Pancreatic cancer

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. The vast majority of cases (about 95%) occur in the part of the pancreas that produces digestive enzymes, known as the exocrine component. Several subtypes of exocrine pancreatic cancers are described, 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 subtypes mainly occur in women or children. Exocrine cancers The exocrine group is dominated by pancreatic adenocarcinoma (variations of this name may add "invasive" and "ductal"), which is by far the most common type, representing about 85% of all pancreatic cancers. This is despite the fact that the tissue from which it arises – the pancreatic ductal epithelium – represents less than 10% of the pancreas by cell volume, because it constitutes only the ducts (an extensive but capillary-like duct-system fanning out) within the pancreas. This cancer originates in the ducts that carry secretions (such as enzymes and bicarbonate) away from the pancreas. About 60–70% of adenocarcinomas occur in the head of the pancreas. Like the 'functioning' endocrine cancers described below, acinar cell carcinomas may cause over-production of certain molecules, in this case digestive enzymes, which may cause symptoms such as skin rashes and joint pain. Cystadenocarcinomas account for 1% of pancreatic cancers, and they have a better prognosis than the other exocrine types. Pancreatic mucinous cystic neoplasms are a broad group of pancreas tumors that have varying malignant potential. 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. Neuroendocrine The small minority of tumors that arise elsewhere in the pancreas are mainly pancreatic neuroendocrine tumors (PanNETs). Neuroendocrine tumors (NETs) are a diverse group of benign or malignant tumors that arise from the body's neuroendocrine cells, which are responsible for integrating the nervous and endocrine systems. NETs can start in most organs of the body, including the pancreas, where the various malignant types are all considered to be rare. PanNETs are grouped into 'functioning' and 'nonfunctioning' types, depending on the degree to which they produce hormones. 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 nonfunctioning types do not secrete hormones in a sufficient quantity to give rise to overt clinical symptoms, so nonfunctioning PanNETs are often diagnosed only after the cancer has spread to other parts of the body. though they are now known to not actually arise from islet cells as previously thought. ==Signs and symptoms==

can be a symptom, due to biliary obstruction from a pancreatic tumor. 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. This is one of the main reasons for the generally poor survival rates. 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). People over 50 who develop diabetes have eight times the usual risk of developing pancreatic adenocarcinoma within three years, after which the relative risk declines. Pancreatic cancer metastasis , at autopsy, showing many large pale tumor deposits, that are secondary tumors derived from pancreatic cancer The metastasis of pancreatic cancer to other organs may also cause symptoms. Typically, pancreatic adenocarcinoma first spreads to nearby lymph nodes, and later to the liver or to the peritoneal cavity, large intestine, or lungs. Cancers in the pancreas may also be secondary cancers that have spread from other parts of the body. This is uncommon, found in only about 2% of cases of pancreatic cancer. 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. ==Risk factors==

Risk factors for pancreatic adenocarcinoma include: • Age, sex, and ethnicity – the risk of developing pancreatic cancer increases with age. Most cases occur after age 65, • Obesity – a body mass index greater than 35 increases relative risk by about half. • Radionuclides – Cesium-137 and Iodine-131. • Family history – 5–10% of pancreatic cancer cases have an inherited component, where people have a family history of pancreatic cancer. The risk escalates greatly if more than one first-degree relative had the disease, and more modestly if they developed it before the age of 50. Hereditary pancreatitis gives a greatly increased lifetime risk of pancreatic cancer of 30–40% to the age of 70. Some people may choose to have their pancreas surgically removed to prevent cancer from developing in the future. Chronic pancreatitis, pancreatic cancer and diabetes mellitus increased in contaminated populations, particularly children and adolescents, after Fukushima and Chernobyl nuclear incidents. At the same time, worldwide pancreatic diseases, diabetes and environmental radiocesium are increasing. • Specific types of food (as distinct from obesity) have not been clearly shown to increase the risk of pancreatic cancer. Alcohol Drinking alcohol excessively is a major cause of chronic pancreatitis, which in turn predisposes to pancreatic cancer, but 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, with smoking a strong confounding factor. The evidence is stronger for a link with heavy drinking, of at least six drinks per day. ==Pathophysiology==

