Pancreatic cancer
Template:Short description Template:Featured article Template:Use American English Template:Use dmy dates Template:Cs1 config Template:Infobox medical condition (new)
Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body.<ref name=NCI2014Def>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A number of types of pancreatic cancer are known.<ref name=WCR2014/>
The most common, pancreatic adenocarcinoma, accounts for about 90% of cases,<ref name="Pishvaian2017"/> and the term "pancreatic cancer" is sometimes used to refer only to that type.<ref name=WCR2014/> These adenocarcinomas start within the part of the pancreas that makes digestive enzymes.<ref name=WCR2014/> Several other types of cancer, which collectively represent the majority of the non-adenocarcinomas, can also arise from these cells.<ref name=WCR2014/>
About 1–2% of cases of pancreatic cancer are neuroendocrine tumors, which arise from the hormone-producing cells of the pancreas.<ref name=WCR2014/> These are generally less aggressive than pancreatic adenocarcinoma.<ref name=WCR2014/>
Signs and symptoms of the most-common form of pancreatic cancer may include yellow skin, abdominal or back pain, unexplained weight loss, light-colored stools, dark urine, and loss of appetite.<ref name=PDQ2014/> Usually, no symptoms are seen in the disease's early stages, and symptoms that are specific enough to suggest pancreatic cancer typically do not develop until the disease has reached an advanced stage.<ref name=PDQ2014/><ref name=NEJM14>Template:Cite journal</ref> By the time of diagnosis, pancreatic cancer has often spread to other parts of the body.<ref name=WCR2014/><ref name="Bond-Smith">Template:Cite journal</ref>
Pancreatic cancer rarely occurs before the age of 40, and more than half of cases of pancreatic adenocarcinoma occur in those over 70.<ref name=NEJM14/> Risk factors for pancreatic cancer include tobacco smoking, obesity, diabetes, and certain rare genetic conditions.<ref name=NEJM14/> About 25% of cases are linked to smoking,<ref name="Wolfgang2013">Template:Cite journal</ref> and 5–10% are linked to inherited genes.<ref name=NEJM14/>
Pancreatic cancer is usually diagnosed by a combination of medical imaging techniques such as ultrasound or computed tomography, blood tests, and examination of tissue samples (biopsy).<ref name=Wolfgang2013/><ref name=Lancet/> The disease is divided into stages, from early (stage I) to late (stage IV).<ref name=Bond-Smith/> Screening the general population has not been found to be effective.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
The risk of developing pancreatic cancer is lower among non-smokers, and people who maintain a healthy weight and limit their consumption of red or processed meat;<ref name=Can2014Meat>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> the risk is greater for men, smokers, and those with diabetes.<ref>Template:Cite journal</ref> There are some studies that link high levels of red meat consumption to increased risk of pancreatic cancer, though meta-analyses typically find no clear evidence of a relationship.<ref>Template:Cite journal</ref><ref name=bjc2011>Template:Cite journal</ref><ref>Template:Cite journal</ref> Smokers' risk of developing the disease decreases immediately upon quitting, and almost returns to that of the rest of the population after 20 years.<ref name="WCR2014">Template:Cite book</ref> Pancreatic cancer can be treated with surgery, radiotherapy, chemotherapy, palliative care, or a combination of these.<ref name=PDQ2014/> Treatment options are partly based on the cancer stage.<ref name=PDQ2014/> Surgery is the only treatment that can cure pancreatic adenocarcinoma,<ref name=Bond-Smith/> and may also be done to improve quality of life without the potential for cure.<ref name="PDQ2014">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=Bond-Smith/> Pain management and medications to improve digestion are sometimes needed.<ref name=Bond-Smith/> Early palliative care is recommended even for those receiving treatment that aims for a cure.<ref>Template:Cite journal</ref>
Pancreatic cancer is among the most deadly forms of cancer globally, with one of the lowest survival rates. In 2015, pancreatic cancers of all types resulted in 411,600 deaths globally.<ref name=GBD2015De>Template:Cite journal</ref> Pancreatic cancer is the fifth-most-common cause of death from cancer in the United Kingdom,<ref name=PCRF2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and the third most-common in the United States.<ref name=SEER2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The disease occurs most often in the developed world, where about 70% of the new cases in 2012 originated.<ref name=WCR2014/> Pancreatic adenocarcinoma typically has a very poor prognosis; after diagnosis, 25% of people survive one year and 12% live for five years.<ref name="ACS-CFF-2010">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=WCR2014/> For cancers diagnosed early, the five-year survival rate rises to about 20%.<ref name="PDQ2014P">{{#invoke:citation/CS1|citation |CitationClass=web }} "The highest cure rate occurs if the tumor is truly localized to the pancreas; however, this stage of disease accounts for less than 20% of cases. In cases with localized disease and small cancers (<2 cm) with no lymph-node metastases and no extension beyond the capsule of the pancreas, complete surgical resection is still associated with a low actuarial five-year survival rate of 18% to 24%."</ref> Neuroendocrine cancers have better outcomes; at five years from diagnosis, 65% of those diagnosed are living, though survival considerably varies depending on the type of tumor.<ref name=WCR2014/>Template:TOC limit
Types
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.<ref name=Harris-2013>Template:Cite book</ref><ref name="pmid22997445">Template:Cite journal (Table 5 outlines the proposed TNM staging system for PanNETs.)</ref>
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.<ref name="NEJM14" /> Nearly all these start in the ducts of the pancreas, as pancreatic ductal adenocarcinoma (PDAC).<ref>Template:Cite book</ref> 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.<ref name="DeVita2011">Template:Cite book Online edition, with updates to 2014</ref> 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.<ref name="NEJM14" />
