sponge-like appearance. This benign tumor forms spaces cysts, giving the tumor a "sponge-like" appearance. Signet Ring Cell Carcinoma - This rare form of pancreatic cancer has a characteristic microscopic appearance. Signet ring cell carcinomas are composed of individual cells with a large mucin globule. This mucin globule pushes the nucleus of the cell to the side, giving the cell a "signet" or ring-like appearance. As the name implies some parts of the neoplasms are solid and some are papillary form finger-like projections. Solid-pseudopapillary neoplasms are considered low-grade cancers, but they have a very good prognosis. Since they can spread to other organs they should be removed completely. This is a smear made by touching a microscope slide to the surface of the tumor. The center star-shaped structure is composed of thin delicate blood vessels the lines radiating out with small tumor cells clinging on to the outside surface of the blood vessels. Undifferentiated Carcinomas - Undifferentiated carcinoma is an extremely aggressive form of pancreatic cancer that lacks a direction of differentiation. This means that under the microscope these cancers do not resemble any normal cell type in the body. As the name "undifferentiated carcinomas with osteoclast-like giant cells" indicates, these cancers have unusually large "giant" cells. This does not mean that the cancer itself is larger than other types of cancer, only that individual cells in this form of cancer are so unusually large that they look like some very large cells osteoclasts found in the normal bone. Undifferentiated carcinoma with osteoclast-like giant cells: This tumor is composed of two cell types. The cancerous cells are the big cells on the right of this image. Neoplasms of the Endocrine Pancreas Neuroendocrine Tumors - These neoplasms are far less common than the exocrine neoplasms listed above. It is very important that endocrine neoplasms be distinguished from nonendocrine because the symptoms and the treatments for the two neoplasms are very different. The neuroendocrine neoplasms may produce highly active hormones and therefore have very dramatic symptoms. There are different kinds, including: Insulinomas produce large amounts of the hormone insulin which can result in hypoglycemia low blood sugar. Glucagonomas produce the hormone glucagon which can result in a very striking skin rash necrolytic migratory erythema. We subscribe to the HONcode principles. Page 15

16 Chapter 9 : What Are Tumors? A pancreatic islet cell tumor is a rare tumor of the pancreas that starts from a type of cell called the islet cell. Causes In the healthy pancreas, cells called islet cells produce hormones that regulate a several bodily functions. Pancreatic ultrasound Pancreatic ultrasound During an endoscopic ultrasound of the pancreas, your doctor inserts a thin, flexible tube endoscope down your throat and into your abdomen. An ultrasound device at the end of the tube emits sound waves that generate images of your pancreas and nearby tissues. If your doctor suspects pancreatic cancer, he or she may have you undergo one or more of the following tests: Imaging tests that create pictures of your internal organs. These tests help your doctors visualize your internal organs, including the pancreas. Techniques used to diagnose pancreatic cancer include ultrasound, computerized tomography CT scans, magnetic resonance imaging MRI and, sometimes, positron emission tomography PET scans. Using a scope to create ultrasound pictures of your pancreas. An endoscopic ultrasound EUS uses an ultrasound device to make images of your pancreas from inside your abdomen. The device is passed through a thin, flexible tube endoscope down your esophagus and into your stomach in order to obtain the images. Removing a tissue sample for testing biopsy. A biopsy is a procedure to remove a small sample of tissue for examination under a microscope. Your doctor may obtain a sample of tissue from the pancreas by inserting a needle through your skin and into your pancreas fine-needle aspiration. Or he or she may remove a sample during EUS, guiding special tools into the pancreas. Your doctor may test your blood for specific proteins tumor markers shed by pancreatic cancer cells. One tumor marker test used in pancreatic cancer is called CA Some doctors measure your levels before, during and after treatment. If your doctor confirms a diagnosis of pancreatic cancer, he or she tries to determine the extent stage of the cancer. Using information from staging tests, your doctor assigns your pancreatic cancer a stage, which helps determine what treatments are most likely to benefit to you. The stages of pancreatic cancer are indicated by Roman numerals ranging from 0 to IV. The lowest stages indicate that the cancer is confined to the pancreas. By stage IV, the cancer has spread to other parts of the body. The cancer staging system continues to evolve and is becoming more complex as doctors improve cancer diagnosis and treatment. Your doctor uses your cancer stage to select the treatments that are right for you. If you have any doubts, get a second opinion. Treatment Treatment for pancreatic cancer depends on the stage and location of the cancer as well as on your overall health and personal preferences. For most people, the first goal of pancreatic cancer treatment is to eliminate the cancer, when possible. Treatment may include surgery, radiation, chemotherapy or a combination of these. Surgery Whipple procedure Whipple procedure The Whipple procedure pancreaticoduodenectomy is an operation to remove the head of the pancreas, the first part of the small intestine duodenum, the gallbladder and the bile duct. The remaining organs are reattached to allow you to digest food normally after surgery. Operations used in people with pancreatic cancer include: Surgery for tumors in the pancreatic head. If your cancer is located in the head of the pancreas, you may consider an operation called a Whipple procedure pancreaticoduodenectomy. The Whipple procedure is technically difficult operation to remove the head of the pancreas, the first part of the small intestine duodenum, the gallbladder and part of the bile duct. In some situations, part of the stomach and nearby lymph nodes may be removed as well. Your surgeon reconnects the remaining parts of your pancreas, stomach and intestines to allow you to digest food. Surgery for tumors in the pancreatic body and tail. Surgery to remove the left side body and tail of the pancreas is called distal pancreatectomy. Your surgeon may also remove your spleen. Surgery to remove the entire pancreas. In some people, the entire pancreas may need to be removed. This is called total pancreatectomy. You can live relatively normally without a pancreas but do need lifelong insulin and enzyme replacement. Surgery for tumors affecting nearby blood vessels. Many people with advanced pancreatic cancer are not considered eligible for the Whipple procedure or other pancreatic surgeries if their tumors involve nearby blood vessels. At a very few medical centers in the United States, highly specialized and experienced surgeons will safely perform these operations with removal and reconstruction of parts of blood vessels in select patients. Each of these surgeries carries the risk of bleeding and infection. After surgery some people experience nausea and vomiting if the stomach has Page 16

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