of pancreatic ductal adenocarcinoma (the most common type of pancreatic cancer), H&E stain Precancerous lesions s of normal pancreas, pancreatic intraepithelial neoplasia (precursors to pancreatic carcinoma) and pancreatic carcinoma, H&E stain Exocrine cancers are thought to arise from several types of precancerous lesions within the pancreas, but these lesions do not always progress to cancer, and the increased numbers detected as a byproduct of the increasing use of CT scans for other reasons are not all treated. If these lesions become large, cause symptoms, or have suspicious features, they can usually be successfully removed by surgery. Invasive cancer The genetic events found in ductal adenocarcinoma have been well characterized, and complete exome sequencing has been done for the common types of tumor. Four genes have each been found to be mutated in the majority of adenocarcinomas: KRAS (in 95% of cases), CDKN2A (also in 95%), TP53 (75%), and SMAD4 (55%). The last of these is especially associated with a poor prognosis. Pancreatic ductal adenocarcinoma cancer cells are known to secrete immunosuppressive cytokines, creating a tumor microenvironment that inhibits immune detection and blocks anti-cancer immunity. Cancer associated fibroblasts secrete fibrous tissue (desmoplasia) consisting of matrix metalloproteinases and hyaluronan which blocks the host's CD8+ T-cells from reaching the tumor. Tumor associated macrophages, neutrophils and regulatory T-cells secrete cytokines and work to create a tumor microenvironment that promotes cancer growth. PanNETs The genes often found mutated in pancreatic neuroendocrine tumors (PanNETs) are different from those in exocrine pancreatic cancer. For example, KRAS mutation is normally absent. Instead, hereditary MEN1 gene mutations give risk to MEN1 syndrome, in which primary tumors occur in two or more endocrine glands. About 40–70% of people born with a MEN1 mutation eventually develop a PanNet. Other genes that are frequently mutated include DAXX, mTOR, and ATRX. ==Diagnosis==

of pancreatic cancer (presumably adenocarcinoma), with a dilated pancreatic duct to the right. The symptoms of pancreatic adenocarcinoma do not usually appear in the disease's early stages, and they are not individually distinctive to the disease. The symptoms at diagnosis vary according to the location of the cancer in the pancreas, which anatomists divide (from left to right on most diagrams) into the thick head, the neck, and the tapering body, ending in the tail. Regardless of a tumor's location, the most common symptom is unexplained weight loss, which may be considerable. A large minority (between 35% and 47%) of people diagnosed with the disease will have had nausea, vomiting, or a feeling of weakness. Tumors in the head of the pancreas typically also cause jaundice, pain, loss of appetite, dark urine, and light-colored stools. Tumors in the body and tail typically also cause pain. Medical imaging techniques, such as computed tomography (CT scan) and endoscopic ultrasound (EUS) are used both to confirm the diagnosis and to help decide whether the tumor can be surgically removed (its "resectability"). Magnetic resonance imaging and positron emission tomography may also be used, In 70–95% of PDAC, KRAS mutations (typically in codon G12) drive uncontrolled cell proliferation through MAPK/ERK signaling. TP53, inactivated in approximately 70% of cases, compromises the normal DNA-damage response and cell-cycle arrest. Loss of CDKN2A occurs in up to 98% of tumors, deleting the p16-dependent G1/S checkpoint. In around 50% of PDACs, SMAD4 is deleted or mutated, disabling TGF-β–mediated growth inhibition. Receiving platinum‐ based therapies in patients with hereditary BRCA1/BRCA2 alterations can sensitize to the treatments. While each gene has a separate function, the combined impact undermines cell-cycle checkpoints and DNA repair. Although routine genetic testing is not routinely performed in pancreatic cancer, the identification of specific mutations may improve prognostic information and facilitate targeted therapies. Staging Exocrine cancers Pancreatic cancer is usually staged following a CT scan. To help decide treatment, the tumors are also divided into three broader categories based on whether surgical removal seems possible: in this way, tumors are judged to be "resectable", "borderline resectable", or "unresectable". When the disease is still in an early stage (AJCC-UICC stages I and II), without spread to large blood vessels or distant organs such as the liver or lungs, surgical resection of the tumor can normally be performed, if the patient is willing to undergo this major operation and is thought to be sufficiently fit. PanNETs The 2010 WHO classification of tumors of the digestive system grades all the pancreatic neuroendocrine tumors (PanNETs) into three categories, based on their degree of cellular differentiation (from "NET G1" through to the poorly differentiated "NET G3"). A different TNM system for PanNETs has been proposed by the European Neuroendocrine Tumor Society. ==Prevention and screening==