The next-most common type, acinar cell carcinoma of the pancreas, arises in the clusters of cells that produce these enzymes, and represents 5% of exocrine pancreas cancers.<ref name="Tobias">Template:Cite book</ref> 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.<ref name="Tobias" />
Pancreatoblastoma is a rare form, mostly occurring in childhood, and with a relatively good prognosis. 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.<ref name="NEJM14" /><ref name="JHM-SGPCRC">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref>Template:Cite journal</ref>
Neuroendocrine
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} The small minority of tumors that arise elsewhere in the pancreas are mainly pancreatic neuroendocrine tumors (PanNETs).<ref name=nomenclature>The PanNET denomination is in line with WHO guidelines for the classification of tumors of the digestive system {{#invoke:citation/CS1|citation |CitationClass=web }} published in 2010. Historically, PanNETs have also been referred to by a variety of terms, and are still commonly called "pancreatic endocrine tumors". See: Template:Cite journal</ref> 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.<ref name="Burns2012"/>
As with other neuroendocrine tumors, the history of the terminology and classification of PanNETs is complex.<ref name=nomenclature/> PanNETs are sometimes called "islet cell cancers",<ref>The Medical Subject Headings indexing system refers to "islet cell carcinoma", which is subdivided into gastrinoma, glucagonoma, somatostatinoma, and VIPoma. See: 2014 MeSH tree at "Pancreatic Neoplasms C04.588.322.475.500" 16 October 2014</ref> though they are now known to not actually arise from islet cells as previously thought.<ref name="Burns2012">Template:Cite journal</ref>
Signs and symptoms
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.<ref name="Lancet">Template:Cite journal</ref> 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).<ref name="Sol PanNET" />
Common presenting symptoms of pancreatic adenocarcinoma include:
- 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.<ref name=Tobias/> It may be slightly relieved by bending forward. 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. In up to two-thirds of people, abdominal pain is the main symptom, for 46% of the total accompanied by jaundice, with 13% having jaundice without pain.<ref name="Bond-Smith"/>
- Jaundice, a yellow tint to the whites of the eyes or skin, with or without pain, and possibly in combination with darkened urine, results when a cancer in the head of the pancreas obstructs the common bile duct as it runs through the pancreas.<ref name="Cruz" />
- Unexplained weight loss, either from loss of appetite, or loss of exocrine function resulting in poor digestion.<ref name="Bond-Smith" />
- The tumor may compress neighboring organs, disrupting digestive processes and making it difficult for the stomach to empty, which may cause nausea and a feeling of fullness. The undigested fat leads to foul-smelling, fatty feces that are difficult to flush away.<ref name="Bond-Smith" /> Constipation is also common.<ref name=Alberts/>
- At least 50% of people with pancreatic adenocarcinoma have diabetes at the time of diagnosis.<ref name="NEJM14"/> While long-standing diabetes is a known risk factor for pancreatic cancer (see Risk factors), the cancer can itself cause diabetes, in which case recent onset of diabetes could be considered an early sign of the disease.<ref name=Pannala2009>Template:Cite journal</ref> 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.<ref name="Bond-Smith" />
Other findings
- Trousseau's syndrome – in which blood clots form spontaneously in the portal blood vessels (portal vein thrombosis), the deep veins of the extremities (deep vein thrombosis), or the superficial veins (superficial vein thrombosis) anywhere on the body – may be associated with pancreatic cancer, and is found in about 10% of cases.<ref name="Wolfgang2013"/>
- Clinical depression has been reported in association with pancreatic cancer in some 10–20% of cases, and can be a hindrance to optimal management. The depression sometimes appears before the diagnosis of cancer, suggesting that it may be brought on by the biology of the disease.<ref name="Wolfgang2013"/>
Other common manifestations of the disease include weakness and tiring easily, dry mouth, sleep problems, and a palpable abdominal mass.<ref name=Alberts>Template:Cite book</ref>
Pancreatic cancer metastasis
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.<ref name="Wolfgang2013"/> Uncommonly, it spreads to the bones or brain.<ref name="AJCC2-PANC">Template:Cite book See p. 95 for citation regarding "... lesser degree of involvement of bones and brain and other anatomical sites."</ref>
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.<ref>Template:Cite journal</ref>
Risk factors
Risk factors for pancreatic adenocarcinoma include:<ref name="NEJM14" /><ref name=WCR2014/><ref name="Bond-Smith" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>Template:Excessive citations inline
- Age, sex, and ethnicity – the risk of developing pancreatic cancer increases with age. Most cases occur after age 65,<ref name=WCR2014/> while cases before age 40 are uncommon. The disease is slightly more common in men than in women.<ref name=WCR2014/> In the United States, it is over 1.5 times more common in African Americans, though incidence in Africa is low.<ref name=WCR2014/>
- Cigarette smoking is the best-established avoidable risk factor for pancreatic cancer, approximately doubling risk among long-term smokers, the risk increasing with the number of cigarettes smoked and the years of smoking. The risk declines slowly after smoking cessation, taking some 20 years to return to almost that of nonsmokers.<ref>Template:Cite journal</ref>
- Obesity – a body mass index greater than 35 increases relative risk by about half.<ref name="Bond-Smith" /><ref>Template:Cite journal</ref>