Apart from not smoking, the American Cancer Society recommends keeping a healthy weight, and increasing consumption of fruits, vegetables, and whole grains, while decreasing consumption of red and processed meat, although there is no consistent evidence this will prevent or reduce pancreatic cancer specifically. A 2014 review of research concluded that there was evidence that consumption of citrus fruits and curcumin reduced risk of pancreatic cancer, while there was possibly a beneficial effect from whole grains, folate, selenium, and non-fried fish. although newer techniques, and the screening of tightly targeted groups, are being evaluated. Nevertheless, regular screening with endoscopic ultrasound and MRI/CT imaging is recommended for those at high risk from inherited genetics. A 2019 meta-analysis found that use of aspirin might be negatively associated with the incidence risk of pancreatic cancer, but found no significant relationship with pancreatic cancer mortality. ==Management==

Exocrine cancer A key assessment that is made after diagnosis is whether surgical removal of the tumor is possible (see Staging), as this is the only cure for this cancer. Whether or not surgical resection can be offered depends on how much the cancer has spread. The exact location of the tumor is also a significant factor, and CT can show how it relates to the major blood vessels passing close to the pancreas. The general health of the person must also be assessed, though age in itself is not an obstacle to surgery. The age of the person is not in itself a reason not to operate, but their general performance status needs to be adequate for a major operation. A resection that includes encased sections of blood vessels may be possible in some cases, particularly if preliminary neoadjuvant therapy is feasible, using chemotherapy and/or radiotherapy. An exploratory laparoscopy (a small, camera-guided surgical procedure) may therefore be performed to gain a clearer idea of the outcome of a full operation. For cancers involving the head of the pancreas, the Whipple procedure is the most commonly attempted curative surgical treatment. This is a major operation which involves removing the pancreatic head and the curve of the duodenum together ("pancreato-duodenectomy"), making a bypass for food from the stomach to the jejunum ("gastro-jejunostomy") and attaching a loop of jejunum to the cystic duct to drain bile ("cholecysto-jejunostomy"). It can be performed only if the person is likely to survive major surgery and if the cancer is localized without invading local structures or metastasizing. It can, therefore, be performed only in a minority of cases. Cancers of the tail of the pancreas can be resected using a procedure known as a distal pancreatectomy, which often also entails removal of the spleen. Different approaches are also used for reconnecting the stomach to the small intestine after a Whipple procedure. A Cochrane review comparing antecolic versus retrocolic routes for the gastrojejunostomy found no clear difference in delayed gastric emptying, mortality, or other major complications. Although curative surgery no longer entails the very high death rates that occurred until the 1980s, a high proportion of people (about 30–45%) still have to be treated for a post-operative sickness that is not caused by the cancer itself. The most common complication of surgery is difficulty in emptying the stomach. Chemotherapy After surgery, adjuvant chemotherapy with gemcitabine or 5-FU can be offered if the person is sufficiently fit, after a recovery period of one to two months. Gemcitabine was approved by the United States Food and Drug Administration (FDA) in 1997, after a clinical trial reported improvements in quality of life and a five-week improvement in median survival duration in people with advanced pancreatic cancer. This was the first chemotherapy drug approved by the FDA primarily for a nonsurvival clinical trial endpoint. Chemotherapy using gemcitabine alone was the standard for about a decade, as a number of trials testing it in combination with other drugs failed to demonstrate significantly better outcomes. However, the combination of gemcitabine with erlotinib was found to increase survival modestly, and erlotinib was licensed by the FDA for use in pancreatic cancer in 2005. The FOLFIRINOX chemotherapy regimen using four drugs was found more effective than gemcitabine, but with substantial side effects, thus only suitable for people with good performance status. This is also true of protein-bound paclitaxel (nab-paclitaxel), which was licensed by the FDA in 2013 for use with gemcitabine in pancreas cancer. By the end of 2013, either singular FOLFIRINOX or gemcitabine in combination with nab-paclitaxel were regarded as good choices for those able to tolerate the side-effects, and singular gemcitabine remained an effective option for