- Radionuclides – Cesium-137 and Iodine-131. <ref>Template:Cite journal.</ref><ref>Venturi, S. | Correlation of Diabetes, Salivary gland cancer and Pancreatic Cancer with Iodine and Cesium Radionuclides.( Russ/Engl).| Juvenis scientia| 2022 |DOI: 10.32415/jscien-tia_2022_8_2_5-14.</ref>
- Family history – 5–10% of pancreatic cancer cases have an inherited component, where people have a family history of pancreatic cancer.<ref name="NEJM14" /><ref>Template:Cite journal</ref> 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.<ref name="Lancet" /> Most of the genes involved have not been identified.<ref name="NEJM14" /><ref name="Reznik2014">Template:Cite journal</ref> Hereditary pancreatitis gives a greatly increased lifetime risk of pancreatic cancer of 30–40% to the age of 70.<ref name="Wolfgang2013"/> Screening for early pancreatic cancer may be offered to individuals with hereditary pancreatitis on a research basis.<ref>Template:Cite journal</ref> Some people may choose to have their pancreas surgically removed to prevent cancer from developing in the future.<ref name="Wolfgang2013"/>
- Pancreatic cancer has been associated with these other rare hereditary syndromes: Peutz–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 ATM and autosomal dominantly inherited mutations in the BRCA2 and PALB2 genes; hereditary non-polyposis colon cancer (Lynch syndrome); and familial adenomatous polyposis. PanNETs have been associated with multiple endocrine neoplasia type 1 (MEN1) and von Hippel Lindau syndromes.<ref name="NEJM14" /><ref name="Wolfgang2013" /><ref name="Lancet" />
- Chronic pancreatitis appears to almost triple risk, and as with diabetes, new-onset pancreatitis may be a symptom of a tumor.<ref name="Wolfgang2013"/> The risk of pancreatic cancer in individuals with familial pancreatitis is particularly high.<ref name="Wolfgang2013"/><ref name="Reznik2014"/>
- Diabetes mellitus is a risk factor for pancreatic cancer and (as noted in the Signs and symptoms section) new-onset diabetes may also be an early sign of the disease. People who have been diagnosed with type 2 diabetes for longer than 10 years may have a 50% increased risk, as compared with individuals without diabetes.<ref name="Wolfgang2013"/> In 2021, Venturi reported that the pancreas is able to absorb in great quantity radioactive cesium (Cs-134 and Cs-137) causing chronic pancreatitis and probably pancreatic cancer with damage of pancreatic islands, causing type 3c (pancreatogenic) diabetes.<ref>Template:Cite journal File:CC-BY icon.svg Text was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.</ref> 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.<ref name="NEJM14" /><ref name=CancerOrg2014/> Dietary factors for which some evidence shows slightly increased risk include processed meat, red meat, and meat cooked at very high temperatures (e.g. by frying, broiling, or grilling).<ref name="bjc2011" /><ref name=CancerOrg2014>{{#invoke:citation/CS1|citation
|CitationClass=web }}, p. 19, "Though evidence is still accumulating, consumption of red or processed meat, or meat cooked at very high temperatures, may slightly increase risk."</ref>
Alcohol
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}
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.<ref name="Wolfgang2013"/><ref name="Pericleous" >Template:Cite journal</ref>
Pathophysiology
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Precancer
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.<ref name="Wolfgang2013"/> Apart from pancreatic serous cystadenomas, which are almost always benign, four types of precancerous lesion are recognized.
The first is pancreatic intraepithelial neoplasia (PanIN). These lesions are microscopic abnormalities in the pancreas and are often found in autopsies of people with no diagnosed cancer. These lesions may progress from low to high grade and then to a tumor. More than 90% of cases at all grades carry a faulty KRAS gene, while in grades 2 and 3, damage to three further genes – CDKN2A (p16), p53, and SMAD4 – are increasingly often found.<ref name="NEJM14"/>
A second type is the intraductal papillary mucinous neoplasm (IPMN). These are macroscopic lesions, which are found in about 2% of all adults. This rate rises to about 10% by age 70. These lesions have about a 25% risk of developing into invasive cancer. They may have KRAS gene mutations (40–65% of cases) and in the GNAS Gs alpha subunit and RNF43, affecting the Wnt signaling pathway.<ref name="NEJM14"/> Even if removed surgically, a considerably increased risk remains of pancreatic cancer developing subsequently.<ref name="Wolfgang2013"/>
The third type, pancreatic mucinous cystic neoplasm (MCN), mainly occurs in women, and may remain benign or progress to cancer.<ref name=Delpu2011>Template:Cite journal</ref> If these lesions become large, cause symptoms, or have suspicious features, they can usually be successfully removed by surgery.<ref name="Wolfgang2013"/>
A fourth type of cancer that arises in the pancreas is the intraductal tubulopapillary neoplasm. This type was recognised by the WHO in 2010 and constitutes about 1–3% of all pancreatic neoplasms. Mean age at diagnosis is 61 years (range 35–78 years). About 50% of these lesions become invasive. Diagnosis depends on histology, as these lesions are very difficult to differentiate from other lesions on either clinical or radiological grounds.<ref name=Rooney2017>Template:Cite journal</ref>
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.<ref name="Wolfgang2013"/> SWI/SNF mutations/deletions occur in about 10–15% of the adenocarcinomas.<ref name=NEJM14/> The genetic alterations in several other types of pancreatic cancer and precancerous lesions have also been researched.<ref name="Wolfgang2013"/> Transcriptomics analyses and mRNA sequencing for the common forms of pancreatic cancer have found that 75% of human genes are expressed in the tumors, with some 200 genes more specifically expressed in pancreatic cancer as compared to other tumor types.<ref name="proteinatlas.org">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Uhlen eaan2507">Template:Cite journal</ref>
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.<ref name="Park 2021">Template:Cite journal</ref>
PanNETs