those who were not. Regimen changes during this period only increased survival times by a few months. Gemcitabine plus taxane improved those results, bettering both OS and QoL (64% RoD versus control group's 77%). The trial involved 16 patients with resectable pancreatic cancer, who were monitored for up to four years. Between 2019 and 2021, participants underwent tumor removal surgery. Researchers then used genetic material from each patient's tumor to create customized mRNA vaccines, designed to help the immune system recognize and attack cancer cells. Patients also received standard treatment alongside the vaccine. Results showed that eight of the 16 participants developed T cells targeting their tumors, indicating an immune response to the vaccine. PanNETs Treatment of PanNETs, including the less common malignant types, may include a number of approaches. Some small tumors of less than 1 cm that are identified incidentally, for example on a CT scan performed for other purposes, may be followed by watchful waiting. For functioning tumors, the somatostatin analog class of medications, such as octreotide, can reduce the excessive production of hormones. If the tumor is not amenable to surgical removal and is causing symptoms, targeted therapy with everolimus or sunitinib can reduce symptoms and slow progression of the disease. Standard cytotoxic chemotherapy is generally not very effective for PanNETs, but may be used when other drug treatments fail to prevent the disease from progressing, Radiation therapy is occasionally used if there is pain due to anatomic extension, such as metastasis to bone. Some PanNETs absorb specific peptides or hormones, and these PanNETs may respond to nuclear medicine therapy with radiolabeled peptides or hormones such as iobenguane (iodine-131-MIBG). Radiofrequency ablation (RFA), cryoablation, and hepatic artery embolization may also be used. Palliative care Palliative care is medical care which focuses on treatment of symptoms from serious illness, such as cancer, and improving quality of life. Because pancreatic adenocarcinoma is usually diagnosed after it has progressed to an advanced stage, palliative care as a treatment of symptoms is often the only treatment possible. Palliative care focuses not on treating the underlying cancer, but on treating symptoms such as pain or nausea, and can assist in decision-making, including when or if hospice care will be beneficial. Pain can be managed with medications such as opioids or through procedural intervention, by a nerve block on the celiac plexus (CPB). This alters or, depending on the technique used, destroys the nerves that transmit pain from the abdomen. CPB is a safe and effective way to reduce the pain, which generally reduces the need to use opioid painkillers, which have significant negative side effects. Other symptoms or complications that can be treated with palliative surgery are obstruction by the tumor of the intestines or bile ducts. For the latter, which occurs in well over half of cases, a small metal tube called a stent may be inserted by endoscope to keep the ducts draining. Palliative care can also help treat depression that often comes with the diagnosis of pancreatic cancer. Both surgery and advanced inoperable tumors often lead to digestive system disorders from a lack of the exocrine products of the pancreas (exocrine insufficiency). These can be treated by taking pancreatin which contains manufactured pancreatic enzymes, and is best taken with food. Difficulty in emptying the stomach (delayed gastric emptying) is common and can be a serious problem, involving hospitalization. Treatment may involve a variety of approaches, including draining the stomach by nasogastric aspiration and drugs called proton-pump inhibitors or H2 antagonists, which both reduce production of gastric acid. Medications like metoclopramide can also be used to clear stomach contents. ==Prognosis==

Pancreatic adenocarcinoma and the other less common exocrine cancers have a very poor prognosis, as they are normally diagnosed at a late stage when the cancer is already locally advanced or has spread to other parts of the body. For locally advanced and metastatic pancreatic adenocarcinomas, which together represent over 80% of cases, numerous trials comparing chemotherapy regimes have shown increased survival times, but not to more than one year. In the less than 20% of cases of pancreatic adenocarcinoma with a diagnosis of a localized and small cancerous growth (less than 2 cm in Stage T1), about 20% of Americans survive to five years. About 1500 genes are linked to outcomes in pancreatic adenocarcinoma. These include both unfavorable genes, where high expression is related to poor outcome, for example C-Met and MUC-1, and favorable genes where high expression is associated with better survival, for example the transcription factor PELP1. ==Distribution==

In 2015, pancreatic cancers of all types resulted in 411,600 deaths globally. It is the sixth-highest cause of death from cancer worldwide. slightly higher than the figure for the UK. The disease is more common in men than women, although the difference in rates has narrowed over recent decades, probably reflecting earlier increases in female smoking. In the United States, the risk for African Americans is over 50% greater than for whites, but the rates in Africa and East Asia are much lower than those in North America or Europe. The United States, Central, and eastern Europe, and Argentina and Uruguay all have high rates. PanNETs The annual incidence of clinically recognized pancreatic neuroendocrine tumors (PanNETs) is low (about 5 per one million person-years) and is dominated by the non-functioning types. Somewhere between 45% and 90% of PanNETs are thought to be of the non-functioning types. Studies of autopsies have uncovered small PanNETs rather frequently, suggesting that the prevalence of tumors that remain inert and asymptomatic may be relatively high. Overall PanNETs are thought to account for about 1 to 2% of all pancreatic tumors. The definition and classification of PanNETs has changed over time, affecting what is known about their epidemiology and clinical relevance. ==History==

Recognition and diagnosis The earliest recognition of pancreatic cancer has been attributed to the 18th-century Italian scientist Giovanni Battista Morgagni, the historical father of modern-day anatomic pathology, who claimed to have traced several cases of cancer in the pancreas. Many 18th and 19th-century physicians were skeptical about the existence of the disease, given the similar appearance of pancreatitis. Some case reports were published in the 1820s and 1830s, and a genuine histopathologic diagnosis was eventually recorded by the American clinician Jacob Mendes Da Costa, who also doubted the reliability of Morgagni's interpretations. By the start of the 20th century, cancer of the head of the pancreas had become a well-established diagnosis. In 2010, the WHO recommended that PanNETs be referred to as "neuroendocrine" rather than "endocrine" tumors. In 1912 the German surgeon Walther Kausch was the first to remove large parts of the duodenum and pancreas together (en bloc). This was in Breslau, now Wrocław, in Poland. In 1918 it was demonstrated, in operations on dogs, that it is possible to survive even after complete removal of the duodenum, but no such result was reported in human surgery until 1935, when the American surgeon Allen Oldfather Whipple published the results of a series of three operations at Columbia Presbyterian Hospital in New York. Only one of the patients had the duodenum entirely removed, but he survived for two years before dying of metastasis to the liver. The first operation was unplanned, as cancer was only discovered in the operating theater. Whipple's success showed the way for the future, but the operation remained a difficult and dangerous one until recent decades. He published several refinements to his procedure, including the first total removal of the duodenum in 1940, but he only performed a total of 37 operations. In the 1970s a group of American surgeons wrote urging that the procedure was too dangerous and should be abandoned. Since then outcomes in larger centers have improved considerably, and mortality from the operation is often less than 4%. ==Research directions==

Early-stage research on pancreatic cancer includes studies of genetics and early detection, treatment at different cancer stages, surgical strategies, and targeted therapies, such as inhibition of growth factors, immune therapies, and vaccines. Bile acids may have a role in the carcinogenesis of pancreatic cancer. A key question is the timing of events as the disease develops and progresses – particularly the role of diabetes, The knowledge that new onset of diabetes can be an early sign of the disease could facilitate timely diagnosis and prevention if a workable screening strategy can be developed. The European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) trial is aiming to determine whether regular screening is appropriate for people with a family history of the disease. Keyhole surgery (laparoscopy) rather than Whipple's procedure, particularly in terms of recovery time, is being evaluated. Irreversible electroporation is a relatively novel ablation technique with potential for downstaging and prolonging survival in persons with locally advanced disease, especially for tumors in proximity to peri-pancreatic vessels without risk of vascular trauma. Efforts are underway to develop new drugs, including those targeting molecular mechanisms for cancer onset, stem cells, A further approach involves the use of immunotherapy, such as oncolytic viruses. Galectin-specific mechanisms of the tumor microenvironment are under study. Because of the highly hypoxic nature of the environment, Hypoxia-activated prodrugs such as CP-506 especially in combination with immunotherapy are also being studied. The nanoparticles assist in the sustained and targeted release of a drug regimen to cancer/tumor-specific sites rather than affecting healthy cells, leading to negligible or no toxicity. == See also ==