The genes often found mutated in pancreatic neuroendocrine tumors (PanNETs) are different from those in exocrine pancreatic cancer.<ref name="Lewis2014">Template:Cite journal</ref> 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.<ref name="MEN1-2012">Template:Cite journal</ref> Other genes that are frequently mutated include DAXX, mTOR, and ATRX.<ref name="Burns2012"/>
Diagnosis
The symptoms of pancreatic adenocarcinoma do not usually appear in the disease's early stages, and they are not individually distinctive to the disease.<ref name="Wolfgang2013"/><ref name="Bond-Smith" /><ref name="Cruz" >Template:Cite journal</ref> 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.<ref name="Cruz" />
People sometimes have recent onset of atypical type 2 diabetes that is difficult to control, a history of recent but unexplained blood vessel inflammation caused by blood clots (thrombophlebitis) known as Trousseau sign, or a previous attack of pancreatitis.<ref name="Cruz" /> A doctor may suspect pancreatic cancer when the onset of diabetes in someone over 50 years old is accompanied by typical symptoms such as unexplained weight loss, persistent abdominal or back pain, indigestion, vomiting, or fatty feces.<ref name="Bond-Smith" /> Jaundice accompanied by a painlessly swollen gallbladder (known as Courvoisier's sign) may also raise suspicion, and can help differentiate pancreatic cancer from gallstones.<ref name="Fitzgerald-2009">Template:Cite journal</ref>
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").<ref name="Bond-Smith" /> On contrast CT scan, pancreatic cancer typically shows a gradually increasing radiocontrast uptake, rather than a fast washout as seen in a normal pancreas or a delayed washout as seen in chronic pancreatitis.<ref>Template:Cite journal</ref> Magnetic resonance imaging and positron emission tomography may also be used,<ref name="NEJM14" /> and magnetic resonance cholangiopancreatography may be useful in some cases.<ref name="Cruz" /> Abdominal ultrasound is less sensitive and will miss small tumors, but can identify cancers that have spread to the liver and build-up of fluid in the peritoneal cavity (ascites).<ref name="Bond-Smith" /> It may be used for a quick and cheap first examination before other techniques.<ref name="ESMOPA" />
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A biopsy by fine needle aspiration, often guided by endoscopic ultrasound, may be used where there is uncertainty over the diagnosis, but a histologic diagnosis is not usually required for removal of the tumor by surgery to go ahead.<ref name="Bond-Smith" />
Liver function tests can show a combination of results indicative of bile duct obstruction (raised conjugated bilirubin, γ-glutamyl transpeptidase and alkaline phosphatase levels). CA19-9 (carbohydrate antigen 19.9) is a tumor marker that is frequently elevated in pancreatic cancer. However, it lacks sensitivity and specificity, not least because 5% of people lack the Lewis (a) antigen and cannot produce CA19-9. It has a sensitivity of 80% and specificity of 73% in detecting pancreatic adenocarcinoma, and is used for following known cases rather than diagnosis.<ref name="NEJM14" /><ref name="Bond-Smith"/>
All those with pancreatic cancer require genetic testing as high risk oncogenic mutations may provide prognostic information and certain mutations with high risk features require first degree relatives to undergo genetic testing as well.<ref name="Park 2021" />
Histopathology
The most common form of pancreatic cancer (adenocarcinoma) is typically characterized by moderately to poorly differentiated glandular structures on microscopic examination. There is typically considerable desmoplasia or formation of a dense fibrous stroma or structural tissue consisting of a range of cell types (including myofibroblasts, macrophages, lymphocytes and mast cells) and deposited material (such as type I collagen and hyaluronic acid). This creates a tumor microenvironment that is short of blood vessels (hypovascular) and so of oxygen (tumor hypoxia).<ref name="NEJM14" /> It is thought that this prevents many chemotherapy drugs from reaching the tumor, as one factor making the cancer especially hard to treat.<ref name="NEJM14" /><ref name="Wolfgang2013"/>
| Cancer type | Relative incidence<ref name="Pishvaian2017">Unless otherwise specified in boxes, reference is: Template:Cite journal</ref> | Microscopy findings<ref name="Pishvaian2017"/> | Micrograph | Immunohistochemistry markers<ref name="Pishvaian2017"/> | Genetic alterations<ref name="Pishvaian2017"/> | |
|---|---|---|---|---|---|---|
| Pancreatic ductal adenocarcinoma (PDAC) | 90% | Glands and desmoplasia | File:Histopathology of pancreatic ductal adenocarcinoma.jpg | |||
| Pancreatic acinar cell carcinoma (ACC) | 1% to 2% | Granular appearance | File:Histopathology of acinar cell carcinoma of the pancreas.jpg | |||
| Solid pseudopapillary tumor | Discohesive tumor nests surrounded by thin fibrous bands. | File:Histopathology of solid pseudopapillary tumor.png Low and high magnification<ref name=SolidPseudopapillary>Image by Mikael Häggström, MD. Reference for features: {{#invoke:citation/CS1|citation |
CitationClass=web
}} Last author update: 4 March 2022</ref> |
| ||
| Adenosquamous carcinoma | 1% to 4%<ref name="SkafidaGrammatoglou2010">Template:Cite journal</ref> | Combination of gland-like cells and squamous epithelial cells. | File:Histopathology of adenosquamous carcinoma of the pancreas.jpg | Positive for:
Negative for: |
||
| Pancreatic neuroendocrine tumor | 5% | Multiple nests of tumor cells | ||||
| Pre-cancer below for comparison: | ||||||
| Precancer: Intraductal papillary mucinous neoplasm (IPMN) |
3% | citation | CitationClass=web
}} Topic Completed: 1 July 2018. Revised: 9 March 2020</ref> Growth within the pancreatic ducts.<ref name="AdsayMino-Kenudson2016">Template:Cite journal</ref> || File:Histopathology of pancreatobiliary intraductal papillary mucinous neoplasm in the pancreas.jpg |
|||
Genetic profile of PDAC
More than 90% of Pancreatic ductal adenocarcinomas (PDAC) contain mutations in genes important for cell-cycle control pathways and genes involved in DNA repair processes, including those commonly mutated in this model of cancer (KRAS, TP53, CDKN2A, SMAD4, BRCA1/BRCA2).<ref name="Cicenas2017">Template:Cite journal</ref>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.<ref name="Cruz" /> The most widely used cancer staging system for pancreatic cancer is the one formulated by the American Joint Committee on Cancer (AJCC) together with the Union for International Cancer Control (UICC). The AJCC-UICC staging system designates four main overall stages, ranging from early to advanced disease, based on TNM classification of Tumor size, spread to lymph Nodes, and Metastasis.<ref name=Cascinu-2010>Template:Cite journal</ref>
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".<ref name="cancer.org">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="Bond-Smith" />
The AJCC-UICC staging system allows distinction between stage III tumors that are judged to be "borderline resectable" (where surgery is technically feasible because the celiac axis and superior mesenteric artery are still free) and those that are "unresectable" (due to more locally advanced disease); in terms of the more detailed TNM classification, these two groups correspond to T3 and T4 respectively.<ref name="Wolfgang2013"/>
- Pancreatic cancer staging (TNM classification)
-
Stage T1 pancreatic cancer
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Stage T2 pancreatic cancer
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Stage T3 pancreatic cancer
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Stage T4 pancreatic cancer
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Pancreatic cancer in nearby lymph nodes – Stage N1
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Locally advanced adenocarcinomas have spread into neighboring organs, which may be any of the following (in roughly decreasing order of frequency): the duodenum, stomach, transverse colon, spleen, adrenal gland, or kidney. Very often they also spread to the important blood or lymphatic vessels and nerves that run close to the pancreas, making surgery far more difficult. Typical sites for metastatic spread (stage IV disease) are the liver, peritoneal cavity and lungs, all of which occur in 50% or more of fully advanced cases.<ref name="Silberman2010">Template:Cite book</ref>
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").<ref name=pmid22997445/> The U.S. National Comprehensive Cancer Network recommends use of the same AJCC-UICC staging system as pancreatic adenocarcinoma.<ref name="NCCN_NET201501"/>Template:Rp Using this scheme, the stage-by-stage outcomes for PanNETs are dissimilar to those of the exocrine cancers.<ref name="NCI_FIG1">National Cancer Institute. Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®) Incidence and Mortality {{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A different TNM system for PanNETs has been proposed by the European Neuroendocrine Tumor Society.<ref name=pmid22997445 />
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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="Pericleous" />
In the general population, screening of large groups is not considered effective and may be harmful as of 2019,<ref>Template:Cite journal</ref> although newer techniques, and the screening of tightly targeted groups, are being evaluated.<ref name="He2014">Template:Cite journal</ref><ref name="Okano2014">Template:Cite journal</ref> Nevertheless, regular screening with endoscopic ultrasound and MRI/CT imaging is recommended for those at high risk from inherited genetics.<ref name="Lancet" /><ref name=ESMOPA>Template:Cite journal</ref><ref name="Okano2014"/><ref>Template:Cite journal</ref>
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.<ref>Template:Cite journal</ref>
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.<ref name="Wolfgang2013"/>
Chemotherapy and, to a lesser extent, radiotherapy are likely to be offered to most people, whether or not surgery is possible. Specialists advise that the management of pancreatic cancer should be in the hands of a multidisciplinary team including specialists in several aspects of oncology, and is, therefore, best conducted in larger centers.<ref name="NEJM14" /><ref name="Wolfgang2013"/>
Surgery
Surgery with the intention of a cure is only possible in around one-fifth (20%) of new cases.<ref name="Bond-Smith" /> Although CT scans help, in practice it can be difficult to determine whether the tumor can be fully removed (its "resectability"), and it may only become apparent during surgery that it is not possible to successfully remove the tumor without damaging other vital tissues. Whether or not surgical resection can be offered depends on various factors, including the precise extent of local anatomical adjacency to, or involvement of, the venous or arterial blood vessels,<ref name="NEJM14" /> as well as surgical expertise and a careful consideration of projected post-operative recovery.<ref>Template:Cite journal</ref><ref name="Mollberg2011">Template:Cite journal</ref> 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.<ref name="Bond-Smith" />
One particular feature that is evaluated is the encouraging presence, or discouraging absence, of a clear layer or plane of fat creating a barrier between the tumor and the vessels.<ref name="Wolfgang2013"/> Traditionally, an assessment is made of the tumor's proximity to major venous or arterial vessels, in terms of "abutment" (defined as the tumor touching no more than half a blood vessel's circumference without any fat to separate it), "encasement" (when the tumor encloses most of the vessel's circumference), or full vessel involvement.<ref name="NCCN-PANC201501">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Template:Rp A resection that includes encased sections of blood vessels may be possible in some cases,<ref name="pmid25339810">Template:Cite journal</ref><ref name="pmid25152577">Template:Cite journal</ref> particularly if preliminary neoadjuvant therapy is feasible,<ref name="pmid25071332">Template:Cite journal</ref><ref name="pmid20422030">Template:Cite journal</ref><ref name="pmid25519932">Template:Cite journal</ref> using chemotherapy<ref name="Mollberg2011" /><ref name="NCCN-PANC201501" />Template:Rp<ref name="pmid25089113">Template:Cite journal</ref> and/or radiotherapy.<ref name="NCCN-PANC201501" />Template:Rp
Even when the operation appears to have been successful, cancerous cells are often found around the edges ("margins") of the removed tissue, when a pathologist examines them microscopically (this will always be done), indicating the cancer has not been entirely removed.<ref name="NEJM14" /> Furthermore, cancer stem cells are usually not evident microscopically, and if they are present they may continue to develop and spread.<ref name="pmid25499079">Template:Cite journal</ref><ref name="pmid25152582">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>
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.<ref name="NEJM14" /><ref name="Wolfgang2013"/> Nowadays, this can often be done using minimally invasive surgery.<ref name="NEJM14" /><ref name="Wolfgang2013"/>
Various techniques exist for reconstructing the pancreas after a Whipple procedure, with the aim of reducing complications such as postoperative pancreatic fistula. A Cochrane review comparing duct-to-mucosa pancreaticojejunostomy with other anastomosis techniques found very low-certainty evidence and no clear differences in fistula rates, mortality, or other major complications.<ref>Template:Cite journal</ref>
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.<ref>Template:Cite journal</ref>
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.<ref name="Wolfgang2013"/> Certain more limited surgical procedures may also be used to ease symptoms (see Palliative care): for instance, if the cancer is invading or compressing the duodenum or colon. In such cases, bypass surgery might overcome the obstruction and improve quality of life but is not intended as a cure.<ref name="Bond-Smith" />
The extent of lymph node removal during pancreatic cancer surgery remains a subject of debate. A Cochrane review comparing standard versus extended lymphadenectomy found no clear evidence that more extensive lymph node removal improves overall survival or reduces cancer recurrence, but it was associated with increased operative time and a greater risk of complications.<ref>Template:Cite journal</ref>
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.<ref name="Lancet"/><ref name=ESMOPA /> In people not suitable for curative surgery, chemotherapy may be used to extend life or improve its quality.<ref name="Wolfgang2013"/> Before surgery, neoadjuvant chemotherapy or chemoradiotherapy may be used in cases that are considered to be "borderline resectable" (see Staging) in order to reduce the cancer to a level where surgery could be beneficial. In other cases neoadjuvant therapy remains controversial, because it delays surgery.<ref name="Wolfgang2013"/><ref name="Lancet"/><ref>Template:Cite journal</ref>
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.<ref name=thota>Template:Cite journal</ref> This was the first chemotherapy drug approved by the FDA primarily for a nonsurvival clinical trial endpoint.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="FDA2005">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref name="Borazanci2014">Template:Cite journal</ref> By the end of 2013, either singular FOLFIRINOX or gemcitabine in combination with nab-paclitaxelTemplate:Tooltip 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.<ref name=thota />
A 2023 meta-analysis found clinical evidence that the FOLFIRINOX regimen provided better overall survival (OS) than gemcitabine plus nab-paclitaxel; both increased the risk of serious grade 3/4 adverse events. An assemblage of 51 studies encompassing 11,333 persons provided comparison of seven different chemotherapy regimens. The previously promoted gemcitabine plus nab-paclitaxel regimen offered insignificant OS or quality of life (QoL) improvement (66% risk of death at 12 months (RoD) versus control group's 63%).<ref name="PMID 39635901">Template:Cite journal</ref> Gemcitabine plus taxane improved those results, bettering both OS and QoL (64% RoD versus control group's 77%).<ref name="PMID 39635901" /> FOLFIRINOX offered the best outcome improving OS and forestalling QoL deterioration (52% RoD versus control group's 77%).<ref name="PMID 39635901" />
Treatment regimens continue to evolve as pharmacology advances. Clinical trials are often conducted to assess novel adjuvant therapies.<ref name="Lancet"/>
Radiotherapy
The role of radiotherapy as an auxiliary (adjuvant) treatment after potentially curative surgery has been controversial since the 1980s.<ref name="Wolfgang2013"/> In the early 2000s the European Study Group for Pancreatic Cancer Research (ESPAC) showed prognostic superiority of adjuvant chemotherapy over chemoradiotherapy.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Lancet" /> The European Society for Medical Oncology recommends that adjuvant radiotherapy should only be used for people enrolled in clinical trials.<ref name=ESMOPA /> However, there is a continuing tendency for clinicians in the US to be more ready to use adjuvant radiotherapy than those in Europe. Many clinical trials have tested a variety of treatment combinations since the 1980s, but have failed to settle the matter conclusively.<ref name="Wolfgang2013"/><ref name="Lancet" />
Radiotherapy may form part of treatment to attempt to shrink a tumor to a resectable state, but its use on unresectable tumors remains controversial as there are conflicting results from clinical trials. The preliminary results of one trial, presented in 2013, "markedly reduced enthusiasm" for its use on locally advanced tumors.<ref name="NEJM14" />
Targeted Therapy
Immunotherapy
Personalized mRNA Vaccines
A 2025 study reports that a phase 1 clinical trial has found promising results for personalized mRNA vaccines as a potential treatment for pancreatic cancer.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The trial involved 16 patients with resectable pancreatic cancer, who were monitored for up to four years.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite journal</ref> Results showed that eight of the 16 participants developed T cells targeting their tumors, indicating an immune response to the vaccine.<ref>Template:Cite journal</ref>
PanNETs
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Treatment of PanNETs, including the less common malignant types, may include a number of approaches.<ref name="NCCN_NET201501">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Falconi2012">Template:Cite journal</ref><ref name="Jensen2012">Template:Cite journal</ref><ref name="Pavel2012">Template:Cite journal</ref> 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.<ref name="NCCN_NET201501" /> This depends on the assessed risk of surgery which is influenced by the site of the tumor and the presence of other medical problems.<ref name="NCCN_NET201501" /> Tumors within the pancreas only (localized tumors), or with limited metastases, for example to the liver, may be removed by surgery. The type of surgery depends on the tumor location, and the degree of spread to lymph nodes.<ref name=pmid22997445/>
For localized tumors, the surgical procedure may be much less extensive than the types of surgery used to treat pancreatic adenocarcinoma described above, but otherwise surgical procedures are similar to those for exocrine tumors. The range of possible outcomes varies greatly; some types have a very high survival rate after surgery while others have a poor outlook. As all this group are rare, guidelines emphasize that treatment should be undertaken in a specialized center.<ref name=pmid22997445 /><ref name="Burns2012"/> Use of liver transplantation may be considered in certain cases of liver metastasis.<ref name="Rossi2014">Template:Cite journal</ref>
For functioning tumors, the somatostatin analog class of medications, such as octreotide, can reduce the excessive production of hormones.<ref name=pmid22997445/> Lanreotide can slow tumor growth.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="Burns2012"/><ref name="ASCOPost20110515Evero">Everolimus Approved for Pancreatic Neuroendocrine Tumors Template:Webarchive The ASCO Post. 15 May 2011, Volume 2, Issue 8</ref><ref>National Cancer Institute. Cancer Drug Information. FDA Approval for Sunitinib Malate Template:Webarchive. Pancreatic Neuroendocrine Tumors</ref> 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,<ref name="Burns2012"/> or in poorly differentiated PanNET cancers.<ref name="Benson2010">Text is available electronically (but may require free registration) See: Template:Cite book</ref>
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).<ref name="Gulenchyn">Template:Cite journal</ref><ref name="Vinik">Template:Cite journal</ref><ref name="Kwekkeboom">Template:Cite journal</ref><ref name="Bodei">Template:Cite journal</ref> Radiofrequency ablation (RFA), cryoablation, and hepatic artery embolization may also be used.<ref name="Castellano">Template:Cite journal</ref><ref name="Singh2014">Template:Cite journal</ref>
Palliative care
Palliative care is medical care which focuses on treatment of symptoms from serious illness, such as cancer, and improving quality of life.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite journal</ref>
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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="Wolfgang2013"/><ref>Template:Cite journal</ref>
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.<ref name="Cruz" /> Palliative care can also help treat depression that often comes with the diagnosis of pancreatic cancer.<ref name="Wolfgang2013"/>
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.<ref name="Bond-Smith" /> 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.<ref name="Bond-Smith" /> Medications like metoclopramide can also be used to clear stomach contents.
Prognosis
| Clinical stage | U.S. five-year survival (%) for 1992–1998 diagnoses | |
|---|---|---|
| Exocrine pancreatic cancer | Neuroendocrine treated with surgery | |
| IA / I | 14 | 61 |
| IB | 12 | |
| IIA / II | 7 | 52 |
| IIB | 5 | |
| III | 3 | 41 |
| IV | 1 | 16 |
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.<ref name="NEJM14" /> Outcomes are much better for PanNETs: Many are benign and completely without clinical symptoms, and even those cases not treatable with surgery have an average five-year survival rate of 16%,<ref name="cancer.org"/> although the outlook varies considerably according to the type.<ref name="Sol PanNET">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref name="NEJM14" /><ref name="thota" /> Overall five-year survival for pancreatic cancer in the US has improved from 2% in cases diagnosed in 1975–1977, and 4% in 1987–1989 diagnoses, to 6% in 2003–2009.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}, Table, p. 18, rates adjusted for normal life expectancy</ref> 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.<ref name="PDQ2014P"/>
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.<ref name="proteinatlas.org"/><ref name="Uhlen eaan2507"/>
Distribution
In 2015, pancreatic cancers of all types resulted in 411,600 deaths globally.<ref name=GBD2015De/> In 2014, an estimated 46,000 people in the US are expected to be diagnosed with pancreatic cancer and 40,000 to die of it.<ref name="NEJM14" /> Although it accounts for only 2.5% of new cases, pancreatic cancer is responsible for 6% of cancer deaths each year.<ref>Template:Cite journal</ref> It is the seventh-highest cause of death from cancer worldwide.<ref name=WCR2014/> Pancreatic cancer is the fifth most-common cause of death from cancer in the United Kingdom,<ref name=PCRF2019/> and the third most-common in the United States.<ref name=SEER2019/>
Globally, pancreatic cancer is the 11th most-common cancer in women and the 12th most-common in men.<ref name=WCR2014/> The majority of recorded cases occur in developed countries.<ref name=WCR2014/> People from the United States have an average lifetime risk of about 1 in 67 (or 1.5%) of developing the disease,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> slightly higher than the figure for the UK.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}; "In 2010, in the UK, the lifetime risk of developing pancreatic cancer is 1 in 73 for men and 1 in 74 for women", noting "The lifetime risk ... has been calculated ... using the 'Current Probability' method; this is a different method used from most other cancer sites since the possibility of having more than one diagnosis of pancreatic cancer over the course of their lifetime is very low"</ref> The disease is more common in men than women,<ref name="NEJM14" /><ref name=WCR2014 /> 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.<ref name=WCR2014 />
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.<ref name="JHM-SGPCRC" /> Somewhere between 45% and 90% of PanNETs are thought to be of the non-functioning types.<ref name=pmid22997445/><ref name="Burns2012"/> Studies of autopsies have uncovered small PanNETs rather frequently, suggesting that the prevalence of tumors that remain inert and asymptomatic may be relatively high.<ref name="Burns2012" /> Overall PanNETs are thought to account for about 1 to 2% of all pancreatic tumors.<ref name="JHM-SGPCRC" /> The definition and classification of PanNETs has changed over time, affecting what is known about their epidemiology and clinical relevance.<ref name="Lewis2014"/>
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.<ref name=Busnardo-1983/>
Regarding the recognition of PanNETs, the possibility of cancer of the islet cells was initially suggested in 1888. The first case of hyperinsulinism due to a tumor of this type was reported in 1927. Recognition of a non-insulin-secreting type of PanNET is generally ascribed to the American surgeons, R. M. Zollinger and E. H. Ellison, who gave their names to Zollinger–Ellison syndrome, after postulating the existence of a gastrin-secreting pancreatic tumor in a report of two cases of unusually severe peptic ulcers published in 1955.<ref name=Busnardo-1983>Template:Cite journal</ref> In 2010, the WHO recommended that PanNETs be referred to as "neuroendocrine" rather than "endocrine" tumors.<ref name=nomenclature/>
Small precancerous neoplasms for many pancreatic cancers are being detected at greatly increased rates by modern medical imaging. One type, the intraductal papillary mucinous neoplasm (IPMN) was first described by Japanese researchers in 1982. It was noted in 2010 that: "For the next decade, little attention was paid to this report; however, over the subsequent 15 years, there has been a virtual explosion in the recognition of this tumor."<ref name="Silberman2010" />
Surgery
The first reported partial pancreaticoduodenectomy was performed by the Italian surgeon Alessandro Codivilla in 1898, but the patient only survived 18 days before succumbing to complications. Early operations were compromised partly because of mistaken beliefs that people would die if their duodenum were removed, and also, at first, if the flow of pancreatic juices stopped. Later it was thought, also mistakenly, that the pancreatic duct could simply be tied up without serious adverse effects; in fact, it will very often leak later on. In 1907–1908, after some more unsuccessful operations by other surgeons, experimental procedures were tried on corpses by French surgeons.<ref name="History">Template:Cite journal</ref>
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.<ref name="History" />
The discovery in the late 1930s that vitamin K prevented bleeding with jaundice, and the development of blood transfusion as an everyday process, both improved post-operative survival,<ref name="History" /> but about 25% of people never left hospital alive as late as the 1970s.<ref name="Thousand" >Template:Cite journal</ref> 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%.<ref name="DeVita2011"/>
In 2006 a report was published of a series of 1,000 consecutive pancreatico-duodenectomies performed by a single surgeon from Johns Hopkins Hospital between 1969 and 2003. The rate of these operations had increased steadily over this period, with only three of them before 1980, and the median operating time reduced from 8.8 hours in the 1970s to 5.5 hours in the 2000s, and mortality within 30 days or in hospital was only 1%.<ref name="History" /><ref name="Thousand"/> Another series of 2,050 operations at the Massachusetts General Hospital between 1941 and 2011 showed a similar picture of improvement.<ref>Template:Cite journal</ref>
Research directions
Template:Update section 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.<ref name="Reznik2014"/><ref name="acs">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> Bile acids may have a role in the carcinogenesis of pancreatic cancer.<ref name="Feng">Template:Cite journal</ref><ref>Template:Cite journal</ref>
A key question is the timing of events as the disease develops and progresses – particularly the role of diabetes,<ref name=acs/><ref name="Pannala2009"/> and how and when the disease spreads.<ref>Template:Cite journal</ref> 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.<ref name=acs/><ref name="Pannala2009"/><ref>Template:Cite journal</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Keyhole surgery (laparoscopy) rather than Whipple's procedure, particularly in terms of recovery time, is being evaluated.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
Efforts are underway to develop new drugs, including those targeting molecular mechanisms for cancer onset,<ref name="Kleger2014">Template:Cite journal</ref><ref name="pmid25152585">Template:Cite journal</ref> stem cells,<ref name="pmid25152582"/> and cell proliferation.<ref name="pmid25152585"/><ref name="Rossi2014_02">Template:Cite journal</ref> A further approach involves the use of immunotherapy, such as oncolytic viruses.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Galectin-specific mechanisms of the tumor microenvironment are under study.<ref name="Ren">Template:Cite journal</ref>
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.<ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref>Template:Cite book</ref> Template:Further
See also
- Gastrointestinal cancer
- Pancreatic Cancer Action Network (organization in the US)
- Lustgarten Foundation for Pancreatic Cancer Research (organization in the US)
- List of people diagnosed with pancreatic cancer
References
External links
Template:Medical condition classification and resources Template:Sister project
Template:Digestive system neoplasia Template:Endocrine gland neoplasia Template:Authority control